Cholinoceptor Antagonists

Question 1

Define Affinity.

Answer 1

The strength with which an agonist binds to a receptor

Question 2

Define Efficacy.

Answer 2

Once the drug has bound to the receptor, the ability of the drug to generate a response - usually involves conformational change of the receptor and activation of intracellular signalling pathways

Question 3

What is the difference between agonists and antagonists in terms of affinity and efficacy?

Answer 3

Agonists – have affinity and efficacy Antagonists – have affinity but NOT efficacy

Question 4

Where are nicotinic receptors found?

Answer 4

In ALL autonomic ganglia On the adrenal medulla At neuromuscular junctions

Question 5

What are nicotinic receptor antagonists also known as?

Answer 5

Ganglion blocking drugs

Question 6

How do nicotinic receptor antagonists work?

Answer 6

There are two types: Classic - block the actual receptor site where ACh would normally bind to stimulate the ion channel to open Ion-channel blockers - these block the ion channel rather than the receptor itself, hence preventing the ions from moving through the pore and generating an AP (i.e. the response) NOTE: a drug can generally block both but is better at blocking one or the other (e.g. may have some affinity to receptor but fits better into ion channel or vice versa)

Question 7

Do ion channel blockers have affinity?

Answer 7

No because they are not binding to a receptor or anything really - they just fit into the ion channel causing a physical obstruction

Question 9

Give two examples of ganglion blocking drugs and state what they are better at blocking.

Answer 9

Hexamethonium - ion channel Trimethaphan - receptor (ligand-binding site)

Question 10

Why do ion channel blockers generally result in an incomplete block?

Answer 10

When the drug is blocking the ion channel, it is NOT COMPLETELY preventing the ions from passing through the channel Some ions can still get through (therefore incomplete block) - the drug is just acting as an obstacle making it more difficult for the ions to get through

Question 11

What does ‘use-dependent block’ mean?

Answer 11

This term is only relevant to the agonists which work as ion channel blockers These drugs work most effectively when the ion channels are open - the ion channel needs to be open in order for the drug to be able to get into it and block it This means that the more agonist that is present at the receptor stimulating opening of the ion channels, the greater of an opportunity the antagonist has to block the channel, thus the more useful and effective the drugs can be NOTE: more agonist present (e.g. ACh) at the receptor means that the tissue is being used more (greater need to generate a response)

Question 12

What determines the effect of ganglion blockade in a tissue?

Answer 12

It depends on which limb of the autonomic nervous system predominates in the particular tissue (at the time at which the effect is being observed, e.g. at rest, during exercise)

Question 13

Which tissues are sympathetic dominated at rest?

Answer 13

Blood vessels - vasoconstriction (to maintain vascular tone) Kidneys - increased renin secretion to maintain enough BP

Question 14

What CVS effects can ganglion blocking drugs cause?

Answer 14

Hypotension At rest the sympathetic nervous system dominates the blood vessels (vasoconstriction) and kidneys (renin secretion) If this (i.e. the SNS branch) is inhibited, then you will get vasodilation and reduced renin secretion (so reduced sodium and water reabsorption) leading to a drop in BP

Question 15

Which tissues are parasympathetic dominated at rest?

Answer 15

Lungs – airways always partially constricted under so that further dilation or constriction can occur when required Eyes – maintains partial pupillary constriction so that pupils can dilate or constrict further as necessary GI tract - increased motility and tone Bladder and ureter - contraction of detrusor; relaxation of trigone and sphincter (promotes emptying of bladder) Exocrine function (secretions: sweating, saliva, GI) NOTE: SNS promotes sweating but sweat glands have muscarnic ACh receptors, therefore included here - there is some sweating at rest, required for temperature regulation, which would be affected by ganglion blockade

Question 16

How does PNS allow for accommodation of the eye?

Answer 16

Accommodation = ability of eye to change its focus from distant to near objects PNS essentially allows near vision PNS causes contraction of ciliary muscles which makes the lens thicker - this leads to greater light refraction (more bending) which is better for focusing on near objects

Question 17

What would the effect of ganglion blockade be on these tissues? Lungs Eyes GI Bladder and ureters Exocrine tissues

Answer 17

Bronchodilation Pupil dilation (blurred vision - because PNS controls accommodation) Loss of GI motility Bladder dysfunction (at rest: retention = inability to empty bladder completely Loss of exocrine function (secretions: sweating, saliva, GI)

Question 19

What is hexamethonium?

