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the study of the biochemical and physiological effects of drugs and the mechanisms of their actions, including the correlation of action and effects of drugs with their chemical structure; also, the relationship between drug concentration and effect.

What the drug does when it gets there. there.

Receptor Theory
The existence of receptors was first inferred from observations of the chemical and physiological specificity of drug effects. Now receptors have been isolated biochemically and genes encoding receptor proteins have been cloned and sequenced. Receptors determine the quantitative relationship between drug dose and pharmacologic effect. Receptors are responsible for the selectivity of drug action. Receptors mediate antagonists. the actions of pharmacologic agonists and

The term receptor has been used operationally to denote any cellular macromolecule to which a drug binds to initiate its effects. Among the most important drug receptors are cellular proteins, whose normal function is to act as receptors for endogenous regulatory ligands particularly hormones, growth factors, and neurotransmitters. The function of such physiological receptors consists of binding the appropriate endogenous ligand and, in response, propagating its regulatory signal in the target cell.

Types of receptors

Intracellular receptor

Transmembrane receptor with own enzyme activity

Ion channels

Sajt enzimaktivitssal rendelkez transzmembrn receptor: jelfog fehrjt aktivl receptor, mely lncreakcit indt el

G-protein coupled receptors

Drug-receptor interactions

Lock and key mechanism



Agonist-Receptor Interaction

Drug-receptor interactions

Induced Fit


Perfect Fit!

Relation between Drug concentration and response


the maximum response of the system to the drug EC50: that concentration of drug that produces a response one-half of the maximum response

Potency and efficacy

Emax(A) = Emax(B) > Emax(C) Pot(A) > Pot(B) or Pot(C) Pot(B) > Pot(C) Pot(B) < Pot(C)

Efficacy is the maximum effect (Emax) of a drug. Potency, a comparative measure, refers to the different doses of two drugs needed to produce the same effect.

Drug-receptor interactions

Competitive Inhibition




Antagonist-Receptor Complex

Drug-receptor interactions

Non-competitive Inhibition






Competitive and Irreversible Antagonists

Receptor antagonists bind to the receptor but do not activate it. In general the effects of these antagonists result from preventing agonists from binding to and activating receptors. Antagonists can be competitive (reversibly displaced by agonists) or noncompetitive (not reversibly displaced by agonists).

Non-competitive antagonism
Some antagonists may form covalent bonds with the receptor at the agonist binding site and, therefore, form an irreversible complex with the receptor.

Other receptor antagonists bind to the receptor at sites unrelated to the agonist binding site. Binding of this antagonist is not reversible or surmountable by increasing [agonist]. Some allosteric effects could potentiate the effects of agonists.

Partial and Full Agonists

Agonists may differ in how tightly they bind to their receptors (potency) and in the effect they produce (efficacy). Some drugs may bind very tightly (are highly potent) but produce only a modest effect (low efficacy). Low efficacy drugs are termed partial agonists while the structurally related drugs which produce a full effect are called full agonists.

Partial agonists are competitive antagonist in the same time

Because the response to B is less than that to A, saturating B reduces the overall response of the system

Partial agonism
The molecular basis is unknown. 1) The partial agonist may fit the receptor binding site well but is less able to promote the receptor conformational change leading to transduction. 2) The receptor may isomerize between 2 states: A (active) and I (inactive)

If the A form has high affinity for the agonist (L), the equilibrium will be shifted in favor of AL and full activation might be achieved. If I and A forms of the receptor share similar affinities for L, both AL and IL will be formed but only AL will produce an effect and the agonists will appear partial.

