7 - Cholinoceptor antagonists Flashcards
Define Affinity.
The strength with which an agonist binds to a receptor
Define Efficacy.
Once the drug has bound to the receptor, the ability of the drug to transduce a response and activate intracellular signalling pathways is its efficacy
What is the difference between agonists and antagonists in terms of affinity and efficacy?
Agonists – have affinity and efficacy
Antagonists – have affinity but NOT efficacy
What are the 2 groups of cholinoreceptors and where are they found?
- nicotinic - found in ALL autonomic ganglia
- muscarinic - found at parasympathetic effector organs and on sweat glands in the SNS
What are the few clinically useful type of nicotinic receptor antagonists called and how do they block the receptor?
Ganglion Blockers
These block the ion channel itself, thus preventing the ions from moving through the pore (it doesn’t block the receptor but the channel itself)
Give two examples of ganglion blocking drugs.
Trimethaphan
Hexamethonium
Compare the affinity of nicotinic receptor antagonists and receptor blocking drugs
NOTE: all drugs can have both effects
NRAs - have affinity
GBDs - no affinity
What does ‘use-dependent block’ mean?
The drugs work most effectively when the ion channels are open.
This means that the more agonist is present at the receptor, the opportunity the antagonist has to block the channel, thus they are more effective when there is more agonist present
NOTE: these drugs can only result in an incomplete block
What determines the effect of ganglion blockade in a tissue?
It depends on which limb of the autonomic nervous system predominates in the particular tissue (at the time e.g. at rest)
Which tissues are sympathetic dominated?
Vasculature
Kidneys
What is the overall effect of ganglion blockade in terms of loss of sympathetic dominance?
Hypotension The (sympathetic-mediated) vasoconstriction is taken away and the ability of the kidneys to increase renin secretion and increase sodium and water reabsorption is also taken away
Which tissues are parasympathetic dominated?
Lungs - causes bronchoconstriction Eyes - maintains partial pupillary constriction at rest Bladder, ureters and GI tract Exocrine functions (secretion)
What would the effect of ganglion blockage be on these parasympathetic dominated tissues?
Bronchodilation Pupil dilation (blurred vision) Bladder dysfunction Loss of GI motility and secretions Decrease in exocrine secretion
What is hexamethonium?
NOTE: more of a channel blocker than a receptor antagonist
It is a ganglion blocker that was the first anti-hypertensive
It has a generalised action and had loads of side-effects
What is trimethaphan and when is it used?
NOTE: more of a receptor antagonist than a channel blocker
The only ganglion-blocking drug that is still in clinical use
It is very potent and used when a controlled hypotension is needed in surgery.
It is very short acting.
In what types of chemicals are nicotinic receptor blockade antagonists found?
Toxins and venoms
How do rector blockade antagonists bind to receptors and how does this make them different from most therapeutic drugs?
These are irreversible – they bind covalently and prevent the ion channels from opening
Give an example of a nicotinic receptor blockade antagonist.
Alpha-bungarotoxin (common krait snake venom)
What are the effects of alpha-bungarotoxin?
targets the skeletal muscle causing paralysis of them and the diaphragm ——> suffocation and death
What are the targets of muscarinic receptor antagonists?
Parasympathetic effector organs and sweat glands
Give four examples of muscarinic receptor antagonists.
Atropine
Hyoscine
Tropicamide
Ipratropium Bromide
What effect do muscarinic receptor antagonists have on the CNS?
(be specific and name the drugs)
The parasympathetic nervous system is important in the CNS in terms of attention, memory and certain sleep pathways.
At low doses atropine can cause mild restlessness
At low doses hyoscine can be a good sedative
At high doses, both drugs can cause CNS agitation
(atropine - excitatory
hyoscine - more sedating)
What is tropicamide used for?
It is used to dilate the pupil to observe the retina (it is used to examine the eye)
What is an important use of muscarinic receptor antagonists with regards to surgery? Why is it useful in this circumstance?
Anaesthetic premedication
It causes dilation of the airways so it is easier to intubate the patient
It reduces secretions thus reducing the risk of aspiration
It also knocks out the effect of the parasympathetic nervous system in decreasing heart rate and contractility (because general anaesthetics will decrease heart rate and contractility anyway)
What can hyoscine be used to treat? Explain how.
Motion Sickness
Muscarinic receptors are important in relaying information from the labyrinth in the inner ear to the vomiting centres.
Muscarinic receptor antagonists can reduce the flow of information from the labyrinth to the brain thus reducing the nausea.
What degenerative disorder of the central nervous system can be treated by muscarinic receptor antagonists?
Explain how.
Parkinson’s Disease
In Parkinson’s disease, many of the nigro-striatal dopamine neurones are lost (these are important in the fine control of movement)
Musarinic receptors have a negative effect on this dopamine signalling so by blocking the muscarinic receptors (knocking out the M4 receptors) you can remove this inhibitory effect and allow the remaining dopaminergic neurones to fire at the maximum rate.
Explain the use of muscarinic antagonists in treating asthma and COPD.
Ipratropium Bromide is used to treat asthma and COPD
It removes the parasympathetic mediated bronchoconstriction
Explain the role of muscarinic antagonists in treating irritable bowel syndrome.
Muscarinic antagonists will reduce smooth muscle contraction, gut motility and gut secretions thus relieving the symptoms of IBS.
State some general unwanted side-effects of muscarinic antagonists.
- Hot as hell (decreased sweating affects thermoregulation)
- Dry as bone (due to reduced exocrine secretions)
- Blind as a bat (due to effects on the accommodation ability of the ciliary muscle – cycloplegia)
- Mad as a hatter (high doses will cause CNS agitation, restlessness, confusion etc.)
How do you treat muscarinic receptor antagonist poisoning (e.g. atropine poisoning)?
Give an anticholinesterase e.g. physostigmine
Describe how botulinum toxin causes paralysis.
It binds to the SNARE complex and prevents the fusion of the vesicles, containing acetylcholine, with the presynaptic membrane thus preventing the release of acetylcholine from the nerve terminal.
This leads to muscle paralysis.
State the overall effects of ganglion blocking drugs on a subject at rest (a type of nicotinic receptor antagonists).
Hypotension Pupil dilation Bronchodilation Bladder dysfunction Decreased GI tone Decreased GI secretions
