Lecture 3-5 Pharmacokinetics I-III PDF

Dr. Rani Qasem Susan Posky Pharmacokinetics Pharmacokinetics I, III,and II andIIIIII Dr. Tariq Alqahtani Dr. Rani Qasem & Dr Mai Ajaji Dr. Rawan Alnafisah PHRB – 301 LECTURES 3-5- Pharmacokine...

Dr. Rani Qasem Susan Posky Pharmacokinetics Pharmacokinetics I, III,and II andIIIIII Dr. Tariq Alqahtani Dr. Rani Qasem & Dr Mai Ajaji Dr. Rawan Alnafisah PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah 1 Lecture Learning Outcomes At the end of the lectures, the students should be able to: 1. Recall the factors that influence drug absorption. 2. Illustrate the methods by which drug absorption can be manipulated. 3. Explain the factors that influence drug distribution. 4. Highlight the importance of drug metabolism for elimination. 5. Define the major chemical pathways of metabolism: oxidation, reduction, hydrolysis, and conjugation. 6. Describe the concept of detoxication versus bioactivation. 7. Know the major sites of drug elimination: liver, kidney, lungs, and first-pass effects. 8. Explain the concept of drug clearance as a combination of metabolism and excretion. 9. Recognise the effects of age, renal disease, and liver disease on drug elimination. PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah 2  Pharmacokinetics Pharmacokinetics is concerned with factors that directly affect the amount of drug that will arrive at the target site, which will determine the intensity of drug action and the duration of action. Pharmacokinetics deals with the ADME Factors: PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah 3 The Fate of Drugs in the Body PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah 4 Drug Absorption PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Absorption Absorption?is the passage of a drug from its site of application (administration) to the bloodstream (plasma). For drugs that act locally ?(e.g. inhalation of a bronchodilator aerosol to treat asthma), absorption is not required. The mere presence of a drug in the blood does not lead to a pharmacological response. – To be effective,? the drug must leave the vascular space and enter the intercellular or intracellular spaces or both. PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah Drug Routes of Administration PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Absorption Absorption is important for all routes of administration except3for intravenous (IV) injection A. Mechanisms of absorption of drugs from the GI tract: PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Factors Affecting Drug Absorption B. Factors affecting the absorption of a drug are:3 3 Water solubility (rate of dissolution) - 2 Lipid or fat solubility - 3 pH Partitioning & 4 Surface area - S Blood flow - 6 Availability of transport mechanisms - PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah 9  Rate of Dissolution All drugs must be in solution (dissolve) before they can be absorbed All body fluids are water-based. Therefore, a drug must be soluble in water in order to be absorbed Dissolution of the drug in aqueous solution is dependent on:? 56 I -- 1. Disintegration of the drug – Disintegration increases the surface area of a drug - 5 4 – Sometimes, the manufacturer tries to hasten disintegration of - tablets by adding starch that swells upon contact with water & 2. pH of the solution PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Rate of Dissolution 2. The pH of the solution The relative acidity or basicity of the fluids into which a drug is placed will affect how rapidly the drug will dissolve. – The pH of the stomach can be as low as 1.0, The pH of the small intestine can range from 6.9 to 7.4, while the pH of the plasma is approximately 7.4. – Weakly acidic drugs (e.g. aspirin) are more soluble in a - basic or alkaline solution like the small intestine. - – Weakly basic drugs (e.g. tetracycline) are more soluble - in an acidic solution like the stomach. - PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Lipid or Fat Solubility Highly lipid-soluble drugs are absorbed more rapidly than drugs with low lipid solubility?because lipid-soluble drugs can [] readily cross the biological membranes. To reach its site of action, a drug must cross a number of biological barriers and membranes. All body membranes are lipid in nature, which are selectively permeable. These membranes will only allow the unionised particles (neither positive nor negative charge) to pass through them. PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  