• “Area of pharmacology that includes the study of the absorption, distribution, metabolism (biotransformation) and excretion (elimination) characteristics of a drug” [‘ADME’]

• “the way in which the body handles a drug”

• The pharmocokinetic processes determine:

1) How rapidly the drug will appear at the target organ

2) In what concentration the drug will appear at the target organ

3) How long the drug will appear at the target organ

• The major pharmocokinetic factors are:

bioavailability; distribution; clearance

A) Absorption

• Movement of drug molecules into body from site of administration

• Process by which drugs gain access into the plasma via the epithelium (eg: oral, rectal, sublingual, inhalational)

• This process is bypassed when the drug is given parenterally

Bioavailability

• the fraction of unchanged drug reaching the systemic circulation following administration by any route: may also refer to the rate at which an administered drug reaches the systemic circulation

• For I.V. administration: bioavailability = 1

• For oral administration: bioavailability = <1 due to:

— incomplete gut absorption

— metabolism in gut, portal circulation or liver prior to entering systemic circulation

B) Distribution

• Process by which the free drug gains access to receptors at target tissue or storage tissues

• Once a drug has been absorbed in the blood, it may be distributed to different physical compartments of the body

• If a drug avidly binds to plasma proteins, it may remain in the vascular compartment until eliminated; small water soluble molecules may be freely distributed in the total body water

• Factors that determine drug distribution are: protein binding; blood flow; membrane permeation; tissue solubility

• In the blood, drugs bound to plasma proteins do so via inert binding sites as opposed to receptor binding sites

• Blood flow determines how rapidly drug molecules are delivered to a given tissue & how effectively the concentration gradient between blood & tissue is maintained

Volume of distribution

• Relates the amount of blood in the body to the concentration of drug in blood or plasma

• Reflects the apparent space available to contain the drug in both the general circulation and the tissues

• Defined in terms of blood or plasma concentrations

• Is dependent on: pKa of drug; degree of plasma protein binding; degree of binding to fat and other tissues in body

C) Clearance

• The measure of the ability of the body to eliminate the drug in ml/min

• Termination of drug effect is sometimes dependent upon excretion from body, more commonly, termination of effect is the result of biotransformation to inactive substances that are then excreted

• Major organs for drug excretion are the kidneys, liver, GIT & lungs

• Other minor routes of drug excretion are sweat and milk

• lungs are the most important route for the elimination of gaseous anaesthetics but are a unimportant route for other drugs

• Drugs are excreted by the kidneys by 2 processes:

1) Passive: - glomerular filtration

- removes molecules up to size of small proteins

- therefore, protein bound drugs are poorly filtered

- nonsaturable process

2) Active: - tubular secretion

- saturable process

Half-Life (t_1/2)

• indicates the time required to reduce the plasma drug value to one half its original value

• The time course of drug in the body depends on the volume of distribution and the clearance

• Disease affects both volume of distribution & clearance, thereby altering t_1/2

D) Biotransformation

• Only small molecules or molecules possessing polar characteristics can be excreted from the kidneys. Most drugs tend to be large, lipophilic and unionized and therefore would be poorly excreted & thus have a prolonged duration of action if their elimination was renally dependent.

• Metabolism of such large, lipophilic, non ionised molecules into a more readily excretable form is the necessary role of biotransformation

• Biotransformation may render a substance less active, more active or even toxic

• Most metabolic biotransformations occur at some point between absorption of the drug into the circulation and its renal elimination

Effect of age

• Increased susceptibility to the pharmacological or toxic activity of drugs occurs in the very young and the elderly

• May be due to differences in drug absorption, distribution, metabolism and elimination

• Drugs may be metabolised at slower rates in the very young due to immature liver and other organs and the elderly due to atrophy etc

• Drugs may be excreted at slower rates in the very young due to immature kidneys and the elderly due to renal atrophy