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 DistributionVd = Amount of drug in the body

Plasma drug concentration

VD = 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 DistributionWater 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

IntracellularCompartment

Drug has large Mol. Wt.OR

Bind extensively to pp

Vd = 4L6% of BW

e.g. Heparin

Drug has low Mol. Wt.Hydrophilic

Distributed in plasma & Interstitial fluid

Vd = 14L21% of BW

e.g. Aminoglycosides

Drug has low Mol. Wt.Hydrophobic

Distributed in three comp.Accumulated in fat

Pass BBB

Vd= 42L60% 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 drugs1000 molecules

% bound

molecules free

999 900

100 1

100-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

circulationPlacental 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

Intomore polar molecules

by oxidation, reduction and hydrolysis

reactions

Phase I Phase II

Conjugation with certain substrate

↑↓or unchanged Pharmacological

ActivityInactive compounds

Phase I Biotransformation• Oxidative reactions: Catalyzed mainly by family of enzymes;

microsomal cytochrome P450 (CYP) monoxygenase system.Drug + O2 + NADPH + H+ → Drugmodified + H2O + 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

09-12-2010 17KLECOP, Nipani