Pharmacokinetics Nursing 2024 PDF

Pharmacokinetics Prof. Samuel B. Kombian Department of Pharmacology and Toxicology SPPS/SoM, UDS, Tamale Nurses, PH, MLSD Adapted from Mr Vitus S Badii’s-Pre-2023 lectures  Pharmacokinetics  Lecture Content Define Pharmacology and its branches...

Pharmacokinetics Prof. Samuel B. Kombian Department of Pharmacology and Toxicology SPPS/SoM, UDS, Tamale Nurses, PH, MLSD Adapted from Mr Vitus S Badii’s-Pre-2023 lectures  Pharmacokinetics  Lecture Content Define Pharmacology and its branches Explain what drugs are, their sources & how they are named Describe elements of Pharmacokinetics (ADME) Absorption Distribution Elimination (metabolism & excretion) Describe clinical relevance of Pharmacokinetics  Pharmacokinetics  Lecture Outcomes/Expectation After this lecture, the students should: Distinguish between Pharmacodynamics and pharmacokinetics Know the sources of drugs and how they are named Know the various elements of pharmacokinetics Be able to describe the roles of adsorption, distribution, elimination of drugs Know the various physical and biological processes that underlie ADME Know the organs and body systems involved in ADME Know the clinical implications of ADME What is Pharmacology??? 4  Comes from Greek words: pharmacon- drug; logos –study  Deals with interaction of exogenously administered chemical molecules (drugs) with the living system  Science that deals with the study of drugs and their interaction with the living system.  Two main Divisions  Pharmacokinetics  Pharmacodynamics  What is Pharmacodynamics??? 5  Pharmacodynamics - The study of the measurable changes/ effects that the drug has on the living system.  It involves the mechanisms/processes by which the drug exerts its effect, when introduced into the living system. Effect  Example, paracetamol is taken to treat headache. How does paracetamol do this. Mechanism  Pharmacokinetics?? 6  Pharmacokinetics: Is the study of the effect of the body on the drug. It involves: absorption ,distribution , metabolism and excretion of the drugs.  That is, the time course of drugs into, within and out of the body.  Once drug is administered it is absorbed, distributed to different parts of the body to the site of action, is metabolized and excreted.  ADME is a dynamic process which may occur simultaneously and not in isolation??  What is a Drug 7  These are any chemical/biological substances used in the treatment, cure, prevention and diagnosis of a disease  ‘’Every drug is a poison’’?? Right Dose???  Example: Paracetamol is used to commit suicide at extreme doses  An Ideal drug is Effective, Safe, Selective in action, Reversible in its effect, Predictable in its effect and Easy to administer  Sources of Drugs 8  Natural  Plant (digitalis, belladonna, cinchona, morphine-opium; artemisinin)  Animal (dry skin of toad –adrenaline; insulin; Exenetide isolated from lizard venom)  Mineral (Kaolin, Iron, Aluminium hydroxide)  Synthetic (prednisolone, pholcodine, fentanyl, pethidine)  Semisynthetic (sulphonamides, thiazide diuretics, heroin, hydroartemisinin, artemether, artesunate)  Recombinant DNA technology  Naming of drugs 9  Chemical name: named using the chemical structure of the drug/ E.g. 3-azido-3-deoxythymidine for Zidovudine  Chemical names are not used in prescribing  Generic/non-proprietary name: names adopted by the scientific bodies like BAN(British Approved Names) and USAN(US Approved Names) councils. Aspirin, Paracetamol/ Acetaminophen, Pethidine/Meperidine  Brand/proprietary name: These are names assigned to drugs by the manufacturer. Viagra for Sildenafil, Clomid or Fertomid for Clomiphene, Tylenol for acetaminophen  PHARMACOKINETICS 10  The time-course of drugs in the living systems:  Looks at the rudiments of Absorption, distribution, metabolism and excretion (ADME) How the drug Comes and Goes??  Absorption 11  Absorption is defined as the process by which a drug proceeds/moves from the site of administration to the site of measurement (?) (usually blood, plasma or serum).  Characterized by:  Rate of absorption  Absorption rate constant (ka) – a function of the rate of absorption  Area under the concentration curve (AUC) Drugs Given Via IV Route???  Drug Liberation 12  For orally, rectally or vaginally administered the drugs to be absorbed:  The dosage form must disintegrate & dissolve in the body fluid to liberate the drug to be absorbed.  