General Classes of Antagonists

Chemical Antagonists: One drug may antagonize the action of a second by binding to and inactivating the second drug. e.g. protamine (a positively charged protein at physiologic pH) binds (sequesters) heparin (a negatively charged anticoagulant) making it unavailable for interactions with proteins involved in the formation of blood clots. Physiological Antagonists: Physicians often prescribe drugs that take advantage of physiologic antagonism between endogenous regulatory pathways. Thus the catabolic actions of glucocorticoids lead to increased blood sugar - an effect opposed by insulin. While glucocorticoids and insulin act on quite different pathways, insulin is sometimes administered to oppose the hyperglycemic action of glucocorticoid hormone - whether resulting from increased endogenous synthesis (e.g. a tumor of the adrenal cortex) or as a result of glucocorticoid therapy. Pharmacological Antagonists: Drugs that bind to receptors but do not act like agonists and, therefore, do not alter receptor function. These antagonists may block the ability of agonists to bind to the receptor by competing for the same receptor site or may bind to another site on the receptor that blocks the action of the agonist. In both cases, the biological actions of the agonist are prevented.

Non-receptor mediated Mechanisms

I. Enzymes: Drugs altering enzyme activity alter processes catalyzed by the enzymes. Examples: Cholinesterase inhibitor, MAO inhibitors, enzyme inducers II. Agents act according to nonpharmacological colligative properties: Mannitol: Changes osmotic balance across membranes and causes urine production (osmotic diuresis). Cholestyramine resin: decreases the amount of cholesterol absorbed from the diet. III. Ion channels: Lidocaine: Blocks sodium channels Verapamil: Block calcium channels Bretylium: Blocks potassium channels Adenosine: Opens potassium channels


Non-receptor mediated Mechanisms

IV. Specific interaction with small molecules or ions: antacids, mesna, heavy metal chelators V. Antimetabolites: Enter biochemical reactions in place of normal substrate competitors Result in biologically inactive product Examples Some anti-neoplastics Some anti-infectives

Drug Response Relationships

Time Response


Dose Response Relationships

- Potency Absolute amount of drug required to produce an effect. More potent drug is the one that requires lower dose to cause same effect - Threshold (minimal) dose Least amount needed to produce desired effects - Emax Greatest response produced regardless of dose used Loading dose: Bolus of drug given initially to rapidly reach therapeutic levels Maintenance dose: Lower dose of drug given continuously or at regular intervals to maintain therapeutic levels

Therapeutic Index

LD50 TI = ED50

Drugs safety margin Must be >1 for drug to be usable Digitalis has a TI of 2 Penicillin has TI of >100

Why dont we use a drug with a TI < 1?

ED50 LD50 = Very Bad!


Factors Altering Drug Responses

Age Pediatric or geriatric Immature or decreased hepatic, renal function Weight Big patients spread drug over larger volume Gender Difference in sizes Difference in fat/water Environment - Heat or cold - Presence or real or perceived threats Fever Shock

Factors Altering Drug Responses

Pathology Drug may aggravate underlying pathology Hepatic disease may slow drug metabolism Renal disease may slow drug elimination Acid/base abnormalities may change drug absorption or elimination


Influencing factors
Genetic effects
Lack of specific enzymes Lower metabolic rate

Psychological factors
Placebo effect

Pediatric Patients
Higher proportion of water Lower plasma protein levels
More available drug

Immature liver/kidneys
Liver often metabolizes more slowly Kidneys may excrete more slowly


Geriatric Patients
Chronic disease states Decreased plasma protein binding Slower metabolism Slower excretion Dietary deficiencies Use of multiple medications Lack of compliance







(L) A D M E R


The Fate of a Drug










Movement from administration site into circulation
Factors Affecting Absorption: Absorption: Formulation factors Tablet disintegration Inert ingredient / solvent effects Solubility Drug pH Concentration Patient factors Absorbing surface Blood flow Environmental pH Disease states Interactions with food, other drugs


