(2) 26: Direct and Indirect Acting Cholinergic Agonists

What is acetylcholine (ACh)?

• ACh = a neurotransmitter (chemical messenger) that sends signals between nerves or from nerves to target cells.

• ACh produces its effects by binding to cholinergic receptors and activates muscarinic and nicotinic receptors.

Types of NS

a. Autonomic NS- Controls automatic body functions (heart, digestion, bladder). The autonomic nervous system has two divisions:

• Sympathetic = fight or flight.

• Parasympathetic = rest and digest.

b. Somatic NS- Controls skeletal muscle

Types of receptor?

a. Nn = neuronal nicotinic, Nerve → Nerve

b. Nm = muscle nicotinic, Nerve → Muscle

c. Muscarinic = Nerve → Organ

Where are Nn, Nm, and muscarinic receptors located, and which neurons release ACh onto them?

Receptor	Location	Who releases ACh?
Nn	Postganglionic neuron at autonomic ganglion and adrenal medulla	Preganglionic neuron
Muscarinic	Parasympathetic target organs	Postganglionic neuron
Nm	Skeletal muscle at NMJ	Somatic motor neuron

define Signaling

What happens inside a cell after its receptor is activated.

Muscarinic and nicotinic receptor signaling

Receptor	Signaling	Main idea
M1, M3, M5	Gq → ↑ IP3/DAG → ↑ Ca²⁺	Generally stimulatory
M2, M4	Gi → ↓ cAMP	Generally inhibitory
Nn, Nm	Ligand-gated Na⁺/K⁺ channels	Depolarization (turning cell on)

Easy memory:

• Odd M (1, 3, 5) → Gq (ODD MAKES A QUEEN)

• Even M (2, 4) → Gi (EVEN MAKE AN INFLUENCER)

• Nicotinic → ion channel, not GPCR.

M2	Heart → bradycardia
M3	Smooth muscle contraction and secretions

define Cholinergic agonists

• drugs that produce ACh-like effects.

• They are also called cholinomimetics or parasympathomimetics.

What are the 2 types of agonists?

• Direct-acting agonist

• Indirect-acting agonist

Direct-acting agonist

• Drug binds receptor → activates receptor.

Indirect-acting agonist

• Inhibits AChE → ↑ ACh → prolonged receptor stimulation.

• Normally, AChE (acetylcholinesterase) breaks down ACh.

WHAT ACh DOES TO THE BODY? (OVERALL!)

rest and digest

Physiological effects of ACh

Give me the organ with its major receptor and effect.

Organ	Receptor	Effect
Brain (CNS)	M1, M4, M5	Learning memory sleep
Glands	M3 (M1 contributes to saliva)	↑ Saliva, tears, sweat,
Eye	M3	Miosis accommodation ↓ IOP
Heart	M2	↓ Heart rate, conduction, contractility
Blood vessels	M3	Vasodilation through NO
Lungs	M3	Bronchoconstriction ↑ secretions
Urinary bladder	M3	Detrusor contracts + sphincter relaxes → urination
GI tract	M3	Smooth muscle contracts + sphincter relaxes → ↑ digestion and defecation.

Physiological effects of ACh

Eye

• Miosis: Iris sphincter contracts → pupil gets smaller.

• Accommodation: Ciliary muscle contracts → zonules relax → lens becomes rounder → near vision.

• ↓ IOP: Ciliary muscle contracts → ↑ aqueous humor drainage → ↓ eye pressure.

Physiological effects of ACh

Heart

• Negative chronotropic → ↓ heart rate.

• Negative dromotropic → ↓ conduction velocity.

• Negative inotropic → ↓ force of contraction.

memory trick-

• Chrono = Clock → slower heart rate.

• Dromo = Delivery → slower conduction.

• Ino = Intensity → weaker contraction.

Drug group overview

• DIRECT-ACTING MUSCARINIC AGONISTS

• DIRECT-ACTING NICOTINIC AGONISTS

• INDIRECT-ACTING CHOLINERGIC AGONISTS

DIRECT-ACTING MUSCARINIC AGONISTS

broken into 2 categories:

1. Choline esters: Have chemical structures similar to ACh.

   • Acetylcholine, methacholine, carbachol, bethanechol

2. Alkaloids/analogs: Have different chemical structures from ACh.

   • Pilocarpine, cevimeline.

DIRECT-ACTING MUSCARINIC AGONISTS

drugs/receptors

Drug	Receptors
ACh	Muscarinic + nicotinic
Carbachol	Muscarinic + nicotinic
Bethanechol	Mainly muscarinic
Pilocarpine	Partial muscarinic
Cevimeline	M1 + M3 (high M3 affinity)

DIRECT-ACTING MUSCARINIC AGONISTS

topics covered for each drug?

• MOA

• Important

• Uses

• Adverse Effects

DIRECT-ACTING MUSCARINIC AGONISTS

Carbachol

MOA: Activates M3 in eye → miosis + ↓ IOP.

Important:

• Muscarinic + nicotinic agonist.

• Carbamoyl group → resistant to cholinesterase degradation.

