CLINICAL PHARMACOLOGY 2003 (PART 24)

Anyone who administers drugs acting on cardiovascular adrenergic mechanisms requires an understanding of how they act in order to use them to the best advantage and with safety. Adrenergic mechanisms Classification of sympathomimetics: by mode of action and selectivity for adrenoceptors Individual sympathomimetics Mucosal decongestants Shock Chronic orthostatic hypotensionAdrenaline, noradrenaline and dopamine are formed in the body and are used in therapeutics. The natural synthetic path is: tyrosine — dopa — dopamine — noradrenaline — adrenaline.Classification of sympathomimeticsBY MODE OF ACTION Noradrenaline is synthesised and stored in adrenergic nerve terminals and can be released from these stores by stimulating...
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CLINICAL PHARMACOLOGY 2003 (PART 24)22 Adrenergic mechanisms and drugs SYNOPSIS Adrenaline, noradrenaline and dopamine are formed in the body and are used in therapeutics. Anyone who administers drugs acting on The natural synthetic path is: cardiovascular adrenergic mechanisms requires tyrosine —> dopa —> dopamine —> noradrenaline —> an understanding of how they act in order to adrenaline. use them to the best advantage and with safety. Adrenergic mechanisms Classification of sympathomimetics: by mode of action and selectivity for adrenoceptors Classification of Individual sympathomimetics sympathomimetics Mucosal decongestants Shock Chronic orthostatic hypotension BY MODE OF ACTION 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 beAdrenergic mechanisms replenished by i.v. infusion of noradrenaline, and abolished by reserpine or by cutting the sympatheticThe discovery in 1895 of the hypertensive effect of neuron. Sympathomimetics may be classified as thoseadrenaline (epinephrine) was initiated by Dr Oliver,a physician in practice, who conducted a series of that act:experiments on his young son into whom he injected 1. directly: adrenoceptor agonists, e.g. adrenaline,an extract of bovine suprarenal. The effect wasconfirmed in animals and led eventually to the iso- 1 Compounds which ... simulate the effects of sympatheticlation and synthesis of adrenaline in the early 1900s. nerves not only with varying intensity but with varyingMany related compounds were examined and, in precision ... a term ... seems needed to indicate the types of1910, Barger and Dale invented the word sympatho- action common to these bases. We propose to call itmimetic1 and also pointed out that noradrenaline sympathomimetic. A term which indicates the relation of the action to innervation by the sympathetic system, without(norepinephrine) mimicked the action of the involving any theoretical preconception as to the meaning ofsympathetic nervous system more closely than did that relation or the precise mechanism of the action/ Bargeradrenaline. G, Dale H H 1910 Journal of Physiology XLI: 19-50. 447 22 ADRENERGIC MECHANISMSAND DRUGS noradrenaline, isoprenaline (isoproterenol), same year, Ahlquist hypothesised that this was due methoxamine, xylometazoline, oxymetazoline, to two different sorts of adrenoceptors (a and (3). metaraminol (entirely); and dopamine and For a further 10 years, only antagonists of a-receptor phenylephrine (mainly) effects (a-adrenoceptor block) were known, but in2. indirectly: by causing a release of noradrenaline 1958 the first substance selectively and competitively from stores at nerve endings, e.g. to prevent p-receptor effects ((3-adrenoceptor block), amphetamines, tyramine; and ephedrine dichloroisoprenaline, was synthesised. It was, how- (largely) ever, unsuitable for clinical use because it behaved3. by both mechanisms (1 and 2, though often as a partial agonist, and it was not until 1962 that with a preponderance of one or other): other pronethalol (an isoprenaline analogue) became the synthetic agents. first (3-adrenoceptor blocker to be used clinically. Unfortunately it had a low therapeutic index and Tachyphylaxis (rapidly diminishing response to was carcinogenic in mice, and was soon replaced byrepeated administration) is a particular feature of ...