The form and ease of liberation impact on how fast or slow it will be absorbed  ADME = LADME Enteric coated drugs e.g. aspirin are design to resist liberation in the stomach. Mostly to protect against direct irritation in stomach. Must be swallowed whole and not chewed. Cell Membrane as a Barrier 13 Absorption Via Passive Diffusion 14 Passive diffusion involves the passage of drugs across a cell membrane from an area of high drug concentration, such as the GIT, to an area of low drug concentration, such as in the blood. E.g. Digoxin & Aspirin.  rate of diffusion is directly proportional to the concentration gradient (First order kinetics) Drugs which are: lipid solubility molecular size (small) degree of ionization Transport Via facilitated passive diffusion 15  Transfer with the help of carriers without the use of energy (ATP)  Glucose absorption from the GUT is carried mainly via Na+/glucose cotransport (SGLT-1). This uses energy from Na+ to drive Glucose entry into blood  Transfer of glucose into RBC  Few drugs utilise this, eg. transport of vitamin B12 across the GIT  Absorption Via Active Transport 16  Active transport uses energy to transport drug molecules against a concentration gradient, which usually occurs at specific sites in the small intestine.  The majority of drugs that are absorbed via active transport share a similar structure with endogenous substances: e.g. vitamins, sugars and amino acids.  Transport via Pinocytosis 17 Another emerging suggested mechanism of drug transport in via pinocytosis  In pinocytosis, fluid or particles are engulfed by a cell. The cell membrane engulfs/encloses the fluid or particles, then fuses again, forming a vesicle that later detaches and moves to the cell interior.  Energy expenditure is required. Pinocytosis probably plays a small role in drug transport, except for protein drugs??  Factors affecting Absorption 18  Rate of absorption depends on:  Liberation time  Nature or form (polar or non polar) of the drug  The molecular size of drug Physiochemical Digoxin, steroids, aspirin properties  pH and ionization: Ionized drugs are poorly absorbed while unionized drugs are lipid soluble and are well absorbed. Ionization affects absorption 19 CH3COOH 𝐶𝐻3𝐶𝑂𝑂 + H+ − Acidic Favours Un-ionization Medium NH3 + H+ 𝑁𝐻4 + Favours Un-ionization Basic Medium  Environmental pH and Ionization 20 If we put an acidic drug in an environment with a lot of H+ (low pH) what will this equilibrium do? HA ↑ 𝐻 + + − 𝐴 Non-ionized form predominates! A real live, actual clinical question... 21 Phenobarbital is an acidic drug. In the stomach will it exist mostly in ionized or non-ionized form? How will this affect Phenobarbital’s absorption?  22 Moral of the story... Acidic drugs are best absorbed from (strongly) acidic environments Basic drugs are best absorbed from (strongly) basic environments So... 23 To  absorption of an acidic drug e.g. Aspirin… acidify the environment To  absorption of an acidic drug… alkalinize the environment...  Absorption Cont’d 24  Area and vascularity of the absorbing surface???  Gastrointestinal motility: Decrease in Gastric emptying time and increase intestinal motility Increases absorption Decreases absorption  Absorption Cont’d 25  Presence of food : Drugs may form complexes with food, such complexes are poorly absorbed.e.g. Tetracycline chelate Ca present in food, so absorption ↓.  Diseases: Diseases of the gut like malabsorption and achlorhydria result in reduced absorption of drugs.  First-pass Metabolism 26  First pass metabolism is the metabolism of the drug during its passage from the site of absorption to the systemic circulation. it is also called pre-systemic metabolism or first pass effect.  Drugs given orally may be metabolized in the gut wall and in the liver before reaching the systemic circulation. The extent of FPM differs from drug to drug and person to person.  FPM may result in partial to total inactivation of the drug. when it is partial , it can be compensated by giving higher dose of particular drug, e.g. nitroglycerin, salbutamol.  First Pass Metabolism 27 Destroyed by Destroyed Not Destroyed Not GI acids by GI Absorbed by liver absorbed Enzymes Enters into Dose systemic circulation Bioavailability: the fraction of the administered dose reaching the systemic circulation Bioequivalence: it is the study of comparison bioavailability of different formulation of the same drug.  