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NS > Pharmacology of cholinergic transmission > Flashcards

Pharmacology of cholinergic transmission Flashcards

1
Q

Two types of receptors for ACh?

A

Nicotinic

Muscarinic

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2
Q

Subunit composition of nicotinic muscle receptor subtype

A

(α1)2β1,δ,ε

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3
Q

Where is the nicotinic receptor found in the muscle?

A

at the skeletal neuromuscular junction

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4
Q

What agonists act on the nicotinic receptor of NMJ?

A

ACh, nicotine (weak), suxamethonium

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5
Q

Antagonists that act on nicotinic receptor of NMJ?

A

Pancuronium, tubocurarine

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6
Q

Subunit composition of the ganglionic subtype receptor

A

(α3)2(β4)3

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7
Q

Where is this ganglion found?

A

autonomic ganglia

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8
Q

Subunit compoisiton of CNS subtype of the nicotinic receptor

A

α4)2(β2)3 or (α7)5

found in the brain

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9
Q

Agonists and antagonists act on the nicotinic receptor in the ganglia and brain?

A

agonists: ACh, nicotine, DMPP

(dimethylphenylpiperazinium)

antagonists: hexamethonium, trimetaphan

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10
Q

Structure of muscarinic receptors?

A
  • metabotropic, G-protein coupled receptors
  • single protein molecule of 400-1000 amino acids
  • 7 transmembrane spanning domains
  • extracellular N-terminus
  • 5 molecular subtypes of MAChR
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11
Q

Where are M3 receptors found in the body?

A
  • pupil constriction
  • ciliary muscle contraction
  • lacrimal gland & salivary gland- increased secretion
  • airway smooth muscle- bronchoconstriction
  • exocrine glands- secretion
  • smooth muscle contraction in upper GI tract- increase in motility
  • dilation of sphincters in upper GI tract
  • gland secretion in upper GI tract
  • smooth muscle contraction of bladder
  • dilation of blood vessels in genitalia
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12
Q

Where are M2 receptors found?

A
  • in SA node to decrease heart rate
  • in AV node to decrease conduction velocity
    (no effect on ventricular muscle)
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13
Q

Location and action of M1 receptors

A

Gastric acid secretion in upper GI tract

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14
Q

describe M1 muscarinic receptors

A
  • GPCR
  • found in CNS, enterochromaffin cells in the stomach to regulate gastric acid secretion
  • when activated: activation of PLC/IP3/DAG signalling leading to closure of potassium channels
  • effects include gastric acid secretion and nerve cell excitation
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15
Q

explain the PLC/IP3/DAG signalling pathway

A

PLC- phospholipase C
IP3- inositol 1,45 triphosphate
DAG- diacylglycerol
PIP2

M1 receptor activation by acetylcholine

beta and gamma subunits leave producing the active form of the receptr

Phospholipase
C catalyses the hydrolysis of the phospholipid PIP2

Results in formation of IP3- stimulates release of calcium and activation of calcium dependent responses e.g. smooth muscle contraction

DAG is formed which stimulates protein kinase C

phosphorylation of target proteins

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16
Q

Action of M2 receptors

A
  • GPCR
  • found in CNS and pacemaker cells (AVN, SA)
  • cellular response- reduction in heart rate and reduction in conduction velocity
  • inhibition of adenyl cyclase (AC) leading to reduced levels of cAMP and opening of potassium ion channels
  • key effects- decreased heart rate, nerve cell inhibition
17
Q

adenylyl cyclase- cAMP signallng pathway

A

stimulation of adneylyl cyclase

causes ATP to converto cAMP
cAMP activates protein kinase A
phosphorylation of targtet proteins

Gs protein (beta adrenoreceptor) stimulates adenylyl cyclase

Gi protein (M2 receptor) inhibits adenylyl cyclase

18
Q

Action of M3 receptors

A
  • GPCR
  • found widespread throughout the body on smooth muscle in GI tract, airways, secretory glands and bladder
  • cellular response when activated- activation of PLC/IP3/DAG signalling pathway leading to closure of potassium channels
  • leading to bronchoconstriction, increased GI motility, galnd secretion, bladder emptying, contraction of ciliary muscle and pupil constriiction
19
Q

What drugs affect ganglia?

A

nicotinic receptor agonists and antagonists

20
Q

Nicotinic receptor agonists

A

ganglion stimulants

preferentially activate nicotinic receptors in autonomic ganglia

e.g. nicotine, lobeline, DMPP

no clinical use

21
Q

CNS and peripheral effects of nicotine

A

CNS effects
Drug dependence and tolerance due to complex action of nicotine on nicotinic receptors in the CNS ((α4)2(β2)3 subtype
• Increased alertness
• Arousal
• Enhanced learning
• Reduced anxiety and tension
Peripheral effects
• Tachycardia; increased cardiac output, BP
• Reduced GI motility
• Sweating
• Nausea and vomiting for first time smokers
• Tolerance develops to peripheral effects
Harmful effects of smoking
• Cancer, coronary artery disease, emphysema

