Vous êtes sur la page 1sur 97

General and Systemic Veterinary Pharmacology

VPT311

URVISHMISTRY
AAU

1|U R V I S H M I S T R Y

Contents
HistoryofPharmacology...................................................................................................................................................8 Ancientmedicine......................................................................................................................................................8 PreChristianera......................................................................................................................................................8 Mediaevalmedicine..................................................................................................................................................8 Revoltsinmedicine...................................................................................................................................................8 Modernmedicine......................................................................................................................................................8 Scopeofpharmacology.................................................................................................................................................9 Branchesofpharmacology...........................................................................................................................................9 Termsanddefinitions.....................................................................................................................................................10 Pharmacologyrelatedterms.......................................................................................................................................10 Drugrelatedterms......................................................................................................................................................10 Doserelatedterms ......................................................................................................................................................11 Sourcesofdrugs..............................................................................................................................................................11 PlantsourcesofDrugs................................................................................................................................................11 Alkaloids..................................................................................................................................................................11 Glycosides...............................................................................................................................................................12 Oils..........................................................................................................................................................................12 Tannins....................................................................................................................................................................12 Saponins..................................................................................................................................................................12 Resins......................................................................................................................................................................12 Gums.......................................................................................................................................................................12 Mineralsource............................................................................................................................................................12 Animalsourceofdrugs...............................................................................................................................................12 Syntheticsourcesofdrugs..........................................................................................................................................13 Microbialsourceofdrugs...........................................................................................................................................13 Pharmacokinetics:principlesofdrugactivity................................................................................................................. 13 Routesofadministration............................................................................................................................................13 Oraladministration.................................................................................................................................................13 Intravenousroute...................................................................................................................................................14 Subcutaneousandintramuscularroutes................................................................................................................ 15 Otherparenteralroutes..........................................................................................................................................16 Localadministration ................................................................................................................................................16 Structureofbiologicalmembranes............................................................................................................................... 17 Fluidmosaicmodels....................................................................................................................................................17 Functionsofmembranes............................................................................................................................................17 1|U R V I S H M I S T R Y

2|U R V I S H M I S T R Y Passageofdrugsacrossmembranes.............................................................................................................................. 17 Passivediffusion ..........................................................................................................................................................17 Carriermediatedtransfusion......................................................................................................................................18 Facilitateddiffusion .....................................................................................................................................................18 Activetransport..........................................................................................................................................................18 Pinocytosisandphagocytosis.....................................................................................................................................19 Filtration......................................................................................................................................................................19 Absorptionofdrugs........................................................................................................................................................19 AbsorptionofdrugsfromGItract ............................................................................................................................... 20 Roleofionizationandlipidsolubilityindrugabsorption........................................................................................... 20 HendersonandHeselbelchequation...................................................................................................................... 20 Absorptionofdrugsafterparenteraladministration................................................................................................. 21 Absorptionofdrugsafterinhalationortopicaladministration .................................................................................. 21 Distributionofdrugs.......................................................................................................................................................22 Plasmaproteinbindingofdrugs.................................................................................................................................22 Plasmaproteinbinding...............................................................................................................................................23 Tissuestorageofdrugs...............................................................................................................................................23 Barrierstodrugdistribution.......................................................................................................................................23 Biotransformationofdrugs/xenobiotics:drugmetabolism........................................................................................... 24 Sequelaeofbiotransformationreactions................................................................................................................... 25 PhaseIBiotransformationoxidationreactionsandothers...................................................................................... 25 PhaseIreactions.........................................................................................................................................................25 PhaseIIreactionssyntheticreactions...................................................................................................................... 26 Enzymeinductionandinhibition................................................................................................................................26 Excretionofdrugs...........................................................................................................................................................27 Renaleliminationofthedrugs....................................................................................................................................27 Hepaticandotherroutesofadministration............................................................................................................... 29 Pharmacokineticparameters..........................................................................................................................................29 Importantpharmacokineticparameters.................................................................................................................... 30 Modelsinpharmacokinetics.......................................................................................................................................30 Drugaccumulation......................................................................................................................................................31 PrinciplesofDrugactivityPharmacodynamics............................................................................................................ 31 Modesofdrugaction..................................................................................................................................................31 Enzymemediateddrugaction....................................................................................................................................31 Receptormediateddrugaction..................................................................................................................................32 Termsrelatedtodrugreceptorbinding..................................................................................................................... 32 2|U R V I S H M I S T R Y

3|U R V I S H M I S T R Y Receptorsstructureandfunction.................................................................................................................................33 Receptortheories.......................................................................................................................................................33 Functionsofreceptors................................................................................................................................................34 Typesofreceptors......................................................................................................................................................34 Secondmessengersystems........................................................................................................................................34 Doseresponsecurve.......................................................................................................................................................35 Plotting........................................................................................................................................................................35 Featuresofdoseresponsecurve................................................................................................................................35 Quantaldoseresponsecurve.....................................................................................................................................35 Factorsmodifyingdrugaction........................................................................................................................................35 Factorsaffectingdrugaction......................................................................................................................................35 Adverseeffectsofdrugs.................................................................................................................................................36 Typesofadverseeffects.............................................................................................................................................37 Druginteractions........................................................................................................................................................37 Drugscreeninganddrugdiscovery .................................................................................................................................38 Drugdiscovery............................................................................................................................................................38 Drugscreening............................................................................................................................................................39 Preclinicalsafetyandtoxicitytesting.......................................................................................................................... 39 Clinicaltrials................................................................................................................................................................40 Bioprospecting...........................................................................................................................................................41 Assayofdrugs.............................................................................................................................................................42 Biopharmaceuticalsandgenetherapy........................................................................................................................... 42 Biopharmaceuticals.....................................................................................................................................................42 Genetherapy..............................................................................................................................................................42 Gastrointestinalpharmacology...................................................................................................................................43 Sialagogues(sialics)andantisialagogues(antisialics)................................................................................................. 43 Sialagogues..............................................................................................................................................................43 Antisialogogues.......................................................................................................................................................43 Stomachics..............................................................................................................................................................43 Appetitestimulants.....................................................................................................................................................43 Emetics........................................................................................................................................................................44 Antiematics.................................................................................................................................................................45 Prokinetics...................................................................................................................................................................46 Ulcermanagement......................................................................................................................................................46 Antacids ...................................................................................................................................................................46 HistaminereceptorsH2antagonist...................................................................................................................... 47 3|U R V I S H M I S T R Y

4|U R V I S H M I S T R Y Sucralfate................................................................................................................................................................47 Protonpumpantagonists.......................................................................................................................................47 Cytoprotectivedrugs ...............................................................................................................................................48 Digestantsandpurgatives ...............................................................................................................................................48 Cholereticsandcholagogues......................................................................................................................................48 Purgativesandlaxatives..............................................................................................................................................48 Classification...........................................................................................................................................................49 Generalmechanismofaction.................................................................................................................................49 Osmoticpurgatives.................................................................................................................................................49 Irritantpurgatives...................................................................................................................................................50 Bulkpurgatives........................................................................................................................................................51 Lubricantpurgatives...............................................................................................................................................52 Choice,indications,combinations,abuseofpurgatives ............................................................................................. 52 Antidiarrheal...................................................................................................................................................................53 Opioids........................................................................................................................................................................53 Anticholinergics...........................................................................................................................................................54 Protectantsandadsorbants........................................................................................................................................54 Antisecretorydrugs.....................................................................................................................................................55 Protectants..................................................................................................................................................................55 Rumenpharmacology.....................................................................................................................................................55 Oesophagealgrooveclosure.......................................................................................................................................55 Ruminotorics...............................................................................................................................................................56 Rumenantacids ...........................................................................................................................................................56 Antizymotics................................................................................................................................................................56 Cardiovascularpharmacology.........................................................................................................................................56 Classesofdrugsactingonheart.................................................................................................................................56 Effectsofdrugsactingonheart..................................................................................................................................57 Congestiveheartfailure..............................................................................................................................................57 Cardiacglycosides...........................................................................................................................................................57 Chemistryofcardiacglycosides..................................................................................................................................58 ................................................................................................................ 58 Mechanismofactiononcardiacglycosides Pharmacologicaleffectsofcardiacglycosides............................................................................................................ 58 Pharamacokinetics......................................................................................................................................................59 Therapeuticusesofcardiacglycosides....................................................................................................................... 59 Digitalization...............................................................................................................................................................59 Adversereactionsofcardiacglycosides..................................................................................................................... 59 4|U R V I S H M I S T R Y

5|U R V I S H M I S T R Y Treatmentofcardiacglycosidestoxicity ..................................................................................................................... 60 Precautionsanddruginteractions.............................................................................................................................. 60 Druginteractions........................................................................................................................................................60 OtherdrugsusedinCHF.............................................................................................................................................60 Antiarrhythmicdrugs......................................................................................................................................................60 Typesofarrhythmia....................................................................................................................................................60 Arrhythmia..................................................................................................................................................................61 Antiarrhythmicdrugs..................................................................................................................................................61 Classification...............................................................................................................................................................61 Actionsofsodiumchannelblockers........................................................................................................................... 62 Adrenergicblockers..............................................................................................................................................63 Actionsonpotassiumcurrents...................................................................................................................................63 ActionsofCachannelblockers.................................................................................................................................63 Clinicalusesofantiarrhythmicdrugs.......................................................................................................................... 64 AdverseeffectsofAntiarrhythmicdrugs.................................................................................................................... 64 Adverseextracardiaceffects...................................................................................................................................64 Vasodilatorsandantihypertensivedrugs....................................................................................................................... 65 DirectactingVasodilators...........................................................................................................................................65 Indirectlyactingvasodilators......................................................................................................................................66 Clinicaluses.................................................................................................................................................................66 Vasoconstrictors..........................................................................................................................................................66 Clinicalusesofvasoconstrictors.................................................................................................................................66 Classificationofantihypertensivedrugs......................................................................................................................... 66 Antihypertensivedrugs...............................................................................................................................................67 Hematinic,coagulantsandanticoagulants..................................................................................................................... 68 Haematinics.................................................................................................................................................................68 Coagulants ...................................................................................................................................................................69 Anticoagulants............................................................................................................................................................70 Invitroanticoagulants................................................................................................................................................70 Systemicanticoagulantsinvivo............................................................................................................................... 70 Clinicalusesofanticoagulants....................................................................................................................................70 Coumarinderivatives..................................................................................................................................................70 Heparinantagonist ......................................................................................................................................................71 Respiratorypharmacologyexpectorants..................................................................................................................... 71 Expectorants...............................................................................................................................................................71 Inhalantexpectorants.................................................................................................................................................71 5|U R V I S H M I S T R Y

6|U R V I S H M I S T R Y Ingestedexpectorants................................................................................................................................................71 Mucolytics...................................................................................................................................................................71 Decongestantsandantitussives ......................................................................................................................................72 Decongestants .............................................................................................................................................................72 Antitussives.................................................................................................................................................................72 Directlyactingantitussives.........................................................................................................................................72 Centrallyactingantitussives.......................................................................................................................................73 Bronchodilators...............................................................................................................................................................73 Methylxanthene.........................................................................................................................................................74 Sympathomimetic.......................................................................................................................................................74 Parasympatholyticsspasmolytics ............................................................................................................................. 75 Corticosteroids............................................................................................................................................................75 NSAIDs.........................................................................................................................................................................75 Antihistaminics............................................................................................................................................................75 Mastcellstabilizers.....................................................................................................................................................75 Respiratorystimulants................................................................................................................................................76 Diuretics..........................................................................................................................................................................76 Physiologicaldiuresis..................................................................................................................................................76 Classificationofdiuretics............................................................................................................................................76 Osmoticdiuretics........................................................................................................................................................76 Carbonicanhydraseinhibitors....................................................................................................................................77 Loopdiuretics..............................................................................................................................................................77 Thiazidederivatives....................................................................................................................................................78 Potassiumsparingdiuretic..........................................................................................................................................79 Xanthinesandmercurial.............................................................................................................................................80 Drugsactingonurogenitalsystems................................................................................................................................80 Alkalizationofurine....................................................................................................................................................80 Acidificationofurine...................................................................................................................................................80 Ecbolics ........................................................................................................................................................................81 Tocolytics....................................................................................................................................................................81 Fluidtherapy...............................................................................................................................................................81 Choiceoffluid.............................................................................................................................................................82 PharmacotheraputicsofHormones................................................................................................................................83 Administrationofhormones.......................................................................................................................................83 Corticotrophinsandrelatedpeptides......................................................................................................................... 83 Insulin..........................................................................................................................................................................84 6|U R V I S H M I S T R Y

7|U R V I S H M I S T R Y Pharmacologicalactionsofinsulin.............................................................................................................................. 84 Preparationsofinsulin................................................................................................................................................84 Oralhypoglycemicdrugs.............................................................................................................................................85 Thyroidhormone........................................................................................................................................................85 Thyroidinhibitors........................................................................................................................................................86 Generalprinciplesincorticosteroidstherapy............................................................................................................. 86 AntiinflammatoryandsodiumretainingpotenciesofGlucocorticoids ..................................................................... 87 ReproductivehormonesandVitamins........................................................................................................................... 88 Hormonesinfluencingreproductivefunctions........................................................................................................... 88 Anteriorpituitarygonadotropins................................................................................................................................88 Placentalgonadotropins.............................................................................................................................................89 Estrogens.....................................................................................................................................................................89 Progesterone...............................................................................................................................................................90 Androgens...................................................................................................................................................................90 Anabolicsteroids.........................................................................................................................................................91 Posteriorpituitaryhormones...................................................................................................................................91 Pharmacotherapeuticsoffatsolublevitamins........................................................................................................... 91 Pharmacotherapeuticsofwatersolublevitamins...................................................................................................... 92 Drugsactingonskinandmucousmembranes............................................................................................................... 93 Counterirritants ...........................................................................................................................................................93 Penetrationenhancers ................................................................................................................................................93 Adsorbants..................................................................................................................................................................94 Demulcents.................................................................................................................................................................94 Emollients ....................................................................................................................................................................94 Astringents..................................................................................................................................................................94 Otheragentsusedonskins.........................................................................................................................................94 Bioenhancers,immunostimulantsandimmunosuppressors......................................................................................... 95 Bioenhancers...............................................................................................................................................................95 Immunostimulants......................................................................................................................................................95 Immunosuppressant...................................................................................................................................................95

7|U R V I S H M I S T R Y

8|U R V I S H M I S T R Y

History of Pharmacology

Ancientmedicine PreChristianera Mediaevalmedicine Revoltsinmedicine Modernmedicine Chinesemedicineistheearliestandrecordsdatedabout2500B.C.availabletodaygiveanideaaboutthe medicalknowledgeofChinese. InChinesemedicine,theuseofEphedraorMahuangasatonichasbeenreported. AyurvedaorIndianMedicineisequallyancient.ToformthescienceoflifenamelyAyurveda,Charaka, SushrutaandVagbhatamadeacompilationofoldandnewdrugsinthecureofdiseases. Egyptianmedicineisalsoveryancient.TheEbersPapyrusdatedabout1500B.C.givesacollectionofdrugs prevalentinEgyptatthattime,theirclassificationandtheiruse.Someofthedrugsemployednowsuchas, castoroilandpomegranatebarkarementionedinthispapyrus. Greekmedicineissaidtobetheoriginofmodernmedicineandtherapeutics.Hippocratesinfifthcentury B.C.separatedmedicinefromreligionandwasknownasthefatherofmedicine. Helaiddowncertainprinciplesonwhichmodernmedicineisbuilt.AccordingtoHippocratesthefour elementsofnaturenamelywater,fire,airandearthgaverisetothefourhumorsofthebodynamelyblood, phlegm,yellowbileorurineandblackbile.Anyimbalanceinoneormoreofthesehumorsinflicted sufferings. GalenwasafamousGreekPhysicianwhopracticedinRome.Hisnameisstillusedtorefersomedrugsas galenicaldrugs.Hewasthefatherofpolypharmacy. Galenicaldrugsarepharmaceuticalscompoundedbymechanicalmeans,mostlyofthevegetablematerial. Paracelsusintroducedinorganicchemicalslikemercuryintomedicine.HecalledthisIatroChemistryor medicinalchemistry. Heinducedpractitionerstouselaudanum(anopiumpreparation),sulphur,iron,coppersulphate,potassium sulphate,mercurialsandtincturesandfluidextractofvariousplantsfortreatmentofdiseases. Bythebeginningof19thcenturytheprincipleofshotgunprescriptionflourished(Shotgunprescriptionis onethatcontainsanumberofsubstanceswithnotherapeuticefficacy.Itisaresultofignorantattemptto curethedisease,nomatterwhatmaybeitsnature). Gregoryadvocatedmethodslikevenesection,leechingemeticsanddrasticpurgatives.Largedosesof purgativesweregiven.Thepatienteithersurvivedordied.Thissortofsymptomatictreatmentwasreferred toasallopathymeaning'othersuffering'.Thistermallopathyisnowbeingusedtorefermodernmedicine. SamuelHahnemannintroducedhomeopathymeaningsimilarsufferingatthecommencementof19th century.InGreek,homosmeanssameandpatheiameanssuffering.Hewasknownasthefatherof homeopathy.Homeopathyintroducedbyhimhadtwonewerprinciplesthatlikecureslikeanddilution potentiatestheactionofdrugs. Buccheim,aprofessorofDorpatUniversitywhowasknownasthefatherofPharmacologysetupthefirst laboratorytostudypharmacology.Hediscardedmanyremediesbecauserationalscientificactionor explanationcouldnotbedemonstratedinhislaboratory. Bythemiddleofthe19thcentury,modernmedicinehadbroughttofightdiseaseonlyoneeffectiveweapon ie.immunizationagainstsmallpox. 8|U R V I S H M I S T R Y

Ancient medicine

Pre- Christian era


Mediaeval medicine

Revolts in medicine

Modern medicine

9|U R V I S H M I S T R Y Laterinquicksuccessioncametheanaestheticsandantiseptics.Inthelastquarter,thecausativeorganisms formalaria,plaque,choleraetc.wereidentified. Beginninginthe20thcentury,thefreshwindofsyntheticchemistrybegantorevolutionisethe pharmaceuticalindustryandwithitthescienceofpharmacology. Newsyntheticdrugs,suchasbarbituratesandlocalanaesthetics,begantoappearandtheeraof antimicrobialchemotherapybeganwiththediscoveryofarsenicalcompoundsforthetreatmentofsyphilis byPaulEhrlichin1909.Hewasknownasthefatherofchemotherapy. FurtherbreakthroughscamewiththediscoveryofsulphonamidesbyGerhardDomagkin1935andthe developmentofpenicillinduringworldwarII. Theadditionofdrugstothetherapeuticjungleisgrowingwithrapidpacefromthelaterhalfofthe 20thcentury.

Scope of pharmacology

Pharmacologyisthesciencewhichinvolvesallaspectsoftheactionofdrugsonlivingsystem.Itisthestudy ofthetherapeuticvalueand/orpotentialtoxicityofchemicalagentsonbiologicalsystems.Ittargetsevery aspectofthemechanismsforthechemicalactionsofbothtraditionalandnoveltherapeuticagents. Importantandinterrelatedareasare:pharmacodynamicsandpharmacokinetics. Pharmacodynamicsisthestudyofhowdrugsactonthebodywhilepharmacokineticsisthestudyofhowthe bodyactsondrugs.Pharmacodynamicandpharmacokineticaspectsoftheactionofchemicalagentsare applicabletoallrelatedareasofstudy,includingtoxicologyandtherapeutics. Toxicologyisthestudyoftheadverseortoxiceffectsofdrugsandotherchemicalagents.Itisconcerned bothwithdrugsusedinthetreatmentofdiseaseandchemicalsthatmaypresenthousehold,environmental, orindustrialhazards. Therapeuticsfocusesontheactionsandeffectsofdrugsandotherchemicalagentswithphysiological, biochemical,microbiological,immunological,orbehavioralfactorsinfluencingdisease.Eachoftheseareasis closelyinterwovenwiththesubjectmatterandexperimentaltechniquesofphysiology,biochemistry, cellularbiology,microbiology,immunology,genetics,andpathology.TheultimategoalofPharmacologyisto designchemicalagentstocure,ameliorate,orpreventdisease

Branches of pharmacology

Neuropharmacologyisthestudyofneurophysiologicalorneurobiochemicalfunctionsofthenervoussystem includingthebrain,spinalcord,andthenervesthataremodifiedbydrugaction. Cardiovascularpharmacologyconcernstheeffectsofdrugsontheheart,thevascularsystem,andthose partsofthenervousandendocrinesystemsthatparticipateinregulatingcardiovascularfunction. Molecularpharmacologydealswiththebiochemicalandbiophysicalcharacteristicsofinteractionsbetween drugmoleculesandthoseofthecell.Itismolecularbiologyappliedtopharmacologyandtoxicology. Biochemicalpharmacologyisthestudyofactionofdrugsanddrugmetabolism,howdrugsinteractwith, andinfluences,thephysiologyoftheorganism. Behavioralpharmacologystudiestheeffectsofdrugsonbehavioroforganism.Itincludestopicssuchasthe effectsofpsychoactivedrugsonthephenomenaoflearning,memory,wakefulness,sleepandthebehavioral consequencesofexperimentalinterventioninenzymeactivityandbrainneurotransmitterlevelsand metabolism. Endocrinepharmacologyisthestudyofdrugsthatareeitherhormonesorhormonederivatives,ordrugs thatmaymodifythesectionsofnormallysecretedhormones. Clinicalpharmacologyistheapplicationofpharmacodynamicsandpharmacokineticstopatientswith diseases,italsoincludespharmacogeneticcomponent.Clinicalpharmacologistsstudyhowdrugswork,how theyinteractwiththegenomeandwithotherdrugs,howtheireffectscanalterthediseaseprocess,and howdiseasecanaltertheireffects.Clinicaltrialdesign,thepreventionofmedicationerrors,andthe optimizationofrationalprescribingarecriticalcomponentsofclinicalpharmacology. Chemotherapyistheareaofpharmacologythatdealswithdrugsusedforthetreatmentofmicrobial infectionsandmalignancies.Chemotherapeuticagentsselectivelyinhibitthegrowthof,orkill,theinfectious agentorcancercellwithoutseriouslyimpairingthenormalfunctionsofthehost. 9|U R V I S H M I S T R Y

10|U R V I S H M I S T R Y Toxicologyisthescienceofadverseeffectsofchemicals/drugsonlivingsystems.Italsoincludesproblems ofdrugsafety,effectsofdrugoverdosage. Pharmacyisaseparatedisciplineinthehealthsciences.Itistheprofessionresponsibleforthepreparation, dispensingandappropriateuseofmedication,andprovidesservicestoachieveoptimaltherapeutic outcomes.

Terms and definitions


Pharmacology related terms

Pharmacologyisthesciencethatembracestheknowledgeofthehistory,source,physicalandchemical properties,compounding,biochemicalandphysiologicaleffects,mechanismofaction,absorption, distribution,biotransformationandexcretionofdrugs.Itisalsodefinedasanexperimentalsciencedealing withthepropertiesofdrugsandtheireffectsonlivingsystem. Pharmacodynamicsisthestudyofthebiochemicalandphysiologicaleffectsofdrugsandtheirmechanism ofaction.Itistheresponseoftheorganismtotheactionofadrugintheabsenceofadisease. Pharmacodynamicsis'whatthedrugdoestothebody'. Pharmacokineticsisthestudyoftheactionsofthedrugsinthebodyoveradefinedperiodoftime.Itdeals withtheabsorption,distribution,biotransformationandexcretionofthedrug.Pharmacokineticsis'whatthe bodydoestothedrug'. Pharmacometricsisthestudyofthetechniquesusedinthemeasurementofdrugeffectstothe administereddoseofdrug. Pharmacogeneticsisthestudyofgeneticallydeterminedvariationsinanimalsthatarerevealedbythe effectofdrugs. PharmacogenomicsThistermdescribestheuseofgeneticinformationtoguidethechoiceofdrugtherapy onanindividualbasis.. Pharmacoepidemiologyisthestudyofdrugeffectsatthepopulationlevel.Itisconcernedwiththe variabilityofdrugeffectsbetweenindividualsinapopulationandbetweenpopulations. Pharmacoeconomicsaimstoquantifyineconomictermsthecostandbenefitofdrugsusedtherapeutically. Pharmacyisthesciencethatdealswiththepreparation,formulation,manufacture,standardization, preservationanddispensingofdrugs.Thetermpharmacyalsoindicatestheplacewheredrugsare dispensedorsold. Pharmacognosyisthestudyofthesourceofdrugs.Italsodealswiththephysicalandchemicalpropertiesof drugs. Materiamedicaisanobsoletedidacticsubjectthatwasconcernedwithpharmacy,posology, pharmacognosyandindicationsfortherapeuticuseofthedrug. Metrologyisthestudyofweightsandmeasuresasappliedtothepreparationandadministrationofdrugs. Chronopharmacologyisthesudyofhowtheeffectsofdrugsvarywithbiologicaltimingandendogenous periodicities. Pharmacovigilanceisthescienceandactivitiesrelatingtothedetection,assessment,understandingand preventionofadverseeffectsoranyotherdrugrelatedproblem. Pharmacoepidemiologyisthestudyoftheuseofandtheeffectsofdrugsinlargenumbersofpeople.

Drug related terms

Drugisanychemicalagentexceptfoodthatisusedtopromoteorsafeguardthehealthofhumanbeingsor animals.Itisalsodefinedasanysubstanceorproductthatisusedorintended,tobeusedtomodifyor explorephysiologicalsystemsorpathologicalstatesforthebenefitoftherecipient.Theworddrugisderived fromaFrenchwordDroguemeaningadryherb.

10|U R V I S H M I S T R Y

11|U R V I S H M I S T R Y Overthecounterdrugsarethosepreparationsthatcanbesoldwithoutanyprescriptionbecausetheycan beadequatelylabeledforlaymanuse. Prescriptiondrugsaredrugsthatcanbeusedonlyontheorderofalicensed veterinarian/physician/dentist/surgeonbasedonaprescription.Theyarealsoknownaslegenddrugs. Essentialdrugsareagentsthatsatisfythehealthcareneedsofmajorityofthepopulation.Theyshould thereforebeavailableatalltimesinadequateamountsandinappropriatedosageform. Prodrugsaredrugsthatareinactiveorhavealoworderofactivityintheformadministeredandare metabolisedtotheactiveforminthebody. Harddrugsaredrugsusedfornonmedicalpurposesthatareliabletodisabletheindividualseriouslyasa functioningmemberofthesocietybyinducingseverepsychologicaland/orphysicaldependence.eg.Heroin Softdrugsaredrugsusedfornonmedicalpurposesthatarelessdependenceproducing.Theremaybe psychologicaldependencebutnotphysicaldependence,exceptwithheavydose.eg.Amphetamine. Nootropicdrugsaredrugsthataffecttheintellect.Thesedrugsareclaimedtoenhancelearning,increase brainresistancetostressincludinghypoxiaandstimulatebrainmetabolismespeciallyinsenilepatients.eg. Piracetam Orphandrugsaredrugsorbiologicalproductsusefulfordiagnosis/treatment/preventionofararedisease conditionforwhichthereisnoreasonableexpectationthatthecostofdevelopingandmarketingitwillbe recoveredfromthesalesofthatdrug.Eg.Acetylcysteine.Thesedrugsmaybelifesavingforsomepatients, butarenotcommerciallyavailable. Placeboisavehicleforcurebysuggestionandissurprisinglyoftensuccessfulthoughonlytemporarily.Itcan beusedasacontrolinscientificevaluationofdrugsandtobenefitorpleaseapatientnotby pharmacologicalactionsbutbypsychologicalmeans(Latin:PlaceboIshallbepleasingoracceptable). Placeboreactorisanindividualwhoreportchangesofphysicalandmentalstateaftertakinga pharmacologicallyinertsubstance.

Dose related terms

Doseofthedrugisanestimateamountofadrug,thatwhenadministeredbyaparticularroutetoacertain speciesismostlikelytoproduceacertainintensityofresponse.Itisthequantityofmedicationtobe administeredatonetime.Dosageisthedeterminationandregulationofdoses. Posologyisthestudyofthemedicinedosages,whichvarieswiththespeciesofanimals,theintendedeffect ofthedrugandtheindividualtoleranceorsusceptibility. Loadingdoseisoneoraseriesofdosesthatmaybegivenattheonsetoftherapywiththeaimofachieving thetargetconcentrationrapidly. Maintenancedoseisaseriesofrelativelysmalldosesthatfollowtheloadingdoseinordertomaintainan effectiveconcentrationinthebiophase.

Sources of drugs
Plant sources of Drugs

Manydrugsavailablefromplantsareeventodayusedinthetreatmentofpathologicalconditions. Withtheincreasingtendencyfortheuseofalternatemedicine,thissourcehasgainedmoreimportancein therecentpast. Thepharmacologicalactivitiesofplantsareattributedtocertainactiveprinciplesinplants.Theyare alkaloids,glycosides,fats,oils,tannins,saponinsetc. Alkaloidsarenitrogenoussubstancesobtainedfromvariouspartsoftheplant.Alkaloidscontainingoxygen aresolidsandcomparativelynonvolatile(cocaine)whilethosethatdonotcontainoxygenareliquidsand volatile(nicotine,lobelineandconiine). Alkaloidsareinsolubleinwaterwhiletheirsalts(atropinesulphate,caffeinecitrate)aresolubleinwater. Alkaloidsarebittertotaste.Theyareincompatiblewiththealkalies,tannicacidandheavymetals. Alkaloidsrepresentthewasteproductsofplantmetabolismandtheirnamesendwithine. 11|U R V I S H M I S T R Y

Alkaloids

12|U R V I S H M I S T R Y Alkaloidsshouldbeadministeredinsmallquantitiesandwhengiveninexcesstheymayproducedeath withoutmuchpostmortemchangesfordiagnosis.(Adrenalineisconsideredasanimalalkaloid).

Glycosides

Glycosidesarenonnitrogenoussubstancesobtainedfromplants. Theglycosidesonhydrolysisyieldtwomoleculesnamelyasugarmoleculeandagenineoraglycone molecule. Sugarhelpsinthedissolutionofthepreparationwhilethepharmacologicalactionrestswiththeaglycone. Whenthesugarmoleculeisglucose,theglycosideisknownasglucoside. Cardiacglycosidesdigitalis,strophanthusandsquillplayamajorroleinthetreatmentofcongestivecardiac failure. Cyanogeneticglycosideisoneinwhichhydrocyanicacidisreleasedonglycolysis. Therearetwotypesofoilsnamelyfixedoilsandvolatileoils. Volatileoilsarealsoknownasessentialoils. Castoroil,coconutoiletc.arefixedoilswhileturpentineoil,eucalyptusoiletc.arevolatileoils. Fixedoilsareobtainedbyexpressionwhilevolatileoilsareobtainedbydistillation.(Mineraloilsareobtained fromtheearthandsomeaeusedpharmacologically.Eg:Liquidparaffin.) Thesearenonnitrogenousphenolderivativesfoundespeciallyinleavesandbark. Theyareastringentinnatureandforminkysolutionswithferricsalts.Catechuatannicacidisusedinthe controlofdiarrhoea. Eg:Blackcatechu,Palecatechu Thesearenonnitrogenoussubstancesresemblingglycosides. Theyaresolubleinwaterandonshakingtheygivepersistentfoam.Whenthesaponinistoxicitisknownas sapotoxin. Onhydrolysissaponinssplitintosugarandaglycone(sapogenin). Eg:Fenugreek,Ginsengetc. Thesearesolidbrittlesubstancesformedfromterpenesbyoxidation.Theyareinsolubleinwater. Resincanbeoleoresin,gumresinorbalsams. Eg:Asafoetida,Camphor,Storax Gumsaredriedexudatesobtainedbyincisiononstemsofvariousplants. Theyformajellywithwater. Eg:Gumacacia

Oils

Tannins

Saponins

Resins

Gums

Mineral source

Metallicandnonmetallicmineralsprovidevariousinorganicmaterialsnotavailablefromplantsoranimals. Mineralsourcesareusedastheyoccurinnatureorcanbecombinedwithotheringredients. Thedrugsthatareincludedinthiscategoryincludemetalsandtheirsalts,nonmetals,metalloids,acids, alcoholsandcoaltardrugsetc. Examplesare:sodiumchloride,coppersulphate,magnesiumsulphate,potassiumpermanganate,etc. Theyareusedinthepurifiedformasdrugs.

Animal source of drugs


Thebodyfluidsorglandsofanimalsarealsonaturaldrugsources.Thedrugsobtainedfromanimalsourcesinclude: hormones,suchasinsulin 12|U R V I S H M I S T R Y

13|U R V I S H M I S T R Y oilsandfats(usuallyfixed),suchascodliveroil enzymes,whichareproducedbylivingcellsandactascatalysts,suchaspancreatinandpepsin vaccines,whichincludesuspensionsofkilled,modified,orattenuatedmicroorganisms,orantigenic materialsobtainedfromthese.

Synthetic sources of drugs


Anumberofdrugssynthesizedinthelaboratoryareusedmostcommonly. Evennaturalproductssuchashormones,antimicrobialsetc.arealsosynthesizedinthelaboratory.

Microbial source of drugs

Microbesprovideanimportantsourceofdrugsespeciallytheantibiotics.Alltheantibioticsusedagainsta varietyofpathogensandalsocancerareobtainedfromfungi,bacteriaoractinomycetes.Somesystemic drugslikeergotalkaloids(fungalsource)arealsoobtainedfrommicrobes. Eg:PenicillinfromPenicilliumnotatum Streptomycin,Tetracyclines,ChloramphenicolfromStreptomycessp.

Pharmacokinetics: principles of drug activity


Routes of administration

Routesofdrugadministrationcanbedividedintothreemainclassesasenteral,parenteralandtopical. o Enteraladministrationreferstoadministrationofdrugsviathegut. o Parenteral(parbeyond,enteralintestinal)administrationcoversintravenous,intramuscular, subcutaneous,intraperitonealetc. o Topicalapplicationreferstoapplicationofdrugsontheskinandmucousmembrane. Factorsgoverningthechoiceofrouteare: o Physicalandchemicalpropertiesofthedrug(solid/liquid/gas;solubility,stability,pH,irritancy) o Siteofdesiredactionlocalizedorgeneralized o Rateandextentofabsorptionofthedrugfromdifferentroutes o Effectofdigestivejuicesandfirstpassmetabolismofthedrug o Rapiditywithwhichtheresponseisdesired(routinetreatmentoremergency) o Accuracyofdosagerequired(intravenousandinhalationneedfinetuningofdose) o Conditionofthepatient(unconscious,vomiting)

Oral administration
Dosageformsavailablefororaluseinclude Liquids:Aqueoussolutions,suspension(dispersionofasolidinaliquid)andemulsion(dispersionofaliquid inliquid) Solids:Powders,tablet,entericcoatedtablet,capsule,granules Fortabletsandcapsulesthefactorsthataffecttheactualamountofthedrugabsorbedoravailableinclude disintegration,coating,adjuvantsused,compression,drugparticlesizemicronization,amountofthedrug, chemicalform(salt),physicalstate(amorphousorcrystalline,solvatedoranhydrous)andlocalpHofthe absorptivearea. Advantagesoforalroute Generallythesafestroute 13|U R V I S H M I S T R Y

14|U R V I S H M I S T R Y Economical Convenientandrelativelysimpleforowner Noneedforsterileequipment Systemicdistributioncanbeachieved Disadvantages Absorptionmaybevariable Gastricirritationmaycausevomiting Notusefulifanimalisvomiting Requirescooperationofpatient,whichisnotusuallyforthcominginaveterinarypatient Drugsmaybedestroyedbygastricacidity,gutflora,mucosalenzymesandliverenzymes Onsetofeffectisusuallyslow Notgenerallypreferredinruminantssincethedruggetsdilutedinthevoluminousruminalcontents Whenantimicrobialsareadministeredtoruminantsorallyforalongerdurationoftime,theymayaffectthe microbialecosystemoftherumen Presenceoffoodandotherdrugsmayaltertheabsorptionpatternleadingtounpredicatabilityinthe desiredaction. Entericcoatedpreparations Drugsthataredestroyedbythegastricjuiceorthatcausegastricirritationcanbeadministeredorallywitha coatingthatpreventsdissolutionintheacidicgastriccontents. Theydissolveoncetheyreachtheduodenumandreleasetheactivedrug.Onsetofdrugactioncan bedelayedwithentericcoatedtablets. Sublingualtablets Drugsthatarelipidsolubleandnonirritatingcanbeadministeredsublingually,sothatabsorptiondirectly fromtheoralcavityisachievedwhenarapidresponseisrequired,particularlywhenthedrugiseither unstableatgastricpHorrapidlymetabolisedbytheliver.Eg.Glyceryltrinitrate. Drugsabsorbedbymouthpassdirectlyintothesystemiccirculationwithoutenteringtheportalsystemand soescapethefirstpassmetabolism.Thistypeoftabletisusefulinthetreatmentofanginapectoriswhere thedrugentersdirectlyintothesystemiccirculationandprovidesimmediateeffect.Oncetherequired effecthasbeenachieved,theexcesstabletcanbespitoff. Timedreleasepreparations Timedreleasepreparationsaredesignedtoproduceslowuniformreleaseandabsorptionofthedrugovera periodof8hoursormore.Theyarealsoknownasspansulesortimesules. Advantages o Lessfrequentadministration o Lastsovernight o Druglevelsaremoreconstantanddonotpeakaftereachadministration(lesstoxiceffects) o Goodforshortactingdrugs Disadvantages o Marketedpreparationsaresometimesnotreliable o Dissolutionratesmaybeirregular o Notneededforlongactingdrugs o Notgoodforabrieftherapeuticeffect Rectaladministration Thisrouteofadministrationisusefulwhentheanimalisunconsciousorvomiting. Rectalabsorptionisoftenincompleteanderratic. Drugscanbeadministeredrectallyintheformofenemaorsuppository. Irritantandunpleasantdrugscanbeadministeredperrectum.However,rectalinflammationmayoccurdue tohighlyirritantdrugs.

