Cholinoceptor antagonists Flashcards
Define affinity
The strength with which an agonist binds to a receptor
Both agonists and antagonists will have affinity for the 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
Only agonists possess efficacy
Where are nicotinic receptors found
In ALL autonomic ganglia- even before adrenal gland
At neuromuscular junctions
Where are muscarinic receptors found
At parasympathetic effector organs and on sweat glands
What are the few clinically useful nicotinic receptor antagonists called and how do they block the receptor?
Ganglion Blocking drugs
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.
Hexamethonium- better at blocking the channel- use as anti-hypertensive obsolete
Trimethaphan- better at blocking the ACh receptor- short-lived- preferred use
Why is the term cholinoceptor antagonist not technically correct
GBDs can act to both antagonise the receptor AND/OR physically block the ion-channel itself.
Classical antagonism is where the receptor is physically blocked- therefore blocking the ion channel doesn’t technically agree with this definition
Do cholinoceptor antagonists have affinity
it depends
if they block the receptor- yes
if they block the ion channel- no
What does the term ‘use-dependant’ 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 the more useful and effective the drugs can be
i.e when the ion channel is more active- are likely to be open- allowing the drug to enter the channel and physically block it
In classical antagonism, if we have more ACh, is the antagonist more effective
No
Opposite to use-dependant effect for ion channel blockers
Agonist (ACh) would simply outcompete the antagonist
What does the term ‘incomplete block’ mean
Incomplete blocking – Ion-channel blockade is only partial (as some ions still pass through).
due to the use-dependence of the block, the drugs do not completely block the channels, reducing function significantly but not completely
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)
PSNS innervation n on the heart and lungs is dominant at rest
So GBD would inhibit the PSNS effects on these tissues at rest
Which tissues are sympathetic dominated
Vasculature and kidneys
Liver and adipose to (reduced glycogenolysis, gluconeogensis, and reduced lipolysis)
Describe the differing effects of the SNS on the vasculature
Blood vessels in skeletal muscle- dilatation
Blood vessels in skin, mucous membrane and splanchnic area- constriction
Which of the following effects would
be observed at rest after treatment
with a ganglion blocking drug?
PSNS is dominant at rest
therefore will inhibit PSNS effects
would see bronchodilation and increased heart rate
Which tissues are parasympathetic dominated
Lungs – causes bronchoconstriction
Eyes – maintains partial pupillary constriction at rest
Bladder, ureters and GI tract
Exocrine functions
What is the effect of a GBD on the PSNS dominated tissues at rest
Bronchodilation Pupil dilation (blurred vision) Bladder dysfunction Loss of GI motility and secretions and tone Decrease in exocrine secretion
Describe the CVS effects of GBDs
CVS effects; hypotension – blood vessel vasoconstriction inhibited ( so vasodilation) and kidney renin secretion inhibited (so no AngII).
Fluids are lost
Describe the smooth muscle effects of GBDs
Smooth muscle effects; pupil dilation, decreased GI-tone, bladder dysfunction, bronchodilation.
Describe the effect of GBDs on exocrine secretions
Decreased exocrine secretions
What is hexamethonium
the first anti-hypertensive drug used but LOTS of side effects as very general.
o Primarily an ion-channel blocker (so not a lot of affinity).
Side effects include loss of bladder control
What is trimetephan
very potent ganglion blocking drug used to produce controlled peri-operative hypotension for short duration (blocks receptor)
used for when you want hypotension during surgery, IV-administered, short acting.
o Primarily a receptor antagonist (so has affinity).
o BOTH drugs can however both antagonise and block nicotinic receptors.
Short acting
Describe the effect of GBDs on postural hypotension
In practice, the main effect is a marked fall in arterial blood pressure resulting mainly from block of sympathetic ganglia, which causes arteriolar vasodilatation, and the block of cardiovascular reflexes. Venoconstriction, which occurs normally when a subject stands up and prevents a fall in central venous pressure and cardiac output, is reduced. Standing thus causes a sudden fall in arterial pressure (postural hypotension) that can cause fainting.
Describe the effect of GBDs on postexcercise hypotension
The vasodilatation of skeletal muscle that occurs during exercise is normally accompanied by vasoconstriction elsewhere (e.g. splanchnic area) produced by sympathetic activity. Ganglion blockers prevent this adjustment, so the overall peripheral resistance falls leading to postexercise hypotension.
What do lots of venoms and toxins target
nAChrS
Issue is with somatic nervous system- venoms and toxins are designed to target these
Target diaphragm
Can’t move or breath- paralyses prey
Describe alpha-bungarotoxin
found in snake venom and causing skeletal muscle/diaphragm paralysis
powerful toxin from common snake (common krait, Bungarus careleus)
True antagonist- binds covalently to the receptor
Tissue would have to replace receptor to restore function
- In what types of chemicals are nicotinic receptor blockade antagonists found?
