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Yr 2 LCRS - Pharm > 7 - Cholinoreceptor Antagonists > Flashcards

7 - Cholinoreceptor Antagonists Flashcards

1
Q

What differs between the interaction of agonists and antagonists with receptors?

A

Both agonists and antagonists possess affinity

Only agonists possess efficacy

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2
Q

What is a ‘Use-Dependent Block’?

A

Drug’s effectiveness is proportional to how much the system is being used/how open the channels are.

e.g. local anesthetics are ‘use dependent’ (i.e. the degree of block is proportional to the rate of nerve stimulation). This indicates that more drug molecules (in their protonated form) enter the sodium channels when they are open and cause more inactivation.

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3
Q

What drug has efficacy for muscarinic acetylcholine receptors?

A

To have efficacy, the drug must be an agonist of the receptor.

Therefore, the answer is acetylcholine.

ACh is a selective agonist in the case.

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4
Q

What is another name for Nicotinic Receptor Antagonists?

A

Ganglion Blocking Drugs

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5
Q

Where are Nicotinic Receptors found?

A

At all ganglion in the parasympathetic and sympathetic systems

At the Adrenal Medulla (even though this is only one nerve)

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6
Q

What is the mechanism of action for Nicotinic Receptor Antagonists?

A
  • By binding to the receptor and blocking it
    OR
  • Block ion channel that the receptor opens (don’t 100% block the channel, incomplete)
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7
Q

What are examples of Nicotinic Receptor Antagonists?

A

Hexamethonium

Trimetaphan

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8
Q

Do Nicotinic Receptor Antagonists have affinity and efficacy?

A

They have affinity as receptor antagonists (no efficacy because they are antagonists not agonists)

They do not have affinity or efficacy as ion channel blockers.

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9
Q

Do nicotinic receptor antagonists affect the parasympathetic or sympathetic nervous system?

A

Because they are at all ganglia and the adrenal medulla, they can affect either system.

Therefore, which system is mainly blocked is based on which system is dominant at the time of drug administration.

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10
Q

What would be observed at rest after treatment with a ganglion blocking drug (nicotinic receptor antagonist)?

A

At rest, parasympathetic system is dominant.

Therefore parasympathetic system is blocked.

As a result, you would observe sympathetic effects such as:

  • increased heart rate
  • bronchodilation
  • detrusor relaxation
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11
Q

Why do ganglion blocking drugs (nicotinic receptor antagonists) cause hypotension?

A

At rest, the drug increases heart rate because it blocks the parasympathetic system so this is not relevant.

However, the only system involved in the blood vessels of skin/mucous mems/splanchnic area and the kidneys is the sympathetic which normally is causing:

  • vasoconstriction of blood vessels
  • increased renin secretion

Therefore, by blocking these effects you get:

  • vasodilation of blood vessels
  • decreased renin secretion

These effects lower blood pressure.

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12
Q

Why are ganglion blocking drugs (nicotinic receptor antagonists) not used as treatment as antihypertensives despite their ability to lower blood pressure?

A

They can cause many side effects because they interfere with ANS. Because people are largely at rest, the parasympathetic system is blocked and the drugs would cause:

  • decreased G.I. tone and motility
  • bladder dysfunction by constriction of trigone/sphincter and relaxed detrusor
  • pupil dilation
  • bronchodilation
  • decreased secretions in gut (problems digesting food)
  • decreased sweating (because only sym system involved so it is blocked)
  • thick, viscous saliva
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13
Q

What is blocked when an organ/function is only controlled by the sympathetic nervous system, even at rest?

A

Despite being at rest, if an organ/function is only controlled by the sympathetic nervous system, then this system is going to be dominant both at rest and when active.

In these organs/functions, the sympathetic system is always blocked and you lose whatever function was being carried out by the SNS.

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14
Q

What are 2 examples of ganglion blocking drugs (nicotinic receptor antagonists)?

A

Hexamethonium

Trimetaphan

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15
Q

What are the overall functions of Hexamethonium and Trimetaphan?

A

Hexamethonium
= first ever effective anti-hypertensive
= lots of side-effects
= more of an ion-channel blocker than a receptor antagonist

Trimetaphan
= used during surgery to induce hypotension
= reduce blood flow to tissues being operated on
= short-acting
= good if you need a quick, controlled response
= more of a receptor antagonist than an ion-channel blocker

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16
Q

What is an example of a toxin able to bind to nicotinic receptors and how does it work?

A

alpha-bungarotoxin

  • from krait snakes
  • irreversible
  • completely blocks receptor
  • very dangerous in somatic NS
  • there are nicotinic receptors at the end of the axon that goes onto skeletal muscle
  • blocking this paralyses skeletal muscle
17
Q

Where are muscarinic receptors found?

A

Predominantly found in parasympathetic system at effector organs

Can also be found in sympathetic system at specific effector organs e.g. sweat glands

18
Q

What are 3 examples of Muscarinic Receptor antagonists?

A
  • Atropine
  • Hyoscine
  • Tropicamide
19
Q

What are some chemical features of atropine and hyoscine (muscarinic receptor antagonists)?

A
  • Both relatively lipid soluble

- Structurally very similar

20
Q

What is different about the responses of Muscarinic Receptor antagonists and Nicotinic Receptor antagonists?

A
  • Muscarinic have a more selective response

- Therefore, muscarinic result in fewer side effects

21
Q

What physiological responses are influenced by muscarinic receptor antagonists?

