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LCRS 1 - Pharmacology > Cholinomimetics > Flashcards

Cholinomimetics Flashcards

1
Q

How do directly acting cholinomimetics produce their biological actions?

A
  • Muscarinic receptor agonists
  • Stimulate muscarinic receptors
  • Similar structure to ACh
  • Can be choline esters or alkaloids
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2
Q

How do indirectly acting cholinomimetics produce their biological actions?

A
  • Inhibit acetylcholinesterase
  • Tf increase [ACh] in synapse
  • Increase effect of normal parasympathetic nerve stimulation
  • Can be reversible or irreversible
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3
Q

Why are directly acting cholinomimetics more selective?

A

You can use an M1, M2, M3 etc. receptor selective agonist, whereas indirectly acting cholinomimetics inhibit acetylcholinesterase everywhere

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4
Q

What are muscarinic receptor agonists used for clinically?

A
  • Glaucoma
  • Xerostomia (radiation-induced dry mouth)
  • Acute post-operative and postpartum non-obstructive urinary retention
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5
Q

What are the pharmacokinetic properties of muscarinic receptor agonists?

A
  • Half-life = 3-4 hours
  • Admin: pilocarpine -eye drops - glaucoma
  • Admin: bethanecol - orally active
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6
Q

What are anticholinesterases used for clinically?

A

Physostigmine:

  • Glaucoma
  • To treat atropine poisoning i.v.

Neostigmine:

  • Reversal of non-depolarising NM block (tubocurarine)
  • Myasthenia gravis

Ecothiopate:
- Glaucoma

Donepezil + tacrine = Alzheimer’s

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7
Q

What are the signs and symptoms of anticholinesterase poisoning?

A 
CNS excitation 
Convulsions
Unconsciousness
Resp depression
Death
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8
Q

How is anticholinesterase poisoning treated?

A
  1. IV atropine (competitive reversible muscarinic receptor antagonist) to block overstimulation
  2. Artificial respiration
  3. IV pralidoxime to unblock enzymes
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9
Q

Where are muscarinic M3 receptors found?

A

Salivary glands
Bronchial/visceral smooth muscle
Sweat glands
Eye

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10
Q

Where are muscarinic M4 and M5 receptors found?

A

CNS

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11
Q

Are muscarinic receptors generally excitatory of inhibitory?

A

Excitatory except M2 receptors on heart - inhibitory - decrease HR

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12
Q

What type of receptors are muscarinic receptors?

A

Type 2

G-protein coupled

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13
Q

What specific type of G-protein coupled receptors are M1, 3 and 5 Rs?

A

Gq protein linked

Stimulates PLC to increase production of IP3 and DAG

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14
Q

What specific type of G-protein coupled receptors are M2 and 4 Rs?

A

Gi protein linked
Inhibitory
Reduces cAMP production

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15
Q

How does the structure of nicotinic receptors in muscle and in ganglion differ?

A

Muscle = 2 alpha + beta + delta + epsilon subunits

Ganglion = 2 alpha + 3 beta

Subunit combination determines ligand binding properties

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16
Q

What are nicotinic receptors?

A

Ligand gated ion channels

17
Q

How do ACh effects on nicotinic vs. muscarinic receptors differ?

A

Relatively weak on nicotinic

18
Q

What are the general effects of cholinomimetics?

A
  • Decrease HR and CO
  • Increase exocrine gland activity
  • Increase non-vascular SM contractility
  • Miosis (constriction)
19
Q

How do the effects of anticholinesterases (indirect cholinomimetics) differ with dosage?

A

Low dose: enhanced muscarinic activity

Moderate dose:
Further enhancement of muscarinic activity
Increased transmission at all autonomic ganglia

High dose:
Depolarising block at autonomic ganglia and NMJ
Nicotinic receptors overstimulated and shut down

20
Q

How do reversible anticholinesterase drugs work?

A

Alkaloids, e.g. physostigmine, neostigmine

  • Carbamyl esters inactivate enzyme by transferring their carbamyl group
  • Carbamylated enzyme reactivated by slow (mins) hydrolysis
  • Increases duration of ACh activity in synapse
21
Q

Which anticholinesterases can cross the BBB?

A

Physostigmine

Non-polar

22
Q

How do irreversible anticholinesterase drugs work?

A
  • Organophopshate compounds
  • Labile group (flouride or organic) inactivate enzyme by phosphorylation
  • Inactivated phosphorylated enzyme is stable
  • Tf recovery depends upon synthesis of new enzyme (weeks)
23
Q

Why does recovery from irreversible anticholinesterases take days or weeks?

A

Recovery requires production of new enzymes, which takes time

24
Q

Where are nicotinic cholinoceptors found other than the ANS?

A

Somatic NS

But they differ pharmacologically from those found in the ANS

25
Q

What are the pharmacological responses to systemic administration of a muscarinic receptor agonist?

A
  • Contraction of ciliary muscle (allows near vision)
  • Contraction of sphincter pupillae (constricts pupil + aids IOF drainage)
  • Lacrimation, salivation, sweating (SNS), increased bronchial, GI secretions
  • Decrease HR
  • NO release from vascular endothelial cells via M3 receptors –> VSM relaxation –> TPR decrease
  • Decrease BP (drop in HR, CO + vasodilation)
  • Contraction of non-vascular smooth muscle –> bronchoconstriction, increased gut motility, increased bladder emptying
26
Q

Why do choline-esters (bethanechol) have a longer duration of action than acetylcholine?

A

Bethanechol is resistant to degradation by acetylcholinesterase

27
Q

Why is pilocarpine (muscarinic agonist) useful in the treatment of glaucoma?

A

In glaucoma, the angle between cornea and iris narrows –> reduces drainage of IOF via canals of Schlemm

Pilocarpine (muscarinic agonist):

  • Causes iris contraction –> pupil constriction
  • Opens up angle
  • Aids fluid drainage
  • Decreases intraocular pressure
28
Q

What are the main unwanted effects of pilocarpine (muscarinic agonist)?

A
  • Blurred vision
  • Sweating
  • GI disturbance + pain
  • Hypotension
  • Resp distress
29
Q

How are the 2 types of cholinesterases distributed? What is their substrate specificity?

A

Acetylcholinesterase:
ALL cholinergic synapses (peripheral and central)
Highly selective for ACh

Butyrylcholinesterase:
In plasma and most tissues
NOT in cholinergic synapses
Broad substrate specifcity (hydrolyses other esters)
Principal reason for low plasma [ACh]
30
Q

Where do anticholinesterase drugs have the potential to act?

A

At ALL cholinergic synapses

Including NMJ and in the CNS

31
Q

Do anticholinesterases exert more powerful effects on NM transmission or the ANS?

A

ANS

32
Q

Why are anticholinesterases used in treatment of Alzheimer’s

A
  • ACh is important in learning and memory

- Potentiation of central cholinergic transmission relieves AD symptoms, but does not affect degeneration

33
Q

What are the pharmacokinetic properties of anticholinesterases?

A
  • Physostigmine (reversible) half life = 30mins
  • Ecothiopate (irreversible) admin = eye drops (glaucoma); duration of action = weeks
  • Physostigmine can cross BBB
  • Hydrolysed by cholinesterases, microsomal liver enzymes

LCRS 1 - Pharmacology (33 decks)

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