Mechanism of Action and Systemic Effects
N-cholinomimetics stimulate neuronal nicotinic receptors. Because these receptors are located in both sympathetic and parasympathetic ganglia, the resulting pharmacological response is typically mixed.
- Cardiovascular System: Sympathomimetic effects predominate. Activation of sympathetic ganglia, release of catecholamines (epinephrine and norepinephrine) from the adrenal medulla, and stimulation of the vasomotor center via carotid bodies lead to vasoconstriction, tachycardia, and elevated blood pressure. A brief initial bradycardia may occur due to simultaneous parasympathetic ganglion stimulation.
- Gastrointestinal Tract: Parasympathomimetic effects dominate. Excitation of intramural ganglia increases intestinal tone and significantly enhances peristalsis.
- Exocrine Glands: Secretory activity is initially increased, though high (toxic) doses cause inhibition.
Pharmacology of Nicotine
Nicotine is the primary alkaloid found in tobacco leaves (Nicotiana tabacum). Structurally, it is a tertiary amine containing pyridine and pyrrolidine rings. It is highly lipophilic, allowing it to readily cross the blood-brain barrier.
CNS Effects: Nicotine triggers the release of dopamine and other biogenic amines, producing subjective rewarding sensations and strong psychological dependence. Its effect on the respiratory center is dose-dependent: low doses stimulate respiration, while high doses cause depression, potentially leading to complete respiratory arrest (paralysis). Furthermore, high doses provoke tremors, seizures, and stimulate the chemoreceptor trigger zone of the vomiting center.
Pharmacokinetics: Nicotine is rapidly absorbed through the respiratory mucosa and intact skin. It is metabolized by the liver and excreted by the kidneys (both unchanged and as metabolites). The half-life is only 1.5 to 2 hours, and tolerance develops rapidly.
Toxicity: Acute poisoning (via skin or mucosal contact) presents with hypersalivation, vomiting, diarrhea, initial bradycardia followed by tachycardia, elevated blood pressure, dyspnea, and seizures. Death results from respiratory center paralysis; primary management involves mechanical ventilation. Chronic poisoning from smoking leads to chronic bronchitis, lung cancer, and cardiovascular disease.
Lobeline and Cytisine: Clinical Applications
Unlike nicotine, the alkaloids lobeline (from Lobelia inflata) and cytisine (from Laburnum and Thermopsis species) have found limited medical applications.
- Smoking Cessation Aids: Formulated as tablets (such as cytisine preparations), these agents bind to nicotinic receptors as partial agonists, serving as replacement therapy to reduce severe withdrawal symptoms.
- Reflex Respiratory Stimulation: Administered intravenously, these agents stimulate receptors in the carotid body, reflexively stimulating the respiratory center in the medulla oblongata. This effect is very short-lived (2 to 5 minutes). Clinical indications are rare: neonatal asphyxia (when mechanical ventilation is unavailable) and carbon monoxide poisoning.
Important Clinical Limitation: These agents are effective only if the reflex excitability of the medulla oblongata is intact. They are completely ineffective in poisonings caused by sedative-hypnotics or general anesthetics, as these drugs block the reflex arc.