Transport of drugs

Membranes and Absorption

Hydrophilic Heads

Lipid Bilayer
Hydrophobic Tails

Small, uncharged

H2O, urea, CO2, O2, N2 Glucose Sucrose H+, Na+, K+, Ca2+, Cl-, HCO3-


Large, uncharged Small charged ions




Transportation of drugs through membranes

- Passive diffusion - Facilitated diffusion - Active transport - Endocytosis - Filtration

passive transportation of drugs

diffusion filtration

- Lipid: aqueous drug partition coefficients described the ease with which a drug moves between aqueous and lipid environments - Ionization state of the drug is an important factor: charged drugs diffuse-through lipid environments with difficulty. - pH and the drug pKa, important in determining the ionization state, will influence significantly transport - ratios of lipid-to-aqueous-soluble forms for weak acids and bases described by the Henderson-Hasselbalch equation:

pKd = pH + lg HA A-

+ pKd = pH + lgBH B

uncharged form: lipid-soluble charged form: aqueous-soluble, relatively lipid-insoluble (does not pass biological membranes easily)


Acids HA Bases H+ + B

Release/Donate H+ H+ + ABind/Accept H+ HB+



pKa = 6

pKa = 7


For example: ASPIRIN

Ionized form


Non-ionized form

Conclusion: Acidic drugs are best absorbed from acidic environments Basic drugs are best absorbed from basic environments Ion-trapping! Placenta, stomach, milk, kidney

Sav Ers Ampicillin Szalicilsav Acetilszalicilsav Fenilbutazon Szulfadiazin Hidralazin Fenobarbitl Fenitoin Brsav Aszkorbinsav

pK 2,5 3,0 3,5 4,5 6,5 7,1 7,4 8,3 9,2 11,5

Bzis Terbutalin Atropin Efedrin Kinin Lidokain Kodein Rezerpin Papaverin Diazepam Koffein

pK 10,1 9,7 9,6 8,4 7,9 7,9 6,6 6,4 3,2 0,8 Morfin 99,999 99,99 99,9 99 90 50


Nagyon gyenge pH 3 4 5 6 7 8

Szalicilsav Dikumarol Aminofenazon 50 90 99 99,9 99,99 99,999 0,1 1 10 50 90 99 99 90 50 10 1 0,1


Special Carriers: Peptides, amino acids, glucose are examples of molecules then enter cells through special carrier mechanisms. Active transport describes an energy requiring process which is saturable, meaning that transport is probably against the concentration gradient and involves a finite number of carriers, hence the process must be saturable when all carrier sites are filled. Facilitated diffusion, while not requiring "energy" is also saturable (limited number of carrier sites) Saturable (unlike passive diffusion) because of limited number of carrier sites--once those sites are filled, transport rates cannot be increased. A property of carrier systems is that process is subject to inhibition by other small molecules.

Endocytosis and exocytosis: Entry into cells by very large substances (e.g., iron vitamin B12 -- each complexed with its binding protein -- movement across intestinal wall into the blood) Neurotransmitter system examples for exocytosis: Following neuronal electrical activation of nerve endings, two steps may be initiated: - Storage vesicles containing neurotransmitter fuse with cell membranes followed by - release or diffusion of contents into the extracellular region.


Types of endocytosis



receptor dependent phagocytosis

Routes of administration

Oral cavity(?) stomach small intestine large intestine rectum

sublinqual nose lungs skin eyes injections: i.v.; i. m. s.c.; i.c. i.a.; i.p. i.card.


Per os - oral cavity (?) - stomach: pH = 1 2 - small intestine: pH = 5-6 1. duodenum: short for the absorption, ~15-20 cm 2. jejunum: 1.1 m long 3. ileum: 1.5 m long -large intestine: important in diarrhoea, - rectum: Absorption into superior hemorrhoidal veins then enters the portal venous system then to the liver (possible first pass effect) and finally into the systemic circulation. Low rectal administration of drug may allow the drug to enter the systemic circulation without passing through the liver. Generally unpredictable pharmacological responses for the above reasons. Rectal mucosal irritation possible.