pH Partitioning The degree of ionisation of drugs depends on?the local pH of the solution in which the drug is dissolved, which influences their lipid–water partition coefficient and M hence their ability to diffuse through membranes. Ionisation is the process whereby a substance breaks down into positively and negatively charged particles. HA * H+ + A- has to be(weak) Drug in order to be reversable B + H+ BH+ Therefore, the drugs can exist in either a charged or uncharged form. PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  a Other Factors Affecting Drug Absorption Absorption &Surface area: The larger the surface area, the faster absorption will be. –[Orally administered drugs are usually absorbed from the small intestine rather than from the stomach.J Absorptiona Blood flow: Drugs are absorbed most rapidly from sites where blood flow is high. Availability of transport mechanisms: Channels and pores Transport systems Direct penetration of cell membrane (diffusion). PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah X PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah X Bioavailability and Bioequivalence C. Bioavailability and Bioequivalence Bertram-Ralph E, Amare M. Factors affecting drug absorption and distribution. General bioequivalence profile of generic vs brand products. Anaesthesia & Intensive Care Medicine. 2023 Feb 17. Mastan S, Latha TB, Ajay S. The basic regulatory considerations and prospects for conducting bioavailability/bioequivalence (BA/BE) studies–an overview. Comparative Effectiveness Research. 2011 Mar 22:1-25. PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah 16 Drug Distribution PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Distribution Distribution,1drug movement from the blood to the interstitial space of tissue and into cells. PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Distribution Once a drug has entered the blood, the rate at which it penetrates tissues and other body fluids depends on:? 1. Blood flow to tissue (perfusion rate): Normally, most tissue is well perfused. In certain pathological conditions (e.g. abscesses & tumours), there is a limited blood supply. 2. The ability of a drug to exit the vascular system. PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Exiting the Vascular System Drugs in the vascular system leave the blood at the capillary bed, which depends on: 1. Capillary permeability: – Capillaries of the CNS (BBB). – Agents that affect capillary permeability (e.g. histamine) or capillary blood-flow rate (e.g. norepinephrine). PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Exiting the Vascular System 2. Extent of plasma protein and specific organ binding – Drugs can form reversible bonds with various proteins in the body (plasma albumin, large molecule = 69000 D) – Drugs can exist in the blood as either bound or unbound (free) – Bound drugs are?pharmacologically inactive - – Bound drugs are considered as drug reservoirs - – Anionic (weak acid) and hydrophobic drugs – Protein binding restricts drug distribution – Source of drug interactions e.g. warfarin (99%), gentamicin (10%) & Active unbound :. PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Y - Talevi, A., Bellera, C.L. (2021). Drug Binding to Plasma Proteins. In: The ADME Encyclopedia. Springer, Cham. https://doi.org/10.1007/978-3-030- 51519-5_53-1 PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Drug Elimination Drug elimination?is the irreversible loss of drugs from the body. Drug elimination occurs by two processes: – Metabolism:? involves enzymatic conversion of one chemical entity to another – Excretion:2consists of elimination from the body of a chemically unchanged drug or its metabolites PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah Drug Metabolism PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Drug Metabolism Drug Metabolism -Biotransformation ? It is the process by which the drug is chemically converted to a metabolite. & The liver is the chief organ?of drug - metabolism. It is richly supplied with blood, of which 1100 X ml is received each minute from the intestines through the portal vein and 350 ml through the hepatic artery, comprising nearly 1/3 of cardiac output. PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Drug Metabolism 1 The main purpose of drug metabolism?is to ‘detoxify’ 2 drugs and render them less pharmacologically active. Important exceptions: – Where the metabolite is more active (prodrugs) e.g. Erythromycin-succinate (less irritation of GI) → Erythromycin – Where the metabolite is toxic (e.g. acetaminophen metabolites) – Where the metabolite is carcinogenic If the drug metabolism is delayed, drug accumulation may occur. PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Drug Metabolism There is a close relationship between drug metabolism and the normal biochemical processes occurring in the body: – Drug metabolism involves many pathways associated with the synthesis of endogenous. – Many of the enzymes involved in drug metabolism are principally designed for the metabolism of endogenous compounds. – These enzymes metabolise drugs only because the drugs resemble the natural compound. PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Drug Metabolism The liver is the principal site of drug metabolism: * Doesn't need metabolize Hydrophilic - ↳ can be metabolized – Hydrophilic vs. lipophilic drug Other sites2of drug metabolism include the gut, lungs, skin, --- kidneys and others. - PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Drug Metabolism For orally administered compounds: – Intestinal metabolism – Liver metabolism: ‘First-pass effect’ – Enterohepatic recycling – Gut microorganisms PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Read Consequences of Drug Metabolism 1. Inactivation of drugs 2. Promotion of renal excretion by increasing drug polarity (water solubility) 3. Increased effectiveness of drugs 4. Activation of ‘prodrugs’ 5. Increased drug toxicity PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Consequences of Drug Metabolism A. 2 Active drug → inactive metabolites 8 B. Inactive drug → active/enhanced activity X e.g. Cyclophosphamide → liver → aldophosphamide → liver → carboxyphosphamide I → tumor → phosphoramide mustard and acrolein & C. Active drug → active metabolites X e.g. Phenacetin → Acetaminophen (paracetamol) O D. Active drug → toxic metabolites X e.g. Isoniazide → Acetylisoniazide PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Read Special Considerations in Drug Metabolism Age; the liver is not fully developed in infants Induction or inhibition of drug-metabolising enzymes First-pass effect, rapid hepatic inactivation of certain oral drugs (e.g. Nitroglycerine 99.9%, Propranolol 70%) Nutritional status, cofactors Competition between drugs PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Phases of Drug Metabolism o Drug metabolism involves two kinds of biochemical reactions,7 which usually decrease lipid - - solubility, thus increasing renal elimination: - - Phase I reactions are? catabolic (e.g. oxidation, reduction or hydrolysis). Phase II reactions are3synthetic (anabolic). PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Phase I Reactions Phase I reactions involveSmodification of the chemical structure of the drug by adding or exposing a small polar functional group (-OH, -SH, -NH2, -COOH, etc.), a process known as--- ‘functionalisation’. – It involves a hepatic microsomal mixed function oxidase system (cytochrome P450). – Metabolites are often inactive and sufficiently polar (hydrophilic) & to be excreted readily. & – However, some metabolites are more chemically reactive (i.e. more toxic or carcinogenic). – The functional group serves as the point for the phase II reactions. PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  X Cytochrome P450 Humans have 18 families of cytochrome P450 genes and 43 subfamilies: – CYP1 drug metabolism (3 subfamilies, 3 genes, 1 pseudogene) – CYP2 drug and steroid metabolism (13 subfamilies, 16 genes, 16 pseudogenes) – CYP3 drug metabolism (1 subfamily, 4 genes, 2 pseudogenes) – CYP4 arachidonic acid or fatty acid metabolism (5 subfamilies, 11 genes, 10 pseudogenes) – CYP5 Thromboxane A2 synthase (1 subfamily, 1 gene) – CYP7A bile acid biosynthesis 7-alpha hydroxylase of steroid nucleus (1 subfamily member) – CYP7B brain-specific form of 7-alpha hydroxylase (1 subfamily member) – CYP8A prostacyclin synthase (1 subfamily member) – CYP8B bile acid biosynthesis (1 subfamily member) – CYP11 steroid biosynthesis (2 subfamilies, 3 genes) – CYP17 steroid biosynthesis (1 subfamily, 1 gene) 17-alpha hydroxylase – CYP19 steroid biosynthesis (1 subfamily, 1 gene) aromatase forms estrogen – CYP20 unknown function (1 subfamily, 1 gene) – CYP21 steroid biosynthesis (1 subfamily, 1 gene, 1 pseudogene) – CYP24 vitamin D degradation (1 subfamily, 1 gene) – CYP26A retinoic acid hydroxylase, important in development (1 subfamily member) – CYP26B probable retinoic acid