Answer 19

It is a ganglion blocker that was the first anti-hypertensive It has a generalised action (i.e. acted on all the nicotinic receptors in the various body tissues) and therefore had lots of side-effects

Question 20

Explain what ‘short acting’ means in the context of drugs. (NOTE)

Answer 20

Short acting = short biological half-life Half-life is generally reduced by metabolism: either simply by converting the active metabolite into an inactive one (so plasma cleared of active drug) OR even if it is converted into a more active one, either way metabolites are made to be easier to excrete meaning they can be cleared from the plasma more efficiently There are different enzymes systems in the body to metabolise different drugs - if the enzyme system for a certain drug is more active or present at a higher concentration, this could mean that the metabolism happens faster → faster clearance from plasma → shorter half-life

Question 21

State the overall effects of ganglion blocking drugs on a subject at rest.

Answer 21

Hypotension Pupil dilation Bronchodilation Bladder dysfunction Decreased GI motility and tone and decreased secretions Decreased GI secretions

Question 22

What is trimethaphan and when is it used?

Answer 22

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 - effects lost quickly

Question 24

In what types of chemicals are nicotinic receptor antagonists commonly found?

Answer 24

Toxins and venoms

Question 25

How do these nicotinic receptor antagonists found in toxins and venoms work?

Answer 25

They bind to the actual receptor site (rather than blocking the ion channel) However, the binding is irreversible – covalent binding (very strong bonds) By doing this they permanently prevent the ion channels from opening - this tissue has to be completely replaced (new tissue, new ion channels) in order for the ion channels to be functioning again This is a long complex process so essentially not having functioning ion channels and effecting autonomic neural transmission for this period of time is VERY DANGEROUS

Question 26

What is important about the structure of muscarinic receptor antagonists?

Answer 26

Their structure is slightly different from ACh - gives them a higher affinity for the muscarinic receptor which is important to allow effective competitive blockade Their structure also means that although they bind, they don’t generate a response (no efficacy) - could be that the binding of a certain missing group is the one that generates the response The antagonists tend to be similar in structure to each other - this is because they are specific to the muscarinic receptor (unlike ACh which can bind to nicotinic receptors too)

Question 27

What could slight differences in structure between antagonists result in?

Answer 27

Difference in which receptor SUBtype they are more selective for Difference in distribution (e.g. one is more permeable into CNS so greater volume of distribution)

Question 28

Where are muscarinic receptors found?

Answer 28

At parasympathetic effector organs and on sweat glands (sympathetic cholinergic effector)

Question 28

Give an example of a nicotinic receptor blockade antagonist.

Answer 28

Alpha-bungarotoxin (common krait snake venom)

Question 29

Give four examples of muscarinic receptor antagonists.

Answer 29

Atropine Hyoscine Tropicamide Ipratropium Bromide

Question 30

What are nigro-striatal neurones?

Answer 30

Neurones which project from the substitute nigra to the striatum (2 sets of nuclei within the basal ganglia - subcortical structures) - REPHRASE

Question 31

What effect do muscarinic receptor antagonists have on the CNS?

Answer 31

All 5 types of muscarinic receptor are present in the CNS and they have different functions including attention, memory and certain sleep pathways. Atropine: Normal dose – little effect on CNS (makes sense because it is not very good at permeating the CNS so has a lower chance of getting though the BBB at lower dose) Toxic dose - Mild restlessness → Agitation (CNS has some permeability for drug so penetration more likely at higher doses) Hycosine: Normal dose – Sedation, amnesia (has effects at the normal/therapeutic dose as it has a greater CNS permeating ability) Toxic dose – CNS depression or paradoxical CNS excitation (when this happens, patients tend to have pain with it) NOTE: paradoxical CNS excitation is much less common - not clear why this would happen instead of CNS depression Generally differences in symptoms between the two antagonists are due to the slight difference in structure which could mean it affects different receptor subtypes (e.g. atropine is less M1 selective) and maybe structural differences could affect distribution within the brain

Question 32

What is tropicamide used for?