Intravenous route
Parenteraladministration Whileconsideringparenteraladministration,thepointsofimportanceinclude o Volumetobeadministered 14|U R V I S H M I S T R Y

15|U R V I S H M I S T R Y o Concentrationofthedrug o pH o Toxicity o Viscosity o Particlesize,ifsuspensionisused o Adjuvantusedinthepreparation Ingeneral,parenteraladministrationrequiresskillofinjectionanduseofsterileequipment.Parenteral preparationsarenormallyusedassolutionsorsuspensions. Intravenousadministration Advantages o Extremelyrapidonsetofaction o Initialabsorptionstepisbypassed o Druglevelscanbecontrolledmoreaccurately o Suitableforirritantdrugs o Suitableforlargevolumesofdrugs Disadvantages o Mostdangerousrouteastoxicitycaneasilyoccur o Drugsmustbeinaqueoussolution o Mustbeperformedslowly o Onceinjected,drugcannotberetrieved Sitesforvenipunctureindifferentspecies Cattle,sheepandgoatAtanypointalongthewholelengthofthejugularveininthejugularfurrow,onthe venterolateralaspectoftheneckoneitherside HorseExternaljugularveininthejugularfurrowonlyinthecranialpartoftheneck. PigAuricularvein Dogsaphenousveinonthemedialaspectofthelegorrecurrenttarsalveinonthedorsalaspectoftheleg.

Subcutaneous and intramuscular routes


Subcutaneousadministration Thisrouteisusefulwhenslowandcontinuousabsorptionisrequired.Theformulationmustbeisotonicand atphysiologicalpH. Certaindrugsthatareirritatingcancauseseverepainandnecrosis.Therateofdistributionofthedrugis largelydependentonbloodflowandhence,therateofdistributioncanbeslowedbyincludinga vasoconstrictor. Warmthorvigorousmassagewillincreasedistribution.Additionofhyaluronidasecanenhancedrug dispersion.Thisenzymehydrolysesthehyaluronicacidpolymersthatcomprisestheintercellularcementand thusfacilitatesdiffusionthroughthetissues. Specialisedsubcutaneouspreparationsincludedermojetandpelletimplantation. Dermojetisaprocesswherenoneedleisused.Ahighvelocityjetofthedrugsolutionisprojectedfroma microfineorificeusingagunlikeimplement.Thesolutionpassesthroughthesuperficiallayerandgets depositedinthesubcutaneoustissue.Itisessentiallypainlessandsuitableformassinoculation. Pelletimplantationprovidessustainedreleaseofthedrugoverweeksormonths.Thepelletimpregnated withthedrugisimplantedinthesubcutaneoustissue.Sialistic(nonbiodegradable)andbiodegradable implantsareused. Crystallinedrugispackedintubesmadeofsuitablematerialandimplantedundertheskin.Constantblood levelscanbemaintainedasthedrugisreleaseduniformlyoveraperiodoftime.Ifnonbiodegradable implantisused,itshouldberemovedafterthespecifiedperiodoftime. Sitesforsubcutaneousinjectionindifferentspecies Cattle,sheepandgoatFoldofflankextendingfromthecaudoventralabdominalwalltothecraniomedial aspectofthethighnearstiflejointorlooseskinonthelateralaspectoftheneck. HorseLooseskinonthelateralaspectoftheneck.Normallysubcutaneousinjectionisnotpreferredin horses. DogFoldoftheflank 15|U R V I S H M I S T R Y

16|U R V I S H M I S T R Y Intramuscularadministration Drugsinaqueoussolutionarerapidlyabsorbedafterintramuscularadministration.However,veryslow constantabsorptionoccursifthedrugisadministeredinoilorsuspendedinotherrepositoryvehiclesas depotpreparations.Itcanbeusedforrelativelyirritantdrugsandsuchdrugsmustbeadministereddeep intramuscularly.Intramuscularinjectionsarealwayspainfulandlargevolumescannotbeinjected. Adisadvantageofthisrouteisthepossibilityofimproperdepositioninnerves,bloodvessels,fatorbetween musclebundlesinconnectivetissuesheaths.Wheneverdrugsareadministeredintramuscularly,itisalways advisabletoconfirmthattheneedleisnotinthebloodvessel. Sitesforintramuscularinjectionindifferentspecies: Cattle,sheepandgoat1.Hindlimba)Glutealregioncoveredbyglutealmusclesandb)posterioraspectof thighbetweenthesemimembranousandsemitendinous.(Insheepandgoat(b)ispreferred). 2.NeckIntheheavymusclesonthecaudodorsalaspectoftheneck.Needlecanpiercethroughthe followingstructuresskin,fascia,trapezius,rhomboideus,spleniusandcomplexus,dependinguponthe lengthoftheneedleandforceapplied.Thissiteispreferredonlyinwellbuiltanimals.Careshouldbetaken toavoidvertebralcolumnandthedorsalbranchoftheXIcranialnerve. Inindigenouscattlewithhump,humpisalsopreferredtoadministerintramuscularly. HorseNeckregionandbrisketregion(pectoralmuscles) DogHindlimbbetweenthesemimembranosusandsemitendinosus.

Other parenteral routes


Intraperitonealadministration Thisrouteisparticularlyusefulinlaboratoryanimalmedicineandneonatalanimalsandforthe administrationoflargevolumes. Thereisaverylargeabsorbingareaandabsorptionisrapid.Thereisadangerofinfectionandperitoneal adhesions.Thusitisnotusedroutinely.Peritonealdialysisisbecomingmorefrequentlyusedinsmall animalswithrenalfailureandrenalinsufficiency. Intradermaladministration Thisrouteisusedmainlyfordiagnosticpurposeseg.forTuberculinandJohnintestingincattleandalsofor hypersensitivitytestingbeforeadministeringsomedrugsknowntoinducehypersensitivity. Intrathecaladministration Inthisroutethedrugisadministeredthroughthemembranesenclosingthecentralnervoussysteminthe lumbarareaorintothecisternamagna. Itisoccasionallyusedforradiographicexaminationsandchemotherapyofcentralnervoussysteminfections andneoplasms. Epiduraladministration Thisrouteismainlyusedtoanaethetiseanimalsforsurgerylikeparturitionincattle. Thedrugisadministeredbetweenthefirstandsecondcoccygealvertebrae. Intraarticularadministration Thisrouteisusedtoadministerantiinflammatoryagentsintothejointcapsule. Theotherparenteralroutesofdrugadministrationrarelyusedareintraarterial,intramedullary, intratesticular,intracardiacetc.

Local administration

Localadministrationofdrugsreferstoexternalapplicationorapplicationtoalocalizedsitesuchaseye.ear. mucousmembranesetc. Someofthelocalsitesofadministrationinclude: o Skin:Applicationofdrugsontotheskinsuchaspowder,lotion,ointmentetc. o Mucousmembrane: Mouthandpharynx:mouthwash,gargle,paintetc. Eye,earandnose:Drops,spray,irrigation GItract:nonabsorbabledrugssuchaskaolin,antacids,someantibioticswhichareintended toremainwithintheGItractandnotabsorbed 16|U R V I S H M I S T R Y

17|U R V I S H M I S T R Y Bronchiandlungs:aerosol,inhalations Vagina:Pessary,bolus,tablets Rectum:Suppository,enemaetc. o Tissues:Drugscanbeadministeredtosomeofthetissuebutareintendedtoactonlyonthesiteof absorption.eg.Intraauricular,intrathecal o Arterial:Somedrugsaregivenintraarteriallytoactonthelocalizedareasuppliedbytheartery.Eg: angiography,anticancerdrugs.

Structure of biological membranes


Fluid mosaic models

Biologicalmembranesmaybeviewedasmosaicsoffunctionalunitscomposedoflipoproteincomplex. Mostmembranesarecomposedofafundamentalstructurecalledtheunitmembraneorplasma membrane,thatis80to100Athick,surroundssinglecellsandnuclei. Complexbarrierssuchastheintestinalepitheliaandtheskinarecomposedofmultiplesofthisfunctional structure. Theplasmamembraneconsistsofabilayerofthiclipidswiththeirhydrocarbonchainsorientedwithinto formacontinuoushydrophobicphaseandtheirhydrophilicheadsorientedoutward. Individuallipidmoleculesinthebilayercanmovelaterally,makingthemembranefluid,flexibile,electrically resistantandrelativelyimpermeabetohighlypolarmolecules. Thisviewofmembranestructureisknownasthefluidmosaicmodel. o Membraneproteinsembeddedinthebilayerservesasreceptorstoelicitelectricalorchemical signalingpathwaysandprovideselectivetargetsfordrugaction. o Theproteinsareabletofreelyfloatthroughthemembraneandsomeoftheintrinsicones,which extendthroughthefullthicknessofthemembrane,surroundfineaqueouspores.Paracellular spacesorchannelsalsoexistbetweencertainepithelialorendothelialcellsandotherproteinshave enzymaticorcarrierproperties. o Biologicalmembranesbehaveasiftheywerelipoidspuncturedbyaqueousporesandallowdrugs andphysiologicalmaterialscrossbypassiveorcarriermediatedprocess.Whichmechanismoperates isdeterminedbythephysicochemicalpropertiesofdrugsandtheoptionsavailableinthe membrane.

Functions of membranes
Membranesperformthefollowingfunctions: 1. Theyprovidestructuralstabilitytothecell 2. Theyactasbarriersrestrictingtheentryofsubstancesinsidethecell. 3. Theyprovidevitalcommunicationthroughtheentryofmessengersforvariouscellularprocesses.

Passage of drugs across membranes


Passive diffusion

Passivediffusionisarandommovementofdrugmoleculesfromanareaofhigherconcentrationtoanarea oflowerconcentration.Whenadrugisinjectedintothebody,itpassivelydiffusesfromtheinjectionsiteto areasoflowerconcentration,eventuallyreachingabloodcapillaryandenteringthesystemiccirculation.In thisprocessnocellularenergyisexpendedandnotransportcarrierproteinisinvolved.Hencethe termpassivediffusionisused. Manydrugspassthroughthebiologicalmembranessuchascellmembranesbypassivediffusion.Foradrug topassivelydiffusefromonesidetoanother,thedrugmustdissolveinthemembranethatiscomposedof phospholipids,anddiffusedowntheconcentrationgradient. Passivediffusioncontinuesuntilenoughmoleculeshavepassedfromanareaofhigherconcentrationtoan areaoflowerconcentrationtillequilibriumisattainedoneithersideofthemembrane.Drugmolecules continuetomove,however,suchthatanequalnumbermoveintoandoutofboththeareas. 17|U R V I S H M I S T R Y

18|U R V I S H M I S T R Y Passivediffusionisthemostimportantmechanismformajorityofdrugs.Lipidsolubledrugsdiffuseby dissolvinginthelipoidalmatrixofthemembrane.Therateoftransportbeingproportionaltolipid:water partitioncoefficientofthedrug. Passivediffusionismostlydependentupon: o Concentrationgradient(greateristhedifferenceintheconcentrationofthedrugonthetwosidesof themembrane,fasterisitsdiffusion) o Drugmolecularsize(smallermoleculesmovemorerapidlythanbiggermolecules) o Lipophilicnatureofthemolecule(higherthelipidsolubilityhigheristhediffusion) o Temperature(lowerthetemperature,slowerthediffusion) o Thicknessofthemembrane(thethickerthemembranetheslowerthediffusion)

Carrier mediated transfusion


InCarriermediatedtransport,thedrugcombineswithacarrierpresentinthemembraneandthecomplex thentranslocatesfromonesideofthemembranetotheother. Thecarriersforpolarmoleculesappeartoformahydrophobiccoatingoverthehydrophyllicgroupsandthus facilitatepassagethroughthemembranes.Substancespermittingtransitofionsacrossmembranesare calledionophores. Carriertransportisspecific,saturableandcompetitivelyinhibitedbyanaloguesthatutilisethesamecarrier. Intestinalabsorptionsometimesdependsoncarriermediatedtransport. Examplesofcarriermediatedtransportare: levodopaistakenupbyacarrierthatnormallytransportsphenylalanine; Fluorouracilistransportedbythesystemthatcarriesnaturalpyrimidines; ironisabsorbedviaaspecificcarrieronthesurfaceofthemucosalcellsinthejejunumand CalciumisabsorbedbymeansofavitaminDdependentcarriersystem. Thiscarriermediatedtransportisoftwotypes,namely o facilitateddiffusionand o activetransport

Facilitated diffusion

Facilitateddiffusionisatransportmechanismacrossbiologicalmembranesthatinvolveaspecialcarrier moleculeinthemembranewhichfacilitatesthemovementofcertainmoleculesacrossthemembrane. Asinpassivediffusion,facilitateddiffusioninvolvesnoenergytomovethedrugmoleculesandthedirection ofthedrugmovementisdeterminedbytheconcentrationgradient. Inaddition,oncetheequilibriumisattained,thenumberofdrugmoleculescrossingthemembraneineither directionremainsthesame. Thisprocessproceedsmorerapidlythansimplediffusionandeventranslocatesnondiffusiblesubstrates, butalongtheirconcentrationgradient. However,thetransportermaybecomesaturatedandothercompoundsmaycompeteorinhibitthe transport. Examplesoffacilitateddiffusionare: o VitaminB12absorbedfromthegut. o Transportofsugarsandaminoacidsacrossmembranes.

Active transport

Likefacilitateddiffusion,activetransportalsoinvolvesaspecializedcarriermolecule.However,inactive transportadrugmoleculeistakenupbyaspecializedcarriermoleculeinthemembraneandthecell expendsenergytomovethedrugmoleculesacrossortoresetthecarriermoleculeforthenexttransport movement. Unlikediffusioninwhichthedirectionofnetdrugmovementisdeterminedbytheconcentrationgradient, activetransportcanmovedrugmoleculesagainsttheconcentrationgradient(fromareasoflower concentrationtoareasofhigherconcentration). 18|U R V I S H M I S T R Y

19|U R V I S H M I S T R Y Glucoseentrywithincellisfacilitateddiffusionwhilepassageacrossgastricmucosaandexcretionby proximalrenaltubularcellsisactivetransport. Drugsrelatedtonormalmetabolitesareactivelyabsorbedfromthegutbyaromaticaminoacidtransport processes. Drugsactivelytransportedmaypotentiallyreachveryhighconcentrationswithincellsthattheyexertatoxic effecteg.aminoglycosideantibiotics. Whentheenergyproductionofthecellisdisrupted(suchastoxicities),activetransportofdrugmolecules acrossbiologicalmembranesmaybeprevented. Nonspecificactivetransportofdrugsandtheirmetabolitesoccursinrenaltubulesandhepaticsinusoids separatelyfororganicacidsandorganicbases.Certaindrugshavebeenfoundtobeactivelytransportedinto thebrainandchoroidplexusalso. Examplesforactivetransportarelevodopacrossingthebloodbrainbarrier,secretionsomedrugsintothe bileandsecretionofmanyorganicacidsandbasesbyrenaltubularcells.

Pinocytosis and phagocytosis


Pincytosis(Celldrinking)andphagocytosis(Celleating) Drugmoleculesmayenteracellbybeingphysicallyengulfedbythecell.Inbothpinocytosisand phagocytosis,aportionofthecellularmembranesurroundsthedrugmoleculeandtakesitwithinthecell. Intheseprocessestransportacrossthecellmembraneisfacilitatedbyformationofvesicles.Thisisanactive processandrequiresthecelltoexpendenergy.Iftheengulfedparticleisnotsusceptibletoenzyme degradation,itwillpersistlikeparticlesoftalcordropletsofliquidparaffin. Pincytosisandphagocytosisareespeciallyimportantformovementoflargedrugmoleculessuchascomplex proteinsorantibodiesthatwouldotherwisebeunabletoenteracellorpassintactthroughamembrane barrier.Theabsorptionofimmunoglobulinsthroughthegutmucosaofyoungcalvesdependson phagocytosis. Pinocytosisandphagocytosisareoflittleinterestinpharmacology.

Filtration

Filtrationisthepassageofdrugsthroughaqueousporesinthemembraneorthroughparacellularspaces. Thiscanbeacceleratedifhydrodynamicflowofthesolventisoccurringunderthehydrostaticorosmotic pressuregradient. Lipidinsolubledrugscrossbiologicalmembranesbyfiltrationiftheirmolecularsizeissmallerthanthe diameterofthepores.Majorityofthecellshaveverysmallporesanddrugswithhighermolecularweight willnotbeabletopenetrate.Howevercapillaries(exceptthoseinbrains)havelargeporesandmostdrugs canfilterthroughthesepores. Passageofdrugsacrosscapillariesisdependentontherateofbloodflowthroughthemratherthanonlipid solubilityofthedrugorpHofthemedium. Filtrationseemstoplayalmostaminorroleindrugtransferwithinthebodyexceptforglomerularfiltration, removalofdrugsfromCSFandpassageofdrugsacrosshepaticsinusoidalmembrane.

Absorption of drugs

Absorptionisthemovementofdrugfromthesiteofadministrationtocirculation. Oftentheentirequantityofadministereddrugdoesnotreachthesystemiccirculation.Onlythefractionof drugthatwasabsorbedisavailableforaction. Duringtheprocessofabsorption,thequantityofdrugabsorbedandalsotherateofdrugabsorbed determinethedrugaction. Inallroutesofadministration,exceptwithintravenousadministration,thedrugshavetocrossthebiological membranesforenteringthesystemiccirculationandhencearegovernedbyfactorsaffectingpassage ofdrugsacrossmembranes.

19|U R V I S H M I S T R Y

20|U R V I S H M I S T R Y

Absorption of drugs from GI tract

Beforeadrugcanbeabsorbed,itmustdissolveintheaqueouscontentsofthegut.Thus,theactualamount ofthedrugpresentinadoseisonlyoneofthefactorsthatwillaffecttheamountofdrugactuallyabsorbed oravailable. Factorsaffectingabsorptioninclude o Molecularsizeofthedruganditsconcentration o Degreeofionization(dependsonthepKaofthedrugandpHofthemedium) o Lipidsolubilityoftheneutralornonionizedformofthedrug. o Chemicalorphysicalinteractionwithcoadministeredpreparationsandfoodconstituents o Pharmaceuticalpreparationanddosageform,especiallytheirdisintegrationrateanddissolution rate o Gastricmotilityandsecretionaswellasgastricemptying o Intestinalmotilityandsecretionaswellasintestinaltransittime o Fluidvolumewithinthegastrointestinaltract o Osmolalityoftheintestinalcontents o Intestinalbloodandlymphflow o Disruptionofthefunctionalandstructuralintegrityofthegastricandintestinalepithelium o Drugbiotransformationwithintheintestinallumenbymicrofloraorwithinthemucosabyhost enzymes o Volumeandsurfaceareaoftheabsorbingsurface.Stomachhasarelativelysmallsurfacearea comparedtotheduodenum.Henceabsorptionismoreintheduodenum. o Presenceoffoodinthestomach.Normallyinfullstomachthereisadelayinabsorptionbecausethe druggetsdilutedinthestomachcontents.

Role of ionization and lipid solubility in drug absorption

Manydrugsareweakelectrolytesie.theycanionizetoagreaterorlesserextent,accordingto environmentalpH.Usuallymostmoleculesarepresentpartlyintheionizedandpartlyintheunionised state. Thedegreeofionizationinfluenceslipidsolubilityand,inturn,theirabsorption,distributionandelimination. Thedegreetowhichthesedrugsarelipidsoluble(nonionized,theforminwhichdrugsareabletocross membranes)isdeterminedbytheirpKaandthepHofthemediumcontainingthedrug. pKaofadrugisthepHatwhich50%ofthedrugisionizedand50%isnonionized. InmonogastricanimalswithalowstomachpH,weakacidssuchasaspirinwithapKaof3.5tendtobebetter absorbedfromthestomachthantheweakbasesbecauseoftheacidicconditions. Weakbasesarepoorlyabsorbedfromthestomachbecausetheyexistmostlyintheionizedstateinthe acidicenvironmentofthestomach.Weakbasesarebetterabsorbedfromthesmallintestinewherethe environmentalpHismorealkaline. HendersonHasselbalchequationisusedtocalculatethepercentofadrugthatexistsinionizedformorto determinetheconcentrationofadrugacrossthebiologicmembrane.

Henderson and Heselbelch equation

Giventhisformula,ifadrugishavingapKaof4.4,andgiventhepHofplasmaandgastricmucosaare7.4 and4.4respectively,then

20|U R V I S H M I S T R Y

21|U R V I S H M I S T R Y

Absorption of drugs after parenteral administration

Drugsinjectedintramuscularlyorsubcutaneouslymayreadilydiffusethroughtissuefluidandreacha capillarytobeabsorbed.Anythingthatinterfereswithdiffusionofthedrugfromthesiteofadministration oraltersthebloodflowtotheinjectionsitecandelayabsorptionofthedrug.Themajorfactorthat determinestheabsorptionisthebloodflowtothemuscle. Aqueoussolutionsofdrugsareusuallyabsorbedfromintramuscularinjectionsitewithin1030minutes providedthebloodflowisunimpaired.Fasterorslowerabsorptionispossible,dependingonthe concentrationandlipidsolubilityofthedrug,vascularityofthesite,volumeofinjection,theosmolalityof thesolutionandotherpharmaceuticalfactors. Absorptionofdrugsfromsubcutaneoustissuesisinfluencedbythesamefactorsthatdeterminetherateof absorptionfromintramuscularsites.Somedrugsareabsorbedasrapidlyfromsubcutaneoustissuesasfrom muscles,althoughabsorptionfrominjectionsitesinsubcutaneousfatisalwayssignificantlydelayed. Increasingthebloodsupplytotheinjectionsitebyheating,massageorexercisehastenstherate ofabsorption.Spreadingandabsorptionofalargefluidvolume,whichhasbeeninjectedsubcutaneously maybefacilitatedbyincludinghyaluronidaseinthesolution.

Absorption of drugs after inhalation or topical administration


Thevolatileandgaseousanaestheticsarethemostimportantgroupofdrugsadministeredbyinhalation. Thesesubstancesenterthecirculationbydiffusionacrossthealveolarmembranes.Sincetheyallhave relativelyhighlipidwaterpartitioncoefficientsandgenerallyarerathersmallmolecules,theyequilibrate practicallyinstantaneouslywiththebloodinthealveolarcapillaries. Particlescontainedinaerosolsmaybedeposited,dependingonthesizeofthedroplets,onthemucosal surfaceofthebronchiorbronchioles,oreveninthealveoli. Absorptionofdrugsfromtopicalsitesofapplication 21|U R V I S H M I S T R Y

22|U R V I S H M I S T R Y Drugsmaybeabsorbedthroughtheskinfollowingtopicalapplication.Theintactskinallowsthepassageof smalllipophilicsubstances,butefficientlyretardsthediffusionofwatersolublemoleculesinmostcases. Highlylipidsolublepreparationsmaybeabsorbedinconsiderableproportionsencouragingtheuseofthe topicalrouteespeciallyinveterinarypractice.Pouronpreparationsofanthelminticsisatypicalexample. Lipidinsolubledrugsgenerallypenetratetheskinslowlyincomparisonwiththeirratesofabsorption throughtheotherbodymembranes.Absorptionofdrugsthroughtheskinmaybeenhancedbyinunctionor morerarelybyiontophoresisifthecompoundisionized.Certainsolventslikedmethylsulfoxidemay facilitatethepenetrationofdrugsthroughtheskin. Damaged,inflamedorhyperemicskinallowsmanydrugstopenetratethedermalbarriermuchmore readily.Thesameprinciplesthatgoverntheabsorptionofdrugsthroughtheskinalsoapplytothe applicationoftopicalpreparationsontheepithelialsurfaces. Manydrugstraversethecorneaatratesthatarerelatedtotheirdegreeofionizationandlipidsolubility. Thusorganicbasessuchasatropine,ephedrineandpilocarpineoftenpenetratequitereadily,whereasthe highlypolaraminoglycosideantibioticsgenerallypenetratecorneapoorly.

Distribution of drugs
Drugstakenthroughoutthebodybybloodstream Onceabsorbed,itgetsdistributedtoothertissueswhichhadnodrug Thefactorsthatgovern Lipidsolubility,pH,pKaetc. Bloodflowtotheorgan Bindingandtissueaffinityofdrugs Circulatorydisorders,kidneydiseases Competitionamongdrugsforbindingsites Bloodflowratelimitingstepindistribution HighlyperfusedorganssuchasLiver,Kidney,GItract,Brain,Lungsreceiverapidlyhighlevelsofdrug. Lesserlevelsareachievedinlessperfusedorganslikemuscle,fattissue.

Plasma protein binding of drugs


Drugstendtobecomeassociatedwithseveralbloodconstituents. Manydrugsareboundtoplasmaproteins. Itisonlytheunboundorfreefractionofadrugthatcandiffuseoutofcapillariesintotissues. Factorsaffectingplasmaproteinbindinginclude o Drugconcentration o Numberofdrugbindingsitesontheprotein o Proteinconcentration o Lipidsolubilitythereisagoodcorrelationbetweenthisandthebindingofpenicillinsand tetracyclines o Weakacidslikepenicillinsareboundmoreextensivelythanweakbases o Competingmolecules o Speciesvariation o Disease Albuminandotherplasmaproteinsareessentiallycontainedwithinbloodvesselsandsothedistributionof drugsthatareboundisrestricted.Whenmorethan7080%ofthedrugisboundtoplasmaprotein,itacts asacirculatingreservoirforthedrug. Whentwoormoredrugscanbindtothesamesiteoftheplasmaproteins,administrationofaseconddrug maysignificantlyaffectthebindingofthefirstdrug. Atitstherapeuticconcentrationwarfarinis97.4%bound.Ifatherapeuticdoseofthenonsteroidalanti inflammatorydrugphenylbutazoneisadministered,boundwarfarindecreasesto92%.Thusfreewarfarin increasesfrom2.6to8%.Thisincreasestheanticoagulanteffectofwarfarinconsiderably.Italsoreducesits halflifefrom18.4to9.6hourssinceitisalsomoreavailableforbiotransformationandexcretion.

22|U R V I S H M I S T R Y

23|U R V I S H M I S T R Y Changesinbindinghavethegreatesteffectontheproportionoffreedrugwhenthepercentboundishigh. Reducingthebindingfrom98%to96%willdoubletheamountoffreedrugfrom2%to4%andthusthehalf lifeofthedrugwouldbereducedmuch. Thedrugproteinbindingreactionisreversibleandobeysthelawofmassaction. Drug+protein=>Drugproteincomplex Acidicdrugsareboundprimarilytoalbuminandbasicdrugsareboundprimarilyto1acidglycoprotein. Bindingdoesnotpreventadrugfromreachingitssiteofactionbutitslowstherateatwhichadrugreaches aconcentrationsufficienttoproduceapharmacologiceffect. Drugproteinbindinglimitsglomerularfiltrationoraneliminationprocess,becausebounddrugcannotbe filtered.However,bindingdoesnotlimittheeliminationofdrugsbyactivesecretionormetabolizedbythe liver,becausethefractionofthedrugthatisfreeistransportedandmetabolized. Whenfreedrugconcentrationislowered,thereisrapiddissociationofthedrugreceptorcomplexto maintaintheamountofdruginthefreestate.

Plasma protein binding

Somedrugsthatbind Toalbumin NSAIDs Barbiturates Phenytoin Penicillins Tetracyclines Toalpha1 acidglycoprotein Verapamil Lidocaine Bupivacaine Quinidine Prazosin

Drugswithinthesamegroupbindvariably Eg.Sulfonamides: Sulfamethazine30%,Sulfadiazine50% Sulfamethoxazole60%,Sulfisoxazole90%

Tissue storage of drugs


Somedrugsaccumulateinspecifictissues Examplesare HeartDigoxin LiverChloroquine,digoxin,cadmium Kidneydigoxin,chloroquine,cadmium Irisatropine Boneandteethtetracycline Adiposetissuethiopentone,ether,DDT storageinfatlongduetopoorbloodsupply MercuryRBC Arsenic=Nailandhair Thesespecificstoragesitesaretobeborneinmindwhenthesedrugsareadministeredorintreatingtheirtoxicities Redistribution OccursinhighlyfatsolubledrugsInitiallytakenupbybrain,heart,kidney Laterdepositedinlessvasculartissuesmuscle,fat Onredistribution,plasmaconcentrationfallsleadingtolossofdrugaction Onrepeateddoses,thesesitesfillupleadingtolongeractionofthedrug.

Barriers to drug distribution


Bloodbrainbarrier:(BBB) Aphysical/functionalbarrierwhichdoesnotpermitionizedandnonlipidsolubledrugstopassthroughinto theCentralNervousSystem

23|U R V I S H M I S T R Y

24|U R V I S H M I S T R Y ItismainlyformedbytheendothelialcellsoftheCNSbloodvessels.Itspurposeistoprotectthebrainfrom thechemicalenvironmentoftherestofthebodyduetothedelicatebalancebetweenexcitationand inhibitionmaintainedwithintheCNS. Thebraincapillariesdonotcontainfenestrations(holes).Therearemoretightjunctionsinbraincapillaries decreasingtherateofdiffusionthroughinterstitialspaces.Glialcellsensheaththebraincapillariesproviding asecondsetofcellmembraneswhichmustbetraversedaswellasasecondintracellularcompartment wherecellularmetabolicprocessescantransformenteringsubstances ChemicalorenzymaticbarrierMonoAmineOxidase,cholinesteraseThisbarrierprevents5HT, catecholamines,AChfromentryintoCNS Carriermediatedtransporttofacilitateexitofdrugs Highlylipophilicdrugsentereasilybecausetheycrossmembranes.(Fig.18)Unionizedformsofdrugsenter moreeasilythanionizedforms.Penicillin,streptomycin,gentamicindonotcrosstheBBB ChloramphenicolcancrosstheBBB Placenta Virtuallynotabarrier Anydrugtakenbymotherislikelytoaffectthefetus Hencecaremustbetakenwhileadministeringdrugstopregnantanimals.Onlyhighlyioniseddrugsand drugswithlowlipidsolubilityareexcludedfrompassingthroughtheplacenta. Itisimportantfromthepointofviewofteratogenicityofdrugs Milk Governedbyrulesofpassageacrossmembranes. Themammaryglandepithelium,liketheotherbiologicalmembranesactasalipidbarrierandmanydrugs readilydiffusefromtheplasmaintothemilk. ThepHofmilkvariessomewhat;butingoatsandcowsitisgenerally6.56.8ifmastitisisnotpresent. Weakbasestendtoaccumulateinmilkbecausethefractionofionized,nondiffusibledrugishigher.Agents deliveredbyintramammaryinfusioncandiffuseintotheplasmatoagreaterorlesserdegreebasedonpH differencesandthepKaofthedrug. IncowsMaximumResidueLevels(MRL)inmilkhasbeenrecommendedformanydrugstominimisehuman exposurerisk. Incaseofdrugadmnistration,milktobediscardeduptowithdrawaltime.

Biotransformation of drugs/xenobiotics: drug metabolism


Thechemicalalterationofdrugsinthebody Torendernonpolarlipidsolublecompoundsintopolarwatersolublecompoundstoenhancetheirexcretion fromthebody Intendedtoprotectbodyfromtheforeignsubstancesbymakingthemlesstoxicandeasilyexcreted Primarysiteliver Otherimportantsitesarekidney,intestine,lungsandplasma GeneralPatternofbiotransformationbiphasic

24|U R V I S H M I S T R Y

25|U R V I S H M I S T R Y

Sequelae of biotransformation reactions


Biotransformationreactionscanleadtoanyoneofthefollowing: Inactivationmostdrugsarerenderedpharmacologicallyinactive o Example:Manydrugsmorphine,chloramphenicol,procaineetc. Formationofactivemetabolitethemetaboliteformedpossessesbiologicalactivity o Ciprofloxacinfromenrofloxacin o OxyphenbutazonefromPhenylbutazone o Salicylicacidfromaspirin Inactivedrugtoactivedrug(Prodrug)Aninactivedruggetsconvertedintoanactivemetaboliteonceit undergoesbiotransfomationinsidethebody o Example: Hetacillintoampicillin Prontosiltosulfanilamide Lessactiveorinactivedrugisconvertedintoamoretoxicdrug(Lethalsynthesis) o Example: Parathiontoparaoxon Fluoroaceticacidtofluorocitrate

Phase-I Biotransformation - oxidation reactions and others


Althougheverytissuehassomeabilitytometabolizedrugs,theliveristheprincipalorganofdrug metabolism.Othertissuesthatdisplayconsiderableactivityincludethegastrointestinaltract,thelungs,the skinandthekidneys. Drugbiotransformationinvivocanoccurbyspontaneous,noncatalysedchemicalreactions(Hofmann degradation),whichhoweverisveryrare. Thevastmajorityofxenobioticsundergobiotransformationthereactionsofwhicharecatalysedbyspecific cellularenzymes.Atthesubcellularlevels,theseenzymesmaybelocatedintheendoplasmicreticulum, mitochondria,cytosol,lysosomesoreventhenuclearenvelopeorplasmamembrane. Manydrugmetabolisingenzymesarelocatedinthelipophilicmembranesoftheendoplasmicreticulumof theliverandothertissues.Whentheselamellarmembranesareisolated,theyreformintovesicles calledmicrosomes.Theroughmicrosomestendtobededicatedtoproteinsynthesisandthesmooth microsomesarerelativelyrichinenzymesresponsibleforoxidativedrugmetabolism.Theycontainthe importantclassofenzymesknownastheMixedFunctionOxidasesormonooxygenasesorCYP450 enzymes(CytochromeP450enzymesystem) Microsomalenzymes/mixedfunctionoxidases catalyseoxidativeandglucuronideconjugationreactions RequiresmolecularO2,CYP450(ahemeprotein),NADPH(reducednicotinamideadeninedinucleotide phosphate) NADPH+CYP450(A)+H+AH2+NADP+ AH2+O2activeoxygencomplex Drug+activeoxygencomplexoxidizeddrug+A+H2O

Phase I reactions
Reaction Oxidativereactions NandOdealkylation Aliphaticandaromatichydroxylation NOxidation Sulphoxideformation Example phenacetin,morphine Phenobarbital,phenytoin Guanethidine,acetaminophen Chlorpromazine 25|U R V I S H M I S T R Y

26|U R V I S H M I S T R Y Deaminationofamine Desulfuration Hydrolysisofestersandamides Reduction a.Azoreduction b.Nitroreductionhloramphenicol


Amphetamine Thiobarbital,parathion Procaine Prontosil Chloramphenicol

Nonmicrosomalreactions MonoAmineOxidase(forbiogenicandotheramines) Esterases(forcholineanddietaryesters) Dehydrogenases(foralcoholsandaldehydes)

Phase II reactions - synthetic reactions


Conjugationofafunctionalgrouptothedrugoritsmetabolitetomakeitwatersoluble ThepresenceofOH,COOH,NH2,SHgroupsfavourformationofconjugates(thesegroupsareaddedto (or)exposedinPhaseI) Glucuronidation Themostimportantreactionmostdrugsincl.endogenoussteroidsandbilepigmentsundergothis reaction. Glucuronideconjugationtakesplaceinmicrosomes. ThesourceofglucuronideisUDPGAthroughglucuronyltransferase. Theproductishighlysolubleandisexcretedbyurine(ifMW<300500)orviabile(if>500) Betaglucuronidaseinintestinemayliberatetheactivedrugwhichisagainreabsorbedandundergoes enterohepaticrecirculationwhichleadstolongerdurationofactionofthedrug Sulfateconjugation(nonmicrosomal) Formsetherealsulfateseg.Phenols,acetaminophen,morphineandendogenousheparin,chondroitinand somesteroids Acetylation(nonmicrosomal) Acetylatesareformedeg.SulphonamidesacetylCoAisthedonor Acetylatesarepoorlysolubleinwaterandlipidandarelikelytocausecrystalluria Methylation(nonmicrosomal) AddsmethylradicalsTheaminoacidsmethionineandcysteinearethedonors eg.Histamine,adrenaline,sexsteroids Glycineconjugation(nonmicrosomal) Notamajorpathway,eg.Salicylates Glutathioneconjugation Notamajorpathwayformsmercapturicacidsimportantforremovaloftoxicradicals(superoxides, epoxidesandtoxicintermediates) Ribonucleoside/Ribonucleotidesynthesis Thesereactionsareimportantfortheactivationofpurineandpyrimidineantimetbolitesusedincancer therapy Drugconjugateswereoncebelievedtorepresentterminalinactivationeventsandassuchhavebeenviewed astruedetoxificationreactions. However,thisconceptmustbemodified,sinceitisnowknownthatcertainconjugationreactionsmaylead totheformationofreactivespeciesresponsibleforthehepatotoxicityofthedrug.

