Lec 8 Cholinergic Flashcards
1
Q
What is an example of a muscarinic agonist?
A
acetylcholine
2
Q
What are two examples of nicotinic agonists?
A
nicotine
acetylcholine
3
Q
What is an example of a muscarinic antagonist?
A
atropine
4
Q
What is an example of an acetylcholinesterase inhibitor?
A
physostigmine
5
Q
What is an example of a ganglionic blocker?
A
hexamethonium
6
Q
What is an example of a neuromuscular blocker?
A
tubocurarine
7
Q
What are cholinomimetic drugs?
A
Mimic action of acetylcholine
8
Q
What tissues do muscarinic agonists normally affect?
A
- nerve
- heart and smooth muscle
- glands and endothelium
9
Q
what tissues to nicotinic agonists normally affect?
A
- neuromuscular end plate
- skeletal muscle
- autonomic ganglion cells
10
Q
What are two types of direct acting cholinoceptor stimulants?
A
alkaloids
choline esters
11
Q
M1 muscarinic receptor [location, G protein, cell effect]
A
- located in neurons
- Gq/11
- Activates IP3/DAG
12
Q
What type of receptors are muscarinic receptors? Where are they located?
A
- g protein coupled receptors [GPCRs]
- at end organs primarily of PNS
- work through secondary messengers
13
Q
M2 muscarinic receptor [location, G protein, cell effect]
A
- located in neurons, heart, smooth muslce
- Gi/o
- inhibits cAMP production
- activates K+ channels via B-gamma subunits
14
Q
M3 muscarinic receptor [location, G protein, cell effect]
A
- located in glands, endothelium, smooth muscle
- Gq/11
- activates IP3/DAG cascade
15
Q
What type of receptors are nicotinic? Location? Permeable to what ions?
A
- 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
16
Q
Nicotine as a drug?
A
- nicotinic agonist
- binds nicotinic receptors on postsynaptic neuron of ganglion synapse in both PNS/SNS divisions of ANS
17
Q
Nm nicotinic receptors [location, effect]
A
- in skeletal muscle neuromuscular junction [NMJ]
- causes membrane depolarization [ligand gated Na, K, Ca influx/efflux]
18
Q
Nn nicotinic receptors [location, effect]
A
- in CNS, postganglionic neuron of ANS
- causes membrane depolarization [ligand gated Na, K, Ca influx/efflux]
19
Q
Mech of muscarinic synapse at end organ [heart example]
A
- 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
20
Q
Synthesis of acetylcholine?
A
- 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
21
Q
Mech of acetylcholine release
A
- 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
22
Q
How does acetylcholine signal terminate?
A
- acetylcholinesterase [AChE] expressed on postsynatpic membrane
- hydrolyzes acetylcholine in synapse to acetic acid and choline
23
Q
What is an example of an anticholinesterase? What is effect?
A
- physostigmine
- inhibits acetylcholinesterase [which breaks down ACh], thus indirect cholinergic agonist
24
Q
2 effects of physostigmine on heart?
A
- slows [SA node]
- decreases atrial contractile force
25
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
26
2 effects of physostigmine on bronchioles?
- bronchoconstriction
| - increased secretions
27
effect of physostigmine on vascular?
- no effect because no parasympathetic innervation
28
Effect of physostigmine on GI?
more contraction --> increased motility
29
Effect of physostigmine on eye?
miosis [pupil constriction]
30
Effect of physostigmine on sweat glands?
increased secretion
31
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
```
32
What does mnemonic Killer Bs mean?
```
Effect of cholinesterase poisoning
Killer B's
- bradycardia
- bronchospasm
- bronchorrhea
```
33
What does mnemonic SLUDGE mean?
```
Effect of cholinesterase poisoning
SLUDGE
- salivation
- lacrimation
- urination
- defecation
- GI upset
- Emesis
```
34
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
35
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
36
What is effect of nicotine on end organs?
- variable since stimulates both sympathetic and parasympathetic
- reflects dominant tone for that organ
37
Effect of nicotine given systemically on ANS?
- stimulates sympathetic and parasympathetic postganglionic neurons
38
What is effect of nicotine in somatic nervous system?
- activates Nm receptors to induce contraction [just like when ACh released]
39
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
40
Two sites of action of nicotinic agonists?
1. ganglionic stimulant [activates PNS/SNS]
| 2. skeletal muscle contraction [Nm, NMJ]
41
What does a ganglionic stimulant do?
- activates nicotinic ganglionic receptors [Nn] in both sympathetic and parasympathetic
- causes increase in primary tone of each tissue
42
What are two synonyms for muscarinic antagonists?
- antimuscarinic
| - parasympatholytic
43
What is the prototype muscarinic antagonist?
atropine
44
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
45
Effect of Hexamethonium on heart?
tachycardia [because dominant tone is parasympathetic]
46
Mech of action of muscarinic antagonists
- reversible competitive antagonists at M receptors
| - block access of acetylcholine/cholinomimetics
47
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]
48
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
49
Effect of Hexamethonium on heart?
tachycardia
50
Effect of Hexamethonium on arterioles?
vasodilation - increased peripheral blood flow, hypotension
51
Effect of Hexamethonium on veins?
dilation - peripheral pooling blood, decreased venous return, decreased cardiac output
52
Effect of Hexamethonium on iris?
mydriasis
53
Effect of Hexamethonium on ciliary muscle?
cycloplegia - focus to far vision
54
Effect of Hexamethonium on GI?
reduced tone and motality
constipation
decreased gastric and pancreatic secretions
55
Effect of Hexamethonium on urinary bladder?
urinary retention
56
Effect of Hexamethonium on salivary glands?
xerostomia
57
Effect of Hexamethonium on sweat glands?
anhidrosis
58
Effect of Hexamethonium on genital tract?
decreased stimulation
59
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
60
what side effect of ganglionic blockers is reason they are not clinically used?
othostatic hypotension
61
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]
62
What is use of tubocurarine [curare]?
- neuromuscular blocker
- used as muscle relaxant before surgery/intubation
- produces flaccid paralysis of skeletal muscle
63
What important cholinesterase inhibitor can cross the blood-brain barrier?
physostigmine
64
When is acetylcholine used as a drug clinically?
for opthalmic indications
65
Whats another name for muscarinic agonists? [hint starts with a p]
parasympathomimetics
66
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
67
What is effect of muscarininc agonists? [on HR, bronchus, sweating]
- bradycardia
- bronchoconstriction
- diaphoresis
68
What main difference between effect of muscarinic agonists and anticholinesterase?
- muscarinic agonists dilate vasculature, decrease diastolic BP
- vs anticholinesterases have no effect on vasculature
69
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
70
3 names of rmuscarinic antagonists
- parasympatholytics
- antimuscarinics
- atropinics
71
Effect of atropine
- dry mouth, difficulty with near vision, tachycardia, etc
72
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
```
