Selectivity For Adrenoceptors

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The following classification of sympathomimetics and antagonists is based on selectivity for receptors and on use. But selectivity is relative, not absolute; some agonists act on both a- and p-receptors, some are partial agonists and, if enough is administered, many will extend their range. The same applies to selective antagonists (receptor blockers), e.g. a Pj-selective adrenoceptor blocker can cause severe exacerbation of asthma (a \i2 effect) even at low dose. It is important to remember this because patients have died in the hands of doctors who have forgotten or been ignorant of it.3

Adrenoceptor agonists (Table 22.1)

a + p effects, nonselective: adrenaline is used as a vasoconstrictor (a) with local anaesthetics, as a mydriatic and in the emergency treatment of anaphylactic shock, for which condition it has the right mix of effects (bronchodilator, positive cardiac inotropic, vasoconstriction at high dose).

fXj effects: noradrenaline (with slight P effect on heart) is selectively released physiologically where it is wanted; as therapeutic agents for hypotensive states (excepting septic shock) dopamine and dobutamine are preferred (for their cardiac inotropic effect). Also having predominantly a, effects are imidazolines (xylometazoline, oxymeta-

3 While it is simplest to regard the selectivity of a drug as relative, being lost at higher doses, strictly speaking it is the benefits of the receptor selectivity of an agonist or antagonist, which are dose-dependent. A 10-fold selectivity of an agonist at the |ij-receptor, for instance, is a property of the agonist that is independent of dose, and means simply that 10 times less of the agonist is required to activate this receptor compared to the P2-subtype.

zoline), metaraminol, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine: some are used solely for topical vasoconstriction (nasal decongestants).

a2 effects in the central nervous system: clonidine.

P effects, nonselective (i.e. pt + pj): isoprenaline (isoproterenol). Its uses as bronchodilator (P2), for positive cardiac inotropic effect and to enhance conduction in heart block (p^ p2) have been largely superseded by agents with a more appropriately selective profile of effects. Other agents with nonselective P effects, ephedrine, orciprenaline, are also obsolete for asthma.

Pj effects, with some a effects: dopamine, used in cardiogenic shock.

P1 effects: dobutamine, used for cardiac inotropic effect.

P2 effects, used in asthma, or to relax the uterus, include: salbutamol, terbutaline, fenoterol, pirbuterol, reproterol, rimiterol, isoxsuprine, orciprenaline, rit-odrine.

Adrenoceptor antagonists (blockers)

See page 474.

Effects of a sympathomimetic

The overall effect of a sympathomimetic depends on the site of action (receptor agonist or indirect action), on receptor specificity and on dose; for instance adrenaline ordinarily dilates muscle blood vessels (P2; mainly arterioles, but veins also) but in very large doses constricts them (a). The end results are often complex and unpredictable, partly because of the variability of homeostatic reflex responses and partly because what is observed, e.g. a change in blood pressure, is the result of many factors, e.g. vasodilatation (p) in some areas, vasoconstriction (a) in others, and cardiac stimulation (P).

To block all the effects of adrenaline and noradrenaline, antagonists for both a- and P-receptors must be used. This can be a matter of practical importance, e.g. in phaeochromocytoma (see p. 495).

Physiological note. The termination of action of noradrenaline released at nerve endings is by:

• reuptake into nerve endings where it is stored and also subject to MAO degradation

• diffusion away from the area of the nerve ending and the receptor (junctional cleft)

• metabolism (by extraneuronal MAO and COMT).

These processes are slower than the very swift destruction of acetylcholine at the neuromuscular junction by extracellular acetylcholinesterase seated alongside the receptors. This difference reflects the differing signalling requirements: almost instantaneous (millisecond) responses for voluntary muscle movement versus the much more leisurely contraction of arteriolar muscle to control vascular resistance.

Synthetic noncatecholamines in clinical use have tj/ of hours, e.g. salbutamol 4h, because they are more resistant to enzymatic degradation and conjugation. They may be given orally although much higher doses are required. They penetrate the central nervous system and may have prominent effects, e.g. amphetamine. Substantial amounts appear in the urine.

Pharmacokinetics

Catecholamines (adrenaline, noradrenaline, dopamine, dobutamine, isoprenaline) (plasma t;/2 approx. 2 min) are metabolised by two enzymes, monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). These enzymes are present in large amounts in the liver and kidney and account for most of the metabolism of injected catecholamines. MAO is also present in the intestinal mucosa (and in nerve endings, peripheral and central). Because of these enzymes catecholamines are ineffective when swallowed, but noncatecholamines, e.g. salbutamol, amphetamine, are effective orally.

Adverse effects

These may be deduced from their actions (Table 22.1, Fig. 22.1). Tissue necrosis due to intense vasoconstriction (a) around injection sites occurs as a result of leakage from i.v. infusions. The effects on the heart (pj) include tachycardia, palpitations, cardiac arrhythmias including ventricular tachycardia and fibrillation, and muscle tremor (p2). Sympathomimetic drugs should be used with great caution in patients with heart disease.

The effect of the sympathomimetic drugs on the pregnant uterus is variable and difficult to predict, but serious fetal distress can occur, due to reduced placental blood flow as a result both of contraction of the uterine muscle (a) and arterial constriction (a). P2-agonists are used to relax the uterus in premature labour, but unwanted cardiovascular actions can be troublesome. Sympathomimetics were particularly likely to cause cardiac arrhythmias ([3, effect) in patients who received halothane anaesthesia (now much less used).

Sympathomimetics and plasma potassium.

Adrenergic mechanisms have a role in the physiological control of plasma potassium concentration. The biochemical pump that shifts potassium into cells is activated by the (^-adrenoceptor agonists (adrenaline, salbutamol, isoprenaline) and can cause hypokalaemia. P2-adrenoceptor antagonists block the effect.

The hypokalaemia effects of administered (P2) sympathomimetics may be clinically important, particularly in patients having pre-existing hypokalaemia, e.g. due to intense adrenergic activity such as occurs in myocardial infarction,4 in fright (admission to hospital is accompanied by transient hypokalaemia), or with previous diuretic therapy, and taking digoxin. In such subjects the use of a sympathomimetic infusion or of an adrenaline-containing local anaesthetic may precipitate a cardiac arrhythmia. Hypokalaemia may occur during treatment of severe asthma, particularly where the P2-receptor agonist is combined with theophylline.

P-adrenoceptor blockers, as expected, enhance the hyperkalaemia of muscular exercise; and one of their benefits in preventing cardiac arrhythmias

4 Normal subjects, infused i.v. with adrenaline in amounts that approximate to those found in the plasma after severe myocardial infarction, show a fall in plasma K of about 0.8 mmol/1 (Brown M J1983 New England Journal of Medicine 309:1414).

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Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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