Oral Administration: Most convenient, most economical Disadvantages: emesis (drug irritation of the gastrointestinal mucosa) digestive enzymes/gastric acidity destroys the drug unreliable or inconsistent absorption due to food or other drug effects metabolism of the drug by gastrointestinal flora Factors determining rate of drug effect onset: Primary factor: Rate & absorption extent by GI tract Absorption Site: mainly small intestine because of large surface area Drug ionization state: nonionized (lipid-soluble) forms favor absorption weak acids may be highly ionized in the alkaline intestinal pH (not favoring absorption) but this effect is counterbalanced by the large surface-area effect drugs which are weak acids are readily absorbed in the stomach


First-Pass Effect Drugs absorbed from the GI tract passes through the portal venous system then through the liver and finally into the systemic circulation when drugs interact with receptors in target tissues.

Extensive hepatic metabolism/extraction result in minimal drug delivery to the systemic circulation for certain agents. Drugs with large first pass effect exhibit significant differences in pharmacological effects comparing oral vs. IV administration

Parenteral Administration Ensures active drug absorption subcutaneously intramuscular injection: more rapid/predictable than oral administration route only route of administration acceptable for: uncooperative patients unconscious patients Factors the determine rate of systemic absorption: absorbing capillary membrane surface area drug solubility in interstitial fluid aqueous channels (vascular endothelium) promote high diffusion rates of drugs, independent of their lipid solubility Advantages of IV administration rapid/precise blood drug levels obtained (e.g., no first-pass effect) Irritant drugs: more comfortably administered (blood vessels relatively insensitive); drug rapidly diluted (particularly if administered into large forearm vein)


Types of injections
Intravenous injection: rapid therapeutic response, nearly instant absorption, most dangerous Intravenous infusion (iv drip): plasma levels can be easily controlled Intramuscular injection: slower response, larger amounts can be injected, depends on perfusion quality Subcutaneous injection: aqueous solutions absorbed quickly (e.g. insulin), depends on perfusion quality

Other parenteral routes of administration: Lungs Skin

Inhalation: volatile drugs some general anesthetics Bronchodilators via nebulizers

Transdermal: easy to use convenient for certain applications (e.g. nicotine patch)



AUCi.v. = 1 Bioavailability: AUCp.o./AUCi.v.

transzportlt vagy metabolizlt mennyisg transzportlt vagy metabolizlt mennyisg

transzportlt vagy metabolizlt mennyisg

First Pass Effect




Drug Response Relationships

Dose Response Time Response


Gygyszerek eloszlsa a szervezetben

L A D M E R Liberci Abszorbci Disztribci Metabolizmus Exrecio Redisztribci

After absorption, the drug is distributed via plasma to organs and the site of action. The rate and extent depends upon: blood flow to each organ (more blood flow = more drug distributed) organs with high blood flow: lungs, kidney, liver, heart, brain systems with low blood flow: skeletal muscle, bone, adipose tissue binding of drugs to plasma proteins and tissue components permeability of tissue membranes. For lipophilic drugs, tissue membrane presents little barrier. Tissue uptake will continue until equilibrium is established between tissue and blood.


Compounds distribute differentially within body. Plasma protein binding may limit distribution Lipophillic compounds may accumulate in fatty tissues Liver, kidneys and other excretory organs often show high concentrations of compounds. Concentrations in brain are often very different from plasma concentrations - BBB Distribution can be studied using 14C-labeled compounds

Protein Binding
Human Serum Albumin

Most drugs: bound to some extent to plasma proteins Major plasma proteins important for drug binding include: albumin lipoproteins 1 -acidic glycoprotein Extent of protein binding important for drug distribution since only unbound fraction may diffuse across biological membranes Volume of distribution (Vd): inversely proportional to protein binding Drug clearance: influenced by protein binding since only the unbound drug fraction may reach and serve as substrate for drug metabolizing enzymes


Small changes in fraction of drug bound significantly influences free plasma concentration for highly plasma protein bound drugs, e.g. warfarin, propranolol, phenytoin, diazepam For example: a drug that is 98% protein-bound --following a decrease to 96% protein-bound results then a twofold increase in plasma drug concentration Characteristics of drug-protein binding Extent of protein binding: parallels drug lipid solubility Drug-plasma albumin binding -- often nonselective many drugs with similar chemical/physical properties may compete for the same protein-binding sites Renal failure: may decrease drug bound fraction (may not require changes in plasma albumin or other plasma protein concentration; suggesting elaboration of a metabolic factor from the kidney that competes with drug-plasma protein binding sites)

