cholinergic pharmacology

Question 1

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

Answer 1

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

Question 2

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

Answer 2

Gi, inhibits the adenylyl cylcase and decrease intracellular cAMP

Question 3

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

Answer 3

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 `

Question 4

M1, M2, and M3 act on which part

Answer 4

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

Question 5

M1 effects

Answer 5

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

Question 6

M2 effects

Answer 6

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

Question 7

M3 effects

Answer 7

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

Question 8

mAChR agonists?

Answer 8

muscarine, pilocarpine

Question 9

what can mACh agonoists be used for clincally?

Answer 9

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

Question 10

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

and which one is preferred to muscarine?

Answer 10

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.

Question 11

what is methancholine used for?

Answer 11

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

Question 12

what is bethanechol used for

Answer 12

post operative treatment of urinary retention

Question 13

mAChR antagonists

Answer 13

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

Question 14

effects of atropine

Answer 14

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

Question 15

scopolamine effects and what is the difference with it and atropine

Answer 15

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

Question 16

what is pirenzipine (it is a mAChR antagonist)

Answer 16

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

Question 17

what is the ipratropium/tiotropium used for

Answer 17

reduce bronchospasm - bronchodilatory

Question 18

what are tropicamine / cyclopentate eyedrops used for

Answer 18

dilate the eye pupil, for the fundoscopic exam

Question 19

what is benzotropine and what does it treat (single)

Answer 19

parkinsons

Question 20

what is the acetycholine reversible

Answer 20

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

Question 21

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

Answer 21

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

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

Question 22

Nm gives what response:

Answer 22

1. end plate depolarisation
2. skeletal muscle contraction

Question 23

Nn gives what response:

Answer 23

1. depolraisation and firing of postganglionic neurons
2. secretion of catecholamimnes

Question 24

Nn: ganglion stimulating drugs examples and what they do

(agonists of NAChR)

Answer 24

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

Question 25

Nn: ganglionic blocking drugs

Answer 25

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

Question 26

Nm: what are the types of neuromuscular blocking durgs

Answer 26

non-depolarising and depolarising

Question 27

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

Answer 27

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

Question 28

examples of non-depolarising blocking agents

Answer 28

pancuronium vecuronium tubocurarine

Question 29

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

Answer 29

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

Question 30

pk of non-depolarising drugs (Nm)

Answer 30

quanternary ammonium, poorly absorbed and given in IV efficiently excreted from the kidneys, does not cross the placenta competitive antagonist

Question 31

what is an example of depolarising blocking agent

Answer 31

suxamethoium

Question 32

what is suxamethonium?

Answer 32

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

Question 33

side effects of suxamethonium:

Answer 33

bradycardia cardiac arrhythmia release of K+ in burned or injured patients incraesed IOP

Question 34

what type of cholinesterase blockers are there (classification)

Answer 34

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

Question 35

what is one example of short acting anticholinesterase

Answer 35

edrophonium

Question 36

what is edrophonium and what can it be used for

Answer 36

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

Question 37

what are some examples of intermediate/ medium acting anticholinesterases

Answer 37

neostigmine and pyridostigmine

Question 38

why are medium acting and short acting anticholinesterases act reversibly?

Answer 38

short-acting - quanternary ammonium medium acting - carbamyl, possesing basic group both interact with anionic site of AChE

Question 39

what are some examples of long acting irreversible drugs?

Answer 39

echothipate, dyflos

Question 40

structure and MOA of long acting reversibel drugs

Answer 40

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)

Question 41

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

Answer 41

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)

Question 42

what do u understand by the neurotoxicity of organophosphates?

Answer 42

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.

Question 43

what can be used to reverse the neurotoxicity of organophosphates?

Answer 43

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

Question 44

state the 6 steps of acetylcholine synthesis and productio

Answer 44

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.

Question 45

5 targets of ACh transmission

Answer 45

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

Question 46

mechanism of botulinum toxin

Answer 46

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