Direct acting cholinergic drugs and anticholinesterases

Direct acting cholinomimetics=Drugs that bind directly to muscarinic or nicotinic receptors to mimic acetylcholine

Indirect acting cholinomimetics=Drugs that inhibit acetylcholinesterase → increase ACh concentration at synapse → prolonged cholinergic stimulation

Choline esters examples=Acetylcholine

Methacholine

Alkaloid examples=Pilocarpine

Nicotine

Reversible anticholinesterases examples=Edrophonium

Neostigmine

Irreversible anticholinesterases examples=Organophosphates (Sarin

Soman

Acetylcholine clinical use=Not used clinically

only experimental due to rapid hydrolysis

Methacholine use=Bronchial hyperreactivity test (diagnosis of asthma)

Methacholine adverse effect=Bradycardia and cardiovascular suppression

Bethanechol use=Atonic bladder

paralytic ileus (stimulates GI/GU smooth muscle)

Pilocarpine uses=Glaucoma (↓ IOP)

Xerostomia (dry mouth)

Pilocarpine adverse effects=Salivation

sweating

Pilocarpine origin=South American shrub Pilocarpus Jaborandi

isolated in 1875

Nicotine receptor target=Nicotinic receptors at autonomic ganglia and NMJ

Muscarinic receptor subtypes=M1 gastric parietal cells

M2 myocardium/presynaptic

Nicotinic receptor subtypes=NM at neuromuscular junction

NN at autonomic ganglia

M1 receptor action=↑ gastric acid secretion

M2 receptor action=↓ heart rate

↓ contractility

M3 receptor action=Smooth muscle contraction

glandular secretion

M4/M5 receptor action=CNS modulation and stimulation

Cardiac effects of muscarinic agonists=Negative chronotropy

inotropy

Vascular effects of muscarinic agonists=Vasodilation via NO release from endothelium (M3)

GI effects of muscarinic agonists=↑ peristalsis

↑ secretion

GU effects of muscarinic agonists=Detrusor contraction

sphincter relaxation → facilitate voiding

Eye effects of muscarinic agonists=Miosis

cyclospasm

Respiratory effects of muscarinic agonists=Bronchoconstriction

↑ tracheobronchial secretions

Miscellaneous gland effects=↑ sweating

lacrimation

Contraindications for muscarinic agonists=Asthma

peptic ulcer

Signs of muscarinic toxicity=Nausea

vomiting

Antidote for muscarinic toxicity=Atropine (competitive muscarinic antagonist)

Edrophonium mechanism=Short‑acting reversible AChE inhibitor

binds electrostatically by weak hydrogen bonds

Edrophonium duration=2–10 minutes (short lived action)

Edrophonium uses=Diagnosis of myasthenia gravis

differentiate myasthenic vs cholinergic crisis

Neostigmine mechanism=Intermediate‑acting AChE inhibitor

forms moderately stable bond hydrolyzed slowly

Neostigmine uses=Treatment of MG

paralytic ileus

Physostigmine properties=Intermediate‑acting AChE inhibitor

highly lipid soluble

Physostigmine uses=Glaucoma

atropine poisoning

Donepezil properties=Long‑acting

lipophilic

Donepezil use=Treatment of Alzheimer’s disease

Myasthenia gravis definition=Autoimmune disorder with antibodies blocking ACh receptors at NMJ → muscle weakness

Myasthenia gravis common symptom=Ptosis (droopy eyelids

>75% of patients)

Other MG symptoms=Diplopia

limb weakness

Myasthenic crisis=Too little drug → low ACh → paralysis

Cholinergic crisis=Excess drug → excessive ACh → depolarization block → paralysis

Edrophonium test in myasthenic crisis=Improves muscle strength briefly

Edrophonium test in cholinergic crisis=Worsens muscle weakness

Preferred drug for MG=Neostigmine (safer

less CNS penetration than physostigmine)

Anticholinesterase overdose effect=Persistent depolarization with no repolarization → paralysis

respiratory failure

Organophosphate mechanism=Irreversible AChE inhibition → covalent bond → enzyme aging prevents reactivation

Organophosphate examples=Sarin

Soman

Organophosphate poisoning symptoms=SLUDGEM (Salivation

Lacrimation

Organophosphate poisoning treatment=Decontamination

Pralidoxime (before aging)

Pralidoxime mechanism=Reactivates AChE by binding to anionic site and removing inhibitor (only before aging)

Mushroom poisoning source=Amanita muscaria (contains muscarine in low concentration)

Mushroom poisoning symptoms=Salivation

sweating

Mushroom poisoning treatment=Atropine (competitive muscarinic antagonist)

Clinical scenario MG=40‑year‑old woman with MG on neostigmine → returns with weakness (could be missed dose or overdose)

Missed neostigmine dose effect=Low ACh at NMJ → paralysis → myasthenic crisis

Excess neostigmine dose effect=Excess ACh → depolarization block → paralysis → cholinergic crisis

Differentiation of crises=Edrophonium improves myasthenic crisis

worsens cholinergic crisis

Neostigmine additional uses=Paralytic ileus

atonic bladder

Physostigmine additional use=Treatment of atropine poisoning

Donepezil adverse effects=GI upset

insomnia

Anticholinesterase overdose danger=Respiratory failure due to paralysis

Muscarinic agonist systemic adverse effects=Salivation

diaphoresis

Muscarinic agonist contraindication in asthma=Risk of bronchoconstriction and asthmatic attack

Muscarinic agonist contraindication in peptic ulcer=↑ gastric acid secretion exacerbates ulcer symptoms

Muscarinic agonist contraindication in coronary disease=Myocardial suppression and vascular effects compromise coronary blood flow

Atropine role in poisoning=Blocks muscarinic receptors

reverses muscarinic toxicity signs

Organophosphate enzyme aging=Bond becomes permanent

cannot be broken

Pralidoxime timing=Effective only if given before enzyme aging occurs

SLUDGE mnemonic=Salivation

Lacrimation

SLUDGEM extension=Miosis

Muscle spasm added to SLUDGE

Edrophonium binding type=Electrostatic and hydrogen bonds

reversible and short lasting

Neostigmine bond type=Moderately stable bond with AChE

hydrolyzed slowly

Physostigmine lipid solubility=Highly lipid soluble

crosses BBB

Donepezil duration=Long acting

once daily dosing

Organophosphate bond type=Strong covalent bond with AChE

hydrolyzed extremely slowly

Organophosphate decontamination=Remove contaminated clothes

wash skin

Atropine dosing in organophosphate poisoning=1–2 mg IV every 5–15 minutes until signs reverse (dry mouth

mydriasis)

Pralidoxime molecular action=Quaternary nitrogen attracted to anionic site of AChE

removes inhibitor

Muscarinic receptor type=G‑protein coupled receptors (M1–M5)

Nicotinic receptor type=Ionotropic receptors (NM

NN)

M1 receptor location=Gastric parietal cells

M2 receptor location=Myocardium

presynaptic terminals

M3 receptor location=Smooth muscle of glands/viscera

sweat glands

M4/M5 receptor location=CNS

Nicotinic NM receptor location=Neuromuscular junctions

Nicotinic NN receptor location=Autonomic ganglia

M3 receptor eye effects=Miosis

cyclospasm

M3 receptor GU effects=Detrusor contraction

sphincter relaxation → voiding

M3 receptor respiratory effects=Bronchoconstriction

↑ secretions

M1 receptor GI effect=↑ gastric acid secretion

M2 receptor cardiac effect=↓ HR

↓ contractility