Tissue binding-accumulation
Many drugs accumulatein tissues at higher concentrations than dose in the extracellular fluids. Tissue binding usually occurs with cellular constituents: proteins phospholipides nuclear proteins Reversible Bound drugs serve as a reservoire: fat lipid-soluble drugs Physical solution low blood flow sudden reduction of weight bone tetracyclines, heavy metals adsorption, incorporation slow release! local destruction, radioactive drugs


Barriers (BBB, Placental)

The blood brain barrier consists of cell tightly packed around the capillaries of the CNS.

Non-protein bound, non-ionized, and highly lipid soluble P-glycoproteins

Placental barrier
lipid solubility plasma binding Ionization

fetal plasma pH < mother plasma pH Ion trapping!!!


Drug metabolism can occur in every tissue (e.g. gut, lung and kidney). However, the major drug metabolizing enzymes (DMEs) are expressed at the highest levels in the liver, which thus serves as the major organ of metabolic clearance

Drug metabolism serves to control the exposure of a potentially harmful substance. Usually via oxidation of a lipophilic xenobiotic, DMEs increase the polarity and aqueous solubility thus facilitating its elimination from the body.
Absorption I. phase Drug modified metabolite Drug ineffective metabolite Drug conjugation metabolism II. phase conjugation conjugation elimination



DMEs also help to regulate endogenous function (e.g. cytochrome P450s are involved in steroid and fatty-acid metabolism; and the glucuronosyl-S-transferase, UGT1A1, is involved in the clearance of bilirubin)


DMEs broadly classified into two types of reactions: Phase I Metabolism: Introduces or reveals functional groups (usually polar) to help drug excretion. Three types of phase I metabolism will be discussed: oxidative reductive hydrolytic Phase II Metabolism: Attaches a solubilizing group to the drug (or to a Phase I metabolite). Examples of groups that are commonly attached: glucuronide - glutathione sulfate - acetate glycine/glutamine (amino acids) - methyl Others

Drug Metabolism: Phase I A. Oxidations Most oxidations are catalyzed by the cytochrome P450 enzyme superfamily which is located primarily in the liver. This family of enzymes catalyzes a fairly small set of reactions that act on essentially infinite possibilities of chemical compounds. When P450 enzymes is exposed to CO they have a strong UV-VIS absorption at 450 nm (hence the name). The enzymes are conjugated to heme and the mechanism of oxidation is fairly well understood now.


Mechanism of microsomal oxidation

S(RH) +O2 +NADPH +H+ T(ROH) +H2O + NADP+

The CYP 450 system

Other 26%

CYP1A2 13%

Relative Amounts of Individual Human Hepatic CYPs

CYP2A6 4%

CYP3A 30% CYP2E1 7% CYP2D6 2% Shimada et al., JPET: 1994 CYP2C 18%

CYP2B6 <1% CYP2C8 1.7% CYP2C19 2.7%

CYP2C9 13.6%

Lasker et al., Arch. Bioch. Biophys:1998


Human Cytochromes P450 and their Relative Contribution to Hepatic CYP3A Drug Metabolism 40-50% 60% of drugs are metabolized primarily by CYPs

CYP2C19 4% CYP2A6 2%

CYP2C9 10%

CYP1A2 CYP2E1 6% 5%

CYP2D6 30%

Types of microsomal oxidation reactions:

reaction type A. Oxidation aromatic hydroxylation aliphatic hydroxylation epoxidation N-hydroxylation O-dealkilation N-dealkilation S-dealkilation Deamination S-oxidation Dechlorination oxidative desulfuration
R1 O













CH3 NH2 S R1
S P O R2 O R3

S R1
O R3 R2

+ NH3


O P R1 O



Non microsomal oxidation:

