Medical Pharmacology at a Glance. Michael J. Neal

bound to the receptors can be determined and estimations made of K_A and B_max (number of binding sites). Binding assays are widely used to study drug receptors, but have the disadvantage that no functional response is measured, and often the radiolabelled drug does not bind to a single class of receptor.

Localization of receptors

      The distribution of receptors, e.g. in sections of the brain, can be studied using autoradiography. In humans, positron‐emitting drugs can sometimes be used to obtain images (positron emission tomography [PET] scanning) showing the location and density of receptors, e.g. dopamine receptors in the brain (Chapter 27).

Tachyphylaxis, desensitization, tolerance and drug resistance

      When a drug is given repeatedly, its effects often decrease with time. If the decrease in effect occurs quickly (minutes), it is called tachyphylaxis or desensitization. Tolerance refers to a slower decrease in response (days or weeks). Drug resistance is a term reserved for the loss of effect of chemotherapeutic agents, e.g. antimalarials (Chapter 43). Tolerance may involve increased metabolism of a drug, e.g. ethanol, barbiturates (Chapter 3), or homeostatic mechanisms (usually not understood) that gradually reduce the effect of a drug, e.g. morphine (Chapter 29). Changes in receptors may cause desensitization, e.g. suxamethonium (Chapter 6). A decrease in receptor number (downregulation) can lead to tolerance, e.g. insulin (Chapter 36).

3 Drug absorption, distribution and excretion

      Most drugs are given orally and they must pass through the gut wall to enter the bloodstream (left of the figure, ). This absorption process is affected by many factors (left), but is usually proportional to the lipid solubility of the drug. Thus, the absorption of non‐ionized molecules (B) is favoured because the latter are far more lipid soluble than ionized molecules (BH⁺), which are surrounded by a ‘shell’ of water molecules. Drugs are absorbed mainly from the small intestine because of the latter's large surface area. This is true even for weak acids (e.g. aspirin), which are non‐ionized in the acid (HCl) of the stomach. Drugs absorbed from the gastrointestinal tract enter the portal circulation (left, ) and some are extensively metabolized as they pass through the liver (first‐pass metabolism).

      Drugs that are sufficiently lipid soluble to be readily absorbed orally are rapidly distributed throughout the body water compartments (). Many drugs are loosely bound to plasma albumin, and an equilibrium forms between the bound (PB) and free (B) drug in the plasma. Drug that is bound to plasma proteins is confined to the vascular system and cannot exert its pharmacological actions.

      If a drug is given by intravenous injection, it enters the blood and is rapidly distributed to the tissues. By taking repeated blood samples, the fall in plasma concentration of the drug with time (i.e. the rate of drug elimination) can be measured (right, top graph). Often the concentration falls rapidly at first, but then the rate of decline progressively decreases. Such a curve is called exponential, and this means that, at any given time, a constant fraction of the drug present is eliminated in unit time. Many drugs show an exponential fall in plasma concentration because the rates at which the drug elimination processes work are themselves usually proportional to the concentration of drug in the plasma. The following processes are involved.

      1 Elimination in the urine by glomerular filtration (right, ).

      2 Metabolism, usually by the liver.

      3 Uptake by the liver and subsequent elimination in the bile ( solid line from liver).

      A process that depends on the concentration at any given time is called first order; most drugs exhibit first‐order elimination kinetics. If any enzyme system responsible for drug metabolism becomes saturated, then the elimination kinetics change to zero order, i.e. the rate of elimination proceeds at a constant rate and is unaffected by an increased concentration of the drug (e.g. ethanol, phenytoin).

Routes of administration

      Drugs can be administered orally or parenterally (i.e. by a nongastrointestinal route).

      Oral Most drugs are absorbed by this route and, because of its convenience, it is the most widely used. However, some drugs (e.g. benzylpenicillin, insulin) are destroyed by the acid or enzymes in the gut and must be given parenterally.

      Intravenous injection The drug directly enters into the circulation and bypasses the absorption barriers. It is used:

       where a rapid effect is required (e.g. furosemide in pulmonary oedema);

       for continuous administration (infusion);

       for large volumes; and

       for drugs that cause local tissue damage if given by other routes (e.g. cytotoxic drugs).

      Intramuscular and subcutaneous injections Drugs in aqueous solution are usually absorbed fairly rapidly, but absorption can be slowed by giving the drug in the form of an ester (e.g. antipsychotic depot preparations, Chapter 27).

      Other routes These include inhalation (e.g. volatile anaesthetics, some drugs used in asthma) and topical (e.g. ointments). Sublingual and rectal administration avoids the portal circulation, and sublingual preparations in particular are valuable in administering drugs subject to a high degree of first‐pass metabolism.

Distribution and excretion

      Distribution around the body occurs when the drug reaches the circulation. It must then penetrate tissues to act.

      The t_1/2(half‐life) is the time taken for the concentration of drug in the blood to fall by half its original value (right, top graph). Measurement of t_1/2 allows the calculation of the elimination rate constant (K_el) from the formula:

      where K_el is the fraction of drug present at any time that would be eliminated in unit time (e.g. K_el = 0.02 min⁻¹ means that 2% of the drug present is eliminated in 1 min).

      The exponential curve of plasma concentration (C_p) against time (t) is described by: