Amfetamines

Amfetamine has had multifarious uses. It is now obsolete for depression and as an appetite suppressant, and its use in sport is abuse (see before). There is concern that its illicit use as a psychostimulant is widespread. Amfetamine is a racemic compound: the laevo-form is relatively inactive but dexamphet-amine (the dextro- isomer) finds use in medicine. Amfetamine will be described, and structurally-related drugs only in the ways in which they differ.

Mode of action. Amfetamine acts by releasing noradrenaline (norepinephrine) stored in nerve endings in both the CNS and the periphery. As with all drugs acting on the central nervous system, the psychological effects vary with mood, personality and environment, as well as with dose.

Subjects become euphoric and fatigue is postponed. Although physical and mental performance may improve, this cannot be relied on; subjects may be more confident and show more initiative, and be better satisfied with a more speedy performance that has deteriorated in accuracy. On the other hand there may be anxiety and a feeling of nervous and physical tension, especially with large doses, and subjects develop tremors and confusion, and feel dizzy. Time seems to pass with greater rapidity. The sympathomimetic effect on the heart, causing palpitations, may intensify discomfort or alarm. Amfetamine increases the peripheral oxygen consumption and this, together with vasoconstriction and restlessness, leads to hyperthermia in overdose, especially if the subject exercises.

Dependence on amfetamine and similar sympathomimetics occurs; it is chiefly psychological, but there is a withdrawal syndrome, suggesting physical dependence; tolerance occurs.

Mild dependence on prescribed amfetamines became common, particularly amongst people with unstable personalities, depressives and tired, lonely housewives. In the 1960s, adolescents began to turn to amfetamines for occasional use to keep awake to have 'fun' and then as an aid to the challenges normal to that stage of life. Unfortunately, drugs provide only the temporary solution of avoidance and postponement of such challenges, retarding rather than assisting progress to maturity.

As well as oral use, i.v. administration (with the pleasurable 'flash' as with opioids) is employed. Severe dependence induces behaviour disorders, hallucinations and even florid psychosis, which can be controlled by haloperidol. Withdrawal is accompanied by lethargy, sleep, desire for food and sometimes severe depression, which leads to an urge to resume the drug.

Pharmacokinetics. Amfetamine (t/, 12 h) is readily absorbed by any usual route and is largely eliminated unchanged in the urine. Urinary excretion is pH dependent; being a basic substance, elimination will be greater in an acid urine.

Interactions are as expected from mode of action, e.g. antagonism of antihypertensives; severe hypertension with MAOIs and (3-adrenoceptor blocking drugs.

Acute poisoning is manifested by excitement and peripheral sympathomimetic effects; convulsions may occur; also, in acute or chronic overuse, a state resembling hyperactive paranoid schizophrenia with hallucinations develops. Hyperthermia occurs with cardiac arrhythmias, vascular collapse and death. Treatment is chlorpromazine with added antihypertensive, e.g. labetalol, if necessary; these provide sedation and a- and (3-adrenoceptor blockade (not a P-blocker alone), rendering unnecessary the enhancement of elimination by urinary acidification.

Chronic overdose can cause a psychotic state mimicking schizophrenia. A vasculitis of the cerebral and/or renal vessels can occur, possibly due to release of vasoconstrictor amines from both platelets and nerve endings. Severe hypertension can result from the renal vasculitis.

Structurally-related drugs include dexamfet-amine (used for narcolepsy and in attention deficit hyperactivity disorder (ADHD) see p. 387), methylphenidate (used for ADHD), tenamfetamine (Ecstasy, see p. 189), phentermine, diethylpropion, and pemoline.

METHYLXANTHINES (XANTHINES)

The three xanthines, caffeine, theophylline and theobromine, occur in plants. They are qualitatively similar but differ markedly in potency.

• Tea contains caffeine and theophylline.

• Coffee contains caffeine.

• Cocoa and chocolate contain caffeine and theobromine.

• The cola nut ('cola' drinks) contains caffeine.

Theobromine is weak and is of no clinical importance.

Mode of action. Caffeine and theophylline have complex and incompletely elucidated actions, which include inhibition of phosphodiesterase (the enzyme that breaks down cyclic AMP, see p. 191), effects on intracellular calcium distribution, and noradrenergic function. When theophylline (as aminophylline) is used alongside salbutamol in asthma its action adds up to increased benefit to the bronchi, but increased risk to the heart.

Pharmacokinetics. Absorption of xanthines after oral or rectal administration varies with the preparation used. It is generally extensive (> 95%). Caffeine metabolism varies much between individuals (tX 2-12 h). Xanthines are metabolised (more than 90%) by numerous mixed function oxidase enzymes, and xanthine oxidase. (For further details on theophylline, see Asthma.)

