Sympatholytics

Mechanism of action: cellular level

Sympatholytics act exclusively presynaptically. Their main task is to leave the nerve terminal without a neurotransmitter. This process can be divided into several stages:

1. The drug penetrates into the varicose thickening and accumulates in the membrane of vesicles (granules where the neurotransmitter is stored).
2. Vesicular transport pumps are blocked.
3. Dopamine ceases to enter the granule. Since norepinephrine is synthesized from dopamine directly inside the vesicle, the synthesis of new neurotransmitter is completely halted.
4. In parallel, the reuptake of already formed norepinephrine from the cytoplasm back into the vesicle is blocked.
5. All norepinephrine that ends up unprotected in the cytoplasm undergoes oxidative deamination by the enzyme monoamine oxidase (MAO).

As a result, the vesicles are completely emptied, and when a nerve impulse arrives in the synaptic cleft, there is simply nothing to be released. A similar process of catecholamine depletion occurs in the chromaffin tissue of the adrenal glands.

Hemodynamics and parasympathetic shift

The key clinical effect of sympatholytics is hypotensive. Due to the weakening of sympathetic control, the following occur:

• Decrease in cardiac output (heart rate and contractility drop).
• Decrease in total peripheral vascular resistance (blood vessels dilate).

However, the removal of sympathetic influence does not pass without a trace: the parasympathetic nervous system (vagus nerve) begins to dominate in the body. This is clearly manifested in the gastrointestinal tract. The patient experiences a sharp increase in the secretion of digestive glands and enhanced intestinal motility. Clinically, this threatens with diarrhea and exacerbation of gastric ulcer. M-cholinolytics (e.g., atropine) are used to relieve these undesirable effects.

Reserpine characteristics and pharmacokinetics

Reserpine (Reserpinum) is an indole derivative capable of crossing the blood-brain barrier. Because of this, it depletes neurotransmitter stores (norepinephrine, dopamine, and serotonin) not only in the periphery but also in the brain. In the past, this property was even used to achieve a mild antipsychotic effect, but today the drug is no longer used in psychiatry.

The action of reserpine develops very slowly. Binding to vesicles is irreversible, so to restore impulse transmission, the neuron must synthesize new granules. Because of this, even after complete withdrawal of the drug, the hypotensive effect persists for up to two weeks. In modern practice, reserpine is prescribed for essential hypertension, usually as part of combination drugs (Adelphane-Eidrex, Cristepine, Triresid K).

Side effects and strict contraindications

In addition to diarrhea and bradycardia, peripheral vasodilation often causes persistent nasal congestion (mucosal edema). For another representative of the group — guanethidine — orthostatic collapse is extremely characteristic.

Central complications from high doses of reserpine include:

• Drowsiness, lethargy, and impaired concentration.
• Drug-induced parkinsonism — severe extrapyramidal disorders arising from a lack of dopamine in the neostriatum.
• Severe depression — if it appears, the drug is discontinued immediately.

Important interaction: MAO inhibitors (nialamide) are used to treat reserpine-induced depression to restore the balance of catecholamines in the central nervous system. However, they can be prescribed only after the complete withdrawal of the sympatholytic; otherwise, an uncontrolled release of neurotransmitters and a severe hypertensive crisis are possible.

The drug is strictly contraindicated in depressive states, Parkinson's disease, pheochromocytoma, and peptic ulcer disease.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Mechanism of orthostatic collapse upon administration of guanethidine.
• The phenomenon of receptor sensitization during denervation.
• The role of MAO inhibitors in correcting the side effects of reserpine.
• Differences in blood-brain barrier permeability for various sympatholytics.
• Principles of combination therapy for hypertension (thiazide diuretics + sympatholytics).

Other topics in the section "Drugs Acting on Adrenergic Synapses"

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