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Life Control > Drug Action on Chemical Transmission > Flashcards

Drug Action on Chemical Transmission Flashcards

1
Q

What are the main steps in chemical transmission?

A
  • NT synthesis
  • packaging and storage of NT in vesicles
  • arrival of AP at the synaptic terminal
  • depolarisation of terminal to activate VDCC + Ca2+ influx
  • Ca-dependent release of NT (exocytosis)
  • NT binds to postsynaptic receptors and induce cascade
  • uptake/breakdown of NT
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2
Q

What is the membrane potential change during a AP in neurons?

A

normal resting ~- 70mV

AP: depolarisation to -30 mV

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3
Q

What are the relative [Ca2+] concentrations in and out of the neuron?

A

intracellular: 1.5-2mM
extracellular: 100nM

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4
Q

What is the relative distance of a synapse?

A

a fraction of a micron (~ 1 angstrom)

allows quick transmission of NT

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5
Q

What is the rationale behind blocking Na+ channels (voltage dependent)?

A

Na+ channels responsible for upstroke of AP

will prevent AP generation and propagation along axon

this inhibits synaptic transmission by stopping presynaptic terminal depolarisation

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6
Q

What are eg of drugs which act by blocking Na+ channels and therefore APs?

A

LOCAL ANAESTHETICS

e. g. lignocaine
- physical block to the channel pore in its open conformation
- prevents AP conduction and synaptic transmission in sensory nerves
- stops pain input to brain
- no pain sensation

ANTI-EPILEPTICS

e. g. phenytoin
- prevents excess synaptic transmission during high frequency firing
- this reduces the AP firing frequency (don’t want to block completely)
- this high frequency AP firing occurs in the CNS (seizures)

TRICYCLICS ANTI-DEPRESSANTS
e.g. amitriptyline
used at low doses to treat neuropathic pain
also Na+ channel blockers, similar MoA to local anaesthetics

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7
Q

What is use-dependence? How is it helpful clinically?

A

characteristic means that these drugs have a preference for a particular type of target

e.g. phenytoin will preferentially inhibit high frequency APs

clinical benefit: won’t have the systemic adverse effects and therefore can tailor the therapeutic impact

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8
Q

What is the rationale behind using drugs to inhibit VDCC (Ca2+)?

A
  • prevent Ca2+ influx
  • prevent exocytosis of NT
  • inhibit synaptic transmission

however aim to restrict actions not completely block (v. dangerous)

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9
Q

What are eg of drugs which act by blocking Ca++ channels and therefore APs?

A

ANALGESICS

e. g Ziconotide
- synthetic form of omega-conotoxin (potent VSCC blocker)
- 100x more potent than morphine
- prevents synaptic release of NT involved in pain signal conduction

used for severe chronic pain or neuropathic pain

given via intrathecal injection (into CSF)

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10
Q

How does conotoxin-containing analgesics work?

A

target and block N-type Ca2+ channels
these are prevalent in the pre-synaptic terminals specifically
Blocks stimulus - sensory afferent fibre transmission
no transmission to brain and pain interpretation

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11
Q

How is acetylcholine synthesised?

A

choline + acetyl coA -> acetylcholine + ACh
(by chalice acetyltransferase ChAT)

choline is found in liver and fish diet, and taken up by choline carrier from synapse by the pre-synaptic terminal)

acetyl coA: from Krebs cycle

Hence elevated BMR, greater the ACh synthesis

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12
Q

Where is ACh synthesised in the NS?

A
  • NMJ
  • ganglia
  • PNS post-ganglionic fibres
  • CNS
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13
Q

What are ganglia?

A

nerve bundles outside of the CNS

meeting point of pre- and post- neurone fibres from ANS

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14
Q

What is the association of disease and ACh synthesis?

A

Alzheimers disease

association with reduced ACh synthesis and release

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15
Q

Why are ChAT inhibitors considered biological weapons?

A

ChAT: choline acetyltransferase

e.g. fa64a

block ACh synthesis -> no transmission -> affects muscles (NMJ) and breathing (phrenic)
results in asphyxiation and paralysis

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16
Q

How can we modulate cholinergic transmission clinically?

A

Don’t want to impair ACh synthesis but can modulate its release pharmacologically

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17
Q

How does the clostridium botulinum toxin work?

A

bacteria produces toxin: causes botulism
toxin enters terminal and degrades ACh vesicles (overall reduction available ACh for release)

ANS and motor fibres inhibited by lack of ACh -> paralysis and respiratory collapse

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18
Q

How does botox work?

A

very low levels of botulinum toxin used to produce local paralysis
cosmetic + clinical uses

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19
Q

How can botox be used for clinical uses?

A
  • achalasia: paralyse muscle surrounding LES

- excessive sweating (localised benefit)

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20
Q

How is botulism treated?

A

inhibition of ACh release can cause paralysis and respiratory collapse

supportive care e.g. mechanical ventilation until the toxin can be cleared from the patient’s system

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21
Q

How does BETA-BUNGAROTOXIN act?

