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Nicotinic Ganglionic Blocker


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]


References

[1] Biaggioni I, The Pharmacology of Autonomic Failure: From Hypotension to Hypertension. Pharmacological reviews. 2017 Jan;     [PubMed PMID: 28011746]
[2] Nickell JR,Grinevich VP,Siripurapu KB,Smith AM,Dwoskin LP, Potential therapeutic uses of mecamylamine and its stereoisomers. Pharmacology, biochemistry, and behavior. 2013 Jul;     [PubMed PMID: 23603417]
[3] Grassi G,Ram VS, Evidence for a critical role of the sympathetic nervous system in hypertension. Journal of the American Society of Hypertension : JASH. 2016 May;     [PubMed PMID: 27052349]
[4] Papke RL, Merging old and new perspectives on nicotinic acetylcholine receptors. Biochemical pharmacology. 2014 May 1;     [PubMed PMID: 24486571]
[5] Zoli M,Pucci S,Vilella A,Gotti C, Neuronal and Extraneuronal Nicotinic Acetylcholine Receptors. Current neuropharmacology. 2018;     [PubMed PMID: 28901280]
[6] Esler M, The sympathetic nervous system through the ages: from Thomas Willis to resistant hypertension. Experimental physiology. 2011 Jul;     [PubMed PMID: 21551268]
[7] Hocevar A,Tomsic M,Praprotnik S,Hojnik M,Kveder T,Rozman B, Parasympathetic nervous system dysfunction in primary Sjögren's syndrome. Annals of the rheumatic diseases. 2003 Aug;     [PubMed PMID: 12860722]
[8] Dale RC,Schroeder ET, Respiratory paralysis during treatment of hypertension with trimethaphan camsylate. Archives of internal medicine. 1976 Jul;     [PubMed PMID: 938175]
[9] Young JM,Shytle RD,Sanberg PR,George TP, Mecamylamine: new therapeutic uses and toxicity/risk profile. Clinical therapeutics. 2001 Apr;     [PubMed PMID: 11354389]
[10] Fahmy NR,Soter NA, Effects of trimethaphan on arterial blood histamine and systemic hemodynamics in humans. Anesthesiology. 1985 May;     [PubMed PMID: 2581479]
[11] Kumagai K,Nakada K,Kikuchi K,Mori H, [Effect of induced hypotension on damage to renal tubular cells]. Masui. The Japanese journal of anesthesiology. 1989 Oct;     [PubMed PMID: 2573742]
[12] Warner WA,Shumrick DA,Caffrey JA, Clinical investigation of prolonged induced hypotension in head and neck surgery. British journal of anaesthesia. 1970 Jan;     [PubMed PMID: 5416306]