Pharmacokinetics Lecture Notes PDF

 Pharmacokinetics Absorption Distribution For endogenous Metabolism (Biotransformation) Elimination compounds Excretion For exogenous...

 Pharmacokinetics Absorption Distribution For endogenous Metabolism (Biotransformation) Elimination compounds Excretion For exogenous compounds  PHARMACOKINETICS Outside Inside Drug Drug Stomach - Oral Route of Administration Intestine Absorption Sites of Metabolism Metabolism Plasma Drug &/or Other Excretion Metabolites Body Fluids ABSORPTION  Absorption 1. pH – Physicochemical properties 2. Carrier (transporter) protein expression 3. Presystemic/First-pass elimination: Elimination (via metabolism or excretion) of a fraction of a drug before reaching ! systemic circulation i.e. Drug can be metabolized in gut epithelia or in portal blood & most commonly in liver &/or liver can excrete drug into bile b4 to entry into ! sys circulation. 1st pass elimination may be 0-100 %. 4. Blood flow to absorption site 5. Total surface area available for absorption site 6. Delivery of drug to absorption site 7. Contact time at absorption site  Uncharged Acidic drug 1-pH BH+ B+ H+ HA A- + H+ Uncharged Basic drug Most drugs are weak acids or weak bases. The non-ionized/uncharged/non-polar form only passes through membranes more readily (lipid diffusion). Concentration of the uncharged form is determined by: 1) The pH at site of transfers -Acidic drug in acidic media → uncharged but in alkaline media will be ionized/Polar -Basic drug in alkaline media → uncharged but in acidic media will be ionized/Polar 2) The pKa of drug pKa (reflect the strength of interaction of a drug with H+) ie. the lower the pKa the more acidic the drug & vice versa  Absorption 5. Delivery of drug to absorption site (Peristalsis ↑ 𝒐𝒓 ↓) 6. Total surface area available for absorption site Intestine is the main absorption site of oral drugs: Intestine surface area ~1000-fold > Stomach Intestine blood flow is much greater > Stomach 7. Contact time at absorption site Anything decreases contact time at intestine → decreases the EXTENT of drug absorption (e.g. Severe diarrhea) 8. Blood flow to absorption site  Bioavailability Bioavailability = Fraction of unchanged drug reaching the systemic circulation following administration by any route i.e. after absorption or 1st pass effect. IV dose → 100% bioavailability Other routes → bioavailability may be skeletal muscles > adipose tissue, skin, viscera) 2. Capillary permeability 3. Binding to plasma proteins 4. Chemical nature of drug Factors Affecting Distribution 2. Capillary permeability Determined by: 1. Capillary structure 2. Drug (Size & Lipophilicity) Capillary structure: In liver & spleen: large, lose slit In brain: Tight slit junctions between junctions between endothelial cells → endothelial cells → restricting large part of basement membrane is distribution of drug to it → exposed. Constituting Blood brain barrier Factors Affecting Distribution 2. Capillary permeability Determined by: 1. Capillary structure 2. Drug (size & lipophilicity) To enter brain: Drugs must pass through endothelial cells membrane (only lipid-soluble drugs) or Actively transported  Dimethylsulfoxide C) Intracarotid arterial is effective and safe for delivery of therapeutics for central nervous system malignancies. ICAHM osmotically alters endothelial cells and tight junction hyperosmolar mannitol integrity to achieve BBBD. D Factors Affecting Distribution 3. Binding to PLASMA PROTEINS (reversible) Free Gives long duration To maintain [D] as a constant fraction of the total drug in plasma Clinical Significance during drug prescription 1-This is source of drug interaction for e.g. Warfarin 99% bound and 1% is free and enough to produce effect. Thus if the physician prescribed another drug with high PL Pt binding capcity, this will lead to discplacement of another amout of wafarin from PL Ptn and increase the % of free form, thus will lead to dramatic toxicity. 2-Adjust and Decrease dose of these drugs in disorders like liver dis, nephrotic syndrome, pregnant  Volume of Distribution (Vd)  Volume of Distribution (Vd) Vd is theoretical volume that necessary to contain the total amount of administered drug at the same concentration measured in plasma (mg/L). Drug enters the body and carried by water → distributes into body water compartments: Intravascular fluid Extravascular fluid Plasma Interstitium Cytosol (~ 4L) (~10 L) (~28 L) Extracellular Intracellular (~42 L /70 Kg) 4L 14 L 42 L  Volume of Distribution (Vd) Plasma Interstitium Cytosol Plasma Interstitium Cytosol Plasma Interstitium Cytosol 1. Plasma compartment ( plasma Medium → mainly present in plasma > extravascular water Vd Lowest Vd → completely retained within plasma Exceptionally large → highly sequestered in cellular sites e.g. in brain, liver, bone, adipose tissue (obese) e.g. Chloroquine (in liver), Ca2+ & tetracycline (in bones), thiopental, BDZs, Fluoxetine (in Brain).  