• Limited systemic use due to unpredictable nicotinic effects.

Uses:

• Miotic during eye surgery

• ↓ IOP after cataract surgery.

Adverse effects:

• Corneal clouding, retinal detachment,

• sweating, flushing,

• abdominal cramps, headache.

Memory: Carbachol = eye surgery.

DIRECT-ACTING MUSCARINIC AGONISTS

Bethanechol

MOA: M3 agonist in bladdeer→ Detrusor contracts + sphincter relaxes → urination; ↑ GI motility.

Important:

• Mainly muscarinic.

• Carbamoyl group → Resistant to cholinesterase degradation.

Uses:

• Postoperative/postpartum nonobstructive urinary retention

• retentive neurogenic urinary atony.

Adverse effects:

• GI upset, bronchoconstriction/asthma,

• flushing

• headache, orthostatic hypotension,

Memory: Bethanechol = bladder.

DIRECT-ACTING MUSCARINIC AGONISTS

Pilocarpine

MOA: M3 effects (on eyes/galnd) → miosis, ↓ IOP, ↑ gland secretions.

Important: Partial muscarinic agonist

Uses:

• Open-angle glaucoma.

• Presbyopia (difficulty seeing nearby objects).

• Xerostomia (dry mouth) after head/neck radiation.

Key adverse effects:

• Sweating/rhinitis/urinary frequency

• abnormal vision

• nausea/dizziness

Memory: Pilocarpine = pupil + saliva.

DIRECT-ACTING MUSCARINIC AGONISTS

Cevimeline

MOA: M1/M3 agonist (high M3 affinity) → ↑ saliva, tears, and sweat.

Important: Longer-lasting saliva-producing action and fewer adverse effects than pilocarpine, as described in class.

Use: Xerostomia caused by Sjögren's syndrome.

Key adverse effects:

• Excessive sweating/salivation, rhinitis

• visual disturbances

• cough, fatigue, insomnia,

Memory: Cevimeline = Sjögren's dry mouth.

Excessive muscarinic activity

DUMBBELS

Letter	Symptom
D	Diarrhea/defecation
U	Urination
M	Miosis
B	Bradycardia
B	Bronchoconstriction
E	Emesis (vomiting)
L	Lacrimation (tears)
S	Salivation/sweating

Direct-acting nicotinic agonists

drugs?

• Nicotine

• Varenicline

Direct-acting nicotinic agonists

Nicotine

MOA: Activates nicotinic receptors in autonomic ganglia, NMJ, and CNS.

Know:

• Stimulates sympathetic and parasympathetic pathways.

• Dose-dependent effects.

• Initial stimulation → prolonged strong stimulation can cause ganglionic paralysis.

• CNS dopamine release → reward/addiction.

• Glutamate contributes to learning/memory associated with reward.

Use: Low-dose nicotine replacement for smoking cessation.

Direct-acting nicotinic agonists

Varenicline

MOA: Partial nicotinic agonist at α4β2 receptors.

Use	MOA
Chantix — smoking cessation	Modulates dopamine release → reduces cravings
Tyrvaya — dry eye	Nasal spray stimulates trigeminal parasympathetic pathway → ↑ basal tears

Adverse effects mentioned:

• Smoking cessation:

  • Nausea/headache

  • vivid dreams/insomnia

  • possible behavioral changes.

• Dry-eye nasal spray:

  • Sneezing/cough

  • throat irritation, nasal irritation/pharyngitis.

INDIRECT-ACTING CHOLINERGIC AGONISTS

topics discussed?

1. MOA

2. Effects of AChE inhibitors

3. Drug classification

4. Drugs

5. Disease treated: Myasthenia gravis

   • What it is?

   • How does Pyridostigmine treat it?

INDIRECT-ACTING CHOLINERGIC AGONISTS

MOA

Acetylcholinesterase inhibitors

• MOA: Inhibit AChE → ↑ ACh at synapse → prolonged muscarinic and nicotinic stimulation.

• Enzymes help break down acetylcholine (ACh).

  • AChE - normally breaks down ACh at cholinergic nerve endings (synapse)

  • Butyrylcholinesterase (BChE) - metabolizes (break down) ACh outside synapses, including in plasma.

• Effects occur at:

  • Muscarinic receptors on organs.

  • Autonomic ganglia (Nn).

  • Adrenal medulla (Nn) → release of epinephrine/norepinephrine.

  • Skeletal NMJ (Nm).

  • CNS.

• 🚨 Professor emphasized: Indirect drugs cause ACh to accumulate, so they can activate multiple cholinergic pathways rather than a single receptor type.

INDIRECT-ACTING CHOLINERGIC AGONISTS

Effects of AChE inhibitors

Location	Effect
Eye	Miosis, ↓ IOP
GI	↑ Tone/motility and secretions
CVS — moderate dose	Mild bradycardia, ↓ BP, ↓ cardiac output
CVS — high dose	Paradoxical tachycardia, hypertension, arrhythmias
NMJ — moderate dose	Muscle fasciculations, tremors
NMJ — high dose	Desensitization, flaccid paralysis, respiratory collapse

INDIRECT-ACTING CHOLINERGIC AGONISTS

Why high-dose CVS effects change:

↑ Sympathetic/adrenal catecholamine effects → can override bradycardia → tachycardia/hypertension.