Reaction type II. Amino oxidation III. Dehydrogenation substrate




Reaction type Azoreduction Nitroreduction karbonil reduction Substrate R N = N R1 R NO2
R C O R1

Product(s) R NH2 + R1 NH2 R NH2



O R1








Substrates, Inducers & Inhibitors of Human CYPs

CYP1A2 Caffeine Imipramine Tacrine Theophylline R-warfarin Ciprofloxacin Furafylline Mibefradil Ticlopidine Insulin Omeprazole (Cruciferous vegetables) (Char-grilled meat) (Tobacco) CYP2C9 Diclofenac Losarten Phenytoin Tolbutamide S-warfarin Fluconazole Isoniazid Sulfaphenazole Paroxetine CYP2C19 Omeprazole Phenytoin Indomethacin R-warfarin CYP2D6 Bufuralol Codeine Desipramine Lidocaine CYP2E1 Acetaminophe n Ethanol Chlorzoxazone Sevoflurane CYP3A4 Nifedipine Erythromycin Midazolam Testosterone Ketoconazole Erthyromycin Grapefruit juice Ritonavir



Cimetidine Ketoconazole Paroxetine Ticlopidine

Quinidine Methadone Cimetidine Fluoxetine



Rifampin Secobarbital

Prednisone Rifampin

None identified

Ethanol Isoniazid (Starvation)

Carbamazepi ne Phenobarbital Phenytoin Rifampin


Risks associated with CYP enzyme inhibition or induction

Inhibition of CYP enzymes
Decreased degradation of comedicated drugs Increased drug plasma concentrations Risk of severe adverse events

Induction of CYP enzymes

Increased degradation of comedicated drugs Decreased drug plasma concentrations Loss of pharmacological effect Risk of severe secondary effects

Non-CYP Drug Metabolizing Enzymes (I)

Non-CYP Oxidations Monoamine Oxidase (MAO; mitochondrial) oxidatively deaminates endogenous substrates including neurotransmitters (dopamine, serotonin, norepinephrine, epinephrine); drugs include triptans Alcohol & Aldehyde Dehydrogenase (non-specific enzymes; liver cytosol) ethanol metabolism Xanthine Oxidase (XO) converts hypoxanthine to xanthine, and then to uric acid (drugs include theophylline, 6-mercaptopurine. Allopurinol is a substrate and inhibitor of xanthine oxidase Flavin Monooxygenases (FMOs; membrane-bound & NADPHdependent) catalyze oxygenation of nitrogen, phosphorus, sulfur; particularly facile formation of N-oxides (e.g. cimetidine)


Phase II reactions: conjugation


GST-A GST-P UGTs GST-T GST-M NAT2 NAT1 others HMT: histamine methyltransferase; TPMT: thiopurine methyltransferase; COMT: catechol O-methyltransferase; UGT: Uridine Glucuronosyl-S-Transferases; ST: Sulfotransferase; GST: Glutathione-S-Transferases

Evans and Relling, Science (1999)

Phase II reactions: conjugation

Reaction Glucuronideconjugation Sulphateconjugation Metilation Acetylation Amino acid conjugation Glutathioneconjugation Substrate ArOH, ROH, RCOOH, sulfonamides ArOH, ROH, ArNH2 ArOH, ROH, NH2R ArNH2, RNH2, ArCOOH, sulfonamides Epoxides, hydroxylamines Endogenous reagent UDP-glucuronic acid 3phosphoadenosine -5-phosphosulfate S-adenosylmethionine Acetyl-CoA Glicin Glutamin Glutathione enzyme UDPGT

Sulpho transferase Methyl transferase Acetyl transferase Acil-CoA-amino acid transferase Glutathione-Stransferase



Routes of exretion: urine, bile, lung, saliva, milk, sweat

Most compounds are excreted in the urine or feces.
Metabolism in Liver Drug in Intestine Absorption Drug in Portal Blood Conjugates Phase-1 Betaglucuronidase Conjugates in Intestines Bile Drug in Blood

