Pharmacokinetics PDF

Pharmacokinetic ● By dr. Ahmed S. Ali 1 Final pharmacokinetics 2024 - 15 January 2024 Learning outcomes 1. Recall Concepts relevant to Pharmacokinetic process 2. understanding Terms & Variables affecting rug absorption and distribution 3.Understanding Terms &Variables affecting metabolism and...

Pharmacokinetic ● By dr. Ahmed S. Ali 1 Final pharmacokinetics 2024 - 15 January 2024 Learning outcomes 1. Recall Concepts relevant to Pharmacokinetic process 2. understanding Terms & Variables affecting rug absorption and distribution 3.Understanding Terms &Variables affecting metabolism and elimination 2 2 Final pharmacokinetics 2024 - 15 January 2024 WHAT IS PHARMACOLOGY? • The study of how drugs affect a biological system PHARMACOLOGY Pharmacokinetics - what the body does to the drug Pharmacodynamics - what the drug does to the body 3 Final pharmacokinetics 2024 - 15 January 2024 Summary of PK process (ADME) *** A : Absorption, the movement of drug from the site of administration to the blood circulation. – The term commonly used to describe the rate and extent of drug input is bioavailability. Drugs administered by intravenous routes exhibit essentially 100% bioavailability. D : Distribution, the process by which drug diffuses or transfers from intravascular to extravascular spaces (body tissues). M :Metabolism, the chemical conversion or transformation of drugs into compounds which are easier to eliminate. E : Excretion, the elimination of unchanged drug or its metabolite from the body via renal, biliary, or pulmonary routes. 4 Final pharmacokinetics 2024 - 15 January 2024 PK is the quantitative study of drug movement in, through and out of the body 5 5-1 Final pharmacokinetics 2024 - 15 January 2024 PK is the quantitative study of drug movement in, through and out of the body 5 5-2 Final pharmacokinetics 2024 - 15 January 2024 6 Final pharmacokinetics 2024 - 15 January 2024 Route of administration and PK Parenteral (IV) Inhaled Oral (SC, IM) Transdermal Topical Rectal 7 Final pharmacokinetics 2024 - 15 January 2024 Some Factors Affecting Drug Absorption (oral route ) ● ● ● ● Mechanism of transport – Most drugs absorbed by passive diffusion. – Few drugs requires active transport Low molecular weight Less than 250 dalton Lipid soluble , (unionized ) drugs , usually well absorbed ATP Active transport ADP + Pi HA HA ABH+ Many Other factors ( see bioavailability ) **Ionized drug poorly absorbed The diagram explains the active transport & effect of ionization on absorption of drugs from GIT 8 Final pharmacokinetics 2024 - 15 January 2024 ●*** Bioavailability :Fraction of a drug that reaches systemic circulation ( active form ) ●It is affected by rate and extent of drug absorption after a particular route of administration Amoxicillin shows very good bioavailability after oral administration 9 Final pharmacokinetics 2024 - 15 January 2024 √Some factors affecting oral absorption or Bioavailability ● Factors related to the drug – – – – Physiochemical properties Stability in GIT Lipid solubility Mol wt ● Factors related to the formulation Syrup ready for absorption > tablet – – Sustained release tab. slow absorption ● Factors related to the patient – Physiological : age related change in Gastric pH, motility , gastric emptying time – Pathological : certain disease e.g. diarrhea , vomiting ● Remember pH = Pka + log (ionized/ unionized ) 10 Final pharmacokinetics 2024 - 15 January 2024 Explain the correlation between physiochemical properties and oral bioavailability Not absorbed orally Well absorbed orally Gentamicin Theophylline Heparin 12000–15000 g/mol 11 Final pharmacokinetics 2024 - 15 January 2024 Explain why change formulation of certain drugs e.g. Cyclosporine A may lead to altered clinical response These formulations of Cyclosporine A show different bioavailability 12 Final pharmacokinetics 2024 - 15 January 2024 Explain why oral paracetamol may show slow effect in some situations Delayed absorption of orally administered analgesic drugs in case of migraine 13 Final pharmacokinetics 2024 - 15 January 2024 Provide example of interaction with food with drugs ● Complexes of ciprofloxacin with antacid ● Complex of tetracycline and calcium in milk or Fe , Al or Mg in antacid ● These complexes are poorly absorbed Tetracycline metal complex 14 Final pharmacokinetics 2024 - 15 January 2024 Why insulin may show poor response after repeated injections in the same site ? Lipodystrophy Reduced absorption of SC injection 15 Final pharmacokinetics 2024 - 15 January 2024 Drug Distribution ● ***Distribution is the process by which the drug reversibly transferred from the blood to the extra cellular fluids & tissues . … ● Drugs may distribute into the following compartments: – Plasma – Interstitial Fluid (extracellular) – Intracellular Fluid 16 Final pharmacokinetics 2024 - 15 January 2024 Some Factors affecting drug distribution Drug Chemical structure Mol.wt , polarity, lipid solubility Binding to blood components (, RBC, plasma albumin) Age : body composition ( water, lean body & fat ) Physiological state : pregnancy.