Académique Documents
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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
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
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.
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.
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
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
Anumberofdrugssynthesizedinthelaboratoryareusedmostcommonly. Evennaturalproductssuchashormones,antimicrobialsetc.arealsosynthesizedinthelaboratory.
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.
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.
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
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.
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)
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
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.
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
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
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.
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.
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
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.
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.
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.
Somedrugsthatbind Toalbumin NSAIDs Barbiturates Phenytoin Penicillins Tetracyclines Toalpha1 acidglycoprotein Verapamil Lidocaine Bupivacaine Quinidine Prazosin
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.
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25|U R V I S H M I S T R Y
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
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
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
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
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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
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.
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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.
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
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
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
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
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)
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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.
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
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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
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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
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.
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
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).
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
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.
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
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.
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
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.
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.
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
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
Cardiovascular pharmacology
Classes of drugs acting on heart
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
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
Pharamacokinetics
Absorptiondiffersamongthedigoxinpreparations. Prepareddigitaliscauseslocalirritationandvomitinginpiganddogandforthesespeciesdigitalisglycoside shouldbegiven. Inruminants,oraladministrationofglycosidesleadstodestructionofthedrugandhenceitispreferableto givethedrugparenterally. Plasmaproteinbindingishighwithdigitoxin. Excretionofthedrugisbythekidneys. Enterohepaticrecyclingincreasesthedurationofactionofthedrug. Theuseofthesedrugsindogsandcatsisnotuncommon. However,theabsorptionofdigoxinfromthegastrointestinaltractthoughadequatemaydiffersomewhat amonganimalsandcanbeinfluencedbyfeedingtimes.
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.
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).
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60|U R V I S H M I S T R Y
Drug interactions
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
Classification
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)
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
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.
64|U R V I S H M I S T R Y Dose:Dogs0.05mg/kgi.vslowly,repeatevery5minutesoral0.52mg/kg.q.8h
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
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
Clinical uses
Clinicalusesofvasodilatorsinclude Hypertension, Cardiacfailureand Shock
Vasoconstrictors
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
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
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70|U R V I S H M I S T R Y Ethamsylate
Anticoagulants
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.
Coumarin derivatives
Heparin antagonist
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
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.
Antitussives
Coughsedativesorantitussivescausedepressionofthecoughcentreandreducetheincidenceofcoughing. Theyshouldnotbeusedwhenrespiratorysecretionsarecopiousunlesscoughingisexcessiveandcausing exhaustion(thisstateisuncommoninanimals). Antitussives,whichdiminishthefrequencyofcoughing,areofbenefitwhencoughingispainful,non productive,distressing,exhaustingandlikelytoexacerbateorevencauselungdamage. Theyactbyinterferingwiththecoughreflex,eitheratthelevelofthesensoryendingsintheupper respiratorytract,oratthelevelofcentralnervoussystem. Astrongantitussiveshouldnotbeusedwithanexpectorantbecauseincreasedfluidneedstoberemovedby coughingbuttheantitussivewillreducecoughing. Althoughsomeantitussivessuchasdextromethorphanareusedwithexpectorants,thecoughsuppression producedisnotsufficienttohinderremovalofexcesssecretions.
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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
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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.
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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
Antihistaminics
Respiratory stimulants
Respiratorystimulantsareagentsusedtoimproverespiration.
Diuretics
Diureticsareagentsthatincreasethesaltandwaterexcretionbyanactiononthekidneys. Diureticseffectiveforthetreatmentofedemahavebeenavailablesincethe16thcenturyandmercurous chloridewasknownbyParacelsustobediuretic. In1930,Swartzdiscoveredthattheantimicrobialsulfanilamidecouldbeusedtotreatedemainpatients withcongestiveheartfailureduetoanincreaseinrenalexcretionofNa+. Mostmoderndiureticsweredevelopedwhensideeffectsofantibacterialdrugswerenoted,whichincluded changesinurinecompositionandoutput. Exceptforspironolactone,diureticsweredevelopedempirically,withoutknowledgeofspecifictransport pathwaysinthenephron. Theyareusedmainlyincasesofcardiacfailure,oedemaandhypertension.
Physiological diuresis
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.
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
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
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
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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
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
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
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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
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.
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.
Preparations of insulin
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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.
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
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.
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
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.
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
B2Riboflavin
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
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
94|U R V I S H M I S T R Y Suitableuseofpenetrationenhancerswouldhelpincreasethebioavailabilityofagentsgivenintradermally.
Adsorbants
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
Astringents
95|U R V I S H M I S T R Y Vehicles
Immunostimulants
Immunosuppressant
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