Answer 32

It is used to dilate the pupil by paralysing the iris sphincter (circular) muscle (preventing contraction) to observe the retina - used to examine the eye NOTE: contraction of iris dilator (radial) muscle → pupil dilation (SNS innervated)

Question 34

What degenerative disorder of the central nervous system can be treated by muscarinic receptor antagonists? Explain how.

Answer 34

Parkinson’s Disease - In Parkinson’s disease, many of the nigro-striatal dopamine neurones are lost D1 receptors in the striatum respond to the dopamine released by the neurones - effect of receptor stimulation: fine control of muscle movement and tone - CHECK Muscarinic M4 receptors can suppress the D1 receptor function (prevents overstimulation of D1 receptors) Therefore, by blocking these you can remove this inhibitory effect on the D1 receptors and allow them to be stimulated as much as possible by the dopamine released from the remaining dopaminergic neurones

Question 35

What is an important use of muscarinic receptor antagonists with regards to surgery? Why is it useful in this circumstance?

Answer 35

Anaesthetic premedication It causes dilation of the airways - useful if anaesthetic is being inhaled It reduces secretions such as saliva which can cause problems if they then enter the airways (greater risk of inhaling secretions in the airways are dilated and muscles are relaxed etc - NOTE: you do breathe under anaesthetic; generally assisted under GA) 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 you don’t want a double effect) - maintains resting HR rather than lowering it completely → important for maintaining brain perfusion ALSO certain anti-muscarinics have a sedative effect

Question 36

Why is ipratropium bromide proffered over atropine in treating asthma and COPD?

Answer 36

Ipratropium bromide is positively charged, so doesn’t cross lipid membranes very well Therefore, once inhaled into the lungs, the effects are fairy localised (doesn’t really diffuse out of lungs) → limits side effects (esp systemic)

Question 37

What can hyoscine be used to treat? Explain how.

Answer 37

Motion Sickness During motion, visual information from the eyes and information relating to balance and posture from the labyrinth (inner ear) is integrated at the vestibular nucleus If there is a sensory mismatch here (i.e. the information from both places isn’t correlating with each other) then in some people this mismatch is relayed to the vomiting nucleus → motion sickness This is a cholinergic pathway (i.e. vomiting centre have muscarinic ACh receptors) so can be prevented using a muscarinic receptor antagonist NOTE: given as a hycosine patch

Question 38

Explain the use of muscarinic antagonists in treating asthma and COPD.

Answer 38

Ipratropium Bromide is used to treat asthma and COPD It counteracts the parasympathetic mediated bronchoconstriction → bronchodilation and symptomatic relief NOTE: atropine can also be used but ipratropium bromide is preferred because it helps localise the effects as once inhaled into lungs, it tends to stay there (doesn’t diffuse out that much) → limits (systemic) side effects

Question 39

Explain the role of muscarinic antagonists in treating irritable bowel syndrome (IBS).

Answer 39

Muscarinic antagonists will reduce smooth muscle contraction, gut motility and gut secretions (i.e. slows down gut action) thus relieving the symptoms of IBS (where gut is hyper-reactive - i.e. everything is overactive)

Question 39

State some general unwanted side-effects of muscarinic antagonists.

Answer 39

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 = paralysis of ciliary muscle; not contracting) Mad as a hatter (high doses will cause CNS agitation, restlessness, confusion etc.)

Question 39

How do you treat muscarinic receptor antagonist poisoning (e.g. atropine poisoning)?

Answer 39

Give an anticholinesterase e.g. physostigmine This increases ACh concentrations in the synapse to overcome the competitive inhibition by the antagonist

Question 39

Describe how botulinum toxin causes paralysis.

Answer 39

It binds to the SNARE complex and prevents the fusion of the vesicles with the presynaptic membrane and release of ACh from the nerve terminal - i.e. prevents exocytosis If this happens at a NMJ, this leads to skeletal muscle paralysis (as skeletal muscles have nicotinic receptors which respond to ACh)