Cholinergic Agonists and Antagonists Flashcards
1
Q
Direct acting cholinergic agonists
A
Stimulate muscarinic or nicotinic receptors directly
Alkaloids and Choline esters
2
Q
Indirect acting cholinergic agonists
A
Increase the amount of ACh available to act on mAChR and nAChR
Stimulate effector organs
Stimulate (followed by depression) muscle and ganglia
Stimulate (sometimes depress) receptors in the brain
(Reversible and irreversible)
3
Q
Choline esters
A
Quaternary ammonium groups - not absorbed to CNS
Hydrolyzed by AChE: ACh > methacholine > carbachol > bethanechol (longest lasting)
MOA: direct cholinergic agonists
4
Q
Alkaloids
A
Uncharged tertiary - well absorbed, can go to CNS
Basic (acidification of urine helps elimination)
MOA: direct cholinergic agonists
5
Q
Muscarine (in mushrooms)
A
Quaternary amine
Highly toxic
Can enter CNS
6
Q
M1
A
Nerves
7
Q
M2
A
Heart, nerves, smooth muscle
8
Q
M3
A
Glands, smooth muscle, endothelium
Predominates in most organs
9
Q
M4
A
CNS (brain > SC)
10
Q
M5
A
CNS (brain > SC)
11
Q
Nm
A
Skeletal muscle and NMJ
12
Q
Nn
A
Postganglionic cell body, dendrites, CNS (SC > brain)
13
Q
IP3 and DAG cascade
A
M1, M3, M5
14
Q
Inhibition of cAMP production
A
M2 and M4
15
Q
Activation of K+ channels
A
M2
16
Q
Na+ and K+ depolarizing ion channel
A
Nm and Nn
17
Q
Skeletal muscle receptors
A
ONLY nAChR (nicotinic) Binding these receptors with agonist leads to depolarizing blockade
18
Q
Depolarizing blockade
A
Binding AChR with greater affinity cause disorganized depolarization and doesn’t allow muscle cell to repolarize
Leads to flaccid paralysis/muscle relaxation
Ex. Succinylcholine
19
Q
Prolonged presence of nAChR agonist
A
Abolishes effector response - postganglionic neuron stops firing
Skeletal muscle cells relax
20
Q
General parasympathetic effects
A
Pupil constriction, accommodation, salivation, bronchiole constriction, lung secretions, gastric secretions, increase motility, diarrhea, urination
**INCREASE with agonist
21
Q
PS and Eye
A
Constrict sphincter, increase aqueous humor flow
22
Q
PS and Cardio
A
Only M2 mAChR
Reduce peripheral resistance
Atria > Ventricle - decrease rate and contractile strength
Release EDRF - relax SM around blood vessels
Small dose - slight BP decrease, increase HR reflex
Large dose - bradycardia and hypotension
23
Q
PS and GI
A
Increase glandular secretions (salivary and gastric especially)
M3 - direct contraction
M2 - indirection contraction
Sphincter relaxation
24
Q
PS and GU
A
Sphincter relaxation
Increase voiding
25
CNS - excitatory mAChRs
Increased cognitive function
26
CNS - inhibitory mAChRs
Tremors, hypothermia, and analgesia
27
CNS - nAChR activation
Dose dependent
| Can have severe CNS consequences
28
PNS - nAChR activation
Simultaneously fire parasympathetics and sympathetics
Cardio - sympathetic dominates
GI/GU - parasympathetic dominates
29
Direct agonist use in Eye
Glaucoma - Increase flow via contraction (Replaced by beta blockers and prostaglandin derivatives)
Accommodative estropia - Cross eyed from accommodation error
30
Direct agonist for GI/GU
```
Bethanechol:
Increase tone of stomach and intestines
Increase tone of lower esophageal sphincter
Fix urinary retention
**Beware of bowel obstruction
```
Pilocarpine and Cevimeline:
Increase salivary secretions
31
Muscarinic direct agonist overdose
Treat with Atropine
| N/V/D, urination, salivation, sweating, cutaneous vasodilation, bronchial constriction
32
Muscarinic direct agonist contraindications
**Asthma
Hyperthyroidism
Coronary insufficiency
Acid-peptic disease
33
Nicotinic direct agonist acute toxicity
```
Nicotine only common source