Enzyme induction and inhibition


Enzymeinhibition SomedrugsonrepeatedadministrationhavetheabilitytoinhibitcytochromeP450enzymeactivity. Thesedrugscauseareductioninthemetabolismofotherdrugsthatareadminsteredsubsequently. 26|U R V I S H M I S T R Y

27|U R V I S H M I S T R Y Somedrugsthatactasinhibitorsarechloramphenicol,cimetidine,dicumarol,oralcontraceptives,ethanol andisoniazid.Thisisanimmediateprocessduetodirectinhibitionoftheenzymeorcompetitionamong drugsfortheenzymesite Asaresulttheconcentrationofdrugincreasesleadingtoincreaseddrugeffect Enzymeinductionorstimulation SomedrugsonrepeatedadministrationhavetheabilitytoinducecytochromeP450byenhancingitsrate ofsynthesisorbyreducingitsrateofdegradation. Inductionresultsinanaccelerationofmetabolismandusuallyinadecreaseinthepharmacologicactionof theinducerandalsoofcoadministereddrugs. Increaseinenzymeconcentrationduetoinductionofproteinsynthesis(hencecalledINDUCERS)andtakes longtimetosetinandoncetheinducingdrugisstopped,takeslongtimetoreturntooriginalvalues. Somedrugsthatactasinducersaregriseofulvin,phenobarbital,phenylbutazone,phenytoinandrifampin. Significanceofenzymeinduction/inhibition Inhibitorsprolongtheactivityofcoadministereddrugs Italsoincreasesthetoxiceffectsofunchangeddrugs,ifany Drugmetabolismvariesinsmokersandalcoholics(inhumanpatients) Incaseofcombinedadministration,alterationofdosemayberequired Factorsaffectingbiotransformation Age:Biotransformationispoorinneonatessinceenzymesystemsarenotwelldeveloped.Biotransformation ispoorinoldanimals,too Disease:Diseasesoftheliverhepatitis,cirrhosisetc..andalsodiseasescausinglowbloodflowtoliversuch asCHF,shocketc.willalterbiotransformation Speciesdifferences: o Catsaredeficientinglucuronidation(lowlevelofglucuronyltransferase) o Dogslackacetylation o Pigshavelowcapacityforsulfation o Geneticdifferencesdoexistinhumanracesinmetabolizingmanydrugs(eg..metoprololinman) o Losartananantihypertensiveeffectiveinmanbutlesssoindogssincetheactivemetaboliteis notformedindogs o Rabbitspossessatropinasethereforedonotsufferfromtoxicityduetoatropine(indeadlynight shadepoisoning) Coadministrationofotherdrugsinducerorinhibitor Habitslikealcoholismandsmokingorindustrialpollutants,pesticidesmayaltermetabolismofsomedrugs Firstpassmetabolism Referstotheprocessofmetabolismofadrugbeforeitreachessystemiccirculation. Normallyhappensindrugsadministeredbyoralroute.Besidesoralroute,itcanoccurintopical(skin)and lungs,too(howeveratlowlevels) Effectsoffirstpassmetabolism: o Increasedoraldoseofthedrug o Unpredictableabsorptionoforaldosevariationamongindividualsindrugaction o Oralbioavailabilityincreased,ifthereisliverdisease Enterohepaticrecirculation Somedrugsafterbiotransformationbyglucuronideconjugation,undergobiliaryexcretion.Inthelarge intestinetheyaredetachedfromtheconjugate,leadingtoreleaseoffreedrugwhichisabsorbedagainand entersliver.Thusthedrugrecirculatesleadingtolongerdurationofaction. Eg:Phenalpthaelinusedaspurgative.

Excretion of drugs
Renal elimination of the drugs
Routesofelimination

27|U R V I S H M I S T R Y

28|U R V I S H M I S T R Y Drugsareexcretedmainlybythekidneysintotheurineandbytheliverintothebileandsubsequentlyinto thefeces. Alveolareliminationisofmajorsignificancewheninhalantanaestheticsareused.Themainfactorsgoverning eliminationbythisrouteareconcentrationinplasmaandalveolarairandtheblood/gaspartitioncoefficient. Otherlesscommonroutesofeliminationincludemilk,saliva,tearsandsweat.Thesalivaryrouteofexcretion isimportantinruminantsbecausetheysecretesuchvoluminousamountsofalkalinesalivaandmammary excretionisimportantinlactatinganimals. Renaleliminationofdrugs Thebasicfunctionsofthekidneysaretomaintainthevolumeandcompositionofbodyfluids,controlacid basebalance,eliminateendproductsofmetabolismandeliminateforeigncompoundslikedrugs. Thekidneysconstitutelessthan1%ofthetotalbodyweight,butreceiveabout25%ofthecardiacoutput. Afferentarteriolesfromtherenalarterysupplybloodtotheglomerulusatarterialpressureandabout20% ofthisisconvertedtoglomerularultrafiltrate. Furtherabsorptionandreabsorptiontakesplaceatvariouspointsalongthenephron.Thefinalproductis onlyablut1%ofthevolumeoftheoriginalglomerularfiltrate. Inthekidneys,circulatingdrugsareclearedfromthebloodthroughfiltrationandactivesecretion. Reducedrenalbloodflowdecreasesfiltrationofdrugsintheglomerulus,resultingindecreasedelimination. Thisisthereasonforreduceddosageofthedruginolderanimalswithreducedrenalfunctionandinanimals withhypotension. Theporesizeoftheglomerularcapillariesisabout40Ao.Theglomerularultrafiltratewillthereforecontain solubledrugsandothermoleculesincludingsmallproteins.Albuminisnotfilteredandhencedrugsthatare boundtoplasmaproteinsarealsonotfiltered.Theglomerularfiltrationratehasamajoreffectonrenal clearanceofdrugs. Increasedglomerularfiltrationresultsinmorerapidremovalofdrugmoleculesfromthesystemic circulation. Intheproximalconvolutedtubules,thereisactivesecretionofionizeddrugsintothelumen.Thisensures thatdrugs,whichareproteinboundareexcreted.Thetransportsystemsarenonspecificandareoftwo types.Onetransportsystemtransportsorganicacidsandtheothertransportsorganicbases.Secretionof drugmoleculesrequiressignificantenergy.Anythingthatinterfereswithcellularenergyproductionreduces theexcretionofthesedrugsfromthebody.Tubularsecretionbeinganactiveprocess,itcanbesuppressed bycompetingsubstances.Drugsexcretedbyacarriermediatedprocessintheproximaltubuleinclude: Acids PenicillinG Ampicillin Sulfosoxazole Phenylbutazone Furosemide Probenecid paminohippurate Bases Procainamide Dopamine Neostigmine Nmethylnicotinamide Trimethoprim

Glucuronicacidconjugates Etherealsulphates

FromtheproximalconvolutedtubulethedrugmovestotheloopofHenle,wheresomedrugsare reabsorbedfromthefiltrateintocirculation.Thisoccursbypassivediffusion.Drugmoleculesthatare nonionizedarereabsorbedwhilethosethatareionizedareexcreted.Butthedegreeofionizationdepends onthepHofurineandalterationsinurinarypHcanaltertheeliminationofdrugs. 28|U R V I S H M I S T R Y

29|U R V I S H M I S T R Y Highlylipidsolubledrugswillberapidlyreabsorbedfromthekidneytubule.Forthisreasonexcretionoflipid solubledrugsoftenoccurafterconversiontomorepolarmetabolite.Eventhough,manyproteinbound drugsareactivelysecretedintotheproximaltubule,reabsorptionmaybefavouredespeciallywithdrugs thatarelargelyproteinboundinplasma. IncaninetheurinarypHrangefrom5.07.0andinherbivorestheurinarypHmayrangefrom7.08.0. ExcretioncanbeenhancedfordrugsexcretedbythekidneysbyalteringthepHoftheurine.Forpractical purposesthisprinciplecanbeappliedonlytoweakacidicorweakbasicdrugswithpH5.08.0.Quarternary drugsarepolaratallurinepH.Theyareeliminatedrapidlybecausetheycannotbereabsorbed.

Hepatic and other routes of administration


Hepaticeliminationofdrugs Hepaticallyeliminateddrugsusuallymovebypassivediffusionfromthebloodintothehepatocytefrom wheretheyaresecretedintothebileormetabolisedfirstandthensecretedintothebile. Thebilethenconveysthistotheduodenum.Inacuteliverdiseasesandinchronicdegenerativeprocesses likecirrhosis,theliversabilitytometaboliseand/oreliminatedrugsisreduced.Thereforethedoseofthe drugseliminatedbylivermustbereducedinliverdisordersinordertopreventdrugaccumulationintoxic concentrations. Cholereticsorahighfatintakepromotebileflowandtherefore,biliaryexcretionandenhancethehepatic secretionofdrugs.Broadspectrumantibacterialagentsareexpectedtodiminishthehydrolyticactionof intestinalfloraandthus,maypreventeffectiveenterohepaticcycles. Largepolarmolecules(molecularweight>300)areoftenexcretedandarenotreabsorbedintheintestine. Theabilitytoexcretepolarcompoundsinbilewithmolecularweightsbetween300and500isgoodindog, chickenandrat,moderateincatandsheepandpooringuineapig,rabbit,monkeyandman. Compoundsthatundergobiliaryexcretion Unchangeddrugsandendogenous substances Erythromycin Clindamycin Digitoxin Steroidhormones Compoundsexcretedasglucuronide conjugates Chloramphenicol Trimethoprim Sulphadimethoxine Morhine

Excretionofdrugsinmilk Thisrouteofexcretionhasboththerapeuticandpublichealthimportance. Theprinciplesofexcretionthroughthemammaryglandaresimilartothoseactinginthekidneys,namely thediffusionofunionisedlipidsolubleformsofthedrugsdiffusingthroughtheepithelialcellsofthe mammarygland. ThepHofplasmaandmilkareimportantfactors.Sincemilkisusuallymoreacidicthanplasmathebasic compoundsmaybeslightlymoreconcentratedandacidiccompoundsarelessconcentratedinmilkthan plasma. ExcretionofdrugsisalteredincasesofmastitisduetochangesinthepHofmilk.

Pharmacokinetic parameters
Pharmacokinetics Themathematicaldescriptionofdrugconcentrationinthebody Theimportanceofkineticstudy: Forarrivingatthedosageregimen(doseamountanddosinginterval) Forunderstandingtheabsorption,distribution,metabolismandexcretionofdrugs Forcomparisonofdrugroutes Forcomparisonofdifferentformulations(bioequivalence) Asanessentialpartofanydrugdevelopmentstudy 29|U R V I S H M I S T R Y

30|U R V I S H M I S T R Y Fortherapeuticdrugmonitoring

Important pharmacokinetic parameters


Mostimportantparameters t1/2,ClB,Vd,AUC Halflife(t1/2)Plasmahalflifethetimetakenfortheplasmaconcentrationtobereducedtohalfitsoriginalvalue Eliminationhalflife(t1/2)thehalflifecalculatedfromtheeliminationcurve(logdoseinyaxisvstime) t1/2b=0.693/(eliminationrateconstant)(where=slopeofthecurvex2.303) Longerthehalflifelongeristhedurationofaction Atonet1/250%ofdrugiseliminated Attwot1/275%ofdrugiseliminated(50+50%ofremaining50) Atthreet1/287.5%ofdrugiseliminated At4t1/293.75%ofdrugiseliminated AUC=AreaUndertheconcentrationtimeCurve Calculatedbythetrapezoidalrule. Importantincalculatingbioavailabilityandotherparameters VolumeofDistribution(Vd) Itisdefinedastheamountofbodyfluidcontainingthedruganapparentnotanaccuratevaluethedrug tobeequallydistributedinthewholebodyfluid. Vd=dosegiven/conc.ofthedruginplasma Foramoreaccuratedescription, o Vdarea=Dose/xAUCfori.v.(or)DosexF/xAUCfornoni.v. Vdisindicativeofextentofdrugpenetration. MoredistributiongreaterVd HighlyproteinboundandtissuebounddrugshavehigherVd DrugswithhigherVdpreferredfortreatmentinremotesitesskin,bone,muscle,etc. Clearance(Cl) Totalbodyclearance(ClB)Anindexofefficiencyofdrugelimination Definedasthevolumeofbodyfluidclearedofthedrugperunittime Foragivendrugbythegivenroute,ClandVdarecharacteristicandhelpindosedetermination Vd=Cl/

Models in pharmacokinetics
LinearvsNonlineardrugelimination Ifrateofeliminationproportionaltoplasmaconcentration linearorfirstorder(constantfractionofthedrugeliminatedperunittime) occursformostnormalkineticprocesses. Ifrateofeliminationisconstantirrespectiveofconcentration>nonlinearorzeroorderreaction(constant amountofthedrugeliminatedperunittime) Occursintoxicity,saturablemechanismsofelimination, Atveryhighdose,reactionchangesfromfirstordertozeroorder Conc.increasesdisproportionatelywithincreaseindose Compartmentalmodels Amathematicaldescriptionofprocessesbasedonthenumberofphases.Onecompartmentortwo compartmentormulticompartmentaconceptofimaginarydivisionofthebodyintonumberof compartments.Thecompartmentsdonotcorrelatetoanyphysicaloranatomicalcompartments Asinglecompartmentmodelconsistsofonlyoneeliminationphase.Atwocompartmentmodelconsistsofa rapiddistributionphaseandasloweliminationphase Usually,IcompartmentindicatesbloodandhighlyperfusedtissuesandIIcompartmentindicatesperipheral tissues.Inrarecasesathirdcompartmentcorrespondingtoadeepertissuecomponent. Eliminationisonlyfromcentralcompartment Mostdrugsfollowtwocompartmentopenmodelswithfirstorderprocessesofabsorptionandelimination 30|U R V I S H M I S T R Y

31|U R V I S H M I S T R Y

Drug accumulation

Infirstorderkinetics,onrepeateddosewithinthecompleteeliminationofthepreviousdose,drug accumulatesinthebody. Plateau(steadystate)achievedwithin45halflives.TheCssistheaverageofmin.andmax.ofthesteady stateortheplateaustate. Forlongtermtherapy,itisaimedtohavethetherapeuticconc.asCss TargetCp=Css Doserate=(targetCpxCl)(mg/kgpertime)/F Insomecasesimmediatehigherdoseistobegiven(otherwisetargetCpwillbereachedonlyafter45half lives) Insuchcases,Loadingdose=(targetCpxVd)/F

Principles of Drug activity Pharmacodynamics


Modes of drug action
Pharmacodynamicswhatthedrugdoestothebody? Principlesofdrugaction Drugsdonotimpartnewfunctionsexceptgenetherapies Basictypesofdrugactionsare: Stimulationenhancementofexistinglevelofaction o Eg.adrenalineonheart,pilocarpineonsalivarygland Depressionselectivediminutionofactivityofspecializedcells o Eg.barbituratesonCNS,Acetylcholineonheart Irritationanonselective,oftennoxiousstimuli.Mildirritationonsomecells(skin,connectivetissue) stimulatesomefunctionsforabeneficialeffect. o Eg.Bitters,topicalcounterirritantsbutsevereirritationinflammation,necrosis,damage Replacementofnaturalsubstanceseg..hormonaltherapy,deficiencies Cytotoxicityeg.Antibacterials,antivirals,anticanceragents Mechanismsofdrugaction Physicalactionphysicalpropertyofthedrugcausesthemainaction Eg.massofthedrugbulklaxatives Adsorptioncharcoal Osmosismannitol Radioactivity131Iforhyperthyroidism Radioopacityascontrastmedia(barum) Chemicalactionchemicalpropertyofthedrugresponsibleforaction AntacidsAlOH2 acidifiers,NH4Cl alkalinizers,NaHCO3 oxidizersKmnO4,H2O2 chelatingagentsCaNaEDTA,BAL,Pencillamine

Enzyme mediated drug action


EnzymesareubiquitousbiologicalcatalystsmaintargetsofdrugactionsDrugseitherincreaseordecrease enzymemediatedreactionsStimulationisdonebyendogenoussub.(cofactors)vitaminsandminerals Rateofreactionincreases Enzymeinductionmicrosomalinductionbydrugsincreasedsynthesisofproteins Enzymeinhibitionamostcommonmodeofdrugaction Nonspecificmetalsalts,acids,alkalisinhibitnonspecifically Specificparticularenzymeaffectedeithercompetitiveornoncompetitive Competitivecompetitionwithnormalsubstrate Equilibratingtype 31|U R V I S H M I S T R Y

32|U R V I S H M I S T R Y Increasingtheconcentrationofnormalsubstratereversesdrugaction Eg.sulfonamidesandPABAforfolatesynthetaseneostigmineandAchforcholinesterase Nonequilibratingtype Reactwiththesamesiteasthatofsubstratebutformstrongcovalentbondsorhaveveryhighaffinitythan thenormalsubstrateeg..organophosphatesformcovalentbondwithcholineesterasemethotrexate 50,000timesmoreaffinityfortheenzymeDHFRthanDHFAcid Noncompetitivereactswithsomeothersiteandnotonthecatalyticsitebutalterstheenzymelossof catalyticpropertyeg..aspirinCyclooxygenasedisulfiramaldehydedehydrogenasedigoxinNa+K+ATPase

Receptor mediated drug action


Mostimportanttypeofdrugaction Receptorisabindingsitewithinbiologicaltissuesforeitherendogenousorexogenous(!!!)substances Macromoleculessituatedonthesurfaceofthecellorinsidethecell Regulatecriticalfunctionslikeenzymeactivity,permeability,structuralfeatures,etc Evidence Manydrugsshowstructuralspecificityminorsubstitutionalterstheeffect. Stereospecificityofdrugsdpropranolollessactivethanlisomer,lnoradrenalinemorepotentthand noradrenaline antagonismbetweensubstancesofcloselyrelatedstructuressomechemicalidentityLangley(1878) proposedthetermreceptivesubstance ThisideadevelopedbyClark(1920)propoundedtheReceptoroccupationtheoryD+RDRE(effect) Thepostulatesofthetheoryare: o Intensityofresponsefractionofreceptorsoccupied;maximalresponsewhenallreceptorsare occupiedallornoneactionofdrugoneachreceptoreachreceptoriseitherfullyactivatedornot atalldrugandreceptorhavestructurallylockandkeyarrangement

Terms related to drug receptor binding


Agonists Agonistsareagentsthatmimictheeffectsoftheendogenousregulatorycompound. Agonistsmaybedefinedasdrugsthatpossessaffinityforaparticularkindofareceptorandhastheability tocauseachangeinthereceptorthatgivesrisetoanobservableeffect.Theirvalueinclinicalpracticeoften restsontheirgreatercapacitytoresistdegenerationandthusactsforalongerdurationthanthenatural substancestheymimic.Forthisreason,bronchodilatationproducedbysalbutamollastslongerthanthat inducedbyadrenaline. Thepropertiesexhibitedbyagonistsincludeaffinity,intrinsicactivity,maximalefficacy,potency,selectivity andspecificity. Affinityofaligand(drugorendogenoussubstance)isameasureofitscapacitytobindtothereceptor. Affinitymayvarygreatlyamongagonistsaswellasantagonists.Intrinsicactivityisameasureoftheabilityof theagonistreceptorcomplextoinitiatetheobservedbiologicalresponse.Afullagonisthasanintrinsic activityof1. Maximalefficacyreflectstheupperlimitofthedoseresponserelationshipwithouttoxiceffectsbeing evident.Agonistsdifferfromeachotherinthisregard. Potencyreferstotherangeofconcentrationsoverwhichanagonistproducesincreasingresponses.Highly potentdrugsproducetheireffectsatlowerconcentrations;thismayimpartanadvantagetotheirclinical use,providedtheincreaseinpotencyisnotaccompaniedbyanincreaseintoxicity. Agonistsintheiroccupationofreceptorsexhibitselectivityandspecificity.Fewagonistsaresospecificthat theyinteractonlywithasinglesubtypeofreceptor.However,severalagonistsdoshowevidencesof selectivityforcertainsubpopulationofreceptors. Fullagonists Fullagonistsareagoniststhatproduceamaximalresponsebyoccupyingallorafractionofreceptors. Partialagonists

32|U R V I S H M I S T R Y

33|U R V I S H M I S T R Y Partialagonistsaredrugsthatactbothasagonistsandantagonists.Thesedrugsinadditiontoblocking accessofthenaturalagonisttothereceptorarecapableofalowdegreeofactivation.Theseagentsproduce lessthanamaximalresponseevenwhentheyoccupyallofthereceptors. InverseagonistsSomesubstancesproduceeffectsthatarespecificallyoppositetothoseofagonistsandare calledasinverseagonists. Antagonists Theseareagentsthatarethemselvesdevoidofanyintrinsicactivitybutcausetheeffectsbyinhibitionofthe actionofanagonist.Drugsthathavenoactivatingeffectwhatsoeveronthereceptoraretermedaspure antagonists. Theyaresufficientlysimilartothenaturalagonisttoberecognizedbythereceptorandtooccupywithout activatingit,therebypreventingthenaturalagonistfromexertingitseffect. Downregulation Whentissuesarecontinuouslyexposedtoanagonist,thenumberofreceptorsdecreasesandthismaylead toareductioninthenumberofreceptors.Thismaybeareasonfortachyphylaxis. Upregulation Prolongedcontactwithanantagonistleadstoformationofnewreceptorsandthisphenomenonisknownas upregulation. Sparereceptors Thistermreferstotheproductionofamaximaltissueresponsewhenonlyafractionofthetotalnumberof receptorsisoccupied. EC50:TheconcentrationofanagonistthatproduceshalfmaximaleffectisknownasEC50. IC50:TheconcentrationofanantagonistthatproduceshalfmaximalinhibitionisknownasIC50.

Receptors - structure and function


Receptor theories
Occupationtheories A.J.Clarkpropoundedtheoccupationtheorywhichassumesthattheextenttowhichatissueisdependent ontheproportionofitsreceptorpopulationthathasbeenoccupiedbyadrugandmaximalresponseis reachedwhenallthereceptorsareoccupied.Hepresumedthateachoccupiedreceptordeliveredaconstant unitofresponseandthatthisindividualoccupancystimuliwassummatedinmathematicalfashiontogivea linearlyproportionalresponse.Butthistheorywasnotapplicableinallsituations.Inthecaseofpartial agonistsamaximalresponsecouldnotbeexhibitedeventhoughallthereceptorswereoccupied. E.J.Ariens,dividedthebiologicalresponseintotwoseparateparametersnamelyaffinityandintrinsic activity.Affinitydescribedthebindingofthedrugtothereceptorandwasassumedtobegovernedbymass action.Intrinsicactivitywasrelatedtotheabilityofthedrugtoinduceaneffectafterbinding.The assumptionsarethesameasthoseforClarkestheory.However,thenotionofpartialagonismcanbe accountedforbyassumingalowerintrinsicactivityforapartialagonistthanforafullagonist.Again,a discrepancybetweenEC50andKDvaluesandtheobservationsofsparereceptorscouldnotbeexplained. R.P.Stephenson,assumedthatthedrugreceptorcomplexprovidesastimulustothetissuesandthatthe stimulusisdirectlyproportionaltothefractionofreceptorsoccupied.Theresponseisthenrelatedtothe stimulusbyanunspecifiedfunction.Theproportionalityfactorbetweenthefractionaloccupancyofthe receptorpopulationwasdefinedastheefficacy.Theefficacyofadrugreferstotheactionofthedrugto producearesponseinagiventissue.Anadditionalparameter,intrinsicactivitywasdefinedtodescribethe stimulantactivityofthedrugitselfindependentofthetissue.TheproblemwithStephensonsmodelisthat theexactlinkbetweeneffectandoccupancyremainsunclear. Ratetheory RatetheorywasdevelopedbyW.D.M.Patonandpostulatesthatthebiologicalresponseisproportionalto therateatwhichthedrugcombineswiththereceptorthatis,eachassociationofthedrugwithreceptor resultsinaquantumofexcitation.Thisimpliesthatanagonistmustdissociaterapidlyfromthereceptorto enableothersuccessfulassociationsandsubsequentgenerationofquantumofexcitation.

33|U R V I S H M I S T R Y

34|U R V I S H M I S T R Y Ontheotherhand,anantagonistisassumedtodissociateslowlytopreventthegenerationofotherquanta ofexcitation.Thus,dissociationrateconstantwasconsideredtobethefactor,whichdeterminedwhethera ligandwasanagonist,antagonistorpartialagonist.Theexperimentalanalysisofdrugdissociationratesdid notsupportthismodel. Allosterictheories Twoallostericmodelsoriginallydevelopedtodescribeenzymeregulationhavebeenproposed. Theideaoftheallosterictheoryisthatreceptorscanexistinavarietyofdiscreteconformationalstates differingintheirabilityofthatstatetoproducearesponse. Ligandstheninteractwiththereceptorinsuchawaysoastocontroltheconformationalstate.These modelsdefinepreciselytherelationshipbetweenbindingandeffect. Receptorssubservetwoessentialfunctionviz.,recognitionofthespecificligandmoleculeandtransduction ofsignalwitharesponse.Accordingly,thereceptorhasaligandbindingdomain(spatiallyandenergetically suitableforbindingthespecificligand)andeffectordomain,whichundergoesafunctionalconformational change.

Functions of receptors
Thefunctionsofreceptorsare Topropagateregulatorysignalsfromoutsidetowithintheeffectorcellwhenthemolecularspeciescarrying thesignalcannotitselfpenetratethecellmembrane Toamplifythesignal Tointegratevariousextracellularandintracellularregulatorysignals Toadapttoshorttermandlongtermchangeswithregulatorymilieuandmaintainhomeostasis.

Types of receptors

TypeIChannellinkedreceptors(ligandgatedionchannelsorinotropicreceptor)Thesearealsoknownas ionotropicreceptors.Thesearemembranereceptorsthatarecoupleddirectlytoionchannelsandarethe receptorsonwhichfastneurotransmittersact.Examplesincludenicotinicacetylcholinereceptorsand glutamatereceptors. TypeIIGProteincoupledreceptors(metabotropicreceptors)Thesearealsoknownasmetabotropic receptorsor7transmembranespanningreceptors.Theyaremembranereceptorsthatarecoupledto intracellulareffectorsystemsviaaGprotein.Thisclassincludesreceptorsformanyhormonesandslow transmitters.Examplesincludemuscarinicacetylcholinereceptorsandadrenergicreceptors. TypeIIIKinaselinkedreceptorsThesearemembranereceptorsthatincorporateanintracellularprotein kinasedomainwithintheirstructure.Theyincludereceptorsforinsulin,variouscytokinesandgrowth factors.Closelyrelatedarereceptorslinkedtoguanylatecyclasesuchastheatrialnatriureticfactorreceptor. TypeIVReceptorsthatregulategenetranscription(nuclearrecptors)Thesearealsoknownasnuclear receptors,thoughsomeareactuallylocatedinthecytosolratherthanthenuclearcompartment.They includereceptorsforsteroidhormonesandthyroidhormone.

Second messenger systems

Manyhormones,neurotransmitters,autacoidsanddrugsactonspecificmembranereceptors,the immediateconsequenceofwhichisactivationofacytoplasmiccomponentofthereceptor,whichmaybean enzymesuchasadenylatecyclase,guanylcyclaseoractivationofatransportsystemoropeningofanion channel. Thesecytoplasmiccomponentswhichcarryforwardthestimulusfromthereceptorsareknownassecond messengers.Thereceptoritselfisthefirstmessenger. ExamplesofsecondmessengersarecAMP,cGMP,Ca2+,GProteins,IP3,DAGetc. cAMPservesassecondmessengerforadenosine,opioid,VIP,2andadrenoceptorsandH2receptors. cGMPservesassecondmessengerforangiotensinreceptor. IP3andDAGserveassecondmessengersfor1adrenoceptors,H1receptorsandcholecystokinin. cAMPhasvariedregulatoryeffectsoncellularfunctions,forexample,energymetabolism,celldivisionand celldifferentiation,iontransport,ionchannelfuntion,smoothmusclecontractilityetc. 34|U R V I S H M I S T R Y

35|U R V I S H M I S T R Y cGMPhasbenidentifiedincardiaccells,bronchialsmoothmusclecellsandothertissues.Formosteffects producedcAMPseemstobestimulatorywhilecGMPseemstobeinhibitoryinnature.WhenthecAMPand cGMPsystemsarebothepresentinasinglecellortissue,theyarelinkedtoreceptorsthroughwhichdrugs produceoppositeeffects. IP3andDAGaredegradationproductsofmembranephospholipidbytheenzymephospholipaseC.

Dose response curve


Plotting

Asthenameindicatesthisreferstotheplottingofthedosevsresponse,withthedoseinXaxisand responseinsomemeasurableunitsintheYaxis. Thefeaturesofthecurvesoobtainedwillprovideusefulinformationabouttheactionofthedrugorin comparisonamongdrugs.

Features of dose response curve


Plottingofdoseresponsecurve EffectYaxisandDoseXaxishyperbola EffectYaxisandLogDoseXaxissigmoidcurve Bytakinglogdosealinearrelationshipin3070%rangegivesapossibilityofpredictionofresponsein thisrange Responseisproportionaltoanexponentialfunctionofthedose Logdoseresponsecurvesareusedto o displaywiderangeofdoseeffect o compareagonistsandantagonists Potencyamountofdrugrequiredtoelicitaresponse Relativepotencymoremeaningfulthanabsolutepotency o Eg.DrugA(potency10mg)morepotentthandrugB(100mg) A10timesmorepotentthanBrightwardshiftofDRcurveiflesspotent Potencyneednotmeanclinicalsuperiority EfficacythemaximaleffectproducedbyadrugandreferstothepeakobtainedintheDRcurve. Eg.Morphineproducesveryhighanalgesiathatcannotbeobtainedwithanydoseofaspirin Morphinehighlyefficaciousthanaspirin

Quantal dose response curve


QuantalDRcurveduetobiologicalvariation(diff.amongindividualsinresponsetosametreatment)the responsetodrugdoseinapopulationoccursasafrequencydistribution. Acumulativefreq.Distribution(as%ofindividualsshowingeffectplottedagainstlogdose>yieldsthe quantalDRcurve Thedosethatproducesdesiredeffectin50%ED50 Thedosethatproducesdeathin50%LD50 Therapeuticindex=LD50/ED50

Factors modifying drug action


Factors affecting drug action
Factorsmodifyingdrugaction: Bodysize:influenzestheconc.achievedatthesiteofaction.Dosesarenormallygivenforadultsofmedium build.Inextremecasesdosetobeactuallycalculatedbasedonperkgdose. o Bodysurfaceareaisalsoanimportantparameterusedincalculationofdoseforanticancerdrugs o (BSAinsq.m.=KxBWinGrams2/3x104(K=10fordogs,10.1cats) Age:drugbehaviordiffersininfantsandchildren.lowGFR, 35|U R V I S H M I S T R Y

36|U R V I S H M I S T R Y o BloodBrainBarriermorepermeable,absorptionisalteredpoormetabolizingcapacityupto4weeks ofage o Intheold,poormetabolizingcapacity,lowPPbinding,slowerAbsorptiondosealterationneeded inbothcases Sex:Femalessmallerinsizeandmayneedlowerdose. o Pregnancyinducedchangesdelayedabsorption,plasmaalbuminfalls,acidglycoproteinincreases, renalbloodflowincreases,inductionofCYP450enzymesalltheseaffectthekineticsofdrug o Besidespossibilityofdrugaffectingfetusortheyoungonesthromilk Specieschangesinsp.inthepatternofmetabolismrabbitsresist o Atropine,dogsarepooracetylators,catsdeficientinglucuronidation RaceBlacksneedhigheratropinetodilatepupilMongolsneedlowerdose o FewerreportsofaplasticanemiaafterchloramphenicoluseinAsianscomparedtotheWest Dietandplaneofnutritiondrugactionpredictableingoodplaneofnutrition GeneticsG6PDdeficiencyhemolysiswithantimalarialagentsMalignanthyperthermiaafterhalothanein somehumanindividualsandpigs Routeofadministration:Besideskinetics,insomecasesroutemayalteractioneg.MgSO4orally purgation,skindecreaseswelling,i/vCNSandcardiacdepressionIodineantisepticandantigoitre EnvironmentInsecticides,tobaccosmoke,charcoalbroiledmeatinducemetabolism. o Hypnoticstakenatnightatbedworkwell. Psychologicalbeliefs,attitudes,expectationsmoreinhumans o Placebo(LatinIshallplease)usedintrialsandtotreatotherwisenormalpatients(hypochondriacs) o Placebosinduceendorphinsinbrainanalgesia Diseasestates DiseasesofGItractorallygivendrugsalteredabsorption LiverdiseasesBioavailabilityofdrugswithFirstpassmetabolism IncreasedRenaldiseaseaffectsexcretionofdrugs Inalltheabovechangeofdoseneeded. ImmunocompetenceNormallyinveryyoungandveryoldpatientsimmunityiscompromised.So, bacteriostatictobereplacedbybactericidals Druginteractionsphysicalorchemicalinactivationorincompatibility Fooddruginteractionsavailabilityoffooddelaysabsorption. Ingredientsoffoodmaycausespecificinteractions PharmacologicalInteractionsmaybebeneficialepinephrine+localanaestheticspreanaesthetics, antibacterialcombinations penicillin+probenecid,ampicillin+sulbactamharmfulinteractionsaminoglycosideswithNeuromuscular blockingagents Enzymeinhibitorsandinducers ToleranceandTachyphylaxisToleranceistherequirementofhigherdosetoproducegivenresponse Naturalindividuallesssensitivetodrug(rabbits) Acquiredbyrepeateduseofthedruginanindividualwhowasinitiallyrespondingmaybeduetofaster eliminationofthedrugonlonguseorchangesinreceptorsensitivity(downregulation) Crosstolerancetoleranceamongcloselyrelateddrugs(morphineandpethidine) Tachyphylaxisrapiddevelopmentoftoleranceafteronlyafewdoses Seeninephedrine,tyraminewhichdepletestoresofcatecholamines

Adverse effects of drugs


Adverseeffectsofdrugs Anyundesirableorunintendedconsequenceofdrugadministrationmaybetrivial,seriousorfatal Alldrugsarecapableofproducingsideeffects Definition:Anynoxiouschangewhichissuspectedtobeduetoadrugatnormaldoses,requirestreatment ordecreaseindoseorcautioninfutureuseofthedrug. Notuncommonseenin1025%ofthecases.Stilldrugsareusedconsideringthebenefitvsrisk 36|U R V I S H M I S T R Y

37|U R V I S H M I S T R Y Predictable(typeI)basedonthepharmacologicalpropertiesofthedrug.Sideeffects,toxiceffectsanddrug withdrawalsymptoms Unpredictable(typeII)basedonpeculiaritiesofthepatientandnotonknowndrugeffect. Severity Minornotherapyneeded Moderatemayneedchangeindrug/oritsdosageorprolonghospitalstay Severepotentiallylifethreatening,causespermanentchangeorrequiresintensivemedicaltreatment Lethalcontributestothedeath Preventionofadverseeffectsofdrugs FollowingstepstominimizeADE o Avoidinappropriateuses o Usecorrectdoseandrouteofthedrug o Considerprevioushistoryofreactions,ifany o Findoutifanyotherallergicdiseaseexisted,andtakecaution o Ruleoutharmfulinteractionsamongdrugsprescribed o Adoptcorrectdrugadministrationtechnique o Carryoutcorrectlab.procedurestoruleoutreactions

Types of adverse effects


Sideeffectexpectedeffectandunavoidableeg..drynessofmouthinatropinetreatment Secondaryeffectindirectconsequencesofaprimaryeffecteg..weakeningofhostimmunityby corticosteroidsflareupofTB Toxiceffectduetooverdosage.eg..Paracetamolinducedliverdamage,comabybarbiturates,auditory disturbanceinstreptomycin Intoleranceappearanceoftoxiceffectsattherapeuticdosesinsomeindividuals..eg..onlyfewdosesof carbamazepineataxiainsomepatients Idiosyncracygeneticallydeterminedabnormalreactivitytoachemicalandalsosomeuncharacteristic reactionstodrugsegg.Barbiturateinducedexcitementandconfusioninsomepatients. Drugallergyimmunologicallymediatedreactionnotrelatedtotheactionofthedrug (hypersensitivitybutnotsuprsensitivity)needsaprimingdoseandtheseconddoseproducesviolent reactions.drugactsasantigen(hapten)andcapableofstimulatingthebodytoproduceAntibodiesagainst it. TypeIanaphylactic(Immediatehypersensitivity)itching,urticaria,asthmaetc.. TypeIIcytolyticcausesdecreaseofbloodcellsandorgandamage TypeIIIArthusreactiononvascularendotheliumserumsickness,fever,arthralgiaetc.. TypeIV(delayedhypersensitivity)takesmorethan12htodevelopeg..contactdermatitis,rashes,fever etc.. Treatmentstoppingtheoffendingdrug,administrationofantihistamines,glucocorticoids,adranalineetc.. Examplesofdrugscausinghypersensitivity:Penicillin,sulfonamide,tetracycline,salicylates,quinolones,Anti TBdrugs,etc PhotosensitivitycutaneousreactionduetodruginducedsensitizationoftheskintoUVlightorradiation. Eg..phenothiazine(phototoxic),sulfonamide,griseofulvin(photoallergic) Dependencepsychologicalpatientfeelsthathewillbealrightonlyifhetakesthedrug Withdrawalreactionsfornonaddictivedrugs..eg..seizuresonwithdrawalofanantiepilepticdrug. Teratogenicityabilitytocausefetalabnormalitieseg..thalidomide,anticancerdrugs,tetracyclines. Mutagenicityandcarcinogenicity.eg..anticancerdrugs,estrogen,radioactivity,tobaccoetc.. Druginduceddiseases(iatrogenicphysicianinduced)eg..ulcerbyNSAIDs..

