PHARM 6: Cholinomimetics Flashcards

1
Q

Define cholinomimetics.

A

Cholinomimetics = drugs that mimic the action of Ach in the body

  • they are parasympathomimetic drugs
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2
Q

Describe the synthesis of Ach

A
  • Ach = synthesized from acetyl CoA + choline
  • via Choline Acetyltransferase (CAT)
  • Ach is pumped into vesicles
  • await signal
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3
Q

Describe the release of Ach

A
  • depolarization causes opening of VGCC
  • causes influx of Ca2+
  • causes exocytosis of Ach
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4
Q

What enzyme breaks down Ach?

A
  • acetylcholinesterase
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5
Q

Compare differences between muscarinic + nicotinic effects

A

Muscarinic effects:

  • can be replicated by muscarine
  • can be abolished by low doses of muscarinic antagonist ATROPINE
  • corresponds to those of parasympathetic stimulation
  • after atropine blockade, larger doses of Ach can induce effects similar to those caused by nicotine.
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6
Q

What are the three main receptor subtypes of muscarinic receptors and where are they located?

A

M1

  • CNS
  • Salivary Glands
  • stomach

M2
- Heart

M3

  • Salivary Glands
  • Bronchial/ Visceral Smooth muscle
  • sweat glands

note:
M4/5 = in CNS

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7
Q

Muscarinic Receptors are generally excitatory / inhibitory

the except is ____

A

Muscarinic Receptors are generally excitatory

the except is M2 (inhibitory)

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8
Q

All Muscarinic receptors = Type __ receptors

M1/3/5 =

M2/4 =

A

All Muscarinic receptors = Type 2 receptors
(G Protein Coupled)

M1/3/5 = Gq protein linked receptor —> stimulates PLC to increase production of IP3 + DAG

M2/4 = Gi protein linked receptor —> (inhibitory) reduces production of cAMP

odd = Gq
even = Gi
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9
Q

Nicotinic Receptors =
_______ gated ion channels

with __ subunits

There are 2 main types of nicotinic receptor
in the _____ and in the _____

A

Nicotinic Receptors =
LIGAND gated ion channels

with 5 subunits
(ALPHA, BETA, GAMMA, DELTA, EPSILON)

There are 2 main types of nicotinic receptor
in the MUSCLE and in the GANGLION

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10
Q

What are the 3 main muscarinic effects on the eye?

A
  1. contraction of the ciliary muscle
    (for near vision)
  2. Contraction of sphincter papillae
    (constricts pupil + increases drainage of intraocular fluid)
  3. Lacrimation
    (tears)
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11
Q

What is Glaucoma?

A

Glaucoma = Increase in Intraocular pressure

  • can cause damage to optic nerves + retina
  • can lead to blindness
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12
Q

What generates aqueous humour?

A
  • generated by capillaries of the ciliary body

- flows into anterior chamber of eye

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13
Q

what is the role of the aqueous humour?

A
  • to supply o2 and nutrients to lens + cornea

- as they don’t have a blood supply

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14
Q

Describe the drainage of aqueous humour

A
  • diffuses forwards across the lens
  • then across the cornea
  • drains through canals of scheme
  • back into the venous system
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15
Q

What happens in angle closure glaucoma?

A

angle between cornea + iris becomes narrowed

- this narrowing reduces drainage of intraocular fluid via the canals of schlemm

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16
Q

How would you treat angle closure glaucoma?

A
  • give these patients a muscarinic agonist (stimulates muscarinic receptors)
  • which causes contraction of the iris
  • this opens up angle increases drainage of intracocular fluid through then canal of schlemm
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17
Q

What are muscarinic effects on the heart + cardiovascular system?

Where are M2 receptors specfically found?

A
  • M2 receptors are inhibitory
  • slows down the heart rate
  • decreases cardiac output
  • causes vasodilation
  • -> causes drop in BP

M2 receptors found in atria + in both nodes.

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18
Q

What are muscarinic effects on vasculature?

A
  • Ach acts on vascular endothelial cells –> to stimulate NO release
  • via M3 receptors
  • NO induces –> VSMC relaxation
  • causes decrease in TPR
19
Q

What are the muscarinic effect on Non vascular smooth muscle?

A
  • Non vascular smooth muscle with parasympathetic innervation:
    (OPPOSITE TO VSMC)
    –> it contracts

so
LUNGS - bronchoconstriction
GUT - Increased motility
BLADDER - Increase bladder emptying

20
Q

What are muscarinic effects on exocrine glands?

A
  • Salivation
  • increase bronchial secretions
  • increased GI secretions
  • Increased sweating
21
Q

What are typical agonists at muscarinic receptors? (2)

directly acting cholinomimetic drugs

A
  1. choline esters (bethanechol)

2. alkaloids (pilocarpine)

22
Q

Describe the muscarinic agonist Pilocarpine

what is it useful for?
what are some side effects?

A
  • non selective muscarinic agonist
  • good lipid solubility
  • half life = 3-4 hr

USES
- useful for local treatment for glaucoma

SIDE EFFECTS

  • blurred vision
  • sweating
  • GI disturbance
  • Hypotension
  • Respiratory distress
23
Q

Describe the muscarinic agonist Bethanechol

what is it useful for?
what are some side effects?

