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LCRS Year 2 - Pharmacology and Therapeutics > Lecture 7 - Cholinoceptor Antagonists > Flashcards

Lecture 7 - Cholinoceptor Antagonists Flashcards

1
Q

What are the two types of cholinoceptor?

A

Nicotinic

Muscarinic

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2
Q

Where are muscarinic and nicotinic cholinoceptors found?

A

Nicotinic
- All autonomic ganglia and adrenal medulla
- Neuromuscular plates
Muscarinic
- On effector organs (parasympathetic NS) and sweat glands (sympathetic NS)

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3
Q

What are affinity and efficacy defined as?

A

Affinity - The strength with which a molecule binds to a receptor

Efficacy - The ability to transduce a response and activate intracellular pathways following binding to a receptor

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4
Q

What do agonists and antagonists show in terms of affinity and efficacy?

A

Agonists - Show affinity and efficacy (binding + response)

Antagonists - Show affinity but NO efficacy (binding but no response)

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5
Q

Are the effects of the drugs the same throughout the body or are they tissue-specific and why is this?

A

The effects are tissue-specific
- This is because in different tissues, different branches of the autonomic nervous system are dominant. If the sympathetic system is dominant, then these effects will be lost. If the parasympathetic system is dominant, then these effects will be lost.

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6
Q

Sympathetically dominated tissues include the kidneys and blood vessels. What will the administration of a nicotinic cholinoceptor antagonist cause? (CVS, kidney, gut blood vessels)

A

Sympathetically driven responses in kidneys and blood vessels to increase blood pressure are reduced.

  • Hypotensive effect
  • Reduced renin secretion, sodium/water retention
  • Reduced vasoconstriction in the gut
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7
Q

Parasympathetically dominated tissues are more common, which type of cholinoceptor antagonist, muscarinic or nicotinic, will have their main effect be on the parasympathetic nervous system? (Think back to where and in which nervous system is each type of receptor found)

A

Muscarinic - receptors found on effector organs innervated parasympathetically as well as sweat glands.

Predominantly parasympathetic effects inhibited, sweating also inhibited

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8
Q

What are the clinically useful types of nicotinic receptor antagonist drugs called? (remember where nicotinic receptors are found)

A

Ganglion-blocking drugs

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9
Q

What are the two ways by which ganglion-blocking drugs work?

A
  • Blocking the ion channel-linked receptor

- Blocking the ion channel itself

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10
Q

Do ganglion blocking drugs interfere with parasympathetic, sympathetic action, or both?

A

BOTH

- Nicotinic receptors found in ganglia of both para/sympathetic nervous systems so blocks both

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11
Q

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

A

Hexamethonium

Trimetaphan

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12
Q

Nicotinic receptor antagonists’ blocking ability is referred to as a “use-dependent block”. What does this mean and can these drugs achieve complete block or only incomplete?

A

Use-dependent block means these drugs work most effectively when the ion channels are open as there is more opportunity for the antagonist to block the ion channel
- Therefore the more agonist is present, as a result of the tissue being used, the more ion channels will be open and the more ion channels can be blocked.

These drugs only result in incomplete block, they do no completely switch off function but slow it down considerably

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13
Q

Why is hexamethonium historically relevant and why was it removed from clinical use?

A
  • First antihypertensive developed.
  • It had very generalised action thus the side effect profile was very large e.g. loss of bladder control, pupil dilation and loss of GI motility
  • Therefore superseded by more selective antihypertensives
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14
Q

Trimetaphan is the only ganglion blocking drug currently in circulation. Why is it not used very often, when is it used and why?

A
  • Very potent
  • Used during surgery when a controlled hypotension is needed
  • Very short acting so effects are lost quickly
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15
Q

Trimetaphan and hexamethonium are ion channel blocking nicotinic antagonists. What do receptor blockade antagonists interfere with, are they usually reversible or not, what type of substances are these usually, and how do they induce their effect?

A
  • Interfere with the receptor rather than the ion channel
  • Usually irreversible
  • Usually venoms and toxins
  • Bind covalently to the receptor and prevent the ion channels being opened leading to total loss of autonomic function such as paralysis of the skeletal muscle and diaphragm = suffocation and death (e.g. snake venom)
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16
Q

Muscarinic receptor antagonists are more therapeutically useful than nicotinic. Why is this and what are two examples?

A
  • Much more specific, only targeting parasympathetic organs and sweat glands
  • Atropine and Hyoscine
17
Q

Which of the 5 muscarinic receptor subtypes are atropine and hyoscine selective for?

A

M1 and M5

18
Q

What are the CNS effects of atropine at normal (low) dose and toxic dose?

A

Normal dose
- Little effect

Toxic dose
- Mild restlessness –> agitation

19
Q

What are the CNS effects of hyoscine at normal (low) dose and toxic dose?

A

Normal dose
- Sedation, amnesia

Toxic dose
- CNS depression or paradoxical CNS excitation (if patient in pain)

20
Q

Atropine and Hyoscine have opposite effects on the CNS at toxic dose. Why is this?