Drug interactions

Aveterinarianisoftenposedwiththenecessityoftreatingapatientwithmorethanonedrug simultaneously.Itishighlyprobablethatonedrugmightaffecttheactionoftheother,theresultofwhich maybebeneficialorharmfultothepatient.Aclinicianshouldpossessadequateknowledgeaboutsuch interactionstoavoidanyadverseeffects. 37|U R V I S H M I S T R Y

38|U R V I S H M I S T R Y Drugsexhibitsynergismorantagonism Synergism:Itisthecooperationbetweentwodrugswherethepresenceofonedrugfacilitatesorincreases theactionoftheother.Itcanbeoftwotypes: o Synergismadditive(1+1=2)theneteffectisonlythesumoftheindividualeffects.eg.Aspirin+ paracetamol(analgesic+antipyretic),ephedrine+theophylline(bronchodilator) o Supraadditiveorpotentiation(1+1=3)neteffectismorethanthesumoftheindividualeffects o Sulfonamide+trimethoprim(bacteriostaticbecomesbactericidal),Ach+physostigmine (inhibitionofbreakdown) Antagonism:Referstoadecreaseorreversalofthepharmacologicresponseofonedrugbyanotherdrug. Thedrugwhichantagonizestheactionofonedrugiscalledanantagonist.Antagonismisofthefollowing types: o Antagonism(1+1=0or<1) o Canbe physicalbasedonphysicalpropertyadsorptionofalkaloidsbycharcoal chemicalbasedonchemicalpropertyantacidslikeNaHCO,chelatingagentsBAL,EDTA forheavymetals Physiologicalorfunctional o histamineandadrenalineonbronchialmuscle o Insulinandglucagonsonbloodsugar Receptorantagonismantagonistbindswiththereceptorandinhibitsgenerationofresponsemaybe competitiveornoncompetitive CompetitiveandNoncompetitive Competitiveantagonism:Theantagonistischemicallysimilartotheagonistandcompeteforthesame bindingsite.Theantagonistblockstheeffectoftheagonistandtheantagonisticeffectcanbeovercomeby increasingtheconcentrationoftheagonist.Itisalsocalledsurmountableantagonism.Eg:acetylcholineand itsantagonistatropine. Noncompetitiveantagonist:Theantagonistisnotchemicallyrelatedtotheagonistbutmodifiesthebinding oftheagonisttothereceptorbybindingtoanothersite.Theantagonisticeffectcannotbeovercomeby increasingtheconcentrationoftheagonist.Itisalsocalledunsurmountableantagonism.Eg:Acetylchloline anddecamethonium. Pharmacokineticantagonism:whereonedrugalterstheactionoftheotherdrugbypreventingorreducing anyoneofthepharmacokineticprocessessuchasabsorption,distribution,biotransformationandexcretion. Eg:Antacidspreventtheabsorptionofotherdrugs(absorption) Aspirindisplaceswarfarinfromitsplasmaproteinbindingsite(distribution) Microsomalinducersandinhibitorsmodulatethemetabolismofotherdrugs(biotransformation) Probenecidantagonizespenicillinexcretionbycompetingforthebindingsite(excretion)

Drug screening and drug discovery


Drug discovery
Mostnewdrugsordrugproductsarediscoveredordevelopedthroughoneofthefollowingmethods: 1. Identificationorelucidationofanewdrugtarget. 2. Rationaldrugdesignbasedonanunderstandingofbiologicalmechanisms,drugreceptorstructure,enzymes sitesetc. 3. Chemicalmodificationofanexistingmolecule. 4. Screeningforbiologicactivityofnaturalproducts,previouslydiscoveredchemicalentities,andlibrariesof peptides,nucleicacids,andotherorganicmolecules. 5. Theexplosivegrowthinbiotechnologyandcloninghaspavedthewaytoidentifygenestoproducepeptides andproteins.Effortscontinuetofocusonthediscoveryofnewtargetsandapproaches,basedonstudies withgenomics,proteomics,nucleicacidsandmolecularpharmacologyfordrugtherapy. 6. Combinationsofknowndrugstoobtainadditiveorsynergisticeffectsorarepositioningofaknowndrugfor anewtherapeuticuse. 38|U R V I S H M I S T R Y

39|U R V I S H M I S T R Y

Drug screening

Drugscreeningreferstoasequenceofexperimentsandcharacterizationusingavarietyofbiologicassaysat themolecular,cellular,organsystem,andwholeanimallevelstodefinetheactivityandselectivityofthe drug.Forexample,antiinfectivedrugsmaybetestedagainstavarietyofinfectiousorganismssome ofwhichareresistanttostandardagents. Themoleculewillalsobestudiedforabroadarrayofotheractionstoestablishthemechanismofactionand selectivityofthedrug.Thiswillrevealanysuspectedandunsuspectedtoxiceffects. Occasionally,anunexpectedtherapeuticactionisdiscoveredbychance..Itbecomesveryimportantto developsuitablepreclinicalinvitroandinvivomodelstopredictdrugaction. Duringdrugscreening,studiesareperformedtodefinethepharmacologicprofileofthedrugatthe molecular,cellular,system,organ,andorganismlevels. Atthemolecularlevelthedrugwouldbetestedforreceptorbindingactivitytotargetrecptors,metabolizing enzymesetc. Atthecellularlevel,thedrugwouldbestudiedtodeterminewhetheritstimulatesorinhibitsthecellular function. Attheorganlevelthepharmacologicactivityandselectivityfortheorganstudiedwouldbestudied.Isolated organstudiesesp.smoothmusclesandotherinvitropreparationscanbeused. Wholeanimalstudiesaregenerallynecessarytodeterminetheeffectofthedrugonorgansystemsand diseasemodels.Cardiovascularandrenalfunctionstudiesofallnewdrugsaregenerallyfirstperformedin normalanimals. Whereappropriate,studiesondiseasemodelswouldbeperformed.Evidencewouldbecollectedon durationofactionandefficacyfollowingoralandparenteraladministration. Iftheagentpossessedusefulactivity,itwouldbefurtherstudiedforpossibleadverseeffectsonothermajor organsystems,includingtherespiratory,gastrointestinal,endocrine,andcentralnervoussystems. Thesestudiesmightsuggesttheneedforfurtherchemicalmodificationtoachievemoredesirable pharmacokineticorpharmacodynamicproperties.Forexample,oraladministrationstudiesmightshowthat thedrugwaspoorlyabsorbedorrapidlymetabolizedintheliver;modificationtoimprovebioavailability mightbeindicated. Ifthedrugwastobeadministeredlongterm,anassessmentoftolerancedevelopmentwouldbemade.For drugsrelatedtoorhavingmechanismsofactionsimilartothoseknowntocausephysicaldependence, abusepotentialwouldalsobestudied.Foreachmajoractionfound,apharmacologicmechanismwouldbe sought. Theoutcomeofthisscreeningprocedureiscalledaleadcompound,i.e.,aleadingcandidateforasuccessful newdrug.

Preclinical safety and toxicity testing


Alldrugsaretoxicatsomedose.Tocorrectlydefinethetoxicitiesofdrugsandthetherapeuticindex comparingbenefitsandrisksofanewdrugisanessentialpartofthedrugdevelopment. Mostdrugcandidatesfailtoreachthemarket,duetothelimitationsoftoxicity. Leaddrugsthatsurvivetheinitialscreeningandprofilingproceduresmustbecarefullyevaluatedfor potentialrisksbeforeandduringclinicaltesting. Althoughnochemicalcanbecertifiedascompletely"safe"(freeofrisk),theobjectiveistoestimatetherisk associatedwithexposuretothedrugcandidateandtoconsiderthisinthecontextoftherapeuticneedsand durationoflikelydruguse. Toxicitytestingistimeconsumingandexpensive.Twotosixyearsmayberequiredtocollectandanalyze dataontoxicityandestimatesoftherapeuticindexbeforethedrugcanbeconsideredreadyfortestingin humans. Largenumbersofanimalsmaybeneededtoobtainvalidpreclinicaldata.Owingtothesituationarisingout ofconcernsofanimalusage,animaltestinghasbecomeapublicissueandsomesegmentsofthepublic attempttohaltallanimaltestingintheunfoundedbeliefthatithasbecomeunnecessary. Extrapolationsoftherapeuticindexandtoxicitydatafromanimalstohumansarereasonablypredictivefor manybutnotforalltoxicities. 39|U R V I S H M I S T R Y

40|U R V I S H M I S T R Y

Clinical trials

Ineachofthethreeformalphasesofclinicaltrials,volunteersorpatientsmustbeinformedofthe investigationalstatusofthedrugaswellasthepossiblerisksandmustbeallowedtodeclineortoconsentto participateandreceivethedrug. Inphase1,theeffectsofthedrugasafunctionofdosageareestablishedinasmallnumber(2550)of healthyvolunteers.Ifthedrugisexpectedtohavesignificanttoxicity,asisoftenthecaseincancerandAIDS therapy,volunteerpatientswiththediseaseareusedinphase1ratherthannormalvolunteers. o Phase1trialsaredonetodeterminewhetherhumansandanimalsshowsignificantlydifferent responsestothedrugandtoestablishtheprobablelimitsofthesafeclinicaldosagerange. o Thesetrialsarenonblindor"open";thatis,boththeinvestigatorsandthesubjectsknowwhatis beinggiven.Manypredictabletoxicitiesaredetectedinthisphase. o Pharmacokineticmeasurementsofabsorption,halflife,andmetabolismareoftendoneinphase1. o Phase1studiesareusuallyperformedinresearchcentersbyspeciallytrainedclinical pharmacologists. Inphase2,thedrugisstudiedinpatientswiththetargetdiseasetodetermineitsefficacy. o Amodestnumberofpatients(100200)arestudiedindetail.Asingleblinddesignisoftenused,with aninertplacebomedicationandanestablishedactivedrug(positivecontrol)inadditiontothe investigationalagent. o Phase2trialsareusuallydoneinspecialclinicalcenters(eg,universityhospitals). o Abroaderrangeoftoxicitiesmaybedetectedinthisphase. Inphase3,thedrugisevaluatedinmuchlargernumbersofpatientswiththetargetdiseasesometimes thousandstofurtherestablishsafetyandefficacy. o Usinginformationgatheredinphases1and2,phase3trialsaredesignedtominimizeerrorscaused byplaceboeffects,variablecourseofthedisease,etc.Therefore,doubleblindandcrossover techniquesarefrequentlyused. o Phase3trialsareusuallyperformedinsettingssimilartothoseanticipatedfortheultimateuseof thedrug.Theinvestigatorsareusuallyspecialistsinthediseasebeingtreated. o Certaintoxiceffects,especiallythosecausedbyimmunologicprocesses,maybecomeapparentonly inphaseIII. Phase4beginsonceapprovaltomarketadrughasbeenobtained. o Thisconstitutesmonitoringthesafetyofthenewdrugunderactualconditionsofuseinlarge numbersofpatients. o Thecarefulandcompletereportingoftoxicitybyphysiciansaftermarketingcanrevealsomeside effectsmayafterchronicdosing. o Severalhundredthousandpatientsmayhavetobeexposedbeforethefirstcaseisobservedofa toxicitythatoccurswithanaverageincidenceof1in10,000. o Phase4hasnofixedduration

40|U R V I S H M I S T R Y

41|U R V I S H M I S T R Y

Bio prospecting

Referstothesearchforusefulapplications,processorproductwithcommercialvalueinthebiosphere. Itisthemanipulationofnaturesbountytofindnewersubstanceswitheconomicimportance. Manyofthedrugsinvoguetodayhavecomefromtraditionalknowledgeontheuseoftheplantsinvarious biodiversityregions. Afterthediscoveryofpenicillin,asystematicsearchofsoilbacteriaandmicrobeshaveledtothediscovery oflargegroupsofantibiotics,whichareverysuccessfullyemployedinthetreatmentofmanybacterial infectionsinmanandanimals. Scientistsareonaconstantsearchintothedeepestandfarthestcornersoftheearthforanewproductto beusedasadrugformanydiseases. Bioprospectinghasitsownissuesandconcerns.Oftenitleadstomanynewdrugdiscoveriesandtreatment ofdiseasesbuttheindigenouspeoplewhowereinstrumentalarelefttolanguishwithnosupportandcredit. Successfulbioprospectingrequiresthedevelopmentofasustainablemodelinwhichabenefitsharing systemisevolvedamongindustries,ecosystemandtheprojectedcommunities. Cureformanyadreadeddiseasesmustbehiddenintheremotestforests,deepoceansandhighest mountainsandbioprospectingisaninstrumenttouncoversuchnewknowledge. Whenperformedinalargescaleoperation,theeffortisreferredtoasmassbioprospecting. Experiencesfromthemassbioprospectingeffortsdemonstratethatmassbioprospectingisacomplex process,involvingexpertisefromdiverseareasofhumanendeavors,whatisimportantistherecognitionof issuesongeneticaccess,priorinformedconsent,intellectualpropertyandthesharingofbenefitsthatmay ariseasaresultoftheeffort. 41|U R V I S H M I S T R Y

42|U R V I S H M I S T R Y Futuremassbioprospectingendeavorsmusttakeheedofthelessonslearnedfrompastandpresent experiencesintheplanningforasuccessfulmassbioprospectingventure.

Assay of drugs
Assayofdrugsreferstothequantitativeestimationofadrug/itsactivecomponentinaformulation. Itiscarriedoutforthefollowingpurposes: o Totestthepurityofadrugpreparation. o Tocomparethepotencyofadrugwiththatofastandard. o Toassesstheefficiencyofpreparationwhilepurifyingthedrugfromamixture/naturalproduct. Assaysareofdifferenttypes Chemicalassay o Inthistheconcentrationofdrugisdeterminedbychemicalmethodssuahasspectrophotometry, fluorometry,HPLCormassspectroscopy.Thesemethodsuseoneofthephysiochemicalproperties ofthecompoundssuchasabsorbance,fluorescence,polarity,chargetomassratioetc.Theseare themostcommonlyusedmethods. Bioassay o Inthistheconcentrationofbiologicallyactivecomponentinaunitquantityofthetestdrugis comparedtotheresponseproducedbythestandardorreferencedrug.Bioassaysaremore cumbersomebutlessaccuratewhencomparedtochemicalassays.Eg:assayofhistamineinisolated guineapigileum,assayofacetylcholineinfrogrectusabdominismuscleandassayofantibiotics usingbacteria. Immunoassay o Thisiscommonlyusedfortheassayofhormones.Themethoddependsonthebindingbetweenthe radiolabelledhormoneandthecorrespondingantibody.Themethodishighlysensitivetodetect minutequantitiesofthehormonesinbodyfluids.

Biopharmaceuticals and gene therapy


Biopharmaceuticals

Thesearetherapeuticagentsproducedthroughbiotechnologicalmeans,butnotbyconventionallaboratory (chemical)synthesis. Biopharmaceuticalshavetheiroriginfromtheadvancementintheknowledgeofbiotechnologyand molecularcellbiology. BiopharmaceuticalspopularlycalledasDesignerProteinsarethepromisingtherapeutictollsofthefuture. Examplesarefunctionalhumanpeptidessuchas: o ADH,oxytocin,GnRH,ACTH,TSH/TRH,Calcitonin,Insulin,Somatostatin,GrowthHormone, Cyclosporinetc.,and o Enzymes/proteins(Streptokinase,Asparaginase,DNAase,glucocerebrosidase,erythropoietin, clottingfactors,interferons,MonoclonalAntibodies,Vaccinesetc)Daclizumab(Zenopox). GeneticallyengineeredhumanIgG(immunosuppressantmonoclonalantibodybindsspecificallytoachainof IL2receptor)usedtolowertherateofrejectionphenomenoninkidneytransplantrecipients. ThroughDNArecombinanttechnology,bacteriaareinducedtoproducehormoneslikeinsulinandgrowth hormoneandenzymeslikeLasparaginase.

Gene therapy

Itmeanspreventionortreatmentofdiseasesthroughmanipulationofgenefunction.Itisdonebyinsertion ofspecificgenes(therapeuticgenes)exogenouslyintotheanimalcells. Itinvolvesreplacingthedefectivegeneorsupplementationtoanonfunctionalgeneorsuppressionofan abnormalgene. RecombinationDNAtechnologyformsthebasisofsynthesisoftherapeuticgenes. Genedeliveryintohostishighlycomplicatedanddifferentfromthatofconventionaldrugdeliverysystems. Theprocessinvolvesinsertingatherapeuticgenefirstintoavector(Viralvectors:RetroorAdenovirusesor NonviralVectors:Liposomes,microspheresandplasmidDNA). 42|U R V I S H M I S T R Y

43|U R V I S H M I S T R Y Avectorwiththegeneisthenintroducedintothepatientthrougheitherinvivoorexvivomeans. Theinvivomethodinvolvesinjectingthesuspensionofthevectorhavingthetherapeuticgeneintravenously orintothetargettissue/organ. Theexvivomethodinvolvesfirstinsertingthetherapeuticgeneintostemcellsobtainedfromthepatient( bloodorbonemarrow)andinjectthesameintothepatient. Genetherapyiscurrentlyaimedattreatmentofdiseasesnotrespondingtoconventionaldrugtherapy,such asinheritedmetabolicdiseasesthrougheithercorrectionofadeficiencyorblockadeofanabnormal metabolicreaction. Itisalsoappliedtoinducesynthesisofadeficientproteininthehostscellsandtreatmentofavarietyof cancers(melanoma,renalcarcinoma,lungcancer,cysticfibrosisetc)certainimmunedeficienciesand infectiousdiseases(likeHIV).

Gastro intestinal pharmacology


Sialagogues (sialics) and antisialagogues (antisialics)
Sialagogues

Sialogoguesareagentsthatincreasethevolumeofsaliva,therebyincreasingtheappetiteandthe digestabilityoffood. Suchremediesareusedinlargeanimalpracticeastonics. Increasedsalivationisobtainedbyadministeringsubstancesthatstimulatetastebudslikethevegetable bitters. Substanceswiththistypeofactivityincludegentian,quassiaandnuxvomica. Increaseinsalivationisalsoachievedonadministrationofparasympathomimetics. Antisialagogues(antisialics)areagentsthatdecreasethevolumeofsalivarysecretions. Theantisialagogueeffectmayberequiredduringsurgeryofthemouthorafterexcisionofsalivarycysts. Parasympatholyticdrugshaveantisialagogueeffect.Atropineorglycopyrrolatearecommonlyusedto reducesecretionsasapremedicantduringsurgerytoreducesalivaryandbronchialsecretions. Stomachicsareagentsthatincreasethetoneandfunctionofstomachandincreaseappetite. Eg:Bitterstomachicssuchasginger,gentian,chirata.Theseplantbasedpreparationsstimulatethetaste budsandreflexlystimulatethestomach.

Antisialogogues

Stomachics

Appetite stimulants

Inappetanceoranorexiaiscommonindiseasestatesandtheresultantmalnutritioncandelayrecoveryand mayaggravatetheunderlyingdisease. Thevariouswaysbywhichappetitecanbeimprovedare: o Enteralalimentationwithliquidsupplementsisusefulinsmallanimals o Smallamountsofpalatablefoodshouldbeofferedatfrequentintervals.Warmingthefoodmay enhanceappetiteincarnivores o Variousdrugsareusedfortheshorttermstimulationofappetite. Benzodiazepinese.g.,Diazepam,Oxazepam Theantiserotonergiceffectdepressesthesatietycenterinthehypothalamus. Benzodiazipinesareusedmostfrequentlyincatsandlessfrequentlyinhorses,dogs andgoatsforashorttermstimulationofappetiteafterwhichtheeffectsdiminish. Diazepamcanbeadministeredorally,intravenously,intramuscularlyonceortwice daily, Oxazepamcanadministeredoncedailyorally. Theadverseeffectsincludesedationandataxia. Cyproheptadine 43|U R V I S H M I S T R Y

44|U R V I S H M I S T R Y Cyproheptadineactsasaserotoninandahistamine(H1)antagonistandsuppresses thesatietycenterinthehypothalamus. Cyproheptadinestimulatesappetiteincatsandinhumans,butnotindogs. AdverseeffectsincludesCNSexcitementandmarkedaggressivebehaviourincats. Glucocorticoidse.g.,Prednisolone,Dexamethasone Glucocorticoidsstimulateappetiteduetoglucocorticoidinducedeuphoria. Insmallanimalsprednisoloneordexamethasoneisadministeredintramuscularly oncedailyoreveryotherdaywhereasinlargeanimalsitisadministered intramuscularlyoncedaily. Adverseeffectsofglucocorticoidsincludeimmunosuppressionandgastric ulceration. Bitterslikeplantderivedcompoundssuchasnuxvomica,chiretta,ginger Theseareusedassalivarystimulantsandtheireffectonappetiteisquestionable. However,bittersareacomponentoftonicsforappetitestimulationinlargeanimals intraditionalmedicine.

Emetics
Emeticsareagentsthatinducevomitionandareclassifiedas centrallyactingand reflexactingemetics. Themainareainthebrainresponsibleforvomitingisthevomitingcenter.Thisareaislocatedinthelateral reticularformationofthemedulla. Itreceivesinputfrommanyareaslike: o Chemoreceptortriggerzone:Thisislocatedinthefloorofthefourthventricleanditpicksup circulatingchemicals/toxinsintheblood(e.g.bacterialfoodpoisoningtoxins,drugsusedfor chemotherapy)andcausevomiting. o Vestibularapparatus o Tractussolitariusvagalafferentsfromthegut,heartandtestes o Directinputfromgut(reflex) Theneurotransmittersinvolvedintheemeticresponseare o OntheCTZ:5HT3,D2 o Onthevagalafferents:5HT3 o Inthevomitingcenter:Muscarinic,H1receptors Centrallyactingemetics Thisincludes: ApomorphineisaD2agonistthatactsontheCTZtocausevomiting. o Apomorphineiscontraindicatedincatsasitmaycauseextremeexcitementincat. o Apomorphinecanbeadministeredsubcutaneouslyorasalamella(eyetablet)intheconjunctival sac. o Sinceapomorphinedepressestheemeticcentre,repeateddosingisnotrecommendedwhenthe initialdosingisieffective. Xylazineisusedasanemeticincats. SyrupofIpecacunhaisalsousedasanemetic. o Itactsbothcentrallyandlocally(reflexly)asanemetic. o Itirritatesthegastricmucosaandwithin1530minutesafteradministrationemesisisobserved. o Itproducesatoxicmetaboliteandhenceifemesisdoesnotoccurafteradministeringthesyrup,it shouldberemovedbyadministeringagastriclavage. o Highconcentrationsofipecacarecardiotoxic. o Animalswithipecacoverdosemayexhibitarrhythmias,hypotensionandmyocarditis. o Activatedcharcoal(aconstituentofuniversalantidote)shouldnotbeadministeredwithipecacas thecharcoaladsorbsthesyrupofipecacandpreventsitfromirritatingthegastricmucosaandin turnproducingemesis. Locallyactingemetics 44|U R V I S H M I S T R Y

45|U R V I S H M I S T R Y Warmwater Warmsaturatedsodiumchloridesolution Sodiumchloridecrystalsplacedatthebackofthetongue Sodiumcarbonateascrystals Coppersulphate50mlofa1%solution Zincsulphate50mlasa1%solution Freshlygroundmustardpaste Hydrogenperoxideasa3%solution Clinicalusesofemeticsinclude removalofingestedpoison(exceptwhencorrosivepoisonsofpetroleumproductshavebeeningested) emptyingthestomachcontentsinemergencysurgery Emeticsshouldnotbeadministeredinanunconsciouspatient,weakanddebilitatedpatientandpatients withclinicalcircumstanceslikepregnancy,bowelobstructionsandhernia.

Antiematics
Antiemeticsareagentsthatareusedtocontrolemesis Specieslikethehorses,rabbitsandrodentsareunabletovomit. Protractedvomitingisundesirableindogs,catsandotherspecies. Vomitingusuallyoccurssecondarytoanotherdiseaseprocess.Iftheprimarycauseistreatedthenvomiting disappears. Antiemeticsareusefulinmotionsickness,uremia,liverdisease,endotoxemia,canineparvovial gastroenteritisandincancerchemotherapy. Useofantiemeticsmaymasktheprimarydisease. Prolongedvomitingleadstoelectrolyteandacidbaseimbalancesanddehydration.Antiemeticsmayalsobe locallyactingorcentrallyacting. Centrallyactingantiemetics Phenothiazinederivatives Anumberofphenothiazinederivatives(chlorpromazine,promethazine,prochlorperazine,trifluopromazine etc.)areclassifiedasbroadspectrumantiemetics. Theyactbyblockingthechemoreceptortriggerzoneatlowdosesandtheemeticcentreinthebrainat higherdoses. PromethazineisaH1antagonist(classicalantihistaminic)whichalsohasantimuscarinicactions.Itisvery effectiveatpreventingmotionsickness(sincethevestibularafferentsinputinthevomitingcenterwhichhas H1andmuscarinicreceptors). ProchlorperazineisaD2antagonistandhasnoantipsychoticeffects.Itisusefulasanantiemeticaswellas fordizziness.Ithasminoranticholinergiceffects.SinceitblocksD2receptorselsewhere(e.g.substantia nigra),itmaycauseextrapyramidaleffects. Chlorpromazine,anotherphenothiazine,canalsobeusedasanantiemetic,althoughittendstobesedative. Italsohasantipsychoticeffects. Hyoscine(scopolamine)isamuscarinicantagonist(M2).Itisusedasapatchbehindtheearforcontrolling CTZmediatedvomiting. MetoclopromideisaD2antagonistwhichisalsoaweak5HT3antagonist.Itincreasesthemotilityofthegutin theupperregions(doesnotcausediarrhoeaonlyfacilitatesgastricemptying).Itisusefulingastricstasisin anumberofspeciesincludingthecattleandhorses.Metoclopromidewillhelptheabsorptionofdrugs becauseitstimulatesgastricemptying.Thisdrugisusefulinvomitingassociatedwithvagalafferents(gut disorders,heart,testes,gutirritantsallstimulatethe5HT3receptoronthevagalafferents). Ondansetronisa5HT3antagonistandisapotentantiemetic.Itisveryeffectiveinpatientsreceivingcancer chemotherapy.ItcanalsobeusedforCTZnausea. Locallyactingantiemetics H2antagonistslikecimetidine,ranitidineetc.Thesedrugsreducetheacidoutputandhencedecreasethe irritatingeffectsonacidstomachlining.Asaconsequence,afferentsignalstovomitingcentresare decreased.Antacidslikesodiumbicarbonatearealsouseful. 45|U R V I S H M I S T R Y

46|U R V I S H M I S T R Y

Prokinetics

Prokineticsareagentsthatpromotegastricmotilityandthushastentheprocessofemptyingofthegastric contentsintotheintestine,becauesoftheirabilitytoevacuatethegastriccontentstheyareofvalueas antiemetics. Theyarealsoindicatedingastritis,gastricrefluxanddyspepsia.Theyareknowntoactvia5HT4receptors. Eg:Cisapride,metoclopromide,tegeserodetc.

Ulcer management
Factors Factorsthatplayaroleinpepticulcerformationingastricandduodenalulcers: o Ulcerogenicfactorsinclude acidhypersecretion pepsin drugs(NSAIDs,corticosteroids,ethanol,chemotherapeuticagents,cigarettes) infection tumors stressheadtrauma,shock/sepsis,emotional alterationofprotectivefactors disruptionofmucosalintegrityand decreasedbicarbonatesecretion Symptomsofulcersareduetoacombinedeffectofhydrochloricacidandpepsin. Acidcausespainbutnottissuedamage. Pepsin,whichisactivatedinacidenvironment,digestsmucosal,muscularandvascularlayersofstomach& intestines. Gastric(stomach)ulcersarenotduetotoomuchacid. Alkalinerefluxfromintestinesmayinflamegastricmucosa. Duodenal(intestinal)ulcersareduetoincreasedacidsecretioninstomach. Whenstomachemptiesintointestinesthereistoomuchacidforpancreaticsecretionstoneutralizeandthis aciderodestissues. MostcommoncausesareH.pyloriandNSAIDsaswellasgastrinhypersecretion. Goalsofdrugtherapyforulcersinclude neutralizeexistinggastricacidantacids inhibitacidsecretionH2antagonists,protonpumpinhibitors treatinfection(H.pylori)antibiotics,bismuthsubsalicylate protectulcerfromfurtherdamagesucralfate

Antacids
Antacidsareagentswhichneutralizeexcessacid. Someofthecommonlyusedantacidsincludesodiumbicarbonate,aluminiumhydroxideanddihydroxy aluminium,calciumcarbonateandmagnesiumhydroxide. Theweakbasereactswiththegastrichydrochloricacidtoformasaltandwater. ThisreactioncausesanincreaseinthegastricpHandabovepH4,pepsinisinactive. Antacidsdifferin o neutralizingcapacitydeterminesdosage o timetoonsetsloworrapid o durationofactionlongorbrief o sideeffectconstipationvs.diarrhea o potentialtoproduceelectrolytedisturbances o convenienceliquidvs.tablet o palatability o cost Sodiumbicarbonate Ithasarapidonsetofaction. 46|U R V I S H M I S T R Y

47|U R V I S H M I S T R Y Butitisnotanidealantacidduetothereboundacidityi.e.,stimulationofacidproductiononcethepH exceeds4,duetogastrinsecretion. Assodiumbicarbonateisreadilyabsorbedintosystemiccirculation,italterssystemicpHandproduces electrolytedisturbances. Thisinturnmayleadtoedema,hypertensionorheartfailure. Aluminiumhydroxide Theinsolublealuminumchloridethatisformedduetothereactionofhydrochloricacidandaluminium hydroxideoftencausesconstipation. Italsobindswithtetracyclinetoinhibititsabsorption. Calciumcarbonate Theabsorptionof~10%ofcalciumchloridemayresultinhypercalcemia(muscleweakness,kidneystone formation)andreboundgastricacidity. Constipationmayoccurwithhighdoses. Magnesiumhydroxide Thiscausesprolongedneutralizingeffectduetoslowstomachemptying. Poorabsorptionofmagnesiumsaltsmayresultindiarrhoea. Combinationsofaluminumorcalciumcontainingantacidswithmagnesiumcontainingantacidscannullify theadverseeffectsonbowelfunction.

Histamine receptors H2 antagonist


Endogenoushistaminereleasedfromparacrineenterochromaffinlikecellsormastcellsstimulatesparietal H2receptors. HistamineactivatesacyclicAMPpathway,activatesH+_K+ATPaseandleadstoincreasedH+ingastric lumen.H2receptorantagonistscanblockthishistamineinducedsecretionandarehelpfulreducingacid secretionduringulcers. ExamplesofH2receptorantagonistsincludecimetidine,ranitidine,famotidine,nizatidineetc. Ingeneral,thesedrugsarewelltoleratedwithfewsideeffects(lessthan3%withcimetidineand<1%with otherdrugs). Cimetidineexhibitsantiandrogenicpropertiesleadingtodecreasedspermcount,gynecomastiaandalso inhibitshepaticdrugmetabolism. InhibitionofcytochromeP450activitybycimetidineleadstopotentialdruginteractions. Thisfeatureisnotseenwithranitidine,famotidineandnizatidine. Itisacomplexofsulfatedsucroseandaluminumhydroxideandisknownasgastricbandaid. SucralfatepolymerizestoaviscousgelatapHlessthan4. Itcombineswithproteinsandadherestoulcerformingabarrierresistanttoacidandpepsinandbindsto bilesaltswhichareimplicatedinulcerpathogenesis. Itprecipitatessurfaceproteinsattheulcerbaseandactsasaphysicalbarrierpreventingacid,pepsinand bilefromcomingincontactwiththeulcerbase. Itdoesnotdecreasegastricacidsecretionorneutralizeacidorstimulatehealing. Thedrugrequiresanacidicenvironmenttobemoreeffective. Itisaseffectiveascimetidineorantacidsathealingpepticulcersandisusefulintreatinggastricreflux. ItisaGastricprotective. Use:Sucralfateisusedinthetreatmentofgastricandduodenalulcersindogs,catsandfoals. Adverseeffect:Constipationmayoccurwithlongtermtherapy. Itinteractswithmanydrugsandshowntointerferewithabsorptionoftetracyclines,fluoroquinolones, cimitidine,phenytoinanddigoxin. Protonpumpinhibitorsarealsocalledasacidblockers.Examplesofthisgroupofdrugsareomeprazole, lansoprazole,pantoprazoleetc.

Sucralfate

Proton pump antagonists

47|U R V I S H M I S T R Y

48|U R V I S H M I S T R Y ThesedrugsirreversiblyinhibitK+H+ATPaseprotonpumpingastrointestinalparietalcellsi.e.inhibitsentry ofH+ionentryintolumen. ThesedrugsalsoappeartohaveantimicrobialactivityagainstH.pylori. Thesedrugsbreakdownintheacidenvironmentofthestomachandmustbegivenorallyasentericcoated preparationsandtheyhaveshortplasmahalflivesbutarelongacting. Theyinhibithepaticdrugmetabolismandareverywelltolerated. ThesedrugshealduodenalulcersmorerapidlythanH2antagonists. Theyareusedprimarilyforulcersrefractorytoothertreatmentsandarealsousedforrefluxesophagitisand managementofgastrinomas.

Cytoprotective drugs
Misoprostol,ananalogueofprostaglandin(PGE1)analogisusedasacytoprotectivedrug. Prostaglandins(membranederivedsecondmessengers)haveprotectiveactionsongastricmucosa. Theyincreasemucosaformationandincreasesreleaseofbicarbonate(HCO3). Adverseeffectsarenotcommonexceptdiarrhoeaandabdominalcramping. Asthisdrugmaycauseabortion,itisnotrecommendedforuseinpregnantanimals. Itisusedforshorttermmanagementofpepticulcersandalsotoreducegastrointestinalirritation associatedwithNSAID(aspirinlikedrugs)therapy. DrugsthateradicateHelicobacterpyloribacteria multipleantibiotics(metronidazole+amoxicillinortetracycline) bismuthsubsalicylate MosteffectivetreatmentisacombinationofmultipleantibioticswithH2antagonistorprotonpump inhibitorfor6months.