CNS simulation
Skeletal muscle depolarization blockade
Respiratory paralysis
HTN and cardiac arrhythmias
Treat with atropine and diazepam (no muscle recovery)
```
34
Acetylcholine use
Intraocular during surgery
| Rarely systemically given
35
Methacholine use
Treat airway hyperreactivity if no asthma
| Rarely used due to risk of bronchospasm
36
Bethanechol use
Urinary retention and heartburn
**selective mAChR
Little cardiovascular effect
37
Carbachol
Glaucoma or miosis during surgery
38
Cevimeline
Treat xerostomia
| *Metabolized with p450 pathway and eliminated in urine
39
Pilocarpine
Treat xerostomia
Glaucoma or miosis as well
**selective mAChR
40
Varenicline (Chantix)
```
Smoking cessation
**selective nAChR alpha4beta2 in brain
Reduce craving and withdrawal
90% eliminated unchanged in urine
Potential psych side effects :(
```
41
Indirect agonists MOA
Inhibiting cholinesterase and allowing more ACh to interact with receptors therefore increase parasympathetic effects
42
Alcohol AChE Inhibitors
Positively charged quaternary
Reversible binding to AChE (electrostatic interactions and H bonding)
Ex. Endrophonium
43
Carbamic acid esters AChE inhibitors
Positive or neutral, quaternary or tertiary
Reversible binding to AChE (covalent bonds that are later hydrolyzed)
**Ex. Neostigmine, pyridostigmine, physostigmine
44
Organophosphate AChE inhibitors
Insecticides, nerve gases
Neutral and lipid soluble - CNS toxicity, readily absorbed everywhere including skin and lungs
Irreversible binding to AChE (very stable bond, aging increase phosphorus-enzyme bond)
Little excretion/metabolism
**Need to regenerate AChE as well as counteract ACh overload
45
Quaternary and charged AChE inhibitors
```
Poor absorption, insoluble in lipids (NO CNS)
Parenteral preferred
Act preferentially at NMJ
Duration determined by complex stability
**Neostigmine, pyridostigmine
Edrophonium, echothiophate, ambenonium
```
46
Tertiary and uncharged AChE inhibitors
Well absorbed - including CNS
More toxic
**Physostigmine
Donepezil, tacrine, rivastigmine, galantamine
47
Eye, GI, GU and Respiratory + AChE inhibitors
Same effect as direct cholinomimetics
48
Cardio and AChE inhibitors
Parasympathetic tone dominates
| Modest bradycardia, fall in CO, little or no decrease in BP
49
NMJ and AChE inhibitors
Therapeutic levels can increase strength of contraction
| Too much can cause blockade
50
Reversal of pharmacologic paralysis using AChE inhibitors
Reverse effects of nondepolarizing nerve blockers
**Neostigmine and edrophonium
Treat atony of GI and GI
51
AChE inhibitor and Glaucoma
Same effect as direct agonist but not commonly used
52
AChE inhibitor and dementia
Tacrine came first
Donepezil, rivastigmine, galantamine, and physostigmine preferred
Parkinsonian dementia also benefits
53
Compounds with anticholinergic properties
Atropine, antihistamines, tricyclic antidepressents, sleep aids, cold preparations
54
Antidote for anticholinergic compounds
AChE inhibitor
| **Physostigmine (can cross BBB)
55
AChE inhibitor with nondepolarizing neuromuscular blocking agents
Blockade will diminish
| Exception: mivacurium
56
AChE inhibitor with Succinylcholine
Enhance phase 1 block
| Antagonize phase 2 block
57
AChE inhibitor with direct agonists
Enhance the effects
58
AChE inhibitor with beta blockers
May enhance bradycardic effects
59
AChE inhibitor with systemic corticosteroids
May enhance muscle weakness
60
AChE inhibitor acute intoxication
Increased parasympathetics
Ex. pesticides, veterinary vermifuges
Ingestion - GI first
Skin - sweating and muscle fasciculations
Lipid soluble agents have serious CNS involvement
