Drug Distribution Handout PDF

Drug distribution MD3001 1 Lecture overview Factors that affect drug distribution Specialised barriers Fluid compartments Volume of distribution What is drug distribution? Movement of a drug to/from blood and tissues of the body Where does it get to/where doesn’t it? Helps understand the relati...

Drug distribution MD3001 1 Lecture overview Factors that affect drug distribution Specialised barriers Fluid compartments Volume of distribution What is drug distribution? Movement of a drug to/from blood and tissues of the body Where does it get to/where doesn’t it? Helps understand the relative proportions of drug in the tissues, and to predict dose/response/risk Factors that affect distribution Cardiac output and blood flow Plasma protein binding Lipid solubility Degree of drug ionisation pH of compartments Capillary permeability Relative organ perfusion Organ Kidneys Liver Heart Brain Skeletal muscle Fat Cardiac output (%) 20 10 4 13 20 2 Blood flow (ml/min/100g tissue) 450 25 70 55 3 1 Initial rate of distribution of drugs depends heavily on blood flow Albumin binding Predominate plasma binding protein (40g/L) • Lipid-soluble drugs bind non-specifically • Weak acids bind to a specific, saturable site What would competition at saturable sites do to free drug levels in the plasma? Lipid solubility Hydrophilic drugs are highly soluble in aqueous, polar media. Lipophilic drugs are soluble in fats and non-polar solutions. Rate of distribution dependent on diffusion characteristics of the drug Rate of distribution dependent on the rate of delivery to tissues (e.g. blood flow) Drug ionisation Many drugs are weak acids or bases • Ionised:unionised ratio depends on pH • Ionised drugs have low lipid solubility  Ionised drugs will not diffuse across cell membranes Adapted from Rang & Dale 7e Capillary diffusion Diffusion Surface area Time Continuous Fenestrated Discontinuous Naish p614 Blood brain barrier Blood brain barrier Physical barrier Functional barrier Characteristics of drugs that may pass the BBB? Can disease state change the ability of drugs to pass through the BBB? Other specialised barriers / compartments Placenta Tight endothelial cell junctions in maternal and fetal capillaries Partially protective, except with: – lipid soluble drugs – unionised forms of weak acids and bases Chronic abscesses Avascular tissue compartments Lung infection Local low PO2 and high PCO2 cause vasoconstriction Body fluid volumes Fluid substance Volume (litre) Extracellular fluid 15 Plasma Interstitial fluids (3) (12) Intracellular fluids 27 Total body water 42 Large, water-soluble molecules (for a 70kg adult) (e.g. mannitol) Highly plasmabound molecules Highly charged molecules Very large molecules (e.g. heparin) Small, water-soluble molecules (e.g. ethanol) Bones? Teeth? Adipose tissue? Plasma steady state conc. (Css) The Css value reached depends on: the rate of drug administered (K0) volume of plasma cleared of drug per unit time (CL) The time taken to reach Css depends on: elimination half-life (t1/2) t1/2 directly depends on the volume of distribution (Vd) and inversely on the clearance (CL) of drug from the body: t1/2 = ln2 x Vd CL Volume of distribution Thomson, 2000 Paediatric and Perinatal Drug Therapy Volume 4, Issue 1, 2000 Volume of distribution The apparent volume of distribution (Vd) of a drug is: total amount of drug in the body blood plasma concentration of drug Vd is the theoretical volume required to account for the amount of drug in the body Units are in litres (L) or sometimes L/kg of body weight. Volume of distribution Fluid substance Volume (litre) Extracellular fluid 15 Plasma Interstitial fluids (3) (12) Intracellular fluids 27 Total body water 42 (for a 70kg adult) Drug A = Vd of 0.2 L/kg Drug B = Vd of 0.6 L/kg Drug C = Vd of 6.0 L/kg Vd is a theoretical volume and may suggest physiological compartments, but may also exceed them! Single compartment model of distribution Assumes rapid mixing of drug in plasma Assumes drug in plasma is in rapid equilibrium with drug in extravascular tissues Two compartment model of distribution e.g. blood and wellperfused tissues. e.g. poorly perfused tissues. Clinical relevance Vd varies with: –Height –Weight –Age –Fluid accumulation • ascites • oedema • pleural effusion –Accumulation of fat Clinical relevance: Using the volume of distribution The apparent volume of distribution (Vd) of a drug is: total amount of drug in the body (A) blood plasma concentration of drug (C) i.e Vd = A/C Can be rearranged to A = C x Vd So IF you know the Vd, you can calculate what amount of drug (i.e. the dose) will give a certain plasma concentration… Main points The chemical properties of a drug will dictate how it can distribute The volume of distribution is a key factor for determining a drug’s half life Vd is not always physiologically possible! Drugs may distribute into more than one compartment Learning outcomes To describe the factors which affect drug distribution once they are absorbed into the blood stream. To define what is meant by the volume of distribution (Vd) of a drug and perform basic interpretation of what a Vd indicates. To relate Vd to clinical parameters (e.g. how changes in Vd influence the elimination half-life of a drug, or how patient-specific factors may influence Vd).