Digestants and purgatives


Choleretics and cholagogues
Cholereticsareagentsthatincreasethevolumeofsecretionofbile Bileacids(e.g:cholicacid,chenodeoxycholicacid) o Semisyntheticbileacidderivatives(e.g:dehydrocholicacid) o Sodiumsaltsofbileacids Mechanismofaction o Bilesaltsstimulatecholeresis(bileflow) o Bilesaltsemulsifylipids,enhancingthedigestionofffatsandtheabsorptionoflongchainfattyacids. Uses o Bilesaltsandacidstreatvigorousmaldigestionsyndromescharacterizedbysteatorrhea(e.g: pancreatitisandbilesaltdeficiency). Cholagogues Theseareagentsthatpromotetheflowofbilefromtheliverandgallbladder.Eg:licorice,ursodeoxycholic acid.

Purgatives and laxatives


Purgativesaredrugswhichcausemarkedintensificationofintestinalactivityandresultsintheexpulsionof intestinalcontentfromthecolonandrectum. Thetermsaperientandcatharticarealsoappliedtodescribethepurgatives.Adistinctionismadeaccording totheintensityofaction. Laxativeoraperient:aremilderinaction,eliminationofsoftbutformedstools Purgativesorcathartic:arestrongeractionresultinginmorefluidevacuation. Laxativeandcatharticsareusedfor: o Reliefofacutenondietaryconstipation o Removalpoisonsfromthegastrointestinaltract o Preventionoftenesmusinadvancedpregnancyorprolapse 48|U R V I S H M I S T R Y

49|U R V I S H M I S T R Y o Evacuationofthebowelpriortosurgeryorradiography Manydrugsinlowdosesactaslaxativeandinlargerdosesaspurgatives. Typeofstoolsandlatencyofactionofpurgativesemployedinusuallyrecommendeddoses Softformedfeces Semifluidstools Wateryevacuation (take13days) (take68hours) (within13hours) Bulkforming Docusates Liquidparaffin Lactulose Phenolphthalein Salinepurgatives Bisacodyl Castoroil Senna

Classification

Bulkformingagents:Dietaryfiberlikebran,Psyllium(Plantago),Ispaghula Stoolsofteningagents:Docusates(DioctylSodiumsulfosuccinate) Lubricantagent:Liquidparaffin Stimulant(contact)purgativeagents: o Diphenylmethane,Phenolphthalein,Bisacodyl o Anthroquinones(emodins),Senna,Cascarasagrada o Fixedoils:castoroil Osmoticpurgativeagents: o Magnesiumsalts:sulfate(Epsomsalt),hydroxide,oxide o Sodiumsalts:sulfate(glauberssalt),phosphate o Sodiumpotassiumtartrate o Sodiumphosphateandsodiumtartrate o mixtures(Fleetmixtures) o Lactulose Allpurgativesincreasethewatercontentoffecesby: o Ahydrophilicorosmoticaction,retainingwaterandelectrolytesintheintestinallumenincrease volumeofcoloniccontentandmakeiteasilypropelled. o Actingonintestinalmucosatodecreasenetabsorptionofwaterandelectrolyteintestinaltransitis enhancedindirectlybyfluidbulk o Increasingpropulsivemotilityasprimaryactionallowinglesstimeforabsorptionofsaltandwater asasecondaryeffect Certainpurgativesincreasemotilitythroughanactiononthemyentericplexus. Laxativesmodifythefluiddynamicsofthemucosalcellandmaycausefluidaccumulationingutlumenby oneormoreofthefollowingmechanisms: o inhibitingNa+K+ATPaseofvilluscellsimpairingelectrolyteandwateradsorption o Stimulatingadnylylcyclaseincryptcellsincreasingwaterandelectrolytesecretion o Enhancingprostaglandinsynthesisinmucosawhichincreasessecretion o Structuralinjurytoabsorbingintestinalmucosalcells. Osmoticcatharticsarenonabsorbableorpoorlyabsorbablesaltsorpolymersthatosmoticallyretainwaterin theintestinallumen.Solutesthatarenotabsorbedintheintestineretainwaterosmoticallyanddistendthe bowelincreaseperistalsisindirectly. Allinorganicsaltsusedasosmoticpurgativeshavesimilaractiondifferonlyindose,palatabilityandriskof systemictoxicity. Theyhavearapidonsetofactionthatbeginsinthesmallintestine. Osmoticcatharticsarethecatharticsofchoiceforeliminationofpoisons. Magnesiumsulfateandmagnesiumoxideareadministeredorally515g;bitterintaste Sodiumsulfate1015gisadministeredorallyorviaastomachtubeasa6%solution 49|U R V I S H M I S T R Y

General mechanism of action

Osmotic purgatives

50|U R V I S H M I S T R Y Sodiumphosphate612g Sodiumpotassiumtartrate(Rochellessalt)815g Polytheleneglycolelectrolytesolutionsareadministeredorallypriortocolonoscopy Sodiumphosphateandsodiumtartratemixturesareadministeredrectallytodogs.Incats,theyproduce hyperphosphatemiaandshouldnotbeused. Thesaltsmentionedabovearedissolvedin100200mlofwter,produce12fluidevacuationwithin123 hourswithmildcramping,casuenearlycompleteemptyingofbowels. Smallerdoseshavemilderlaxativeaction. Magnesiumionsreleasecholecystokininwhichmayaidpurgativeactionofmagnesiumsalts. Magnesiumsaltsarecontraindicatedinrenalinsufficiency,whilesodiumsaltsshouldnotbeusedinpatients sufferingformCongestiveHeartFailureandothersodiumretainingstates. Repeateduseofsalinepurgativescancausefluidandelectrolyteimbalance. Lactulose Itisasemisyntheticdisaccharideoffructoseandlactosewhichisnotdigestedorabsorbedformsmall intestinebutretainswater. Itisbrokendowninthecolonbythecolonicbacteriatoosmoticallymoreactiveproducts. Flatulenceiscommon,crampsoccurinfewcases.Nauseamaybeproducedbecsueofunpleasanttaste. Itisnotpreferredforconstipation. Lactulosecausesreductionofbloodammoniaby2550%inpatientswithhepaticencephalopathy. ThebreakdownproductsoflactuloseareacidicandreducethepHofstools. Ammoniaproducedbybacteriaincoloninconvertedtoionizedammoniumandisnotabsorbed.

Irritant purgatives

Irritant/Stimulant/contactcatharatics:(e.g:castoroil,aloes,senna,cascarasagarada) Irritantcatharticsareplantderivatives. Theyarepowerfulpurgativesandoftenproducegriping. Theywerethoughttoirritatetheintestinalmucosaandthusstimulatemotoractivity. Itaccumulateswaterandelectrolytesinthelumenbyalteringabsorptiveandsecretoryactivityofthe mucosalcell. TheyinhibitNa+K+ATPaseatthebasolateralmembraneofvillouscellstransportofNa+andaccompanying waterintotheinterstitiumisreduced. SecretionisenhancedbyactivatedcAMPincryptcellsandbyincreasedprostaglandinsynthesis. Largerdosesofstimulantpurgativescancauseexcespurgation,fluidandelectrolyteimbalance. Hypokalemiacanoccuronregularuse.Routineandlongtermusemustbeavoided,producescolonicatony. Theymayreflexlystimulategraviduterus,hencecontraindicatedinpregnancyandalsoinsubacuteand chronicintestinalobstruction. CastoroilisablandvegetableoilobtainedfromtheseedsofRicinuscommunis. Itiscleavedbypancreaticlipasesinthesmallintestinetoyieldirritantricinoleates,whichstimulate peristalsisandreducefluidabsorption.Thisishydrolyzedintheileumbylipasetoricinoleicacidandglycerol. Ricinoleicacidbeingpolarispoorlyabsorbed. Aloe,sennaandcascarasagradacontainanthroquinoneglycosidesthatarehydrolyzedinthelargeintestine toyieldtoirritantanthraquinonesemodinsSennaismostpopularlyused. Unabsorbedinthesmallintestine,theyarepassedtothecolonwherebacterialiberatetheactiveanthrol formwhicheitheractslocallyorisabsorbedintocirculationexcretedinbiletoactonsmallintestine. Thustheytake67hourstoproduceaction. Theyaresecretedinmilksufficienttocausepurgationinthesucklingyoungones. Itisoneoftheoldestpurgativesused. Itmainlycontainstriglyceridesofricinolenicacidwhichisapolarlongchainfattyacidwhich Itwasbelievedtoirritatethemucosaandstimulateintestinalcontraction. Theprimaryactionhasnowbeenshowntobedecreasedintestinalabsorptionofwaterandelectrolytes,and enhancedsecretionbyadetergentlikeactiononthemucosa. 50|U R V I S H M I S T R Y

51|U R V I S H M I S T R Y Itcausesmorphologicaldamageofvillustipandperistalsisisincreased. Duetoitsunpalatibility,frequentcrampingandviolentaction,possibilityofdehydrationandafter constipationmucosaldamageitisnolongerfavoured. SennaisobtainedfromleavesandpodofcertainCassiasp,whileCascarasagradaisthepowderedbarkof thbuckthorntree. Anthraquinones Anthraquinonesstimulatesmoothmuscleandincreasecolonicmotility. Becausetheyactinthelargeintestine,theironsetofactionisslow.Usuallygivenatnighttimewhichcausea single,softbutformedevacuationgenerallyoccursinthemorning. Crampsandexcessivepurgingoccurissomecases. Theactiveprincipleisbelievedtoactonthemyentricplexustoincreaseperistalsisanddecrease segmentation. Theyalsoinhibitsaltandwaterabsorptioninthecolon. SennaanthraquinonehasbeenfoundtosimulatePGE2intheratintestine. Regularuseagecausescolonicatonyandmucosalpigmentation. Aloeespeciallyreleasestheanthraquinoneemodin,whichhasaffinitytowardsthesigmoidflexureofthe horsesintestine,andproducesthecatharticeffect. Irritantcatharticsareadministeredorallytorelieveacuteconstipationinsmallandlargeanimals. Diphenylmethanes Phenolphthaleinisanindicatorandisinuseaspurgativesinceearlierdays.Itturnsurinepinkifalkaline. Bisacodylisalateradditionandmorepopular. Diphenylmethanesarepartlyabsorbedandreexcretedinbile,enterohepaticcirculationismoreimportant inphenolphthateinwhichcanproduceprotractedaction. Bisacodylisactivatedintheintestinebydeacetylation. Theirprimarysiteofactionisinthecoloninwhichoneortwosemiformedmotionsoccurafter68hours. Phenolphathalein:60130mg:tobeadministeredatnighttime Bisacodyl(Dulcolax)5mg,10mgtablet Adverseeffects Thesedosesofphenolphthaleinproducefluidevacuationsandcramps.Morphologicalalterationsinthe colonicmucosaislikelytooccurandmakesmucosamoreleaky. Bisacodylsuppositoryactsbyirritatingtheanalandrectalmucosaleadingtoreflexincreaseinmotility causingevacuationin2040minutes.Itmaycauseinflammationandmucosaldamage.

Bulk purgatives
Bulklaxatives(e.g:methylcellulose,agar,psyllium,wheatbran) Dietaryfibresconsistsofunabsorbablecellwallandotherconstituentsofvegetablefoodcellulose,pectins, glycoproteinsandotherpolysaccharides. Branisabyproductofflourindustryconsistsof40%dietaryfibre.Itabsorbswaterintheintestines,swells, increaseswatercontentoffeces.softensitandfacilitatescolonictransit. Osmoticallyactiveproductsmaybeformedinthecolonbybacterialdegradationofpectinsetc.,whichactto retainwater. Dietaryfibresupportsbacterialgrowthincolonwhichcontributetothefecalmass. Certaindietaryfibres(gums,lignins,pectins)bindbileacidsandpromotetheirexcretioninfecesleadingto enhancementofdegradationofcholesterolinliverandtherebyplasmaLDLcholesteolislowered. Increasedintakeofdietaryfibresisthemostappropriatemethodforpreventionandtreatmentoffunctional constipation. Itisthefirstlineapproachformostdogsandcatsinthetreatmentofsimpleconstipation. Prolongedintakeofbranandotherbulkformingagentsreducesrectosigmoidintraluminalpressurerelives symptomsofirritableboweldiseaseandcolonicdiverticulosis. Itisalsousefulwhentenesmusatstoolshastobeavoided. Demerits Unpalatable,2040g/dayneedstobeingested. Fulleffectrequiresdailyadministrationforatleast34days. 51|U R V I S H M I S T R Y

52|U R V I S H M I S T R Y Itdoesnotsoftenfecesalreadypresentincolonorrectum. Flatulencemayoccur. Psyllium(Plantago)andIspaghula Containnaturalcolloidmucilage,whichformsagelatinousmassbyabsorbingwater,312gofrefinedhusk freshlymixedwithwaterormilkandtakendailyactsin13days. Itshouldnotbeswalloweddry(mayleadtooesophagealimpaction) Ispaghulahusk(refined) Plantagohusk Methylcelluloseandcarboxymethylcellulosearesemisyntheticcolloidalhydrophilicderivativesofcellulose;46 g/dayissatisfactorytoproducelaxativeeffect. Mechanismofaction Bulklaxativescontainhydrophiliccolloids,whichabsorbwaterandincreaebulk. Bulkstimulativeslargebowelperistalsis Wheatbranisadministeredorallybyaddingtothediet. Thelaxativeeffectoccurswithin13days. Generousamountofwatermustbegivenwithallbulkformingagents. Itshouldnotbeusedinpatientswithgastriculcerations,adhesions,stenosisandwhenfecalimpactionisa possibility

Lubricant purgatives
Lubricants,mineraloil(liquidpetroleum)andwhitepetroleumlubricateandsoftenfeces. Liquidparaffinisaviscousliquid;amixtureofpetroleumhydrocarbons.Itwasintroducedasalaxative earlier.Itispharmacologicallyinert.Whentakenfor23days,itsoftensstoolsandissaidtolubricatehard scybalibycoatingthem. Dose:1530ml/dayoilassuchorinemulsifiedformindog Disadvantages Itwillbeveryblandandunpleasanttoswallowbecauseofoilyconsistency Smallpassesintotheintestinalmucosa,carriedintothelymphandmayproduceforeignbodygranulomain theintestinalsubmucosa,mesentericlymphnodes,liverandspleen. Probalilityofcausinglipidpneumoniabecauseoftricklingintolungswhileswallowing Carriesfatsolublevitaminswithitintothestoolsleadingtodeficiency Leakageoftheoilpastanalsphinctermayembarrassandstainthefloor Mayinterferewithhealingintheanoractalregion. Henceadvisableforoccasionaluseandthattoopostoperatively. Surfactants Docusatesisananionicsurfactantthatactsinthelargeboweltohydrateandsoftenfecesbyanemulsifying action. Itcausesnetwateraccumulationintheintestinallumenbyanactionontheintestinalmucosa.Itemulsifies thecoloniccontents. Beingadetergent,itcandisruptthemucosalbarrierandenhanceabsorptionofmaynonabsorbabledrugs, e.gliquidparaffinshouldnotbecombinedwithit.Eg:Cellubril,Laxiconascapsules Dose:100200mg/day;actsin13days.Itisamildlaxative;speciallyindicatedwhenstrainingaststools mustbeavoided. Crampsandabdominalpaincanoccur.Itisbitterintaste.Liquidpreparationsmaycausenauseaandis hepatotoxiconprolongedusage.

Choice, indications, combinations, abuse of purgatives


Choiceanduseofpurgatives Laxativesareimportantfortheirharmfulnessastheyarefortheirvalueinmedicine. Alllaxativesarecontraindicatedin: o Ananimalofundiagnosedabdominalpain,colicorvomiting o Organicconstipationduetostrictureorobstructioninbowel,hypothryroidism,hypercalcemia, malignanciesanceratindrugslikeopioids,sedatives,,anticholinergicsetc., 52|U R V I S H M I S T R Y

53|U R V I S H M I S T R Y Validindicationsoflaxativesare FunctionalconstipationSpastic(irritablebowel)andAtonic(Sluggishbowel) Recumbentanimals Tenesmus Bowelsurgery,endoscopyu,abdominalXray Afteranthelminticstreatment Food/drugpoisoning. Combinedpreparationsofpurgatives Agarol:Liquidparaffin+Phenolphthalein+Agar Cremaffin:Milkofmagnesia+Liquidparaffin+Phenolphthalein Julax:Bisacodyl+Casanthrol Laxatin:Sennosides+Docusates PursennidIN:Purifiedsennaextract+docusates. Purgativeabuse Chronicuseofpurgativesmustbediscouraged. Oncethepurgativehabitforms,itisdifficulttobreak. Dangersofpurgativeabuseare: o Flairingofintestinalpathology,ruptureofinflamedbowel o Fluidandelectrolyteimbalance,speciallyhypokalemia o Steatorrhoea,malabsorptionsyndrome o Proteinlosingenteropathy o Spasticcolitis

Antidiarrheal

Generalconsiderations o Acutediarrheamayrespondtosymptomatictherapywithantidiarrhealdrugs,butchronicdiarrhea requiresadefinitivediagnosisandspecifictherapy. Oralrehydrationtherapyrepresentsasignificantadvanceintreatingdiarrheaintheabsenceofvomiting. Inadditiontoglucoseoraminoacids,orboth,thesesolutionscontainsodiumchloride,potassiumchloride, sodiumbicarbonate,andpotassiumphosphate. Sodiumglucoseandsodiumaminoacidlinkedabsorptionbytheenterocyteremainintacteveninthe presenceofmoderatedamagetotheintestinalvilli,providingthedrivingforceforwaterandelectrolyte absorptionformthelumentoreplacefecallosses. Opiates o Paregoricisacamphoratedtinctureofopium o Diphenoxylateisasyntheticcongenerofmepridine.Lomotilisdiphenoxylateplusatropine

Opioids
Loperamide Loperamideisasyntheticpiperidineopioid Itisanopiateanaloguewithweakanticholinergicproperty. Becauseofpoorwatersolubilitylittleisabsorbedformtheintestine. Entryintobrainisnegligible. Inadditiontoitsopiatelikeactiononmotility,italsoinhibitssecretion. Itimprovesfecalcontinencebyenhancinganalsphinctertone. Mechanismofaction OpiatesinhibitAChrelease. Theresultantincreasedgastrointestinalrhythmicsegmentationanddecreasedpropulsivemotilityslowthe transittimeofluminalcontentsandincreaseabsorption Inaddition,opiatesdirectlystimulateabsorptionoffluidandelectrolyteviamuopiatereceptorsintheCNS andintestinalmucosa. Codeine 53|U R V I S H M I S T R Y

54|U R V I S H M I S T R Y Antidiarrhealactionisprimarilyattributedtoitsperipheralactiononsmallintestineandcolon. Itdoesnothavecentraleffects,buitproducedependance. Itshouldbeusedonlyforashortperiod. Diphenoxylate Itisanopioidchemicallyrelatedtopethidine:usedexclusivelyasconstipatingagent. Theantidiarrhealactionisprominent,butbecauseitisabsorbedsystemicallyandcrossesbloodbrainbarrier CNSeffectsmayoccur. Atropineisaddedinanonpharmacologicaldosetodiscourageabuse. Abuseliabilityisratedlowandoverdosewillproducedisturbingatropinicsideeffects. Use:Opiatesareeffectiveinthesymptomatictreatmentofacutediarrhea. Administration Paregoricisadministeredorally23timesdailytodogsandcatsoncedailytocalvesandfoals Diphenoxylateisadministeredorally23timesdailytodogsandcats Loperamideisadministeredorally12timesdailytodogsandcats Codeineisadministeredorally23timesdailytodogsandcats. Adverseeffects:bacterialovergrowthintheintestinallumenofanimalswithinfectiousdiarrheamayresult fromslowedintestinaltransittime. Incats,excitatoryreactionsrenderopiateusecontroversial. Paregoricisacamphoratedtinctureofopium. Diphenoxylateisasyntheticcongenerofmepridine. Lomotilisdiphenoxylateplusatropine.

Anticholinergics
Anticholinergicagents Methscopolamine.Otherdrugsincludeaminopentamide,propanthelineandisopropamide,whicharealso effectiveasantiemetics Mechanismofaction Anticholinergicsinhibitpropulsiveandnonpropulsivegastrointestinalmotility. Theyalsoinhibitnormal,cholinergicallymediatedbasalsecretionsofthegastrointestinaltract. Uses Anticholinergicagentsmaybeusedtotreatdiarrhea:however,theyareofquestionablebenefitinthis capacitybecausediarrheaismorecommonlyassociatedwithhypomotilitythanhypermotility Anticholinergicagentsmaybeusedtotreatgastrointestinalspasm Administration Aminopentamideisadministeredorally,intramuscularlyorsubcutaneouslyevery812hours Propanthelineisadministeredorallyevery8hours Isopropamideisadministeredorallyevery12hours Adverseeffects Adverseeffectsofanticholinergicsincludexerostomia,xerophthalmia,lossofvisualaccommodation, tachycardia,urineretention,paralyticileusandconstipation. Anticholinergicsarecontraindicatedinpatientswithglaucoma.

Protectants and adsorbants


Kaolinpectinsuspensions(20%kaolin(hydratedaluminiumsilicate)and1%pectin(apolygalacturonicacid carbohydratepolymer) Bismuthsubsalicylate. Mechanismofaction Protectivesandadsorbentsadsorbtoxinsandprovideaprotectivecoatingoninflamedmucosa. Bismuthsubsalicylatehasanantiprostaglandinactioninadditiontoitsadsorbentproperties. Uses:Protectantsandadsorbentsareusedforthesymptomatictherapyofacutediarrhea.Adsorbentsmay decreasefluidityoffeceswithoutactuallydecreasingfecalwaterloss,therebylimitingtheirusefulness. Adminsitration 54|U R V I S H M I S T R Y

55|U R V I S H M I S T R Y Kaolinpectinsuspensionsareadministeredorallyevery46hours.Kaolinpectiniseffectiveindogs,cats, birds,horses,cattle,sheepandwine. Bismuthsubsalicylateisadministeredorallyevery46hours.Bismuthsubsalicylateisapprovedforusein dogs,horses,cattleandwine.Salicylateshouldnotbeadministeredtocats. Adverseeffects:Bismuthsubsalicylatemayproducedarkfeces,whichshouldnotbeconfusedwithmelena.

Antisecretory drugs

Sulfasalazine(Salicylazosulfapyridine)itisacompoundof5aminosalycylicacid(5ASA)withsulfapyridine linkedthroughanazobond. The5ASAisoflowsolubilityanditispoorlyabsorbedfromtheileum. Theazobondissplitbycolonicbacteiatorelease5ASAandsulfapyridine. Theformerexertsalocalantiinflammatoryeffect,probablybyinhibitingprostaglandinsynthesis(andother mediatorslikeleukotrienes,PAFaswellasmigrationofinflammatorycellsintobowlwall),decreases mucosalsecretionaffordsconsiderablereliefinulcerativecolitisandrelatedinflammatoryboweldisease. Givenduringanexacerbationitreducesnumberofstools,abdominalcrampsandfeverbutislesseffective thancorticosteroids:maybeemployedformildtomoderateexacerbation. Thebeneficialeffectofsulfasalazineisclearlynotduetoanyantibacterialaction(bowelfloraremains largelyunaffected)sulpyridinemoietyonlyservestocarry5ASAtothethecolonwithoutbeingabsorbed proximally. However,partofthereleasedsulfapyridineisabsorbedinthecolonandisresponsibleforadverseeffects likerashes,fever,jointpain,haemolysisandblooddyscrasias. Nausea,vomiting,headacheandanemiaareotherfrequentsideeffects.Maleinfertilityisreported. Sulfasalazinehasalsobeenusedasadiseasemodifyingdruginrheumatoidarthritistheabsorbed sulfapyridineappearstoberesponsibleforthetherapeuticeffect.

Protectants
Adsorbants Ispaghula Psyllium Methylcellulose Sulfasalazine Mesalazine Bismuthsubsalicylate Atropine Octreoxide Irritablebowel Ileostomy/colostomydiearrhea Ulcerativecolitis Otherinflammatoryboweldiseaes Travellersdiarrhea Nervous,druginduceddiaerrhea Carcinoid,VIPsecretingtumour

Antisecretory

Antimotility(opioids) Codeine Noninfectiveormildtravelersdiarrhea Diphenoxylateatropine Idiopathicdiarrhea Lopramide Afteranalsurgery,colostomy.

Rumen pharmacology
Oesophageal groove closure

Theoesophagealgroovereflexiswelldevelopedinsucklingneonatesbutbecomeslessreliableinolder animals. Bypassingtheruminoreticulumcanhaveseveraladvantages. Drugsadministereddirectlyintotheruminoreticulumareabsorbedveryslowlywhencomparedwith abomasaldelivery. Moreoverdrugsmaybedegradedbyruminalmicroflora(eg:chloramphenicolanddigitalisglycoside)orthe drugsmaybeharmfultothebeneficialmicrobes(eg;tetracyclines,penicillinandsulfonamides). Oraladministrationofmedicamentsintendedforthelocalintestinaleffect(eg:purgatives,antidiarrhoeals, contrastmediaandsomeanthelmintics)shouldbeprecededbyadministrationofanappropriateofsalt solutiontoclosethereticulargroovetoavoidruminoreticulardispersion. 55|U R V I S H M I S T R Y

56|U R V I S H M I S T R Y 5%coppersulphate,5%zincsulphate,10%sodiumbicarbonateor10%sodiumsulphatecanbe administeredatdosesof60mltocattletobringaboutclosureofoesophagealgroove. 12%coppersulphateisusefulinsheep.Onsetofreflexresponsetakesabout510secondsandthegroove mayremainclosedforupto60seconds. Sucklingisastrongstimulusforthisreflexeveninadults.Itisbesttoallowsickcalvesandlambstodrink medicatedmilkfromanippletoassureabomasaldeliveryandrapidabsorption. Administrationofliquidmedicationtoruminantsorallymayresultinspontaneousclosureofthereticular grooveinacertainnumberofcalveswhichresultsinancompleteorpartialruminoreticularbypass. Whenstimulated,buccalandpharyngealreceptorsactivateavagalreflexthatclosesthegroovewithing25 seconds:effectslastfor60seconds. Milk,sodiumbicarbonate(10%tocalves)orcoppersulphate(5%tocalves,2%tolambs)butnotwatermay beusedtoinduceesophagealgrooveclosure.

Ruminotorics

Ruminotoricsareagentsandmixturesthatpromoteforestomachfunction(fermentationandmotility). Typicallysuchmixturesconsistbitterslikenuxvomicatostimulatesalivationandperhapsruminal contractions, alkalinizingcompoundslikemagnesiumoxidetoelevatealowruminalfluidpH, galactogenicsubstancelikeglycerol, mineralslikecobaltascofactorsformicrobialenzymefunctionand saltslikephosphateasbufferstomaintainosmolality. Bitters:(e.g:nuxvomica,ginger,capsicum)stimulatesalivationwhichmayenhancerumenfunction, however,theefficacyofbittersisminimal.Bittersareadministeredorally. Cholinergics(e.g:neostigmine,bethenachol)transientlyincreasethefrequency,butnotthestrength,of contractionsinrumenatony.Cholinergicsareadministeredsubcutaneously. Opiateantagonists(e.g:naloxone)stimulateextrinsiccontractionswhenadministeredparenterally.Opiate antagonistsareusefulforthetreatmentofendotoxininducedrumenstasis. RumenfluidtransferOralinoculationofviablerumenbacteriaandprotozoaisthemosteffectivemeansof restoringrumenfunctionfollowingcorrectionoftheprimarycauseofstasis

Rumen antacids
Rumenantacids(e.g:magnesiumoxide,magnesiumcarbonate,aluminiumhydroxide,calciumcarbonate, ammoniumcarbonate) Antacidsareusedtotreatmildcasesoflacticacidiosisresultingformcarbohydrateengorgement. Theseagentsareadministeredorallyevery812hoursSystemicalkalosismayresultfromoverdose especiallyofmagnesiumoxide.

Antizymotics

Antizymoticsareagentsthatusedtocontolfermentationintheruminantforestomach.Whenorally administeredtheseagentsactbyinhibitingmicrobialgrowthintherumen. Theyareofuseinconditionssuchasbloatwheretheeisuncontrolledfermentation.Eg:Formalein, turpentineoil.

Cardiovascular pharmacology
Classes of drugs acting on heart

Drugsactingontheheartcanbeclassifiedinto Drugsthatdirectlyaffectthemyocardialcellswhichincludes o autonomicneurotransmittersandrelateddrugs o cardiacglycosidesandotherinotropicagents o antidysrhythmicorantiarrhythmicdrugs Drugsthataffectthecardiacfunctionindirectlythroughactionselsewhereinthevascularsystemcalcium antagonistsactingbothdirectlyonthemyocardialcellsandindirectlybyrelaxingthearterioles. 56|U R V I S H M I S T R Y

57|U R V I S H M I S T R Y Autonomictransmittersandrelateddrugs Bothsympatheticandparasympatheticsystemsexertatoniceffectontheheartatrest. Themaineffectsofsympatheticactivityontheheartare o positiveinotropiceffect(increasedforceofcontraction) o positivechronotropiceffect(increasedheartrate) o increasedautomaticity o repolarisationandrestorationoffunctionfollowinggeneralisedcardiacdepolarisation o Reducedcardiacefficiency. Theparasympatheticeffectsinclude o cardiacslowingandreducedautomaticity o decreasedforceofcontraction o inhibitionofAVconduction

Effects of drugs acting on heart


Theeffectofdrugsontheheartmaybeexpressedas Inotropiceffectifitaffectsthecontractility Chronotropicifitaffectstherhythmicity Dromotropicifitaffectstheconductivity Bathmotropicifitaffectstheexcitability Tonotropicifitaffectsthetonicity.

Congestive heart failure


Heartfailureisaglobaltermforthephysiologicalstateinwhichcardiacoutputisinsufficientinmeetingthe needsofthebodyandlungs.Oftentermed"congestiveheartfailure"orCHF,thisismostcommonlycaused whencardiacoutputislowandthebodybecomescongestedwithfluid. Commoncausesofheartfailureinclude: myocardialinfarction ischemicheartdisease, hypertension, valvularheartdisease Cardiomyopathy. Itmayalsooccurdueto severeanemia, Gramnegativesepticemia, beriberi(vitaminB1/thiaminedeficiency), thyrotoxicosis, arteriovenousfistulae, arteriovenousmalformations.

Cardiac glycosides
Themainsourceofcardiacglycosidesisfromthefoxglovefamily. Theireffectivenessincardiacfailurewas,describedbyWilliamWitheringin1775.Hepublishedhisclassic monographAnaccountofthefoxgloveandsomeofitsmedicinaluses:withpracticalremarksondropsyon usedbyanoldwomanofShorpshireandotherdiseasesin1785. Initiallykidneywasthoughttobethetargetorgan Thecardiacglycosidesareuniqueinthattheynotonlyimprovethecontractilityofthemyocardium,butalso reducetheheartsdemandforenergyandoxygen. Thesedrugsalsodeceasetheconductionofcertainimpulseswithintheheartandthereforedecreasethe heartrate. Sourceofglycosides DigitalispurpureaorPurplefoxglve(leaf)Digitoxin,Gitoxin,Gitalin DigitalislanataorWhitefoxglove(leaf)Digitoxin,Gitoxin,Digoxin 57|U R V I S H M I S T R Y

58|U R V I S H M I S T R Y Strophanthuskombe(seed)StrophanthinK Strophanthusgratus(seed)StrophanthinG(Ouabain) Thevetianeriifolia(nut)Thevetin ConvallariamajalisConvallotoxin Bufovulgaris(Toadskin)Bufotoxin

Chemistry of cardiac glycosides


Cardiacareglycosidesthatcontainanaglycone(genine)andasugarmoiety.(chemicalstructurepicture hyperlink) Thesugarmoietyconsistsofonetofoursugarresidues. Thepharmacologicalactivityrestswiththeaglyconeandthesugarhelpsinthepharmacokineticproperties. Theaglyconeconsistsofacyclopentanoperhydrophenanthereneringstructureattachedtoa5or6 memberedunsaturatedlactonering.

Mechanism of action on cardiac glycosides

CardiacglycosidesproducetheiractionbyinhibitionofNa+,K+transportsystem(Na+,K+ATPase) InhibitionofthissodiumpumpresultsinincreasedintracellularNa+concentration NormallysodiumisbroughtintothecellinexchangeforCalciumduringtheplateauphase BecauseoftheelevatedintracellularNa+,sodiumcalciumexchangerisnotfunctional,leadingtoelevated intracellularCa++levels Ca++formsacomplexwithtroponinandtropomyosinallowingactinandmyosinfilamentstocometogether Musclecontracts AlteredNa+,K+andCa++levelsarethebasisforboththetherapeuticandtoxiceffectsofthecardiac glycosides.

Pharmacological effects of cardiac glycosides


Positiveinotropiceffectisnoticedbyimprovedemptyingandreductioninsizeofthedilatedfailingheart. Themusclecontractsmorequicklyandmorepowerfullyforthesamefillingstimulusandforthesame oxygenconsumption. Sovenouspressureisreduced,oedemafluidisreabsorbedandbloodpressureincreases. 58|U R V I S H M I S T R Y

59|U R V I S H M I S T R Y Negativechronotropiceffectsbydirectstimulationofthevagalcentreandbyslowingtherateofpassageof impulsesthroughtheconductingsystem. Diureticeffectduetoincreasedbloodflowandincreasedglomerularfiltrationrate.

Pharamacokinetics

Absorptiondiffersamongthedigoxinpreparations. Prepareddigitaliscauseslocalirritationandvomitinginpiganddogandforthesespeciesdigitalisglycoside shouldbegiven. Inruminants,oraladministrationofglycosidesleadstodestructionofthedrugandhenceitispreferableto givethedrugparenterally. Plasmaproteinbindingishighwithdigitoxin. Excretionofthedrugisbythekidneys. Enterohepaticrecyclingincreasesthedurationofactionofthedrug. Theuseofthesedrugsindogsandcatsisnotuncommon. However,theabsorptionofdigoxinfromthegastrointestinaltractthoughadequatemaydiffersomewhat amonganimalsandcanbeinfluencedbyfeedingtimes.

Therapeutic uses of cardiac glycosides


Congestiveheartfailure. ArrhythmiasbydepressingtheAVnodalconductivityandincreasingrefractoriness.

Digitalization
Digitalisglycosideshaveanarrowmarginofsafety. Initialadministrationoflargedoseindivideddoses.(2448hrs) Followedbymaintenancedose. Loadingdoseindogs o Slowmethod5equalpartsfor48hrs o Rapidmethod3equalparts@6hrinterval. o Intensivemethodhalfdoseinitially,onefourthafter6hrsandoneeightheachafter4hrintervals o Digitoxin0.110.22mg/kgtotalloadingdose Maintenancedose0.011mg/kg@12hrintervalsindogs Thereisaconsiderable,individualvariationinresponsetotheseglycosides.

Adverse reactions of cardiac glycosides


Riskoftoxicityisgreaterinpatientswithadvancedheartdisease,inhighdosage,renaldisease,ageand hypothyroidism. Factorsthatincreasemyocardialsensitivitytodigitalistoxicityincludemyocardialdiseaseorischemia, hypokalemia,highserumcalciumandlowserummagnesium. Symptomsoftoxicitycanbegroupedascardiacsymptomsandnoncardiacsymptoms. Cardiacsymptomsoftoxicity o Sinusbradycardia, o SAblock, o AVblock,tachycardia, o prematureventricularcontraction Noncardiacsymptomsoftoxicity gastrointestinaldisturbanceslikeanorexia,nausea,vomitingfatigueandmuscleweakness CNSeffectslikeconfusion,hallucination,restlessness,insomnia,drowsinessandoccasionallyovert psychoses Visualeffectslikehazyvision,difficultyinreading,photophobia,chromatopsia(yelloworgreencolour appearance) gynaecomastia(antiadrenergiceffect).

59|U R V I S H M I S T R Y

60|U R V I S H M I S T R Y

Treatment of cardiac glycosides toxicity


Withholdcardiacglycosides Withholdpotassiumdepletingdiuretics Administerpotassiumsalts Administerantiarrhythmicsifarrhythmiasappeartobelifethreatening Administeragentslikeactivatedcharcoaltobinddigoxininthegastrointestinaltract.