A

found in snake venom

prevents ACh release

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22
Q

How does LATROTOXIN work?

A

found in black widow spider venom

causes massive release of ACh

this makes the NMJ enter a refractory period where the over-stimulation has resulted in inhibition

AP cannot occur until the membrane has been repolarised back to its resting potential

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23
Q

Where does ACh act?

A

SA node
decreased pacemaker frequency
=> bradycardia

Airways
bronchiole constriction
resp failure

NMJ
twitching initially
paralysis long term

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24
Q

What causes Myasthenia gravis?

A

Auto-antibodies raised against ACh receptor

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25
Q

How is (released) ACh in the synapse terminated?

A

degraded by acetylcholinesterase (AChE)

this is located at the post-synaptic membrane

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26
Q

What does acetylcholinesterase do?

A

breakdown of ACh

into choline and acetate

choline is taken up by choline carrier back into the pre-synaptic terminals

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27
Q

What do anti-cholinesterases do?

A
  • enhance + prolong cholinergic transmission
  • increased PNS action (bradycardia and bronchoconstriction)
  • increased NMJ actions (twitching, paralysis)
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28
Q

How are anti-cholinesterases classified?

A

depending on duration of effect:
- SHORT ACTING
e.g. edrophonium
diagnostic, improvs myasthenia gravis

  • MEDIUM ACTING
    e.g. neostigmine
    reverse neuromuscular block and GI atony after surgery
  • LONG ACTING
    e.g. organophosphates, Sarin etc
    irreversible
    need new/nascent ACh synthesis to overcome
    v. dangerous as will cause muscle paralysis and asphyxiation
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29
Q

How does edrophonium improve Myasthenia gravis Sx?

A

= short acting anti-cholinesterase

increases the [ACh] which helps to displace the auto-antibodies which are blocking the ACh receptors on post-synaptic membrane

30
Q

What is the MoA of botulinum?

A

prevents release of vesicles containing NT

31
Q

What is the MoA of NICOTINIC AGONISTS?

A

ACh, Nic, CCh

e.g. suxamethonium
Binds to nicotinic receptors
causes hyperstimulation
-> sustained depolarisation
-> this results in inactivation of the Na+ channels
-> used as muscle relaxant prior to RSI/intubation
-> initially causes twitching and then full muscle paralysis

32
Q

What is the MoA of NIC ANTAGONISTS?

A

e.g. hexamethonium (ganglia), vercuronium (NMJ)

outcomes ACh for its receptors on the post-synaptic membrane

33
Q

Where are NIC receptors located?

A
  • NMJ

- ganglia

34
Q

Where are MUS receptor located?

A

effector/en organs

35
Q

What is the MoA of PRALIDOXIME?

A

reactivates esterase

allowing normal breakdown of ACh

36
Q

What is the MoA of ANTI-CHOLINESTERASES?

A

eg. organophosphates, donezapil

prevents degradation of ACh -> sustained activation of ACh receptors on post-synaptic membrane
-> twitching and then paralysis as receptors will be inactivated/refractory period

37
Q

What are e.g. of MUS agonist?

A
  • bethanecol (urinary retention Rx)

- pilocarpine (glaucoma Rx)

38
Q

What are e.g. of MUS antagonist?

A
  • atropine

- cyclopentolate

39
Q

Where does synthesis of NA occur?

A

sympathetic post-ganglionic fibres
CNS

these adrenergic neurons will express dopamine hydroxylase (needed to convert dopamine to NA)

40
Q

Where does synthesis of adrenaline occur?

A

within adrenal medulla

dopamine -> NA -> adrenaline

NA -> adrenaline (catalysed by phenylethanolamine N-methyl transferase- PNMT)

41
Q

How are NA/adrenaline synthesized?

A

Tyr -> DOPA -> DA

DA -> NA -> adrenaline

42
Q

Where is dopamine hydroxylase located in sympathetic neurones?

A

= dopamine beta-monooxygenase (DbM)

within vesicles
needs pH5.5 for catalysis (?) like PAM

43
Q

What is CARBIDOPA?

A

peripheral DOPA decarboxylase inhibitor (can’t cross BBB)

reduces side effects and dose needed of DOPA

44
Q

What enzymes are expressed in the adrenal medulla in order to make Adrenaline?

A

tyrosine -> Adrenaline

tyrosine hydroxylase (DOPA)
dopamine decarboxylase (DA)
dopamine hydroxylase (NA)
phenylethanolamine N-methyl transferase, PMNT (Adrenaline)
45
Q

Where is NA stored once synthesised?

A

packaged into vesicles by vesicular monoamine transporter (VMAT)
stored in vesicles
often in complex with ATP (ATP also a NT)
at noradrenergic synapses

46
Q

What is Reserpine?

A

inhibits vesicular monoamine transporter (VMAT)
NA can’t be packaged into vesicles and is subsequently degraded in the cytosol

reduces [NA} over time, reducing adrenergic transmission

used as early Rx for HTN

47
Q

What effects do sympathomimetics cause?

