Adrenergic mechanisms and drugs

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. 

The discovery in 1895 of the hypertensive effect of adrenaline (epinephrine) was initiated by Dr Oliver, a physician in practice, who conducted a series of experiments on his young son into whom he injected an extract of bovine suprarenal. The effect was confirmed in animals and led eventually to the isolation and synthesis of adrenaline in the early 1900s. Many related compounds were examined and, in 1910, Barger and Dale invented the word sympathomimetic and also pointed out that noradrenaline (norepinephrine) mimicked the action of the S5rmpathetic nervous system more closely than did adrenaline. 

Adrenaline, noradrenaline and dopamine are formed in the body and are used in therapeutics. The natural synthetic path is tyrosine — dopa dopamine — noradrenaline —  

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. 

indirectly by causing a release of noradrenaline from stores at nerve endings, e.g. amphetamines, tyramine and ephedrine (largely) 

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Propranolol is a prototype of this series of drugs and is the oldest and most widely used nonselective )3-adrenoblocker. It possesses antianginal, hypotensive, and antiarrhythmic action. Propranolol is a cardiac depressant that acts on the mechanic and electrophysio-logical properties of the myocardium. It can block atrioventricular conductivity and potential automatism of sinus nodes as well as adrenergic stimulation caused by catecholamines nevertheless, it lowers myocardial contractility, heart rate, blood pressure, and the myocardial requirement of oxygen. 

The other group of drugs acting on catecholamine recycling are the true reuptake inhibitors, which block the amine pump of the reuptake-1 mechanism in central adrenergic, dopaminergic, and serotonergic neurons. 

Apart from causing very well known cardiotoxic effects, phenothiazine derivatives can accumulate in lung epithelial cell membranes and therefore cause severe respiratory disorders. In the study performed by Ito et al. [279] it was found that CPZ (9) inhibited transepithelial Cl transport, mainly due to two mechanisms influence on the beta-adrenergic receptor and inhibition of basolateral potassium channels. The authors of this study also suggested that the recorded effects could result from the electrostatic interactions between the drug molecules and negatively charged components of the inner leaflet of the plasma membrane. 

When this enzyme is inhibited, the concentrations of norepinephrine within adrenergic neurons increase and drugs that stimulate its release can bring about an exaggerated response. Interactions between MAO inhibitors and indirectly acting sympathomimetic amines (e.g., amphetamine) develop by this mechanism. If amphetamine is administered to a patient whose stores of norepinephrine have been increased by MAO inhibition, the patient may experience severe headache, hypertension (possibly a hypertensive crisis), and cardiac arrhythmias. The serious consequences associated with these interactions contraindicate the use of these agents in combination. 

The antihypertensive mechanism of the rauwiloid alkaloids primarily involves depletion of catecholamines from stores by blocking their reuptake mechanism and thereby storage in neuronal vesicles. The effect is widespread both peripherally and centrally, and includes NE, DA, and 5-HT (serotonin). Depletion of the amines affects blood vessels, the heart, adrenal medulla, and possibly other tissues as well. Since it is the reuptake and not the release of NE that is inhibited in the postganglionic adrenergic neuron, the existing pool must be fully depleted before antihypertensive effects become apparent. The drug also binds to vesicular membranes for days, accounting for the irreversibility of the process. 

This drug depletes neuronal stores of norepinephrine. The drug enters the adrenergic nerve terminus through the synaptic reuptake mechanism, and is transported into the adrenergic vesicle. Once in the vesicle, it displaces norepinephrine from the vesicle to the cytoplasm, where it is degraded by monoamine oxidase (MAO). 

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