( reduced albumin , larger amount of body fluids Rate of blood flow Capillary permeability ( see figure of blood brain barrier Diseases • • • Liver disease ( low plasma protein levels ) Renal impairment ( uremia, low albumin ) Diabetes ( increase free Fatty acid ) • Cystic fibrosis ( increase blood volume 17 ) Final pharmacokinetics 2024 - 15 January 2024 *Effect of Blood flow on drug distribution Blood flow to brain, liver, kidney is greater than skeletal muscles, ● Adipose tissues has lower blood flow ● Blood flow to the liver is important for drugs subjected to significant metabolism. ● *** Redistribution Ex propofol (Diprivan):. Produces rapid anesthesia but ● has short duration (3-5 minutes) Why? See the web Although it has 2-4 hour half life 18 Final pharmacokinetics 2024 - 15 January 2024 Influence of Capillary permeability on drug distribution ( details are not requested ) ● .. ● General body capillaries allow drug molecules to pass freely into the surrounding tissue 19 Brain capillaries have a dense-walled structure and are surrounded by glial cells (lipid). This prevents many drug molecules from entering the surrounding tissue Final pharmacokinetics 2024 - 15 January 2024 Binding of drugs to proteins to plasma proteins ●Many drugs bound to circulating plasma proteins such as albumin ●albumin: binds many acidic drugs and a few basic drugs β-globulin and an α1acid glycoprotein have also been found to bind certain basic drugs ●Free drug is the pharmacology active form. ( interact with receptors ) 20 Bound drug albumin Final pharmacokinetics 2024 - 15 January 2024 Many factors can increase the fraction of unbound drug ● ● Renal impairment ( uremia ) (low albumin) Low plasma albumin levels (<20-25g/L) – E.g. chronic liver disease, malnutrition ● Late pregnancy – Increased albumin production, but diluted by increased blood volume ● Displacement from binding site by other drugs – e.g. Phenytoin , warfarin , tolbutamide ● Saturation of plasma protein binding site e.g.. valproic acid 21 Final pharmacokinetics 2024 - 15 January 2024 Clinical significance of Protein Binding ❑ Protein binding is a dynamic state ( reversible ) ❑ Higher free drug level may associated with certain disease states ( decrease binding ) or using other drugs. (competition for binding ) Clinically significant for drug with high plasma protein binding In neonate, higher free level of drugs strongly bound to albumin ❑ ❑ 22 Final pharmacokinetics 2024 - 15 January 2024 Drug - METABOLISM *** Drugs may converted to less toxic/effective metabolites (this is usually occurs ) more toxic/effective metabolites ( sometimes occurs ) ● Individual variation in drug metabolism may be genetically determined ● Metabolism may be induced or inhibited by other drugs; foods or environmental factors ● liver is the main site of drug metabolism ● … 23 Final pharmacokinetics 2024 - 15 January 2024 Many Factors affecting drug metabolism I. Genetic factors II. Liver disease o e.g. acetylation status ( fast & slow, normal ) e.g. INH Advanced liver cirrhosis III. IV. o o Other drugs hepatic enzyme inducers hepatic enzyme inhibitors Age ( extremes ) Impaired hepatic enzyme activity o Elderly o Children < 6 months (especially premature babies) those population are likely to show reduced clearance and longer half life of drugs which their eliminations depends on liver metabolism 24 Final pharmacokinetics 2024 - 15 January 2024 First Pass Metabolism Drug biotransformation that occurs before the drug reaches its site of action. •Occurs Primarily in the Liver from portal (gut) 25 Final pharmacokinetics 2024 - 15 January 2024 Clinical importance of first –pass clearance * 1. May render a drug less effective by mouth e.g. Morphine 2. Higher oral dose is needed to produce the same effect of IV dose e.g.. propranolol 3. We use alternative route of administration to avoid first pass effect e.g. sub-lingual nitroglycerin 26 Final pharmacokinetics 2024 - 15 January 2024 Induction & Inhibition 27 Final pharmacokinetics 2024 - 15 January 2024 28 Final pharmacokinetics 2024 - 15 January 2024 Enzyme induction ● ● ● is a process in which a molecule (e.g. a drug) induces (i.e. enhances) the metabolizing capacity of certain