Nicotinic Ganglionic Blocker
- Article Author:
- Suraj Kaushal
- Article Editor:
- Prasanna Tadi
- Updated:
- 7/8/2020 8:48:27 AM
- For CME on this topic:
- Nicotinic Ganglionic Blocker CME
- PubMed Link:
- Nicotinic Ganglionic Blocker
Indications
Nicotinic ganglion receptors found in the autonomic ganglia are involved in both sympathetic and parasympathetic transmission. These receptors classify as neuronal nicotinic (Nn) cholinergic receptors, and they are on postganglionic efferent neurons. The activation of the Nn receptor is mediated by the release of acetylcholine from preganglionic efferent neurons. Interruption of acetylcholine-receptor binding at the level of the autonomic ganglia results in complete interruption of both sympathetic and parasympathetic signaling.[1] Mecamylamine is one of the first nicotinic ganglion blockers widely used as a therapeutic agent, and it was originally introduced as an antihypertensive medication.[2] Increased sympathetic activity results in vascular vasoconstriction, and subsequently elevated blood pressure, as a result of Alpha-1 receptor stimulation. Mecamylamine's ability to blockade sympathetic activity at the level of the autonomic ganglia explains its long-time usage as an antihypertensive agent.[1][3]
FDA approved indications for selected nicotinic ganglion blockers (off-label uses indicated when applicable):
Mecamylamine:
- Indications: Moderately severe to severe essential hypertension, Uncomplicated malignant hypertension
- Administration: Oral tablets
- Notes: Mecamylamine exhibits excellent gastrointestinal absorption. It a secondary amine and thus can cross the blood-brain barrier. For this reason, mecamylamine has been the object of research for potential use in the treatment of Tourette's, smoking cessation, and depression.[4]
Trimethaphan:
- Indications: Controlled blood pressure reduction during surgery, Hypertension emergencies
- Administration: Intravenous infusion
- Notes: It is worth noting that Trimethaphan is particularly useful for the prevention of hemorrhage secondary to a dissecting aortic aneurysm.
Hexamethonium
- Notes: Experimental use only
Mechanism of Action
Acetylcholine (ACh) is a neurotransmitter released from cholinergic neurons which binds two types of receptors: muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively).[5] Nicotinic ganglion receptors found in the autonomic ganglia are involved in both sympathetic and parasympathetic transmission. These receptors classify as neuronal nicotinic (Nn) cholinergic receptors, and they are on postganglionic efferent neurons.[1] Nn receptors are Cys-loop ligand-gated ion channels that, upon binding ACh, undergo a conformational change and become permeable to ions such as Na+, K+, and Ca2+, resulting in signal propagation through the postganglionic efferent neuron.[5] Nicotinic ganglion blockers exhibit a noncompetitive antagonism of Nn receptors, which results in blockade of signal transduction.[2] The blockade of Nn receptors at the level of the autonomic ganglia results in decreased sympathetic output, which reduces blood pressure, thereby producing the therapeutic effect.[1][3]
Administration
Mecamylamine is available in tablet form, and clinicians can prescribe it for oral administration in cases of moderately severe to severe essential hypertension, as well as in uncomplicated cases of malignant hypertension. However, mecamylamine is no longer regularly prescribed for this purpose, as more effective pharmacological agents have since been developed. Trimethaphan is available as an IV infusion and can be useful for blood pressure control during surgery.
Adverse Effects
Administration of nicotinic ganglion blockers results in blockade of acetylcholine-receptor binding at the level of the autonomic ganglia causing a complete interruption of both sympathetic and parasympathetic signaling.[1] Activation of the sympathetic nervous system results in vascular vasoconstriction, and blockade of the sympathetic nervous system can result in adverse effects such as hypotension.[6] The parasympathetic nervous system is involved in salivation, gastrointestinal motility/digestion, urination, and pupillary constriction. Blockade of the parasympathetic nervous system can result in adverse effects such as dry mouth, paralytic ileus, urinary retention, and increased intraocular pressure.[7]
Contraindications
The general suggestion is that the situation of each patient is individually taken into account when considering the use of nicotinic ganglion blockers. The indications above outline when the use of these drugs is appropriate, and it is the responsibility of the physician to be aware of the adverse effects of the agent utilized. A risk analysis is necessary when considering the use of nicotinic ganglion blockers; this involves a careful and systematic review of a patient’s vitals, physical status, hemodynamic status, and pertinent medical history (i.e., past medical problems, past surgical history, past/current medications, allergies, alcohol/illicit drug use).