A

All Parasympathetic effects + Sweating (sympathetic, due to weird exception of placement of muscarinic receptors)

  • pupil constriction
  • ciliary muscle contraction
  • trachea/broncuole cnstriction
  • detrusor contraction in bladder
  • relaxation of bladder trigone and sphincter
  • copious, watery saliva
  • decreased HR and contractility
  • increased GI motility and tone
  • increased GI secretions
  • increased skin sweating (sympathetic)
22
Q

What are the effects of Muscarinic Receptor Antagonists on the CNS?

A

Atropine

  • normal dose: little effect
  • toxic dose: mild restlessness, agitation
  • –> this is because it is less M1 selective
  • —> doesn’t have a CNS effect at a therapeutic dose

Hyoscine

  • normal dose: sedation, amnesia
  • toxic dose: CNS depression or paradoxical CNS excitation associated with pain
  • –> this is because it has greater permeation into the CNS
  • –> does have an influence at a therapeutic dose).
23
Q

Why does atropine being less M1 selective reduce its effect on the CNS compared to hyoscine at a therapeutic dose?

A

M1 is a CNS receptor

  • atropine is less selective than hyoscine
  • hyoscine is more lipid soluble

Therefore, hyoscine is has a greater effect on the CNS

24
Q

Outline an example of a Muscarinic Receptor Antagonist used clinically in ophthalmology

A

Tropicamide

  • muscarinic antagonist
  • causes pupil dilation via the iris muscle
  • used to examine the retina
25
Q

Outline how Muscarinic Receptor Antagonists can be used clinically as anaesthetic premedication

A

Blocks parasympathetic effects

  • e.g. bronchoconstriction therefore more anaesthetic can enter the lungs
  • e.g. less salivary gland secretes, reduce aspiration
  • e.g. slightly increase HR and contractility

Hyoscine, due to its CNS effects at low doses, can be used as the sedative component.

26
Q

What can be Muscarinic Receptor Antagonists be used for clinically?

A
  • Opthamalogy for retinal examinations
  • Anaesthetic Premedication
  • Neurological for motion sickness etc
  • Parkinson’s
  • Respiratory problems e.g. asthma/obstructive airway disease
  • GI symptoms (IBS)
27
Q

Outline how Muscarinic Receptor Antagonists can be used clinically for neurological symptoms

A

Motion Sickness

  • hyoscine patch treatment
  • motion sickness is a sensory mis-match
  • visual info and ear info for balance doesn’t match up
  • mainly because of the hippocampus
  • memory in hippocampus
  • controls eye movements to maintain vision whilst in motion
  • activates vomiting centre

Hyoscine interferes with the vomiting signal

28
Q

Outline how Muscarinic Receptor Antagonists can be used clinically for Parkinson’s Disease

A

Normal Physiology:
- Dopaminergic neurones coming from sub nigra
- Release Dopamine
- Binds to D1 receptors on neurones in striatum
- Allows for fine control of movement
D1 Receptor is stimulatory
M4 Receptor is inhibitor

In Parkinson’s:

  • some dopaminergic neurones lost
  • less dopamine
  • less fine control of movement

Muscarinic Receptor Antagonists:

  • not first line treatment
  • want to remove physiological control on the system by losing M4 inhibition
  • want to enhance any D1 effects
29
Q

Outline how Muscarinic Receptor Antagonists can be used clinically for Respiratory problems

A

Asthma/Obstructive Airway Disease

  • ipratropium bromide used
  • has quaternary nitrogen
  • charged, polar group on end of molecule
  • useful because its polar, it doesn’t diffuse out of lung effectively
  • control it local

= block bronchoconstriction of parasympathetic system

30
Q

Outline how Muscarinic Receptor Antagonists can be used clinically for GI problems

A

Irritable Bowel Syndrome

  • reduces overactive bowel
  • blocks parasympathetic effects
  • decreases motility, tone and secretions

Some M3 selective antagonists can be used, target smooth muscle, less side effects.

31
Q

What are the main side effects of muscarinic receptor antagonist use?

A

Hot as Hell = decreased sweating and thermoregulation

Dry as a Bone = decreased secretions

Blind as a Bat = cyclopegia

Mad as a Hatter = CNS disturbance

32
Q

What is cyclopegia?

A

Paralysis of the ciliary muscle of the eye

33
Q

What occurs in atropine poisoning?

A

Atropine is a muscarinic receptor selective antagonist

  • binds to the receptor
  • outcompetes ACh for the receptor
  • all parasympathetic effects and sweating are blocked
34
Q

How is atropine poisoning treated?

A

Using anticholinesterases

  • Blocks AChE
  • Increases ACh in cleft
  • Greater ability to outcompete atropine

Physostigmine is used instead of ecothiopate because it is the most selective and it is reversible (whereas ecothiopate is irreversible)

Bethanechol could also be used

35
Q

How does Botulinum Toxin cause issues in the body?

A
  • Gets into neurone
  • Inactivates SNARE Complex
  • Affects exocytosis of ACh from the pre-synaptic bulb
  • If systemic, loss of nicotinic effects on skeletal muscle
  • Can be lethal

In botox, a less dangerous form is used. Want to localise the effect of the toxin. Can paralyse sweat glands intentionally using botox.

36
Q

What are Parasympatholytics?

A

A substance or activity that reduces the activity of the parasympathetic nervous system.

37
Q

How toxic is Botulinum Toxin?

A

Most toxic protein known in existence

A single gram of crystalline toxin, evenly dispersed and inhaled, would kill more than 1 million people.

Yr 2 LCRS - Pharm (44 decks)

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