Precautions and drug interactions


Hypokalemiawillleadtoincreaseddigitalistoxicity Inelderlypatientsandinpatientswithrenalandseverehepaticdiseasethetoxicitywillbehigher Thyrotoxicosisreducestheresponsivenesstodigitalis Myxoedemaincreasestheresponsivenesstodigitalis PartialAVblockmaybeconvertedtocompleteAVblock

Drug interactions

Diureticspotassiumdepletingdiureticsprecipitatedigitalistoxicitywhilepotassiumsparingdiuretics reducetherenalexcretionofdigitalis Calciumprecipitatesdigitalistoxicity Quinidinereducesbindingtoproteinsandtherebyincreasetheconcentrationandtoxicityofdigitalis Verapamilanddiltiazemincreaseplasmaconcentrationsofdigoxin Antacidsandneomycinreduceabsorptionofdigitalis.

Other drugs used in CHF


Phosphodiesteraseinhibitorsliketheophylline. Diureticslikefurosemidetoincreasewaterandsodiumexcretion,decreasepreloadandrelievesymptomsof pulmonaryandsystemiccongestion Vasodilatorslikehydralazine ACEinhibitorslikeenalapril,lisinopriletc. Adrenergicalpha1agonistslikeprazosin Calciumchannelblockerslikenifedipine

Antiarrhythmic drugs
Types of arrhythmia

Sinusbradycardialowsinusrate<60beats/min. Sinustachycardiahighsinusrateof100180beats/minasoccursduringexerciseorotherconditionsthat leadtoincreasedSAnodalfiringrate. Atrialtachycardiaaseriesof3ormoreconsecutiveatrialprematurebeatsoccurringatafrequency >100/min;usuallyduetoabnormalfocuswithintheatriaandparoxysmalinnature.Thistypeofrhythm includesparoxysmalatrialtachycardia(PAT). Atrialfluttersinusrateof250350beats/min. Atrialfibrillationuncoordinatedatrialdepolarizations. JunctionalEscapeRhythmSAnodesuppressioncanresultinAVnodegeneratedrhythmof4060beats/min (notprecededbypwave). AVblocksaconductionblockwithintheAVnode(oroccasionallyinthebundleofhis)thatimpairsimpulse conductionfromtheatriatotheventricles. Supraventriculartachycardia(SVT)usuallycausedbyreentrycurrentswithintheatriaorbetweenventricles andatriaproducinghighheartratesof140250. Ventricularprematurebeats(VPBs)causedbyectopicventricularfoci;characterizedbywidenedQRS. Ventriculartachycardia(VT)highventricularratecausedbyaberrantventricularautomaticityorby intraventricularreentry;canbesustainedornonsustained(paroxysmal);characterizedbywidenedQRS; ratesof100to200beats/min;lifethreatening. 60|U R V I S H M I S T R Y

61|U R V I S H M I S T R Y Ventricularflutterventriculardepolarizations>200/min. Ventricularfibrillationuncoordinatedventriculardepolarizations VentricularfibrilfirstdegreeAVnodalblocktheconductionvelocityisslowedsothatthePRintervalis increasedtogreaterthan0.2seconds.Canbecausedbyenhancedvagaltone,digitalis,betablockers, calciumchannelblockers,orischemicdamage. SeconddegreeAVnodalblocktheconductionvelocityisslowedtothepointwheresomeimpulsesfrom theatriacannotpassthroughtheAVnode.thiscanresultinPwavesthatarenotfollowedbyARS complexes.forexample,1or2PwavesmayoccuralonebeforeoneisfollowedbyaQRS.WhentheQRS followsthePwave,thePRintervalisincreased.Inthistypeofblock,theventricularrhythmwillbelessthan thesinusrhythm. ThirddegreeAVnodalblockconductionthroughtheAVnodeiscompletelyblockedsothatnoimpulsesare abletobetransmittedfromtheatriatotheventricles. QRScomplexeswillstilloccur(escaperhythm),buttheywilloriginatefromwithintheAVnode,bundleof his,orotherventricularregions.Therefore,QRScomplexeswillnotbeprecededbyPwaves. Furthermore,therewillbecompleteasynchronybetweenthePwaveandQRScomplexes. Atrialrhythmmaybecompletelynormal,butventricularrhythmwillbegreatlyreduceddependinguponthe locationofthesitegeneratingtheventricularimpulse. Ventricularratetypicallyrangefrom30to40beats/min. WOLFFPARKINSONSYNDROMEAnaccessorypathway(BundleofKent)thatconnectstheatriaandthe ventricles,inadditiontotheAVnode.Thisaccessorypathwaydoesnotsharetherateslowingpropertiesof theAVnode,andmayconductelectricalactivityatasignificantlyhigherratethantheAVnode

Arrhythmia

Arrythmiaisanyabnormalpatternofelectricalactivityintheheart.Normallythewavesofdepolarization followaspecificsequence,startingintheSAnodeandendingwiththecontractionofthe ventricles.Sometimesanotherareaofthemyocardiumorconductingsystembeginstodepolarizeoutof sequenceormorerapidlythantheSAnode,disruptingthenormalelectricpattern. Arrhythmiasaredividedintotwogeneralgroups:thosethatresultinanincreasedheartrateandthosethat resultinadecreasedheartrate. Arrhythmiasarefurthersubdividedintogroupsaccordingtothelocationoftheectopicfociorlesioncausing arrhythmia. Asupraventriculararrhythmiaindicatedthatthecauseoftheproblemisabovetheventricle. Aventriculararrhythmiaindicatesthattheproblemoriginatesintheventricles. Theabnormalsiteofdepolarizationiscalledanectopicfocus. AnectopicfocusintheventriclesmaybeindicatedontheECGasasinglelargebizarrewave.Multiple prematureventricularcontractionscauseflutter.Iftheconductiondisturbanceissevere,thehearthasno coordinatedcontractionsandtheconditionisreferredtoasventricularfibrillation.

Antiarrhythmic drugs

Antiarrhythmicsareagentsusedtocontrolectopicfociorreversedisorganizedconductionofelectrical impulsesthroughtheheart Althoughresearchhasprovidedsomeinformationregardingthecellularmechanismsofarrhythmiasandthe modeofactionofantiarrhythmicdrugs,thegeneralapproachtotherapyremainsempirical.

Classification

Antiarrhythmicsorantidysrhythmicsareclassifiedasfollows. o ClassIdrugsactbyblockingthesodiumchannel.Theyaresubdividedinto3subgroups,IA,IB,andIC, basedeffectsonphase0deploarizationandrepolarization: SubclassIAdrugshavemoderatepotencyatblockingthesodiumchannelandalsousually prolongrepolarization(increaseQRS)Eg.quinidne,procainamide,disopyramide SubclassIBdrugshavethelowestpotencyassodiumchannelblockers,producelittleifany changeinactionpotentialduration,andusuallyshortenrepolarization.Eg.lidocaine, phenytoin 61|U R V I S H M I S T R Y

62|U R V I S H M I S T R Y SubclassICdrugsarethemostpotentsodiumchannelblockingagents,andhavelittleeffect onrepolarization(increasePR,increaseQRS)Eg.flecainide,encainide o ClassIIdrugsactindirectlyonelectrophysiologicalparametersbyblockingbetaadrenergicreceptors (increasingPR).eg.propranolol o ClassIIIdrugsactbymechanismsthatarenotwellunderstood(interferencewithpotassium conductanceisonepossiblemechanism),butacttoprolongrepolarization(increaserefractoriness), withlittleeffectontherateofdepolarization(QT).eg.sotalol,amiodarone o ClassIVdrugsactbyblockingthevoltagesensitivecalciumchannels.Theyslowtheconductionin theSAandAVnodeswhereactionpotentialpropagationdependsonslowinwardcalciumcurrent. eg.verapamil,nifedipine Inadditiontotheaboveclasses,thereisalsoamiscellaneousgroupofdrugsthatincludesdigoxin, adenosine,andalinidine(achloridechannelblocker). o Drugswithinaclassarenotnecessarilyclinicallysimilar:apatientmayrespondwelltoonedrugina givenclass,butnotanother. o Almostallofthecurrentlyavailabledrugshavemultipleactions;inagivenpatient,itisdifficultto establishwhichactionisresponsiblefortheaction o Themetabolitesofsomedrugscontributetoorareprimarilyresponsiblefortheirantiarrhythmic actions(e.g.procainamideanditsmetabolite,Nacetylprocainamide;encainideanditsmetabolite, 3methoxyOdesmethylencainide)

Actions of sodium channel blockers

Theenhancementofsodiumchannelblockseeninrapidlydepolarizingtissuehasbeentermed"use dependentblockade"andisthoughttoberesponsiblefortheefficacyofthesedrugsinslowingand convertingtachycardiaswithminimaleffectsonconductioninnormaltissuesstimulatedatnormal physiologicalrates. Atheorytoexplainusedependentblockade,termedthemodulatedreceptortheory(MRT),hasbeen proposedandusedtoexplainmanycharacteristicsofthesodiumchannelblockers. ThistheoryisbasedonathreestatemodelforthesodiumchanneloriginallyproposedbyHodgkinand Huxley: Thethreenormalchannelstatesare:Resting,Open(orActivated),andInactive 62|U R V I S H M I S T R Y

63|U R V I S H M I S T R Y o Undernormalrestingconditions,thesodiumchannelsarepredominantlyintheRestingstateand arenonconducting. o Whenthemembraneisdepolarized,thesodiumchannelsOpenandconductsodium,resultinginthe inwardsodiumcurrentthatmakesthemajorcontributiontophase0oftheactionpotential o TheinwardsodiumcurrentrapidlydecaysaschannelsmovetotheInactivestate o ThereturnoftheInactivechanneltotheRestingstateistermedreactivationandisvoltageand timedependent. o Thetheoryassumesthatsodiumchannelblockerdrugsbinddifferentchannelstateswithdifferent affinitiesandthatdrugbindingaltersthetransitionratesbetweendifferentstates. o DrugbindingresultsintransitionstoR*,O*,andI*channelstates.These"*"stateshavedifferent transitionratesbetweenstatesthanthenormalchannelstates. o ThemostclinicallyusefuldrugswouldhaveaffinityfortheOpenand/orInactivestate,andthereby exhibitusedependentblockade. o DrugswithhighaffinityfortheRestingstatewouldbetoxic.

Adrenergic blockers

Thedrugsinthisclasssuppressadrenergicmediatedectopicactivity.Themembersofthegrouplike propranololblockthebetareceptorsofthecardiactissue.ItdecreasesslopeofPhaseIVdepolarizationand automaticityinSAnode. Propranololisusefulintreatingsinustachycardia,extrasystolesprovokedbyexerciseoremotion. SotalolisbetablockerwithalsoClassIIIactivity. Esmololisashortactingdrugforemergencycontrolofventricularrate

Actions on potassium currents


Potassiumcurrents,predominantlythecurrentknownasthedelayedrectifier,areresponsiblefor repolarizingthemembraneduringtheactionpotential. Blockofpotassiumcurrentsduringtheplateauphaseoftheactionpotentialisthoughttobethemechanism ofactionofmanydrugsthatprolongtherefractoryperiod. Drugsthatarethoughttoact,atleastinpart,byinhibitingpotassiumcurrentsincludequinidine,sotalol,N acetylprocainamide,andamiodarone. Thesedrugstendtohaveahigherpropensitytocausetorsadesdepointes(aproarrhythmiaalsoreferredto asdruginducedlongQTsyndrome). Mostoftheavailabledrugsthatprolongrepolarizationexhibitnegativeratedependence,whereaspositive ratedependence(i.e.greaterefficacyintachycardias)istheidealcharacteristicfordrugsusedtoconvert spontaneoustachycardia. Somedrugsusedtotreathypertensionandangina(nicorandil,pinacidil,andseveralotherdrugs)activateor openpotassiumchannelsandtherebyacttoshortenrefractorinessofmyocardialtissuewhichleadsto arrhythmogenicstatesinanimalmodels.

Actions of Ca channel blockers


Mostclinicalventriculararrhythmiasareneitherpreventednorsuppressedbycalciumchannelblockers CalciumchannelblockersareusefulintreatingarrhythmiasinvolvingreentrywithintheAVnodeandinthe rareformsofmonomorphicventriculartachycardiaseeninpatientswithstructurallynormalmyocardium Manyofthecalciumchannelblockersalsohavetheabilitytoblocksodiumchannels,probablyduetothe similarityintheiraminoacidsequences(sequencehomology) Calciumchannelblockadeisenhancedbyverapamil(andtoalesserextentbydiltiazem)asthefrequencyof depolarizationisincreased Diltiazem ForSVTs,hypertension Dose:Dogs0.1250.35mg/kgi.v,chronicmanagement0.51.5mg/kgp.oq8h Cats0.51mg/kgp.o Ferrets(hypertrophiccardiomyopathy)27.5mg/kgp.otwicedaily Verapamil 63|U R V I S H M I S T R Y

64|U R V I S H M I S T R Y Dose:Dogs0.05mg/kgi.vslowly,repeatevery5minutesoral0.52mg/kg.q.8h

Clinical uses of antiarrhythmic drugs

ClassIdrugs:Qunidineandprocainamideareseldomusedinarrhythmiasnowbecauseoftheirsideeffects. Disopyramideisusedinatrialfibrillation.Lignocaineisusedintravenouslytotreatventriculartachycardia andpreventventricularfibrillation.(Preparationscontainingadrenalinealongwithlignocaineshouldnotbe used). ClassIIdrugs:Thesedrugsareusedinpatientsrecoveringfrommyocardialinfarction.Theyarealsoused prophylacticallyagainstrecurrenttachycardia. ClassIIIdrugs:Thesedrugsareusefulinsupraventricularandventriculararrhythmias. ClassIVdrugs:Verapamilisusedtopreventrecurrenceofsupraventriculartachycardia,toreduceventricular rateinpatientswithatrialfibrillation.Thesedrugsaredangerousandineffectiveinventriculararrhythmias.

Adverse effects of Antiarrhythmic drugs

Oneofthemostcommonandseriousadversecardiaceffectsisproarrhythmia(arrhythmiaironically precipitatedbyantiarrhythmictherapy)whichcanoccurin520%ofpatientstreatedwithClassIandClassIII drugs. ClassIdrugs(Sodiumchannelblockers): o Proarrhythmiceffect o Dosedependentnegativeinotropiceffect SubclassIA(especiallyquinidine)Torsadesdepointes("twistingofthepoints"): o Usuallyoccurswithinthefirstweekoftherapy o PreexistingprolongedQTintervalsmaybeindicatorofsusceptibility o Potentiatedbybradycardia o Oftenassociatedwithconcurrentelectrolytedisturbances(hypokalemia,hypomagnesemia) SubclassICVentriculartachycardia ClassIIdrugs(Betablockers): o Sinusbradycardia o Atrioventricularblock o Depressionofleftventricularfunction ClassIIIdrugs(Potassiumchannelblockers): o Sinusbradycardia o Torsadesdepointes ClassIVdrugs(Calciumchannelblockers): o Atrioventricularblock o Negativeinotropicaction

Adverse extra cardiac effects

Oneofthemostcommonandseriousadversecardiaceffectsisproarrhythmia(arrhythmiaironically precipitatedbyantiarrhythmictherapy)whichcanoccurin520%ofpatientstreatedwithClassIandClassIII drugs. ClassIdrugs(Sodiumchannelblockers): o Proarrhythmiceffect o Dosedependentnegativeinotropiceffect SubclassIA(especiallyquinidine)Torsadesdepointes("twistingofthepoints"): o Usuallyoccurswithinthefirstweekoftherapy o PreexistingprolongedQTintervalsmaybeindicatorofsusceptibility o Potentiatedbybradycardia o Oftenassociatedwithconcurrentelectrolytedisturbances(hypokalemia,hypomagnesemia) SubclassICVentriculartachycardia ClassIIdrugs(Betablockers): o Sinusbradycardia o Atrioventricularblock 64|U R V I S H M I S T R Y

65|U R V I S H M I S T R Y o Depressionofleftventricularfunction ClassIIIdrugs(Potassiumchannelblockers): o Sinusbradycardia o Torsadesdepointes ClassIVdrugs(Calciumchannelblockers): o Atrioventricularblock o Negativeinotropicaction

Vasodilators and antihypertensive drugs


Direct acting Vasodilators
Directlyactingvasodilatorsproducetheiractionmainlybyinterferingwiththeavailabilityofcalciumfor vasoconstriction. CalciumentryispreventedeitherbyblockingvoltagedependentCa2+channelsorbycausing hyperpolarization. DrugsproducevasodilatoractivitybyalteringCa2+releasefromthesarcoplasmicreticulumorreuptakeinto itandenzymesthatdetermineCa2+sensitivity. Thesemechanismsareexemplifiedbycalciumantagonists,potassiumchannelactivatorsanddrugsthat influencecytoplasmicconcentrationsofcyclicneucleotides. Nitrates Amylnitrate,isosorbidedinitrate,glyceryltrinitrate(nitroglycerine)areusedasvasodilators. Theseareavailableasoraltablets,buccaltablets,sublingualtablets,inhalationpreparations,topicalpatches (sustainedrelease)andtopicalointment. Nitroglycerinealsohelpstodilatecoronarybloodvessels. Thesedrugscauseadirectrelaxationofarterialandvenoussmoothmusclesbyactingasasourceofnitric oxidewhichisreleasedandcausesdirectrelaxation. Toxicityincludeshypotension,methemoglobinaemiaanddermatitis. Calciumchannelblockers Thesedrugscausegeneralizedvasodilatation,thoughindividualagentsdifferinregionaldistributionofthe effectbyreducingintracellularavailabilityofCalciumions. Drugsunderthiscategoryincludeverapamil,diltiazem,nifedipine,nimodipineandamlodipine. Potassiumchannelactivators ThesedrugsrelaxsmoothmusclesbyselectivelyincreasingthemembranepermeabilitytoK+. Thishyperpolarizesthemembrane,switchingoffvoltagedependentCa2+channelsandinhibitingaction potentialgeneration. Drugsunderthiscategoryincludecromokalin,pinacidil,minoridilanddiazoxide. Agentsthatactbyincreasingcyclicnucleotideconcentration Cyclaseactivation o ManydrugsrelaxvascularsmoothmusclebyincreasingthecellularconcentrationofeithercGMPor cAMP. o Dopaminehasmixedvasodilatorandvasoconstrictoractions,but,isusedtherapeuticallytodilate therenalvasculaturewhereitincreasesthecAMPbyactivatingadenylatecyclase. Nitroprusside o Isaverypowerfulvasodilatorwithlittleeffectsoutsidethevascularsystem. o Itbreaksdownunderphysiologicalconditionstoyieldnitricoxide,whichproducesthe vasodilatationeffect. o Toxicitytonitroprussideincludesexcessivevasodilatationandaccumulationofthiocyanate. o Thisdrugalsohasaveryshorthalflifeandmustbeadministeredbyintravenousrouteasafreshly preparedsolution. Natriureticpeptidescausevasodilatationbyactivatingguanylatecyclase. Phosphodiesteraseinhibitorsliketheophyllinecanalsocausevasodilatation. Vasodilatorswithunknownmechanismofaction 65|U R V I S H M I S T R Y

66|U R V I S H M I S T R Y Hydralazine o Actsmainlyonarteriesandarteriolescausingafallofbloodpressureaccompaniedbyreflex tachycardia. o Thisdrugproducesanincreaseinthestrokevolumeandisusefulinmitralinsufficiency. Ethanol o Dilatescutaneousbloodvesselscausingthefamiliardrunkardsflush.

Indirectly acting vasodilators


Thisconsistsoftwogroupsnamely o Thosethatinhibitsympatheticallymediatedvasoconstriction.Drugscaninhibitsympathetic pathwayatanypointfromthecentralnervoussystemtotheperipheralnervousterminal.Prazosina selective1adrenergicantagonistreducesmeanarterialpressure. o thosethatinhibitrenninangiotensinsystem Renininhibitors Severaldrugsinhibitreleaseofrennin,butthismechanismofactionisnotofimportance. Reninactivityinhibitorslikeenalkirenhavebeendeveloped.Buttheirclinicaluseisnotappreciable. ACEinhibitors CaptoprilwasthefirstACEinhibitortobedeveloped.OtherACEinhibitorsincludeenlapril,lisinopril, ramipril,perindoprilandtrandolaprl. Thesedrugsareusefulinhypertension,cardiacfailure,myocardialinfarction,diabeticnephropathyand progressiverenalfailure. AngiotensinIIreceptorsubtypeantagonists LosartanisaorallyactivepureantagonistofAT1receptor. Theyarebeingtriedinelderlypatientswithheartfailure.

Clinical uses
Clinicalusesofvasodilatorsinclude Hypertension, Cardiacfailureand Shock

Vasoconstrictors

1adrenergicagonistsanddrugsthatreleasenoradrenalinefromthesympatheticnerveterminalsorinhibit itsreuptakecausevasoconstriction. SomeeicosanoidslikethromboxaneAandseveralpeptideslikeendothelin,angiotensinandvasopressinare alsopredominantlyvasoconstrictors.

Clinical uses of vasoconstrictors


Clinicalusesofvasoconstrictorsinclude nasaldecongestion coadministrationwithlocalanaesthetics vasopressinmaybeusedtostopbleedingfromoesophagealvaricesinpatientswithportalhypertension causedbyliverdiseases.

Classification of antihypertensive drugs


Theseareagentsusedtoreducetheelvatebloodpressure.Theycanbeclassifiedbasedonthemechanismofaction asunder: Agentsinterferingwithsympatheticactivity o Alphaadrenergicreceptorblockers:Phentolamine,tolazoline,prazosin, o Betaadrenergicbolckers:Propranolol,Atenolol,Metoprolol o AlphaandBetaadrenergicblocker:Labetalol o Agentsinterferingwithsentralsympatheticactivity:Clonidine Vasodilators 66|U R V I S H M I S T R Y

67|U R V I S H M I S T R Y o Nitrates:Amylnitrate,isosorbidedinitrate,glyceryltrinitrate(nitroglycerine)areusedas vasodilators. o Calciumchannelblockers:Drugsunderthiscategoryincludeverapamil,diltiazem,nifedipine, nimodipineandamlodipine. o Potassiumchannelactivators:Drugsunderthiscategoryincludecromokalin,pinacidil,minoridiland diazoxide. o Agentsthatactbyincreasingcyclicnucleotideconcentration:Nitroprusside o Vasodilatorswithunknownmechanismofaction:Hydralazine o AgentsactingthroughinhibitionofAngiotensin AngiotensinConvertingenzymeinhibtors:Enalapril,Captopril AngiotensinReceptorblocker:Losartan

Antihypertensive drugs
Firstlineantihypertensivedrugs ACEinhibitors AT1antagonists adrenergicblockers Calciumchannelblockers Diuretics Diuretics Thiazidesandrelateddrugsaredrugsofchoiceinuncomplicatedhypertension Thiazidesaremildantihypertensives Effectiveinelderlypatients o TheyareeffectiveinIsolatedsystolichypertension, o lowreninhypertension o Obesewithvolumeoverload Theyareindicatedinhypertensioncomplicatedby o Heartfailure o RiskofCoronaryarterydisease o Diabetes Diureticsshouldbeavoidedin o Patientswithabnormallipidprofile o Pregnancyinducedhypertension ACEInhibitors/AT1blockers Firstchoicedruginallgradesofessentialaswellasrenovascularhypertension ACEinhibitorsshouldbeavoidedin o Bilateralrenalarterystenosis o Pregnancy o Hyperkalaemia Mostappropriateantihypertensivesinpatientswith o Diabetes o Nephropathy/chronickidneydisease o Leftventricularhypertrophy o Congestiveheartfailure o PostMyocardialInfarction o Gout o Dyslipidemia Theyappeartobemoreeffectiveinrelativelyyoungpatients ACEinhibitorsproducepersistentcough(duringthefirsttwoweeks)anddysguesia(lossoftastesensation). blockers Mildantihypertensive Theyareindicatedasantihypertensiveinpatientswith o Stableheartfailure 67|U R V I S H M I S T R Y

68|U R V I S H M I S T R Y o Postmyocardialinfarction o Highcoronaryarterydiseaserisk Highlysuitablefor o Patientswithcoexistinganxietyortachycardia o Relativelyyoungnonobesepatients o Highreninhypertensivepatients o Migrainepatients o Pregnantindividuals Contraindicatedin o Peripheralvasculardisease o Pulmonarydiseaseasthma,COPD o CardiacdiseaseConductiondefects,decompensatedheartfailure o Abnormallipidprofile CalciumChannelblockers Preferredin o Elderlyhypertensivepatientswhohavepoorarterialwallcompliance o Isolatedsystolichypertension o Asthma/COPDpatients o Pregnanthypertensive o Diabetes Preventsrecurrentstroke Verapamilanddiltiazemshouldbeavoidedin o Congestiveheartfailure,cardiacconductiondefects Dihydropyridinesshouldbeavoidedin o Ischaemicheartdisease o Postmyocardialinfarction o Gastroesophagealreflux o Maleswithprostateenlargement

Hematinic, coagulants and anticoagulants


Haematinics
Haematinicsareagentswhichareusedinthetreatmentofanaemiaandgenerallyactbystimulationofhaemoglobin synthesisoferythropoiesis. Iron Ironisnecessaryforhamoglobinformation.Itisavailableinthediet. Howeveroftenitissupplementedforthetreatmentofdeficiencyofironbygivingasoralorparenteral preparation. Oralpreparationshouldbesuppliedasferroussulphate,gluconateandfumarate.Theusualdoseis100300 mg/kgfordogsand50100mg/kgforcats. Parenteralpreparationscanbeadministerediforalpreparationsarenotfeasible.Irondextrancanbegiven asasingleinjectionat23daysofageinneonatalpigs. Copper Copperisutilizedasacofactorinthesynthesisofhaemoglobin.Copperdeficiency,ifsuspectedistreatedby administeringcoppercontainingsaltssuchascoppersulphateorcopperglycinate. Cobalt CobaltisutilizedforthesynthesisofVitaminB12.SupplementationisbysulafateorchlorideofCobalt@0.2 to0.5gm/dayforcattleor0.050.1gm/dayforsowthroughfeedororaldrenching. Folicacid FolicacidisalsoessentialforsynthesisofDNAandRNAandthussynthesisofRBCs.Anaemiaduetofolic aciddeficiencyiscalledmegaloblaticanaemia.Folicacidisalsoavailablebydietfromyeast,liver,vegetables etc.Supplementationoffolicacidcanbegivenasoralsupplements@25mg/kg/day. 68|U R V I S H M I S T R Y

69|U R V I S H M I S T R Y VitaminB12 VitaminB12isessentialforDNAsynthesis.DeficiencyofVitaminB12causesnuclearmaturationanddivision andcausesperniciousanaemia.Supplementationisgivenbyparenteralpreparationsofcyanocobalamin@ 25g/kg. Erythropoietin Itisaglycoproteinhormoneproducedbyrenalperitubularcellsinresponsetohypoxicsignalsreceivedin thekidney.Itisessentialfornormalerythropoiesis.Thisactsonbonemarrowtostimulateerythropoiesis. Erythropoietinisindicatedinanaemiaduetochronicrenalfailure.Thesyntheticformoferythropoietin Epoetinalfaisavailableandisgivensubcutaneousinjections. Anabolicsteroids Thesearetestosteronelikecopoundswithproteinanabolicactivity.TheyincreasecirculatingRBCmass. Theyareindicatedinchronicnonregenerativeanaemias.Nandrolone,Stanozalolareproducysthatare availabletobegivenbyoralroute.

Coagulants
Coagulantsareagentsthatpromotecoagulationofblood.Variouscoagulantsusedare Thromboplastin Thrombopalstin(thrombokinase)isproducednaturallybyplateletsanddamagedtissue. Commercialthromboplastinisanextractofcattlebraininnormalsaline. Itisappliedlocallyasahaemostaticincapillaryoozing,inthetreatmentofepistaxis. Thrombin Thrombinisanenzyme,whichconvertsfibrinogenintofibrin. Bovinethrombinisapowdersuppliedwithsuitablediluent. Itisusedinarrestingcapillaryhaemorrhageandinconjunctionwithfibrinogenorfibrinfoamforthis purpose. Fibrinogen Fibrinogenisusedinassistingtheadhesionofgraftsofskinandmucousmembraneasa2%solution. Fibrin Fibrinisavailableasfibrinfoamintheformofstripsofafinewhitesponge. Thesestripsaresoakedinthrombinsolutionandplacedoverthesiteofhaemorrhageorinthecavity. Coagulationoccursimmediately. Oxidisedcellulose Itshouldbeapplieddryandwhenitswellsformsabrowngelatinousmasswhichmaytakeabout7daysor moretobeabsorbed. Calciumalginate Thisconsistsofcalciumoramixtureofcalciumandsodiumalginates. Itisanabsorbablehaemostatic. Absorbablegelatinsponge Thisispreparedfromgelatinandtreatedwithformaldehyde,heated,whiskedintoafoamandfreezedried. Thisspongeisinsolubleinwater,butcanbewetted. Miscellaneouslocalhaemostaticsincludestrongsolutionofferricchloride,alumandtannicacid. o Freshbloodorplasma o VitaminK VitaminK1(fromplants,fatsoluble)Phytonadione VitaminK2(producedbybacteria)Meanquinone VitaminK3(i)FatsolubleMenadione WatersolubleMenadionesodiumbisulfite,Menadionesodiumdiphosphate o Miscellaneous Fibrinogen Antihaemophilicfactor Tissueextract Adrenochromemonosemicarbazone Rutin

69|U R V I S H M I S T R Y

70|U R V I S H M I S T R Y Ethamsylate

Anticoagulants

Anticoagulantsareagentsthatinhibitcoagulationofbloodeitherinvitroorinvivo. Theinvitroanticoagulantsareusefulinthecollectionofbloodforlaboratoryanalysisorforblood transfusion

In vitro anticoagulants

Anticoagulantsusefulforbloodcollectionforlaboratoryuseinclude o Sodiumoxalate20%solutionat0.01ml/mlofblood o Sodiumcitrate25%solutionat0.01ml/mlofblood o Edetatedisodium(EDTA)2%solutionat0.01ml/mlofblood o Heparinsodium75IU/10mlofblood Anticoagulantsusefulforbloodcollectionfortransfusioninclude o Sodiumcitratesolutionat10ml/90mlofbloodcontainingSodiumcitrate2.5g,sodiumchloride0.9 ganddistilledwatertomake100ml o ACDsolutionAcidcitratedextrosesolutionat15ml/100mlofbloodcontainingSodiumcitrate2.5 g,citricacid0.8g,dextrose2.5ganddistilledwatertomake100ml o Heparinsodiumat400to600IU/100mlofwholeblood Inadditiontotheaboveagentsapplyingcoldat2to5Corcollectingbloodinareceptaclehavingsmoothor unwettablewallslikesiliconcoatedreceptaclescanalsobeusedtocollectbloodwithoutcoagulation.

Systemic anticoagulants in vivo


Heparin Heparinisusedbothasinvitroandinvivoanticoagulant.Heparinisusedparenterallyasananticoagulant. Ithasdirectandalmostinstantaneousactiononthecoagulationprocess. Heparinispresentinmastcellsalongwithhistamineandserotoninandispreparedcommerciallyfrom bovinelungandporcineintestinalmucosa. Heparinisahighlynegativelychargedmucopolysaccharidehavinglargermolecularsizeandhenceis administeredparenterally. Heparinprolongstheclottingtimeofbloodbothinvivoandinvitro. Heparinpreventsfibrinformationintheprocessofcoagulation. ItincreasestheactivityofantithrombinIII. AntithrombinIIItheninhibitstheconversionofprothrombintothrombinbythromboplastin. AntithrombinIIIalsodirectlyinactivatesthrombininthepresenceofheparin. Heparindecreasesaldosteronesecretion,increasestheconcentrationoffreethyroxine. Itslowswoundhealinganddepressescellmediatedimmunity.

Clinical uses of anticoagulants


Prophylaxisandtreatmentofvenousthrombosisandpulmonaryoedema Inatrialfibrillationwithembolisation Inthediagnosisandtreatmentofchronicconsumptivecoagulopathies. Asananticoagulantinbloodtransfusion Forthepreventionofclottinginatrialandcardiacsurgery Forpreventionofcerebralthrombosis

Coumarin derivatives

Coumarinisnormallypresentinsomespeciesofsweetcloverandhasnoanticoagulantactivity. Thederivativesofcoumarinnamelydicumarol(bishydroxycoumarin)andwarfarinarecoumarinderivatives. Warfarinsodiumisthedrugofchoiceandistheprototypecoumarinderivativeanticoagulant. Coumarinderivativesareusedasoralanticoagulants. TheyarevitaminKantagonists. Theytakeabout812hourstoproducetheiraction. 70|U R V I S H M I S T R Y

71|U R V I S H M I S T R Y Theyarewidelyusedinsecondaryprophylactictreatmentofvenousthrombosisandpulmonaryembolism. Aspirin,cimetitidine,phenylbutazone,oxyphenbutazone,cotrimoxazole,metronidazoleanddisulfiram increasetheresponsetoanticoagulants.

Heparin antagonist

Protaminesulphateisastronglybasiclowmolecularweightproteinobtainedfromthespermofcertainfish. Givenintravenouslyitneutralizestheheparinweightforweight. Intheabsenceofheparin,protaminesulphateitselfactsasaweakanticoagulant

Respiratory pharmacology expectorants


Expectorants

Expectorantsincreasethefluidityandvolumeofrespiratorysecretions,andintheearlystagesof inflammationrelievespainandtendstoreduceslightlytheincidenceofcoughing. Thecontributionofexpectorantstotherapeuticsuccessisslightandtheirmainroletodayisascomponents ofcompoundcoughremediesfororaladministration. Expectorantsareclassifiedasinhalantexpectorants,ingestedexpectorantsandmucolyticexpectorants.

Inhalant expectorants

Theinhalantsarestillusedalone. Theseagentseitherheatedordissolvedinsteamingwaterareintendedforinhalationinaconfinedair space. Animals,atleastinitially,appeartoresentthestrongodourandthesteam. Thewholeprocedureistroublesome,and,becauseofthesteamgeneratingapparatus,potentially dangerous. Smallanimalsarebestsimplyexposedtosteamforrepeatedshortperiodsortoanaerosolofwater generatedbypumpandfedintoafacemaskorasmall,enclosedcage. Theseproceduresareeffectiveinchronicrespiratorydiseaseandaresupportedbyappropriate physiotherapydesignedtoaidthedrainageandexpulsionoftheliquefiedexudates. Inhalantexpectorantsincludebenzoin,eucalyptusoilandothervolatileoils,andwoodtarsandoilssuchas turpentineoroneofitsrefinedfractions,liketerebene.

Ingested expectorants

Systemicexpectorantsofdiverseoriginsareavailable. Thesearealladministeredbymouth. Somearenauseantsandcaninducevomiting,butareadministeredinsubemeticdoses. Othersareabsorbedfromthegutandareexcreted,atleastinpart,viathebronchialmucosa. Reflexornauseantexpectorantsincludeipecaacuanha,squill,balsamoftoluandcocillana,allofwhichareof vegetableorigin. Ipecacuanhacontainsanemeticalkaloid,emetineandsquillcontainsaglycosidewithemeticand cardiotonicproperties. Bronchialsecretionsarestimulatedasaphysiologicalpreludetovomiting. Locallyacting,systemicallyadministeredexpectorantsofvalueinchronicconditionsarerepresentedby sodiumiodideandpotassiumiodide. Theiodideisrapidlyexcretedthroughthebronchialmucosaandincreasesitssecretoryactivity. Ammoniumchlorideisoneofthemanyammoniumsalts,whichhavebeenusedasexpectorantsdespitelack ofagreementastotheirmodeofaction. GuiacolandGlycerylguiacolate(guaifenesin),aderivativeofguiacolobtainedfromcreosotearecommon stimulantexpectorantsincoughmedications,

Mucolytics

Mucolyticsassistinpreventingorremovingmucusplugsthatcauseatelectasisandthismayprogressto bronchiectasis.Sodiumacetylcysteinesolution20%isinhaledintheformofsprayoraerosol.Thesulphydryl 71|U R V I S H M I S T R Y

72|U R V I S H M I S T R Y groupofacetylcysteinebreaksdisulphidebondsintheglycoproteinsinexudates.Thedrugshareswith DMSOthepropertyofscavenginghydroxylradicals. Itcausesmildirritationtotherespiratorytract,butitsotherwisesafeandsuccessfulineffectingtherapid liquefactionofmucopurulentmaterials. Severalminutesofexposurerepeatedtwoorthreetimesaday,perhapswithpositivepressure,givesthe bestresults. Acetylcysteineisalsousedasanintravenousantidoteforacetaminophentoxicityincats. Bromhexineisofvalueinachievingliquefactionandimprovedflowcharacteristicsofmucusbyincreasingits volumeanddecreasingitsviscidity. Itisavailableinsolutionorasapowder,aloneormixedwithantibacterialagents. Bromhexinebringsaboutanincreaseinthecontentofimmunboglobulinandoxytetracyclineinbronchial secretions,presumablybyincreasingmembranepermeability. Thedrugimproveslysosomalfunctionandthatlysosomalenzymeshydrolysethemucopolysaccharidefibers ofmucous. Thedoserateis1mg/kgbodyweighttwicedailyinsmallanimalsand0.10.25mg/kgbodyweightin horses,eitherorallyorparenterally,for7days. Dembrexineisofvalueintreatingequinesandforitsactiononthesecretoryactivityofserousglandularcells inrespiratorymucosae. Themucusofmodifiedcompositionandhencedecreasedviscosityissecreted. Suchmucusismoreamenabletomucociliaryclearanceandcausespeedierreductionincoughingand cessationofmucusproductionintreatedanimals. Theproductcanbeadministeredintravenouslyorbymouthatadoserateof0.30.5mg/kgtwicedailyfor10 days.

