Cholinoceptor Antagonists Flashcards
Define Affinity.
The strength with which an agonist binds to a receptor
Define Efficacy.
The ability of a drug to transduce a response + activate intracellular signalling pathways
What is the difference between agonists and antagonists in terms of affinity and efficacy?
Agonists: have affinity + efficacy
Antagonists: have affinity but NOT efficacy
Where are nicotinic receptors found?
In ALL autonomic ganglia
At neuromuscular junctions
Where are muscarinic receptors found?
At parasympathetic effector organs + on sweat glands
What are the few clinically useful nicotinic receptor antagonists called and how do they block the receptor?
Ganglion Blockers
Either block receptor or block the ion channel itself, thus preventing the ions from moving through the pore (usually an incomplete block, just reduces amount getting through)
Give 2 examples of nicotinic receptor antagonists
Hexamethonium (better at blocking ion channel)
Trimethaphan (better at blocking receptor)
What does ‘use-dependent block’ mean?
Drugs work most effectively when the ion channels are open.
The more agonist present, the more opportunity the antagonist has to block the channel, thus the more useful + effective the drugs can be
What determines the effect of a nicotinic receptor antagonist in a tissue?
Which limb of the ANS dominates in that particular tissue (at that time e.g. at rest). You observe a loss of function of that systems effects.
In which tissues is the SNS dominant?
Vasculature
Kidneys
What is the overall effect of nicotinic receptor antagonism in terms of loss of sympathetic dominance?
Hypotension
SNS vasoconstriction is lost: drug allows dilation, TPR decreases, BP decreases
SNS secretion of renin is lost, thus can’t increase Na+ + water reabsorption, so blood volume decreases
Which tissues are parasympathetic dominated?
Lungs: causes bronchoconstriction
Eyes: maintains partial pupillary constriction at rest
Bladder, ureters + GI tract
Exocrine functions
List 5 effects of nicotinic receptor antagonism on PNS dominated tissue?
Bronchodilation Pupil dilation (blurred vision) Bladder dysfunction Decreased GI motility + secretions Decrease in exocrine secretion
What is hexamethonium?
Nicotinic receptor antagonist- the 1st anti-hypertensive
It has a generalised action + many side-effects
What is trimethaphan and when is it used?
Nicotinic receptor antagonist in clinical use
It is very potent + used when a controlled hypotension is needed in surgery.
Very short acting.
In what types of chemicals are nicotinic receptor blockade antagonists found?
Toxins
Venoms
How do many venom nicotinic receptor antagonists have their effect?
Bind covalently (irreversibly) + prevent ion channels from opening. Main target= skeletal muscle, cause paralysis
Give an example of a nicotinic receptor antagonist.
Alpha-bungarotoxin
What are the targets of muscarinic receptor antagonists?
Parasympathetic effector organs
Sweat glands
Give 4 examples of muscarinic receptor antagonists.
Atropine
Hyoscine
Tropicamide
Ipratropium Bromide
What are the effects of a normal and toxic dose of Atropine on the CNS?
Normal: little effect
Toxic: CNS agitation
What is tropicamide used for?
To dilate the pupil to observe the retina
What is an important use of muscarinic receptor antagonists (e.g. Tropicamide) with regards to surgery? Why is it useful in this circumstance?
Anaesthetic premedication
Blocks bronchoconstriction= dilated airways (good for inhaling anaesthetic)
Reduces secretions: reduces risk of aspiration
Blocks PNS effect of decreasing HR + contractility (because GA will decrease HR + contractility anyway)
Sedative effect
What can hyoscine be used to treat? Explain how.
Motion Sickness
Muscarinic receptors relay posture + balance info. from the labyrinth in the inner ear to the vomiting centres.
Hyoscine reduces the flow of info. from the labyrinth to the brain thus reducing nausea.
What degenerative disorder of the central nervous system can be treated by muscarinic receptor antagonists? Explain how.
Parkinson’s Disease
In PD: nigro-striatal dopamine neurones are lost (important in fine control of movement)
Musarinic receptors have a negative effect on dopamine signalling, so by blocking the M4 receptors you remove this inhibitory effect + allow remaining D1 receptors to be more responsive
Name the muscarinic antagonist used in treatment of asthma and COPD and explain its MOA
Ipratropium Bromide is used to treat asthma + COPD
Removes the parasympathetic mediated bronchoconstriction.
We try to localise effects by making this drug polar to keep it in the lungs
How do muscarinic antagonists treat symptoms of irritable bowel syndrome?
Reduce smooth muscle contraction, gut motility + gut secretions
State 4 general unwanted side-effects of muscarinic antagonists.
Hot as hell (decreased sweating effects thermoregulation)
Dry as bone (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 cause CNS agitation, restlessness, confusion)
How do you treat muscarinic receptor antagonist poisoning (e.g. atropine poisoning)?
Give an anticholinesterase e.g. physostigmine.
Allows ACh to accumulate + outcompete the atropine
Describe how botulinum toxin causes paralysis.
Binds to + blocks SNARE complex
Prevents exocytosis of ACh from pre-synaptic nerve terminal
Leads to muscle paralysis
State 7 effects of nicotinic receptor antagonists on a subject at rest.
Hypotension Pupil dilation (increases light sensitivity) Bronchodilation Bladder dysfunction Decreased GI tone Decreased GI secretions Decreased sweat production
What are the effects of a normal and toxic dose of Hyoscine on the CNS?
Normal: Sedation
Toxic: CNS depression (greater penetration into CNS)
When in botulinum toxin used clinically?
To remove wrinkles
To paralyse sweat glands
(must be VERY careful to localise to specific tissue)
