Cholinoceptor antagonists Flashcards
Differentiate effects of blocking nicotinic and muscarinic receptors
Muscurinic only present at effector organs of PNS, and SNS sweat gland
Nicotinic present in all autonomic ganglia, so will interfere with whole ANS
So muscarinic more selective
What are ganglion blocking drugs?
nicotinic receptor antagonists, but only kind of.
Nicotinic receptors are type 1 (connected to ion channel), and ganglion blocking drugs block the ion channel AND the receptor. Most do ‘a bit of both’. Interfere with both SNS and PNS (but of course interferes more with whatever is dominant at the time!)
Example of ganglion blocking drugs
Hexomethonium (historical) and trimetaphan
Effects of ganglion blocking drugs on the kidney and blood vessels
Kidneys and blood vessels are SNS dominated, so usually more renin secretion thus sodium and water reabsorption, and vasoconstriction in the gut.
Blockage has a HYPOTENSIVE effect, as these sympathetic effects reduced
T/f agonists and antagonists have efficacy but only agonists have affinity
F! Both have affinity, only agonists can cause a response
Explain use dependent block
Which drugs display these
SHOWN BY GANGLION BLOCKING DRUGS
The more that the acetylcholine binds, and the ion channel is opened, the better the drug works (because there are more ion channels to block). No drug is completely effective at blocking ion channels
Why do ganglion blcoking drugs cause hypotension
At rest, PNS is the main effect. Blocking PNS to the heart would actually increase BP so NOT a heart mediated effect.
In blood vessels, block sympathetic effect (more dilation, reduction of vascular tone) leads to reduced TPR and decrease BP.
AND
Kidney- renin (has effects on BP via vasoconstrictor ATII but also aldosterone) reduced so BP also reduced
Effects of ganglion blocking drugs
‘messy drugs’ because they interfere with both ANS so lots of side effects:
Whenever it asks for effects, consider whether at rest or not….
these effects below can be remembered because they basically just BLOCKING parasympatehtic effects at rest
SMOOTH MUSCLE: pupil dilation, reduced GI tone, bladder dysfunction and bronchodilation
EXOCRINE: decreased secretions e.g. in gut, sweat, saliva reduced and so are brochial secretions
So not clinically that useful
Use of hexamethonium and trimetaphan, what are their actions mostly
Hexamethonium not really used now but was the 1st antihypertensive
Trimetaphan only used in surgery to reduce BP (so you don’t get bleeds in tissues you’re working on) short acting.
See drug table
Hexamethonium more of a channel blocker, trimetaphan more of a receptor antagonist.
Example of toxin using nicotinic receptor antagonists
alpha-bungarotoxin binds covalently so irreversibly to nicotinic receptors (parralysis of skeletal muscle is the biggest effect- although it does block autonomic function too)
What physiological responses are going to be affected by muscarinic receptor antagonists
Pupil constriction + ciliary muscle control
Bronchoconstriction
Detrusor contraction/relaxation of trigone and sphincter
Copious, watery secretion
Increased sweating (REMEMBER THIS IS NOT PNS IT’S SNS BUT STILL MUSCARINIC!!!)
Reduced rate and contractility of heart
Increased motility, tone and secretions in the gut
2 examples of muscarinic receptor antagonists
Hyoscine and atropine (see drugs table)
CNS side effect of musc. receptor antag.
Account for the difference in CNS effects of hyoscine and atropine
CNS (atropine none at normal dose, toxic dose leads to mild restelessness up to aggitation.
Hyoscine amnesia/sedation normal dose leading to CNS depression or paradoxical CNS excitation WITH PAIN
Perhaps because hyoscine permeates into CNS better, and also because it is more M1 selective, may cause these effects
Outline how fine movement is affected in parkinsons and the aims of treatment so how you’d treat it
Usually, dopaminergic neurons from the substantia nigra release dopamine onto the striatum to affect movement. The dopamine being released the acts on D1 receptors on striatal neurons
M4 receptors are present ON THE STRIATUM (not on dopaminergic neurons), and they are inhibitory so they reduce D1 receptor activation.
In Parkinsons you want to reduce the M4 stimulation so you get less inhibition of the remaining dopaminergic neurons.
So M4 receptor antagonism INCREASES DOPAMINE RECEPTOR ACTIVATION on striatal neursons and does not impact on dopamine release from dopaminergic neurons coming from substantial nigra
State the general side effect of muscarinic receptor antagonists
Hot as hell (less sweating so poorer thermoregulation)
Dry as a bone (less secretions)
Blind as a bat (cycloplegia, lens under PNS control)
Mad as a hatter (CNS disturbance)
Outline atropine poisoning with exampes of drugs that could be used to treat it
Treat with bethancol (directly acting cholinomimetic)/ecothiopate (but this is irreversible so probably not)/physostigmine
Mostly physostigmine
How can physostigmine reduce effects of atropine poisoning?
It inhibits acetylcholinesterase, so ACh builds up more and can form more complexes with the receptor, so will outcompete atropine
How does the botulinum toxin work?
It’s a parasympatholytic (as are the muscarinic antagonist) and it works by preventing the movement of ACh into the synaptic cleft, by interfering with the snare complex (ca2+ inlux –> exocytosis). Dangerous toxin if systemic because of impact on nicotinic skeletal muscle
Clinical use of botox?
Inject into local areas in skeletal muscle to paralyse it and prevent frowns
Explain the use of musc. receptor ant. in premedication for anaesthetic
Anaesthetic premediation: blocks bronchoconstriction (so opens up the lungs so anaesthetic can penetrate); blocks copious, watery secretion from salivary gland; blocks decrease in heart rate and contractility and sedative component if hyoscine
Explain the use of musc. receptor ant. in neurological condition
Neurological: motion sickness (see below)
Parkinson’s: block the M4 receptor which enhances activation of D1 receptors on striatal neurons
Explain the use of musc. receptor ant. in respiratory medicine
Respiratory: Asthma and COPD- it block constriction.
Explain the use of musc. receptor ant. in GI
GI- used for irritable bowel syndrome, as it blocks the increased motility and tone and blocks the increased secretions. Use M3 receptor selective antagonist to reduce side effects (M3 largely targets smooth muscle
Explain the use of musc. receptor ant. in ophthalmic
Can be used to dilate the pupil- tropicamide used to examindation of the retina
What is cycloplegia and what could be cause
=paralysis of ciliary muscle
due to presbyopia (loss of lens elasticity with age) or muscarinic antagonist
T/f atropine would be used in respiratory conditions as a musc. antagonist. If not, why not.
F. Ipratropium bromide (over atropine because the ipratropium bromide doesn’t diffuse into the blood it stays local. It doesn’t diffuse because it is polar due to the quarternary nitrogen)
Account for the difference in the CNS effect of atropine vs hyoscine, despite their structure being so similar!
So why is atropine not having CNS effect at therapeutic dose but hyoscine does?
- Atropine less M1 effective than hyoscine
- Hyoscine greater permeation into CNS as it’s more lipid soluble
What is the effect of muscarinic receptor antagonist in motion sickness
Motion sickness is a sensory mismatch between visual system and labyrinth (regarding balance and posture).
The sensory information is coordinated.
Activate the vomiting centre –> nausea
Cholinergic system.
Muscarinic receptor antagonist (hyoscine) gets into the brain, prevents the cholinergic system from activating the vomiting centre.
This is prevention of the transmission of the sensory mismatch from part of the brain to the vomiting centre
What can be taken for motion sickness
Hyoscine patch!
Effects of atropine poisoning
CNS agitation (at high dose) increased HR and contractility?