A
  • Atropine is less M1 selective than Hyoscine
  • Hyoscine also penetrates the brain better, where M1 is predominantly found

These factors combined mean Hyoscine has a larger effect at a lower dose

21
Q

How do M1,2,3,4,5 affect tissue response and how do they do so? (goes some way to explaining atropine’s depressive effect and hyoscine’s excitatory effect)

A

M1,3,5 - Increase phospholipidase C, INCREASED tissue response

M2,4 - Decrease adenylyl cyclase, DECREASED tissue response

22
Q

What are the 6 clinical areas of use of muscarinic cholinoceptor antagonists?

A 
Ophthalmic 
Anaesthetic
Neurological
Parkinson's Disease
Respiratory
Irritable Bowel Syndrome
23
Q

What are the ophthalmic clinical uses of muscarinic cholinoceptor antagonists and which drug is used?

A

Retinal exam
- Blocks muscarinic receptors in the iris leading to:
Pupil dilation (mydriasis) and Muscle relaxation (cycloplegia)
- Can now observe the back of the retina

24
Q

How are muscarinic cholinoceptor antagonists used in anaesthesia?

A

Anaesthetic premedication

  • Bronchodilation
  • Reduced salivary secretions (prevents aspiration of lungs)
  • Slight increase in heart rate (protects against anaesthetic-induced bradycardia)
25
Q

What is the neurological use of muscarinic cholinoceptor antagonists?

A

Hyoscine patch to treat motion sickness

  • Reduces flow of information from labyrinth of inner ear to vomiting centres of the brain
  • This reduces the sensory mismatch between eyes and balance which causes the nausea
26
Q

What is the use of muscarinic cholinoceptor antagonists in treating Parkinson’s Disease?

A

Muscarinic receptor blockers block M4 receptors to increase the effectiveness of the D1 receptors

  • M4 receptors dampens response to available dopamine by inhibiting D1 receptors
  • Blocker administration alleviates the inhibition and improves sensitivity to dopamine
27
Q

What is the use of muscarinic cholinoceptor antagonists in treating respiratory conditions and what are two drugs that are used?

A

Induces bronchodilation to treat asthma/obstructive airways disease
- Ipratropium Bromide and atropine

28
Q

What is Ipratropium Bromide a derivative of, what part of its structure prevents it from diffusing from the lungs into the bloodstream, how does this affect its side effect profile, why does it not cross the blood brain barrier and does this mean it does or doesn’t have CNS side effects?

A
  • Derivative of atropine
  • Large ammonium group prevents it diffusing into bloodstream from lungs
  • Decreases the side effect profile (less systemic distribution = fewer side effects)
  • Possesses a high positive charge (needs to be uncharged to be lipid-soluble and cross BBB)
  • This prevents it from having CNS side effects

Good egg of a drug in respiratory usage

29
Q

How do muscarinic cholinoceptor antagonists treat irritable bowel syndrome?

A

Interfere with parasympathetic effect on GI tract resulting in decreased motility and tone

  • IBS has increased GI transit with motility and tone increased causing high intra-colonic pressure = pain
  • With decreasing of motility and tone, some intra-colonic pressure is relieved and the pain with it
30
Q

What are the four unwanted side effects of muscarinic cholinoceptor antagonists and what are the four phrases used to remember them?

A

“Hot as hell” - reduced sweating and loss of thermoregulation

“Dry as a bone” - reduced secretions

“Blind as a bat” - Cycloplegia (ciliary muscle paralysis, accommodation affected)

“Mad as a hatter” - CNS disturbance

31
Q

What does an excess of atropine do, what is given to treat atropine poisoning and how does the treatment work?

A

Overloads the system, all ACh receptors blocked

  • Anticholinesterases such as PHYSOSTIGMINE given
  • Prevent breakdown of acetylcholine by acetylcholinesterase so increases concentration of ACh in the synapse allowing ACh to outcompete the atropine until the atropine has been eventually cleared from the body
32
Q

How does Botulinum toxic interfere with acetylcholine transmission?

A

Toxin is a protease enzyme - breaks down an important SNARE protein

  • SNARE proteins allow fusion of ACh-filled vesicles with pre-synaptic membrane
  • Toxin impairs this so no ACh can be released into the synapse
  • The most toxic protein known
33
Q

What are the two main clinical uses of BoTox?

A
  • Remove wrinkles by paralysing the skeletal muscle (requires careful local administration)
  • Treat excessive sweating
34
Q

What are the 6 main effects of nicotinic receptor antagonists (ganglion blocking drugs)?

A 
Hypotension
Pupil dilation
Bronchodilation
Bladder dysfunction
Decrease in GI tone
Decrease in secretions
35
Q

Why do nicotinic receptor antagonists cause postural (orthostatic) hypotension?

A

Renin production in kidney is decreased

  • Less angiontensinogen converted to angiotensin I
  • Less vasoconstriction
  • Less aldosterone release from adrenal cortex
  • Reduced sodium and water reabsorption, decreased extracellular fluid volume

All combine to result in hypotension

LCRS Year 2 - Pharmacology and Therapeutics (14 decks)

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