Excretion in Feces

Excretion in Urine


Elimination: exretion
Kidneys = primary site Mechanisms dependent upon: I. Passive glomerular filtration: small molecules (<15000) unbound drugs only II. Active tubular transport: weak acides and bases pl.: penicillin, Chlorotiaside, salicilates, histamine Partial reabsorption: passive diffusion, active transportation, pH, pK, changing urin pH Renal disease Slows excretion Prolongs effects

Passive diffusion and active transport Biliary excretion is usually the major route of elimination of compounds with a molecular weight of more than 400500 Da. Many compounds that are eliminated in bile as glucuronide conjugates are hydrolysed in the small intestine by bacterial flora that secrete the enzyme glucuronidase. After hydrolysis the unchanged drug is reabsorbed, metabolized and re-excreted as a glucuronide conjugate: enterohepatic recycling


Other routes: I. Exhaled air II. Sweat III. Saliva IV. Breast milk V. Hair


General anesthetics, ethanol, menthol

II. Non-ionized, lipid soluble drugs, passive diffusion III. In the mouth saliva is swallowed-same c as in the plasma IV. More acidic than plasma-basics concentrated, acides less V. Forensic importance

Factors Altering Drug Responses

Age: pediatric or geriatric Immature or decreased hepatic, renal function Weight Big patients spread drug over larger volume Gender Difference in sizes Difference in fat/water distribution Environment Heat or cold Presence or real or perceived threats Fever, Shock Pathology Hepatic disease may slow drug metabolism Renal disease may slow drug elimination Acid/base abnormalities may change absorption or elimination


Pediatric Patients Higher proportion of water Lower plasma protein levels More available drug Immature liver/kidneys Liver often metabolizes more slowly Kidneys may excrete more slowly

Geriatric patients Chronic disease states Decreased plasma protein binding Slower metabolism Slower excretion Dietary deficiencies Use of multiple medications Lack of compliance

Drug-Drug Interactions Drug interaction: when one drug affects the pharmacological response of a second drug given at the same time. may be due to: pharmacodynamic and pharmacokinetic effects Consequences of drug interactions: increased drug effects; decreased drug effects; desired consequences; adverse or undesired effects Adverse effects: Interaction results impede absorption competition for the same plasma protein-binding sites one drug may affect metabolism of another by either enzyme induction or enzyme inhibition one drug may change the renal excretion rate of the other.

j gygyszerek ksrleti s Klinikai farmakolgiai vizsglata

I. a molekula felfedezse, azonostsa II. preklinikai vizsglatok (in vitro, ex vivo s in vivo toxikolgiai s farmakolgiai llatksrletes illetve humn sejt/szvetkultra modellek) III. humn fzis I vizsglatok IV. humn fzis II vizsglatok V. humn fzis III vizsglatok VI. trzsknyvi benyjts s elbrls VII. fzis IV s poszt-marketing (PMS) vizsglatok


Preklinikai fzis (Fzis 0)

A molekula felfedezse: szintzis extrakci kombinatorikus kmia fizikai, kmiai tulajdonsgok in vitro, ex vivo, in vivo, ED50 in vivo, LD50, akut, krnikus in vivo

A vegylet jellemzse: Hatstani vizsglatok: Toxikolgiai vizsglatok: Kinetikai vizsglatok:


Humn vizsglatok (fzis I-IV)

Fzis I.: farmakokinetikai vizsglatok egszsges nkntesek tolerlhatsg, vrhat hats nkntes betegek gygyszer hats vizsglatok terpis rtk sszehasonlt vizsglatok nkntes betegek

Fzis II.:

Fzis III.:

Trzsknyvezs Fzis IV.: alkalmazs sorn felmerl j adatok

Literature: CORINA IONESCU and MINO R. CAIRA: Drug Metabolism Current Concepts Alfred Goodman Gilman: The pharmacological basis of therapeutics