(for systemic and local effect)
Intravenous (bolus or infusion)
An i.v. bolus, i.e. rapid injection, passes round the circulation being progressively diluted each time; it is delivered principally to the organs with high blood flow (brain, liver, heart, lung, kidneys).
Advantages are that the i.v. route gives swift, effective and highly predictable blood concentration and allows rapid modification of dose, i.e. immediate cessation of administration is possible if unwanted effects occur during administration. The route is suitable for administration of drugs that are not absorbed from the gut or are too irritant (anticancer agents) to be given by other routes.
Disadvantages are the hazard if a drug is given too quickly, as plasma concentration may rise at such a rate that normal mechanisms of distribution and elimination are outpaced. Some drugs will act within one arm-to-tongue (brain) circulation time which is 13 ± 3 seconds; with most drugs an injection given over 4 or 5 circulation times seems sufficient to avoid excessive plasma concentrations. Local venous thrombosis is liable to occur with prolonged infusion and with bolus doses of irritant formulations, e.g. diazepam, or microparticulate components of infusion fluids, especially if small veins are used. Infection of the intravenous catheter and the small thrombi on its tip are also a risk during prolonged infusions.
Blood flow is greater in the muscles of the upper arm than in the gluteal mass and thigh, and also increases with physical exercise. (Usually these influences are unimportant but one football-playing patient who was given an intramuscular injection of a sustained-release phenothiazine developed an extrapyramidal disorder towards the end of the game, presumably due to too rapid absorption of the drug.)
Advantages are that the route is reliable, suitable for irritant drugs, and depot preparations (neuroleptics, hormonal contraceptives) can be used at monthly or longer intervals. Absorption is more rapid than following subcutaneous injection (soluble preparations are absorbed within 10-30 min).
Disadvantages are that the route is not acceptable for self-administration, it may be painful, and if any adverse effects occur to a depot formulation, it cannot be removed.
Advantages are that the route is reliable and is acceptable for self-administration.
Disadvantages are poor absorption in peripheral circulatory failure. Repeated injections at one site can cause lipoatrophy, resulting in erratic absorption (see Insulin).
As a gas, e.g. volatile anaesthetics.
As an aerosol, e.g. P2-adrenoceptor agonist bron-chodilators. Aerosols are particles dispersed in a gas, the particles being small enough to remain in suspension for a long time instead of sedimenting rapidly under the influence of gravity; the particles may be liquid (fog) or solid (smoke).
As a powder, e.g. sodium cromoglicate. Particle size and air flow velocity are important. Most particles above 5 micrometres in diameter impact in the upper respiratory areas; particles of about 2 micrometres reach the terminal bronchioles; a large proportion of particles less than micrometer will be exhaled. Air flow velocity diminishes considerably as the bronchi progressively divide, promoting drug deposition peripherally.
Advantages are that drugs as gases can be rapidly taken up or eliminated, giving the close control that has marked the use of this route in general anaesthesia from its earliest days. Self-administration is practicable. Aerosols and powders provide high local concentration for action on bronchi, minimising systemic effects.
Disadvantages are that special apparatus is needed (some patients find pressurised aerosols difficult to use to best effect) and a drug must be nonirritant if the patient is conscious. Obstructed bronchi (mucus plugs in asthma) may cause therapy to fail.
For local effect, e.g. to skin, eye, lung, anal canal, rectum, vagina.
Advantage is the provision of high local concentration without systemic effect (usually12).
Disadvantage is that absorption can occur, especially when there is tissue destruction so that systemic effects result, e.g. adrenal steroids and neomycin to the skin, atropine to the eye. Ocular administration of a P-adrenoceptor blocker may cause systemic effects (any first-pass elimination is bypassed) and such eye drops are contraindicated for patients with asthma or chronic lung disease.13 There is extensive literature on this subject characterised by expressions of astonishment that serious effects, even death, can occur.
For systemic effect. Transdermal delivery systems (TDS) release drug through a rate-controlling membrane into the skin and so into the systemic circulation. Fluctuations in plasma concentration associated with other routes of administration are largely avoided, as is first-pass elimination in the
12 A cautionary tale. A 70-year-old man reported left breast enlargement and underwent mastectomy; histological examination revealed benign gynaecomastia. Ten months later the right breast enlarged. Tests of endocrine function were normal but the patient himself was struck by the fact that his wife had been using a vaginal cream (containing 0.01% dienestrol) initially for atrophic vaginitis but latterly the cream had been used to facilitate sexual intercourse which took place two to three times a week. On the assumption that penile absorption of oestrogen was responsible for the disorder, exposure to the cream was terminated. The gynaecomastia in the remaining breast then resolved (Di Raimondo C V et al 1980 New England Journal of Medicine 302:1089).
13 Two drops of 0.5% timolol solution, one to each eye, can equate to 10 mg by mouth.
liver. Glyceryl trinitrate and postmenopausal hormone replacement therapy may be given this way, in the form of a sticking plaster attached to the skin14 or as an ointment (glyceryl trinitrate). A nasal spray containing sumatriptan may be used to treat migraine.
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