Cholinomimetic Drugs

Cholinomimetic drugs, also known as parasympathomimetics or cholinergic agonists, increase acetylcholine (ACh), which acts on cholinergic muscarinic and nicotinic receptors. Other cholinomimetic drugs result in a net cholinergic effect by inhibiting the cholinesterase enzyme. Muscarinic receptors are found in the CNS and are part of the parasympathetic nervous system, which responds to cholinomimetics. Nicotinic receptors are found in the CNS at the neuromuscular junction. Physiologic effects on muscarinic receptors include bronchoconstriction, lacrimation, and bradycardia. Physiologic effects on nicotinic receptors include vasoconstriction, tachycardia, and elevated blood pressure. Cholinergic activation of muscarinic receptors on vascular endothelial cells cause an increase in nitric oxide, which diffuses to the adjacent vascular smooth muscle cells, resulting in smooth muscle relaxation/vasodilation and a paradoxical effect of the cholinomimetics on bronchial smooth muscle (constriction) and vascular smooth muscle (relaxation). Clinical uses of cholinomimetic agents include treatment of dementia, glaucoma, and as an aid for smoking cessation. The primary adverse effect of cholinergic drugs is overstimulation of the parasympathetic nervous system. Symptoms result from excessive levels of ACh in synapses, glands, smooth muscles, and motor endplates.

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Chemistry and Pharmacodynamics

Acetylcholine (ACh) is a prototype direct-acting cholinergic drug. Cholinomimetics are direct activators of both the muscarinic and nicotinic cholinergic receptors.

Overview

  • A neurotransmitter at various synapses, nerves, and motor endplates in muscles:
    • Nerve impulse → ACh stored in the vesicles is released into the synaptic cleft → binds to a postsynaptic receptor → depolarization
    • ACh is degraded by the acetylcholinesterase (AChE) enzyme (present at tissue receptor sites and on RBCs)
  • ACh is released from sympathetic and parasympathetic neuronal terminals on:
    • Lacrimal glands 
    • Salivary glands
    • Sweat glands
  • Overall effects are “wet”: tearing, sweating, and salivation

Mechanism of action and physiologic effects

  • Muscarinic cholinergic receptors: 
    • All 5 types (M1, M2, M3, M4, and M5) are G protein-coupled receptors → increased intracellular levels of calcium, which lead to:
      • Glandular secretion at exocrine glands
      • Vascular smooth muscle relaxation
      • ↓ Heart rate and contractility
  • Muscarinic receptor locations → effects:
    • Autonomic ganglia and exocrine glands: ↑ salivary/gastric acid secretion and diaphoresis
    • Blood vessel endothelium: M3 receptors → smooth muscle relaxation → vasodilation
    • Respiratory: M3 receptors → smooth muscle contraction → bronchoconstriction
    • Stomach: M1 receptors → increase gastric acid secretion 
    • Intestine: M3 receptors → increase peristalsis, contract the gastroesophageal sphincter, and relax the pyloric sphincter
    • Eye: M3 receptors → pupillary constriction (miosis)
    • Heart: M2 receptors lead to:
      • ↓ Heart rate due to sinoatrial (SA) node suppression
      • ↓ Conduction velocity and increased refractory period in the atrioventricular (AV) node
      • ↓ Contractility (negative inotropy)
    • Genitourinary:
      • Contraction of the detrusor muscle
      • Relaxation of the trigone and internal urethral sphincter
      • Men and women: erectile tissue stimulation
  • Nicotinic cholinergic receptors:
    • Ionotropic: act on ion channel receptors (e.g., calcium channels) (do not confuse with inotropic):
      • Receptor is activated →  ion channel opens → net Na+ influx → depolarization at the postsynaptic membrane 
      • Action potential in muscle fiber → muscle contracts
    • Located at the neuromuscular junction → skeletal muscle contraction
Cholinergic terminal neurotransmission and effects of cholinomimetic drugs

Cholinergic terminal neurotransmission and the effects of cholinomimetic drugs:
Acetylcholine (ACh) is released into the synaptic cleft, the choline transporter (CHT) uptakes choline into the presynaptic neuron, and the vesicular ACh transporter (VAChT) uptakes ACh into the storage vesicle.
Nondepolarizing neuromuscular blockers (NMBs) antagonize nicotinic receptors at neuromuscular junctions. Rocuronium is used in anesthesia. Lambert-Eaton myasthenic syndrome (LEMS) produces autoantibodies blocking presynaptic calcium (Ca+) channels, causing decreased ACh release into the synaptic cleft and muscle weakness. Pyridostigmine is an AChE inhibitor used to treat myasthenia gravis. Nicotine (in cigarettes) agonizes and varenicline (used for smoking cessation support) partially agonizes nicotinic ACh receptors. Succinylcholine, a depolarizing NMB, agonizes ganglionic nicotinic receptors, leading to receptor desensitization and neuromuscular blockade. Donepezil (for dementia) inhibits the breakdown of ACh, leading to ↑ ACh in the synaptic cleft. Cholinomimetics (e.g., bethanechol for neurogenic bladder) and pilocarpine agonize muscarinic receptors.
Na+/K+ channel: sodium/potassium channel

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Classification and Pharmacokinetics

Cholinomimetic drugs either act directly on cholinergic receptors or inhibit AChE (the enzyme breaking down ACh). Important points about the pharmacokinetic properties of the medications include onset, duration, metabolism, and availability.