How Route affects bioavailability 28  A drug given by the intravenous has an absolute bioavailability of 1 (F=1 or 100% bioavailable)  While drugs through other routes usually have an absolute bioavailability of less than one.  The absolute bioavailability is the area under curve (AUC) non-intravenous divided by AUC intravenous in % terms Body compartments & Drug Distribution 29  All of the fluid in the body (referred to as the total body water), in which a drug can be dissolved, can be roughly divided into three compartments: Intravascular (blood plasma found within blood vessels) Extravascular - interstitial/tissue (fluid surrounding cells) Intracellular (fluid within cells, i.e. cytosol)  The distribution of a drug into these compartments is dictated by its physical and chemical properties The Total Body water =40L 30 Vascular Extravascular Intracellular 3L 9L 28 L 4% BW 13% BW 41% BW  Drug Distribution 31  The process of reversible transfer of drug to and from the site of measurement (usually blood or plasma). Rate and Extent of drug distribution is determined by:  how well the tissues and/or organs are perfused with blood  the binding of drug to plasma proteins and tissue components  the permeability of tissue membranes to the drug molecule (BBB, placenta).  Characterised by volume of distribution (Vd)  Volume of distribution (Vd) 32  Volume within which drug appears to be distributed (Apparent Vd), if the concentration throughout the body were equal to that in plasma (assuming single compartment)  Relates drug concentration in plasma to the total Amount in the body: (Vd = A/Cp)  Determinants  Plasma protein binding  Result in small Vd  Tissue binding  Protein, Fat  Result in large Vd  Vd Contd 33  Clinical importance  In overdose, haemodialysis effective for small Vd (salicylate)  Haemodialysis not effective for large Vd ( pethidine) Loading dose = Vd x Cp Cp = effective plasma conc.  Plasma Binding Proteins 34  Many drugs bind to plasma proteins  Albumin (acidic drugs, eg warfarin, NSAIDs)  Alpha-1 acid glycoprotein (basic drugs, eg quinine)  Lipoproteins (basic drugs)  Globulins (hormones) Only free form of a drug can bind to targets to produce pharmacological effect Drug-PBP Interactions 35  Plasma Binding Proteins 36  Warfarin is highly protein bound (99%). Aspirin binds to the same site on serum proteins as does Warfarin. If a patient on Warfarin also takes aspirin, what will happen? 1) Why? 2) Why do we care?  Examples of highly protein bound drugs: phenobarb, Phenytoin, valproic acid , tetrahydrocannabinol, NSAIDS, Acetazolamide, metolazone, cisplatin and vincristine  Clinical implications of changes in protein binding 37  Changes in extent of protein binding may occur during: Disease and nutrition (liver, poor protein diet). Protein binding displacement interactions.  eg valproate displaces phenytoin – increases free phenytoin, compensate with increased clearance.  Clinically relevant effects if: >90% of drug is protein bound eg phenytoin, warfarin Small volume of distribution.  Blood-Brain Barrier 38 The blood brain barrier consists of cells tightly packed around the capillaries of the CNS. What characteristics must a drug possess to easily cross this barrier? WHY???  39 E L I M I N A T I O N  Elimination 40  Elimination is the irreversible loss of drug from the site of measurement (blood, serum, plasma).  occurs by one or both of:  Metabolism  Excretion  Characterised by:  Clearance (CL): Vol of blood cleared of drug per unit time ( l/h, ml/min)  Half-lifeof elimination (t1/2): time it takes for initial conc to fall by half)  METABOLISM 41  Process of conversion of one chemical form to another chemical form  Resulting metabolites (usually) that possess little or none of the activity of parent drug  Active metabolites  Allopurinol a XO Inhibitor – Oxypurinol which is long acting.  Propranolol a non-selective b-antagonist: active metabolite - 4-hydroxypropranolol  Reactive (sometimes toxic) metabolites may be formed e.g  paracetamol – N-Acetyl-para-benzoquinone-imine (NAPQI)  Inactive metabolite: loss of pharmacological activity  Processes of Metabolism 42  Main site – Liver (rich in enzymes)  Other sites – kidney, lungs, gut mucosa  Two main Phases, I and II are involved 1. Phase I: change by oxidation, reduction and hydrolysis  Chemically active site often introduced  Mixed function oxidases (cytochrome P450 enzymes) – most important reaction  E.g. paracetamol, midazolam, diazepam.. Phase I: The Most Important Enzymes 43  Microsomal cytochrome P450 monooxygenase family of enzymes, which oxidize drugs  Act on structurally unrelated drugs  Metabolize the widest range of drugs  CYP family of enzymes 44  WHY CYP450 enzymes???  > 50 isoforms  Major source of catalytic activity for drug oxidation It’s been estimated that 90% or more of human drug oxidation can be attributed to 6 main enzymes: CYP1A2 CYP2D6 CYP2C9 CYP2E1 CYP2C19 CYP3A4 In different people and different populations, activity of CYP oxidases differs.  Variability in metabolism 45  These enzymes exist as isoforms and may determine the rate of metabolism of food and drugs  Fast metabolizers: these are the more active form of the enzymes with high turn over rate. They quickly metabolizes drugs and food which leads to quick attenuation of activity  Slow metabolizers: These are more indolent forms of the enzymes which carry out metabolism more slower than they should have  Importance??  Pharmacogenetics/Pharmacogenomics?? Pharmacogenetics is the study of genetic causes of individual variations in drug response whilst pharmacogenomics deals with the impact of multiple mutations in the genome that may determine the patient's response to drug therapy.  Phase II 46  Phase II (Synthetic reaction)  water soluble substance present in the body like glucuronic acid, sulfuric acid, acetic acid or an amino acid combine with the drug to form highly polar compounds easily excreted by the kidneys.  large molecules are excreted through the bile.  E.g.  morphine, paracetamol, salicylates (glucuronic acid)  oral contraceptives, paracetamol (sulphates)  Isoniazid, phenelzine (acetyl group) Relevance of phases of metabolism 47  Main function of phase I reactions is to prepare chemicals for phase II metabolism and subsequent excretion  Phase II is the true “detoxification” step in the metabolism process  Phase II Reactions 48  Conjugation reactions:  Glucuronidation (on -OH, -COOH, -NH2, -SH groups)  Sulfation (on -NH2, -SO2NH2, -OH groups)  Acetylation (on -NH2, -SO2NH2, -OH groups)  Amino acid conjugation (on -COOH groups)  Glutathione conjugation (to epoxides or organic halides)  Fatty acid conjugation (on -OH groups Paracetamol (Acetaminophen) toxicity 49 Modulation of CYP450 Enzymes 50  Inhibitors: cimetidine, fluconazole:  prolong action of drugs and may lead to toxicity  inhibit action of pro-drugs (those biotransformed to active agents)  Inducers: barbiturates, carbamazepine, phenytoin, rifampicin, alcohol:  shorten action of drugs (may lead to decreased effect)  increase effects of pro-drugs Inhibitors & inducers of microsomal enzymes 51  Metabolism cont’d. 52  Liver disease  Slows metabolism  Prolongs effects  Dose adjustment/contraindications  EXCRETION 53  Defined as the irreversible loss of a drug in a chemically unchanged or unaltered form  Primary site – kidney (liver important, lungs, milk, faecal matter)  Renal excretion  Glomerular filtration (MW less than 10, 000, i.e. almost all drugs)  Renal tubular excretion – cells of proximal tubule actively transport ions using transporters (OATs-organic anion transporter and OCTs-organic cation transporter)  Renal tubular reabsorption  Renal Disease and Excretion 54  Renal disease  Slows excretion  Prolongs effects  Dose adjustment in disease conditions Active Tubular Transport 55  Probenecid is moved into the urine by the same transport pump that moves many antibiotics. Why is probenecid sometimes given as an adjunct to antibiotic therapy?  Urine pH and Elimination 56  A patient has overdosed on phenobarbital. Phenobarbital is an acid. If we ‘alkalinalize’ the urine by giving bicarbonate what will happen to the phenobarbital molecules as they are filtered through the renal tubules?  Biological Half-life (t1/2) 57  Time taken to eliminate 1/2 of the total drug amount  Shorter t1/2 may need more frequent doses  Exceptions: Dosing for drugs with “hit and run” mechanisms of action (e.g. Aspirin for antiplatelet activity, omeprazole)  Hepatic disease may increase t1/2 A drug has a half life of 20 minutes. You give a patient a 58 dose of 300mg. How much of the drug would remain after 1 hour?  59 THANK YOU Sources: ??