microsomal enzyme. Stimulate specific CYP e.g. CYP3A4 Enhance Metabolism of certain drugs which are substrate for the same enzyme This leads to lower drug level Reduce pharmacological effect ( possibly therapeutic failure ) N.B enzyme induction involves protein synthesis .Therefore, it needs time up to 3 weeks to reach a maximal effect 29 Final pharmacokinetics 2024 - 15 January 2024 Enz. Induction clinical examples) ● ● ● ● anti-epileptic drugs. Phenytoin,, induces CYP1A2, CYP2C9, CYP2C19 and CYP3A4. Substrates for the latter may be drugs with critical dosage, like amiodarone (antiarrhythmic) or carbamazepine, whose blood plasma concentration may decrease because of enzyme induction Carbamazepine (antiepileptic drug ) increases its own metabolism ( auto induction ) Tobacco smoking induces CYP1A2 (example substrates are clozapine/olanzapine (antipsychotic)), Saint-John's wort (a common herbal remedy) induces CYP3A4, 30 Final pharmacokinetics 2024 - 15 January 2024 Enz Inhibiting Drugs ● It is the decrease of the rate of metabolism of certain drug caused by another drug . ● This will lead to the increase of the concentration of the target drug and leading to the increase of its toxicity ● Inhibition of the enzyme may be due to the competition on its binding sites , so the onset of inhibition is short may be within 24h. NB ; Inhibition = decrease of drug metabolism ( certain drugs ) 31 Final pharmacokinetics 2024 - 15 January 2024 Drug Metabolism (cont’d) *** Drug ● Two Phases: I and II Phase I – Phase I: conversion to lipophilic – Phase II: conjugation more water soluble ● ● Oxidation Reduction Hydrolysis Activation/Inactivation Phase I involves the cytochrome P-450 system Ultimate effect is to facilitate elimination Phase II Glucuronidation Conjugation Products 32 Final pharmacokinetics 2024 - 15 January 2024 Factors affecting biotransformation ● ● ● ● ● ● ● ● race (CYP2C9; warfarin (bleeding) phenytoin (ataxia) Losartan (less cleared but less activated as well); also fast and slow isoniazid acetylators, age (reduced in aged patients & neonates) GENDER (m/f ) : (usually little differences) species ( not clinically important); clinical or physiological condition e.g. cystic fibrosis. other drug administration (induction or inhibition) food (charcoal grill , induce CYP1A)(grapefruit juice --CYP3A4) first-pass (pre-systemic) metabolism. 33 Final pharmacokinetics 2024 - 15 January 2024 EXCRETION ( Overview ) As a PK term excretion means: The removal of intact drug molecule from the body ● Generally urine is the main route, ● Occasionally in bile , possible in . in milk ● volatile agents (general anesthetics) via lungs ● It is important for drugs that mainly eliminated by renal route ● Renal elimination is greatly affected by age & gender. ● Some drugs are nephrotoxic and reduce elimination of other drugs ● 34 Final pharmacokinetics 2024 - 15 January 2024 renal excretion of drugs • 1-Filtration •Passive process (Pressure driven); Small molecules Most proteins not filtered. Drugs which are extensively protein bound . will also not be filtered 2-Active secretion require Energy ;Two separate mechanisms for acids & bases Saturable; Possible interactions 3-Re-absorption Depends on urine flow & PH of urine ( state of drug ionization & lipid solubility ) In case of toxicity of certain drugs insure adequate urine flow & appropriate pH that insure ionization 35 Final pharmacokinetics 2024 - 15 January 2024 Ion trapping Urine pH varies (4.5 - 8.0). Consider a barbiturate overdose. Sodium bicarbonate may be given to make the urine alkaline Urine body pH 8.0 Non-ionized Rest of pH 7.4 Non-ionized Ionized Ionized Barbiturate moves into urine - eliminated from body. 36 Final pharmacokinetics 2024 - 15 January 2024 Creatinine clearance ● http://reference.medscape.com/ calculator/creatinine-clearance-cockcroftgault 37 Final pharmacokinetics 2024 - 15 January 2024 Provide an example of Genetic polymorphism of acetylation process on clinical response to INH Plasma conc. in 267 patients after 9.8 mg/kg ionized orally Regularly updated information on human P450-polymorphisms is available at http://www.imm.ki.se/CYPalleles/. 38 Final pharmacokinetics 2024 - 15 January 2024 Half-life, what is the clinical importance ?? ● ● Another important property of first order kinetics is the half-life of elimination( t 1/2.) The half-life is the time taken for the plasma concentration to fall to half its original value. Thus if Cp = concentration at the start and Cp/2 is the concentration one half-life later then 39 Final pharmacokinetics 2024 - 15 January 2024 ‫ﻛﺑﺳوﻟﺔ اﻟﻠطف‬ 40 Final pharmacokinetics 2024 - 15 January 2024