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Pharmacology and Therapeutics > 6. Cholinomimetics > Flashcards

6. Cholinomimetics Flashcards

1
Q

What are cholinomimetics?

A
  • Drugs that mimic the action of ACh in the body

* Parasympathomimetic drugs

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2
Q

What is muscarine?

A
  • Selective muscarinic agonist

* Can replicate muscarinic effects

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3
Q

How can muscarinic effects be abolished?

A

Low doses of atropine

- a muscarinic antagonist

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4
Q

What happens after an atropine blockade?

A

• Muscarinic actions blocked
• Large dose of ACh produced
• Induce effects similar to those caused by nicotine
(• Nictonic receptors are in all autonomic ganglia/motor neurones)

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5
Q

What are the 3 main muscarinic receptors and what do they do?

A

M1
• CNS - excitation
• Salivary glands
• Stomach - stimulates HCl release

M2
• Heart (atria and in both nodes) - decreases heart rate

M3
• Salivary glands
• Bronchial/Visceral smooth muscle
• Swear glands
• Eye
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6
Q

Where are M4 and M5 found?

A

CNS

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7
Q

Are muscarinic receptors generally excitatory or inhibitory?

A

Excitatory (apart from M2 on heart)

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8
Q

What type of receptor are muscarinic receptors?

A

Type 2 (G-protein coupled)
• M1, M3, M5: Gq => stimulates PLC to increase IP3 and DAG
• M2, M4: Gi => inhibitory - reduces cAMP

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9
Q

Describe the structure and types of nicotinic receptors

A
  • Ligand gated ion channels
  • 5 subunits (α, β, γ, δ, ε)
  • Combination of subunits determines ligand binding properties
  • Muscle - 2α, β, δ, ε
  • Ganglion - 2α, 3β
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10
Q

How does the effect of ACh on nictonic receptors compare to that of muscarinic receptors?

A

Relatively weak on nicotinic

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11
Q

What are the 3 main muscarinic effects on the eye?

A
  • Contraction of the ciliary muscle (near vision)
  • Contraction of sphincter pupillae (circular muscles) - constriction of pupil (miosis) - increased drainage of intraocular fluid
  • Lacrimation
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12
Q

What is glaucoma?

A
  • Increase in intraocular pressure

* Can damage the optic nerves and retina => blindness

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13
Q

Where is the aqueous humour generated and what does it do?

A
  • Generated by capillaries of ciliary body
  • Flows into anterior chamber of the eye
  • Supplies oxygen and nutrients to the lens and cornea as they don’t have a blood supply
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14
Q

How does the aqueous humour drain?

A
  • Diffuses forwards across the lens then across the cornea

* Drains through the canals of Schlemm back into the venous system

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15
Q

What is Angle-closure glaucoma?

A
  • Angle between cornea and iris becomes narrowed

* Reduced drainage of intraocular fluid via canals of Schlemm

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16
Q

How can you increase drainage of intraocular fluid in a aptient with glaucoma?

A

• Administer muscarinic agonist
- contraction of iris - opens up angle
• Increased drainage through the canals of Schlemm

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17
Q

Describe how ACh achieves its muscarinic effect on the heart

A
  • ACh on M2 AChR
  • Decrease in cAMP
  • Decreased Ca2+ entry => decreased CO
  • Increased K+ efflux => decreased heart rate
  • Drop in BP
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18
Q

Describe the muscarinic effects on vasculature

A
  • Although most blood vessles have no parasympathetic innervation, they do have receptors
  • ACh acts on vascular endothelial cells (M3) => NO release => VSMC relaxation
  • Decreased TPR
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19
Q

Describe the muscarinic effects on non-vascular smooth muscle

A
  • Responds in opposite way to VSMCs
  • Contracts
  • Lungs - bronchoconstriction
  • Gut - increased peristalsis/motility
  • Bladder - increased emptying
20
Q

What are the muscarinic effects on exocrine glands

A
  • Salivation
  • Increased bronchial secretions
  • Increased GI secretions (HCl production)
  • Increased sweating
21
Q

Summarise the muscarinic effects in the body

A
  • Decreased heart rate
  • Decreased BP
  • Increased sweating
  • Difficulty breathing
  • Bladder emptying
  • GI pain
  • Increased salivation and tears
22
Q

What are the 2 types of cholinomimetics?

A
  • Directly acting (usually muscarinic receptor agonists)

* Indirectly acting

23
Q

What are the 2 types of muscarinic receptor agonists?