Classification

  • ACh:
    • Both muscarinic and nicotinic actions
    • Rapidly hydrolyzed by AChE
  • Some agents stimulate either the nicotinic or the muscarinic receptors.
  • Direct-acting cholinomimetics:
    • Choline esters
      • ACh
      • Bethanechol
      • Methacholine
    • Plant alkaloids:
      • Nicotine
      • Muscarine
      • Pilocarpine
  • AChE inhibitors are indirect-acting cholinomimetics (AChE inhibiting, causing a net-positive cholinergic effect):
    • Reversible:
      • Donepezil and rivastigmine (used in the treatment of Alzheimer disease)
      • Neostigmine and physostigmine (used to reverse the effects of anesthesia/neuromuscular blockade)
      • Pyridostigmine (used in the treatment of myasthenia gravis)
    • Irreversible:
      • Malathion (antiparasitic for lice)
      • Isoflurophate (in eyedrops for glaucoma)
      • Sarin (used in nerve gas for bioterrorism)

Pharmacokinetics

Table: Onset and duration of AChE inhibitors
DrugOnsetDuration
Neostigmine (reversible)10–15 minutes1–2 hours
Physostigmine (reversible)3–8 minutes45–60 minutes
Pyridostigmine (reversible)Oral myasthenia gravis: 30–45 minutesOral: 3–6 hours
IV myasthenia gravis: 2–5 minutesIV: 2–3 hours
IV = intravenous
Table: Bioavailability and metabolism of AChE inhibitors
DrugBioavailabilityMetabolism
Central AChE inhibitors
Donepezil (reversible)
  • Well absorbed orally
  • Bioavailability: 100%
  • Hepatic CYP3A4
  • Hepatic CYP2D6
  • Glucuronidation
Rivastigmine (reversible)
  • Rapid oral absorption
  • Bioavailability: approximately 40%
Inactivated by cholinesterases
Peripheral AChE inhibitors
Neostigmine (reversible)Poor oral absorption
  • Inactivated by cholinesterases
  • Hepatic metabolism
Physostigmine (reversible)Inactivated by cholinesterases
Pyridostigmine (reversible)
  • Inactivated by cholinesterases
  • Hepatic metabolism
Sialogogues
PilocarpineReadily absorbed orallyInactivated by cholinesterases
Prokinetic/promotility agent
BethanecholPoor oral absorptionNot susceptible to degradation by cholinesterases

Clinical Indications

Cholinomimetic drugs are used to treat many conditions, including dementia, glaucoma, and as an aid in smoking cessation.

Table: Muscarinic agonists
DrugMechanismIndications
Bethanechol
  • Stimulation of cholinergic muscarinic receptor on the detrusor muscle → detrusor contraction
  • Stimulation of cholinergic muscarinic receptor in the GI tract → increases gastric motility
  • ↑ Pressure in the lower esophageal sphincter
  • Neurogenic bladder
  • Urinary retention
CarbacholDirect stimulation of muscarinic receptor in the eye → constriction of ciliary muscle and contraction of iris → ↑ aqueous humor outflow → ↓ intraocular pressure (IOP)Miosis for surgery (intraocular injection)
Pilocarpine
  • Stimulates secretion of exocrine glands
  • Direct stimulation of muscarinic receptor in the eye → ↓ IOP
  • Oral forms treat xerostomia.
  • Ophthalmic drops ↓ IOP and treat glaucoma and mitosis induction.
MethacholineInhaled → stimulates muscarinic receptors on bronchial smooth muscle → airway contractionDiagnostic test for asthma
Table: Nicotinic agonists
DrugMechanismIndications
Nicotine
  • Activates mesolimbic dopamine (reward) pathway
  • Stimulates nicotinic receptors at the autonomic ganglia → peripheral effects (e.g., tachycardia, diaphoresis, and nausea) decline with repeated doses
Smoking cessation
SuccinylcholineStimulates motor endplate ACh receptorsNeuromuscular blockade induction and maintenance (anesthesia)
Varenicline (Chantix)
  • Alleviates nicotine withdrawal symptoms by partial agonism of nicotinic receptors
  • Antagonist in the presence of nicotine
Most effective monotherapy for smoking cessation
Table: Acetylcholinesterase inhibitors
DrugMechanismIndications
Donepezil (Aricept)AChE inhibitorTreatment of Alzheimer dementia (all stages)
Galantamine (generic)AChE inhibitor and nicotinic receptor modulatorTreatment of mild-to-moderate Alzheimer dementia
NeostigmineAChE inhibitor
  • NMB reversal
  • Requires coadministration of anticholinergic agent (e.g., glycopyrrolate) to prevent bradycardia
Physostigmine (unavailable until end of 2022)AChE inhibitor
  • Treatment of anticholinergic syndrome
  • NMB reversal
PyridostigmineAChE inhibitor
  • Treatment of myasthenia gravis
  • Military preexposure prophylaxis for organophosphate (nerve gas) exposure
  • Nondepolarizing NMB reversal
  • Requires coadministration of anticholinergic agent (e.g., glycopyrrolate) to prevent bradycardia
RivastigmineAChE inhibitor
  • Mild-to-moderate Alzheimer dementia
  • Dementia of Parkinson disease
AChE: acetylcholinesterase
NMB: neuromuscular blockade

Adverse Effects and Contraindications

The primary adverse effects of cholinergic drugs are the consequence of overstimulation of the parasympathetic nervous system. Symptoms result from excessive levels of ACh in the synapses, glands, smooth muscles, and motor endplates.