A

activation of SNS

  • tachycardia
  • increased TPR
  • increased CO
  • hypertension
  • pupillary dilation
48
Q

What is the tyramine “cheese effect”?

A

tyramine: found in meats, cheese and chocolates

able to enter pre-synaptic terminal and displace NA into the cleft
usually tyramine is inactivated by MAO in the IGI tract

but in pt on MAOi (anti-depressant)- tyramine can cause hypertensive crisis (due to excess NA in cleft)

known as the “cheese effect”

49
Q

How do amphetamines work?

A

binds to and reverses action of monoamine uptake transporters (normally clear NA from the cleft)

-> more NA in the cleft
AND
uncouples NA from vesicles
-> more NA in cytosol as released by transporter

50
Q

How does a cold cause vasodilation of nasal blood vessels?

A

cold: invasion by virus -> inflammation in respiratory epithelial surfaces -> vasodilation of nasal blood vessels -> runny nose

51
Q

How does Ephedrine work?

A

[derivative of amphetamine]
used as a decongestant
causes vasoconstriction of nasal blood vessels (used topically)

52
Q

How do adrenergic neurone blockers work?

A

inhibition of NA release
(cause reduction of BP)

e.g. guanethidine, clonidine

53
Q

How does guanethidine work?

A

transported by uptake 1 into vesicle
competes with NA for packaging into vesicles
prevents conversion of AP into exocytosis if NA into cleft

54
Q

Why does alpha adrenoreceptor activation inhibit NA release?

A

alpha 2 receptors: negative feedback on (beta-driven) SNS activity
inhibits NA release from SNS neurones

55
Q

How does clonidine work?

A

stimulates pre-synpatic alpha-2 receptors (peripherally)
reduces NA release

stimulates alpha-2 receptors in CNS
reduce SNS activity

can be used to Rx hypertensive crises when other methods are ineffective

56
Q

Where does sympathetic drive work?

A

originates at ventrolateral medulla (brainstem)

nerve roots at thoracic and lumbar regions

57
Q

How is NA signalling inactivated in the synaptic cleft?

A

NA taken up by UPTAKE 1 receptor into pre-synaptic terminal

NA then recycled into nascent vesicles
OR
metabolised by MAO (neurons) or COMT (non-neuronal sites e.g. adrenal medulla)

58
Q

What are the different UPTAKE receptors used to inactivate NA signalling?

A

UPTAKE 1:
high affinity
present at neuronal sites, ANS, CNS

UPTAKE 2:
low affinity
present at non-neuronal sites (eg end organs)

59
Q

What is COMT?

A

present in the adrenal medulla to catabolise NA

= Catechol-O-methyltransferase

60
Q

How is NA levels linked to disease?

A

reduced NA levels associated with low mood (depression)

hence why inhibiting MAO (NA catabolism) can elevate NA signalling and mood

61
Q

How do Tricyclic anti-depressants work?

A

(also cocaine)
inhibits Uptake 1
therefore potentiates NA signalling in the synaptic cleft

62
Q

How do MAOi work?

A 
e.g. moclobemide
reduced NA catabolism 
more NA recycled and packaged into nascent vesicles 
potentiates adrenergic transmission 
used as anti-depressant
63
Q

How does a-methyltyrosine impact adrenergic transmission?

A

blocks NA synthesis in pre-synaptic terminal

64
Q

How does guanethidine work on adrenergic transmission?

A

prevents release of NA vesicles

65
Q

How do alpha-1 modulators work on adrenergic transmission?

A

Agonists:
NA > Adrenaline
Phenylephrine
stimulate vascular SNS smooth muscle

Antagonists:
prazosin (anti-hypertensive)

66
Q

What are examples of beta 1 receptor modulators?

A

work predominantly at the SA node and drive RAAS (renin secretion)

Agonists increase adrenergic transmission:

  • Adrenaline > NA
  • dobutamine
  • dopamine

Antagonists block adrenergic transmission:

  • atenolol
  • propanolol
67
Q

What are examples of alpha 2 receptor modulators?

A

agonists inhibit adrenergic transmission
- clonidine

antagonists allow adrenergic transmission (no inhibition)
- yohimbine

68
Q

What are e.g. of adrenergic reuptake inhibitors?

A

cocaine
tricyclic anti-depressant
amphetamine

69
Q

What are e.g. of beta 2 receptors modulators in adrenergic transmission?

A

agonists increase transmission in airways:

  • adrenaline = noradrenaline (activity)
  • salbutamol

antagonists inhibit transmission

  • butoxamine
  • propanolol
70
Q

How does tetanus toxin work?

A

prevents release of glycine in the CNS

inhibitory NT

71
Q

How does ketamine work?

A

NMDA antagonist

72
Q

How does nalonxone work?

A

opioid antagonist

works on post-synaptic receptors

Life Control (25 decks)

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