Lecture 2 Flashcards
1
Q
what are the two types of cholinergic receptors
A
Nicotinic, Muscarinic
2
Q
Most used cholinergic receptor in drug manipulation
A
Muscarinic
3
Q
Which nicotinic and muscarinic receptors are used in therapeutic targeting
A
Nm, Nn & M1, M2, M3
4
Q
What is a cholinergic agent
A
Parasympathetic mechanism involving ACh receptors
5
Q
What does a direct agonist do in para sympathomimetic mechanism
A
activates cholinoreceptors
6
Q
what does an indirect agonist do in a parasympathomimetic mechanism
A
Stimulate ACh release or inhibit ACHe
7
Q
Many drugs exhibit ______ side effects
A
Anticholinergic
8
Q
does acetylcholine have a higher affinity for nicotinic or muscarinic receptors`
A
muscarinic
9
Q
What kind of tissue is M1 located in
A
Post ganglionic
10
Q
M2 tissue location
A
Heart
11
Q
M3 tissue location
A
Smooth muscle, exocrine glands, endothelium
12
Q
M4 and M5 tissue location
A
CNS
13
Q
mnemonic to remember GPCR mechanism of muscarinic receptors
A
QIQIQ
14
Q
Mnemonic to remember GPCR mechanism of Adrenergic receptors
A
A1- Q
A2- I
B1,2,3- S
QISS
15
Q
Gq pathway mevhanism
A
DAG—->IP3 and PLC and Ca2+
16
Q
Gi mechanism of GPCR
A
Inhibition of adenylyl cyclase, K+ channel activation
17
Q
WHich muscarinic receptor opposes B1 receptor in heart
A
M2
18
Q
Most common muscarinic receptor
A
M3
19
Q
Where is M3 found in the body
A
Smooth muscle, exocrine and endothelium
20
Q
6 steps of ACh synthesis
A
1 choline transported into presynaptic nerve terminal by sodium dependent choline transporter (inhibited by Hemicholium)
2 ACh is synthesized from choline +acetyl CoA by enzyme choline acetyl transferase
3 ACh transported into storage vesicle by second carrier (VAT) (inhibited by vesamicol)
4 ACh binds to cholinoreceptors on post synaptic cell
5 Terminated by ACHe
6 Autoreceptors and receptors on pre synaptic nerve inhibit via Feedback mechanism
21
Q
Acetylcholine structure
A
COOH-CH2-CH2-N+-(CH3)3
22
Q
methacholine vs acetylcholine
A
CH3 added to BETA carbon in methacholine
23
Q
Acetylcholine vs Carbacol
A
COOH replaced by COON
24
Q
Bethanechol vs Acetylcholine
A
Beta carbon added and H2N added
25
Why is the methyl on B carbon in methacholine
Increases muscarinic binding and decreases nicotinic binding
26
PSNS symptoms of muscarinic agonist poisoning and why
Bradychardia, M2 decreases HR
Diarrhea and cramps, M3 contracts Walls
Bronchoconstriction, M2 and M3 lead to bronchoconstriction
salivation- M3 increases secretion
Visual disturbances- M3 in eye
27
SNS symptoms of muscarinic agonist poisoning and why
Sweating- a1 secretes sweat
Hypotension- uninnervated muscarinic receptors in blood vessel mediating vasodilation via Norepinephrine
28
Muscarinic agonist effect on heart
decrease in HR, conduction and force due to M2 activation
29
Muscarinic agonist effect on exocrine glands
Increases in secretion (Lachrymal, Tracheobronchial, salivary, digestive, sweat glands) sue to M3 activation
30
Muscarinic agonist effect on smooth muscle
M3 increases contraction while M2 inhibits relaxation
31
Muscarinic agonist effect on sphincters
M3 relaxation
32
stereoisomeric preference of cholinergic receptors
Only (+) sterochemistry binds well
33
How does pilocarpine treat glaucoma
M3 agonist leads to contraction of ciliary muscle
34
Why are antimuscarinic drugs contraindicated in glaucoma
M3 will be targeted by antimuscarinic drugs, we need M3 to contract ciliary muscle
35
When ACh is modified to carbachol what changes
ACHe sensitivity decreases, both still used for miosis in surgery and glaucoma
36
ACHe modified to pilocarpine ACHe sensitivity and change in use
Not sensitive, used in glaucoma
37
ACHe modified to bethanechol ACHE sensitivity and change in use
No ACHe sensitivity and is used for urinary retention and post op ileus
38
ACH and carbachol receptors
M & N
39
Bethanechol and pilocarpine receptors
M
40
varenicline
nicotinic
41
clinical use of pilocarpine
Glaucoma and dry mouth
42
Clinical use of bethanechol
GI stimulation or treatment of urinary retention
43
methacholine clinical use
Test for hyperactive airways
44
Carbachol clinical use
Ocular (surgery/glaucoma)
45
Varenicline (chantix) use
Smoking cessation
46
PSNS side effects Mnemonic
DUMBBELSS
Diarrhea, urination, miosis, Bronchoconstriction, bradycardia, Emesis, Lacrimation, salivation, sweating
47
mechanism of varenicline
Neuronal nicotinic partial agonist that blocks nicotine binding
48
Indirect acting ACHe inhibitor 3 examples (reversible)
Physostigamine, neostigamine, edrophonium
49
Irreversibe ACHe inhibitor
Organophosphate
50
Difference between the mechaism of direct vs indirect cholinergic agonist
Indirect do not bind to the receptor. They act as ACHe inhibitors, indirectly affecting the amount of ACh in the system. Direct agonists bind and act as muscarinic receptor agonists
51
Types of cholinesterases
Plasma cholinesterase and acetylcholinesterase
52
Difference between acetylcholinesterase and plasmacholinesterase
ACHe is located in synapse and it is selective to ACh. Plasma cholinesterase is located in the plasma and it is selective for ACh, SUX and procaine
53
Highest turnover rate of any enzyme
AChe
54
How is ACh hydrolyzed by ACHe
Esteric site in ACHe has serine that binds ester group on ACh and the anionic site binds the positive nitrogen. This breaks the bond.
