Distribution

Lecture 8

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

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)

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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

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Displacement of Class-I Drug

Alter plasma binding of drugs

1000 molecules

% bound

molecules free

999 950

50 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

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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-insol 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

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Metabolism

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 (cont.)

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.

Excretion

Drug Excretion Excretion is the removal of drug from body

fluids and occurs primarily in the urine.

Other routes of excretion from the body include in bile, sweat, saliva, tears, feces, breast, milk and exhaled air.

LONGITUDNAL SECTION OF KIDNEY

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Renal Excretion

Glomerular filtration depends on: Renal blood flow & GFR; direct relationship Plasma protein binding; only free unbound drugs are

filtered

Tubular Secretion in the proximal renal tubule mediates raising drug concentration in PCT lumen

Organic anionic & cationic transporters (OAT & OCT) mediate active secretion of anionic & cationic drugs

Passive diffusion of uncharged drugs Facilitated diffusion of charged & uncharged drugs Penicillin is an example of actively secreted drugs

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Renal Excretion

Tubular re-absorption in DCT: Because of water re-absorption, urinary D concentration

increases towards DCT favoring passive diffusion of un-ionized lipophillic drugs

It leads to lowering urinary drug concentrationo Urinary pH trapping: Chemical adjustment of urinary pH can inhibit or enhance

tubular drug reabsorption For example, aspirin overdose can be treated by urine

alkalinization with Na Bicarbonate (ion trapping) and increasing urine flow rate (dilution of tubular drug concentration)

Ammonium chloride can be used as urine acidifier for basic drug overdose treatment

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Drug Elimination

Pulmonary excretion of drugs into expired air: Gases & volatile substances are excreted by this route No specialized transporters are involved Simple diffusion across cell membrane predominates. It depends on: Drug solubility in blood: more soluble gases are slowly excreted Cardiac output rise enhance removal of gaseous drugs Respiratory rate is of importance for gases of high blood solubility Biliary excretion of few drugs into feceso Such drugs are secreted from the liver into the bile by active

transporters, and then into duodenumo Examples: digoxin, steroid hormones, some anticancer agentso Some drugs undergo enterohepatic circulation back into systemic

circulation

CLEARANCE:-

Is defined as the hypothetical volume of body fluids containing drug from which the drug is removed/ cleared completely in a specific period of time. Expressed in ml/min. CL = kVD, k: elimination rate constant

09-12-2010 26KLECOP, Nipani

Clearance It is ability of kidney, liver and other organs to eliminate drug

from the bloodstream Units are in L/hr or L/hr/kg Used in determination of maintenance doses Drug metabolism and excretion are often referred to

collectively as clearance The endpoint is reduction of drug plasma level Hepatic, renal and cardiac failure can each reduce drug

clearance and hence increase elimination T1/2 of the drug

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Half-life (t1/2)

Half-life: is a derived parameter, completely determined by volume of distribution and clearance.

(Units = time) As Vd increases t1/2 increases