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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.

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distribution
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
Apparent Volume of Distribution

Vd = Amount of drug inthe 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 distribution water body compartments
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)

slide4

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
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
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
Alter plasma binding of drugs

1000 molecules

900

999

% bound

1

100

molecules free

100-fold increase in free pharmacologically

active concentration at site of action.

EffectiveTOXIC

slide9
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

Slit junctions

Brain capillary

Glial cell

Tight junctions

Endothelial cells

barriers to drug distribution
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
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.

Metabolism

slide12
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
Reactions of Drug Metabolism

Phase I

Phase II

Conversion of

Lipophyllic molecules

Into

more polar molecules

by

oxidation, reduction and hydrolysis

reactions

Conjugation with certain substrate

↑↓or unchanged

Pharmacological

Activity

Inactive compounds

phase i biotransformation
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
phase i biotransformation continue
Phase I Biotransformation (continue)
  • 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 ii biotransformation
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.