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Parasympathomimetic drugs

Last updated: April 16, 2021

Summary

Parasympathomimetic drugs activate the parasympathetic nervous system (PSNS). As the neurotransmitter of the PSNS is acetylcholine (ACh), parasympathomimetics are also called cholinomimetic agents. These are classified according to whether they act as direct agonists of acetylcholine receptors (AChR) or indirect agonists of AChR (also called anticholinesterase inhibitors). While direct agonists act by binding directly to muscarinic or nicotinic ACh receptors, indirect agonists prolong the action of endogenous acetylcholine by inhibiting acetylcholinesterase (AChE). Direct agonists of AChR are used topically in ophthalmology to induce miosis, while indirect agonists are used to treat conditions such as postoperative ileus, urinary retention, and myasthenia gravis.

Overview

Overview of direct and indirect parasympathomimetics
Classification	Drugs	Mechanism of action	Pharmacological characteristics	Indications
Direct parasympathomimetics	Bethanechol	Bind to muscarinic/nicotinic AChR → direct AChR agonism	No nicotinic agonism ^[1] Resistant to AChE	Postoperative and neurogenic ileus and urinary retention: ↑ bladder smooth muscle tone
	Carbachol		Nicotinic and muscarinic agonism ^[2] Resistant to AChE	Open-angle and closed-angle glaucoma Alleviates intraocular pressure Causes miosis
	Cevimeline		Predominantly muscarinic agonism ^[3]	Keratoconjunctivitis sicca (Sjogren syndrome): ↑ sweat and saliva production
	Pilocarpine		Predominantly muscarinic agonism ^[4] Resistant to AChE Can cross blood-brain barrier (tertiary amine)	Open-angle and closed-angle glaucoma ↑ Contraction of ciliary muscle of the eye ↑ Contraction of pupillary sphincter Xerostomia (e.g., in Sjogren syndrome): ↑ sweat, tears, and saliva production
	Methacholine		Predominantly muscarinic agonism ^[5] Can not cross blood-brain barrier (quaternary amine)	Diagnosis of bronchial hypersensitivity (see “Bronchial challenge test”): activates muscarinic receptors on airway smooth muscle
Indirect parasympathomimetics	Neostigmine	Inhibit AchE → ↓ breakdown of ACh → ↑ ACh levels	Can not cross the blood-brain barrier (quaternary amine)	Myasthenia gravis Postoperative and neurogenic ileus and urinary retention Postoperative reversal of neuromuscular blockade
	Pyridostigmine		Can not cross the blood-brain barrier (quaternary amine) Typically used with glycopyrrolate, hyoscyamine, or propantheline to control side effects	Myasthenia gravis (longer action compared to neostigmine): improves muscle strength
	Edrophonium		Very short duration of action (∼ 10 minutes) ^[6]	Diagnosis of myasthenia gravis (Edrophonium test)
	Physostigmine		Lipophilic Can cross the blood-brain barrier (tertary amine)	Atropine overdose (antidote) Glaucoma
	Distigmine		Longer duration of action than pyridostigmine and neostigmine	Postoperative ileus and urinary retention Myasthenia gravis
	Echothiophate		Irreversible AChE inhibitor Long-acting	Glaucoma
	Donepezil Rivastigmine Galantamine		Centrallly acting AChE inhibitors	Alzheimer disease

Pharmacodynamics

Effects of parasympathomimetics on the different receptor types ^[7]
ACh receptors	Organ/tissue	Effects of parasympathomimetics
M1, M4, M5	Central nervous system	Influences neurologic functions (e.g., memory)
M2	Heart	↓ Heart rate and atrial contractility Slows down AV conduction (can cause AV block)
M3	Smooth muscle	Gastrointestinal: ↑ intestinal peristalsis Genitourinary: ↑ bladder contraction ↑ Detrusor muscle tone Relaxes the internal urethral sphincter Airway Bronchoconstriction ↑ Bronchial secretions Eye Miosis Accommodation Blood vessels: vasodilation
M3	Exocrine glands	↑ Secretions Sweat Gastric acid
Nicotinic	Skeletal muscle	↑ Muscle contraction and tone

Adverse effects

Direct parasympathomimetics

Local side effects: blurred vision due to miosis when applied to the eyes
Systemic side effects: identical to those of indirect parasympathomimetics (see below)

Indirect parasympathomimetics

Cardiovascular symptoms
- Bradycardia
- Hypotension
Gastrointestinal symptoms
- Diarrhea
- Nausea
- Abdominal pain
Genitourinary symptoms: uncontrolled urination
Exocrine glands
- ↑ Sweating
- ↑ Salivation
- ↑ Gastric secretion
Ocular symptoms
- Miosis
- Lacrimation
CNS-related symptoms: can culminate in coma
- Hypoventilation
- Lethargy
- Tremor
- Restlessness
- Anxiety
- Ataxia
Musculoskeletal symptoms
- Weakness
- Paralysis → peripheral neuromuscular respiratory failure
- Spasms
- Fasciculations

Cholinergic crisis (cholinergic syndrome)

Definition: potentially life-threatening acetylcholine receptor overstimulation
Etiology: poisoning with organophosphates (e.g., parathion)
Pathophysiology: irreversible acetylcholinesterase inhibition
Epidemiology: most commonly seen in farmers, as organophosphates are used as insecticides
Clinical presentation
- Muscarinic effects
  - Excess of secretions, including salivation, sweating, lacrimation, urination, defecation, and emesis
  - Miosis and blurred vision
  - Bradycardia
  - Bronchospasm
  - Bronchorrhea
- Nicotinic effects: blockage at the neuromuscular junction (similar mechanism observed in succinylcholine)
- Systemic effects
Treatment: antimuscarinic agents
- Atropine
- Pralidoxime

DUMBBBELLSS: Diarrhea, Urination, Miosis, Bradycardia, Bronchospasm, Bronchorrhea, Emesis, Lacrimation, Lethargy, Sweating, and Salivation are the main symptoms of cholinergic crisis.

We list the most important adverse effects. The selection is not exhaustive.

References

Bethanechol. https://pubchem.ncbi.nlm.nih.gov/compound/Bethanechol. . Accessed: November 4, 2020.
Carbachol. https://pubchem.ncbi.nlm.nih.gov/compound/5831. . Accessed: November 4, 2020.
Weber J, Keating GM. Cevimeline. Drugs. 2008; 68 (12): p.1691-1698. doi: 10.2165/00003495-200868120-00006 . | Open in Read by QxMD
Pilocarpine. https://pubchem.ncbi.nlm.nih.gov/compound/Pilocarpine. . Accessed: November 4, 2020.
Methacholine. https://pubchem.ncbi.nlm.nih.gov/compound/Methacholine. . Accessed: November 4, 2020.
Edrophonium. https://pubchem.ncbi.nlm.nih.gov/compound/Edrophonium. . Accessed: November 4, 2020.
Acetylcholine receptors (muscarinic), introduction. http://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=2. Updated: August 10, 2015. Accessed: February 18, 2017.