#11 Cholinergic drug Pharmacology Flashcards
(72 cards)
1
Q
Cholinergic neurotransmission is important in the ___ and ____.
A
CNS and PNS
2
Q
What are the 2 types of Cholinergic receptors?
A
Nicotinic and Muscarinic
3
Q
What do Nicotinic Cholinergic Receptors do?
A
- Bind nicotine
- Ligand activated ion channel (Local depolarization at post synaptic membrane due to Na+ influx)
- Receptors contain 5 subunits and bid two molecules of agonist.
4
Q
Tell me about Skeletal muscle Nicotinic cholinergic receptors….
A
Molecular biology is fairly simple:
Adult skeletal muscle: 2 alpha1 (bind ACCh) and one each of Beta, E and Sigma.
Fetal Skeletal muscle: 2 alpha1 (bind ACCh); one each of Beta, Gamma and Sigma
5
Q
Tell me about CNS Nicotinic cholinergic receptors…
A
Molecular biology is complicated:
- Alpha2-alpha7 subunits
- Beta2-Beta4 subunits
(many combinations of 5 subunits: potential for complex pharmacology)
6
Q
What do Muscarinic Cholinergic receptors do?
A
- Bind Muscarine
- G protein coupled receptors.
- There are 5 different types of muscarinic receptors (M1-M5)
7
Q
________ are linked to G-alpha-q.
A
M1,M3,M5
8
Q
______ are linked to G-alpha-i.
A
M2 and M4
9
Q
What do the M1, M3, M5 receptors do?
A
Link to G- Alpha-q and activate DAG and IP3 signaling
10
Q
What do the M2 and M4 receptors do?
A
Link to G-alpha-i and inhibit adenylate cyclase
11
Q
Describe direct acting of Cholinergic agonist…
A
Bind to muscarinic or nicotinic AcCh receptor or both.
12
Q
Describe indirect acting of Cholinergic agonist…
A
Cholinesterase inhibitor
13
Q
__________ has a profound effect on the duration of action of cholinergic agonists.
A
Hydrolysis by Cholinesterase
14
Q
Describe the Hydolysis of acetylcholine…
A
Hydrolyzed rapidly, shortest duration of action
* Non selective between Muscarinic and Nicotinic
15
Q
Describe the hydrolysis of Methacholine…
A
Hydrolyzed slower, somewhat longer duration of action
*Muscarinic selective
16
Q
Describe the hydrolysis of Carbachol…
A
Not hydrolyzed, longer duration of action
*Mainly Nicotinic selective
17
Q
_______ agonists are much more clinically relevant.
A
Muscarinic
18
Q
What are the steps in neuromuscular transmission? 4 steps
A
- Activation of nicotinic AcCh receptors
- Local depolarization leads to action potential
- Post-synaptic depolarization leads to release of Ca++ from the Sarcoplasmic reticulum.
- Releasee of Ca++ from the sarcoplasmic reticulum leads to muscle contraction.
19
Q
What do Odd numbered muscarinic receptors do?
A
Activate phospholipase C and promote Ca++ release
20
Q
What do Even numbered muscarinic receptors do?
A
inhibit adenylatecyclase
21
Q
_______ receptors on the sphincter muscle mediate pupil contraction and ciliary muscle contraction.
A
M3
22
Q
Cardiac muscle contains _____ receptors.
A
M2
23
Q
Activation of M2 receptors in the heart do what?
A
Reduce cardiac output
24
Q
Vascular endothelial cells express _____ receptors.
A
M3
25
What does activation of M3 receptors in vascular endothelium do?
Produce vasodilation
26
What is the mechanism for vasodilation via M3 receptors?
1. activation of M3 receptors increase Ca++ in endothelial cells.
2. Ca++/Calmodulin activate NOS to produce NO.
3. NO travels to the smooth muscle cell, enhances cGMP production. leading to muscle relaxation (Enhances myosin light chain phosphatase activity)
27
Which receptors mediate the bronchial muscle contraction?
M3
28
What are the Gastrointestinal effects of Muscarinic receptor activation?
Mostly contractile, yet sphincter muscle is relaxed by M2
29
What are the secretory gland effects of muscarinic receptor activation?
