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cholinergic pharmacology Flashcards

1
Q

M1, 3, 5 is what type of GPCR and their actions?

A

Gq, activates IP3 and DAG, increases intracellular levels - smooth muscle contraction or excocytosis of more stuff?

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2
Q

M2, 4 is what type of GPCR and what are their actions?

A

Gi, inhibits the adenylyl cylcase and decrease intracellular cAMP

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3
Q

Muscarinic receptors stimulate the parasympathetic system, parasympathomimetics, what are the actions of muscarinic agonists?

A

decreased HR and contractility, decreased IOP (hence can treat glaucoma), constriction of constrictor pupillae, bronchoconstriction, GI: increase SM contraction and relaxation of sphincters, secretagogue: increased salivatory, lacrimation and stomach acid secretion

ACh-mediated sympathetic vasodilation via the release of NO as well `

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4
Q

M1, M2, and M3 act on which part

A

M1: neural
M2: cardiac
M3: glandular, smooth muscle

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5
Q

M1 effects

A

gastric acid secretion, slow excitation of ganglion and gut motility increased

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6
Q

M2 effects

A

heart: decreased rate and force of heart contractions (due to decreased AV node conduction frequency and increased AV nodal delay) and inhibition of neurotransmitter release

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7
Q

M3 effects

A

more glandular i guess, then gastric acid secretion, glandular secretion (salivary, sweat, exocrine pancrease), smooth muscle contraction (gut, bladder), pupillary constrcition, ciliary muscle contracts, (gut) relaxes sphincters and ctronacts wall

vasofilation via NO

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8
Q

mAChR agonists?

A

muscarine, pilocarpine

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9
Q

what can mACh agonoists be used for clincally?

A

treatment of glaucoma (decreases the IOP, opens the trabecular meshwork at the canal of Schlemm), xeriostomia

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10
Q

do you remember the 4 strucuture sof the:
acetylcholine
methacholine
bethanechol
carbachol

and which one is preferred to muscarine?

A

the CH3 on the beta carbon is more muscarinic specific

Methacholine and bethanechol are muscarinic specific

carbachol and bethanachol are resistant to hydrolysis by AChE.

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11
Q

what is methancholine used for?

A

used to induce bronchospasm in asthmatic patients, and help with the diagnosis of asthma, investingating airway responsiveness

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12
Q

what is bethanechol used for

A

post operative treatment of urinary retention

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13
Q

mAChR antagonists

A

atropine, scopolamine (hyoscine), tropicamine / cyclopentate eyedrops, ipratropium / tiotropium, benztropine

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14
Q

effects of atropine

A

non-selective, competiive reversible antag (M1-5)

uncharged, neutral, can be absorbed and penetrates the CNS,BBB, acting centrally

half life of 4h

used for the treatment of sinus bradycardia after MI, eye (glau), increased salivatory and sweat gland secretion

used to reverse the central idk the movie thing im not sure

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15
Q

scopolamine effects and what is the difference with it and atropine

A

about hte same, just that it has greater CNS effects and can affect the short term memory (amnesia)

clinical use is the for nausea post op and strongly helps with motion sickness

symptomatic relief of GI secretion, and improve the imaging of GIT

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16
Q

what is pirenzipine (it is a mAChR antagonist)

A

competive antagonist of M1
cannot cross the BBB, no CNS effects

treats peptic ulcers and duodenal ulcers, reduces gastric secretion and reduced muscle spasms, decreased gastric motility and delayed gastric emptying

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17
Q

what is the ipratropium/tiotropium used for

A

reduce bronchospasm - bronchodilatory

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18
Q

what are tropicamine / cyclopentate eyedrops used for

A

dilate the eye pupil, for the fundoscopic exam

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19
Q

what is benzotropine and what does it treat (single)

A

parkinsons

20
Q

what is the acetycholine reversible

A

when a large dose of ACh is given after stropine, it produces nicotinic effects and initial rise of bp due ot the sitmulation of sympathetic ganglia and consequent vasoconstriction and a secondary rise due the secretion of adrenaline

