Lec 8 Cholinergic Flashcards
What is an example of a muscarinic agonist?
acetylcholine
What are two examples of nicotinic agonists?
nicotine
acetylcholine
What is an example of a muscarinic antagonist?
atropine
What is an example of an acetylcholinesterase inhibitor?
physostigmine
What is an example of a ganglionic blocker?
hexamethonium
What is an example of a neuromuscular blocker?
tubocurarine
What are cholinomimetic drugs?
Mimic action of acetylcholine
What tissues do muscarinic agonists normally affect?
- nerve
- heart and smooth muscle
- glands and endothelium
what tissues to nicotinic agonists normally affect?
- neuromuscular end plate
- skeletal muscle
- autonomic ganglion cells
What are two types of direct acting cholinoceptor stimulants?
alkaloids
choline esters
M1 muscarinic receptor [location, G protein, cell effect]
- located in neurons
- Gq/11
- Activates IP3/DAG
What type of receptors are muscarinic receptors? Where are they located?
- g protein coupled receptors [GPCRs]
- at end organs primarily of PNS
- work through secondary messengers
M2 muscarinic receptor [location, G protein, cell effect]
- located in neurons, heart, smooth muslce
- Gi/o
- inhibits cAMP production
- activates K+ channels via B-gamma subunits
M3 muscarinic receptor [location, G protein, cell effect]
- located in glands, endothelium, smooth muscle
- Gq/11
- activates IP3/DAG cascade
What type of receptors are nicotinic? Location? Permeable to what ions?
- ligand-gated channels
- permeable to Na, K, Ca
- only at ganglia
- —– postsynaptic neuron of ganglion synapse in both PNS/SNS
- —– neuromuscular junction of somatic motor nerves
Nicotine as a drug?
- nicotinic agonist
- binds nicotinic receptors on postsynaptic neuron of ganglion synapse in both PNS/SNS divisions of ANS
Nm nicotinic receptors [location, effect]
- in skeletal muscle neuromuscular junction [NMJ]
- causes membrane depolarization [ligand gated Na, K, Ca influx/efflux]
Nn nicotinic receptors [location, effect]
- in CNS, postganglionic neuron of ANS
- causes membrane depolarization [ligand gated Na, K, Ca influx/efflux]
Mech of muscarinic synapse at end organ [heart example]
- ACh released from varicosities along axon
- ACh interacts with M receptor
- M receptor linked to K+ channel causes hyperpolarization
- Voltage-dependent opening of pacemaker Na current channel shifts to negative potential
- phosphorylation of L-type Ca channels is reduced
Synthesis of acetylcholine?
- precursor choline actively taken up in terminal by choline transporter [Na/Cl dependent co-transport]
- ACh synthesized from choline and acetyl CoA in axon terminal by choline acetyltransferase [ChAT]
- ACh packed in vesicle
Mech of acetylcholine release
- action potential in axon reaches terminal
- voltage-gated Ca channels open
- increased intracellular Ca causes protein on vesicle membrane [VAMPs] to form complex with protein on cell membrane [SNAPs]
- vesicle fuses with cell membrane and releases ACh into synaptic cleft
How does acetylcholine signal terminate?
- acetylcholinesterase [AChE] expressed on postsynatpic membrane
- hydrolyzes acetylcholine in synapse to acetic acid and choline
What is an example of an anticholinesterase? What is effect?
- physostigmine
- inhibits acetylcholinesterase [which breaks down ACh], thus indirect cholinergic agonist
2 effects of physostigmine on heart?
- slows [SA node]
- decreases atrial contractile force
What is physostigmine?
- An anticholinesterase - inhibits acetylcholinesterase
- indirect cholinergic agonist since increases amount of ACh in synaptic cleft
- reversible inhibitor
- can cross blood brain barrer
2 effects of physostigmine on bronchioles?
- bronchoconstriction
- increased secretions
effect of physostigmine on vascular?
- no effect because no parasympathetic innervation
Effect of physostigmine on GI?
more contraction –> increased motility
Effect of physostigmine on eye?
miosis [pupil constriction]
Effect of physostigmine on sweat glands?
increased secretion
2 mnemonics for cholinesterase poisoning? what 2 things can lead to this?
caused by insecticides, nerve gases SLUDGE - salivation - lacrimation - urination - defecation - GI upset - Emesis Killer B's - bradycardia - bronchospasm - bronchorrhea
What does mnemonic Killer Bs mean?
Effect of cholinesterase poisoning Killer B's - bradycardia - bronchospasm - bronchorrhea
What does mnemonic SLUDGE mean?
Effect of cholinesterase poisoning SLUDGE - salivation - lacrimation - urination - defecation - GI upset - Emesis
What is effect of acetylcholine as a drug?
- non-selective with muscarinic and nicotinic, agonist for both
- its a choline ester - so is a substrate for acetylcholinesterase
- activates muscarinic and nicotinic receptors
What is subunit configuration of Nn vs Nm? Why is this important?