A
  • Choline esters (bethanechol)

* Alkaloids (pilocarpine)

24
Q

Explain the use of pilocarpine

A

• Derived from leaves of the plant Pilocarpus

  • Non-selective muscarinic agonist (stimulates ALL muscarinic receptors)
  • Good lipid solubility and half life of 3-4 hours
  • Useful to treat glaucoma - constricts sphincter pupillae and opens up canals of Schlemm
25
Q

What are the side effects of Pilocarpine and Bethanechol

A 
General effects of parasympathetic discharge
• blurred vision
• sweating
• GI pain/nausea
• hypotension
• bradycardia
• respiratory difficulty
26
Q

Explain the use of Bethanechol

A
  • Very similar to ACh - M3 receptor SELECTIVE agonist
  • Resistant to degradation by acetylcholinesterase
  • Limited access to brain
  • Half life of 3-4 hours
  • Used to assist bladder emptying and enhance gastric motility
27
Q

What are indirectly acting cholinomimetic drugs?

A
  • Drugs that inhibit acetylcholinesterase
  • This increases ACh in the synapse
  • This increases the effect of normal parasympathetic nerve stimulation
28
Q

Give some examples of reversible anticholinesterases

A
  • Physostigmine
  • Neostigmine
  • Donepezil
29
Q

Give some examples of irreversible anticholinesterases

A
  • Ecothiopate
  • Dyflos
  • Sarin
30
Q

What do cholinesterase enzymes do and what are the 2 different types?

A

• Metabolise ACh to choline and acetate

  • Acetylcholinesterase
  • Butyrylcholinesterase
31
Q

Describe the 2 cholinesterases

A

Acetylcholinesterase
• In all cholinergic synapses (peripheral and central)
• Very rapid action
• Highly selective for ACh

Butyrylcholinesterase
• Found in plasma and most tissues - NOT cholinergic synapses
• Broad substrate specificity - hydrolyses other esters
• Principle reason for low plasma ACh
• Variation of effects in populations (genetic variation)

32
Q

What is the effect of a low dose of cholinesterase inhibitor?

A

Enhanced muscarinic activity

33
Q

What is the effect of a moderate dose of cholinesterase inhibitor?

A
  • Further enhancement of muscarinic activity (than low dose)

* Increased transmission at ALL autonomic ganglia (muscarinic and nicotinic)

34
Q

What is the effect of a high dose of cholinesterase inhibitor?

A
  • Depolarising block at autonomic ganglia and neuromuscular junction
  • Nicotinic receptors overstimulated - shut down
35
Q

How do reversible anticholinesterase drugs work?

A
  • Physostigmine and neostigmine
  • Donate a carbamyl group to the enzyme - blocking active site
  • ACh blocked from binding
  • ACh activity therefore increases
  • Carbamyl group removed by slow hydrolysis
36
Q

How does physostigmine specifically work and what it it used for?

A

(• Reversible anticholinesterase)
• Naturally occurring tertiary amine from Calabar beans
• Acts at postganglionic parasympathetic synapse
• Half life of 30mins
• Used in glaucoma - drainage of intraocular fluid
• Treats atropine poisoning - increases ACh to outcompete atropine (atropine is a competitive muscarinic antagonist - surmoutable)

37
Q

What type of compounds are irreversible anticholinesterase drugs?

A

Organosphosphate compounds

38
Q

Give some examples of irreversible anticholinesterase drugs

A
  • Ecothiopate (only one in clinical use - others are insecticides/nerve gas)
  • Dyflos
  • Sarin
  • Parathion
39
Q

How do irreversible anticholinesterase drugs work

A
  • Rapidly react with enzyme active site
  • Leave a large blocking group - stable and resistant to hydrolysis
  • Recovery requires production of new enzymes (days/weeks)
40
Q

What is ecothiopate used for and what are the side-effects?

A

(• Irreversible anticholinesterase)
• Eye drops in treatment of glaucoma
• Has prolonged duration of action
• Side-effects are that of parasympathetic discharge (sweating, blurred vision, GI pain etc.)

41
Q

What type of anticholinesterases can cross the blood-brain barrier?

A

Non-polar e.g. physostigmine, nerve agents

42
Q

What is the effect of a low dose of anticholinesterase drugs on the CNS?

A
  • CNS excitation

* Possibility of convulsions

43
Q

What is the effect of a high dose of anticholinesterase drugs on the CNS?

A
  • Unconsciousness
  • Respiratory depression
  • Death
44
Q

What is Donepezil and Tacrine useful in treating and why?

A
  • Alzheimer’s disease
  • ACh important in learning and memory
  • Potentiation of central cholinergic transmission relieves AD symptoms
  • Does not affect degeneration
45
Q

What does exposure to nerve agents lead to and how can it be treated?

A
  • Increased muscarinic activity => CNS excitation => depolarising NM block
  • Reduction in acetylcholinesterase - too much ACh

Treatment
• IV atropine - blocks ACh overstimulation
• respirator (due to respiratory depression)
• IV pralidoxime - unblocks enzymes

Pharmacology and Therapeutics (33 decks)

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