hydroxylase (1 subfamily member) – CYP26C probable retinoic acid hydroxylase (1 subfamily member) – CYP27A bile acid biosynthesis (1 subfamily member) – CYP27B Vitamin D3 1-alpha hydroxylase activates vitamin D3 (1 subfamily member) – CYP27C unknown function (1 subfamily member) – CYP39 7 alpha hydroxylation of 24 hydroxy cholesterol (1 subfamily member) – CYP46 cholesterol 24-hydroxylase (1 subfamily member) – CYP51 cholesterol biosynthesis (1 subfamily, 1 gene, 3 pseudogenes) lanosterol 14-alpha demethylase PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Drug Metabolism - Oxidation Oxidation reactions NOT catalysed by Cytochrome P450: – Flavin-containing monoxygenase system Present mainly in liver but some in gut and lung Oxidises compounds containing sulfur and nitrogen – Alcohol and aldehyde dehydrogenase – Xanthine oxidase – Monoamine oxidase (MAO) Catalyses oxidative deamination of endogenous catecholamines (epinephrine) PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Phase II Reactions Phase II reactions involve addition or conjugation -- of the functional group of phase I with endogenous molecules to produce inactive and more water-soluble metabolites that can be readily excreted from the body. – Conjugation with Glucuronic acid (glucuronide) Sulfuric acid Acetic acid Amino acids PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Phase I and II Reactions &Exam Phase I reactions usually precede phase II reactions. In some cases, the xenobiotic already has a - functional group that can be conjugated in a - phase II reaction without going through a phase I reaction. PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Drug Metabolism - Phase II Glucuronidation (α-d-glucuronic acid): & – The quantitatively most important phase II pathway - for drugs and endogenous compounds – Enterohepatic recycling may occur due to gut glucuronidases. – Requires enzyme UDP-glucuronosyltransferase (UGT) itemen – Genetic family of enzymes with approximately 16 isoforms in human PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Prior Knowledge Drug Metabolism - Phase I and II Products (metabolites) are generally more water soluble. These reactions products are ready for (renal) excretion. There are many complementary, sequential and competing pathways. Phase I and phase II metabolisms form a coupled interactive system interfacing with endogenous metabolic pathways. PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah X Phase I and II Reactions PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah Drug Excretion PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah * Exam (clearance Excretion Excretion, the movement of a drug and/or its metabolites out of the body. - The kidney as excretory organ: most drugs are eliminated in urine either chemically unchanged or as metabolites. Non-renal routes of drug excretion – Bile, faeces (enterohepatic circulation) – Lungs – Sweat – Saliva – Breast milk PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  Renal Excretion 1. Glomerular filtration: Free drug (not bound to albumin) having molecular weights < 5000 flows - through the capillary into the glomerular filtrate. 2. Passive tubular reabsorption: The drug, if uncharged, may diffuse out of the nephric lumen, back into systemic circulation. – Manipulating the urinary pH to increase the ionised form of the drug in the lumen to minimise the amount of back-diffusion. – [Weak acids3can be eliminated by alkalinisation of - the urine, – whereas elimination of weak bases may be - increased by [acidification of the urine.3 3. Active tubular secretion: Secretion of drugs that were not filtered occurs by energy-intensive active transport systems. PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah  # ready discussed Other Routes of Drug Clearance This includes via the intestines, the bile, the lungs and breast milk in nursing mothers, among others. – The faeces are primarily involved in elimination of - - unabsorbed orally ingested drugs or drugs that are secreted directly into the intestines or in bile. – The lungs are primarily involved in the elimination of anaesthetic gases (e.g. halothane and isoflurane). – Elimination of drugs in breast milk is clinically relevant as a potential source of undesirable side effects for the infant. Toxicology & – Excretion of most drugs via sweat, saliva, tears, hair - and skin occurs only to a small extent. - PHRB – 301 LECTURES 3-5- Pharmacokinetics I, II and III Dr. Tariq Alqahtani/Dr. Rawan Alnafisah