DISTRIBUTION The body is a container in which a drug is distributed by blood (different flow to different organs) - but the body is not homogeneous. Factors affecting drug delivery from the plasma: A- blood flow: kidney and liver higher than skeletal muscles and adipose tissues. B- capillary permeability: 1- capillary structure: blood brain barrier 2- drug structure C- binding of drugs to plasma proteins and tissue proteins

Apparent Volume of Distribution Vd = Amount of drug in the body Plasma drug concentration V D = Dose/Plasma Concentration  It is hypothetical volume of fluid in which the drug is disseminated.  Units: L and L/Kg  We consider the volume of fluid in the body = 60% of BW  60 X 70/100 = 42 L

Drug Distribution Water Body Compartments Drugs may distribute into Plasma (Vascular) Compartment:  Too large mol wt  Extensive plasma protein binding  Heparin is an example  Extracellular Fluid Low mol wt drugs able to move via endothelial slits to interstitial water Hydrophilic drugs cannot cross cell membrane to the intracellular water  Total Body Water; Low mol wt hydrophobic drugs distribute from interstitial water to intracellular Plasma (4 litres) Interstitial Fluid (11 litres) Intracellular Fluid (28 litres) 3

Plasma Compartment Extracellular Compartment Intracellular Compartment Drug has large Mol. Wt. OR Bind extensively to pp Vd = 4L 6% of BW e.g. Heparin Drug has low Mol. Wt. Hydrophilic Distributed in plasma & Interstitial fluid Vd = 14L 21% of BW e.g. Aminoglycosides Drug has low Mol. Wt. Hydrophobic Distributed in three comp. Accumulated in fat Pass BBB Vd= 42L 60% of BW e.g. Ethanol

Plasma protein binding  Many drugs bind reversibly to plasma proteins especially albumin  D + Albumin↔ D-Albumin (Inactive) + Free D  Only free drug can distribute, binds to receptors, metabolized and excreted.

Clinical Significance of Albumin Biding  Class I: dose < available albumin binding sites (most drugs)  Class II: dose > albumin binding sites (e.g., sulfonamide) Drugs of class II displace Class I drug molecules from binding sites→ more therapeutic/toxic effect In some disease states → change of plasma protein binding  In uremic patients, plasma protein binding to acidic drugs is reduced Plasma protein binding prolongs duration Sulfonamide 7 Displacement of Class-I Drug

Alter plasma binding of drugs 1000 molecules % bound molecules free fold increase in free pharmacologically active concentration at site of action. Effective TOXIC

Capillary permeability  Endothelial cells of capillaries in tissues other than brain have wide slit junctions allowing easy movement of drugs  Brain capillaries have no slits between endothelial cells, i.e tight junction or blood brain barrier  Only carrier-mediated transport or highly lipophilic drugs enter CNS  Ionised or hydrophilic drugs can’t get into the brain Liver capillary Endothelial cells Glial cell 9 Brain capillary Slit junctions Tight junctions

Barriers to Drug Distribution  Blood-Brain barrier: Inflammation during meningitis or encephalitis may increase permeability into the BBB of ionised & lipid-insoluble drugs  Placental Barrier: Drugs that cross this barrier reaches fetal circulation Placental barrier is similar to BBB where only lipophilic drugs can cross placental barrier 10

Metabolism It is enzyme catalyzed conversion of drugs to their metabolites. Process by which the drug is altered and broken down into smaller substances (metabolites) that are usually inactive. Lipid-soluble drugs become more water soluble, so they may be more readily excreted.

Most of drug biotransformation takes place in the liver, but drug metabolizing enzymes are found in many other tissues, including the gut, kidneys, brain, lungs and skin. Metabolism aims to detoxify the substance but may activate some drugs (pro-drugs).

Reactions of Drug Metabolism Conversion of Lipophyllic molecules Into more polar molecules by oxidation, reduction and hydrolysis reactions Phase I Phase II Conjugation with certain substrate ↑↓or unchanged Pharmacological Activity Inactive compounds

Phase I Biotransformation Oxidative reactions: Catalyzed mainly by family of enzymes; microsomal cytochrome P450 (CYP) monoxygenase system. Drug + O 2 + NADPH + H + → Drug modified + H 2 O + NADP + Many CYP isoenzymes have been identified, each one responsible for metabolism of specific drugs. At least there are 3 CYP families and each one has subfamilies e.g. CYP3A. Many drugs alter drug metabolism by inhibiting (e.g. cimetidine) or inducing CYP enzymes (e.g. phenobarbital & rifampin). Pharmacogenomics

Oxidative reactions: A few drugs are oxidised by cytoplasmic enzymes. – Ethanol is oxidized by alcohol dehydrogenase – Caffeine and theophylline are metabolized by xanthine oxidase – Monoamine oxidase Hydrolytic reactions: Esters and amides are hydrolyzed by: – Cholineesterase Reductive reactions: It is less common. – Hepatic nitro reductase (chloramphenicol) – Glutathione-organic nitrate reductase (NTG) Phase I Biotransformation (continue)

Phase II Biotransformation Drug molecules undergo conjugation reactions with an endogenous substrate such as acetate, glucuronate, sulfate or glycine to form water- soluble metabolites. Except for microsomal glucuronosyltransferase, these enzyems are located in cytoplasm. Most conjugated drug metabolites are pharmacologically inactive. – Glucuronide formation: The most common using a glucuronate molecule. – Acetylation by N-acetyltransferase that utilizes acetyl-Co-A as acetate donar. – Sulfation by sulfotransferase. Sulfation of minoxidil and triamterene are active drugs.

LONGITUDNAL SECTION OF KIDNEY KLECOP, Nipani