- Different types of a and B subunits
- allows development of drugs specific for one or the other
What is effect of nicotine on end organs?
- variable since stimulates both sympathetic and parasympathetic
- reflects dominant tone for that organ
Effect of nicotine given systemically on ANS?
- stimulates sympathetic and parasympathetic postganglionic neurons
What is effect of nicotine in somatic nervous system?
- activates Nm receptors to induce contraction [just like when ACh released]
Effect of high levels nicotine or other nACHr agonist?
flaccid paralysis [relaxation] of skeletal muscle due to depolarization blockade: excessive sustained depolarization so voltage-gated Na channels can’t recover
Two sites of action of nicotinic agonists?
- ganglionic stimulant [activates PNS/SNS]
2. skeletal muscle contraction [Nm, NMJ]
What does a ganglionic stimulant do?
- activates nicotinic ganglionic receptors [Nn] in both sympathetic and parasympathetic
- causes increase in primary tone of each tissue
What are two synonyms for muscarinic antagonists?
- antimuscarinic
- parasympatholytic
What is the prototype muscarinic antagonist?
atropine
What is Hexamethonium? Mech?
- selective antagonist at Nn receptors
- ganglionic blocker
- blocks transmission at all ganglia [parasympathetic and sympathetic] so target organs denervated
- effect on each organ is opposite of dominant tone
Effect of Hexamethonium on heart?
tachycardia [because dominant tone is parasympathetic]
Mech of action of muscarinic antagonists
- reversible competitive antagonists at M receptors
- block access of acetylcholine/cholinomimetics
Effect of muscarinic antagonist? How does it effect BP?
- blocks M receptors at parasympathetic end organs
- little effect on BP [M receptors exist on blood vessels but no parasympathetic innervations to these receptors]
What does a ganglionic blocker do? What type of receptor does it block?
- blocks Nn receptors
- produces opposite of primary tone
- effectively removes both sympathetic and parasympathetic input to organs
Effect of Hexamethonium on heart?
tachycardia
Effect of Hexamethonium on arterioles?
vasodilation - increased peripheral blood flow, hypotension
Effect of Hexamethonium on veins?
dilation - peripheral pooling blood, decreased venous return, decreased cardiac output
Effect of Hexamethonium on iris?
mydriasis
Effect of Hexamethonium on ciliary muscle?
cycloplegia - focus to far vision
Effect of Hexamethonium on GI?
reduced tone and motality
constipation
decreased gastric and pancreatic secretions
Effect of Hexamethonium on urinary bladder?
urinary retention
Effect of Hexamethonium on salivary glands?
xerostomia
Effect of Hexamethonium on sweat glands?
anhidrosis
Effect of Hexamethonium on genital tract?
decreased stimulation
Mech of action ganglionic blocker [hexamethonium] on BP
- normally blood vessels have sympathetic tone which causes vasoconstriction to increase BP
- hexamethonium knocks out the dominant tone so get vasodilation and low BP
what side effect of ganglionic blockers is reason they are not clinically used?
othostatic hypotension
Function of neuromuscular blockers? Primary example?
- competitive antagonists as Nm receptors
- block binding ACh to Nm, prevent opening of cation channel –> prevent skeletal muscle contraction
- ex. tubocurarine [curare]
What is use of tubocurarine [curare]?
- neuromuscular blocker
- used as muscle relaxant before surgery/intubation
- produces flaccid paralysis of skeletal muscle
What important cholinesterase inhibitor can cross the blood-brain barrier?
physostigmine
When is acetylcholine used as a drug clinically?
for opthalmic indications
Whats another name for muscarinic agonists? [hint starts with a p]
parasympathomimetics
Why is acetylcholine short lived when administered as IV? What does it activate?
- activates mainly muscarinic receptors = muscarinic agonist
- short-acting because it is a substrate for pseudocholinesterase in plasma and tissues
What is effect of muscarininc agonists? [on HR, bronchus, sweating]
- bradycardia
- bronchoconstriction
- diaphoresis
What main difference between effect of muscarinic agonists and anticholinesterase?
- muscarinic agonists dilate vasculature, decrease diastolic BP
- vs anticholinesterases have no effect on vasculature
Why does exogenous ACh cause vasodilation?
- endothelial cells of intima have M receptors
- when activated, these cells release NO [aka endothelial derived relaxation factor [EDRF]
- NO diffuses to surround vascular smooth muscle
- — activates guanine cyclase, increase cGMP, muscle relaxes, vessel dialtes
3 names of rmuscarinic antagonists
- parasympatholytics
- antimuscarinics
- atropinics
Effect of atropine
- dry mouth, difficulty with near vision, tachycardia, etc
Phrase for atropine poisoning
Blind as a bat mad as a hatter red as a beet hot as hell dry as bone the bowel and bladder loser their tone and the heart runs alone