A
  • M3 AchR
  • selective agonist
  • produced from minot modification of Ach

USES

  • assists bladder emptying
  • enhances Gastric motility

SIDE EFFECTS

  • sweating
  • impaired vision
  • bradycardia
  • hypotension
  • respiratory difficulty
24
Q

What are indirectly acting cholinomimetic drugs?

A

drugs that increase effect of normal parasympathetic nerve stimulation

  • inhibits acetylcholinesterase
  • so therefore increases amount of Ach building up in the synapse
  • -> which increases effect of normal parasympathetic nerve stimulation
25
Q

What are the 2 types of anticholinesterases?

give examples

A
  1. reversible Anticholinesterases
    - physostigmine
    - neostigmine
    - donepezil
  2. Irreversible Anticholinesterases
    - ecothiopate
    - dyflos
    - sarin
26
Q

what is the key function of cholinesterase enzymes?

A
  • to metabolism Ach —> choline + acetate
27
Q

What are the 2 types of cholinesterase?

A

a) Acetylcholinesterase

b) Butyrylcholinesterase

28
Q

Compare between Acetylcholinesterase and Butyrylcholinesterase

A

ACETYLCHOLINESTERASE:

  • Found in ALL cholinergic synapses
  • Very RAPID action
  • highly selective for Ach

BUTYRYLCHOLINESTERASE:

  • found in PLASMA + most TISSUES but NOT in cholinergic synapses
  • has broad substrate specificity
  • it is the principal reason for low plasma acetylcholine
  • shows genetic variation
29
Q

What are the effects of cholinesterase inhibitors at

Low Dose:

Moderate Dose:

High Dose:

A

What are the effects of cholinesterase inhibitors at

Low Dose:
- enhances muscarinic activity

Moderate Dose:
- further enhances muscarinic activity
- there is increased transmission at ALL autonomic ganglia
(due to inc in Ach conc at all cholinergic synapses)

High Dose:

  • causes Depolarising block at autonomic ganglia + neuromuscular junction
  • nicotinic receptors get overstimulated –> shuts down
30
Q

How do reversible anti cholinesterase drugs work?

Give examples

A
  • they compete with Ach for active site on acetylcholinesterase
  • and then donates carbamyl group to the enzyme
  • blocks active site
  • prevents Ach from binding
  • caramel groups = removed by slow hydrolysis
  • INCREASES duration of Ach activity in synapse

e.g physostigmine, neostigmine

31
Q

Where does physostigmine primality act at?

A
  • primarily acts on post ganglionic parasympathetic synapse
32
Q

what is the half life of physostigmine?

A

half life = 30 mins

33
Q

what is physostigmine used for?

why?

A
  • used in glaucoma
  • -> increases drainage of intraocular fluid
  • used in atropine poisoning
  • -> increases conc of Ach at synapse
  • -> so that Ach can outcompete the atropine
34
Q

How do irreversible Anticholinesterase drugs work?

give examples + uses

A
  • they are organophosphate compounds
  • they rapidly react with the enzyme active site
  • leaving a large blocking group
  • blocking group = stable + resistant to hydrolysis

e.g ecothipate (clinical)
dyflos, sarin, parathion (insecticides/ nerve gas)

35
Q

What is the use of ecothipate?

why?

A
  • ecothipate = potent inhibitor of acetylcholinesterase
  • used as eye drop for glaucoma treatment
  • it increases drainage of intraocular fluid + has a prolonged duration of action
36
Q

What are side effects of using ecothipate?

A

side effects –> of parasympathetic discharge

  • sweating
  • blurred vision
  • GI disturbance + pain
  • Bradycardia
  • Hypotension
  • respiratory difficulty
37
Q

effect of Anticholinesterase drugs on CNS at

Low Dose:

High Dose:

A

effect of Anticholinesterase drugs on CNS at

Low Dose:
- CNS excitation with possibility of convulsions

High Dose:
- Unconsciousness, respiratory depression + death

38
Q

Non polar anticholinesterases can/cannot cross the BBB

A

Non polar anticholinesterases can cross the BBB

39
Q

What 2 anticholesterase drugs are used to treat Alzheimer’s disease?

A
  • Donepezil

- Tacrine

40
Q

How does exposure to organophosphates cause severe toxicity?

A
  • causes increase in muscarinic activity
  • causes CNS excitation
  • resulting in depolarizing NM block
41
Q

How would you treat exposure to organophosphate poisoning ?

A

TREATMENT

  • IV atropine
  • patient = put on respirator due to respiratory depression
  • found in first few hrs: patient given Pralidoxime (IV) –> unblocks the enzymes
42
Q

Why do you use Atropine to treat organophosphate poisoning?

A
  • organophosphate poisoning results in massive reduction in activity of acetylcholinesterase
  • which leads to increase in synaptic Ach conc
  • to block Ach from over stimulating the receptors –> you give muscarinic antagonist (ATROPINE)
43
Q

Describe the removal of Ach

A
  • Acetylcholinesterase (bound to basement memb) breaks down Ach
  • into choline + acetate
  • choline is then re uptaken
    and used to produce more Ach
44
Q

list the distribution of muscarinic cholinergic target systems.

A
  • eye
  • salivary glands
  • lungs
  • bladder
  • sweat glands
  • gut
  • heart
  • vasculature