1- General-101 PK Lecure notes.pdf

GENERAL PHARMACOLOGY  INTRODUCTION Pharmacology is the science of drugs1; it tells us the life story of the drug starting from the sources from which the drug is obtained, passing with the dosage forms prepared from these sources, the routes of administration of...

GENERAL PHARMACOLOGY  INTRODUCTION Pharmacology is the science of drugs1; it tells us the life story of the drug starting from the sources from which the drug is obtained, passing with the dosage forms prepared from these sources, the routes of administration of these dosage forms, ending with elimination of these drugs from the body. During the life period of the drug, it is given many types of names; first a chemical name that describes its formula, then it is given a code name during screening & initial evaluation. The promising drug is given a unique generic name. After delivering it for use, the company that sells it may give it another trade or brand name e.g. Acetylsalicylic acid (chemical) Aspirin (generic) Aspro, Rivo or Aspeol (trade). The science of pharmacology is divided into: A) Basic pharmacology which deals with 2 major topics: Pharmacokinetics (PK) which is the effect of the organism on the drug (i.e. absorption, distribution, metabolism and excretion; or simply ADME). Pharmacodynamics (PD); which is the biological effect of the drug on the organism (i.e. the therapeutic effects & adverse effects together with the mechanism of each 2 effect). Page 1 The drug is any chemical substance that can be used for diagnosis, prevention or treatment of a disease and is recognized in pharmacopoeia. The pharmacopoeia is an official book containing a list of approved drugs with the available information about them e.g. British pharmacopoeia (B.P.), United state pharmacopoeia (U.S.P.), Egyptian P. General Prof. M. Abdel-Bary B) Clinical pharmacology which deals mainly with Pharmacotherapeutics (PT). PT includes all the factors related to the use of the drug in therapy of disease e.g. the indications of the drug (together with the dosage forms, the doses, the routes of administrations in each indication & the precautions during its use), the contraindications that prevents the use of the drug, and the drug interactions that might occur from the use of more than one drug. 3 Page General Prof. M. Abdel-Bary  PHARMACOKINETICS A) ABSORPTION During its transport from the site of administration to the systemic circulation, the drug crosses many cell membranes (absorption); part of the drug may be metabolized before reaching the systemic circulation (first pass metabolism) & is eventually lost. The remaining fraction which succeeds to reach the systemic circulation is called the bioavailability. Factors which affect absorption of drugs: 1. Factor related to the dosage form e.g. synthesis techniques & excipients added during preparation can affect the disintegration of the dosage form into particles. 2. Factor related to the drug e.g. the molecular weight, & solubility coefficient of the drug can affect the dissolution of the drug particles into molecules. 4 Page General Prof. M. Abdel-Bary 3. Factor affecting the stability of the drug in gut contents e.g. GIT secretions; food & other drugs taken concomitantly can affect the destruction of the molecules into metabolites. 4. The pH of gut, in relation to the pKa of the drug affects the Ionization of the molecules into ions2. 5. Factor related to the absorptive system e.g. the rate of gastric emptying, GIT transit time, surface area available for absorption3, presence of GIT disease can modify the rate of crossing of the absorptive surface. 5 Page 2 Absorption of drugs –unlike food- is mostly through simple diffusion through the lipid membranes. Ionized form of the drug is water soluble & cannot pass the lipid membranes except through the water filled pores which are too narrow to allow the passage of large drug molecules. Non-ionized form of the drug is lipophilic & can pass easily through lipid membranes. When the pH of the medium =pKa of the drug; 50% of the drug molecules exist in the ionized form & 50% in the non-ionized form. Ionization of weak acids increases at pH > pKa while ionization of weak bases increases at pH < pKa e.g. aspirin (pKa= 3.5) exists mainly in the non-ionized (lipid soluble) form at gastric pH (1.5-2.5). 