Indirectly acting sympathomimetic drugs

In addition to the agonists which stimulate directly adrenergic receptors, a certain number of compounds or drugs act indirectly via endogenous catecholamines by increasing their concentration in synaptic clefts and are called indirectly acting sympathomimetic drugs. The increase of dopamine and noradrenaline concentration can be obtained by different mechanisms, not mutually exclusive:

  1. Increase of synthesis.
  2. Increase of release.
  3. Decrease of reuptake.
  4. Decrease of catabolism.

Increase of concentration of endogenous catecholamines, noradrenaline or dopamine, In synaptic clefts, induces an increase of stimulation of adrenergic receptors. The consequences of this indirect stimulation are predominantly seen on peripheral organs if the drug does not cross the blood-brain barrier and on the CNS if the drug enters easily into brain. Often the same drug has both peripheral and central effects.

Increase in the catecholamine concentration in synaptic clefts has several effects.

  1. on peripheral organs
    It is norepinephrine which plays the essential part. Its increase elicits:
    • cardiac stimulation (beta-1) with reinforcement of contractions, tachycardia, palpitations.
    • vasoconstriction (alpha-1), responsible for increase of peripheral resistances and rise of arterial pressure.
    • other effects: mild bronchodilation (beta-2), mydriasis (alpha-1), difficulty in micturition particularly in case of prostate hypertrophy.
    Generally, effects of indirectly acting compounds are, as compared to directly acting ones, slower to develop, more durable and they attenuate with repetitive administrations, this last effect is called tachyphylaxis.
  2. on central nervous system
    • Increase of noradrenaline in the synaptic cleft seems responsible of mood stimulation (antidepressant effect), of vigilance stimulation and perhaps of an anorectic effect.
    • Increase of dopamine in synapses gives, according to its importance and its cerebral localization, antiparkinsonian and sometimes antidepressant effects and tends to induce addiction.

Drugs with indirect sympathomimetic activity are used as vasoconstrictors, CNS stimulants and anorexiants, antidepressants, antiparkinsonians.

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