Adverse effects

  • Cholinomimetic hyperactivity may result in cholinergic crisis = the same signs and symptoms seen with cholinesterase inhibitor poisoning (nerve gas):
    • Organophosphates inhibit AChE.
    • Reversed by atropine 
    • Symptoms are more severe than the usual side effects of medications:
      • Decreased blood pressure
      • GI: abdominal cramps, diarrhea, and vomiting
      • Blurred vision
      • Pallor
      • Twitching of the facial muscles
  • Mnemonics to remember cholinergic effects:
    • Cholinomimetic muscarinic agonists exert side effects remembered by the mnemonic “SLUDGE“:
      • Salivation                                     
      • Lacrimation
      • Urination                             
      • Defecation/diarrhea
      • Gastric Emptying
    • Also “BBB“:
      • Bradycardia
      • Bronchoconstriction
      • Bronchorrhea (excess mucus discharge)
  • Side effects of AChE inhibitors (e.g., donepezil):
    • Most common: diarrhea
    • AV block
    • Bradycardia
    • Seizures
    • GI bleed
    • Headache
    • Insomnia
    • Mood disturbance (e.g., depression and anxiety)

Contraindications

  • AChE inhibitors:  
    • Cardiac conduction defects (risk of QT prolongation causing ventricular tachycardia)
    • Asthma or chronic obstructive pulmonary disease (COPD)
    • Urinary tract obstruction
    • Seizure history or risk
    • GI bleed history or risk
  • Pilocarpine: Use eye drops to treat glaucoma and oral tablets to treat xerostomia (e.g., Sjögren syndrome):
    • Contraindicated in angle-closure glaucoma
    • Acute iritis 
    • Acute asthma
    • Use caution with hepatic impairment.

Comparison Table

Table: Comparison of cholinomimetics
DrugMechanismIndicationsContraindications
BethanecholDirect-acting choline ester
  • Xerostomia
  • Urinary retention
  • Diabetic neuropathy
  • Asthma
  • Coronary insufficiency
  • Peptic ulcer
  • Hyperthyroidism
PilocarpineDirect-acting plant alkaloid
  • Xerostomia
  • Dry eye
  • Testing for cystic fibrosis
Pregnancy
DonepezilReversible cholinesterase inhibitor
  • Alzheimer disease
  • Lewy body dementia
  • Traumatic brain injury
  • Peptic ulcer
  • Asthma
  • Neuroleptic malignant syndrome
  • AV block
NeostigmineReversible cholinesterase inhibitor
  • Myasthenia gravis
  • Reverse muscle relaxant
  • Mechanical GI obstruction
  • Urinary obstruction
PyridostigmineReversible cholinesterase inhibitor
  • Myasthenia gravis
  • Orthostatic hypotension
  • Mechanical GI obstruction
  • Urinary obstruction
MalathionIrreversible cholinesterase inhibitor
  • Lice
  • Scabies
  • Infants
  • Neonates
AV: atrioventricular

References

  1. Neurotransmitters and Neuromodulators. In: Nelson, L.S., Howland, M., Lewin, N.A., Smith, S.W., Goldfrank, L.R., Hoffman, R.S. Goldfrank’s Toxicologic Emergencies, 11e. New York, NY: McGraw-Hill, 2019.
  2. IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Retrieved October 7, 2021, from https://www.micromedexsolutions.com
  3. Arvanitakis, Z., Shah, R.C., & Bennett, D.A. (2019). Diagnosis and management of dementia: Review. JAMA. 322(16), pp. 1589–1599. https://doi.org/10.1001/jama.2019.4782 
  4. 2019 American Geriatrics Society Beers Criteria Update Expert Panel (2019). American Geriatrics Society 2019 updated AGS Beers criteria® for potentially inappropriate medication use in older adults. Journal of the American Geriatrics Society. https://doi.org/10.1111/jgs.15767 
  5. Rickey, L.M. (2019). Chronic urinary retention in women. UpToDate. Retrieved October 7, 2021, from https://www.uptodate.com/contents/chronic-urinary-retention-in-women
  6. Lexicomp, Inc. (2021). Donepezil and memantine: Drug information. UpToDate. Retrieved October 7, 2021, from https://www.uptodate.com/contents/donepezil-and-memantine-drug-information
  7. Lexicomp, Inc. (2021). Pilocarpine (systemic): Drug information. UpToDate. Retrieved October 7, 2021, from https://www.uptodate.com/contents/pilocarpine-systemic-drug-information

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