Toxins and venoms
- How do receptor blockade antagonists have their effect?
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)
Why aren’t toxins/venoms used therapeutically
nlike therapeutics, toxins/venoms tend to be irreversible - preventing ion channels from opening and leading to total loss of ANS function and skeletal muscle dysfunction too- side effect profile too broad
Whereas muscarinic recpeptor antagonists are more discrete in their actions- more therapeutically useful as more specific - only target PSNS organs and sweat glands e.g. Atropine/Hyoscine
Summarise the muscarinic receptor antagonists
This is mainly a PNS antagonist as the only muscarinic receptor in the SNS is found in sweat glands. o So expect mainly inhibition of PNS. Two examples of MRAs are: o Atropine. o Hyoscine.
Where does atropine originate from
Atropa belladonna
Where does hyoscine originate from
Hypscyamus niger
- Give four examples of muscarinic receptor antagonists.
Atropine
Hyoscine
Tropicamide
Ipratropium Bromide
Summarise the clinical effects of muscarinic receptor antagonist
Pupil dilation Bronchodilation Loss of bladder function Reduced saliva production Increased heart rate Reduced gut secretions
Summarise the CNS effects of muscarinic receptors antagonists
PSNS important for memory and attention - with atropine/hyoscine binding to M1 and M5 receptors - plant derived drugs with similar structure
Compare atropine and hyoscine
Structurally very similar
Despite this- have differing effects on the CNS at the therapeutic dose- hyoscine is despressive, atropine is excitatory
This may be due to the fact that hyoscine is more M1 selective and more lipid soluble, and so it can permeate further into the brain tissue- where different subsets of muscarinic receptors may be found
Describe the CNS effects of atropine at different doses
Normal dose – Little effect (mild restlessness)
Toxic dose - Mild restlessness→Agitation
(Less M1 selective)
Describe atropine poisoning
In atropine poisoning, which occurs in young children who eat deadly nightshade berries, marked excitement and irritability result in hyperactivity and a considerable rise in body temperature, which is accentuated by the loss of sweating. These central effects are the result of blocking mAChRs in the brain
Describe the CNS effects of hyoscine at different doses
Normal dose – Sedation, amnesia
Toxic dose – CNS depression or paradoxical CNS excitation (associated with pain)
(Greater permeation into CNS. Influence at
therapeutic dose)
Describe the main clinical use of tropic amide
It is used to dilate the pupil to observe the retina (it is used to examine the eye)
Makes it easier for there opthamologist to see the eye- as PSNS innervation to the eye is inhibited
administered as eye drops to facilitate fundoscopy
Describe the effects of muscarinic receptor antagonists on the eye
The pupil is dilated (mydriasis) by atropine administration, and becomes unresponsive to light. Relaxation of the ciliary muscle causes paralysis of accommodation (cycloplegia), so that near vision is impaired. Intraocular pressure may rise; although this is unimportant in normal individuals, it is dangerous in patients suffering from narrow-angle glaucoma due to impaired drainage of aqueous humour into the canal of Schlemm (see earlier).
Describe the use of muscarinic receptor antagonists as anaesthetic premedication
Anaesthetic premedication
It causes dilation of the airways so it is easier to intubate the patient- useful if inhaling the aesthetic
It reduces secretions thus reducing the risk of aspiration and choking on own fluids
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, so it protects the heart)
Can be sedative- hysocine
Describe motion sickness
Mismatch between sensory information from the eyes and information from the labyrinth and ears relating to position and balance- this triggers the cholinergic nerve travelling from the vestibular nucleus to the vomitting centre in the brain
Summarise the pathways involved in motion sickness
labyrinth to vestibular nucleus
vestibular nucleus to vomitting centre (cholinergic)
vestibular nucleus to reticular formation
reticular formation to abducens and oculomotor nuclei
vestibular nucleus to abducens nuclei also
abducens nuclei to lateral rectus
oculomotor to levator palpebrae superioris, superior rectus, medial rectus, inferior rectus, and inferior oblique muscles.
The purpose of this system is to Control eye movements to maintain vision whilst in motion
Describe the use of hysocine patches in motion sickness
Lipid soluble so hopefully can access blood stream and cross BBB
Hyoscine additionally has a central anti-emetic effect and is used to prevent motion sickness.
Inhibits the muscarinic receptors in the vomiting centre so the sensory mismatch (from a mismatch from what the eyes see and what the labyrinth reports in balance) cannot induce vomiting when suffering from motion sickness.
