Pharmacokinetics Distribution PDF

Pharmacokinetics Distribution Dr. Yazan Awad Pharm.D, MSc, PhD Faculty of Medicine Girne American University  INTRODUCTION Distribution is the passage of drug molecules to liquid compartments and tissues in the body via transportation a...

Pharmacokinetics Distribution Dr. Yazan Awad Pharm.D, MSc, PhD Faculty of Medicine Girne American University  INTRODUCTION Distribution is the passage of drug molecules to liquid compartments and tissues in the body via transportation across the capillary membrane. The body fluid compartments and volumes in which the drugs are distributed:  DISTRIBUTION The distribution of drugs can occur in 4 patterns throughout the body: Distribution only in plasma: HMW-Dextran, Distribution to all body fluids homogenously: Small and non-ionized few molecules like alcohol, some sulfonamides. Concentration in specific tissues: iodine in thyroid; chloroquine in liver; tetracyclines in bones and teeth; high lipophilic drugs in fat tissue Non-homogenous (non-uniform) distribution pattern: Most of the drugs are distributed in this pattern according to their abilities to pass through the cell membranes or affinities to the different tissues. Factors Affecting the Distribution of Drugs: Diffusion Rate The Affinity of the Drug to the Tissue Components Blood Flow (Perfusion Rate) Binding to Plasma Proteins Factors Affecting the Distribution of Drugs Diffusion Rate: ✓There is a positive correlation between the diffusion rate of the drug and the distribution rate The Affinity of the Drug to the Tissue Components: ✓Some drugs tend to be concentrated in particular tissues. Blood Flow (Perfusion Rate): ✓There is a positive correlation between the blood flow in the tissue and the distribution of the drugs. ✓Kidney, liver, brain and heart have a high perfusion rate (ml/100 g tissue/min) in which the drugs distribute higher; ✓Skin, resting skeletal muscle and bone have a low perfusion rate. ✓The total concentration of a drug increases faster in well-perfused organs. Factors Affecting the Distribution of Drugs Binding to Plasma Proteins: ✓The most important protein that binds the drugs in the blood is albumin for most of the drugs. ✓Especially, the acidic drugs (salicylates, vitamin C, sulfonamides, barbiturates, penicillin, tetracyclines, warfarin, probenesid etc.) are bound to albumin. ✓Basic drugs (streptomycin, chloramphenicol, digitoxin, coumarin etc.) are bound to alpha-1 and alpha-2 acid glycoproteins, globulins, and alpha and beta lipoproteins. Properties of plasma protein-drug binding Saturable: ❖One plasma protein can bind a limited number of drug molecule Non-selective: ❖More than one kind of drug which has different chemical structures or pharmacological effects can be bound to the space on plasma protein Reversible: ❖The bonds between the drug and plasma protein are weak bonds like hydrogen or ionic bonds. Bound fraction Unbound fraction Properties of plasma protein-drug binding Only the free (unbound) fraction of the drug circulating in plasma can pass across the capillary membrane. Bound fraction serves as “drug storage”. Bound fraction Unbound fraction  DISTRIBUTION ❑ Storage (Concentration-Sequestration) of the Drugs in Tissues Stored drug molecules in tissues serve as drug reservoir. The duration of the drug effect may get longer. May cause a late start in the therapeutic effect or a decrease in the amount of the drug effect. ❑ Redistribution: Some drugs (especially general anesthetics) which are very lipophilic, following the injection, firstly (initially) distributes to the well-perfused organs like central nervous system.. Later, the distribution occurs to less perfused organs like muscles. At last, distribution of these drugs shifts to the very low-perfused tissues like adipose (fat) tissue. Redistribution results with the running away of the drugs from their target tissue and last their effect.  DISTRIBUTION ❑ Passage of the drugs to CNS: A blood-brain barrier exists (except in some areas of the brain) which limits the passage of substances. Non-ionized, highly lipophilic, small molecules can pass into the CNS and show their effects. Some antibiotics like penicillin can pass through the inflamed blood-brain barrier while it can’t pass through the healthy one. ❑ Passage of the drugs to fetus: Placenta doesn’t form a limiting barrier for the drugs to pass to fetus. The factors that play role in simple passive diffusion, effect the passage of drug molecules to the fetus. Placental blood flow Molecular size Drug solubility in lipids Fetal pH (ion trapping): fetal plasma pH: 7.0 to 7.2; pH of maternal plasma: 7.4, so according to the ion trapping rules, weak basic drugs tend to accumulate in fetal plasma compared to maternal plasma. Volume of DISRIBUTION (Vd) Volume of Distribution = Amount of drug administered (dose) (mg) / concentration of drug in plasma (mg/L) Most of the times, volume of distribution calculated in this way is not equal to the real total volume of physiological liquid compartments in which the drug is distributed. So it may be called as “apparent volume of distribution (Vd)”. Following a single-dose intravenous administration of a drug, log plasma concentration-time graph is plotted according to the values of plasma concentration taken at particular time points. Then the formula is: Volume of Distribution (Vd) = Dose (iv) / C0’  Volume of DISTRIBUTION To know the volume of distribution (Vd) value of a drug helps us to calculate: The amount of drug found in the body at a particular time from the analyzed plasma drug concentration. The drug dose (loading dose) that has to be given (required) to obtain a desired plasma drug concentration. To find the rate constant for elimination from the formula: Ke = Clearence / Vd