This process involves the transportation of the drug to the target site of action.

During distribution, some drug molecules may be deposited at storage sites and others may be deposited and inactivated. Various factors may influence how and even if, a drug is distributed.

• Blood flow. Distribution may depend on tissue perfusion. Organs that are highly vascular such as the heart, liver and kidneys will rapidly acquire a drug. Levels of a drug in bone, fat, muscle and skin may take some time to rise due to reduced vascularity. The client’s level of activity and local tissue temperature may also affect drug distribution to the skin and muscle.

• Plasma protein binding. In the circulation, a drug is bound to circulating plasma proteins or is ‘free’ in an un-bound state. The plasma protein usually involved in binding a drug is albumin. If a drug is bound, then it is said to be inactive and cannot have a pharmacological effect. Only the free drug molecules can cause an effect. As free molecules leave the circulation, drug molecules are released from plasma protein to re-establish a ratio between the bound and the free molecules. Binding tends to be non-specific and competitive. This means that plasma proteins will bind with many different drugs and these drugs will compete for binding sites on the plasma proteins. Displacement of one drug by another drug may have serious consequences. For example, warfarin can be displaced by tolbutamide producing a risk of haemorrhage, whilst tolbutamide can be displaced by salicylates producing a risk of hypoglycaemia.

• Placental barrier. The chorionic villi enclose the foetal capillaries. These are separated from the maternal capillaries by a layer of trophoblastic cells. This barrier will permit the passage of lipid-soluble, non-ionised compounds from mother to foetus but prevents entrance of those substances that are poorly lipid-soluble.

• Blood-brain barrier. Capillaries of the central nervous system differ from those in most other parts of the body. They lack channels between endothelial cells through which substances in the blood normally gain access to the extracellular fluid. This barrier constrains the passage of substances from the blood to the brain and cerebrospinal fluid. Lipid-soluble drugs eg. diazepam, will pass fairly readily into the central nervous system, where as lipid-insoluble drugs will have little or no effect.

Drug metabolism

Drug metabolism or biotransformation refers to the process of modifying or altering the chemical composition of the drug. The pharmacological activity of the drug is usually removed. Metabolites (products of metabolism) are produced which are more polar and less lipid-soluble than the original drug, which ultimately promotes their excretion from the body. Most drug metabolism occurs in the liver, where hepatic enzymes catalyze various biochemical reactions. Metabolism of drugs may also occur in the kidneys, intestinal mucosa, lungs, plasma and placenta.

Metabolism proceeds in two phases:

• Phase I. These reactions attempt to biotransform the drug to a more polar metabolite. The most common reactions are oxidations, catalysed by mixed function oxidase enzymes. Other phase I reactions include reduction and hydrolysis reactions.

• Phase II. Drugs or phase I metabolites which are not sufficiently polar for excretion by the kidneys, are made more hydrophilic (‘water-liking’) by conjugation (synthetic) reactions with endogenous compounds provided by the liver. The resulting conjugates are then readily excreted by the kidneys.

With some drugs, if given repeatedly, metabolism of the drugs becomes more effective due to enzyme induction. Therefore larger and larger doses of the drug become required in order to produce the same effect. This is referred to as drug tolerance.

Tolerance may also develop as a result of adaptive changes at cell receptors.

Various factors affect a client’s ability to metabolise drugs. These include:

• Genetic differences. The enzyme systems which control drug metabolism are genetically determined. Some individuals show exaggerated and prolonged responses to drugs such as propranolol which undergo extensive hepatic metabolism.

• Age. In the elderly, first pass metabolism may be reduced, resulting in increased bioavailability. In addition, the delayed production and elimination of active metabolites may prolong drug action. Reduced doses may, therefore, be necessary in the elderly. The enzyme systems responsible for conjugation are not fully effective in the neonate and this group of clients may be at an increased risk of toxic effects of drugs.