Cholinergic System Flashcards
Cholinergic receptors
Muscarinic (GPCR)
- m1= neurons, CNS, gastric parietal cells (excitation, Gq, IP3,DAG)
-m2= heart, nerves, smooth muscle (inhibition, Gi, decreased camp, increased k+)
-m3= glands, smooth muscle, endothelium (excitation, Gq, IP3, DAG)
Nicotinic (ligand gated ion channels)
-Nn= a and beta subunit
-Nm= a2byd - pentamer
Transmitter in cholinergic neuron
Acetylcholine
- choline from diet or serine
- acetyl-CoA from glycolysis and TCA cycle, or fat from beta oxidation, can come from proteins in case of starvation
Main cholinergic transmission sites and receptors
- CNS= m1-m5
- Autonomic ganglion = m1, m2 and Nn (both parasymp and symp)
- NMJ = Nn
- Parasympathetic postganglionic nerves= m1-m3
- Some symp. Postganglionic nerves = m
Consequence of cholinergic activation
Eye: contraction (Miosis) and lacrimation - m3
Salivary glands: salivation - m3
Lungs: bronchoconstriction and increases secretion - m3
Heart: SA,AV- negative chronotropic and dromotropic, bradycardia and decreased contraction - m2
Vessels: contraction - m3, relaxation-NO endothelium - m3 (m2)
Smooth muscle: contract/increases motility by m3 and m1, relaxation of sphincters by m3 and m1
Bladder: urination - m3
Skeletal muscles: contraction by Nm
Presynaptic stimulation
- Potassium channel blockers/.
- 4-aminopyridine(fampiridine) used in ms patients. Would cause severe depolarization all over leading to CNS cramps, ph regulation troubles and cardiac arrest, it can also induce epilepsy - Increase in calcium levels
- theoretical option, not practical
- non specific
- toxic, causes cell death - Alpha- latrotoxin
- spider - black widow
- toxic compound
- not specific for parasympathetic
- calcium modulator, increase ca2+ - Activation of stimulatory presynaptic receptors
- m1, b2, at1, some prostaglandins
- depends on pathway
- nmj; a or beta adrenergic - Inhibition of inhibitory presynaptic receptors
- m2, a2, d2
Presynaptic inhibition
- Tetrodotoxin
- block vgsc
- not specific for parasympathetic
- use: LAs
- systemic action is highly toxic - Omega-conitixin
- puffer fish
- inhibit ACh release - Botulinum toxin
- inhibit release if ACh to synaptic cleft, act on SNARE proteins
- used therapeutically
- indication: migraine, strabismus, dystonia
- paralysis of skeletal muscle; few months - Vesamicol
- action on VAT to inhibit storage of ACh - Hemicholinium
- inhibit choline reuptake
- no therapeutic use - Resirpin = experimental
- Inhibition of excitatory presynaptic receptors
- Activation of inhibitory presynaptic receptor
Postsynaptic stimulation groups
- Direct acting - act on receptors to stimulate them
- choline esters (ACh, methacholine, carbachol, betanechol)
- alkaloids ( muscarine, pilocarpine, arecholine, and cevimeline, nicotine, lobeline, coniine, varenicline, succinylchokine) - Indirect acting - act to increase ACh in synaptic cleft
- alcohols = reversible and competitive (edrophonium, tacrine, donepezil, galantamine)
- carbamates = non-competitive, reversible (physostigmine/eserin, rivastigmine, neostigmine, pyridostigmine, ambenonium, demecarium)
- organophosphates =irreversible inhibition (ecothiophate, tabun, soman, sarin, vx, parathion, malathion, diazinon, diamethoate
Choline esters
Acetylcholine
Methacholine
Carbachol
Betanechol
All are quaternary amides, poor GI absorption, poor CNS penetration, direct acting and excreted by kidney
Acetylcholine
- main physiologic compound
- not used for treatment due to rapid degradation by AChE
- can be used in ophthalmology
- both nicotinic and muscarinic affinity
Methachol
- ACh + methyl group
- specific for muscarinic receptors
- indication: diagnosis of bronchial hyperactivity
- slowly degraded by cholinesterase
Carbachol
- ACh + amine group
- resistant to cholinesterase
- long lasting pharmacon
- non-selective
- indication: glaucoma, eye surgery
Betanechol
- resistant to cholinesterase
- selective for muscarinic receptors
- long lasting pharmacon
- indication: GI atony, bladder atony, perioperative urinary retention
Alkaloids - direct acting
- Natural compounds
- muscarine
- pilocarpine
- arecholine
- nicotine
- lobeline
- coniine - Synthetic compounds
- cevimeline
- varenicline
- succinylcholine
Muscarine
- direct acting alkaloid
- selective for muscarinic receptors
- 4 amine
- originates from amanita muscaria
- toxic, not used
Pilocarpine
- direct acting alkaloid
- selective for muscarinic receptors
- 3 amine
- indication: glaucoma, xerostomia, sjögren
- quick acting
Arecholine
- direct acting alkaloid
- not selective, both m and n
- 3 amine
- addictive drug - not used
- euphoric effect
Cevimeline
- direct acting alkaloid
- synthetic
- 3 amine
- m3 selectivity
- indication: xerostomia
