Adrenergic mechanisms and drugs

Chapter 23 Adrenergic mechanisms and drugs






Classification of sympathomimetics



By mode of action


Noradrenaline/norepinephrine is synthesised and stored in vesicles within adrenergic nerve terminals (Fig. 23.1). The vesicles can be released from these stores by stimulating the nerve or by drugs (ephedrine, amfetamine). The noradrenaline/norepinephrine stores can also be replenished by intravenous infusion of noradrenaline/norepinephrine, and abolished by reserpine or by cutting the sympathetic nerve. Sympathomimetics may be classified on the basis of their sites of action (see Fig. 23.1) as acting:



All of the above mechanisms operate in both the central and peripheral nervous systems, but discussion below will focus on agents that influence peripheral adrenergic mechanisms.









History

Up to 1948 it was known that the peripheral motor (vasoconstriction) effects of adrenaline/epinephrine were preventable and that the peripheral inhibitory (vasodilatation) and cardiac stimulant actions were not preventable by the then available antagonists (ergot alkaloids, phenoxybenzamine). That same year, Ahlquist hypothesised that this was due to two different sorts of adrenoceptors (α and β). For a further 10 years, only antagonists of α-receptor effects (α-adrenoceptor block) were known, but in 1958 the first substance selectively and competitively to prevent β-receptor effects (β-adrenoceptor block), dichloroisoprenaline, was synthesised. It was unsuitable for clinical use because it behaved as a partial agonist, and it was not until 1962 that pronethalol (an isoprenaline analogue) became the first β-adrenoceptor blocker to be used clinically. Unfortunately it had a low therapeutic index and was carcinogenic in mice; it was soon replaced by propranolol.


It is evident that the site of action has an important role in selectivity, e.g. drugs that act on end-organ receptors directly and stereospecifically may be highly selective, whereas drugs that act indirectly by discharging noradrenaline/norepinephrine indiscriminately from nerve endings, e.g. amfetamine, will have a wider range of effects.


Subclassification of adrenoceptors is shown in Table 23.1.


Table 23.1 Clinically relevant aspects of adrenoceptor functions and actions of agonists














































































α1-Adrenoceptor effectsa β-Adrenoceptor effects
Eye:b mydriasis  
  Heart1, β2):c
  increased rate (SA node)
  increased automaticity (AV node and muscle)
  increased velocity in conducting tissue
  increased contractility of myocardium
  increased oxygen consumption; decreased refractory period of all tissues
Arterioles: Arterioles:
constriction (only slight in coronary and cerebral) dilatation (β2)
  Bronchi2): relaxation
  Anti-inflammatory effect:
  inhibition of release of autacoids (histamine, leukotrienes) from mast cells, e.g. asthma in type I allergy
Uterus: contraction (pregnant) Uterus2): relaxation (pregnant)
  Skeletal muscle: tremor (β2)
Skin: sweat, pilomotor  
Male ejaculation  
Blood platelet: aggregation  
Metabolic effect: Metabolic effects:
hyperkalaemia hypokalaemia (β2)
  hepatic glycogenolysis (β2)
  lipolysis (β1, β2)
Bladder sphincter: contraction Bladder detrusor: relaxation
Intestinal smooth muscle relaxation is mediated by α and β adrenoceptors.
α2-adrenoceptor effects:a α2 receptors on the nerve ending, i.e. presynaptic autoreceptors, mediate negative feedback which inhibits noradrenaline/norepinephrine release
Use of the term cardioselective to mean β1-receptor selective only, especially in the case of β-receptor blocking drugs, is no longer appropriate.
Although in most species the β1 receptor is the only cardiac β receptor, this is not the case in humans. What is not generally appreciated is that the endogenous sympathetic neurotransmitter noradrenaline/norepinephrine has about a 20-fold selectivity for the β1 receptor – similar to that of the antagonist atenolol – with the consequence that under most circumstances, in most tissues, there is little or no β2-receptor stimulation to be affected by a non-selective β-blocker. Why asthmatics should be so sensitive to β-blockade is paradoxical: all the bronchial β receptors are β2, but the bronchi themselves are not innervated by noradrenergic fibres and the circulating adrenaline levels are, if anything, low in asthma.

a For the role of subtypes (α1 and α2), see prazosin.


b Effects on intraocular pressure involve both α and β adrenoceptors as well as cholinoceptors.


c Cardiac β1 receptors mediate effects of sympathetic nerve stimulation. Cardiac β2 receptors mediate effects of circulating adrenaline, when this is secreted at a sufficient rate, e.g. following myocardial infarction or in heart failure. Both receptors are coupled to the same intracellular signalling pathway (cyclic AMP production) and mediate the same biological effects.




Selectivity for adrenoceptors


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 α and β receptors, some are partial agonists and, if sufficient drug is administered, many will extend their range. The same applies to selective antagonists (receptor blockers), e.g. a β1-selective-adrenoceptor blocker can cause severe exacerbation of asthma (a β2 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.4





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/epinephrine ordinarily dilates muscle blood vessels (β2; mainly arterioles, but veins also) but in very large doses constricts them (α). 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 (β) in some areas, vasoconstriction (α) in others, and cardiac stimulation (β).


To block all the effects of adrenaline/epinephrine and noradrenaline/norepinephrine, antagonists for both α and β receptors must be used. This can be a matter of practical importance, e.g. in phaeochromocytoma (see p. 419).



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Jun 18, 2016 | Posted by in PHARMACY | Comments Off on Adrenergic mechanisms and drugs

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