Muscarinic Agonists and Uses

Muscarinic Agonists: Matching and Uses

• Specific muscarinic agonists can be matched to particular therapeutic applications
• Drugs like carbachol and methacholine work better in the GI and urinary tracts
• Bethanechol is favored for GI and urinary effects due to carbachol's nicotinic effects

Carbachol Considerations

• Carbachol has substantial nicotinic effects, making it the least selective agent for muscarinic receptors
• The side effects of Carbachol make it generally avoided
• Carbachol is less susceptible to antagonism by atropine because it also acts on nicotinic receptors

Bethanechol: Bowels and Bladder

• Bethanechol stimulates smooth muscle in the GI tract and bladder
• Bethanechol can be administered orally or subcutaneously
• Bethanechol treats non-obstructive urinary retention and neurogenic atony of the bladder
• It increases urinary and GI motility

Carbachol: Backup for Glaucoma

• Carbachol serves as a backup medication for glaucoma
• It lowers intraocular pressure
• Nicotinic effects limit it's use, meaning Carbachol has least clinical relevance

Methacholine: Diagnosing Airway Reactivity

• Methacholine, given via inhaler, induces bronchoconstriction
• Methacholine helps diagnose bronchial airway hyperreactivity in those without clinical asthma
• The methacholine challenge test gives methacholine via inhaler to constrict the lungs
• Asthma patients show a hyperactive bronchoconstriction response in this test, indicating a positive result

Pilocarpine and Cevimeline: Xerostomia Treatment

• Pilocarpine can treat glaucoma by increasing fluid drainage, although it’s not a first-line choice
• Pilocarpine and Cevimeline are useful for treating Xerostomia (dry mouth)
• Xerostomia can result from head and neck radiation or Sjogren’s syndrome
• Both medicines can be taken orally to stimulate saliva production
• Muscarinic agonists in glaucoma are used to increase fluid drainage

Muscarinic Agonists: Side Effects and Management

• Muscarinic agonists can cause side effects by over activating the parasympathetic nervous system
• Sweating, which is a function of the sympathetic system can be triggered
• Side effects can include pupil constriction, reduced heart rate, and bronchoconstriction
• Muscarinic agonists should be avoided for people at risk of peptic ulcers
• They can increase gastric acid production
• Other side effects are diarrhea, increased urination (leading to potential incontinence), flushing, salivation, lacrimation, and sweating
• Flushing can result from vasodilation via M3 receptor stimulation and nitric oxide release in blood vessels
• Localized administration, like eye drops or inhalers, can reduce side effects
• Orally taken Bethanechol is not well absorbed keeping the side effects mostly to the GI tract

Managing Toxicity

• Atropine, a muscarinic antagonist, is the primary antidote for muscarinic agonist overdose
• Atropine blocks all muscarinic receptors (M1-M5)
• Epinephrine can also counter severe cardiovascular or bronchoconstrictor effects
• It is considered a physiologic antagonist since it acts on different receptors (alpha and beta) to produce opposing effects

Acetylcholinesterase Inhibitors: Mechanisms

• Acetylcholinesterase inhibitors block the enzyme acetylcholinesterase
• They can be divided into reversible and irreversible inhibitors
• Reversible inhibitors are competitive antagonists that bind temporarily to acetylcholinesterase, diminishing the enzyme's activity for a short time
• Irreversible inhibitors bind with covalent bonds, and produce long-lasting effects
• These inhibitors are toxic and have the potential to be very dangerous

Reversible Inhibitors

• Reversible inhibitors are more therapeutically useful and allow the actions of acetylcholine to persist
• They are described as indirect agonists because they increase acetylcholine levels, which then affects both nicotinic and muscarinic receptors
• This can lead to various side effects due to the wide range of effects from increased acetylcholine

Irreversible Inhibitors

• Irreversible inhibitors have limited therapeutic applications due to their toxicity
• Many were designed as nerve agents, such as sarin or VX
• Organophosphate insecticides like parathion and malathion also act as irreversible acetylcholinesterase inhibitors
• Insecticide or organophosphate poisoning should lead you to think about irreversible acetylcholinesterase inhibitors
• Parathion and malathion are prodrugs activated by cytochrome P450, and are toxic
• Malathion is available in topical lotion for head lice

Mechanism of Action

• Acetylcholinesterase inhibitors work in the synapse, where they prevent the breakdown of acetylcholine
• This leads to increased levels of acetylcholine
• The acetylcholine then has a postsynaptic effect on nicotinic and muscarinic receptors