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
Nicotine
- direct acting alkaloid
- 3 amine
- selective for nicotinic receptors
- indication: poison, smoke cessation
- note: ganglionic stimulant - small dose
Lobeline
- direct acting alkaloid
- high dose is toxic
- selective for nicotinic receptors
- small dose = smoke cessation
Coniine
- direct acting alkaloid
- selective for nicotinic receptors
- highly toxic
Varenicline
- direct acting alkaloid
- synthetic
- partial agonist on nicotinic receptors
- long acting, 24h half-life
- indication; smoke cessation
- note: ganglionic stimulant
Succinylcholine
- direct acting alkaloid
- synthetic
- 4 amine
- selective for Nm
- indication; endotracheal intubation
- note; ganglionic stimulant
Cholinesterase inhibitors
- alcohols
Edrophonium
Tacrine
Donepezil
Galantamine
Edrophonium
- reversible cholinesterase inhibitor
- alcohol
- 4 amine
- water soluble
- dissociates quickly
- half- life: 0.5-2 h
- indication: myasthenia gravis diagnosis, overcome the effect of non-depolarizing muscle relaxant (antidote)
Tacrine
reversible cholinesterase inhibitor Alcohol Lipid soluble 3 amine Indication: Alzheimer’s Hepatotoxic
Donepezil
- reversible cholinesterase inhibitor
- alcohol
- 3 amine
- lipid soluble
- half-life: 50-90h /3 days
- indication: Alzheimer’s
- note: hepatic metabolism
Galantamine
- reversible cholinesterase inhibitor
- alcohol
- lipid soluble
- half-life: 5-7h
Indication: Alzheimer’s
Note: hepatic metabolism 75%
Cholinesterase inhibitors
- carbamates
Physostigmine/eserin Rivastigmine Neostigmine Pyridostigmine Ambenonium Demecarium
Physostigmine/eserin
carbamate
- non- competitive cholinesterase inhibitor
- reversible but takes time
- 3 amine
- lipid soluble
- short acting; 0.5-2h
- indication: glaucoma, atropine poison
Rivastigmine
carbamate
- non- competitive cholinesterase inhibitor
- reversible but takes time
- 3 amine, lipid soluble
- metabolized by AChE and BChE
- long acting: 9 h
- indication; Alzheimer’s and dementia
Neostigmine
carbamate
- non- competitive cholinesterase inhibitor
- reversible but takes time
- 4 amine, water soluble
- short acting: 0.5-2 h
- indication; intestine and bladder atony, myasthenia gravis, antagonize non-depolarizing muscle relaxant and urinary retention
Pyridostigmine
carbamate
- non- competitive cholinesterase inhibitor
- reversible but takes time
- 4 amine, water soluble
- long acting: 3-6 h
- indication: myasthenia gravis, pseudoparalytica intestinal atony, atonic obstipation
Ambenonium
- non- competitive cholinesterase inhibitor
- reversible but takes time
- 4 amine, water soluble
- long lasting: 4-8 h
Indication; myasthenia gravis - carbamate
Demecarium
carbamate
- non-competitive cholinesterase inhibitor
- reversible but takes time
- 4 amine, water soluble
- long acting: 4-6 h
- indication: glaucoma
Organophosphate
- Irreversible inhibition of cholinesterase
- ecothiophate - glaucoma
- tabun, soman, sarin, vx = nerve agent used as war gases
- parathion, malathion, diazinon, diamethoate - insecticides
Therapeutic use of cholinomimetics/stimulation of nicotinic/muscarinic receptors
- glaucoma
- post op and neurogenic lieus, urinary retention
- myasthenia gravis
- reversing the action of neuromuscular blocking agents
- Alzheimer’s
- sjögren
Adverse effects of cholinomimetics
Dumbbels
- diarrhea
- urination
- miosis
- bronchospasm
- bradycardia
- excitation
- lacrimation
- secretion/salivation/sweat
Postsynaptic inhibition
Parasympatholytics - muscarinic antagonists
- tropeins
- non-tropeins
Nicotinic antagonists - ganglionic blockers
- 4 compounds; tetraethylamminum and hexamethonium
- 3 compounds; mecamylamine, trimetaphan
Nicotinic antagonists - skeletal muscle relaxants
Tropeins
Parasympatholytics - m antagonists
- atropine
- scopolamine/hyoscin
- homatropine
- benzotrapine (more soluble than atropine)
- methylatropine
- ipratropium
- tiotropiun
Non-tropines
Muscarinic antagonists
Procyclidine - 3 amine - Parkinson’s Biperiden - 3 amine - Parkinson’s Cyclopentolate - 3 amine - pupil dilator Tropicamide - 3 amine - pupil dilator Oxybutidine - 3 amine - overactive bladder Tolterodine - 3 amine - overactive bladder Solifenacin m3 - 3 amine, overactive bladder Darifenacine m3 - overactive bladder Aclindium - 4 amine - copd, asthma Glycopyrronium - 4 amine
Clinical use of parasympatholytics
Pupil dilation Bronchial asthma Bradycardia, AV block grade 1 Pre or intraoperative medication Antagonize parasympathomimetics effect of —cholinesterase inhibition Peptic ulcer Incontinence Diarrhea Abdominal cramps Parkinson’s Organophosphate poisoning
Adverse effects of parasympatholytics
Abcd
Atropine fever
Blurred vision
Constipation
Dry mouth
Atropine
- m antagonist
- source: atropa belladonna
- 3 amine
- effect: 2-3h, myadriasis 7-10 days!
- dose; 0.3-0.5 mg
- lethal dose; 100 mg, 2mg infants
Indication: eye drops, bradycardia, AV block grade 1, gi/bladder/urinary cramps, cholinomimetics poison
CNS effects; antiemetic effects/motion sickness, restlessness, dyskinesia, raging, hallucinations, epileptiform convulsions, coma and death
Signs of atropine overdose; hot as a hare, blind as a bat, dry as a cracker, red as a beet and mad as a hatter
Scopolamine
- m antagonist
- potato family
- 3 amine
- 2-3 h, myadrisis 3-7 days.
- dose; 0.2-0.4 mg
- lethal dose: 500 mg
- indication: motion sickness. Antiemetic
