Noradrenaline is synthesised and stored in adrenergic nerve terminals and can be released from these stores by stimulating the nerve or by drugs (ephedrine, amfetamine). These noradrenaline stores may be replenished by i.v. infusion of noradrenaline, and abolished by reserpine or by cutting the sympathetic neuron.
Sympathomimetics may be classified as those that act:
1. directly: adrenoceptor agonists, e.g. adrenaline,
1 'Compounds which ... simulate the effects of sympathetic nerves not only with varying intensity but with varying precision ... a term ... seems needed to indicate the types of action common to these bases. We propose to call it "sympathomimetic". A term which indicates the relation of the action to innervation by the sympathetic system, without involving any theoretical preconception as to the meaning of that relation or the precise mechanism of the action.' Barger G, Dale H H 1910 Journal of Physiology XLI: 19-50.
noradrenaline, isoprenaline (isoproterenol), methoxamine, xylometazoline, oxymetazoline, metaraminol (entirely); and dopamine and phenylephrine (mainly)
2. indirectly: by causing a release of noradrenaline from stores at nerve endings, e.g. amphetamines, tyramine; and ephedrine (largely)
3. by both mechanisms (1 and 2, though often with a preponderance of one or other): other synthetic agents.
Tachyphylaxis (rapidly diminishing response to repeated administration) is a particular feature of group 2 drugs. It reflects depletion of the 'releasable' pool of noradrenaline from adrenergic nerve terminals that makes these agents less suitable as, for example, pressor agents than drugs of group 1. Longer-term tolerance (see p. 95) to the effects direct sympathomimetics is much less of a clinical problem and reflects an alteration in adrenergic receptor density or coupling to second messenger systems.
Interactions of sympathomimetics with other vasoactive drugs are complex. Some drugs block the reuptake mechanism for noradrenaline in adrenergic nerve terminals and potentiate the pressor effects of noradrenaline e.g. cocaine, tricyclic antidepressants or highly noradrenaline-selective reuptake inhibitors such as roboxetine. Others deplete or destroy the intracellular stores within adrenergic nerve terminals (e.g. reserpine and guanethidine) and thus block the action of indirect sympathomimetics.
Sympathomimetics are also generally optically active drugs, with only one stereoisomer conferring most of the clinical efficacy of the racemate: for instance laevo-noradrenaline is at least 50 times as active as the dextro- form. Noradrenaline, adrenaline and phenylephrine are all used clinically as their laevo-isomers.
History. Up to 1948 it was known that the peripheral motor (vasoconstriction) effects of adrenaline were preventable and that the peripheral inhibitory (vasodilatation) and the 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 (a and p). For a further 10 years, only antagonists of a-receptor effects («-adrenoceptor block) were known, but in 1958 the first substance selectively and competitively to prevent P-receptor effects (p-adrenoceptor block), dichloroisoprenaline, was synthesised. It was, however, 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 p-adrenoceptor blocker to be used clinically. Unfortunately it had a low therapeutic index and was carcinogenic in mice, and was soon replaced by propranolol (Inderal).
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 stereospeciñcally may be highly selective, whereas drugs that act indirectly by discharging noradrenaline indiscriminately from nerve endings, e.g. amfetamine, will have a wider range of effects.
Subclassification of adrenoceptors is shown in Table 22.1.
All adrenoceptors are members of the G-coupled family of receptor proteins i.e. the receptor is coupled to its effector protein through special transduction proteins called G-proteins (themselves a large protein family). The effector protein differs amongst adrenoceptor subtypes. In the case of p-adrenoceptors, the effector is adenylyl cyclase and hence cyclic AMP is the second messenger molecule. For a-adrenoceptors, phospholipase C is the commonest effector protein and the second messenger here is IP3. It is the cascade of events initiated by the second messenger molecules that produces the variety of tissue effects as shown in Table 22.1 It should be clear that specificity is provided by the receptor subtype, not the messengers.
Complexity of adrenergic mechanisms
Drugs may mimic or impair adrenergic mechanisms:
• directly, by binding on adrenoceptors: as agonists
(adrenaline) or antagonists (propranolol)
TABLE 22.1 Clinically relevant aspects of adrenoceptor functions and actions of agonists
Eye:1 mydriasis Arterioles:
constriction (only slight in coronary and cerebral)
Heart (^.jy3 increased rate (SA node) increased automaticity (AV node and muscle) increased velocity in conducting tissue increased contractility of myocardium increased 03 consumption decreased refractory period of all tissues
dilatation (p2) Bronchi ((J2): relaxation Anti-inflammatory effect:
Inhibition of release of autacoids (histamine, leukotrienses) from mast cells, e.g. asthma in type 1
Skin: sweat, pilomotor Male ejaculation Blood platelet: aggregation Metabolic effect: hyperkalemia
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