Cholinoreceptor antagonists Flashcards
14.10.2019
What qualities do agnoists/antagonists have?
Agonist: affinity and efficacy
antagonist: affinity but no efficacy
Does the drug stay attached for a long time?
No, mostly there is constant binding and unbinding which allows for competition.
Where are nicotinic receptors found?
- within the ganglions in the ANS
- on the adrenal gland
What are nicotinic receptor antagonists also called sometimes?
Ganglion blocking drugs
=> ganglion blocking effect in both the sympathetic and parasympathetic nervous system.
In what ways can nicotinic receptor antagonists work?
- by blocking the receptor
- by blocking the ion channel (so name is slightly wrong)
Name 2 nicotinic receptor antagonists
- hexamethonium (historical drug) -> better at blocking the ion channel
- trimetaphan -> better at blocking the receptor
Hexamethonium
- one of the first antihypertensives
- is better at blocking the ion channel
Trimetaphan
- at the moment most commonly used nicotinic receptor antagonist.
- fairly short acting
- better at blocking the receptor
- Hypotension during surgery - Short acting!
Use dependent block
- refers to the ability to block the ion channel, not the receptor.
- the more open the channels are the better the drug works
- more ACh (agonist) -> drug more effective because the
channels are open and allow entry - Here: incomplete block: the sodium can get through but not as effectively
Do hexamethonium and trimetaphan have affinity?
Hexamethonium: no, it is a physical blockade of the ion channel
Trimetaphan: Yes, it binds to the receptor
Which of the following effects would be observed at rest after treatment with a ganglion blocking drug? a) Increased heart rate b) Pupil constriction c) Bronchodilation d) Detrusor contraction e) Increased gut motility
a)
c)
Why do nicotinic receptor antagonists cause hypotension?
- act on kidney - Renin Angiotensin system
- act on the blood vessles and cause vasodilation - decrease in TPR leads to a decrease in BP
- act on the heart?
What are the effects of nicotinic receptor antagonists on the CVS?
- Hypotension (due to effects on kidney and blood vessles)
- also: affect the heart
What are the effects of nicotinic receptor antagonists on smooth muscle?
- Pupil dilation
- decreased G.I. tone
- bladder dysfunction
- bronchodilation
What do the effects of nicotinic receptor antagonists depend on?
Which system (PS or S) is dominant at that time. If PS is dominant then it blocks these effects.
What are the effects of nicotinic receptor antagonists on secretions?
- decreased secretions (sweat, saliva, GI secretions)
What is a clinical use of trimetaphan?
- Hypotension during surgery -> Short acting!
Alpha - bungarotoxin
- most powerful nicotinic receptor antagonist on the planet
- binds covalently to nicotinic receptor (true receptor antagonist) -> tissue would have to replace the receptor to restore function
- there are ANS effects
- Real issue: skeletal muscle!
Are there many venoms and toxins targeting the nicotinic receptor?
Yes.
What is the most powerful nicotinic receptor antagonist toxin on the planet?
alpha bungarotoxin
-> from the common krait (Bungarus carelueus)
What are venoms/toxins designed to do?
- affect your skeletal muscle so that you cannot move
Are nicotinic receptor antagonists used widely clinically?
- no
- because they are quite messt and have too many side effects
Where are muscarinic receptors found?
- at the end of PS nerves
- sweat glands
-> generally for blocking PS effects
What are the main muscarinic receptor antagonists?
- Atropine
- Hyascine
CNS effects of atropine?
- Normal dose – Little effect
- Toxic dose - Mild restlessness -> Agitation
(Less M1 selective)
CNS effects of Hyascine?
- Normal dose – Sedation, amnesia
- Toxic dose – CNS depression or paradoxical CNS excitation (associated with pain)
(Greater permeation into CNS. Influence at
therapeutic dose)
Why does Hyascine have greater permeation into the CNS?
- slightly more lipid soluble -> can enter deeper in the brain
Why do atropine and hyoscine have such different effects?
- not entirely sure
- maybe because Hyoscine is far more M1 selective (perhaps that is where the sedation comes form)
- Hyoscine is more lipid soluble and perhaps can penetrate deeper into the brain and have effects there.
Ophthalmic effects of muscarinic receptor antagonists?
- e.g. tropicamide
- allows for examination of the retina
- causes pupil dilation
- tropic amide paralyses a muscle
Uses of muscarinic receptor antagonists as anaesthetic pre-medicaiton?
- trachea and bronchioles - blocks constriction
- salivary glands - blocks copious, watery secretion
- heart - blocks decreased rate and contractility (hyptensive effect, protects HR)
+ Sedation (if the right antimuscarinic is used)
How can muscarinic receptor antagonists be used in motion sickness?
- motion sickness = sensory mismatch
- cholinergic nerve goes to vomiting center
- Hyoscine patch can help
Muscarinic receptor antagonists in PD?
- PD = loss of dopaminergic neurones that project from the substantial migrant
- M4R has a suppressive effect on D1R
- blocking the M4R makes D1R more responsive to Dopamine, upregulates D1R function
- reduces the effects of PD
Muscarinic receptor antagonists in respiratory disease?
- e.g. Asthma it obstructive airway disease
- blocks trachea and bronchiole constriction
- e.g. Ipratropium Bromide (more likely to stay in the lungs -> better side effect profile)
- e.g. Atropine
-> local effect wanted, side effects occur if it enters the systemic
Unwanted effects of muscarinic effector antagonsits
Hot as hell - decreased sweating, thermoregulation
Dry as a bone - decreased secretions
Blind as a bat - cyclopegia
Mad as a hatter- CNS disturbance
Cyclopegia
- paralysis of the ciliary muscle of the eye
- resulting in a loss of accommodation.
Muscarinic receptor antagonists in GI disease
- e.g. IBS
- decreases motility and tone
- decreases secretions
M3 receptor antagonists:
Reduce side effects
Which of the following drugs would you administer to treat an atropine overdose? a) Bethanechol b) Ecothiopate c) Hyoscine d) Physostigmine e) Pralidoxime
a) Bethanecol looks like ACh
b) Ecothiopate (irreversible, not used in practice)
d) Physostigmine: main drug used in atropine poisoning
How does Botulinum toxin work?
- blocks SNARE complex
- prevents ACh exocytosis
How can you treat atropine poisoning?
- with anticholinersterase (e.g. physostigmine)
- establishes competitive receptor agonism
Botulinum toxin facts
- most toxic protein known
- 1 gram of crystalline toxin, evenly dispersed and inhaled, would kill more than 1 million people
- 2 molecules are enough to shut down a nerve
- used commonly to remove wrinkles.
- prevents ACh exocytosis
How can you get atropine posioning?
- e.g. berries from atropine plant
SNARE complex
- involved in exocytosis
- blocked by botulinum toxin