22
Q

Nicotinic receptor antagonists

A
  • Also called ganglion blockers
  • Used experimentally but only rarely clinically
  • Examples include hexamethonium and trimetaphan
  • Major effect of ganglion blockers is a reduction in blood pressure (postural hypotension upon standing)
  • Mainly side effects- ‘hexamethonium man’
  • Trimetaphan used clinically to reduce bleeding during surgery
23
Q

Muscarinic receptor agonists

A
  • Also called parasympathomimetics
  • Activate muscarinic receptors but NOT nicotinic receptors and include pilocarpine and bethanacol
  • Limited clinical use because they show little selectively between muscarinic receptor subtypes
  • Pilocarpine eyed drops are used in treatment of glaucoma (pin point pupil and ciliary muscle spasm are side effects)
  • Bethanacol is used as a stimulant laxative and to treat urinary retention
24
Q

What are the parasympathomimetic effects of pilocarpine in gluacome?

A
  1. Contraction of constrictor muscle (M3 receptors): pupil constriction (miosis)
  2. Contraction of ciliary muscle (M3 receptors): suspensory ligaments lose tension and then lens adopts a fatter, spherical shape to accommodate for near vision

Contraction of ciliary muscle; improves aqueous humour flow reducing intraocular pressure (IOP)

25
Q

Muscarinic receptor antagonists

A

• Also called parasympatholytics or anti-cholinergics
• Actions include
 Dilation of pupil (mydriasis); paralysis of ciliary muscle (cycloplegia); increased intraocular pressure (therefore dangerous in glaucoma)
 Dry mouth and skin; increase in body temperature
 Tachycardia
 Bronchodilation
 High doses required to inhibit gastric motility; inhibition of gastric acid secretion
 Inhibition of bladder emptying (urinary retention)
 CNS excitation (restlessness, agitation, disorientation)

26
Q

ATROPINE

A

muscarinic receptor antagonist

to treat sinus bradycardia

27
Q

CYCLOPETOLATE, TROPICAMIDE

A

muscarinic recepto antagonist

used to dilate pupil

28
Q

IPRATROPIUM, TIOTROPIUM

A

to treat asthma and COPD

29
Q

DICYCLOVERINE

A

antispasmodic in IBS

30
Q

PIRENZEPINE (M1 selective)

A

muscarinic receptor antagonist

peptic ulcer

31
Q

OXYBUTYNIN, DARIFENAXIN (M3 selective), TOLTERODINE

A

muscarinic receptor antagonist

to treat urinary incontinence

32
Q

HYOSCINE

A

to treat motion sickness

33
Q

BENXHEXOL, BENZTROPINE

A

to treat PD

34
Q

acetylcholinesterase

A
  • ACh is inactivated following hydrolysis by the enzyme AChE, an extracellular enzyme tethered to cell membranes
  • A soluble form of the enzyme is also found inside cholinergic nerve terminals, inside erythrocytes in cerebrospinal fluid
  • A related enzyme, butyrylcholinesterase (BChE) is found in blood plasma but is also widely distributed in tissues like liver, skin, brain and GI muscle
  • BChE is important in the hydrolysis of ester drugs such as procaine and suxamethonium
35
Q

AChE inhibitors

A

• Also called cholinesterase inhibitors
• Such drugs potentiate the actions of ACh by preventing its breakdown thus prolonging its action in the synapse
• Several classes of AChE inhibitors, distinguished in terms of their duration of action
 Short acting (minutes) eg. edrophonium
 Medium acting (hours) eg. neostigmine, physostigmine
 Long acting (irreversible) eg organophosphates insecticides
• Duration of action is determined by the strength of the bonds formed between the inhibitors and the esteratic site on the enzyme.

36
Q

Actions of AChE drugs

A

• Enhance transmission in all autonomic ganglia and at parasympathetic neuroeffector junctions so have complex effects; largely parasympathomimetic
o Increased secretions (saliva, sweat, gastric acid, mucus, tears)
o Increased smooth muscle tone (bronchoconstriction, increased GI peristaltic activity)
o Miosis, cycloplegia, reduced intraocular pressure
o Bradycardia, hypotension
• With high doses, depolarising block of synaptic transmission at autonomic ganglia can occur
• Tertiary AChE inhibitors and non-polar organophosphates readily penetrate blood brain barrier; produce initial excitation, followed by convulsion and depression, unconsciousness and respiratory failure

37
Q

Clinical uses of AChE drugs

A

• Reverse the effects of non-depolarising muscle relaxants eg. neostigmine
• Used in diagnosis (edrophonium) and treatment (neostigmine) of myaesthenai gravis
• Used in eye drops (physostigmine) to treat glaucoma
Loss of cholinergic neurones with ageing is believed to account for much of the learning and memory deficits in Alzheimers Disease (AD). AChE inhibitors (donepezil, rivastigmine) have been shown to be of some benefit in treating the early stages of AD

NS (7 decks)

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