55
How is ACHe reactivated after splitting ACh.
Water reactivates the enzyme
56
Use of the amino acids in esteric and anionic sites in catalysis
Lower activation energy needed to proceed with the reaction. Speed up the process.
57
Contrast the structures and molecular interactions of edrophonium with acetylcholinesterase
Edrophonium has a positive quaternary nitrogen and and OH group on the ring. Bind to anionic site and block ACh binding. Blocking ACHe activity
58
Is edrophonium reversible or irreversible? Covalent or non-covalent?
Reversible non-covalent
59
Contrast the structures and molecular interactions of stigamines with acetylcholinesterase
Carbamates that covalently modify AChE and are more SLOWLY hydrolyzed than ACh
60
Are carbamates reversible or irreversible? Covalent or non-covalent?
Reversible, covalent
61
What are stigamines
Substrates that are more slowly hydrolyzed than ACh. Do not cross BBB
62
Clinical use of edrophonium
Myasthenia gravis (MG) (very short acting drug)
63
Clinical use of pyridostigamine
Treatment of MG
Reversal of non-depolarizing neuromuscular blockade
Pretreatment for potential nerve gas exposure
64
How is pyridostigmine treatment for nerve gas exposure
Occupies ACHE so nerve gas has nowhere to go.
65
Clinical use of Neostigimine
Used for MG
reversal of non-depolarizing neuromuscular blockade
Post -op urinary retention
66
The only ACHe inhibitor that can cross the BB is
Physostigmine
67
physostigmine clinical use
Antidote to anti-muscarinic poisoning
68
Are organophosphates reversible or irreversible? Covalent or non-covalent
irreversible, covalent
69
What are the uses of organophosphates
For glaucoma
70
What are the organophosphates used in insectiside
Malathion and Diazinon
71
Why are malathion and diazinon rapidly inactivated in mammals
Insects have CYt P450 which metabolize p=5 to p=0, which is extremely toxic. mammals lack Cyt p 450
72
mechanism of organophosphates on ACHe
Organophosphates do not bind anionic site, the bind directly to esteric site and they form a covalent bond
73
Why is organophosphate to toxic
The phosphate covalent bond is extremely stable so it can not be hydrolyzed by water like normal. Water can not reverse hydrolyze it.
74
What is ageing in organophosphates
Ageing happens when a functional group on the organophosphate leaves and forms a negative phosphate. Once ageing happens it can not be detoxified.
75
What can we use to treat organophosphates before ageing happens?
Pralidoxime (2-PAM)
76
Does pralidoxime cross the BBB?
No
77
Since pralidoxime does not cross the BBB, what can we use along with it to treat organophospahte poisoning
Atropine
78
Atropine can not block________ receptors
Nicotinic
79
Why can alzheimers be cured by cholinesterase inhibitors
Alzheimers is loss of cholinergic neurons in brain. So it can be treated with cholinesterase inhibitors
80
How does donepezil slow progression of alzheimers? does it slow the progression of the disease?
Bind to anionic site and block ACh binding. NO it does not slow progressions only enhances cognitive ability
81
Donepezil reversible or irreversible? covalent or non-covalent?
reversible and non-covalent
82
How does rivastigamine (exelon) enhance cognitive ability in alzheimers
By increasing cholinergic function
83
How does Galantamine prevent alzheimers
it is a competitive AChE inhibitor
84
Which drug is an NMDA receptor antagonist to treat alzheimers
Memantine
85
What are NMDA receptors
NMDA receptors are found in the CNS where they are activated by glutamate in areas associated with cognition and memory
86
Why do glutamate regulators improve memory, attention, reason and language in alzheimers pateints
Neuronal loss in alzheimers may be related to increased activity of glutamate
87
Which two drugs are approved for moderate to severe alzheimers
Donepezil and memantine
88
physostigmine clinical use
Treats anticholinergic poisoning, glaucoma and alzheimers
89
organophosphate example. What does it treat
Echothiophosphate, treats glaucoma
90
parasympathomimetic side effects
DUMBBELSS
(diarrhea, urination, miosis, bronchoconstriction, bradycardia, emesis, lacrimation, salivation, sweating
91
treatment for cholinergic agent side effects and toxicity
cholinergic receptor antagonist (atropine)
92
Treatment for cholinergic agent side effects if irreversible
2-PAM (pralidoxime)
