Displacement of protein bound drugs

In theory, if two drugs that can bind to the same sites on human serum
albumin are given together, they will compete for those sites. Thus, if a
patient taking warfarin is given a non – steroidal anti-inflammatory drug
such as indomethacin the non –steroid anti-infalmmatory drug will tend
to displace warfarin from its binding sites to form a new equilibrium. This
type of interaction is discussed in more detail on page 7.12

Drug metabolism

Druga are, in general, lipid soluble compounds that cannot be excreted

as such by the kidney. The process of drug metabolism renders them
more water soluble thus allowing excretion from the body. The main site
of drug metabolism is the liver, but other tissues including skin, lung,
blood and intestinal wall may also contribute, the gut wall is an important
site of drug metabolism during the process of absorption, and drugs
such as isoprenaline, ethinyloestradiol and morphine are, in part,
converted there to inactive compounds by metabolism.

The rate of metabolism of a drug in any individual is usually determined

genetically, but can be changed by environmental factors (see below).
The rate of metabolism of any one drug varies widely from individual to
individual, and a ten-fold variation in the rate of drug metabolism is not
unusual. Metabolites formed are usually less pharmacologically active
than the parent compound but some drugs (e.g. cylophosphanide) are
only active through the production of a metabolite. A ‘prodrug’ (e.g.
norethynodrel and ethynodiol diacetate-producing norethisterone and
talampicilin-producing ampicilin) is the name given to an agent which,
through biotransformation, produces a therapeutically active substance.
The manufacture of a prodrug is of value when, by reducing
gastrointestinal toxicity, or minimizing first pass metabolism, it allows
higher plasma concentrations of therapeutic substances. Other drugs
are active themselves but, in addition, produce metabolites that are also
pharmacologycally active. In some of these cases the metabolite of the
drug has a similiar spectrum of activity to the parent drug (e.g.
propanolol, procainamide or diazepam). Homewer, the metabolite
produced may differ in its pharmacological effects from the parent drug
(e.g. pethidine), whose metabolite norpethidine causes no analgesia but
muscular twitching, or may have specific toxic effects (e.g. paracetamol,
one of whose metabolites is responsible for causing liver necrosis).

Pathway drug metabolism

A variety of biochemical reactions can take place during the metabolism

of a drug to more water soluble compounds. They are of two types;
phase I reactions are those whereby polar groups are introduced into the
molecule by oxidation, reduction or hydrolysis; phase II reactions are
synthetic and involve conjugation of the drug with glucuronic acid,
glycine, sulphate or other groups. Some drugs may only undergo phase
II reactions whilst others may first have to undergo a phase I reaction
before a phase II reaction can take place. The enzymes that metabolize
drugs in the liver are non – specific compared with the enzymes in
intermediary metabolism. Oxidation is the most frequent metabolic
pathway and involves the transfer of molecular oxygen through the
agency of cytochrome P450. At one time it was throught that there was
only one moiety of cytochrome P450, but it now appears that there are
many subtypes of the cytochrome in the lives, each responsible for the
metabolism of different groups of drugs.