Mechanism of Action: Cellular Level
Sympatholytics act exclusively at the presynaptic level. Their primary goal is to leave the nerve terminal without a neurotransmitter. This process can be divided into several stages:
- The drug penetrates the varicosity and accumulates in the membrane of storage vesicles (granules where the neurotransmitter is stored).
- Vesicular transport pumps are blocked.
- Dopamine is prevented from entering the vesicle. Since norepinephrine is synthesized from dopamine directly inside the vesicle, the synthesis of new neurotransmitters is completely halted.
- Simultaneously, the reuptake of pre-formed norepinephrine from the cytoplasm back into the vesicle is blocked.
- All norepinephrine left unprotected in the cytoplasm undergoes oxidative deamination by the enzyme monoamine oxidase (MAO).
As a result, vesicles are completely emptied, and when a nerve impulse arrives at the synaptic cleft, there is simply no neurotransmitter left to release. A similar catecholamine depletion process occurs in the chromaffin tissue of the adrenal medulla.
Hemodynamics and Parasympathetic Shift
The key clinical effect of sympatholytics is antihypertensive. Due to the attenuation of sympathetic control, the following occur:
- Decreased cardiac output (reduced heart rate and myocardial contractility).
- Decreased total peripheral resistance (vasodilation).
However, the removal of sympathetic influence does not go unnoticed: the parasympathetic nervous system (vagus nerve) begins to dominate. This is prominently manifested in the gastrointestinal tract. The patient experiences a sharp increase in digestive gland secretion and enhanced bowel motility. Clinically, this presents a risk of diarrhea and exacerbation of peptic ulcer disease. M-cholinergic antagonists (e.g., atropine) are used to manage these adverse effects.
Properties of Reserpine and Pharmacokinetics
Reserpine (Reserpinum) is an indole derivative capable of crossing the blood-brain barrier. Consequently, it depletes neurotransmitter stores (norepinephrine, dopamine, and serotonin) not only in the periphery but also in the central nervous system. Historically, this property was even used to achieve a mild antipsychotic effect, though the drug is no longer used in psychiatry.
Reserpine's action develops very slowly. Its binding to vesicles is irreversible, so restoring impulse transmission requires the neuron to synthesize new granules. For this reason, even after complete drug discontinuation, the antihypertensive effect persists for up to two weeks. In modern practice, reserpine is prescribed for hypertension, typically as part of combination products (e.g., Adelphane-Esidrex, Cristerpin, Triresid K).
Side Effects and Strict Contraindications
In addition to diarrhea and bradycardia, peripheral vasodilation frequently causes persistent nasal congestion (mucosal edema). Another agent in this group, guanethidine, is strongly associated with orthostatic hypotension.
Central complications from high doses of reserpine include:
- Somnolence, lethargy, and impaired concentration.
- Drug-induced parkinsonism — severe extrapyramidal symptoms resulting from dopamine deficiency in the neostriatum.
- Severe depression — if this develops, the drug must be discontinued immediately.
Important drug interaction: MAO inhibitors (nialamide) are used to treat reserpine-induced depression by restoring the CNS catecholamine balance. However, they can only be administered after complete discontinuation of the sympatholytic; otherwise, an uncontrolled release of neurotransmitters and a severe hypertensive crisis may occur.
The drug is strictly contraindicated in depressive states, Parkinson's disease, pheochromocytoma, and peptic ulcer disease.