Pharmacokinetics Lecture 2024 PDF

Pharmacokinetics ADME 1.Absorption 3. Metabolism 2.Distribution 4. Excretion Dr J Haylor, Medicine, UCLan 2024 Routes of Administration  1. Drug...

Pharmacokinetics ADME 1.Absorption 3. Metabolism 2.Distribution 4. Excretion Dr J Haylor, Medicine, UCLan 2024 Routes of Administration  1. Drug Absorption i. Gastrointestinal Tract ii. First Pass Metabolism iii. Bioavailability  (i) Gastro-Intestinal Tract Sublingual tablets, sprays (glyceryl trinitrate) Oral tablets, capsules (most drugs) Rectal suppositories (diazepam) rectal foams (steroids)  Gastric Emptying and Intestinal Surface Area Gastric Emptying Surface Area important determinant of drug absorption most drugs absorbed from the small intestine  (ii) First Pass Drug Metabolism liver 1st Pass Metabolism  (iii) Bioavailability The ‘bioavailability’ of a drug is the fraction of a dose reaching the systemic circulation after oral dosing. Determinants of Bioavailability Bioavailability of some Commonly used Drug Absorption Drugs Food Lidocaine 15% Can decrease the oral availability of sparingly lipid soluble drugs Propranolol 20% Morphine 30% e.g. food decreases the oral availability of atenolol by 50% Paracetamol 57% Theophylline 81% First-pass metabolism Diazepam 97% 2. Drug Distribution i. Protein Binding ii. Blood Flow iii. Body Compartments Blood Brain Barrier Placental Barrier iv. Cell Membrane  Capacity Acidic drugs of organ bind mainly to albumin Basic drugs bind mainly to α1-acid glycoprotein Blood flow Protein binding A. Perfusion-Rate Limitation B. Permeability-Rate Limitation  Ionisation Acidic brain cell “traps” ionised weak base e.g. morphine ? increased toxicity Brain Ion Trapping SUXAMETHONIUM (Polar; ionized)  (iii) Cell Membrane Extracellular Intracellular GUT BLOOD Fluid (E.C.F.) Fluid (I.C.F.) g.i. capillary cell mucosa endothelium membrane + blood-brain barrier Pharmacokinetics ADME 1.Absorption 3. Metabolism 2.Distribution 4. Excretion  3. Drug Metabolism i. Lipid solubility ii. Phase I drug metabolism iii. Phase II drug metabolism iv. Liver Enzymes : Drug Interactions v. Genetic Polymorphism vi. Prodrugs  Fat soluble drugs Renal Excretion X Hepatic Metabolism Hydrophilic metabolites  Primary metabolite Phase I Drug Excretion Phase II Phase II Conjugate  2.Amide hydrolysis Lidocaine H N O C2H5 N 3. N-dealkylation 1.Aromatic C2H5 hydroxylation  Paracetamol H N O sugar HO sulphate Metabolism glucuronide O H N O glutathione H N O HO S O O Cysteine and mercapturic C6H9O6 O acid conjugates Urinary excretion Urinary excretion Urinary excretion  Liver Enzymes : Drug Interactions Cytochrome P450 family 2C19 2C8 2C9 3A4 2D6 1A2 2E1 Inhibitors Substrates Inducers Erythromycin Midazolam Rifampicin Ketoconazole Cyclosporin Carbamazepine Grapefruit juice Methadone Phenytoin Ritonavir Statins Glucocorticoids Sildenafil St John's Wort   SEDATION Midazolam + Erythromycin (ng/ml) Midazolam (ng/ml) + Rifampicin LOSS OF SEDATION  (v) Genetic Polymorphism 8% of Caucasians lack CYP2D6 They are called "POOR METABOLISERS" The rest are known as "EXTENSIVE METABOLISERS" CYP2D6 metabolises many cardiovascular, psychiatric and analgesic drugs  Pro Drug Hydrolysed Metabolite Ramipril Ramiprilat (Inactive) (Active Antihypertensive) Human liver - Carboxyesterase 1 4. Drug Excretion  Glomerular filtration :- Is restricted by molecular size Is unaffected by lipid solubility Is negligible for highly protein-bound drugs Only unbound drug filtered Glomerular filtration maybe reduced with age and in kidney disease, reducing drug excretion Active secretion in the proximal tubule is able to clear both free and bound drug. Two active secretion pumps have been recognised. Free and bound drug secreted Highly cleared drugs: Clearance = renal blood flow Two pumps: Bases eg. Pancuronium Acids eg. Penicillin Thiazide diuretics  Lipid Solubility Water soluble drugs → urine Lipid soluble drugs → blood  Starvation Fever Alcohol Intake PHENYTOIN Cardiovascular 400mg/day for 14 days Cigarette Function Smoking Liver Age Function GENETIC FACTORS Renal Sex Function Therapeutic Window Gastrointestinal Disease Function Dietary Factors Herbals Drugs “ONE DOSE FOR ALL” DOES NOT WORK  Pharmacokinetics ADME Metabolism Absorption Excretion Distribution Learning Outcomes List the term pharmacokinetics outlining the four phases and describe why an understanding of pharmacokinetics is relevant to drug prescribers