3 The intestine is the largest absorptive surface (200 m2); the lung come next (70 m2). General Prof. M. Abdel-Bary Factors affecting first-pass metabolism of drugs: 1. The route of administration of the drug: the hepatic first-pass effect can be completely avoided by parenteral administration (e.g. verapamil) or sublingual administration (e.g. nitroglycerin). Rectal administration, however, did not completely eliminate the hepatic first pass effect since the blood supply of the upper third of the rectum passes to the liver through the mesenteric circulation 2. The nature of the drug: a. Hepatic first-metabolism occurs for drugs whose liver metabolism is very active e.g. propranolol, nitroglycerin, morphine b. Intestinal mucosal first pass metabolism occurs for tyramine & estrogens c. Pulmonary first pass metabolism occurs for isoprenaline, nicotine & opioids. 3. Hepatic first pass metabolism is largely reduced in situations associated with: 6 Page General Prof. M. Abdel-Bary  Decrease of the portal blood flow (e.g. portal hypertension, treatment with β-blockers e.g. propranolol or H2 receptor blockers e.g. cimetidine) Inhibition of the hepatic enzyme activity (e.g. liver failure, simultaneous use of enzyme inhibitors e.g. chloramphenicol) Calculation of bioavailability: 7 Page Bioavailability (F) = AUC after administration by certain route/ AUC after IVI General Prof. M. Abdel-Bary  B) DISTRIBUTION After absorption; the drug is carried by the blood to various body organs. The amount of the drug delivered to each organ depends on the rate of blood flow to that organ. The drug may be in the free state (either non-ionized lipophilic form or ionized hydrophilic form) or bound state (albumin binding). The bound form cannot enter the organ due to the large size of the drug-albumin complex. The free non-ionized form is allowed to enter the organ freely through the surrounding lipid membranes because of its lipophilicity while the entrance of the free ionized form is limited as they are forced to enter through the narrow water-filled pores in the surrounding. After entrance into the tissue, tissue binding can attract more of the free drug molecules to enter the cell. Thiopental (an IV general anesthetic) distribution is a classic example to demonstrate the iportance of understanding drug distribution for clinical practice: Immediately after injection it is distributed to the brain (because of good blood flow & lipid nature of the CNS) → anesthesia After about 10 minutes, it leaves the brain to the muscles (because of the good blood flow) → Recovery from anesthesia. Finally, it leaves the muscle to stored in adipose tissue (because of high lipid content despite poor blood flow). 8 Page General Prof. M. Abdel-Bary The drugs which do not leave the blood to enter the tissues are said to follow single compartment model of distribution. 9 While the drugs which can enter the tissues are said to follow Page two compartment model of distribution, General Prof. M. Abdel-Bary Distribution may be roughly described by a global parameter called apparent volume of distribution (Vd). Volume of distribution Definition: Vd = amount of the drug in the body / plasma or blood concentration of the drug Importance: 1. It is an estimate of the tissue uptake of drugs4. 2. Drugs with high Vd are not amenable to dialysis5. 3. Estimation of the loading dose (LD)6. Factors affecting Drug distribution & Vd: 10 1. Blood flow (perfusion): Page 4 High Vd e.g. digoxin indicates extensive tissue distribution. 5 Hemodialysis is not resorted to in the treatment of toxicity of drugs with high Vd e.g. TCA 6 LD = Vd * Css/ F (where Css is the steady state concentration of the drug; see later) General Prof. M. Abdel-Bary  2. Lipophilicity: The most important rule in PK is “Membrane penetration  lipophilicity” 1. Lipophilicity facilitates drug absorption 2. Lipophilicity increases Vd, (lipophilic drugs can penetrate into most tissues e.g. CNS & placenta or enter the cells). 3. Lipophilicity enhances hepatic elimination (lipophilic drugs can enter the hepatocytes) 4. Lipophilicity reduces renal excretion (due to enhanced tubular re-absorption) Lipophilicity markedly modifies PK 11 3. Plasma Proteins Binding: Page General Prof. M. Abdel-Bary  Albumin is the main protein that binds drugs. It has basic binding sites with high binding capacity (but low affinity) e.g. for diazepam, propranolol & acidic binding sites with high affinity (but low capacity) e.g. for warfarin, NSAIDs, 1. Binding to plasma proteins may facilitate drug absorption 2. Binding to plasma proteins decreases Vd, (bound drug cannot penetrate into tissues e.g. CNS or enter the cells). 3. Binding to plasma proteins protects the drug from renal excretion (bound drug cannot be filtered) & probably from hepatic metabolism as well7 4. The bound drug (inactive) provides a reservoir that releases the free part (active). 5. Drugs interaction occurs between highly protein-bound drugs that bound to the acidic binding site of albumin e.g. between aspirin and warfarin. The interaction is serious if one of the involved drugs is highly toxic e.g. warfarin. 