What happens in Parkinson’s disease
Loss of dopaminergic neurones which project from the substantia nigra to the striatum
This means that less dopamine is released in the striatum
D1 receptors on neurones in the basal ganglia respond to the dopamine released by the striatum- and the basal ganglia controls tone and fine muscle movement- why we see tremors
Anything unregulated D1R is good- helps the little dopamine released to be more effective- alleviating symptoms
how can muscarinic receptor antagonists be used to treat Parkinson’s disease
Different receptors in the brain regulate each other- don’t want all the receptors switched on and stimulated all the time
The M4 receptor in the brain inhibits the D1 receptor- leading to Parkinson’s disease
nigrostrial dopamine neurones responsible for control of fine movement are lost in Parkinson’s, and those that remain are inhibited by muscarinic receptors, so blocking these (M4 receptors) reduces inhibition to allow the remaining D1 dopamine neurones to fire at 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
Salbutamol (adrenoreceptor agonists) can also be used
How can we localise the effects of ipratropium bromide to the lungs
Based on atropine
But need to localise effects to lungs to reduce the incidence of side effects
Charge up atropine- giving it a quaternary positive nitrogen- less lipid soluble- so making it less likely to enter the blood stream
However in the alveoli, it wants to facilitate the diffusion. of everything into the systemic circulation- so some will still enter the blood stream and cause side effects
- 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.
Will also reduce gut smooth muscle tone
M3 receptor antagonists
Summarise the effects of muscarinic receptors on the G.I system.
Gastrointestinal motility is inhibited by atropine, although this requires larger doses than the other effects listed, and is not complete since excitatory transmitters other than ACh are important in normal function of the myenteric plexus (see Ch. 13). Atropine-like drugs such as hyoscine butylbromide (a quaternary ammonium antimuscarinic agent) relax intestinal spasm and are used for symptomatic relief in pathological conditions in which there is gastrointestinal spasm, as well as in gastrointestinal imaging to improve resolution. Pirenzepine, owing to its selectivity for M1 receptors, inhibits gastric acid secretion in doses that do not affect other systems.
- 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.)
Describe cycloplegia
Paralysis of the lens muscle- no ability to change focus
Relaxation of the ciliary muscle causes paralysis of accommodation (cycloplegia), so that near vision is impaired.
How would you treat atropine poisoning
Which of the following drugs would you administer to treat an atropine overdose?
- Bethanechol – muscarinic receptor agonist.
- Ecothiopate – Irreversible anticholinesterase.
- Hyoscine.
- Physostigmine – anticholinesterase.
- Pralidoxime.
You would want to give a drug that either enhanced ACh activity (anticholinesterase) or inhibits atropine.
Use physostigmine as it’s reversible
What does parasympatholytic mean
A parasympatholytic agent is a substance or activity that reduces the activity of the parasympathetic nervous system
What are the signs and symptoms of atropine poisoning
no sweating, tachycardia, pyrexia, agitation
- 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
It is a paraympatholytic
Describe Botulinum toxin
Botulinum toxin is the most toxic protein known. A single gram of crystalline toxin, evenly dispersed and inhaled, would kill more than 1 million people
Describe the effects of muscarinic receptor antagonists on secretions
Salivary, lacrimal, bronchial and sweat glands are inhibited by very low doses of atropine, producing uncomfortably dry eyes, mouth and skin. Gastric secretion is only slightly reduced. Mucociliary clearance in the bronchi is inhibited, so that residual secretions tend to accumulate in the lungs. Ipratropium lacks this effect.
Describe the effects of atropine on heart rate
Atropine causes tachycardia through block of cardiac mAChRs. The tachycardia is modest, up to 80–90 beats/min in humans, since it has no effect on the sympathetic system, but only inhibition of tonic parasympathetic tone. Tachycardia is most pronounced in young people, in whom vagal tone at rest is highest; it is often absent in the elderly. At very low doses, atropine causes a paradoxical bradycardia, possibly due to a central action. Arterial blood pressure and the response of the heart to exercise are unaffected.
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Treatment of sinus bradycardia (e.g. after myocardial infarction; see Ch. 22): for example, atropine.
Describe the effects of atropine on smooth muscle
Bronchial, biliary and urinary tract smooth muscle are all relaxed by atropine. Reflex bronchoconstriction (e.g. during anaesthesia) is prevented by atropine, whereas bronchoconstriction caused by local mediators, such as histamine and leukotrienes (e.g. in asthma; Ch. 29) is unaffected.
Biliary and urinary tract smooth muscle are only slightly affected in normal individuals, probably because transmitters other than ACh (see Ch. 13) are important in these organs; nevertheless, atropine and similar drugs commonly precipitate urinary retention in elderly men with prostatic enlargement
Describe the uses of muscarinic antagonists in. palliative care
Bowel colic and excessive salivation/respiratory secretion: hyoscine or glycopyrronium.
Describe the uses of muscarinic antagonists on the urinary tract
To relieve symptoms of overactive bladder: for example, oxybutynin, tolterodine, darifenacin.