Decongestants and antitussives


Decongestants

TwomajorcategoriesofdrugsusedasdecongestantsaretheH1antagonistsandsympathomimeticdrugs likeephedrine,pseudoephedrineandphenylephrine. Thealphaadrenoceptoragonistscauseshrinkageoftheswollenmucosaofthenasaltractinallergicorviral rhinitis Examplesareoxymetazoline,xylometazolineetc.

Antitussives

Coughsedativesorantitussivescausedepressionofthecoughcentreandreducetheincidenceofcoughing. Theyshouldnotbeusedwhenrespiratorysecretionsarecopiousunlesscoughingisexcessiveandcausing exhaustion(thisstateisuncommoninanimals). Antitussives,whichdiminishthefrequencyofcoughing,areofbenefitwhencoughingispainful,non productive,distressing,exhaustingandlikelytoexacerbateorevencauselungdamage. Theyactbyinterferingwiththecoughreflex,eitheratthelevelofthesensoryendingsintheupper respiratorytract,oratthelevelofcentralnervoussystem. Astrongantitussiveshouldnotbeusedwithanexpectorantbecauseincreasedfluidneedstoberemovedby coughingbuttheantitussivewillreducecoughing. Althoughsomeantitussivessuchasdextromethorphanareusedwithexpectorants,thecoughsuppression producedisnotsufficienttohinderremovalofexcesssecretions.

Directly acting antitussives


Localactionisachievedbydemulcent;thesweet,syrupyvehiclesinwhichothercoughremediesare dissolved. Demulcents(honeyandsyrup)coat,protectandsootheinflamedmucosaeforabriefperiod. Amorespecificactioninclaimedforbenzonatate,anagentthatdepressestheafferentsensorsofthecough reflexandpulmonarystretchreceptors. Localanestheticscanbeusedtocontrolseverecough. 72|U R V I S H M I S T R Y

73|U R V I S H M I S T R Y

Centrally acting antitussives


Thecoughcentreislocatedinthemedullaoblongata,incloseassociationwiththerespiratorycentre. Specificneuronsinvolvedincoughcoordinationhaveshowntobesuppressedbyantitussives. Codeine(methylmorphine)isanaturallyoccurringalkaloidandhasbeenthemajorantitussive Itsharesmanyotheractionsofmorphineatalesspotentlevel,eg.itisanalgesicandconstipant. Itcanbeconvertedtomorphineinthebody,butthisdoesnotgiverisetohabituationatthedosesusedfor coughcontrol,althoughaddictiontocodeineispossible. Codeineiswellabsorbedfromthegutandowesitssatisfactorydurationofactiontoaslowermetabolism. Codeinedoesnotcauserespiratorydepressionasdomorphine. Codeineiseffectiveatanoraldoseof12mg/kg. Morphineanddimorphine(heroin)canbeusedascoughsuppressant,theiruseisrestrictedtothecontrolof severecoughinterminalstages. Butorphanolisacentrallyactingopioidcoughdepressantthatcauseslittlesedationascomparedtostronger opioiddrugs. Hydrocodoneisanarcoticdrugthatisusedasanantitussiveinwhichsedationiscommonandlongterm administrationresultsinconstipationwithanoverdoseofhydrocodonecausingsevererespiratoryand cardiovasculardepression. Nonnarcoticantitussiveshavebeendevelopedtoincreasethesafetyoftheseagentsforuseinman,inan attempttoretaintheabilityofcodeinetosuppressthecoughcentrebuttolosetheCNSeffectse.g. respiratorydepression,analgesiaandatendencytohabituation. Pholcodeineisabouttwiceaspotentascodeine,nosacapine(ahistaminereleaserindogs)and dextromethorphanareaboutequipotent,anddextrorphanisabouthalfaspotent. Allsharethemildsedativeeffectofcodeineanditsoccasionaltendencytoinducevomiting. Thelevoisomersofdextrorphananddextromethorphanhavebothanalgesicandaddictiveproperties. Oralrouteisconventionalforcoughremedies;theseagentsmaybegivenparenterally.

Bronchodilators

Bronchodilatorscausethesmoothmuscleoftheairwaystorelaxandcanthereforecontributesignificantly tothereliefofdyspnoeaandtheremovalofthestimulusforcoughing. Bronchodilatorsareoftherapeuticrelevanceinthemanagementofrespiratorydiseaseaccompaniedby coughinganddyspnoea. Mostdrugsthatinducebronchodilatationalsoreduceinflammation. BronchodilatorsreverseairwaysmoothmusclecontractionbyincreasingthecAMP,decreasingcGMPor decreasingcalciumionconcentrations. Inadditionthesedrugsalsodecreasemucosaloedemaandareantiinflammatorybecausetheytendto preventmediatorreleasefrominflammatorycells.

73|U R V I S H M I S T R Y

74|U R V I S H M I S T R Y

Methyl xanthene

Methylxanthinesincludethealkaloidscaffeine,theobromineandtheophyllinedrugs,whichhavebeenused asCNSstimulants,diuretics,heartstimulantsandsmoothmusclerelaxants. Itisthesmoothmusclerelaxantproperty,whichisresponsibleforthebronchodilatoreffectofthe xanthines. Thesmoothmusclerelaxantactionisattributedtoinhibitionofphosphodiesterase,theintracellularenzyme thatinactivatescAMP. TheCNSstimulantactionofthesedrugsalsocontributestoimprovedrespiratoryfunction,asalso theimprovementincirculatoryandrenalfunctionincardiacasthmaofdogs. Derivativesoftheophyllinewithsuperiorpharmacokineticpropertiesarenowpreferred. Aminophylline,diprophyllineandetamiphyllinegivenbyslowintravenous,intramuscularorsubcutaneous injectionareeffectiveinreducingairwayresistanceinacutebronchoconstriction. Aminophyllineismoresolublethantheophyllineandisbetterabsorbed.

Sympathomimetic

Adrenaline,isoprenalineandalargenumberofagentscapableofstimulatingbeta2adrenoceptorsareused extensivelyinthecontrolofbronchialasthmainman. Adrenalinehasbothalphaandbetaactionsandismoreusefulinsevereanaphylaxis(adrenalinebitartrate 1:1000solutionforinjection;largeanimals24ml,dogs0.10.3mlintravenouslyoruptodoublethesedoses subcutaneously)whileephedrineanditscongenersareusedprophylacticallyinman. Directactingbeta2agonistsarepreferredfortherapy.Suchcompoundsareexemplifiedbysalbutamol, fenoterolandhexoprenaline.Theseselectiveagentsarerelativelyfreeofdangerouscardiacstimulantside effectsoftheformerlyused,mixed1,2agonistssuchasisoprenaline. Thesympathomimeticsareeffectiveinrelievingthebronchoconstriction,whichfollowsthereleaseof histamineand/or5HTfrommastcellswhosesecretoryactivitytheyalsoinhibit. Administrationasanaerosolreducesthedelaytoonsetofeffecttoafewminutes.However,aerosol inhalationisnotaconvenientmeansofadministrationforanimals.Itisrecommendedinthemanagementof chronicallergies,bronchitis,chronicobstructivepulmonarydiseaseandequineinfluenza.

74|U R V I S H M I S T R Y

75|U R V I S H M I S T R Y

Parasympatholytics spasmolytics

Parasympatholyticssuchasatropinehavebeenusedasabronchodilatorinchronicemphysemainhorses. Therationaleisthatatropineovercomesthemuscariniccholinoceptormediatedbronchoconstriction.The effectisdilationofthelargerairways Atropinederivativese.g.eucatropine,havealsolongbeenusedinpaediatricpreparationsforwhooping cough. Asthesulphate,atropineisroutinelyinjectedpreoperativelytoreduceoreliminatesalivaryandbronchial secretionsduringanesthesia. Thedosebysubcutaneousinjectionis30100mg/kg. Ipratropiumamuscarinicblockingbronchodilator,isusedasanaerosol. Thereductioninvolume,higherviscosityofsecretionsanddecreasedmucociliaryclearance,canbea disadvantage.

Corticosteroids

Thereductionofmucosaledemainbronchiandbronchiolescanbeachievedbyuseofglucocorticoidsto suppresstheinflammatoryresponse. Inmanthecorticosteroidsareusedforsevere,disabling,bronchodilatorresistantasthma. Thesemaybeadministeredorally,parenterallyorasanaerosol. Theirusecarriestherisksofareducedabilitytogightinfectionsandalsotheriskofadrenalcortex suppressioniftheadministrationisprolonged. Theireffectsontheinflammatoryresponseincludemembranestabilization,reducedantibodysynthesis, reducedmediatorreleasefollowingantigenantibodyinteractionsandlessenedfibrosis. Thesedrugsalsoblockuptake2andsoextendthehalflifeofendogenoussympathomimetics. Corticosteroidscanbeusedwithadvantagetocontrolchronicallergictypesummercoughsindogseitherby theoraladministrationofprednisoloneorbytheuseofinjectabledepotpreparations.

NSAIDs

TheintroductionofNSAIDswithhighantiinflammatorypotencyhasmadethisgroupbeneficialasadjuncts alongwithantimicrobials Theylackthesuppressionoftheimmuneresponseseenwiththecorticosteroids. Theirabilitytosuppresstheproductionofthechemicalmediatorsoftheinflammatoryresponseunderlies theirabilitytoreducestructuraldamageandfunctionalimpairmentinthepneumoniclung. Ventilation,gaseousexchangeandpulmonaryhaemodynamicscanallbeimprovedbyNSAIDadministration. Flunixinisespeciallyrecommendedforthispurpose.

Antihistaminics

TheintroductionofNSAIDswithhighantiinflammatorypotencyhasmadethisgroupbeneficialasadjuncts alongwithantimicrobials Theylackthesuppressionoftheimmuneresponseseenwiththecorticosteroids. Theirabilitytosuppresstheproductionofthechemicalmediatorsoftheinflammatoryresponseunderlies theirabilitytoreducestructuraldamageandfunctionalimpairmentinthepneumoniclung. Ventilation,gaseousexchangeandpulmonaryhaemodynamicscanallbeimprovedbyNSAIDadministration. Flunixinisespeciallyrecommendedforthispurpose.

Mast cell stabilizers


Thedrugactsbystabilizingmastcellmembranespreventingdegranulationandthereleaseofchemical mediators(eg.Histamineandleukotrienes)inresponsetoallergens. Adepressantactiononchemosensitiveendingwhichtriggerbronchoconstrictionisalsosuggested. MorerecentlyithasbeenshownalsotopreventthereleaseoftissuedamagingfreeradicalsofIgEactivated platelets. Cromoglycateisnotabronchodilatorandisnoteffectiveintherapidreliefofexistingbronchoconstriction. Ithasgivensufficientimprovementintherespiratoryfunctioninhorseswithchronicobstructivepulmonary disease. 75|U R V I S H M I S T R Y

76|U R V I S H M I S T R Y Adminsitrationisdoneviaaspecialnebulizerandfacemask,80mgoncedailyfor14days.The1015min periodofnebulizationisgenerallywellacceptedbythehorse. Itisavailableasdrugforprotectinghorseswithallergicrespiratorydiseaseagainstpredictableantigen challenge.

Respiratory stimulants
Respiratorystimulantsareagentsusedtoimproverespiration.

Diuretics

Diureticsareagentsthatincreasethesaltandwaterexcretionbyanactiononthekidneys. Diureticseffectiveforthetreatmentofedemahavebeenavailablesincethe16thcenturyandmercurous chloridewasknownbyParacelsustobediuretic. In1930,Swartzdiscoveredthattheantimicrobialsulfanilamidecouldbeusedtotreatedemainpatients withcongestiveheartfailureduetoanincreaseinrenalexcretionofNa+. Mostmoderndiureticsweredevelopedwhensideeffectsofantibacterialdrugswerenoted,whichincluded changesinurinecompositionandoutput. Exceptforspironolactone,diureticsweredevelopedempirically,withoutknowledgeofspecifictransport pathwaysinthenephron. Theyareusedmainlyincasesofcardiacfailure,oedemaandhypertension.

Physiological diuresis

Itisoccasionallydesirabletoprovokediuresisinordertoincreaseurinaryfloworvolumeasinthecaseof treatmentofcystitisortopreventcrystalluriawithsulphonamidetherapy,ratherthanwiththeintentionof reducingbodyfluidvolume. Insuchcasesincreasedwaterintakeissufficient.

Classification of diuretics
Basedontheiractiononthekidneysdiureticsareclassifiedas Diureticsactingdirectlyonthecellsofthenephron o AgentsactingontheascendingloopofHenleEthacrynicacid,frusemide o AgentsactingontheearlydistaltubulesThiazideslikechlorthiazide o AgentsactingontheCollectingtubulesandductsTriamterene,amiloride Diureticsmodifyingthecontentsofthefiltrate o OsmoticdiureticsMannitol o CarbonicanhydraseinhibitorsAcetazolamide Basedontheirmodeofactiondiureticsareclassifiedas o OsmoticdiureticsGlycerine,mannitol,urea,isosorbide o InhibitorsofcarbonicanhydraseAcetazolamide,dichlorphenamidine o InhibitorsofNa+K+2Clsymport(Highceilingloopdiuretics)Frusemide,Ethacrynicacid, Bumetanide o InhibitorsofNa+ClsymportThiazideandthiazidelikedrugs o Potassiumsparingdiuretics InhibitorsofepithelialsodiumchannelsTriamterene,amiloride AntagonistsofaldosteroneSpironolactone o XanthinediureticsTheophylline Itcanalsobeclassifiedas o CardiacdiureticsXanthines o OsmoticdiureticsMannitol,Isosorbide,Urea o NatriureticsMercurials,Thiazides,Acetazolamide

Osmotic diuretics

Theseareinertsubstancesfilteredintotheglomerulus. 76|U R V I S H M I S T R Y

77|U R V I S H M I S T R Y Theirmaineffectisexertedintheproximaltubule,descendinglimbofHenleandthecollectingductwhich arefreelypermeabletowater. Byremaininginthetubularlumen,theseagentscauseanincreaseincolloidosmoticpressureinthetubular lumencausingsuctionofwaterintothetubularlumen. Thereisalsoreducedwaterreabsorptionduetorenalmedullaryhyperemia. ThereisimpairmentofNa+reabsorptionbecausethedilutedsolutioninthelumenreducesthe Na+concentrationgradient,makingitharderforNa+tobereabsorbed. Theyarenotusefulintreatingconditionswithsodiumretention. Thesedrugsareusefulinacutelyraisedintracranialpressureorintraocularpressure. Theyarealsousefulinpreventionofacuterenalfailure. Unwantedeffectsincludetransientexpansionofextracellularfluidvolumeandhyponatraemia,headache andvomiting. Mannitoliscommonlyusedasanosmoticdiureticandhastobeadministeredintravenously. Isosorbidehastheadvantageofbeingabsorbedafteroraladministrationinmonogastricspecies.

Carbonic anhydrase inhibitors


Bicarbonatespenetratetheluminalmembraneonlyveryslowly,anditsabsorptionintheproximaltubuleis heavilydependentonthepresenceofanenzymecarbonicanhydrase. Thisisazinccontainingenzymewhosefunctionistospeeduptheattainmentofequilibriumofthereaction: CO2+H2O>H2CO3 Roleofcarbonicanhydraseindiuresisisthatitiscapableofacceleratingthisreactionineitherdirection. Thisenzymeisfoundwithintheproximaltubulecellsandinassociationwiththeirluminalbrushborder. TheactivatingstepintheprocessofbicarbonateabsorptionisthesecretionofH+intothetubulelumen, whichislargelyresponsibleforthefavourableelectricalgradientdownwhichNa+diffusesintothecell. ThisH+isderivedfromthedissociationofcarbonicacid,whosesupplyisfacilitatedbythepresenceof carbonicanhydrase. Thecarbonicanhydraseinhibitorsinterferewiththeabsorptionofbicarbonatefromtheproximaltubule,by reducingthesupplyofH+tothemembranepumpandbyreducingtherateofabsorptionofcarbonicacid fromthelumen. FilteredbicarbonateisthustrappedintheurinetogetherwithanelectricallyequalamountofNa+andan osmoticallyequivalentamountofwater. Thesedrugscauseanincreasedexcretionofbicarbonatewithaccompanyingsodium,potassiumandwater excretionresultinginanincreasedflowofalkalineurineandmildmetabolicacidosis. TheyarepoordiureticsbecausethereiscompensatoryreabsorptionofNa+isthesegmentsfurtherdownthe nephron. Thesedrugsareusedinglaucomaandinsometypesofepilepsy. Theiractionresultsinadepletionofextracellularbicarbonateandtheireffectisselflimitingastheblood bicarbonatelevelfalls. Sideeffectsaredrowsiness,numbnessandtinglingofthefaceandextremities(duetometabolicacidosis) anddisturbancesofvision. Thisgroupofdrugisrarelyusedasdiuretics. Acetazolamideusedasacarbonicanhydraseinhibitorisaderivativeofasulphonamidebutdoesnotpossess anyantibacterialaction. Acetazolamideisanoncompetitive,irreversibleinhibitorofcarbonicanhydrase.

Loop diuretics

Loopdiuretics(Highceilingdiuretics)arethemosteffectivediuretics AfairlyhighproportionofNa+isalsoreabsorbedintheloopofHenle(22%). TheyareinhibitorsofNa+,K+Clsymport Maineffectofthisgroupofdiureticsisinhibitionofchloridepumpingthroughoutthewholelengthofthe thickascendinglimbofHenle,thusparalysingthekidneysabilitytoconcentrateandtodilutetheurine. 77|U R V I S H M I S T R Y

78|U R V I S H M I S T R Y Theireffectisfromtheluminalsurfaceoftheloopcells. Thesedrugsareextensivelyboundtoplasmaproteinsandrelativelylittleisfilteredintheglomerulus. Theyareactivelysecretedbytheorganicaniontransportersatthesiteofaction.Substances,likeprobenecid whichblockthismechanism,canreducetheirefficacy. ExamplesofLoopdiuretics:Frusemide,BumetanideandEthacrynicacid. Frusemideandbumetamidearesulphonamidederivativeswhileethacrynicacidisnotasulphonamide derivative. Ethacrynicacidmayproduceclinicaldehydrationandacutecirculatorycollapseasitproducessevere diuresisafteradministration. Frusemideproducesrapiddiuresisandhenceisusefulinemergencycases. Itiseasiertocontrolthedegreeofdiuresiswiththisdrugbyvaryingthedoserate. Thereisanincreaseintheexcretionofcalciumandmagnesiumandadecreasedexcretionofuricacid. Theeffectoncalciumismadeuseofinthetreatmentofhypercalcaemia. Theloopdiureticsarereadilyabsorbedfromthegastrointestinaltractandcanalsobeadministered parenterally. Administration Orallyorintravenouslyat15mg/kgindogs. Thiscanbedoubledwithsuccessivedosesuntilaneffectisobtained. Durationofactionis46hours. Inhorsesthedrugisgivenattherateof0.5mg/kgtoreduceincidenceofepistaxis. Incattlegivenorallyat0.51mg/kg,1224hourly.Loopdiureticsareusefulinpatientswithsaltandwater overloadduetoacutepulmonaryoedema,chronicheartfailure,hepaticcirrhosiscomplicatedbyascites, nephroticsyndromeetc. Hypertensionespeciallyifaccompaniedbyrenalimpairment. Acutetreatmentofhypercalcaemia. Untowardeffectsincludepotassiumloss,metabolicalkalosis,depletionofcalciumandmagnesium, hypovolaemiaandhypotension. Localirritationofthegastronintestinaltractandcompetitionwithotherdrugslikedigitalisarenoticed. Aswithotherpotentdiuretics,hyponatraemiacanoccur,butdeafnessisanadverseeffectpeculiartoloop diuretics. Henceconcurrentdosingwithaminoglycosidesiscontraindicated.

Thiazide derivatives
Thiazidediureticsgroupincludeschlorthiazide,hydrochlorthiazide,bendrofluazide,cyclopenthiazide. Thesedrugsaremorepotentthancarbonicanhydrase(CA)inhibitors.Mostthiazidesareweakinhibitorsof CA,butthisisnotthebasisoftheiraction. Siteofactionofthiazidediureticisatthedistaltubule(hencetheyaremediumactingdiuretics)wherethere isonlyasmallamountofreabsorptionofsodiumsincemostoftheNa+isalreadyabsorbedintheearlier partsofthenephron. Inthedistaltubule,Na+isreabsorbedviaaNa+Clcotransport. Thiazidesinhibitthiscotransportmechanism,thuspreventingNa+frombeingreabsorbed. ThiazidesmayalsoinhibittheNa+K+ATPaseindirectly. DuetoNa+K+counterexchangeatthecollectingtubule,potassiumlossmaybeinducedbythesedrugs leadingtoserioushypokalemia. Thethiazidesareactivebymouthaswellasbyparenteraladministration. Theireffectsarefairlyslowinonset. Thiazidesareusedinthetreatmentofoedemaincardiacfailure.Inhepaticcirrhosis,muchK+lossisnot appreciable. HencethiazidesaregiveninconjunctionwithK+tabletsorwithaK+sparingdiuretic. Thiazidesaresecretedinthekidneyviatheorganicacidsecretarysystem. Sideeffects Hypokalemia Increaseinbloodsugar(hyperglycemia),especiallyindiabetics, 78|U R V I S H M I S T R Y

79|U R V I S H M I S T R Y Reducedinsulinalsocausesincreasedglycogenolysisandreducedglycogenesis. Thiazidesmaycauseareducedexcretionofuricacid,leadingtogout.Thethiazidesaresulphonamides,and sosharecrossreactivitywithotherdrugsofthisgroup. Therefore,ifapatientisallergictoasulphonamide,chancesarethatthepatientwillalsobeallergicto thiazides. Photosensitivityandhaemolyticanaemiamayoccur.

Potassium sparing diuretic


Thereare2groupsofdrugsinthiscategory. Theonlything,theyhaveincommonistheirsiteofaction(latedistaltubuleandcollectingduct). Howevertheirmechanismofactionisquitedifferent. o InhibitionofaldosteroneSpiranolactone o InhibitionoftheNa+K+exchangeinthecollectingductTriamterene,Amiloride Aldosteroneantagonists Aldosterone(asteroidhormone)enterstubularcellsandbindstoamineralocorticoidreceptorinthe cytoplasm. ThishormonereceptorcomplexbindstoaresponseelementontheDNA. Bindingresultsintheexpressionofaldosteroneinducedproteinsleadingtoactivationofsilent Na+channels/pumps,alterationofthecyclingofthechannelsandpumps,increasedexpressionofchannels andpumpsandalteredpermeabilityofthetightjunction(zonulaoccludens). AlltheaboveeffectsresultinanincreaseinNa+conductance(reabsorption)andsecretionofK+(Oneofthe complicationsofexcessaldosteronesecretionishypokalemia). Spiranolactonebindstothemineralocorticoidreceptorandpreventsaldosteronefrombinding. Spiranolactoneatruecompetitiveantagonistofaldosteroneenhancesdirectreabsorptionofsodiumin moreproximalareasofthedistaltubules. Thisdrughasaveryslowonsetofaction,whichisnotdosedependent. Itmayexertoestrogenlikeactivity Itisusedincombinationwiththiazidediuretics. Spiranolactoneisnoteffectiveinthepresenceoflowlevelsofaldosterone. Itisavailableonlyfororaladministration. Ifhyperkalemiaoccursasaresultofspiranolactonetoxicity,thiazidediureticscanbeadministered. Triamtereneandamiloride Thesedrugshavealimiteddiureticefficacy. Theyactonthecollectingtubulesandcollectingducts,inhibitingsodiumreabsorptionanddecreasing potassiumexcretion. TriamtereneinhibitsaldosteronespecificATPase. But,isnotdependentonaldosteronelevels. AmilorideblocksNa+channelsintheluminalmembraneaffectingNa+permeability. Boththedrugspromoteexcretionofuricacid. Themainimportanceofthesedrugsliesintheirpotassiumsparingability. Theycanbegivenwithpotassiumlosingdiureticslikethiazidestomaintainpotassiumbalance. TheyareusefulinconditionswhereK+losscannotbetolerated(oftenusedinconjunctionwiththiazides) InhypertensionandcongestiveheartfailureIfapersonisbeingtreatedwithdigoxinfortheirheartfailure, lossofK+canenhancethetoxicityofdigoxin(cardiacglycoside). IfK+isreduced,theactionsofdigoxinareenhancedbecausenormally,digoxinmustcompetewithK+forthe Na+K+ATPase. Byusingthedrugsincombination,thereisanenhanceddiureticeffectandtheaddedbenefitofnotlosing K+. Spironolactoneisusedinprimaryhyperaldosteronism(tumoroftheadrenals)orsecondary hyperaldosteronism(cardiacfailure,hepaticcirrhosis). Sideeffects Hyperkalemia, Metabolicacidosis, 79|U R V I S H M I S T R Y

80|U R V I S H M I S T R Y Gynaecomastia, Impotence, Decreasedlibido, Hirsuitismand Gastricupsets.

Xanthines and mercurial


Xanthines Thesedrugsstimulatecardiacfunctions.Theirdiureticactivitymaystemfromtheresultantincreaseinrenal bloodflowandtherebyanincreaseinglomerularfiltrationrate. Theyalsoexertadirectactionontherenaltubule.Renalresponseismanifestedbyanincreaseinlevelsof sodiumandchlorideinurine. ThereisnosignificantchangeintheurinepHandpotassiumexcretionappearstoberelativelyunaffected. Examplesare:Caffeine,Theophylline Mercurials Diureticactionofmercurialsisassociatedwithsulphydrylgroupsandsotheyinactivatethesodium transportmechanismofthenephron. Forclinicaluse,mercurialsareobsolete

Drugs acting on urogenital systems


Alkalization of urine
AlterationofurinepH Alterationissometimesdesirableasinthecaseofpoisoningandintheexcretionofsomedrugstopreventside effects. Alkalinisationofurine Alkalinisingagentsreducetheirritationofaninflamedurinarytractanddiscouragethegrowthofcertain organismslikeE.coli. Urinecanbemadealkalinebysodiumbicarbonateintravenousadministrationorbypotassiumcitrateoral administration. Sodiumorpotassiumcitrateismetabolisedtoformastablecation(Na+orK+)andalabileanion(citrate). CitrateistakenupforusebytheTCA.TheNa+orK+isexcretedwiththemostcommonanion(HCO3. Hence,therewillbealkalineurine. Administrationanduse Todecreasetheadverseeffectsofsulphonamidesalkalinisationisuseful.Sulphonamidesaregenerally insolubleinacidurine.Theymaythusprecipitateoutandcrystallise.Therefore,toincreasesolubility,the urineismademorealkaline. ToincreasetheexcretionofacidicdrugslikeAspirin,salicylatesandbarbiturates. Alkalinisationofurineincreasestheantibacterialactivityofaminoglycosidesinurinarytractinfection. Alkalinisationoftheurineinusuallyrecommendedtopreventtherecurrenceofuratestonesindogsafter cystotomy.Sodiumbicarbonateat0.5to1.0gisgivenorallythricedaily.

Acidification of urine
Acidificationofurineisusedasatestforrenaltubularacidosis.Acidificationhelpsintheexcretionofcertain drugslikeamphetamine,phencyclidine,quinineetc. Ammoniumchloride,ascorbicacidorcalciumchloridecanbeusedtoacidifyurine. Ammoniumchloride(NH4Cl)ismetabolisedinthelivertoNH4+andCl. TheClisexcretedalongwithNa+. ThebaseconservingmechanismssecreteH+andNH4+intotheurine. Administrationanduses Acidificationincreasesactionofhexamine,penicillinsandtetracyclinesinthetreatmentofurinarytract infections. AcidificationincreasesexcretionofbasicdrugslikePethidineandamphetamine 80|U R V I S H M I S T R Y

81|U R V I S H M I S T R Y

Ecbolics

Theseareagentsthatbringaboutincreaseinuterinecontractions. Oxytocin:Itishormoneoftheposteriorpituitaryreceivedfromthehypothalamus.Ithasamajor physiologicalroleinmilkletdownandlaborinitiation. o Clinicalusesofoxytocin: Forlaborinduction.GivenbyslowI/vindextrosesolution. FormIlkletdown.Onlyinagalacticanimals Fortreatmentofuterineinertiaandforrapdinvolutionofuterus. Toarrestpostparturienthaemorrhage. Forexpulsionofretainedplacenta. o Thedoseofoxytocinis525unitsinbitch,75100unitsincow/mareand3050unitsinsow/ ewe. Oxytocics:Otheragentswhichperformsimilarfunctionsarealsocalledoxytocics. Ergotalkaloids:AlkaloidsfromthefungusClavivepspurpureaviz.ergometrine,ergonovinehaveprominent effectontheuterus.Notpreferredforinductionoflabour.Generallyindicatedforpostparturient haemorrhage,rapidinvolutionofuterus,retainedplacenta. PGF2alpha:Exertspotentstimulantactiononmyometrium.Itisalsopopularlyusedforitsluteolyticeffect.

Tocolytics

Theseareagentsthatinhibituterinecontractions.Theyrelaxuterinesmmothmuscleandmaybeusedto delaylaborandtostopthreatenedabortion. Beta2agonists:Salbutamol,terbutaline,isoxsuprine Calciumchannelblockers:Nifedipine,diltiazem Oxytocinantagonist:Atosiban

Fluid therapy
Fluidtherapyreferstoadministrationoffluidstocompensatethelossoffluidsfromthebodyduetoa varietyofconditionsleadingtodehydration.Fluidlossinthebodycanleadtoshockandcanbecomefatalif unattendedto. Thepurposeoffluidtherapyistocorrectdehydrationoroverhydration,elctrolyteimbalanceand/oracid baseimbalance. Itisalsoindicatedtocorrectacidosis/alkalosis,treatshock,giveparenteralnourishmentorevenstimulate organfunctionsuchaskidney. Fluidvolumeandtype Thetypeofsolutionistobedictatedbyhistory,clinicalsignsandlaboratoryexamination. Thevolumeoffluidisdeterminedtheneedformaintenanceaswellastheneedforreplacementoflost fluid. Fornormalmaintenance,athumbruleof65ml/kg/24hrforadultsand130ml/kg/24hrforyoungonesis calculated. Basedonthis,anormalmaturedogof20kgwouldrequire1300mlfor24hrperiod. Replacementoffluidlossmustbeinadditiontothemaintenancerequirement. Tocalculatefluidlossonemustestimatethedegreeofdehydration. Tocalculatethefluidforreplacementonemustcalculatethedegreeofdehydration. Degreeof dehydration 4% 6% Clinicalsigns historyoffluidloss,leatheryskin,mucousmembranestillmoistand evidenceofthirst skinstillleathery,whenliftedtheskinwillpeakandreturntonormal slowly,haircoatdull,mucousmembranedrybutthetonguestill moist 81|U R V I S H M I S T R Y

82|U R V I S H M I S T R Y 8% Skinwillshowlackofpliabilityandelasticity,theskinlosesturgor (whenliftedwillpeakandstay,mucousmembraneandtonguedry, eyeballswillbesoftandsunken. Signsofcirculatorycollapse SymptomsofAcuteshock

12% 15%

Fluidvolumetoreplace Thevolumeoffluidtoreplacelossoffluidiscalculatethebodyweightmultipliedbydegreeofdehydration. Foreg.,adogweighing20kgwith6%dehydrationisgiven20kgx0.061200mlor1.2liters. Thisisapartfromthemaintenancerequirementof20x65=1300ml. Ratesandadministration Therateofreplacementoffluidsshouldparalleltheseverityofdehydration.Fluidsshouldbeadministered rapidlyatfirstfollowedbydecreasingrates. Mostcommonlyitisagreedthat15ml/kg/hrisareasonablerate.Inseverelydehydratedcasesthiscango upto50ml/kg/hr.Higherratescanoverloadthesystemandmayevencauseoverhydration. Routeofadministration Theroutedependsonthetypeofillness,severity,degreeofdehydration,patientcondition,timeand equipmentavailable. Themostcommonandoverlookedoneistheoralornasogastric.Itistheleastdangerous,withoutstrict asepsis. Perrectaladministrationcanalsobeconsidered.Itmaybedifficulttoretainthefluidespeciallyinthe presenceofgastrointestinaldisease. TheIVrouteisthemostversatile.Itisindicatedforemergencies,severecases.Ithastheadvantageoflarge volumeofadministration.Butmaintenanceofindwellingcatheter,clottingandhematomaandlocationof veinaresomeofthedrawbacks. TheSCrouteishandyincasesofsmallanimalswherelargervolumesneedtobegivebutitisdifficultto locatethevein.Itisirritatingandcanbepainful.Fluidabsorptionismoreslow. IProutealsosuffersformthedrawbackofeasypredispositiontoperitonitis.

Choice of fluid
ProperselectionoffluidbeginsbydeterminingthetypeofdeficitandchoiceoffluidsColloid,crystalloidor combinationofboth Fluid Isotonicsaline (Normalsaline,0.9%) Indications Tocorrectmetabolicacidosis,especiallyaftervomiting

Isotonicdextrosesaline Maintenancetherapy,hypertonicdehydration (0.18%NaCl+4.3%Dextrose) Darrowssolution (0.4%NaCl+0.27%KCl+ 0.58%Sodiumlactate) 5%Dextrose Metabolicacidosisassociatedwithdiarrheal dehydrationandpotassiumloss Hypertonicdehydrationresultingfromwater deprivationorheatstroke;usedinemergencyto providetransientalleviationofhypoglycaemia Metabolicacidosis, Replacementoflossesowingtogastrointestinal dysfunction(vomiting,diarrhea),haemorrhage,burns

CompoundSodiumLactate (Hartmannssolutionor Ringerslactate)

82|U R V I S H M I S T R Y

83|U R V I S H M I S T R Y ClinicalCondition Choiceoffluid Vomiting NormalSaline DextroseSaline Ringerssolution LactatedRingers Darrowsfluid(InchroniccaseswithK+loss)

Diarrhea

Bowelobstruction LactatedRingers(+colloidforshock) Hemorrhage Wholeblood LactatedRingers Colloid Colloid LactatedRingers Dextran+Hartmanns RingersLactate GelatinColloid Foremergencytreatmentofdehydrationand hypoglycaemia SevereAcidosis Replacementforbloodlossintreatinganaemia Effectiveinrestorationofbloodvolumeincasesof hemorrhageorshock. Hypovolemicshock,burns,bloodlossanddiarrhea

Peritonitis Shock

DextroseSaline(0.9%NaCl+ 5%Dextrose) Sodiumbicarbonate(1.3%) Wholeblood Plasmaexpanders Dextran Gelatincolloidalsolution

Pharmacotheraputics of Hormones
Administration of hormones

Administrationofhormonesfallsintotwocategories: o Replacementtherapyand o Additivetherapy Replacementtherapyistheadministrationofthehormonesatphysiologicallevels.Forexampleinsulin, thyroxine,vasopressin,gonadotrophinsandACTHareadministeredatphysiologicallevels. Additivetherapyistheadministrationofthehormonesatpharmacologicallevels(notusuallyrelatedto naturalmetabolicfunctions).Administrationatpharmacologicallevelsmayproducesideeffectsoruntoward effects.Forexampleandrogensandglucocorticoidsareadministeredatpharmacologicallevels. Augmentationistheprocessofincreasingdurationofactionofahormonebycombiningtheprotein hormoneswithcopper,zincorironofheme.