Clinical Significance of Vd -Consideration of Hemodialysis for toxic drugs, Is drug dialysable or not ? -Determine amount of drug consumed during suicidal attempt *givens plasma conc , Vd Vd=Dd/Cp  METABOLISM (BIOTRANSFORMATION) occur in different organs but mainly by liver ❑ Kidney cannot efficiently eliminate lipophilic drugs (readily reabsorbed in DCT) Liver (Phase I & Phase II reactions ) If drug is hydrophilic so mainly not undergoes biotransforamtion called Hard drugs  What is the fate of drug after biotransformation? 1- Inactive metabolite from active drug (Major) 2- Active metabolite from active parent drug e.g. Codeine → morphine (wat sol) 3- Active metabolite from prodrug parent drug e.g. Enalapril → Enalaprilat 4- Toxic metabolite from active parent drug Paracetamol → NAPQI toxic metabolite  Drugs already possessing an –OH, –NH2, or –COOH group may enter Phase II directly without prior Phase I reaction Energy dependent Microsomal/Non-microsomal Mostly oxidation by CYP450 system (microsomal Synthetic Phase = Conjugation reactions with mixed-function oxidases). Other enzymes include endogenous acids (glucuronic, sulfate, acetic, amine, alcohol dehydrogenase, esterases, hydrolase. amino acid, GSH, methylation) If metabolite from Phase I is sufficiently polar, it can be Especially products of glucuronic acid conjugation are excreted by kidneys excreted in bile then intestine Exceptionsn to the status of products or the order of phases 1-The product of conjugation is more polar than parent compounds and inactive except active SO4 derivative of minoxidil. SO4 Minoxidil (Prodrug) Minoxidil SO4 2-Some drugs undergo phase 2 then Phase 1 e,g, Isoniazide is 1st acetylated (Phase 2) then hydrolyzed to Iso-nioctinic acid (phase 1)  Cytochrome P450 System Induction or inhibition of CYP450 enzymes are responsible for PK interactions CYP=Mic enz Induction Liver only? CYP=Mic enz Inhibition Induce enzyme expression Competitive or non-competitive  Drug biotransformation  Drug biotransformation  Drug elimination, Drug response (Tolerance)  Drug blood levels  Toxicity e.g. Paracetamol  Therapeutic and/or Toxic effects  Cytochrome P450 System Clinical significance of CYP450 Drug Interaction 1. Asthmatic patient on Theophylline (Bronchodilator) administered erythromycin (Antibiotic) Theophylline is metabolised by CYP450 and Erythromycin inhibits CYP450 → Theophylline toxicity; unexpected vomiting, tremors 2. Patient on Warfarin (Anticoagulant) and administered ciprofloxacin (Antibiotic) Wafarin metabolised by CYP450 and ciprofloxacin inhibits CYP450 → enhanced bleeding 3. Woman on Contraceptives and given Rifampin (Anti T.B.) which is HME inducer Rifampin induces metabolism of contraceptives → decrease level of contraceptives = Breakthrough pregnancy EXCRETION Regulated by Glomerular filtration of drugs depends on: (1) PP binding of drug (Bound drug to PL Pt will not be filtered) (2) GFR (as GFR increases, filtration increases) (3) Molecular Size of Drug (as the size of Drug increases, the filtration of drug decreases) N.B. Lipid solubility & pH do not affect  Drugs that are not glomerularly filtered leave the glomeruli through efferent arterioles, then actively (ATP-dependant) secreted in PCT. There are two transport systems: 1. Organic anion transport (OAT) for anions 2. Organic cation transport (OCT) for cations *Clinical Significance Competition between drugs for these carriers can occur within each transport system e.g. Penicillin and Probencid → delay in penicillin secretion in urine → elongates the duration of penicillin  As drug moves toward DCT its concentration increases in the filtrate > perivascular space. Uncharged drug may diffuse back into systemic circulation. To minimize this back-diffusion: Change pH of urine to increase the ionized form of drug Ion trapping: Renal elimination of weak acids can be enhanced by urine alkalinization (By Na bicarbonate) Renal elimination of weak bases can be increased by urine acidification (By NH4Cl). For: 1. Unabsorbed oral drugs 2. Drugs secreted directly into intestines 3. Drugs excreted into bile Entero-hepatic recirculation: Drugs excreted in bile, unchanged or conjugated Some of the conjugates are deconjugated back to parent compound by gut flora & are then reabsorbed back to blood = contributes to long duration of the drug This recycling process prolongs stay of drug within body If gut flora is diminished by antibacterial, the conjugated drug is not recycled and is eliminated quickly → breakthrough pregnancy.