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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• 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.
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.
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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