Drug Distribution Lecture Notes PDF

Drug Distribution Alexander K. Nyarko, PhD Sunday, December 8, 20 1 24  Objectives/Outcome To – Understand the concepts of drug distribution – Understand the factors that affect drug Distribution – Appreciate the fac...

Drug Distribution Alexander K. Nyarko, PhD Sunday, December 8, 20 1 24  Objectives/Outcome To – Understand the concepts of drug distribution – Understand the factors that affect drug Distribution – Appreciate the factors that affect drug distribution – Be able to analyse the pharmacological and/or therapeutic implications of altered drug distribution –December Sunday, 24 Be able8, 20 to apply knowledge 2 Bioavailability Drug Absorption  Drug Distribution The reversible transfer of a drug between the blood and the extra vascular fluids and tissues of the body (for example, fat, muscle, and brain tissue) Drugs come into the circulation after absorption From plasma – Drugs cross the capillary membrane into the interstitial space – Drug crosses the cell-membrane to enter into the intracellular Sunday, December 8, 20 fluid 5 24  Factors Affecting Drug Distribution Factors affecting drug distribution – Chemical factors: Molecular weight : – Very large molecules stay in plasma – Large molecules remain in extracellular fluid Binding to plasma proteins: Lim Solubility – Hydrophilic and ionized drugs- may distribute in extracellular space, pKa » Acids » Bases – Lipophilic compounds-readily diffuse into tissues yielding high vol. distr. – Biological factors: – Blood flow to tissues – Initial: Dictated by blood flow (lung(14): Kidney(4): Heart (1), liver (1) mL/min/g – Later: Modified by tissue affinity eg thiopental (muscle, fat; chl (liver), Pb (bone) Capillary: Determined by porosity – pore size 6  Plasma Proteins Plasma consists of – ~90% water – ~8% plasma proteins – ~2% other organic or inorganic species Types of plasma proteins – Albumin – Globulins α1-Globulin α2-Globulin β-Globulin γ-Globulin – Fibrinogen  Binding of Drug to Proteins Many drugs bind to plasma proteins because they have low water solubility – When drugs appear in the circulation A fraction of drug molecules binds with plasma proteins (albumin) A fraction remains free – Plasma Protein Binding Free drug and bound drug always in equilibrium Equilibrium will always be maintained whatever might be the amount of the drug in circulation at any time. Sunday, December 8, 20 8 24  Drug-Protein Binding Affects Drug Distribution When drugs appear in the circulation A fraction of drug molecules bind with plasma protein & another fraction remain free 9  Major Drug-Binding Proteins in Plasma Albumin: binds mostly acidic drugs a1-acid glycoprotein: binds mostly basic drugs Lipoproteins: binds mostly neutral drugs 10  Factors that Affect Bounding Quantity of drug bound depends on: – Free drug concentration – Protein concentration – Affinity for binding sites %Bound = The fraction of unbound drug in plasma varies widely among drugs Sunday, December 8, 20 11 24  Types of Bonds in Drug-Protein Binding Reversible – Weak chemical bonds Hydrogen bonds or van der Waals forces – Equilibrium between bound and unbound fractions occurs with most drugs – Binding can be saturable at high drug concentrations – Binding competitive; results in competitive displacement Irreversible Covalent chemical bonds – accounts for certain toxicities of drugs and carcinogens – 8,e.20g. high doses of acetaminophen Sunday, December 12 24  Relevance of Drug-Protein Binding Drug bound to protein is pharmacologically inactive Drugs bound to proteins do not cross cell membranes Bound drugs have impact on: – Distribution – Metabolism – Excretion Sunday, December 8, 20 13 24 Factors Affecting Drug-Protein Binding Drug – Physicochemical properties – Concentration Protein – Physicochemical properties – Concentration Displacement by co-administered drugs – Salicylic acid (displacer) displaces warfarin when co-administered Sunday, December 8, 20 14 24  Consequences of Strong Plasma Protein Binding Competitive displacement of other drugs Competitive displacement of endogenous compounds Pathophysiology leading to altered plasma protein levels: – Decreased protein level increases free drug concentration – Increased protein level decreases the effect Delayed elimination Delayed onset of effect 15  Protein Binding: Competitive Displacement of Drugs Displacement may occur if:  The drug (e. g. warfarin) is highly protein-bound; and  The displacer (e. g. salicylic acid) occupies most of the binding site.  Protein Binding: Competitive Displacement of Drugs Binding sites are not substrate-specific 2 drugs or substances may compete for binding sites → ↑ [free forms of the substances] → ↑ therapeutic or toxic effects of one or both drugs Case study: Warfarin (anticoagulant) protein bound ~98%. Therefore, for a 5 mg dose, only 0.1 mg of drug is free in the body to work! If patient takes a normal dose of aspirin at same time (normally occupies 50% of binding sites), the aspirin displaces warfarin so that 96% of the warfarin dose is protein-bound. What is the implication for [warfarin]? Answer: Free [warfarin] = 0.2 mg. Thus, free [warfarin] doubles, as if the ingested dose was doubled Consequences---warfarin over dose leading to warfarin toxicity, bleeding Extent of Drug Binding to Proteins Binding Extensive Intermediate Rarely (>90%) (>10% & that of acidic drugs difference? Difference due to basic drugs having higher tissue binding than acidic drugs 51  Vd- Importance and Uses It indicates how much drug must be added to the body in order to achieve a specified concentration in the sampled fluid. It suggests where the drug is likely to be stored in the body or where it might be found i.e. whether its is in a single compartment or multiple compartments. Sunday, December 8, 20 52 24  Vd- Compartments aVolume of Retention Examples distribution (aVd) Heparin, Insulin, < 5L Vascular compartment Warrfarin Extracellular Aspirin, Aprox. 15L compartment Tolbutamide Ethanol , Throughout the body Phenytoin, Or >20L Digoxin, Penetration in various Phenobarb, tissues Morphine Sunday, December 8, 20 53 24 Sunday, December 8, 2024 54  Reading List Reading List Craig, C. R., & Stitzel, R. E. (2004). Modern pharmacology with clinical applications. (6th ed.). Philadelphia: Lippincott Williams & Wilkins. Greenstein, B. & Brook, D. A. (2011) Biological therapeutics, Pharmaceutical Press, London. Karlix, J. L. (2003.). Pharmacogenomics: An introduction for the health care professional.Washington, DC: American Pharmacists Association. Katzung, B. G. (2007). Basic & Clinical Pharmacology (9th ed.). London, England, McGraw-Hill. Parker K. L., Brunton, L. L., & Lazo, J. S. (2006.). Goodman & Gilman’s: The pharmacological basis of therapeutics (11th edn.). New York: McGraw-Hill. Rang, H. P., & Dale, M. M. (2012). Pharmacology (7th ed.). New York: Churchill Livingstone. Tripathi, K. D. (2010). Essentials of medical pharmacology (6th ed.): Jaypee Brothers Medical Publishers Ltd Sunday, December 8, 20 55 24 Questions?