Corticotrophins and related peptides


Corticotrophinreleasinghormone ThishormonestimulatessynthesisandsecretionofACTHbypituitarycorticotrophs. ThishormoneappearstoexertitseffectonACTHreleasethroughbothadenylatecyclaseandcalcium calmodulinsignaltransductionsystems. 83|U R V I S H M I S T R Y

84|U R V I S H M I S T R Y Adrenocorticotrophin ACTHstimulatesthesecretionofglucocorticoids,mineralocorticoidsandadrenalandrogens Itactsbyincreasingtheactivityoftheratelimitingagentinsteroidsynthesisandconvertscholesterolto pregnonolone. ACTHalsostimulatesadrenalhypertrophyandhyperplasia. CorticotrpinandACTHareusedasdiagnostictoolstotestadrenocorticotrophandadrenalfunction reserve.ACTHcanbeusedforallthepurposesforwhichglucocorticoidsarerecommended. TheadvantageofACTHisthatitleadstosuppressionofpituitaryovertimewhileglucocorticoidssuppress thepituitaryandadrenalcortexquickly. ACTHgelpreparationsarederivedfrompigpituitaries.BothporcineandsyntheticACTHarewellabsorbed afterintramuscularadministration. However,itsdisadvantageisthatitcannotbeadministeredbyoralrouteunlikeglucocorticoids.

Insulin
Endocrinepancreas TheBetacellsoftheisletsoflangerhanssecretethepeptidehormoneinsulin. Insulinissecretedinresponsetogastrointestinalpeptidehormones,plasmaconcentrationsofglucose, aminoacidsorfattyacidsandotherlocal(glucagons)orsystemic(acetylcholineandbetaagonists)chemical messengersordrugs(sulphonylureas). Diabetesmellitusisaconditionduetolackofinsulinandischaracterizedbysweeturine,polydipisia,wasting oftissues,developmentofketocidosis,hypersomolarcomaanddeath. In1921BantingandBestextractedtheactivecompoundfrompancreasthatcontrolledhyperglycemiain diabeticdogsandhuman. TherearetwotypesofdiabetesinhumanandtheyareIDDMorTYPEI(Insulindependentdiabetesmellitus) andNIDDMorTypeII(NoninsulindependentDiabetesmellitus). InIDDMthereislackofinsulinandinNIDDMthereisresistancetoinsulin.

Pharmacological actions of insulin


Pharmacologicalactions Insulinbindstospecificcellmembranelocatedreceptors. Thisfacilitatestheentryofglucose,aminoacidsandpotassiumionsintomostcells. Thisreversesthehyperglycemiaofdiabetesmellitusbyallowingexcessglucosetobecomeintracellular. Insidethecell,proteinsynthesisisincreasedandglucoseisphosphorylatedbyATPandhexokinaseandis usedtoderiveenergyorforincorporationintoglycogen. Thestorageofcarbohydrateisfurtheraidedbytheinhibitionoftheactionoftheenzymesofglycogenolysis. Proteinsynthesisisaidedbytheimpairmentofgluconeogenesis. Insulinalsofacilitatesfatdepositionandstronglyinhibitslipolysis. Actionsofinsulininclude o Increasedglucoseuptakeintomuscleandfat o Increasedglycogenesis o Decreasedglycogenolysis o Decreasedgluconeogenesis o Stimulationofgrowth(anabolic) o Decreasedlipolysis o Decreasedproteinbreakdown

Preparations of insulin

Insulinwasoriginallyderivedfromthepancreasofeitherpigoftheox. Thestandardpreparationcontains20,40and80unitsofinsulininonemilliliteroftheinjection. Therateofabsorptionofinsulinanditsdurationofactiondependsonthephysicalstate(crystallineor amorphous,proportionofzinc,solutionorsuspension)andtherouteofinjectionofthechosenformulation.

84|U R V I S H M I S T R Y

85|U R V I S H M I S T R Y Thecomplexedsolutionie.Protaminezincinsulinandglobinofzincinsulinareeffectiveforabout48hours and24hours.But,theplaininsuliniseffectiveonlyfor8hoursandlenteinsuliniseffectivefor1820hours duration. Humaninsulin(Humulin)isaDNArecombinantderivedpreparationofinsulin. Thespecializeddeliverydevicesforinsulinincludeinsulinsyringes,pendevices,inhalationdevices,pumps andimplantablepreparations. Uses o Diabetesmellitusindogs o Acetonemiaincattle(Insulinisapowerfulantiketoticagent.Itisparticularlyusefulinketosisthat occurswithinthefirstweekoflactationandisnonresponsivetoglucoseorglucocorticoidstherapy alone) o Pregnancytoxemiainsheep.

Oral hypoglycemic drugs


Sulphonylureas Theseareagentsthatwerefirstintroducedasoralhypoglycemicagents. Therearetwogroupsofsulphonamidesnamelyfirstandsecondgenerationsulphonylureas. Firstgenerationincludestolbutamide,chlorpropamide,acetohexamideandtolazanide. Secondgenerationincludesglibenclamide,glipizideandgliclazide. Inthepancreaticbetacells,sulphonylureasdecreaseATPdependentpotassiumchannelsintheplasma membrane. Thisresultsindepolarizationandreleaseofinsulin. Presenceofatleast30%functionalbetacellsisessentialfortheactionofsulphonylureas. Thisgroupofdrugsisoftenusedincombinationwithmetformin. Theyareboundtoplasmaproteins,metabolisedbytheliverandexcretedbythekidney. Theycancrosstheplacenta(hencenotusedinpregnancy)andaretobetakenbeforeameal. Sideeffectsincludehypoglycemia,GITeffects,rashandincreasedweight. ThereisinteractionwithNSAIDsandsulphonamides(makinghypoglycemiamorelikely). Ifusedwithalcoholtheywillcauseseverehypoglycemia. Biguanides Thisgroupincludesphenforminandmetformin. Theycauselittleornohypoglycemiainnondiabeticsubjectsanddonotstimulatepancreaticbetacells. Presenceofinsulinisessentialfortheiraction. Theysuppresshepaticgluconeogenesisandglucoseoutputfromtheliver,enhancebindingofinsulintoits receptorsandstimulateinsulinmediatedglucosedisposal. Theyincreaseglucoseuptakeintoskeletalmuscleandmaydecreasetheabsorptionofglucose. Thisgroupofdrugshaveashorthalflifeandareexcretedbythekidney. Sideeffectsincludehypoglycemia,nausea,vomitinganddiarrhea. Meglitidineanalogs Repaglinidelowersbloodglucosebystimulatingthereleaseofinsulinfromthepancreas.Itachievesthisby closingATPdependentpotassiumchannelsinthemembraneofthebetacells.Thisdepolarizesthebeta cells,openingthecells'calciumchannels,andtheresultingcalciuminfluxinducesinsulinsecretion.Eg: repaglinide Thiazolidinediones Itworksasaninsulinsensitizer,bybindingtotheproxisomeproliferatoractivatedreceptors(PPARs)infat cellsandmakingthecellsmoreresponsivetoinsulin.Eg:rosglitazone glucosidaseinhibitor Itisastarchblocker,andinhibitsalphaglucosidase,anintestinalenzymethatreleasesglucosefrom largercarbohydrates.Eg:acarbose

Thyroid hormone

Thethyroidglandsecretesthreemainhormones:thyroxine,triiodothyronineandcalcitonin. 85|U R V I S H M I S T R Y

86|U R V I S H M I S T R Y Thyroxineandtriiodothyronineproducedinthethyroidfolliclesarecriticallyimportantforthenormal growthanddevelopmentandfortheenergymetabolism. Calcitoninproducedintheinterfollicularcellsisinvolvedinthecontrolofplasmacalcium. Thestepsinthyroidhormonesynthesis,storageandsecretioninclude: o uptakeofiodinebythefolliclecells o oxidationofiodineandiodinationoftyrosineresiduesofthyroglobulin o secretionofthyroidhormone Thyroidhormoneisessentialforthenormalgrowthanddevelopment. Deficiencyresultsincretinism. Theyhaveamarkedeffectonthelipid,carbohydrateandproteinmetabolism. BothT3andT4areusedtotreatthyroidhormonedeficiency Lthyroxinesodiumisusedfororaladministration. Itsabsorptionisinfluencedbythepresenceoffoodinthestomach,suralfate,ironandcalcium. Enzymeinducerslikephenytoin,rifampin,carbamazepineincreasethemetabolism

Thyroid inhibitors

Theseareusefulinthetreatmentofthyrotoxicosis,hyperthyroidism,Grave'sdisease Inhibithormonesynthesis(Antithyroid)Propylthiouracil,methimazole,carbimazole InhibitiodinetrappingThiocyanates,perchlorates,nitrates Inhibithormonereleaseiodine,iodidesofsodiumandpotassium,organic,iodine DestroythyroidtissueRadioactiveiodine

General principles in corticosteroids therapy


1. Glucocorticoidsareonlypalliativeanddonotprovidecompletecure 2. Individualvariationsoccurbetweenpatientsintheirresponsetoglucocorticoidstherapyandhencedose needstobeindividualized. 3. Initialdosedependsonseverityofthedisease.Startwithahighdoseinsevereillnessandgraduallyreduce asclinicalsignssubsidewhileinmildcasesstartwiththelowestdoseandenhancethedoseasperneed. 4. Prolongedtherapyathighdosesforseveralweeksmaycauseadrenalatrophy. 5. GlucocorticoidsevenatphysiologicaldosagemayresultinsuppressionofHypothalamopituitaryadrenal axis 6. Itshouldpreferablybeadministeredlocallyratherthansystemicallysincelowsystemiclevelminimally interfereswithcorticalativity. 86|U R V I S H M I S T R Y

87|U R V I S H M I S T R Y 7. Glucocorticoidtherapyshouldnotbeterminatedabruptlysinceitmayinducehypoadrenocorticism.Dosage shouldbeterminatedgraduallyoveraperiodof2weeks. 8. Antiinflammatoryandantiallergytherapy o Largeproportionofdrugsareusedinveterinarypracticetocombatinflammationorallergy o Valuableinthetreatmentofchronicdiseaseoccurringperiodicallyandintheabsenceofknown causes o Usedinthetreatmentofchronicarthritis,tendonitis,bursitis,conjunctivitis,dermatitis,pruritic dermatoses,allergicpulmonarydiseaseandallergicgastroenteritis. o Maybeusedforshortperiodsforshortperiodsinanaphylaxis,angioneuroticedema,urticariaand serumsickness. 9. Itshouldbeusedwithcautionincaseofinfectiousdisease,sinceglucocorticoidswillpromotedissemination ofinfectiousorganismthroughoutthebodyresultinginfulminatinginfectiouscondition.Itisindicatedalong withantibioticsthatareeffectiveinthetreatmentofunderlyinginfection. 10. Glucocorticoidreducescollagensynthesisandtherebyreducestherateofwoundhealing.Glucocorticoids areindicatedinthetreatmentoftraumaticwoundofprepuceofbullssoastopreventrapidhealingthat wouldleadtostrictureformation. 11. AsaphysiologicalreplacementitisusedfortreatmentofAddisonsdisease(Chronicadrenalinsufficiency) andacuteadrenalinsufficiencyinhumanbeings. 12. Glucocorticoidsathighdoseinducesparturitionandcanbeusedtoinduceparturitionincows,ewesetc. However,sincetheyhaveteratogeniceffectsduringearlypregnancy,itshouldbeusedwithcautionin pregnantanimals. 13. Therapyofshock:Earlytreatmentofglucocorticoidimproveshemodynamicsandenhancessurvivalin hemorrhagicandsepticshockbutcontraindicatedinchronicsepsisbecauseofitsimmunosuppressive effects 14. Itcanbeusedtotreatdepressivestatesofpetanimalsandeventemperamentaldairycowssinceitinduces euphoria. 15. Itdepressesimmunesystem.ItsuppressesBlymphocytesproliferationandTlymphocytesactivation. Immunemediatedthrombocytopenia,autoimmunehaemolyticanaemia,collagendiseaselikesystemic lupuserythematosus,polyarteritisnodosarespondtoglucocorticoidtherapy.Forthesamereason,itis contraindicatedduringvaccination o Corticoidsareusedinlargenumberofinflammatoryoculardiseasesuchasallergicconjunctivitis, iritis,iridocyclitis,keratitisastopicalinstillation. o Systemictherapyisusefulinthetreatmentofretinitis,opticneuritis,uveitis. o Contraindicatedincornealulcerssincetheyslowtheprocessofreepithelialisationofcornea. 16. Corticosteroidscanbeusedalongwithotherimmunosuppressantstopreventrejectionreactionduring organtransplantationandskinallograft.

Anti-inflammatory and sodium retaining potencies of Glucocorticoids


Corticosteroid Shortacting(halflife12h) Hydrocortisone Cortisone Fludrocortisone Antiinflammatorypotency Sodiumretainingpotency 1 0.8 10 1 0.8 125 0.8 0.8 0.5 87|U R V I S H M I S T R Y

Intermediateacting(halflife1236h) Prednisone Prednisolone Methylprednisolone 4 5 5

88|U R V I S H M I S T R Y Triamcinolone Longacting(Halflife3672h) Paramethasone Betamethasone Dexamethasone Flumethasone 5 10 10 10 10 0 0 0 0 0

Reproductive hormones and Vitamins


Hormones influencing reproductive functions
Gonadotrophinreleasinghormone(GnRH) Effects AdministrationofGnRHreleasesLHandFSHfromtheanteriorpituitarygland.TheeffectsofGnRHon LH/FSHreleasearedependenton o thedoseandrouteofadministration o theendocrinestatusoftheanimalatthetimeoftreatmentand o thefrequencyofinjection GenerallythereleaseofLHandFSHarehigherfollowingGnRHinjectionwhentheanimalisunderthe influenceofestrogenandlowerinprogesteronedominatedanimals. Uses InjectionofasinglelargequantityofGnRHduringthefollicularphaseoftheestrouscyclestimulates ovulation2448hourslater. o Injectionattheendofasynchronizationscheduleinordertocontrolthetimeofovulationfor schedulingtimesofinsemination o Toovercomedelayedovulationindairycows,particularlyinhighyieldingpostpartumcowsbred within60daysofparturition o Injectionofmaresduringtheestroustotimetheovulationandcoveringinordertomaximizethe chancesofconception o Injectionofcowsatthetimeofinseminationtoincreaseconceptionrate GnRHstimulatesLHandFSHinthemaleandmayhaveauseinanimalswithpoorsemenproducingability. SyntheticGnRHlikegonadorelin,buserelinandfertirelinhavebeenproducedwhichstimulatereleaseof bothFSHandLH. BuserelinwasdevelopedbysubstitutingtwoaminoacidsinnaturalGnRH. Thismodificationhelpedinincreasingresistancetoenzymaticdegradationandanincreasedplasma concentrationofFSHandLHwhichpersistedforseveralhourswasnoticedinmaresandcowsattherapeutic concentrations.

Anterior pituitary gonadotropins


BothLHandFSHareglycoproteinhormones. Theyaresecretedfromthegonadotrophcellsoftheanteriorpituitarygland. Theyconsistoftwopolypeptidesubunits. Thegonadotrophichormonescontroltheestrouscycleofthefemaleandmodulatetesticularfunctionsin themale. Inthefemale,FSHisresponsiblemainlyforgrowthofthefolliclebybindingtogranulosacellsand stimulatingestradiolproduction. 88|U R V I S H M I S T R Y

Effects

89|U R V I S H M I S T R Y LHisresponsibleforfinalmaturationandovulationbybindingtothethecalcellsofthedevelopingfollicle andstimulatingthesynthesisofandrogens. Inthemale,LHbindstoleydigcellsorinterstitialcellslocatedintheconnectivetissuestromaofthetestis andstimulateandrogenproduction. Thegonadotrophinsareavailableasapowderwhichcanbeeasilyreconstitutedbytheadditionofsterile water,salineorappropriatebuffer. Onceintheliquidformtheymustbestoredat4degreecentrigradeandnotsubjectedtoexcessiveagitation topreventdenaturationofprotein. Uses TheusesofLHare o toinduceovulationofamaturefollicle o toleutinizefollicularcysts o toinducefolliculargrowthandovulation. TheusesofFSHare: o toincreasethenumberofovashedinthecattleforsuperovulatorypurposeand o toincreasethelittersizebyincreasingtheovulation.

Placental gonadotropins

Themaintenanceofthecorpusleuteumofpregnancyinsomespeciesisfavouredbytheproductionof chorionicgonadotropin(CG)eg.human(hCG)fromday8 inthemaretheendomaterialcupsproduceahormone(eCG)fromday40toaboutday150(previously calledpregnantmareserumgonadotropin(PMSG)). hCGcontainsmoreofLHthanFSH,whileeCGcontainsmoreofFSHthanLH. hCGismainlyleutienising.Infemaleanimalsthisinducesovulationandreinforcesthesecretionof progesteronebytheovary. hCGwillbindtoLHreceptorsonthegranulos,thecaandlutealcellswithhighaffinityandspecificity. eCGhasLHlikeactivityonlyinthemare,butintheotherspeciesithasmainlyFSHlikeactivity. Inthemareitonlyleutinizefolliclesalreadypresentintheovarybut,intheotherspeciesitstimulates folliculargrowthandovulation. Serumgonadotrophinhasbeenusedtoincreasethenumberofdevelopingfollicleandovulationandoestrus andthusincreasetheincidenceoftwinsincattle. Itisusedtocontrolthetimeofovulationinmaresbecauseintheseanimalsovulationnormallyoccurs towardstheendofalongestralperiod. Itiswidelyusedinthetreatmentofcysticovariandiseaseespeciallywherenymphomaniaispresentand sometimesinthetreatmentofcyrptorchidism. Inmaleanimalschorionicgonadotropinisusedtostimulatethesecretionoftestosteronebythetestes.

Effects

Uses

Estrogens

Thereareanumberofsourcesofestrogensproducedinthebody Theyareproducedfromthegranulosecellsofthefollicle,thecorpusluteumofprimates,theplacentathe adrenalsandthetestes. Oestrogensinfluencethefemalesexcharacteristicssuchasanincreaseinthegrowth,proteinsynthesisand fluidsecretionsofoviduct,uterus,cervixandvagina. Theyalsoaffectmammarydevelopment. Theyinducetheexpressionofbehaviouralestrusinthefemaleandlibidointhemale. Oestrogensalsohavemanyeffectsongeneralbodymetabolismincludingfatdistributionandcontentwithin thebody,mineralmetabolism,bonegrowthandproteinsynthesisinmaytissuesincludingthemuscle. Theyinfluencegonadotrophinsecretionandatlowconcentrationshaveanegativefeedbackeffectonthe hypothalamus,whileathighdoses,intheabsenceofprogesteronetheyhaveapositivefeedbackeffectin femalesresultinginthepreovulatorysurgeingonadotrophinoutput. 89|U R V I S H M I S T R Y

90|U R V I S H M I S T R Y Thetestesofboththeboarandthestallionproduceoestrogensinhighquantitiesandpregnantmares produceawiderangeofestrogenslikeequilin,hippulinandequilenin. Equinemaleurineandtestescontainenormousquantitiesofestrogens. Thenaturalestrogensinclude17betaestradiol,estroneandestriol. Theyhaveloworalactivity. Syntheticsteroidalestrogensincludesimpleesterssuchasestradiolbenzoateorvalerate. Themostcommonnonsteroidalestrogens,whichhaveahighaffinityfortheestradiolreceptor,arethe stilbenes. Theyareorallyactive,highlypotentandarenoteasilymetabolized. Somearegenotoxiccarcinogensandhencetheiruseisprohibited. Clinicaluses Misallianceinthebitch Inductionofoestrusandovulationinanoestrusanimals Controlofthetimeofovulation Controloflifespanofthecorpusluteum Treatmentofpyometraandmummifiedfoetus Obesityduetohypogonadisminbitches Urinaryincontinenceinoldandspayedbitches Analoedemaindogs Regressionofhypertrophiedprostrateglands Caponizationofyoungandoldcockerels Sideeffects Thisincludesgastrointestinalupsets,feminizationinmale,sodiumretentionandoedema. Inchronicoverdosagegenitalerythema,irritation,polydipsiaandpolyuriaarenoticed.

Progesterone

Themainfunctionofprogesteroneistoestablishandmaintainpreganacy,bypreparingtheuterine endometriumforimplantationandbypreventingmyometrialuterinecontractionsduringpregnancy. ItalsoactsasanegativefeedbackhormoneduringtheovariancyclesuppressingLHandFSHsecretion, oestrusandovulation. Insomespecies,itprimesbehaviouralcentresinthebrainandsoallowsestradioltoinducebehavioural estrus. Itisproducedmainlyfromthecorpusluetumandtheplacentaandtoalesserextentfromtheadrenalgland. Inthepregnantanimal,thecorpusleuteumismaintainedforthedurationofpregnancy,exceptinthemare. Insomespeciessuchasthesowandthegoat,thelutealprogesteroneisrequiredthroughoutpregnancy:in otherspeciessuchasthemareandtheewe,theplacentalprogesteroneistheprimarysourceafterday100 inthemareandday55intheewe.

Uses Controlofovulation Inductionofovulation Reduceembryonicloss. Syntheticprogesterones Medroxyprogesterone(MAP)usedtocontrolestrusandovulationinthecyclicewesandtoinduceestrus inanoestrousewes.Itcanbeusedinbitchestosuppresstheonsetofnextestrus. Flurogesteroneacetate(FGA)usedtocontrolorinduceestrousinewes. Melengesterolacetate(MGA)usedtosuppressestrusinheifers Norgestometusedtocontrolorinduceovulation Proligestoneusedtocontrolestrousinbitches.

Androgens

Androgensaresubstanceswhichstimulatethemaleaccessoryorgansandproducethesecondarysex characteristics. Themajorandrogensofimportancearetestosterone,dihydrotestosteroneandandrostenedione. 90|U R V I S H M I S T R Y

91|U R V I S H M I S T R Y Testosteroneisconvertedto: o dihydrotestosteronewhichhasbiologicalactivitywithintestesand o toestradiolwithinthebraintoinducemalelibido. Androgensareproducedintheleydigcellsofthetestesandtestosteroneisalsoproducedintheepididymis ofthestallion. Inthemaleandrogensstimulatespermatogenesis,growth,anddevelopmentandfluidsecretionsofthe testes,secondarymalecharacteristicsandmuscledevelopment. Inthefemale,theyarethemainprecursorsofestrogensynthesiswithinthefollicle. TheyalsoactaspartofthenegativefeedbacksystemtocontrolLHandFSHsecretion. Inanimals,thereareonlylimitedusesofandrogenstocontrolreproduction. Testosteronehasanaboliceffectsleadingtoincreasedproteinsynthesis,retentionofpotassiumand phosphorus,increasedbonegrowth,cartilageandothertissuesandincreasederythropoiesisbysecreting erythropoietin. Theyareusedtotreatinfertilityandimpotencywithvaryingsuccess. Androgensarealsoadministeredtocowsandheiferstousethemasdetectorsofoestrus.

Anabolic steroids

Compoundsstructurallyrelatedtotestosteronebutpossessingproteinanabolicactivitywithminimal androgenicactivityarecalledanabolicsteroids. Thesedrugsareusedmainlyintherapeuticallydebilitatedanimals. Themetabolicactivitiesinclude o Proteinanabolismwithpositivenitrogenbalance o Increasedmusclemassduetoincreasedproteinandglycogencontent o Highretentionofcalciumandphosphorus. Drugsusedarenandroloneandstanozalol. Antiandrogenslikedelmadinoneacetateareusedtocontrolhypersexualityindogsandcats,relieve prostatehypertrophy,tumoursandbehavioralproblemsindogsandcats.

Posterior pituitary hormones


Therearetwoknownposteriorpituitaryhormones: o Vasopressin(ADH)andoxytocin. o Posteriorpituitaryhormonesaresynthesizedinthehypothalamusandtransportedtotheposterior pituitary,wheretheyarereleasedintocirculation. Antidiuretichormone(Vasopresssin) Thishormoneregulateswaterpermeabilityinthedistaltubulesandcollectingductofthenephron. Itisalsoavasoconstrictorandinfluencescardiovascularfunctions. Itisusedinthetreatmentofdiabetesinsipidusandprophylacticallyagainstbleedinginhaemophilia. Oxytocin Oxytocinisproducedinneuronalbodiesinthesupraopticandparaventricularnucleiofthehypothalamus. OytocinstimulatessmoothmusclecontractionsandalsoincludesPGF2alphareleasewhichcausesluteolysis. Uses Speedingtheexpulsionoffoetuswhenuterineinertiaisdiagnosed Aidsintheexpulsionofplacentaldebrisandpromotesinvolutionoftheuterus Inuterineprolapseinjectionofoxytocinatseveralplacesintheorganreducestheengorgementand contractstheeverteduterus.Thushelpsinthereplacementmoreeasily Functionalagalactiaincows Inmastitisincattletoexpeltheinfectedmilkbeforeusinganyantibacterialagents.

Pharmacotherapeutics of fat soluble vitamins


Vitaminsareessentialnutrientspresentinminutequantitiesinfoods.Ifthereisadeficiencyinsupplyof vitamins,deficiencydiseasesoccur.Insuchascenario,supplementationofvitaminsisindicated. Fatsolublevitamins 91|U R V I S H M I S T R Y

92|U R V I S H M I S T R Y Vitamin Deficiencysigns A Keratinizationofepithelium,night blindness,fetalresorption,lowegg prduction,poorhatchability Treatment Farmanimals:100200units /kg/day Poultry:0.070.22gm/kgfeed

Ricketsinyoungandosteomalaciainadults Farmanimals:50100IU/kg/ day Dog:200400IU/kg/day Chicks150300IU/kg/day Musculardystrophyinyoungandwhite musclediseaseorstifflambdiseasein cattle Allyoungstock40mg/kg/day PO; 25mg/kg/dayScorIM OralSwine500mg;Dog30mg /kgandpoultry350mg/bird/ day

Delayedclotting,spontanoushaemorrhage Menadione/Menaphthone Forwarfarinpisoning5mg/kg IM ForSweetcloverpoisoning1.2 mg/kgIM Fordeficiency:Smallanimals2 10mg/dayPO LargeAnimals:100400mg/ dayPO Poultry12gm/tonoffeed

Pharmacotherapeutics of water soluble vitamins


Vitamin B1Thiamine Deficiencysign Brackenfernpoisoning Nervoussigns Treatment Calf550mg Sheep20200mg Cat120mg Dog550mg Horse/Ox100 1000mg POorIMorSC Pig5mg/day Horse40mg/day infeed

B2Riboflavin

Curledtoeparalysisinchicken,anaemia, dermatitis,csoursincalves,lowfertility, eyedischarge,photophobiainhorse

B3pyridoxine

Acrodynia(dermatitis,hyperkeratinization) Sameasthiamine indogs,degenerationofspinaland peripheralnerves Pellagra,Blacktongueindog,roughskin, Oralulcers,diarrhoea,dermatitis Dog510mg/ kgIM Cat1030mg/kg IM Calf25mg/daySC Pig0.10.3gmSC 92|U R V I S H M I S T R Y

Nicotinicacid

93|U R V I S H M I S T R Y or0.20.9gm orally B12 Hydroxycobalamin Biotin Choline Bushsickness,hindlimbweakness, incoordination,hairorwoolloss,stunted growth,anaemia Fattyliveriffedentirelyonwheatration EggwhitecontainsantibiotinfactorAvidin Perosis(slippedtendon)inpoultry Ataxiaindogs,catsandpigs DogandCat24 g/kg/dayIM 100g/chick/day PO Dog550mg/day PO CAt2550mg/kg dayPOorSC Alsoinmilkfeveror ketosisincattleand buffaloes Horse24gmSC Bull12gmSc Cow12gmIVorSC beforemating Dog2575mg/ dayPOorSC

Ascorbicacid (VitaminC)

Nodefinitesigns

Drugs acting on skin and mucous membranes


Counterirritants

Theseareagentsthatarethoughttoactbyproducinganirritantactionontheskinwhichenablesincreased bloodflowtotheappliedarea.Whenanirritantsubstanceproducespainfulstimulusontheskin,itisableto maskthepainfromdeepertissues. Theyalsobringaboutanantiinflammatoryresponseduetoenhancedbloodsupplyandishelpfulintreating localisedconditionssuchastrauma,swelling,painetc. Counterirritantsareverycommonlyemployedinreducingpainandinflammationintraumaticand musculoskeletalconditions. Dependingontheintensityofirritationproduced,counterirritantsareclassifiedasfollows. Rubefacient:Agentsthatproduceamildincreaseinbloodflowatthesiteofapplication. Eg:Iodineointment Vesicant:Agentsthatproduceastifferirritationtoformvesicantsunderneaththeskinwhicharefilledwith serousfluid.Eg:Cantharidine Pustulant:Agentsthatproduceamuchstrongerirritationwhichreachestheunderlyingstructuresandform pustuleswhicharefilledwithpus.Eg.Crotonoil Caustic:Agentsthatproduceveryintenseformofirritationsothattheycorrodetheskinandunderlying structures.Eg:Causticsoda,causticpotash

Penetration enhancers

Chemicalpenetrationenhancersactbyimprovingpenetrationbyreversiblydamagingstratumcorneumor byalteringthestratumcorneumtoreducetheresistancetodiffusion. o Azone&derivates o Ureaandderivatives1dodecylurea,1,3decylurea,propyleneglycol o Terpenecarrone,pulegone,menthone o AproticsolventsDMSO,2pyrrolidone o Surfactantssuchaspolyethyleneglycol 93|U R V I S H M I S T R Y

94|U R V I S H M I S T R Y Suitableuseofpenetrationenhancerswouldhelpincreasethebioavailabilityofagentsgivenintradermally.

Adsorbants

Adsorbantsaresubstanceswhichcanbindnoxiousandirritantsubstances.Whenappliedontheskin,they lessentheirritationandaffordprotectiontotheskin. Example: o Dustingpowder o Starch,Zincoxide,CaCO3 o Boricacidandtalc o Collodion o Dimethicone

Demulcents
(demulcereTosmooth) Theseareinertagentsthatsoothendamagesmucosabypreventingcontactwithairorotherirritants. Highmolecularweightwatersolublecompounds o AlleviatingirritationwithinherentpropertiestoreduceirritationE.g.Glycerin,gelatin,hydroxyl propylcellulose,methylcellulose Glycerin o Lowconcentrationhydratesskin.Howeverinhighconcentration,itdehydratesskin Propyleneglycol o Hygroscopic,bacteriostatic,fungistatic Gumacacia o Colloidalplantcarbohydratesthatswellinwater,formingmucilaginoussolutions.

Emollients

Emollientsareblandoilymaterialsthatsoftenskin Decreasetransepidermalwaterlossandthushelpfulindryskinandcrackedskin Examples o Vegetableoils:Almondoil,Cottonseedoil,Oliveoil,Peanutoil,Cocobutter o Animaloils:Lard,Lanolin,Spermaceti(fromspermwhale) o Petroleumproducts:Liquidparaffin,paraffin

Astringents

Emollientsareblandoilymaterialsthatsoftenskin Decreasetransepidermalwaterlossandthushelpfulindryskinandcrackedskin Examples o Vegetableoils:Almondoil,Cottonseedoil,Oliveoil,Peanutoil,Cocobutter o Animaloils:Lard,Lanolin,Spermaceti(fromspermwhale) o Petroleumproducts:Liquidparaffin,paraffin

Other agents used on skins


Besidestheaboveanumberofotheragentsareusedontheskin.Thesedrugswillbediscussedunderappropriate headings. Keratolytics Theseagentscausetheouterlayeroftheskintoloosenandshed.Theycansoftenkeratinandusedinteh treatmentofdandruffandseborrheicdermatitisEg.Zincpyrithione,sulfurandsalicylicacid Antibacterial Antifungals Corticosteroids Vasodilators Fibrinolytic Antiinflammatoryagents 94|U R V I S H M I S T R Y

95|U R V I S H M I S T R Y Vehicles

Bioenhancers, immunostimulants and immunosuppressors


Bioenhancers
Bioenhancersareagentsthatatlowdosespromoteandaugmentthebioavailabilityorbiologicalactivityof drugs. Herbalbioenhancersareagentsofherbaloriginoranyphytomolecule,whichiscapableofenhancing bioavailabilityand/orbioefficacyofaspecifieddrugornutrientatthelowdosebutitdonotshowtypical pharmacologicalactivity. Theconceptofbioenhancers(herbalorigin)canbetrackedbacktoAyurvedasystemofmedicine.'Trikatu' meaningthreeacidsisanAyurvedicpreparationcontainingblackpepper,longpepperandginger,whichare prescribedroutinelyforavarietyofdiseasesaspartofamultidrugprescription. Herbalbioenhancershavepropertieslikenontoxictohumansandanimals,effectiveatlowconcentrations, easytoformulateandenhanceabsorptionandbioactivityofthedrugornutrient.Herbalbioenhancersare suggestedtoactthroughseveralmechanismsofaction.Variousmechanismsofactionpostulatedforherbal bioenhancersinclude o increaseingastrointestinalbloodsupplyandreductioninhydrochloricacidsecretion, o inhibitionofgastricemptyingtime,gastrointestinaltransitandintestinalmotility, o modificationsinGITepithelialcellmembranepermeability, o cholagogouseffect, o thermogenicandbioenergeticsproperties, o Inhibitionofdrugmetabolizingenzymesandsuppressionoffirstpassmetabolismandstimulationof gammaglutamyltranspeptidase(GGT)activitywhichenhancesuptakeofaminoacids. ImportantIndianHerbalBioenhancers Longpepper(Piperlongum), Blackpepper(Pipernigrum), Ginger(Zingiberofficinale), Liquorice(Glycyrrhizaglabra), Blackcumin(Cuminumcyminum), Cumin/Caraway(Carumcarvi), Garlic(Alliumsativum)and IndianAloe(Aloevera) Thedevelopmentofplantbasedbioenhancersistobetargetedfordrugsthatarepoorlybioavailable,givenfor longerperiodoftime,highlytoxicandexpensive.Further,researchshouldbecarriedouttoevaluateclinical applicationofherbalbioenhancersinmodernhumanandveterinarytherapeutics.

Immunostimulants

Theseareagentsthathavebeenusedtoenhanceanimmuneresponseandarehelpfulasadjunctagentsfor therapy. Mostcommonuseindogsisforthetreamentofchronicrecurrentstaphylococcalpyoderma. StaphagelysateisapreparationofS.aureusandstaphylococcalbacteriophage.ItisbelievedtostimulateT lymphocytesandactivatephagocyticcells. Staphylococcalbacterintoxoidhasbeenusedwithsomesuccessincaninebacterialhypersensitivity. Oneofthemostcommonlyusedimmunomodulatorinveterinarypracticeistheanthelminticlevamisole, whichisadvocatedatonethirdtheanthelminticdoseforimmunomodulatoryactivityforgeneralised immunityenhancementasisrequiredpostvaccination.

Immunosuppressant

Theseareagentsknowntosuppresstheimmuneresponseonadministration.Inhumanbeingstheyarevery commonlyusedintransplantstopreventgraftrejectionandinthetreatmentofautoimmunediseases.In veterinarypracticetoo,theyareveryuseful. 95|U R V I S H M I S T R Y

96|U R V I S H M I S T R Y Glucocorticoidsarethemostcommonlyusedimmunosuppressiveagents.Itisusedforimmunemediated skindisorders. Cyclophosphamide,analkylatingagent,isusedincombinationwithglucocorticoidsforseverecasesof autoimmnunediseasessuchassystemiclupuserythematosus,pempighus,rheumatoidarthritis.Theside effectsincludehaemorrhagiccystitis,fibrosisofthebladder,bonemarrowsuppressionetc. Chlorambucilissloweractingandlesstoxic.Itisadministeredalternatelywithglucocorticoids. Azathioprineismorecommonlyusedforpemphigus. Cyclosporinewhichismostcommonlyusedinmanforgraftrejection,mayalsobeusedinanimalsto preventpempighus,lupusetc.Itispotentiallynephrotoxic,hepatotoxic,toxictoalimentarytract,andbone marrowsuppression.ItblockstheproliferationofactivatedTlymphocytes,byinhibitinginterleukin2,gene activationandRNAtranscription.ItcanbeusedforKeratoconjunctivitissiccaindogs. Dapsoneusedasanantibacterialfortreatingleprosyinman,hasbeenfoundtoinhibtchemotaxis, degranulationofmastcellsandinhibitIgG,IgA,prostaglandinsandalsoTcellresponses.Itisalsousedfor caninepemphigusandlupuserythematosusandallowsfordecreaseinthedoseofglucocorticoids.

96|U R V I S H M I S T R Y