Session 2: Cholinergic Agents

what is the neurotransmitter for the cholinergic system?

acetylcholine

what are the two categories of cholinergic receptors?

muscarinic (mAChR) and nicotinic (nAChR)

Murscarinic receptors binds to...

muscarine

nicotinic receptors bind to....

nictoine

steps in the biosynthesis of acetylcholine

1. serine decarboxylase

2. Choline N-methlytransferase

3. Choline acetyltransferase

metabolism of ACh

acetylcholinesterase hydrolyzes ACh into choline and acetic acid

Direct Acting Muscarinic Agonists

acetylcholine, bethanechol, carbochol, methacholine, pilocarpine

direct acting nicotinic agonists

varenicline, succinylcholine

indirect acting alcohols

edrophonium

indirect-acting carbamates

neostigmine, pyridostigmine, physostigmine, rivstigmine, ambenonium

what receptors are found in the CNS, gastric parietal cells, and enteric neurons?

M1

what receptors are located on smooth muscles, exocrince glands and vascular endothelium?

M3

Muscarinic agonists are best described as:

Parasympathomimetic drugs

Which muscarinic receptor subtypes are Gq-coupled

M1, M3, and M5

Activation of Gq-coupled muscarinic receptors leads directly to activation of which enzyme?

Phospholipase C

Phospholipase C activation results in the formation of the second messengers __________ and __________.

IP3 and DAG

what receptors work to reduce cAMP levels?

M2 and M4 receptors (which are Gi-coupled)

where are M4 receptors located?

CNS and enteric neurons

where are M2 receptors found?

cardiac nodal tissue and smooth muscle

what do M2 receptors do in the heart?

open K channels, slowing HR and producing bradycardia

describe the channels of nicotinic receptors

Ligand-gated ion channels, channel opens when ACh binds to allow sodium influx, which generates depolarization and action potential

where are Nm receptors located and what do they do?

located at neuromuscular junction and triggers skeletal muscle contraction

where are Nn receptors located and what do they do?

autonomic ganglia and the CNS and activation produces effects determined by the downstream autonomic pathway

what do reversible cholinesterase inhibitors do?

bind to the active site of acetylcholinesterase and are hydrolyzed, leaving behind drug residue/carbamyl that is released over minutes to hours . this enhances parasympathetic and neuromuscular transmission

what do irreversible cholinesterase inhibitors do?

organophosphates form a stable covalent bond and last days to weeks. this undergoes "aging", rendering inhibition permanent and requires the synthesis of new enzyme for recovery

what is the antidote that can regenerate new enzymes in "aging" of organophosphates?

pralidoxime, but only if administered before aging occurs

use of bethanechol

stimulate smooth muscle activity in postoperative/postpartum urinary retention, neurogenic bladder, and postoperative ileus

use of pilocarpine

increase salivation in Sjogren syndrome and treat acure angle-closure glaucoma (induces miosis and enhances aqueous outflow)

use of varenicline

smoking cessation (reduces cravings and withdrawal symptoms), partial nicotinic agonist

use of neostigmine

treatment of myasthenia gravis, reversal of non-depolarizing neuromuscular blockade, stimulating GI/urinary tract motility in postoperative ileus and urinary retention

pyridostigmine

longer duration of action, preferred maintenance therapy for myasthenia gravis

endrophonium

very short acting inhibitor, diagnostic to confirm myasthenia gravis, distinguishes myasthenic crisis from cholinergic crisis

physostigmine

can cross the BBB and is the antidote for anticholinergic toxicity (including atropine overdose), can be used topically for acute glaucoma

what drugs offer meaningful cognitive benefit for Alzheimer's disease?

rivastigmine, donepezil, and galantamine (centrally acting inhibitors)

use of echothiphate

used topically in glaucome

use of malathion

treatment for scabies and insecticide

use Amifampridine and 4-aminopyridine,

block potassium channels to improve neuromuscular

transmission in Lambert-Eaton myasthenic syndrome

what is the first line of therapy for myasthenia gravis?

pyridostigmine

what is an alternative drug for myasthenia gravis?

neostigmine can be used when a shorter duration is desired

what is a myasthenic crisis?

results from underdosing and the result is worsened weakness, but can improve with additional cholinesterase inhibitor

what is a cholinergic crisis?

excess medication and weakness accompanied by muscarinic symptoms (secretions and fasciculations), requires dose reduction and atropine for management

muscarinic toxicities

DUMBBELLS, cyclospasm, vasodilation, reflex tachycardia, nausea, vomiting, abdominal cramps, increased GI motility

DUMBBELSS

diarrhea, urination, miosis, bronchospasm and bronchorrhea, bradycardia, CNS excitation, lacrimation, salivation, and sweating

nicotinic toxicities

ganglionic stimulation can lead to hypertension, tachycardia, nausea, and vomiting; fasciculations progress to depolarizing blockade that causes muscle paralysis (failure of the respiratory muscle is most dangerous)

Which combination of toxic effects is characteristic of organophosphate poisoning?

Muscarinic, nicotinic, and CNS toxicity

A patient exposed to parathion presents with excessive salivation, muscle weakness, seizures, and respiratory distress. Which symptom is due to nicotinic receptor overstimulation?

Progressive muscle weakness and paralysis

Which treatment is most effective at regenerating acetylcholinesterase in organophosphate poisoning before enzyme aging occurs?

Pralidoxime