Cholinergic System Flashcards
1
Q
Cholinergic receptors
A
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
2
Q
Transmitter in cholinergic neuron
A
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
3
Q
Main cholinergic transmission sites and receptors
A
- 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
4
Q
Consequence of cholinergic activation
A
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
5
Q
Presynaptic stimulation
A
- 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
6
Q
Presynaptic inhibition
A
- 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
7
Q
Postsynaptic stimulation groups
A
- 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
8
Q
Choline esters
A
Acetylcholine
Methacholine
Carbachol
Betanechol
All are quaternary amides, poor GI absorption, poor CNS penetration, direct acting and excreted by kidney
9
Q
Acetylcholine
A
- main physiologic compound
- not used for treatment due to rapid degradation by AChE
- can be used in ophthalmology
- both nicotinic and muscarinic affinity
10
Q
Methachol
A
- ACh + methyl group
- specific for muscarinic receptors
- indication: diagnosis of bronchial hyperactivity
- slowly degraded by cholinesterase
11
Q
Carbachol
A
- ACh + amine group
- resistant to cholinesterase
- long lasting pharmacon
- non-selective
- indication: glaucoma, eye surgery
12
Q
Betanechol
A
- resistant to cholinesterase
- selective for muscarinic receptors
- long lasting pharmacon
- indication: GI atony, bladder atony, perioperative urinary retention
13
Q
Alkaloids - direct acting
A
- Natural compounds
- muscarine
- pilocarpine
- arecholine
- nicotine
- lobeline
- coniine - Synthetic compounds
- cevimeline
- varenicline
- succinylcholine
14
Q
Muscarine
A
- direct acting alkaloid
- selective for muscarinic receptors
- 4 amine
- originates from amanita muscaria
- toxic, not used
15
Q
Pilocarpine
A
- direct acting alkaloid
- selective for muscarinic receptors
- 3 amine
- indication: glaucoma, xerostomia, sjögren
- quick acting
16
Q
Arecholine
A
- direct acting alkaloid
- not selective, both m and n
- 3 amine
- addictive drug - not used
- euphoric effect
17
Q
Cevimeline
A
- direct acting alkaloid
- synthetic
- 3 amine
- m3 selectivity
- indication: xerostomia
18
Q
Nicotine
A
- direct acting alkaloid
- 3 amine
- selective for nicotinic receptors
- indication: poison, smoke cessation
- note: ganglionic stimulant - small dose
19
Q
Lobeline
A
- direct acting alkaloid
- high dose is toxic
- selective for nicotinic receptors
- small dose = smoke cessation
20
Q
Coniine
A
- direct acting alkaloid
- selective for nicotinic receptors
- highly toxic
21
Q
Varenicline
A
- direct acting alkaloid
- synthetic
- partial agonist on nicotinic receptors
- long acting, 24h half-life
- indication; smoke cessation
- note: ganglionic stimulant
22
Q
Succinylcholine
A
- direct acting alkaloid
- synthetic
- 4 amine
- selective for Nm
- indication; endotracheal intubation
- note; ganglionic stimulant
23
Q
Cholinesterase inhibitors
- alcohols
A
Edrophonium
Tacrine
Donepezil
Galantamine
24
Q
Edrophonium
A
- 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)
25
Tacrine
```
reversible cholinesterase inhibitor
Alcohol
Lipid soluble
3 amine
Indication: Alzheimer’s
Hepatotoxic
```
26
Donepezil
- reversible cholinesterase inhibitor
- alcohol
- 3 amine
- lipid soluble
- half-life: 50-90h /3 days
- indication: Alzheimer’s
- note: hepatic metabolism
27
Galantamine
- reversible cholinesterase inhibitor
- alcohol
- lipid soluble
- half-life: 5-7h
Indication: Alzheimer’s
Note: hepatic metabolism 75%
28
Cholinesterase inhibitors
| - carbamates
```
Physostigmine/eserin
Rivastigmine
Neostigmine
Pyridostigmine
Ambenonium
Demecarium
```
29
Physostigmine/eserin
carbamate
- non- competitive cholinesterase inhibitor
- reversible but takes time
- 3 amine
- lipid soluble
- short acting; 0.5-2h
- indication: glaucoma, atropine poison
30
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
31
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
32
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
33
Ambenonium
- non- competitive cholinesterase inhibitor
- reversible but takes time
- 4 amine, water soluble
- long lasting: 4-8 h
Indication; myasthenia gravis
- carbamate
34
Demecarium
carbamate
- non-competitive cholinesterase inhibitor
- reversible but takes time
- 4 amine, water soluble
- long acting: 4-6 h
- indication: glaucoma
35
Organophosphate
- Irreversible inhibition of cholinesterase
- ecothiophate - glaucoma
- tabun, soman, sarin, vx = nerve agent used as war gases
- parathion, malathion, diazinon, diamethoate - insecticides
36
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
37
Adverse effects of cholinomimetics
Dumbbels
- diarrhea
- urination
- miosis
- bronchospasm
- bradycardia
- excitation
- lacrimation
- secretion/salivation/sweat
38
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
39
Tropeins
Parasympatholytics - m antagonists
- atropine
- scopolamine/hyoscin
- homatropine
- benzotrapine (more soluble than atropine)
- methylatropine
- ipratropium
- tiotropiun
40
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
```
41
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
```
42
Adverse effects of parasympatholytics
Abcd
Atropine fever
Blurred vision
Constipation
Dry mouth
43
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
44
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