INDIRECT-ACTING CHOLINERGIC AGONISTS

Why high-dose NMJ paralysis occurs:

• Persistent depolarization → muscle becomes desensitized → flaccid paralysis.

TWO types of cholinergic drugs affect the heart.

Drug type	Heart effect
Direct muscarinic agonist	M2 → ↓ HR
Indirect AChE inhibitor — moderate dose	↓ HR (bradycardia)
Indirect AChE inhibitor — high dose	↑ HR (tachycardia), ↑ BP

INDIRECT-ACTING CHOLINERGIC AGONISTS

Classification of indirect-acting drugs

Classification	Drugs verbally identified
Reversible, very short acting	Edrophonium
Reversible, intermediate acting	Neostigmine, pyridostigmine, ambenonium
Irreversible, long acting	Echothiophate organophosphate pesticides/nerve agents
Reversible, Centrally acting	Donepezil (Alzheimer's disease)

INDIRECT-ACTING CHOLINERGIC AGONISTS

Drugs we talk about in detail?

1. Neostigmine

2. Pyridostigmine

INDIRECT-ACTING CHOLINERGIC AGONISTS

Neostigmine

MOA: AChE inhibition → ↑ ACh at NMJ → reverses nondepolarizing neuromuscular blockade.

Pharmacokinetics: Active parenterally (injection).

Use: Postoperative reversal of nondepolarizing neuromuscular blocking drugs.

Adverse effects mentioned:

• Bradycardia.

• Nausea, vomiting.

• Insomnia.

• Hypersensitivity reactions.

INDIRECT-ACTING CHOLINERGIC AGONISTS

Pyridostigmine

MOA: AChE inhibition → ↑ ACh at NMJ → improves neuromuscular signaling.

Use: Myasthenia gravis.

Adverse effects mentioned:

• Increased salivation and bronchial secretions (muscarinic).

• Sweating (muscarinic).

• Muscle cramps, fasciculations, weakness (nicotinic).

🚨 Professor emphasized: Know why the muscarinic versus nicotinic adverse effects occur.

INDIRECT-ACTING CHOLINERGIC AGONISTS -

Disease treated: Myasthenia gravis

What it is?

• autoimmune disease causing skeletal muscle weakness.

• What happens:

  • Antibodies interfere with ACh receptors at the NMJ → ACh cannot activate muscles normally → muscle weakness.

INDIRECT-ACTING CHOLINERGIC AGONISTS -

Disease treated: Myasthenia gravis

Why pyridostigmine helps?

Inhibits AChE → ↑ ACh at NMJ → greater stimulation of remaining functional receptors → improved muscle strength.

Organophosphate poisoning

topics discussed

1. MOA

2. symptoms

3. Major cause of death

4. Treatment

Organophosphate poisoning

MOA:

Organophosphate inhibits AChE → ACh accumulates → excessive muscarinic + nicotinic + CNS stimulation.

Organophosphate poisoning

symptoms - overview

• Muscarinic symptoms

• Nicotinic symptoms

• CNS symptoms

Organophosphate poisoning

Muscarinic symptoms

Muscarinic symptoms — SLUDGE

Letter	Symptom
S	Salivation/Sweating
L	Lacrimation (tears)
U	Urination
D	Defecation/diarrhea
G	GI upset
E	Emesis (vomiting)

Also: miosis, bronchoconstriction, bronchial secretions

Organophosphate poisoning

Nicotinic symptoms

• Muscle cramps/fasciculations (twitching)

• Muscle weakness

• Flaccid paralysis

Organophosphate poisoning

CNS symptoms

• Confusion

• Convulsions

• Coma

Organophosphate poisoning

Major cause of death:

respiratory failure.

Organophosphate poisoning treatment

	Atropine	Pralidoxime (2-PAM)
MOA	Competitive muscarinic antagonist	Reactivates inhibited AChE
How	Blocks excess ACh effects at M receptors	Removes organophosphate from AChE before aging
Main action	Treats muscarinic symptoms	Restores AChE activity
Nm paralysis	Does not reverse	Can improve nicotinic weakness

Memory: Atropine blocks the receptor. Pralidoxime restores the enzyme

Pralidoxime:

• Administration: IV infusion/IM.

• Side effects:

  • blurred vision, diplopia

  • headache/dizziness

  • tachycardia/↑ BP.

• Use: organophosphate poisoning.

Distinguishing cholinergic poisoning

Direct muscarinic agonist poisoning	Indirect AChE inhibitor poisoning
Primarily muscarinic symptoms	Muscarinic + nicotinic symptoms
Salivation/diarrhea miosis bradycardia	Same symptoms + muscle cramps/weakness, fasciculations
Muscarinic cardiovascular effects	High doses may also cause tachycardia/hypertension via ganglionic/adrenal stimulation

Professor clarification: ACh is broken down by….

AChE, not removed by reuptake.