Cholinergic Agonists and Antagonists

Cholinergic Transmission Objectives

• Describe the cholinergic transmission in the periphery nervous system (PNS).
• Explain how drugs affect cholinergic transmission.
• Categorize drugs based on their cholinergic or anticholinergic effects.
• Predict a drug's pharmacological effects, and possible adverse effects.
• Describe the nurse’s role in managing patients on parasympathomimetics and anticholinergics.

Overview of Cholinergic System

• Acetylcholine (Ach) packaging is aided by a carrier-mediated transporter.
• Ach releases via Calcium-facilitated exocytosis.
• At the neuromuscular junction, Ach uses nicotinic receptors to initiate action potentials in muscle fibers.
• Ach uses fast cholinergic synapses located at autonomic ganglia.
• Ach uses muscarinic receptors of the parasympathetic nervous system and results in slower transmission.

Actions of Acetylcholine

• Ach activity relies on receptors in the target tissue or effector organ. Affects neurotransmitter enhancement or weakening: nicotinic vs muscarinic.

Muscarinic Actions of Acetylcholine

• Found in the neuroeffector junction.
• Closely resembles parasympathetic activity

Nicotinic Actions of Acetylcholine

• Found in:
  • All autonomic ganglia
  • Neuromuscular junction of voluntary muscles
  • Adrenal medulla

Nicotinic Effects of Acetylcholine

• Stimulates autonomic ganglia, which then affects the parasympathetic and sympathetic systems.
• Affects the neuro-muscular junction and causes contraction of skeletal muscles.
• At low doses it stimulates the CNS, but at high doses it is inhibitory

Muscarinic Effects of Acetylcholine

• Causes smooth muscle contraction in the bronchi (M3), GI tract, and urinary bladder (M2 and M3).
• Causes relaxation of sphincters such as urinary and rectal.
• Increases secretion of sweat, salivary, lachrymal, gastric, and intestinal glands.
• Causes a cardiac depressant effect, mostly via M2 receptor subtype.
• Usually stimulates the CNS, possibly causing hallucination, convulsions, and delirium.

Pharmacological Interventions Related to Acetylcholine

• Mimic Ach at receptor sites.
  • Ganglion
  • Neuromuscular somatic
  • Neuroeffector
• Inhibit choline uptake.
• Inhibit Ach breakdown.
• Block receptors at the ganglion.
• Blockade at the neuromuscular junction.
• Block postsynaptic receptors at the neuroeffector junction on parasympathetic targets.

Parasympathetic Agents

• Parasympathetic Agonists.
• Parasympathetic Antagonists.

Drugs on Cholinergic Transmission

• Drugs are categorized as Cholinergic or Anticholinergic.
• Cholinergic drugs can be:
  • Direct Acting
  • Indirect Acting Reversible Agonists
  • Indirect Acting Irreversible Agonists
• Anticholinergic drugs can be:
  • Muscarinic Antagonists
  • Ganglionic Blockers
  • Neuromuscular Blockers

Cholinergic Agonists - Mechanism of Action

• Direct acting agonists such as Bethanechol and Pilocarpine act directly on cholinergic receptors.
• Indirect acting agonists which also act as Acetylcholinesterase (AChE) inhibitors, bind to AChE, therefore leading to increased levels of Ach in synaptic clefts/nerve endings. They enhance cholinergic transmission at autonomic synapses/neuromuscular junctions.
  • Reversible agents like neostigmine and pyridostigmine.
  • Irreversible AChE inhibitors such as organophosphate pesticides.

Cholinergic Agonists - Therapeutic Use

• Direct-acting parasympathomimetics treat GLAUCOMA.
  • Pilocarpine:
    • Useful for open-angle/primary close-angle glaucoma before surgery and is not a first choice drug, given Q4-8H.
    • It leads to contraction of the ciliary muscles therefore leading to improved drainage of aqueous humor in eye.
    • Available in eye drops and ophthalmic gels.
  • ADR
    • Headache, induced Myopia (Under 50)
    • Reduced visual acuity, especially in pts with cataracts

Indirect-Acting Parasympathomimetics

• Myasthenia Gravis: Drugs include pyridostigmine, neostigmine
  • Symptomatic treatment for Myasthenia Gravis, an autoimmune disorder due to reduced nicotinic receptors for Ach at the neuromuscular junction; improves abnormal muscle fatigue.
  • ADRs include parasympathetic stimulation, bladder and GIT stimulation.
• Reversal of non-depolarizing neuromuscular blockade (antidote): neostigmine.
  • IV neostigmine reverses the effects of muscle relaxants during anesthesia.
• Dementia: donepezil, galantamine are prescribed for symptomatic treatment of mild/moderate dementia in Alzheimer's disease.
• Severe Anticholinergic Toxicity: physostigmine reverses atropine overdose.

