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Distribution Siva Nageswararao Mekala Assistant professor Dept. of clinical pharmacology Faculty of medicine DISTRIBUTION • Distribution is defined as the reversible transfer of drugs between body fluid compartments • Depends upon lipid solubility of the drug, ionization at physiological pH, extent of binding to plasma proteins, and tissue proteins, blood flow to tissues. Volume of Distribution • An abstract concept • Gives information on HOW the drug is distributed in the body • Used to calculate a loading dose 3L Apparent volume of distribution (aVd): • aVd is defined as the hypothetical volume of the body fluid into which a drug is uniformly distributed at a concentration equal to that in plasma ,assuming the body to be a single compartment. TOTAL AMOUNT OF DRUG IN THE BODY aVd = ……………………………………………………….. CONCENTRATION OF THE DRUG IN PLASMA • Lipid insoluble drugs do not enter cells, so aVd is approximates ECF volume . • Drugs extensively bound to plasma proteins eg: warfarin, phenylbutazone, are largely restricted to vascular compartment and have low values Clinical importance of Vd : • Aspirin Vd = 0.1571 L/Kg ; Pethidine Vd = 280 L/Kg • Hemodialysis is useful only for drugs with small volume of distribution e.g. aspirin Factors governing volume of distribution 1. Physicochemical properties of the drug: Lipid soluble and unionized form of drugs readily cross the cell membrane and are widely distributed. Eg: Lignocaine ,Propranolol 2. Degree of plasma protein binding: Drugs that are highly bound to plasma proteins have a low volume of distribution Eg: warfarin, phenytoin 3. Tissue storage : Certain drugs can get sequestrated in some tissues. such drugs have a large Vd Eg: Digoxin is sequestrated in heart, muscle ,liver etc and has Vd is 63L/Kg 4. Disease states: The volume of distribution of drugs can be altered in certain diseases Eg: In CHF ,the Vd of some drugs can be increase due to increase in ECF volume 5. Fat : Lean body mass ratio: Highly lipid soluble drugs get distributed to the adipose tissue. Redistribution • Highly lipid soluble drugs such as Thiopentone sodium , on I.V administration immediately gets distributed to areas of high blood flow such as Brain and causes general anesthesia . • Immediately with in a few minutes ,it recrosses the BBB and gets distributed into the blood and then to the less perfused tissues such as muscle and adipose tissue . • This is called redistribution ,which results in termination of drug action. Blood Brain Barrier (BBB) • The capillary boundary that is present between the blood and brain is called BBB • Barbiturates, diazepam, volatile anesthetics, amphetamine etc – cross BBB • The unique characteristics of brain capillary endothelial cells and pericapillary glial cells constitute the blood-brain barrier. • The lipid insoluble and ionized particles do not cross the BBB. EG: Dopamine , Aminoglycosides • Meningitis, encephalitis - increase the permeability of the BBB eg. penicillin in normal conditions has poor penetration through BBB, but its penetrability increases during meningitis and encephalitis. Placental Barrier : • The lipid membrane between the mother and fetus is called placental barrier. • Unionized and lipid soluble drugs can freely cross the placental barrier. e.g. anesthetics, alcohol, morphine etc. • Quaternary ammonium compounds e.g.. d-TC and substances with high molecular weight e.g.. insulin cannot cross the placental barrier. • The fetal plasma is slightly more acidic than that of the mother (pH 7.0 to 7.2 versus 7.4), so that ion trapping of basic drugs occurs. • Certain drugs when given during pregnancy may cross the placenta and cause various dangerous effects in the foetus called teratogenic effect. Eg: Thalidomide -Phocomelia Tetracyclines – Yellowish discoloration of the teeth Anti thyroid drugs – Foetal goiter Plasma protein binding • To albumin (Acidic drugs ) Barbiturates Benzidiazepines NSAIDS Valproicacid Phenytoin Penicillins Sulfonamides Tetracyclines Tolbutamide Warfarin • To alpha 1 glycoprotein (Basic Drugs ) Beta blockers Bupivacaine Lignocaine Disopyramide Imipramine Methadone Prazocin Quinidine Verapamil Importance of plasma protein binding 1) high plasma protein binding drugs have lower volumes of distribution . 2) bound fraction is not available for action but in equilibrium with free drug in plasma. 3) high degree of plasma binding makes drug longer acting. 4)generally expressed conc. of the drug refer to both bound and free conc. of the drug. 5)one drug can bind to many sites of plasma protein and a plasma protein can bind to many drugs. 6) Displacement of drugs is seen. More than one drug bing to the same site on Albumin . The drug with higher affinity will displace the one having lower affinity and may results in a sudden increase in the free concentration of the drug with lower affinity . E.g.: phenylbutazone and salicylates displace tolbutamide. Indomethacin and phenyl butazone displace warfarin. 7) pathological states like hypoalbuminemia binding is reduced (severe liver disease or the nephrotic syndrome ) In cases of acute-phase reaction response (e.g., cancer, arthritis, myocardial infarction, and Crohn's disease) lead to elevated levels of a1acid glycoprotein and enhanced binding of basic drugs. 8) Highly protein bound drugs have a longer duration of action and hence difficult to remove. • In cases of poisoning, highly plasma protein bound drugs are difficult to be removed by Hemodialysis. Tissue storage: • • • • • • • Skeletal muscle,heart Liver Kidney Thyroid Brain Bone and teeth Adipose tissue - digoxin,emetine - choloroquine, Tetracyclines - chloroquine,digoxin - iodine - chlorpromazine, Isoniazid - tetracyclines,metals - thiopentone , ether