Monitoring
The monitoring of nicotinic ganglion blockers will depend on the patient’s situation and the agent in use. For this reason, monitoring between differing agents will vary. Due to the ability of nicotinic ganglionic blockers to inhibit the sympathetic nervous system and cause hypotension, careful blood pressure monitoring is of particular importance.[6] Trimethaphan toxicity has the potential to cause apnea and respiratory arrest, which necessitates close respiratory tracking to avoid any potential adverse outcomes.[8]
Toxicity
Mecamylamine is a secondary amine and thus demonstrates the ability to cross the blood-brain barrier. At low doses, mecamylamine's central effects are prominent, however its antihypertensive effects less so. The same can be said for its parasympathetic side effects, blockade of which is responsible for many of its troublesome side effects. Mecamylamine is currently be investigating for several other therapeutic uses other than as an antihypertensive, and suggestions are that the drug's toxicity/risk profile is potentially better at lower doses.[9] There have been reported instances of elevated levels of serum histamine in stable patients who were administered trimethaphan IV bolus. Clinical manifestations of elevated serum histamine levels were present.[10] Trimethaphan-induced hypotension resulted in increased urinary excretion of renal tubular cell enzymes N-acetyl beta-D-glucosaminidase (NAG) and gamma-glutamyl transpeptidase (gamma-GTP). In general, it is believed that urinary levels of renal tubular cell enzyme correlate with the injury of renal tubular cells.[11] Some of the more serious reported effects of Trimethaphan toxicity include apnea and/or respiratory arrest. Although the mechanism is not fully understood, the potential for this reaction necessitates close monitoring of a patient's respiratory status when utilizing this agent.[8]
Enhancing Healthcare Team Outcomes
When considering the use of nicotinic ganglion blockers, it is of the utmost importance to do a thorough and complete review of a patient’s circumstances. These agents are no longer commonly used due to the development of more novel pharmaceutical agents. For this reason, it is of particular importance for healthcare professionals to discern if the use of a nicotinic ganglionic blocker is genuinely required. Members of the healthcare team whose involvement is crucial include physicians, nurses, and pharmacists. If it is determined that the use of a nicotinic ganglionic blocker is warranted, there must be an open line of communication between various members of the healthcare team. A patient-centered approach is necessary to determine appropriate dosing, the timing of administration, and the route of administration. Doing so can prevent any serious adverse reactions from affecting the patient. For example, patients with a history of renal disease should be monitored closely due to the blood pressure-lowering effects and the kidney’s particular sensitivity to decreased blood flood. The physician must be cognizant of any potential adverse reactions and must effectively ascertain whether the use of a nicotinic ganglion blocker is warranted. The pharmacist can verify that the prescribed dose is both safe and effective. The nurse can perform regular follow-up checks to ensure the patient is tolerating the drug well.
Controlled hypotension during surgery offers a variety of alleged advantages. The first and principal of which is reduced operative blood loss, subsequently leading to decreased operative time. Secondly, the transfusion requirement becomes reduced, and this translates to a reduced risk of transfusion reaction. Thirdly, controlled hypotension results in a reduction in the anesthesia requirement. The decreased anesthesia requirement allows for more rapid patient recovery time with improved postoperative well-being of the patient.[12] Meticulous consideration of the use of nicotinic ganglion blockers for controlled hypotension during surgery by the anesthesiologist and adequate communication to the nursing staff regarding postoperative care is an example of the interprofessional care that nicotinic ganglion blockers require. Given the potential for adverse effects, the necessity of various healthcare professionals working together as a cohesive interprofessional team who are all cognizant of the patient’s circumstance is paramount when considering the use of nicotinic ganglionic blockers. [Level 5]