distribution the body is a container in which a drug is distributed by blood (different flow to...
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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 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)
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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 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
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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-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