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1

Distribution

•Once a drug has been absorbed it must be available for biological action and distribution to the tissues.

•To be active a drug must then leave the blood stream and enter the inter or intracellular spaces.

•Drug Distribution  refers to the Reversible Transfer of a Drug between the Blood and the Extra Vascular Fluids and Tissues of the body (for example, fat, muscle, and brain tissue).

 

2

Tissue distribution terms

•Plasma protein binding

•Tissue perfusion

•Membrane characteristics

•Blood-brain barrier, Placental, Testis►

•Blood-testes/ovary barrier

•Lipid soluble drugs

•Actively transported

•Transport mechanisms

•Diseases and other drugs (esp renal failure, liver disease, obesity)

•Elimination

3

Plasma protein binding

•Many drugs bind to proteins in the plasma such as albumin or a1-glycoprotein & lipoproteins► (eg phenytoin).

•Only unbound drug is biologically active.

•Binding is reversible.

Amount of bound drug can be changed by:

Renal failure

•Hypoalbuminaemia (low blood albumin)

•Pregnancy

•Other drugs

Saturability of binding

4

Volume of ditribution

  • The volume of plasma that would be necessary to account for the total amount of drug in a patient's body, If that drug were present throughout the body at the same concentration as found in the plasma.
  • The result are expressed in terms of litres per kilogram.

5

Clearance

•Clearance is defined as the theoretical volume from which a drug is completely removed over a period of time.

•Measured in units of time (ml/min).

•Measure of elimination.

•Dependent on concentration and urine flow rate for renal clearance.

•Dependent on metabolism and biliary excretion for hepatic clearance.

 

6

Half life

•The time taken for the drug concentration in the blood to decline to half of the current/initial value.

•e.g if it takes 4 hours for the concentration of a drug in the blood stream to drop from 10mg/L to 5 mg/L then the half life is 4 hours

•Half life depends on the volume of distribution and rate of clearance.

7

Chronic administration

•To have a therapeutic benefit most drugs needed to be given chronically.

•Plasma levels of a drug take many doses before they stabilise, usually 4-5 half-lives.

•This may necessitate a loading dose.

•It is important to know how a particular drug will build up in the body.

 

8

Drug elimination

•This term covers the removal of active drug and matabolites from the body.

•This determines the length of action of the drug.

Made up of 2 parts:

•Drug Metabolism (usually in the liver)

•Drug Excretion (usually in the kidney but also biliary system/gut, lung, milk)

9

Excretion

-The kidneys are the primary organ for drug excretion.

Three principal mechanisms are used:

•  Glomerular filtration

•  Passive tubular reabsorption

•  Active tubular secretion

-Renal damage is therefore important in causing drug toxicity.

10

Glomerular filtration

•The glomerulus filters 190 litres of fluid a day.

•All unbound drugs will be filtered at the glomerulus as long as their molecular size, charge or shape are not excessively large.

•Factors that affect the glomerular filtration rate will reduce the clearance of a drug.

11

Active Tubular Secretion

•Some drugs are actively secreted into the proximal tubule (acidic and basic compounds).

•This is the most important system for eliminating protein-bound cationic and anionic drugs.

12

Passive tubular reabsorption

•As the filtrate moves down the renal tubule any drug present is concentrated.

•Passive diffusion along the concentration gradient allows the drug to move back through the tubule into the circulation.

•Passive diffusion occurs in the distal tubule and collecting duct.

•Only un-ionised drugs such as weak acids are reabsorbed.

•Can also be affected by renal failure.

13

Biliary secretion 1

•The liver secretes 1 litre of bile a day.

•Drugs may be passively or actively secreted into the bile.

•Biliary secretion accounts for 5-95% of drug elimination for many drugs.

•Many drugs are then reabsorbed from the bile into the circulation. This is called entero-hepatic circulation.

•It continues until the drug is metabolised in the liver or excreted by the kidneys.

 

14

Biliary secretion 2 Ø

•Metabolism in the liver often leads to conjugation of the drug.

•The conjugated drug is not reabsorbed from the intestine.

•Damage to the liver may reduce the rates of conjugation and biliary secretion and so allow the build up or reabsorption of  the drug with resultant toxicity.

15

Steady state concentration graph