Pharmacokinetics Lecture 2 - BIOL 2048/9 PDF

BIOL 2048/9 Pharmacology PHARMACOKINETICS Lecture 2 MyEngagem ent: Dr. Charles Birts Join: vevox.app ID: 143-704-739 [email protected] Learning Outcomes Explain the pharmacokinetic processes of abs...

BIOL 2048/9 Pharmacology PHARMACOKINETICS Lecture 2 MyEngagem ent: Dr. Charles Birts Join: vevox.app ID: 143-704-739 [email protected] Learning Outcomes Explain the pharmacokinetic processes of absorption, distribution, metabolism and excretion (ADME). Apply mathematical principles to the pharmacokinetic processes of absorption, distribution and elimination. 1. ABSORPTION Processes that take place between the site of administration and the site of measurement Factors affecting absorption Rapid from gut 1. LIPID SOLUBILITY Slow from intra-muscular Poor for ionic drugs 2. IONISATION (from gut) pH partitioning May limit rate of absorption 3. FORMULATION May limit extent of absorption May limit rate of delivery to 4. GASTRO-INTESTINAL site of absorption FUNCTION May limit time available for absorption 5. FIRST-PASS May limit extent of absorption METABOLISM 3. Formulation For rapid and extensive absorption, the drug has to dissolve, i.e. to produce a molecular solution Large particles do not produce a molecular solution in the gut 3. Formulation Conventional formulation – 250mg Sustained release formulation – 500mg 7 6 Concentration mg/ml Therapeutic 5 range Plasma 4 3 2 1 1 2 3 4 5 6 7 8 9 Time in hours 4. Gastro-intestinal function GASTRIC EMPTYING Which subject has the fastest gastric emptying and 80 why? Nifedipine in plasma SUBJECT 1 60 SUBJECT 2 40 20 0 1 2 3 4 5 6 7 8 9 10 TIME (h) 5. First-pass Metabolism ORAL DRUG DRUG Hepatic vein FIRST-PASS METABOLISM Hepatic portal LIVER vein Oxidation Hydrolysis Conjugation Low GUT WALL DRUG pH Esterases Proteases Conjugation DRUG GUT LUMEN Esterases Proteases Bioavailability - f BIOAVAILABILITY = Fraction of dose passing from the site of administration into the general circulation AS THE PARENT COMPOUND (i.v = 1.0) Common reasons for low 1. Decomposition in the gut lumen bioavailability: 2. First-pass metabolism in the gut wall 3. First-pass metabolism in liver 4. Not absorbed from the gut lumen 5. Tablet does not completely dissolve How can we measure the Bioavailability (F)? Compare the plasma concentration when the same dose is given intravenously and orally. Intravenous Oral 100% gets into the F = AUCoral general circulation AUCiv Area under the curve - AUC Area under the curve - [drug ] [drug] AUC Time Time area under the curve is representative of the total amount of drug that gets into the system Tubocurarine Drug interactions: Drugs affecting first-pass metabolism in the gut wall Important interactions are when inhibition of an enzyme increases the bioavailability of a drug ENZYME DRUG INHIBITORS MONO-AMINE AMINES MAOIs OXIDASE (MAO) (tyramine) (cheese and wine reaction) diastolic BP systolic BP 200 180 160 Pressure (mm Hg) 140 120 Patient given 100 80 gruyere cheese 60 50g Gruyere while on an MAOI 40 20 Pentolamine 2mg I.v. 0 Pentolamine is an -60 -30 0 30 60 90 120 150 180 a-blocker to lower BP Time in minutes Drug interactions: Drugs affecting first-pass metabolism in the gut wall Important interactions are when inhibition of an enzyme increases the bioavailability of a drug ENZYME DRUG INHIBITORS MONO-AMINE AMINES MAOIs OXIDASE (MAO) (tyramine) (cheese and wine reaction CYP3A4 TERFENADINE GRAPEFRUIT JUICE + CYP INHIBITORS (fatal heart arrhythmias) DOPA LEVODOPA CARBIDOPA / BENSERAZIDE DECARBOXYLASE (lower dose + fewer side (LNAAD) effects) Routes of administration ORAL DELAY - due to gastric emptying - influenced by food LESS LIPID SOLUBLE/MORE WATER SOLUBLE DRUGS - ABSORBED SLOWLY MORE LIPID SOLUBLE DRUGS - ABSORBED RAPIDLY F = VARIABLE - first-pass metabolism - too hydrophilic to be absorbed - extremely lipid soluble compounds do not form a solution within the gut lumen SUB-LINGUAL rapid absorption blood drains into systemic circulation high bioavailability RECTAL Routes of administration ORAL delay ; lipid soluble = fast ; water soluble = slow ; F = variable INTRAVENOUS instantaneous ; F = 1 SUBCUTANEOUS lipid soluble = slow water soluble = fast ; F = 1 INTRAMUSCULAR lipid soluble = slow water soluble = fast ; F = 1 INHALATION lipid soluble = fast ; high F TRANS-DERMAL very slow ; low F NASAL rapid ; lipid soluble ; high F  2. DISTRIBUTION The rate and extent of movement of the parent drug from the blood into the tissues after administration and its return from the tissues into the blood during elimination Distribution of drugs PLASMA CELLS membrane UNIONISED UNIONISED UNIONISED IONISED IONISED If the membrane separates fluids at different pH values the drug will concentrate at the pH at which it is most ionised = pH partitioning (Lecture 1) Distribution of drugs PLASMA CELLS DOSAGE RECEPTOR BINDING ELIMINATION UNIONISED UNIONISED IONISED IONISED binding binding to plasma to tissue proteins proteins Drug protein binding Drugs bind to proteins as a reversible equilibrium Drug + Protein Drug – protein complex THE BINDING IS:-  In general it is non specific  low affinity  High capacity  Saturable at high concentrations  Not involved in drug mode of action  Acts as a depot or reservoir of drug Plasma albumin binds acidic (and basic) drugs a1-acid glycoprotein binds basic drugs Drug protein binding Drug + Protein Drug – protein complex NO PROTEIN [unbound] = [total] WITH PROTEIN [unbound] [unbound] = Saturation [total] – [bound] of protein binding sites [total] Drug protein binding interactions Drug + Protein Drug – protein complex WITH OTHER DRUGS Bound Unbound IMPORTANT only if the drug is Alone 98% 2% highly protein bound A second drug can change the + 2nd drug 96% 4% volume of distribution of a drug WITH ENDOGENOUS COMPOUNDS IMPORTANT WHEN: endogenous compound is highly bound and endogenous compound is active or toxic e.g. bilirubin in neonates Interactions affecting extent of drug distribution PLASMA TISSUE FREE DRUG FREE DRUG PROTEIN- PROTEIN- BINDING BINDING Acidic drugs bind to albumin e.g. warfarin Basic drugs bind to a1-acid glycoprotein e.g. propranolol ‘V’ or ‘Vd’ is the ‘Volume of Distribution’ (see Lecture 5) V - DEPENDS ON TOTAL IN TISSUES OR TISSUE BINDING TOTAL IN PLASMA PLASMA BINDING