8/24 Cholinergic Pharmacology - Walworth Flashcards
types of Ach receptors
- 5-subunit ligand-gated ion channel
- nicotinic Ach receptors
- ligand-gated
- ionotropic [receptor IS the channel]
- single-subunit 7-pass-transmembrane protein which couples to a heterotrimeric G protein
- muscarinic Ach receptors
- metabotropic [receptor IS NOT the channel]
- G protein coupled
nicotinic Ach receptors
general features
2 types
have at least 2 alpha subunits → each has binding site for Ach
- when Ach binds, ion channel opens → Na and K move down gradients → rapid depolarization
1. NM : muscle type, end plate receptor - location: skeletal muscle neuromusc end plates
- binding → opening of Na, K channels & depol
- alpha1 subunits in abundance
- 2 alpha1s assoc with beta, gamma, epsilon
- binding of both sites significantly increases chances of channel opening
- NN : neuronal type, ganglion receptor
- location: postgang cell body, dendrites, some presynaptic cholinergic terminals
- binding → opening of Na, K channels & depol
- at least 8 distinct alpha subunits (alpha2-9) and 3 nonalphas are involved
muscarinic Ach receptors
5 types: location, result of binding
metabotropic GPCRs
M1 : CNS neurons, symp postgang neurons, some presyn sites → inc IP3, inc DAG, inc intracellular Ca
M2 : myocardium, smooth muscle, some presyn sites → open K channels, inhibit adenylyl cyclase
M3 : exocrine glands, smooth muscle, vessels (sm muscle, endothelium) → inc IP3, inc DAG, inc intracellular Ca
M4 : pref expressed in CNS (forebrain esp), also in striatum, cortex, hippocampus → open K channels, inhibits adenylyl cyclase
M5 : predominant mAchR in neurons in VTA and substantia nigra → inc IP3, inc DAG, inc intracellular Ca
M1, M3, M5 Gproteins act on second messenger systems (IP3, DAG, intracellular Ca)
M2, M4 Gproteins directly influence K channels
cholinoceptor blocking agents
nicotinic antagonists
- ganglion blockers
- neuromuscular blockers
muscarinic antagonists
- atropine
- scopolamine
- tropicamide
- all 3 of the above: pharmaco of the eye
- benztropine (Parkinson’s)
- ipratropium (COPD)
- tolterodine (incontinence)
cholinoceptor stimulants
nicotinic agonists
- nicotine
- varenicline (smoking cessation)
- succinylcholine (muscle relaxation)
muscarinic agonists
- muscarine
- bethanechol (post-op ileus)
- pilocarpine (Sjogren’s syndrome)
role of Ach receptors in nervous system
PSNS
SNS
somatic/motor
autonomic nervous system
-
parasympathetic
- cardiac and sm muscle, gland cells, nerve terminals
- long pregang neuron : nicotinic receptor
- short postgang neuron : muscarinic receptor 1-5
- cardiac and sm muscle, gland cells, nerve terminals
-
sympathetic
- sweat glands
- pregang : short, nicotinic
- postgang : long, muscarinic
- cardiac and smooth muscle, gland cells nerve terminals
- pregang : short, nicotinic
- postgang : long, alpha/beta adrenergic [majority]
- renal vasc smooth muscle
- pregang : short, nicotonic
- postgang : long, dopaminergic
- sweat glands
-
adrenal medulla
- neuronal type receptors hit adrenal medulla → epi, norepi release
somatic/motor nervous system
-
somatic skeletal muscle
- direct innervation - no relay at a ganglion
- muscle type Ach receptor, NM
cholinergic neurons and nerve terminals
cholinergic neurons synthesize and release Ach
- cotransporter on surface that takes up Na/choline
- cholinacetyltransferase (ChAT) catalyzes acetylation of choline (donor: AcCoA) → ACh
- vesicles take up ACh (via action of vesicle assoc transporter)
- opening of voltage-gated Ca channels triggers Ca influx → fusion of vesicles with membrane → release of ACh into synaptic cleft
- ACh binds to postsyn cell’s cholinoceptors
-
acetylcholinesterase degrades ACh → acetate + choline (taken up by the presyn cell)
* receptors on presyn cell that pick up nt that was released are aka autoreceptors → involved in feedback regulation of nt synthesis and release
targets for pharmacological intervention
action of…
hemicoliniums
vesamicol
botulinum toxin
cholinoceptor agonists/antagonists
acetylcholinesterase inhibitors
1. hemicoliniums interfere with precursor uptake (choline into presyn cell via cotransporter)
2. vesamicol interferes with vesicle associated transporter (ACh entry into vesicles)
3. botulinum toxin interferes with vesicle fusion with presyn membrane
- cholinoceptor agonists stimulate responses (bethanechol, pilocarpine)
* direct-acting cholinomimetic agents
cholinoceptor antagonists block responses (tropicamide, ipratropium, tolterodine)
5. acetolycholinesterase inhibitors allow for increased duration of action of ACh (prevent breakdown of ACh)
- indirect-acting cholinomimetic agents
hydrolysis of ACh by acetylcholinesterase
acetylcholinesterase active site has a Glu residue near Ser residue → attracts ACh
- ACh subsequenlty hydrolyzed in less than 1ms
short acting, reversible inhibitor of AChE
ex, use
edrophonium
- binds weakly, reversibly to anionic tomain of AChE
- rapid renal clearance, brief duration of action
- used to diagnose MG (myasthenia gravis)
intermediate-acting inhibitors of AChE
neostigmine (used for MG, ileus, reversal of neuromusc blockade)
- molecule that resembles ACh
- leads to covalent but reversible association with formation of a carbamate intermediate bonded to Ser residue
- half life of 30min → longer duration of action
*duration of action determined by stability of enzyme-inhibitor complex, not by plasma half-life
other examples for tx:
MG - pyridostigmine, ambenonium
glaucoma - demecarium, physostigmine (crosses bbb, but is used topically)
Alz - rivastigmine (deriv of physostigmine - taking adv of bbb permeability)
long-acting irrev inhibitors of AChE
irreversible covalent bonding that isn’t readily reversible
applications : organophosphate insecticides, chemical warfare agents
- inactivate AChE for 100s of hours!
- lead to ACh excess
signs of cholinergic excess
MUSCARINIC EFFECTS
- CNS stim
- miosis (excessive constriction of pupil)
- reflex tachycardia
- bronchoconst
- excessive GI/GU smooth muscle activity
- increased secretory activity (sweat, airway, GI, lacrimal)
- vasodil
NICOTINIC EFFECTS
- CNS stimulation (convulsions) followed by depression
- neuromusc end plate depolarization / blockade(fasciculations, then paralysis)
cholinergic excess treatment
if insecticide exposure : decontaminate to prevent further absorption
- maintain resp, vital signs
- administer atropine (muscarinic antagonist)
- benzodiazepines for seizures
also can give pralidoxime if caught early
- chemical antagonist → oxime group has high affinity for phosphate group in organophosphates
- can hydrolyze organophosphate, prevent its action (inhibition of AChE)
cholinesterase inhibitor poisining
DUMBBELSS
diarrhea
urination
miosis
bronchospasm
bradycardia
excitation (sk muscle, CNS)
lacrimation
sweating
salivation