TOD can be quick
61
AChE inhibitor antidote
Atropine
Cholinesterase regenerators needed for NMJ
Can add benzodiazepine (anticonvulsant) as well
62
Cholinesterase regenerator
Pralidoxime
| Must be given before aging occurs
63
AChE inhibitor prophylaxis
Pyridostigmine in low doses
64
Antinicotinic drugs
Effect NMJ and ganglia
| Not as clinically useful
65
mAChR blockers
Parasympatholytic - block the effects of parasympathetic discharge
**Think everything opposite of parasympathetics
Prototype - Atropine
66
Tertiary antimuscarinics
Used for eye or CNS
More readily absorbed and distributed
Atropine, tropicamide, benztropine
67
Quaternary antimuscarinics
Elicit effects in periphery
| Ipratropium, glycopyrrolate
68
Metabolism/excretion of antimuscarinics
Effect usually declines rapidly
Excreted in the urine
Except - long lasting in the eye
69
MOA of atropine
Reversible antagonist of mAChRs
Most sensitive are salivary, bronchial, and sweat (gastric is the least sensitive)
**Does not distinguish between types of receptors
70
CNS and antimuscarinics
Low dose: minimal stimulant effect on CNS, mild sedative to brain
Reduce Parkinson tremor
Reduce motion sickness (scopolamine)
71
Eye and antimuscarinics
Dilate, can't accommodate, reduce tears
72
Cardio and antimuscarinics
Mild tachycardia
Prevent CV effects of direct muscarinic agonists
Low dose - initial bradycardia (reflex)
High dose - tachycardia (vagal block)
73
Respiratory and antimuscarinics
Bronchodilation and reduced secretion
74
GI and antimuscarinics
Decreased saliva
Decreased gastric secretions to a lesser degree
Gastric emptying is prolonged and GI transit time prolonged
75
GI and antimuscarinics
Treat urinary incontinence - slow voiding, relax muscle
76
Sweat glands and antimuscarinics
Reduce thermocontrol/sweating even though they are only innervated by sympathetics
*Atropine fever
77
Antimuscarinics and Parkinsons
Reduce tremor
| Benztropine, trihexyphenidyl, procyclidine
78
Antimuscarinics and Motion sickness
Antihistamines
| *Scopolamine
79
Antimuscarinics in anesthesia
Atropine blocks vagal reflexes
| Atropine paired with neostigmine when reversing skeletal muscle relaxation (block increase in parasympathetics)
80
Antimuscarinics in opthalmologic disorders
Mydriasis for long periods
| Prevent synechia formation in uveitis and iritis
81
Antimuscarinics in respiratory disorders
Treat asthma and COPD
Ipratropium
**Tiotropium
82
Antimuscarinics in cardio disorders
Rarely used
| Can alter vagal reflex
83
Antimuscarinics and GI disorders
Treat traveler's diarrhea
| Can be combined with opioid agent to discourage abuse (Lomotil)
84
Antimuscarinics and urinary urgency
Oxybutynin
Trospium
Darifenacin, solifenacin, and tolterodine - selective for M3, less xerostomia and constipation
85
Cholinergic poisoning
No effective treatment for muscarinic effects
| Treat with antimuscarinic and AChE regenerator
86
Pralidoxime
Cholinesterase regenerator
| Charged - only works at NMJ
87
Rapid onset cholinergic poisoning
Adequately treated with Atropine
| Shows signs of DUMBBELLS
88
High concentration of atropine
Dry, blind, red, mad, hot
89
Atropine overdose
Treat with cholinesterase inhibitor
| or treat symptomatically
90
Antimuscarinic contraindications
Glaucoma
History of prostatic hyperplasia (risk for acute urinary retention)
Acid peptic disease (slowed emptying increases discomfort)
91
Pirenzepine
M1 selective antimuscarinic used in other countries for peptic ulcer disease
92
Ganglion blocking drugs
Synthetic amines
*Mecamylamine - can cross BBB
Blocks both - Parasympathetic tone dominates
Use is infrequent
