Direct Acting Cholinergic Agonists

Direct Acting Cholinergic Agonists

• Mimic the effects of ACh by binding directly to cholinoreceptors (muscarinic or nicotinic)
• 2 groups: endogenous choline esters (ACh, bethanechol, carbachol) and naturally occurring alkaloids (nicotine, pilocarpine)
• Longer duration of action than ACh
• Limited clinical usefulness due to lack of specificity

Actions of Direct Acting Cholinergic Agonists

• CVS: decrease in heart rate, cardiac output, and blood pressure
• Smooth muscle: hyperactivity of GI tract and bronchiolar smooth muscle, stimulation of detrusor muscle (urination)
• Exocrine glands: increase in secretions of sweat, saliva, tears, and bronchiolar secretions
• Eye: miosis (constriction of the pupil) and decrease in intraocular pressure (for glaucoma)

Activity of Specific Direct Acting Cholinergic Agonists

• Bethanechol: lacks nicotinic actions, strong muscarinic activity
• Carbachol: both nicotinic and muscarinic activity
• Pilocarpine: muscarinic activity, mainly used in ophthalmology

Indirect Acting Cholinergic Agonists

• Inhibit AChE, leading to accumulation of ACh in synaptic cleft
• Can provoke a response at all cholinoreceptors in the body, including muscarinic and nicotinic receptors of the ANS, NMJ, and brain
• 2 groups: reversible (edrophonium, physostigmine, neostigmine) and irreversible (echothiophate)

Actions of Indirect Acting Cholinergic Agonists

• Edrophonium (short-acting): used in diagnosis of myasthenia gravis
• Physostigmine (intermediate-acting): enhancement of cholinergic transmission at NMJ, bradycardia, hypotension, miosis, contraction of visceral smooth muscle
• Neostigmine (intermediate-acting): stimulates bladder and GI tract, used to manage symptoms of myasthenia gravis
• Echothiophate: generalised cholinergic stimulation, paralysis of motor function, miosis

Adverse Effects of Cholinergic Agonists

• Diarrhea, diaphoresis (increased sweating), miosis, nausea, urinary urgency

Direct Acting Cholinergic Agonists

• Stimulate the parasympathetic nervous system (PNS)
• Mimic the effects of Acetylcholine (ACh) by binding directly to cholinoreceptors (muscarinic or nicotinic)
• Two groups: Endogenous choline esters and Naturally occurring alkaloids

Endogenous Choline Esters

• Include ACh and synthetic esters of choline, such as bethanechol and carbachol
• Have a longer duration of action than ACh
• Show little specificity in their actions, limiting their clinical usefulness

Naturally Occurring Alkaloids

• Include nicotine and pilocarpine
• Have a longer duration of action than ACh
• Show little specificity in their actions, limiting their clinical usefulness

Actions of Direct Acting Cholinergic Agonists

• Cardiovascular system (CVS): decrease heart rate, cardiac output, and blood pressure
• Smooth muscle: hyperactivity of GI tract and bronchiolar smooth muscle, stimulation of detrusor muscle (urination)
• Exocrine glands: increase secretions of sweat, saliva, tears, and bronchiolar secretions
• Eye: miosis (constriction of the pupil) and decrease in intraocular pressure (for glaucoma)

Individual Actions of Direct Acting Cholinergic Agonists

• Bethanechol: lacks nicotinic actions, but has strong muscarinic activity
• Carbachol: has both nicotinic and muscarinic activity
• Pilocarpine: exhibits muscarinic activity, used mainly in ophthalmology

Indirect Acting Cholinergic Agonists

• Inhibit Acetylcholinesterase (AChE), allowing accumulation of ACh in synaptic cleft
• Can provoke a response at all cholinoreceptors in the body, including muscarinic and nicotinic receptors of the ANS, as well as the NMJ and in the brain

Types of Indirect Acting Cholinergic Agonists

• Reversible: edrophonium, physostigmine, neostigmine
• Irreversible: echothiophate
• Reversible are further divided into short-acting and intermediate-acting

Actions of Indirect Acting Cholinergic Agonists

• Edrophonium (short-acting): used in the diagnosis of myasthenia gravis
• Physostigmine (intermediate-acting): enhancement of cholinergic transmission at NMJ, bradycardia, hypotension, miosis, contraction of visceral smooth muscle
• Neostigmine (intermediate-acting): stimulates bladder and GI tract, used to manage symptoms of myasthenia gravis
• Echothiophate: generalizes cholinergic stimulation, paralysis of motor function, miosis

Adverse Effects of Cholinergic Agonists

• Diarrhea
• Diaphoresis (increased sweating)
• Miosis
• Nausea
• Urinary urgency