12 Page 7 However, albumin binding does not protect drugs with very active hepatic metabolism e.g. propranolol; in fact, binding in such case increases delivery of the drug for metabolism General Prof. M. Abdel-Bary  Binding to albumin modifies not only PK but also PD 4. Tissue Binding: some drugs are highly bound in certain tissues e.g. Chloroquine is highly bound to hepatic nucleic acids & retinal nucleoproteins8. Tetracyclines deposit in bone and teeth as they chelate calcium9. 5. Capillary permeability: is usually not limiting factor in distribution except in the blood brain barrier (BBB) where the capillary permeability is low: Non-ionized molecules as 2ry or 3ry amines can cross BBB e.g. general anesthetics, L-DOPA, while ionized molecules as 4ry ammonium compounds cannot cross e.g. neostigmine Some hydrophilic antibiotics can cross BBB in case of meningitis e.g. penicillin G, as meningeal permeability is increased in this particular case. 13 Page 8 This explains its effectiveness in hepatic amoebiasis as well as its ocular toxicity 9 This explains bone deformities & enamel hypoplasia in children General Prof. M. Abdel-Bary  Passage of Drugs to the Fetus A. Example of drugs that can harm the fetus: 1. Morphine → asphyxia neonatorum. 2. Warfarin → fatal hemorrhage & malformation. 3. Thalidomide → phocomelia. 4. Methimazole → fetal goiter and hypothyroidism. B. Examples of drugs that can treat the fetal diseases: 1. Glucocorticoids → for respiratory distress syndrome. 2. Phenobarbitone → for hyperbilirubinaemia. 14 Page General Prof. M. Abdel-Bary  C. ELIMINATION Lipid soluble drugs are eliminated mainly by hepatic metabolism while water soluble drugs are eliminated mainly by renal excretion10. METABOLISM The aim of drug metabolism is to convert lipid soluble drugs into water-soluble metabolites that can be easily excreted. Although, the activity of the drug is usually lost, sometimes metabolism leads to activation of prodrugs (e.g. enalapril is converted into enalaprilate) or a toxic metabolite is formed. Types of metabolic reactions: 1. Non-synthetic, (Phase I): usually converts the parent drug to a more polar metabolite: ❑ Oxydation, e.g. adrénaline ❑ Reduction, e.g. nitrates 15 ❑ Hydrolysis, e.g. ACh, Page 10 Renal elimination of lipophilic drugs is limited since the renal tubules will reabsorb any lipophilic molecules filtered from the glomeruli. Hepatic elimination of hydrophilic molecules is also limited since hydrophilic molecules cannot penetrate the hepatocyte membrane General Prof. M. Abdel-Bary  2. Synthetic, (Phase II): if phase I is not efficient enough for elimination, phase II is resorted to. It includes conjugation e.g. ❑ Sulphation e.g. estrogens ❑ Acétylation, e.g. isoniazide ❑ Glucuronidation e.g. chloramphenicol ❑ etc… Sites of metabolizing enzyme: 1. Microsomal enzymes e.g. cytochrome P450 oxidases or simply “CYP”. CYP is the most important metabolizing enzyme system. This enzyme system is further classified by family, subfamily & gene into many isozymes. The name of each one is designated by the term CYP followed by 3 characters e.g. CYP 2C9: 1) The first Arabic numeral represents the family, 2) The alphabetic letter represents the subfamily & 3) The second Arabic numeral represents its gene. 2. Non-microsomal enzymes e.g. dehydrogenase & esterases 16 Page General Prof. M. Abdel-Bary  Factors affecting drug metabolism: 1. Physiological changes in metabolizing activity due to age & sex. Or Pathological factors which affect hepatic activity e.g. liver cell failure 2. Pharmacogenetic variations in metabolizing enzymes e.g. slow & fast acetylators (see pharmacotherapeutics). 3. Enzyme induction & enzyme inhibition (see pharmacotherapeutics). EXCRETION Routes of Excretion: 1. The kidney is the most important route of elimination. Elimination occurs through: Glomerular filtration for water-soluble molecules whose size are < the glomerular pores11 Active tubular secretion either through acid carrier e.g. for penicillin, probenecid, salicylic acid, or basic carrier e.g. for amphetamine, quinine. 2. Other sites for excretion Lungs e.g. volatile anesthetics Saliva: e.g. iodides Milk: in lactating mothers 12 Bile: e.g. rifampicin Factors affecting renal excretion: Glomerular filtration rate (GFR) Plasma protein binding (PPB) → prevents filtration Drug Lipophilicity (i.e. pH of urine & pKa of the drug) 17 → enhances reabsorption Page 11 Lipophilic drugs are re-absorbed again after filtration & very large or albumin-bound drugs are not filtered 12 The pH of milk is more acidic than that of plasma → basic drugs accumulate in milk. Milk also contains more fat → retention of lipid soluble drugs e.g. morphine, laxatives. General Prof. M. Abdel-Bary  ELIMINATION PARAMETERS These are numerical values commonly used in measuring and describing the extent of elimination. These include the Kinetic orders, Half-life, Clearance, and Extraction Ratio. 