21
Q

what are the 2 nerve subtypes of nictonic receptors and were are they found

A

Nn/N1, found on the neuronal membrane (autonomic ganglia, CNS, adrenal medulla)

Nm/N2, found on skeletal muscle end plate regions at the NMJs

22
Q

Nm gives what response:

A
  1. end plate depolarisation
  2. skeletal muscle contraction
23
Q

Nn gives what response:

A
  1. depolraisation and firing of postganglionic neurons
  2. secretion of catecholamimnes
24
Q

Nn: ganglion stimulating drugs examples and what they do

(agonists of NAChR)

A

nicotine, varencline

nicotine:
CNS, skeletal effects
post-ganglionic depolarisation and firing
adrenal medulla activation and release of NA

varenicline:
partial agonists, stimulating low level agonists activity (in the presence of full agonists, hence copmetivietly binding of nicotine) used fo rsmoking cessation

25
Q

Nn: ganglionic blocking drugs

A

trimethaphan and hexamethonium

both affecting and blocking the sympathetic NS and the parasympathetic NS

decreases BP (blocks symp, leading to arteriolar vasodilation)
reduced venoconstriction upon standing, causing a sudden fall in arterial pressure (postural hypotension)

treating patients wit acute aortic dissecting aneurysms

26
Q

Nm: what are the types of neuromuscular blocking durgs

A

non-depolarising and depolarising

27
Q

what is the difference between the depolarising and non-depolarising blocking drugs

A

non depolarising:
acts as competitive antagonists at the ACh receptors of the endplate, and also blocks the facililatory presynaptive autoreceptors inhibiting hte release of ACh during repeitive stimulation of the motor nerve, resulting in the phenomenum of tetanic fade

depolarising:
similar to the action of ACh, but not degraded by AChE, so it is prolonged depolarisation, but then becomes resistance to depolarisation. receptor changes conformation that allows Na+ channels to close despite the presence of the agonists. cell hence repolarised and cannot be stimualted by ACh.

key difference is the use of cholinesterases:
non-depolarising block can be overcome (competivie)
depolarising block is potentiated

28
Q

examples of non-depolarising blocking agents

A

pancuronium
vecuronium
tubocurarine

29
Q

how can the non-depolarising drugs be overcome (2)

A
  1. anti acetylcholinesterases, e.g. neostigmine
  2. sugammadex, binds to non-depolarising drugs and excreted in the urine
30
Q

pk of non-depolarising drugs (Nm)

A

quanternary ammonium, poorly absorbed and given in IV

efficiently excreted from the kidneys, does not cross the placenta

competitive antagonist

31
Q

what is an example of depolarising blocking agent

A

suxamethoium

32
Q

what is suxamethonium?

A

depolarising agent, causes porlonged depolarisation of the nicotinic receptors.

continued actiavtion causes fasiculation.

MOA:

desensitisation –>

Phase I:
membrane depolarises, resulting in an initial discharge that produce transient fasciculations, followed by flaccid paralysis

Phase II:
membrane repolarises, but the receptor is desensitized to to the effect of ACh

33
Q

side effects of suxamethonium:

A

bradycardia
cardiac arrhythmia

release of K+ in burned or injured patients
incraesed IOP

34
Q

what type of cholinesterase blockers are there (classification)

A

short-acting, intermediate acting and long acting (irreversible)

35
Q

what is one example of short acting anticholinesterase

A

edrophonium

36
Q

what is edrophonium and what can it be used for

A

short-acting antiAChE

can be used to improve muscle stregnth, esp in myasthenia gravies where autoantibodies act against the nicotinic receptor.

can be used to differentiate with anticholinesterase overdose, which muscle strength will not occur

37
Q

what are some examples of intermediate/ medium acting anticholinesterases

A

neostigmine and pyridostigmine

38
Q

why are medium acting and short acting anticholinesterases act reversibly?

