Cholinergic Agonists and Acetylcholinesterase Inhibitors

• Cholinomimetics


  Drugs that activate cholinergic receptors

  
• Major groups of cholinoceptor-activating drugs


  • Receptor agonists
  • Acetylcholinesterase enzyme inhibitors
• Receptor agonists


  Drugs that directly activate cholinergic receptors
• Receptor agonist types


  • Muscarinic
  • Nicotinic
• Acetylcholinesterase enzyme inhibitors


  Drugs that inhibit the enzyme that breaks down acetylcholine
• Muscarinic signaling


  • Acetylcholine released from postganglionic cholinergic axon interacts with muscarinic receptor (M2R) linked to K+ channel opening, inhibition of cAMP synthesis, and reduced pacemaker channel and L-type Ca2+ channel activity

  
• Nicotinic signaling


  • Acetylcholine released from motor nerve terminal interacts with nicotinic receptor subunits to open the channel, allowing Na+ influx and producing an excitatory postsynaptic potential
• Nicotine

  Nicotinic acetylcholine receptor agonist with stimulant and reward effects, used for smoking cessation
• Varenicline


  Partial nicotinic acetylcholine receptor agonist, designed to partially activate this system while blocking nicotine
• Nicotine is contraindicated in infants, children, and pets
• Varenicline adverse effects include nausea, vomiting, abnormal dreams, depressed mood, headache, and insomnia
• Physiologic effects of cholinomimetics


  • Eye: Contraction of iris sphincter muscle and ciliary muscle
  • Heart: Decreased rate, contractility, and conduction velocity
  • Blood vessels: Dilation and constriction
  • Lung: Bronchoconstriction and increased secretions
  • GI tract: Increased motility, relaxation of sphincters, and increased secretions
  • Urinary bladder: Contraction of detrusor, relaxation of trigone and sphincter
  • Glands: Increased secretion
• Cholinergic agonist types

  • Alkaloids
  • Esters
• Bethanechol


  Direct-acting muscarinic agonist that increases bladder muscle tone and contraction to initiate urination
• Carbachol


  Direct-acting muscarinic agonist that constricts the iris and ciliary body to decrease intraocular pressure
• Methacholine


  Direct-acting muscarinic agonist that causes smooth muscle contraction in the airways and increased secretions, used to diagnose bronchial hyperactivity
• Cevimeline


  Direct-acting muscarinic agonist that stimulates exocrine glands like salivary and sweat glands, used to treat xerostomia due to Sjögren's syndrome
• Pilocarpine(alkaloid)


  Direct-acting muscarinic agonist with effects on the eye, used to treat glaucoma and xerostomia
• Methacholine


  Muscarinic receptor agonist (M2, M3)
• Methacholine pharmacokinetics

  Duration: 30 to 45 minutes
• Cevimeline


  Muscarinic receptor agonist (M1, M3)

  
• Pilocarpine


  Muscarinic receptor agonist (M1, M2, M3)
• Myasthenia gravis is an autoimmune disease affecting skeletal muscle neuromuscular junctions
• Antibodies in myasthenia gravis are against the α1 subunits of the nicotinic receptor-channel complex, detected in 85% of patients
• Reduced nicotinic receptor function in myasthenia gravis is due to (1) cross-linking receptors, (2) causing lysis of the postsynaptic membrane, and (3) binding to the nicotinic receptor and inhibiting function

  
• Symptoms of myasthenia gravis include ptosis, diplopia, difficulty in speaking and swallowing, and extremity weakness
• In severe myasthenia gravis, all muscles and even respiration can be affected
• Cholinesterase inhibitors are used to increase available acetylcholine in an attempt to improve symptoms of myasthenia gravis
• Acetylcholine is formed from choline and acetyl-CoA via the activity of choline acetyltransferase (ChAT)
• Excess acetylcholine at synapses is converted to choline and acetate via the activity of acetylcholinesterase (AChE)

  
• Choline is recycled back to the presynaptic neuron via the presence of specific choline transporters such as CHT1

  
• In Alzheimer's disease, there are alterations in high-affinity choline uptake, impaired acetylcholine release, deficits in the expression of nicotinic and muscarinic receptors, dysfunctional neurotrophin support, and deficits in axonal transport in cholinergic neurons

  
• Donepezil


  Reversible cholinesterase inhibitor

  
• Galantamine


  Reversible cholinesterase inhibitor, positive allosteric modulator of neuronal nicotinic acetylcholine receptors
• Rivastigmine


  Reversible cholinesterase inhibitor, relatively specific for brain acetylcholinesterase and butyrylcholinesterase compared with those in peripheral tissues

  
• Partial agonist nicotinic receptors

  Varenicline is a synthetic drug with partial agonist action at nicotinic receptors (nicotinic acetylcholine - nACh); used for smoking cessation.
• Muscarinic contraindication

  • Muscarinic stimulants contract the smooth muscle of the bronchial tree
  • The glands of the tracheobronchial mucosa are stimulated to secrete
• Conditions that are a contraindication to the use of muscarinic drugs


  • Asthma
• Cholinergic ADEs


  • Salivation
  • Lacrimation (tearing, watery eyes)
  • Urination
  • Diaphoresis (sweating)
• Cholinergic ADEs - Constipation is NOT caused by cholinergic activation