Cholinoceptor antagonists

Question 1

Differentiate effects of blocking nicotinic and muscarinic receptors

Answer 1

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

Question 2

What are ganglion blocking drugs?

Answer 2

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!)

Question 3

Example of ganglion blocking drugs

Answer 3

Hexomethonium (historical) and trimetaphan

Question 4

Effects of ganglion blocking drugs on the kidney and blood vessels

Answer 4

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

Question 5

T/f agonists and antagonists have efficacy but only agonists have affinity

Answer 5

F! Both have affinity, only agonists can cause a response

Question 6

Explain use dependent block

Which drugs display these

Answer 6

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

Question 7

Why do ganglion blcoking drugs cause hypotension

Answer 7

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

Question 8

Effects of ganglion blocking drugs

Answer 8

‘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

Question 9

Use of hexamethonium and trimetaphan, what are their actions mostly

Answer 9

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.

Question 10

Example of toxin using nicotinic receptor antagonists

Answer 10

alpha-bungarotoxin binds covalently so irreversibly to nicotinic receptors (parralysis of skeletal muscle is the biggest effect- although it does block autonomic function too)

Question 11

What physiological responses are going to be affected by muscarinic receptor antagonists

Answer 11

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

Question 12

2 examples of muscarinic receptor antagonists

Answer 12

Hyoscine and atropine (see drugs table)

Question 13

CNS side effect of musc. receptor antag.

Account for the difference in CNS effects of hyoscine and atropine

Answer 13

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

Question 14

Outline how fine movement is affected in parkinsons and the aims of treatment so how you’d treat it

Answer 14

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

Question 15

State the general side effect of muscarinic receptor antagonists

Answer 15

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)

Question 16

Outline atropine poisoning with exampes of drugs that could be used to treat it

Answer 16

Treat with bethancol (directly acting cholinomimetic)/ecothiopate (but this is irreversible so probably not)/physostigmine

Mostly physostigmine

Question 17

How can physostigmine reduce effects of atropine poisoning?

Answer 17

It inhibits acetylcholinesterase, so ACh builds up more and can form more complexes with the receptor, so will outcompete atropine

Question 18

How does the botulinum toxin work?

Answer 18

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

Question 19

Clinical use of botox?

Answer 19

Inject into local areas in skeletal muscle to paralyse it and prevent frowns

Question 20

Explain the use of musc. receptor ant. in premedication for anaesthetic

Answer 20

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

Question 21

Explain the use of musc. receptor ant. in neurological condition

Answer 21

Neurological: motion sickness (see below)

Parkinson’s: block the M4 receptor which enhances activation of D1 receptors on striatal neurons

Question 22

Explain the use of musc. receptor ant. in respiratory medicine

Answer 22

Respiratory: Asthma and COPD- it block constriction.

Question 23

Explain the use of musc. receptor ant. in GI

Answer 23

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

Question 24

Explain the use of musc. receptor ant. in ophthalmic

Answer 24

Can be used to dilate the pupil- tropicamide used to examindation of the retina

Question 25

What is cycloplegia and what could be cause

Answer 25

=paralysis of ciliary muscle

due to presbyopia (loss of lens elasticity with age) or muscarinic antagonist

Question 26

T/f atropine would be used in respiratory conditions as a musc. antagonist. If not, why not.

Answer 26

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)

Question 27

Account for the difference in the CNS effect of atropine vs hyoscine, despite their structure being so similar!

Answer 27

So why is atropine not having CNS effect at therapeutic dose but hyoscine does?

1. Atropine less M1 effective than hyoscine
2. Hyoscine greater permeation into CNS as it’s more lipid soluble

Question 28

What is the effect of muscarinic receptor antagonist in motion sickness

Answer 28

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

Question 29

What can be taken for motion sickness

Answer 29

Hyoscine patch!

Question 30

Effects of atropine poisoning

Answer 30

CNS agitation (at high dose) 
increased HR and contractility?