A

short-acting - quanternary ammonium

medium acting - carbamyl, possesing basic group

both interact with anionic site of AChE

39
Q

what are some examples of long acting irreversible drugs?

A

echothipate, dyflos

40
Q

structure and MOA of long acting reversibel drugs

A

pentavalent phosphorus compounds containing a labile group such as F (dyflos) and organic group (echothipate), the groups are released, leading the SerOH phosphorylated.

interacts with teh esteric site, and the inactive phosphorylated usually very stable.

clinclly used fr the treatmet of glaucoma

recovery of the enzymatic acitivty depends on the synthesis of new enzyme molecules (takes weeks)

41
Q

what are the 3 effects of anticholinesterase on:
autonomic postganglionic parasympathetic (cholinergic synpases
CNS
NMJ

A
  1. enhancement of ACh activity at parasympathetic postganglionic synapses (increased secretions….. etc) but hten at higher doses can lead to depolarisation block due to ACh build up
  2. some can penetrate the BBB freely and affect the brain, leading to initial excitation, then convulsions then depression.
    e.g. physostigmine and other non-polar organophosphates
  3. NMJ - repeated firing, twicth tension of the muslce is stimulated
    - helps with non-depolarising block and MG (where there are too few receptors)
42
Q

what do u understand by the neurotoxicity of organophosphates?

A

irreversible right, can causes severe type of delayed peripheral nerve damage and leads to progressive weakness and sensory loss.

within a few hours the phosphorylated enzyme undergoes a chemical change “ageing”, and this makes the enzyme no longer susceptible to the reactivation.

43
Q

what can be used to reverse the neurotoxicity of organophosphates?

A

pralidoxime.

reactives the enz by bringing the oxime group in close proximity to the phosphorylated esteratic site, and lures the phosphate group away from the serine OH group, but must be given before ageing

44
Q

state the 6 steps of acetylcholine synthesis and productio

A
  1. Synthesis: choline is transported from the ECF into the cytoplasm of the neuron by an energy-dependent Na-transporter (this is the rate limiting step). In cytoplasm, cholineacetyltransferase catalyses the reaction of choline with acetyl-coA (from mitochondria).
  2. Storage in vesicles: ACh-H+ antiport (vesicle associated transporter) pumps H+ into vesicle, and vesicles contain ACh, ATP and proteoglycan.
  3. Release: AP reaches the nerve endings, then stimulates Ca2+ influx which triggers the vesicles to be exocytosed, releasing ACh into the synapse.
    There are 2 pools of ACh, “depot” pool positioned near the presynaptic membrane and “reserve” pool which replaces the “depot” pool
    ACh released as discrete quanta (little packages)
  4. Binding of ACh: postsynaptic receptor is activated by the binding of ACh.
  5. Degradation of neurotransmitters in the synaptic cleft: acetylcholinesterase rapidly hydrolyse ACh back into acetate and choline, which is then recycled.
  6. Recycling of choline and acetate: choline might be recaptured into the neuron.
  7. Action of ACh: ACh acting on postsynaptic membrane can cause an increase in its permeability to cations and resulting Na+ influx, causing a depolarisation.
45
Q

5 targets of ACh transmission

A
  1. choline uptake: hemicholinum
  2. Cholineacetyltransferase: naphthyl vinylpyridine (NVP)
  3. Vesamicol inhibits ACh sotrage (ACh-H+ antiporter)
  4. Ca2+ channels inhibited by verapamil
  5. Release mechanism inhibited by botulinum toxin
46
Q

mechanism of botulinum toxin

A

botulinum toxin has light and heavy chains, held together by disulfide bonds, binds to membrane receptor.

endocytosis of BT, disulfide bone, light chainmoves out of the endosomal membrnae and celeaves specific SNARE proteins. SNARE proteins required for the vesicle containing ACh to fuse iwth the membrnae and release the transmitter.

degradation of SNARE proteins
Type B, D, F, G cleaves synaptobrevin (VAMP)
Type A and E cleaves SNAP 25
Type C cleaves syntaxin

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