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YR2 LCRS Pharmacology > 6. Cholinomimetics > Flashcards

6. Cholinomimetics Flashcards

1
Q

what is acetylcholine (ACh) synthesised from and what catalyses the reaction?

A

acetyl CoA + choline

choline acetyltransferase (CAT)

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2
Q

what does depolarisation of the presynaptic knob cause?

A

causes the opening of voltage sensitive calcium channels and the influx of calcium causes exocytosis of ACh

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3
Q

what constitutes a muscarinic effect?

A

those that can be replicated by muscarine (selective muscarinic antagonist) and that correspond to parasympathetic stimulation

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4
Q

give an example of a muscarinic antagonist

A

atropine

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5
Q

what type of receptor do most motor neurones have and how many neurones are involved?

A

mostly cholinergic receptors

single neurone involved

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6
Q

where can the muscarinic receptor subtypes be found?

A

*M1: salivary glands, stomach (HCl release), CNS (excitation)
*M2: heart (decreases HR)
*M3: salivary glands, bronchial/visceral smooth muscle, sweat glands, eye
M4,M5: CNS

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7
Q

what similarities do all the muscarinic receptors share?

A
  • generally excitatory (except M2 on the heart which is inhibitory)
  • all type 2 receptors (G-protein coupled) -> M1, M3 and M5 involve Gq protein with IP3 and DAG, M2 and M4 involve Gi protein with cAMP
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8
Q

what are nicotinic receptors and what 5 units make them up?

A

ligand gated ion channels

subunits: α β γ δ ε

subunit combination determines ligand binding properties of the receptor

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9
Q

what are the 2 main types of nicotinic receptor and what subunits make them up?

A

in the muscle: 2α+ β + δ + ε

ganglion: 2α+ 3β

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10
Q

what are the muscarinic effects on the eye?

A
  • ciliary muscle contracts: accommodation for near vision
  • sphincter pupillae contracts (circular muscle of iris): causes miosis (constriction), increases intraocular fluid drainage
  • lacrimation (tears)
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11
Q

why is the stimulation of muscarinic receptors useful for glaucoma?

A

give patient a muscarinic agonist -> causes contraction of the iris -> opens up the angle and increases drainage of intraocular fluid through the canals of Schlemm

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12
Q

what is the role of aq. humour?

A

to supply oxygen and nutrients to the lens and cornea

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13
Q

what causes angle-closure glaucoma?

A

when the angle between the cornea and iris becomes narrowed, reducing the drainage of intraocular fluid via the canals of Schlemm

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14
Q

what are the muscarinic effects on the heart?

A

M2 receptors found in the atria and in both nodes of the heart are inhibitory

reduced cAMP -> reduced Ca2+ entry -> decreased CO

reduced cAMP -> increased K+ efflux -> decreased HR

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15
Q

what are the muscarinic effects on vasculature?

A

ACh acts on vascular endothelial cells to stimulate NO release via M3 AChR which induces vascular smooth muscle relaxation and results in decreased TPR

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16
Q

what are the muscarinic effects on the CVS?

A
  • decreased heart rate
  • decreased CO die to decreased atrial contraction
  • vasodilation due to NO production
  • drop in BP
17
Q

what are the muscarinic effects on non-vascular smooth muscle?

A

smooth muscle with parasympathetic innervation responds in the opposite way to vascular muscle (contracts):

  • lung: bronchoconstriction
  • gut: increases peristalsis
  • bladder: increased emptying
18
Q

what are the muscarinic effects on exocrine glands?

A
  • salivation
  • increased bronchial secretions
  • increased GI secretions (inc. GI HCl)
  • increased sweating
19
Q

summarise the muscarinic effects

A
  • decreased HR
  • decreased BP
  • increased sweating
  • difficulty breathing
  • bladder contraction
  • GI pain
  • increased salivation and tears
20
Q

what are the directly acting cholinomimetic drugs that are typical muscarinic agonists?