Actions on mental performance. Caffeine is more potent than theophylline, but both drugs stimulate mental activity where it is below normal. They do not raise it above normal; thought is more rapid and fatigue is removed or its onset delayed. The effects on mental and physical performance vary according to the mental state and personality of the subject. Reaction-time is decreased. Performance that is inferior because of excessive anxiety may become worse. Caffeine can also improve physical performance both in tasks requiring more physical effort than skill (athletics) and in tasks requiring more skill than physical effort (monitoring instruments and taking corrective action in an aircraft flight simulator). It is uncertain whether the improvement consists only of restoring to normal performance that is impaired by fatigue or boredom, or whether caffeine can also enable subjects to improve their normal maximum performance. The drugs may produce their effects by altering both physical capacity and mental attitude.

There is insufficient information on the effects on learning to be able to give any useful advice to students preparing for examination other than that intellectual performance may be assisted when it has been reduced by fatigue or boredom. Effects on mood vary greatly amongst individuals and according to the environment and the task in hand. In general, caffeine induces feelings of alertness and wellbeing, euphoria or exhilaration. Onset of boredom, fatigue, inattentiveness and sleepiness is postponed.

Overdose will certainly reduce performance (see chronic overdose, below). Acute overdose, e.g. aminophylline (see p. 559) i.v., can cause convulsions, hypotension, cardiac arrhythmia and sudden death.

Other effects

Respiratory stimulation occurs with substantial doses.

Sleep. Caffeine affects sleep of older more than it does of younger people and this may be related to the fact that older people show greater catecholamine turnover in the central nervous system than do the young. Onset of sleep (sleep latency) is delayed, bodily movements are increased, total sleep time is reduced, there are increased awakenings. Tolerance to this effect does not occur, as is shown by the provision of decaffeinated coffee.45

Skeletal muscle. Metabolism is increased, and this may play a part in the enhanced athletic performance mentioned above. There is significant improvement of diaphragmatic function in chronic obstructive pulmonary disease.

45 The European Union regulations define 'decaffeinated' as coffee (bean) containing 0.3% or less of caffeine (normal content 1-3%).

Cardiovascular system. Both caffeine and theophylline directly stimulate the myocardium and cause increased cardiac output, tachycardia and sometimes ectopic beats and palpitations. This effect occurs almost at once after i.v. injection and lasts half an hour. Theophylline contributes usefully to the relief of acute left ventricular failure. There is peripheral (but not cerebral) vasodilatation due to a direct action of the drugs on the blood vessels, but stimulation of the vasomotor centre tends to counter this. Changes in the blood pressure are therefore somewhat unpredictable, but caffeine 250 mg (single dose) usually causes a transient rise of blood pressure of about 14/10 mmHg in occasional coffee drinkers (but has no additional effect in habitual drinkers); this effect can be used advantageously in patients with autonomic nervous system failure who experience postprandial hypotension (2 cups of coffee with breakfast may suffice for the day). In occasional coffee drinkers 2 cups of coffee (about 160 mg caffeine) per day raise blood pressure by 5/4 mmHg. Increased coronary artery blood flow may occur but increased cardiac work counterbalances this in angina pectoris.

When theophylline (aminophylline) is given i.v., slow injection is essential in order to avoid transient peak concentrations which are equivalent to administering an overdose (below).

Smooth muscle (other than vascular muscle, which is discussed above) is relaxed. The only important clinical use for this action is in reversible airways obstruction (asthma), when the action of theophylline can be a very valuable addition to therapy.

Kidney. Diuresis occurs in normal people chiefly due to reduced tubular reabsorption of Na, similar to thiazide action, but weaker.

Miscellaneous effects. Gastric secretion is increased by caffeine given as coffee (by decaffeinated coffee too) more than by caffeine alone, and the basal metabolic rate may increase slightly (see Skeletal muscle, above).

Preparations and uses of caffeine and theophylline

Aminophylline. The most generally useful prepara tion is aminophylline which is a soluble, irritant salt of theophylline with ethylenediamine (see Asthma).

Attempts to make nonirritant orally reliable preparations of theophylline have resulted in choline theophyllinate and numerous variants. Sustained-release formulations are convenient for asthmatics, but they cannot be assumed to be bioequivalent and repeat prescriptions should adhere to the formulation of a particular manufacturer. Suppositories are available. Aminophylline is used in:

• Asthma. In severe asthma (given i.v.) when f>-adrenoceptor agonists fail to give adequate response; and for chronic asthma (orally) to provide a background bronchodilator effect.

• Acute left ventricular failure (see p. 518).

• Neonatal apnoea; caffeine is also effective.

Caffeine is used as an additional ingredient in analgesic tablets; about 60 mg potentiates NSAIDs; also as an aid in hypotension of autonomic failure and to enhance oral ergotamine absorption in migraine

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