M3 activation stimulates release of glandular contents from secretory glands including salivary glands.
30
What are urinary tract effects of muscarinic receptor activation?
M3 receptors mediate detrusor muscle contraction (aids in voiding the bladder)
31
What are the CNS effects of muscarinic receptor activation?
Couples and not part of common therapeutic strategies.
32
Describe the Pharmacokinetic of cholinergic Agonists regarding amines....
Tertiary amines are better absorbed than Quaternary amines!
| *TEST QUESTION WITH STRUCTURES?
33
What are the Adverse effects of Muscarinic Agonists?
Adverse effects primarily consequences of receptor stimulation:
- SLUD response: salvation, lacrimation, urinination, deification
- Cardio pulmonary effects if intravenous or intramuscular administration is used.
34
There are increased risks of adverse response with muscarinic agonists in....
```
Patients with asthma (bronchoconstriction)
Cardiovascular disease(reduced output)
Ulcers (Lacrimation)
```
35
How are muscarinic agonist typically administered?
Topically is favored
36
What is Anticholinesterase?
AchE is an enzyme that hydrolyzes Ach into Acetic acid and choline.
37
What is the Method of action of Anticholinesterase?
Drugs work by inhibiting the enzyme Acetylcholinesterase which prevents hydrolysis of Ach thus increasing their concertino in the synapse which promotes more Ach action. Since they promote Ach activity without binding to any receptor they are also called indirectly acting cholinergic agonists.
38
Some "Reversible" anticholinestaerases are slowly hydrolyzed by _______.
Cholinesterase
39
What are the main two reversible anticholinesterases?
Physostigmine (tertiary amine)
Neostigmine (quaternary amine)
40
T or F, some anticholinesterases act in a rapidly reversible manner and are not hydrolyzed at all.
True, Ambenonium chloride does this.
41
Organophsphate anticholinesteases act in a completely ______ manner.
Completely irreversible.
* They covalently react with the enzyme and are not hydrolyzed.
* They are only used to kill things!
42
What are the pharmacologic effects of Anticholinesterases?
1. In general, Anticholinesterases produce effects that are similar to the direct acting cholinergic agonists (increase the conc. of acetylcholine at effector site).
* The greater the cholinergic stimulation at the site, the greater the effect. (smooth muscle of ocular system, GI tract, urinary bladder are major sites)
2.Can also produce vasodilator effects through autonomic ganglia. (initially prolong duration and then promote desensitization of nAcCH Receptor)
43
What does Physostigmine (tertiary amine and Anticholineserase) do?
Can produce vasodilatory effects through action in the CNS.
44
What are some of the therapeutic uses of Cholinergic Agonists and Anticholinesterases?
1. Glaucoma (therapy = stimulating the musculature of the iris and colliery body, increasing outflow or deceasing formation of virtuous humor = decreases ocular pressure.)
2. Xerostomia (Therapy = pilocarpine and cevimeline (muscarinic agonists) frequently used to treat dry mouth.)
3. Reversal of Neuromuscular block = Anticholinesterases used to terminate the neuromuscular block of curare-like agents.
4. Anticholinesterases used in treatment of M. Gravis (disease with antibodies directed against nicotinic AcCh receptors)
5. Anticholinesterases that cross blood-brain barrier are used to improve cognitive function in Alzheimer's patients.
45
What can be used to treat dry mouth?
5-10mg Pilocarpine 3x a day (side effects = sweating, chills, nausea and dizziness)
Cevimeline 30mg, 3x a day = less side effects than pilocarpine.
46
______ and _____ are natural Anti-muscarinic drugs.
Atropine and Scopolamine *Both tertiary amines that can be absorbed and cross the blood brain barrier.
47
______ is a quaternary amine of scopolamine.
Methscopolamine
| *Will not cross Blood-brain barrier!
48
What clinical features affect the choice of an anti-muscarinic drug?
Whether your target is CNS or peripheral tissues.
49
In general, treatment with an anti-muscarinic drug places the target under control of ____________.
Sympathetic nervous system
*Exception is the sweat gland where signals from the symp. and parasymp. act upon muscarinic receptors at the targets and are both blocked by the Anti-muscarinic.
50
What are the pharmacologic effects of Anti-muscarinic drugs?
