nicotinic pharmacology Flashcards

1
Q

how do nicotinic receptors differ

A

receptors in autonomic ganglia are different than those in skeletal muscle because they are made up of different subunits
muscle receptors are blocked by tubocurarine
ganglion receptors blocked by hexamethonium (and by tubocuraraine at high concs)

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2
Q

what are steps of cholinergic transmission

A

choline is taken up into neurone, then Ach is synthesised in cytoplasm and packaged into vesicles before normal NT release mechanisms

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3
Q

how might cholinergic transmission be blocked by drugs

A

hemicholinium: prevents uptake of choline

yesamicol prevents packaging of Ach into vesicles

botulinum prevents release of Ach

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4
Q

what are acute effects of nicotine physiologically

A

CNS stimulant effect
increased parasympathetic and sympathetic activity
release of anti diuretic hormone (vasopressin)

smoking does not cause ganglion block but chewing tabacco may

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5
Q

what are physiological effects of ganglion blocking drugs

A

CV: mainly block sympathetic system at heart, dilation of arterioles and veins causing reduction in blood pressure and loss of CV reflexes

effects in GIT: due to parasympathetic block, inhibition of motility and secretion, leading to constipation

in genito-urinary system: due to both parasympathetic and sympathetic block; impotence

loss of accomodation in eye

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6
Q

name ganglion blocking drugs, are they used therapeutically?

A

hexamethonium, not used therapeutically

trimetaphan: occasionally used during surgery to produce hypotension

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7
Q

what are mechanisms for NMJ blocking drugs?

A

block combination of transmitter w receptor

or

production of postsynaptic response

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8
Q

what is a therapeutically used NMJ blocking drug and what is its use and what are other uses of NMJ blockers

A

suxamethonium: to cause muscle paralysis to help with intubation, has fast onset and short duration, rapidly hydrolysed by plasma cholinesterase so action is only 5 mins, if plasma cholinesterase is low activity can be prolonged up to several hours

reasons for low cholinesterase activity may be genetic, liver disease, malnutrition or anticholinesterase drugs

other uses: for abdominal surgery to reduce amount of anaesthesia needed

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9
Q

what are non depolarising NMJ blockers, how do they work and what are their effects

A

they are competitive blockers, work as regular competitive antagonists

usually have long residence in binding site
cause relaxation without preliminary excitation of muscles

relaxant effect is antagonised by anticholinesterases

myasthenia gravis patients more sensitive

tetanic fade is more pronounced

tubocuraraine is competitive blocker

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10
Q

what are depolarising blockers and how do they work and what are their effects

A

they are nAch receptor agonists, resistant to hydrolysis by cholinesterase

cause sustained depolarisation of endplate of muscle fibre

causes muscle fibre membrane to become inexcitable because sodium channels around endplate inactivate

only example in use is suxamethonium

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11
Q

what are features of depolarising block of the NMJ?

A

initial fasciculation (twitching) due to initial depolarisation

may cause hyperkalaemia

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12
Q

what is effect of botulinum toxin (botox)?

A

blocks cholinergic transmission by blocking release of Ach, does not affect post synaptic mechanisms

blocks at NMJ and ganglia

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13
Q

what are the 2 endogenous cholinesterases?

where are they found

A

acetylcholinesterase: a true cholinesterase, found at all cholinergic synapses and in red blood cells, is specific to Ach and similar esters
butyrylcholinesterase: a pseudo cholinesterase, found in plasma, liver and many other tissues, low specificity, can hydrolyse other esters, quicker than AchE

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14
Q

what is the catalytic site on cholinesterase

A

catalytic site on cholinesterase is also called the esteratic site, contains reactive serine OH group

ChE also has an anionic site which binds cationic quaternary ammonium group of Ach

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15
Q

how is Ach hydrolysed

A

Ach binds to 2 sites on cholinesterase

Ach then transfers acetyl group to serine OH of ChE

choline group dissociates and there is spontaneous hydrolysis of acetylated OH group

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16
Q

what is turnover rate of cholinesterase

A

10,000 molecules of Ach per second, Ach released at NMJ normally hydolysed in less than one ms

17
Q

describe a short acting anticholinesterase

A

edrophonium:
quaternary ammonium group

no group complementary to esteratic site
competitive antagonists by binding to the anionic site via an ionic bond

18
Q

what type of anti cholinesterases are there

A

short acting cholinesterase, medium or long acting reversible cholinesterase, long acting or irreversible cholinesterase

19
Q

describe medium/ long reversible acting anti cholinesterases

A

e.g: eserine and neostigimine

bind to both sites and forms an ester bond with serine hydroxyl group of esteratic site

spontaneous hydrolysis is much slower when hydroxyl group is bound to neostigimine than when it is bound to an acetyl group and so enzyme molecule is inactive for several minutes

20
Q

describe long acting/ irreversible anticholinesterases

A

e.g DFP and organophosphates

phosphorylate the serine OH

hydrolysis of phosphorylated enzyme is negligibly slow and recovery requires synthesis of new enzyme

21
Q

what are physiological peripheral effects of anticholinesterases

A

parasympathetic effects: salivation, sweating, increased GIT motility causing vomiting and diarrhoea, bronchoconstrction, bradycardia, pupillary constriction and fall in intraocular pressure

NMJ:
repetitive firing at normal junctions,

restoration of transmission at junctions blocked by competitive blocking agents or in myasthenia gravis

alongside high doses of Ach, there is build up causing depolarising muscular block

22
Q

what are central effects of anticholinesterases

A

mainly excitatory, leading to agitation and convulsions, followed by respiratory depression

23
Q

what are therapeutic uses of anticholinesterases

A

treatment of glaucoma through eye drops of eserine or organophosphate

myasthenia gravis, use of quaternary compounds as they do not reach the brain

reversal of NMJ block following anaesthesia

alleviation of alzheimers symptoms

24
Q

how might irreversible anticholinesterases by antagonised, and why is this used

A

cholinesterase reactivators: after being phosphorylated cholinesterase can be reactivated by oxime compounds

pralidoxime binds reversibly to anionic site, the oxime hydroxyl is at the right distance to react with phosphate group for substitution reaction

treatment of organophosphate poinsoning due to insecticides