1. Kinetic orders Zero order Kinetics (R = C0 * constant) The rate of elimination is constant i.e. a constant amount of drug is eliminated per unit time 18 Page General Prof. M. Abdel-Bary 1. The concentration-time curve is linear13 2. No constant half life 3. No Css is reached; repeated dosing → overshot conc. 4. Modest changes in dose or bioavailability can → toxicity. 5. Examples: ethanol First order kinetics (R=C * constant) The rate of elimination is proportional to the concentration i.e. a constant fraction of drug is eliminated per unit time 19 Page 13 The linear equation is C=A+BT where C=concentration, T=time, A & B are constants. A= the concentration at time 0 & B=the slope of the curve. General Prof. M. Abdel-Bary 1. The concentration-time curve is exponential14 2. It can be adequately described by a constant t½. 3. On repeated dosing; a steady state concentration15 (Css) is reached; Css  dose; Time to reach the steady state concentration (Tss) is approximately 4-5 t½. 4. Modest changes in dose or bioavailability is safe 5. Examples: Most drugs are eliminated by this method Saturation kinetics The drug follows first order kinetics if it is eliminated by very active or non-restricted mechanism e.g. glomerular filtration or metabolism with very active enzyme. If the elimination mechanism is a lazy one; the drug follows zero order kinetics. Sometimes the elimination mechanism is in between; in such case the drug follows first order kinetics at small dose & zero order kinetics at big doses (e.g. phenytoin, theophylline & salicylates). The elimination mechanism is said to be saturated. 20 Page The exponential equation is C=A*. e-BT where C=Concentration, T=time, A & B are constants; 14 e is the base of the natural logarithm (2.718). The constant A= the concentration at time 0; while the constant B is called the elimination rate constant. The term “time constant; Ƭ” (= the inverse of B) is used to describe the exponential relations. After 1 Ƭ; the concentration decreases to 1/e of its initial value. The term “half-life ; t1/2” (=ln ½ /B) is more familiar than the term Ƭ. After 1 t1/2 the concentration decreases to ½ its initial value. 15 Repeated dosing results in increasing the drug concentration & accordingly the rate of elimination increases till the rate of administration becomes equal to the rate of elimination. At this point the Css is reached; actually, after 4 t½ > 95% of the Css is attained General Prof. M. Abdel-Bary  2. Elimination half-life (t1/2) Definition: It is the time required to reduce the plasma concentration of drug to half the initial concentration16. Value of elimination t½: 1. Deciding the dosage interval: If dosage interval = t½ → body stores twice the dose (for most drugs, this is an accepted choice 17). If dosage interval < t½ → more drug accumulation. If dosage interval > t½ → decrease in drug concentration occurs between doses. 21 2. Estimating the time required to attain steady state concentration (Tss): 4-5 t½ Page 16 Elimination half-life = ln ½ / elimination rate constant = 0.693/ elimination rate constant. 17 For drugs with too short t1/2; we may resort to IV infusion or slow release (SR) oral preparations. General Prof. M. Abdel-Bary Factors affecting elimination t½: 1. The state of the eliminating organs i.e. liver & kidney functions 2. The delivery of the drug to the eliminating organs e.g. plasma protein binding limits renal filtration; also drugs with very high Vd may escape from elimination in the tissues. 3. Extraction ratio (E) & Hepatic clearance (Cl liver) Extraction ratio (E) is the fraction of the drug eliminated by the liver. ❑ When E is > 0.6 → clearance is nearly flow-dependent, e.g. propranolol. ❑ When E is < 0.2 → clearance is nearly enzyme-dependent, e.g. warfarin ❑ When E is 0.2-0.6 → clearance is both flow and enzyme dependent, e.g. acetaminophen, chloramphenicol 22 Hepatic clearance (Cl liver) is the volume of blood cleared by the liver per unit time: Cl liver= E * Q where Q=hepatic blood flow Page General Prof. M. Abdel-Bary  4. Systemic clearance (CL) Definition: It the volume of a fluid cleared from the drug per unit time. It is equal to the sum of individual organs clearance i.e. Cl = renal clearance (Clr) + non-renal clearance (Clnr). Factors affecting drug clearance: 1. Blood flow to the clearing organ. 2. Binding of the drug to plasma proteins. 3. Hepatic enzymes activity, GFR and tubular secretion. Significance of Clearance 1. Calculation of elimination rate constant & half life t½=0,693 * Vd/Cl 23 2. Calculation of maintenance dose (MD): MD=Cl * Css Page General Prof. M. Abdel-Bary