Cholinergic Pharmacology Pt 2 Flashcards
1
Q
Cholinergic agonists
A
can interact directly with nicotinic or muscarinic receptors or both (agonists)
2
Q
parasympathomimetics
A
drugs producing only muscarinic effects
3
Q
Direct acting agonists
A
- Choline esters
- Naturally occurring alkaloids
- Ganglionic stimulating agents
4
Q
Carbachol
A
- nicotinic and muscarinic agonist
- choline ester
- longer lasting than but has both nicotinic and musarinc effects
5
Q
methacholine
A
- muscarinic agonist
- choline ester
- mostly muscarinic
- decrease nicotinic effect
- mostly cardiac
6
Q
Choline esters
A
- Carbachol, Methacholine, Bethanechol
- somewhat selective, resistant to action of cholinesterase (hydrolysis) competed to Ach so longer duration fo action
7
Q
Bethanechol
A
- choline ester
- muscarinic specific
- mostly GI and bladder
8
Q
Naturally occurring alkaloids
A
- muscarinic agonists
- muscarine and pilocarpine
9
Q
Ganglionic stimulating agents
A
- nicotinic agonists
- Nicotine
- Lobeline
10
Q
Ganglionic stimulating agents effects
A
- no therapeutic usage
- produce generalized stimulation of autonomic ganglia and mixed symp and parasympathetic responses
- blood pressure increase bc vasoconstriction bc symp ganglia stimuli and release epinephrine from adrenal medulla
- gut motility increase or decrease
- secretion salvia, bronchial mucus, and sweat increased
11
Q
Ganglionic stimulating agents effects at v high doses
A
- at v high doses cause blockade bc depolarization block, reflecting inactivation sodium channels and desensitization nicotinic receptors
12
Q
Anticholinergic/ cholinergic antagonists
A
muscarinic antagonists
13
Q
muscrinic antagonists
A
Atropine, scopolamine, homatropine
14
Q
Muscarinic antagonists fx
A
- competitive inhibitors at parasympathetic neuroeffect junctions
- can block nicotinic sites at V high concentrations
15
Q
muscarinic antagonisti are derived from
A
- alkaloids derived from deadly nightshade, jimosn weed, henbane or synthetic analogs of these products
- these are toxicologically important
16
Q
Pharmacological actions of muscarinic antagonists heart
A
- tachycardia deepening on vagal tone (horse + dog)
17
Q
Pharmacological actions of muscarinic antagonists blood vessels
A
- not innervated (most muscarinc receptor in blood vessels not innervated), little effect
- block vasodilation induced by choline esters
18
Q
Pharmacological actions of muscarinic antagonists GI and urinary tracts
A
decrease tone, motility, and secretions
19
Q
Pharmacological actions of muscarinic antagonists respiratory
A
increase luminal diameter, decrease bronchial secretions
- low doses stimulate respiration high doses inhibit
20
Q
Pharmacological actions of muscarinic antagonists eye
A
relax sphincter muscle of iris and colliery muscles of sense -> mydriasis and cycloplegia (loss ability to accommodate near vision)
-increased intraocular pressure bc canals of Schelmm blocked
21
Q
muscarinic antagonists and glaucoma
A
contraindicated
22
Q
Pharmacological actions of muscarinic antagonists sweating
A
impaired (sympathetic; horse is excetption bc horse is noradernergic sweater)
23
Q
Pharmacological actions of muscarinic antagonists salivation
A
reduced -> dry mouth
24
Q
Pharmacological actions of muscarinic antagonists CNS
A
- moderate doses stimulate medullary and higher centers
- higher doses -> restlessness, disorientation, delirium, hyperthermia (bc of effect on medulla and higher centers)
- even higher doses depression, coma, death bc medullary paralysis
25
Ganglionic blocking agents
- nicotinic antagonists (competirei antagonists)
- non-depolarizing
- block symp and parasympathetic ganglia -> loss tone to organ
- not used in vet med
26
non-depolarizing ganglionic blockers
- hexamethonium (H6) and trimethaphan
27
nonâ-depolarizaing ganglionic blockers fx
competitively compete with ACh for nicotinic receptor sites at ganglia and adrenal medulla
net response organ system depends on predominant tone
28
parasympathetic predominant tone
USE GBH (Use great big hug)
- Urinary bladder
- Salivary gland
- Eye (Iris and ciliary muscle)
- GI
- Bronchioles
- Heart
29
sympathetic predominant tone
AVS
- Arterioles
- Veins
- Sweat glands
30
types ganglionic blocking agensts
- non-depolarizing ganglionic blockers
| - depolarizing ganglionic blockers
31
depolarizing ganglionic blockers
- Nicotine and Lobeline
32
depolarizing ganglion blockers mechanism action
- cause initial sustained depolarization followed by receptor blockade bc inactivation Na+ channels and desensitized receptor
33
nicotine
- depolarizing ganglionic blocker
- also functions as depolarizing blocker at NMJ
- Has been used as incedicide and wildlife capture drug
34
depolarization ganglion blockers poisining
characterized by initial stimulation of ganglia followed by blockade, death caused by antagonist effects (at respiratory muscle NMJs)
35
prejunctional anticholinergics
- antagonists
- don't discriminate between muscarinic and nicotinic synapses/ junctions
- Hemicholinium
- Botulinus Toxin
- Opioids
- Local Anestethics
36
hemicholinium
- HC-3
- blocks choline transport system, little to no effect on choline acetyltransferase
- inhibition choline uptake -> limit synthesis ACh and decrease amount transmitter available for release
37
Botulinus toxin
- prevents release vesicular ACh at all cholinergic fibers
| - peripheral respiratory paralysis -> death
38
Opioids
- stimulate enkephalin receptors in gut -> inhibition of release of acetylcholine
39
Local Anestetics
- block sodium channels and inhibit generation and propagation of action potentials
40
Indirectly acting agonists
- cholinesterase inhibitors
- act on acetylcholinesterase and butyrycholinesterase
3 types:
1. Short acting/ reversible inhibitors
2. Carbamylating Esters
3. Phosphorylating Agents
41
Acetylcholinesterase (AChE(
- true or specific ChE
- normal metabolism for termination of cholinergic transmission
- AChE= generally membrane associated and found in nerve terminals in PNS, NMJ, on erythrocytes, and in gray matter of CNS
42
Butyrylcholinesterase (BuChE)
- aka serum or pseudo cholinesterase
| - generally soluble and found in blood serum and in white matter of CNS
43
Short acting reversible cholinesterase inhibitors
- indirectly acting agonists
| - Enrophonium (Tension)
44
Enrophonium
-aka Tension
the following also true for general short acting reversible cholinesterase inhibitors?:
- shortest acting AntiChE
- Combines with AChE primarily at cation binding site forming rapidly reversible enzyme-inhibitor complex
45
Enrophonium as diagnostic tool
- inhibit Ache get more Ach; if -> more weakness issue is too much Ach as opposed to not enough receptors
46
Carbamylating esters
- type indirectly acting agonist
- Physostigmine (Eserine)
- Neostigmine (prostigmine)
- Pyridostigmine
- all reversibly inhibit ChE for few hours
47
Phosphorylating agents
- aka organophosphates
- essentially irreversibly inhibit ChE and new enzyme must be synthesized for recovery to occur
- importantly clinically for toxicity and poisoning
48
Organophosphates characteristics
- v lipid soluble (except echothiophate)
- high vapor pressures (volatile)
- extremely toxic bc of above characteristics
49
types organophosphates
- phosphates and phosphothionates
50
phosphates examples
- DFP
- Paraoxon
- Dichlorvos
- Echothiophate
51
Phosphothionates
- Parathion
- Malathion
- these must be converted to phosphonates via P450 oxidation enzyme in liver to be active
52
Organophosphates used for
insecticides, pesticides, nerve gas
53
signs cholinesterase inhibitor poisoinig
DUMBBELSS
```
D- D+
U- urination
M- miosis
B- bronchospasm
B- bradycardia
E- Neuromuscular excitation
L- lacrimation
S- sweating
S- salivation
```
54
Pharmacological effects organophosphate poisoning muscarinic
- salivation
- miosis
- V+
- defication
- hyper motility GI tract
- urination
- bradycardia
- hypotension
- severe bronchoconstriction
- excess bronchial secretions
55
Pharmacological effects organophosphate poisoning nicotinic effects
- NMJ: skeletal muscle fasciculations, twitching... patalysis
- ganglia- not observed often, sympathetic usually predominates
56
Pharmacological effects organophosphate poisoning CNS
- ataxia, confusion
57
Pharmacological effects organophosphate poisoning cause of death
usually respiratory failure but bronchoconstriction and convulsions (CNS) can be life threatening too
58
Treatment of organophosphate poisoning
Atropine
| Pralidoxime
59
Atropine
- blocks muscarinic effects overwhelming the system
| - Give IV slowly
60
Pralidoxime
- aka 2-Pam aka protopam, obidoxime, or diacetyl monoxime
- Give IV prior to "aging" (phosphorylation)
- charged so will not cross blood brain barrier and will not reverse CNS effects
- useful for nerve agent poising like nerve gas
61
Mechanism of action organophosphates steps
1. Inhibition (phosphorylation)
2. Reactivation (dephospho rylation)
3. Aging
4. Regeneration/ Recovery
62
Inhibition (phosphorylation)
OP reacts covalently w/ active site AChE
63
Reactivation (dephospho rylation)
spontaneous reactivation can occur but is V slow; 2Pam can reactive enzyme prior to aging
64
Aging
loss of alkyl group, enzyme irreversibly inihibited and v resistant to regneration with 2-PAM
65
Regeneration/ Recovery
if enzyme not reactivated with 2-PAM new AChE must be synthesized only small fraction AChE need to be resynthesizes for full functional recovery
66
Acetylcholine esterase sites and 2-PAM
- anionic site and serine molecule= catalytic site where hydrolysis cleavage event occurs; carbonyl transferred to serine -> stable intermediate that stays bound for longer, site regenerated can accept acetyl choline molecule organophosphates have phosphate bind ot serine -> permanent inactivation of enzyme, pralidoxime (2-PAM) gets phosphate off serine and reactivates enzyme