Cholinergic Agonists - Adverse Effects

• Bradycardia and cardiac arrest.
• Sweating, salivation, and diarrhea
• Diarrhoea
• Bronchial asthma: bronchospasm can result from contraction of smooth muscles due to effect of Ach on muscarinic receptors.

Cholinergic Agonists - Poisoning

• Muscarinic poisoning:
  • Mushrooms have muscarine, a poison that is not degraded by acetylcholinesterase.
  • Causes excessive stimulation of the cholinergic system.
  • Manifests as abdominal cramps, diarrhea, increased secretions, bronchospasms, bradycardia, and miosis.
  • Treated with antidote atropine.
• Organophosphate poisoning:
  • Chemicals such as malathione, and parathione, act as irreversible cholinesterase inhibitors.
  • Treated by providing respiratory, and atropine. (competitive muscarinic antagonist)

Muscarinic Agonists - General

• Muscarinic agonists are direct acting.
• Effects cardiovascularly:
  • Decreases cardiac output, heart rate, contraction force, and blood pressure.
• Smooth muscles:
  • Causes smooth muscle contraction, increased GI motility, bladder muscle tone, and bronchial constriction.
• Increase secretions.
• Pupil constriction. This can be used to target receptors

General Nursing Considerations for Parasympathomimetics

• Monitor for adverse effects, abdominal cramping, muscle cramping, and excessive salivation.
• Advise patients to report nausea, vomiting, diarrhea, and any other adverse effects.
• Direct-acting considerations:
  • Monitor intake and output ratio. Advise patient to be near a bathroom as the drug onset occurs approx. 60 minutes.
  • Monitor blurred vision; advise accordingly.
  • Monitor for orthostatic hypotension.
• Indirect-acting considerations:
  • Monitor muscle strength and neuromuscular status.
  • Schedule medications around mealtime for a therapeutic effect.
  • Monitor for muscle weakness due to a cholinergic crisis, or a myasthenic crisis.

Anticholinergics

• Objectives previously stated.
• Act as muscarinic and nicotinic antagonists.

Antimuscarinics

• Addresses where antimuscarinics act.
• Discusses the selective vs non-selective anti-muscarinic agents

Antimuscarinic Drugs

• Their therapeutic use is based on action in the different organs and tissues by action of muscarinic receptor subtypes (M1, M2, M3, M4, M5).
• They help in the emergency reversal of cholinergic toxicity/overdose such as using atropine.
• Helps manage GIT disorders such as irritable bowel syndrome with Rx dicyclomine, and PUD
  • Can also help in GIT spasms.
• Manages Bronchial Smooth Muscles such as in patients with ASTHMA via ipratropium bromide
• Reduces Cardiac rhythm abnormalities.
• Ophthalmic disorders: Dilated pupil or cycloplegia, this can be done by prescription of cyclopentolate, homatropine, atropine, tropicamide.
• Pre-anesthesia: Reduces excessive respiratory secretions.
• Acts on CNS
  • Reduces Sedation
  • Reduces Motion sickness with scopolamine.
  • Reduces Muscle tremors associated with Parkinson's disease.

Other Drugs with Anticholinergic Properties

• Tricyclic antidepressants: amitriptyline, imipramine, and trimipramine.
• Antipsychotics: clozapine, quetiapine
• First-generation antihistamines: promethazine, diphenhydramine

Clinical Features of Anticholinergic Overdose

• Dry mouth, warm/flushed skin, thirst, tachycardia, arrhythmias, mydriasis, confusion, and agitation.
• Excessive use of tricyclic antidepressants, can cause life-threatening delirium, hallucinations, and psychomotor symptoms.

Nursing Considerations

• Take history as other drugs such as antihistamines may create possible interactions.
• Not recommended in patients with acute angle closure glaucoma.
• Know of available antidote used for anticholinergic overdose/toxicity.

Explore cholinergic agonists' effects on intra-ocular pressure and Myasthenia Gravis treatment with pyridostigmine and neostigmine. Identify receptor types causing bradycardia, and the antidote for muscarinic poisoning. Understand acetylcholine's role in sphincter relaxation.