A
  • choline esters (bethanechol)

- alkaloids (pilocarpine)

21
Q

describe the muscarinic agonist bethanechol

A
  • minor modification of ACh
  • produces an M3 AChR selective agonist
  • resistant to degradation by acetylcholinesterase
  • orally active
  • limited access to brain
  • mainly used to assist bladder emptying and enhance gastric motility
22
Q

describe the muscarinic agonist pilocarpine

A
  • non-selective muscarinic agonist
  • good lipid solubility
  • useful in ophthalmology as a local treatment for glaucoma -> constricts sphincter pupillae and opens up canal of Schlemm to increase IO fluid drainage
23
Q

what are the side effects of bethanechol and pilocarpine?

A

impaired vision, nausea, sweating, hypotension, bradycardia, respiratory distress

24
Q

what do indirectly acting cholinomimetic drugs do?

A

increase effect of normal parasympathetic nerve stimulation by inhibiting acetylcholinesterase to increase ACh in the synapse

25
Q

give an example of a reversible and irreversible anticholinesterase

A

reversible - physostigmine

irreversible - ecothiopate

26
Q

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

A

metabolise ACh into choline and acetate

  1. acetycholinesterase (true)
  2. butyrylcholinesterase (pseudocholinesterase)
27
Q

describe acetylcholinesterase

A
  • found in all cholinergic synapses (peripheral and central)
  • very rapid action
  • highly selective for ACh
28
Q

describe butyrylcholinesterase

A
  • found in plasma and most tissues but not cholinergic synapses
  • broad substrate specificity
  • shows variation in population
  • is principal reason for low plasma ACh
  • shows genetic variation
29
Q

what are the effects of cholinesterase inhibitors at different doses?

A 
LOW DOSE:
- enhanced muscarinic activity
MODERATE DOSE:
- further enhancement
- increased transmission at all autonomic ganglia 
HIGH DOSE (TOXIC):
- depolarising block at autonomic ganglia and NMJ
- overstimulation of nicotinic receptors
30
Q

what do the reversible anticholinesterase drugs physostigmine and neostigmine do?

A

compete with ACh for active site on the cholinesterase enzyme

donates a carbamyl group to the enzyme, blocking the active site and preventing ACh binding

carbamyl group is removed by slow hydrolysis (mins) which increases the duration of ACh activity in the synapse

31
Q

what is physostigmine used to treat and why?

A
  • treats glaucoma (aids IO fluid drainage)
  • treats atropine poisoning

atropine is a competitive muscarinic antagonist and is so surmountable, physostigmine increases the concentration of ACh in the synapse so that it can outcompete atropine

32
Q

what do the irreversible anticholinesterase drugs such as ecothiopate do?

A

rapidly react with the enzyme active site, leaving a large blocking group which is stable and resistant to hydrolysis

recovery may require the production of new enzymes (days/weeks)

33
Q

what is ecothiopate used to treat and why?

A

used as eye drops in glaucoma treatment because it increases IO fluid drainage due to prolonged duration of action

34
Q

what effects do anticholinesterase drugs have on the CNS?

A

non-polar anticholinesterases (e.g. physostigmine) can cross the BBB

low doses: CNS excitation with possible convulsions
high doses: unconsciousness, respiratory depression, death

35
Q

what is used to treat alzheimer’s disease?

A

donepezil and tacrine (anticholinesterases)

ACh is important in learning and memory -> enhancement of central cholinergic transmission relieves AD symptoms and does not affect degeneration

36
Q

what are non-clinical uses of anticholinesterases and what can exposure to these cause?

A

insecticides and nerve agents

exposure can cause organophosphate poisoning: muscarinic activity -> CNS excitation -> depolarising NM block

37
Q

what is the treatment for organophosphate poisoning?

A
  • intravenous atropine which is a muscarinic antagonist on the effector organ
  • patient is put on a respirator because of respiratory destress
  • if found in the first few hours the patient can be given pralidoxime which unblocks the enzymes

YR2 LCRS Pharmacology (32 decks)

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