- Cause pupil dilation
- paralysis of accommodation
* intraocular pressure not significantly affected except in ht case of narrow angle glaucoma, in which anti-muscarinics could cause a serious rise in pressure.
51
Anti-muscarincs are used to produce _______ and diminish mucus production to treat ________.
produce bronchodilation to treat COPD.
52
Anti-muscarinics inhibt _______.
Sweating, and can elevate body temperature.
53
What are the Gastro-intestinal effects of Anti-muscarinics?
They generally inhabit motility. Only inhabit gastric secretions at very high concentrations.
*Anti-muscarinincs Block parasympathetic mediated secretion.
54
What are the effects of Anti-muscarinics on the heart?
- Mild bradycardia often seen
| - *Due to the selective inhibition of pre junctional M2 receptors that limit AcCH release.
55
What are the effects of Anti-muscarinics on the Urinary tract?
Detrusor muscles are relaxed by atropine. Sphincter and trigone muscle are contracted by atropine. These changes cause urinary retention.
56
What are the 5 Therapeutic uses of Anti-muscarinics?
1. Dilate the pupils for ophthalmologic procedures,
2. Treatment of COPD (quaternary amines via inhalation)
3. Diminish salivary secretion before oral procedures.
4. Anti-spasmodics, and anti-ulcer agents (Not very useful b/c of side effects)
5. Antidode to anti-cholinesterases.
57
What are the adverse side effects of atropine?
Increased intraocular pressure, ventricular fibrillation, tachycardia, dizziness, nausea, dry mouth, blurred vision, extreme confusion and hallucinations...
58
What is Anti-cholinergic toxidrome?
A mild set of symptoms:
| warm, dry skin from decreased sweating, blurry lesion, vasodilation and effects on the CNS.
59
How do drugs act at Nicotinic receptors? (3 steps)
1. Transmission of sympathetic and parasympathetic nerve impulses mediated by nicotinic AcCh receptors...
2. Nicotinic receptors are important mediators in the CNS.
3. Post synaptic transmission of Nerve impulse at skeletal muscle mediated by Nicotinic AcCh receptors.
60
What will Nicotine do in the CNS?
Penetrate the BBB and produce CNS effects feeling of week being and decreased irritability.
61
What will Nicotine do in the ANS?
Acts on sympathetic and parasymp. ganglia causing mild cardiovascular stimulation and increased GI activity.
62
Are Ganglionic AcCh receptor blockers used often?
No! Due to too many side effects.
63
Nicotinic AcCh receptors are important mediators in _________.
The CNS
64
_______ that can cross the BBB are used to treat cognitive disfunction in Alzheimer's.
Anticholineresteases
65
Postsynaptic transmission of nerve impulses at skeletal muscle are mediated by _____.
Nicotinic AcCh receptors
66
What happens when there is continued used of a cholinergic agonist binding to the AcCh receptor?
Initially there is opening of the Ion gate (allowing Na+) yet after a while, there is desensitization of the receptor.
67
What do Non-depolarizing blockers do?
These are competitive antagonists of acetylcholine
68
_______ is a depolarizing blocking agent.
Succinylcholine *Has a more rapid onset of action and a shorter duration of action than the non-depolarization blocking agents.
69
How does succinylcholine (depolarizing blocking agent) exhibit its effects?
In 2 phases:
1. Initially it activates AcCh receptors, but the chronic depolarization at the muscle endplate potential leads to activation of voltage-gated Na+ channels and flaccid paralysis.
2. After a while, the chronic exposure to succinylcholine leads to desensitization of AcCh receptor. This is the phase 2 block. Because it is subject to hydrolysis by plasma and liver cholinesterases it has a shorter duration of action than other blocking agents.
70
What is the pharmacologic effects of neuromuscular blocking agents?
Induces flaccid paralysis
71
What are the theraputic uses of neuromuscular blocking agents?
Endotracheal intubation
- Succinylcholine is the the most rapid and drug of choice.
- Rocuronium (Non-depolarizing is second choice)
Non surgical procedures such as bronchoscopy and relaxing vocal cords.
72
What are the adverse side effects of Neuromuscular blocking agents?
Respiratory Failure is the most significant one.
- Arrhythmias
- Bradycardia
