Drug Action on Chemical Transmission Flashcards
What are the main steps in chemical transmission?
- 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
What is the membrane potential change during a AP in neurons?
normal resting ~- 70mV
AP: depolarisation to -30 mV
What are the relative [Ca2+] concentrations in and out of the neuron?
intracellular: 1.5-2mM
extracellular: 100nM
What is the relative distance of a synapse?
a fraction of a micron (~ 1 angstrom)
allows quick transmission of NT
What is the rationale behind blocking Na+ channels (voltage dependent)?
Na+ channels responsible for upstroke of AP
will prevent AP generation and propagation along axon
this inhibits synaptic transmission by stopping presynaptic terminal depolarisation
What are eg of drugs which act by blocking Na+ channels and therefore APs?
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
What is use-dependence? How is it helpful clinically?
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
What is the rationale behind using drugs to inhibit VDCC (Ca2+)?
- prevent Ca2+ influx
- prevent exocytosis of NT
- inhibit synaptic transmission
however aim to restrict actions not completely block (v. dangerous)
What are eg of drugs which act by blocking Ca++ channels and therefore APs?
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)
How does conotoxin-containing analgesics work?
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
How is acetylcholine synthesised?
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
Where is ACh synthesised in the NS?
- NMJ
- ganglia
- PNS post-ganglionic fibres
- CNS
What are ganglia?
nerve bundles outside of the CNS
meeting point of pre- and post- neurone fibres from ANS
What is the association of disease and ACh synthesis?
Alzheimers disease
association with reduced ACh synthesis and release
Why are ChAT inhibitors considered biological weapons?
ChAT: choline acetyltransferase
e.g. fa64a
block ACh synthesis -> no transmission -> affects muscles (NMJ) and breathing (phrenic)
results in asphyxiation and paralysis
How can we modulate cholinergic transmission clinically?
Don’t want to impair ACh synthesis but can modulate its release pharmacologically
How does the clostridium botulinum toxin work?
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
How does botox work?
very low levels of botulinum toxin used to produce local paralysis
cosmetic + clinical uses
How can botox be used for clinical uses?
- achalasia: paralyse muscle surrounding LES
- excessive sweating (localised benefit)
How is botulism treated?
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
How does BETA-BUNGAROTOXIN act?
found in snake venom
prevents ACh release
How does LATROTOXIN work?
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
Where does ACh act?
SA node
decreased pacemaker frequency
=> bradycardia
Airways
bronchiole constriction
resp failure
NMJ
twitching initially
paralysis long term
What causes Myasthenia gravis?
Auto-antibodies raised against ACh receptor
How is (released) ACh in the synapse terminated?
degraded by acetylcholinesterase (AChE)
this is located at the post-synaptic membrane
What does acetylcholinesterase do?
breakdown of ACh
into choline and acetate
choline is taken up by choline carrier back into the pre-synaptic terminals
What do anti-cholinesterases do?
- enhance + prolong cholinergic transmission
- increased PNS action (bradycardia and bronchoconstriction)
- increased NMJ actions (twitching, paralysis)
How are anti-cholinesterases classified?
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
How does edrophonium improve Myasthenia gravis Sx?
= short acting anti-cholinesterase
increases the [ACh] which helps to displace the auto-antibodies which are blocking the ACh receptors on post-synaptic membrane
What is the MoA of botulinum?
prevents release of vesicles containing NT
What is the MoA of NICOTINIC AGONISTS?
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
What is the MoA of NIC ANTAGONISTS?
e.g. hexamethonium (ganglia), vercuronium (NMJ)
outcomes ACh for its receptors on the post-synaptic membrane
Where are NIC receptors located?
- NMJ
- ganglia
Where are MUS receptor located?
effector/en organs
What is the MoA of PRALIDOXIME?
reactivates esterase
allowing normal breakdown of ACh
What is the MoA of ANTI-CHOLINESTERASES?
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
What are e.g. of MUS agonist?
- bethanecol (urinary retention Rx)
- pilocarpine (glaucoma Rx)
What are e.g. of MUS antagonist?
- atropine
- cyclopentolate
Where does synthesis of NA occur?
sympathetic post-ganglionic fibres
CNS
these adrenergic neurons will express dopamine hydroxylase (needed to convert dopamine to NA)
Where does synthesis of adrenaline occur?
within adrenal medulla
dopamine -> NA -> adrenaline
NA -> adrenaline (catalysed by phenylethanolamine N-methyl transferase- PNMT)
How are NA/adrenaline synthesized?
Tyr -> DOPA -> DA
DA -> NA -> adrenaline
Where is dopamine hydroxylase located in sympathetic neurones?
= dopamine beta-monooxygenase (DbM)
within vesicles
needs pH5.5 for catalysis (?) like PAM
What is CARBIDOPA?
peripheral DOPA decarboxylase inhibitor (can’t cross BBB)
reduces side effects and dose needed of DOPA
What enzymes are expressed in the adrenal medulla in order to make Adrenaline?
tyrosine -> Adrenaline
tyrosine hydroxylase (DOPA) dopamine decarboxylase (DA) dopamine hydroxylase (NA) phenylethanolamine N-methyl transferase, PMNT (Adrenaline)
Where is NA stored once synthesised?
packaged into vesicles by vesicular monoamine transporter (VMAT)
stored in vesicles
often in complex with ATP (ATP also a NT)
at noradrenergic synapses
What is Reserpine?
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
What effects do sympathomimetics cause?
activation of SNS
- tachycardia
- increased TPR
- increased CO
- hypertension
- pupillary dilation
What is the tyramine “cheese effect”?
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”
How do amphetamines work?
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
How does a cold cause vasodilation of nasal blood vessels?
cold: invasion by virus -> inflammation in respiratory epithelial surfaces -> vasodilation of nasal blood vessels -> runny nose
How does Ephedrine work?
[derivative of amphetamine]
used as a decongestant
causes vasoconstriction of nasal blood vessels (used topically)
How do adrenergic neurone blockers work?
inhibition of NA release
(cause reduction of BP)
e.g. guanethidine, clonidine
How does guanethidine work?
transported by uptake 1 into vesicle
competes with NA for packaging into vesicles
prevents conversion of AP into exocytosis if NA into cleft
Why does alpha adrenoreceptor activation inhibit NA release?
alpha 2 receptors: negative feedback on (beta-driven) SNS activity
inhibits NA release from SNS neurones
How does clonidine work?
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
Where does sympathetic drive work?
originates at ventrolateral medulla (brainstem)
nerve roots at thoracic and lumbar regions
How is NA signalling inactivated in the synaptic cleft?
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)
What are the different UPTAKE receptors used to inactivate NA signalling?
UPTAKE 1:
high affinity
present at neuronal sites, ANS, CNS
UPTAKE 2:
low affinity
present at non-neuronal sites (eg end organs)
What is COMT?
present in the adrenal medulla to catabolise NA
= Catechol-O-methyltransferase
How is NA levels linked to disease?
reduced NA levels associated with low mood (depression)
hence why inhibiting MAO (NA catabolism) can elevate NA signalling and mood
How do Tricyclic anti-depressants work?
(also cocaine)
inhibits Uptake 1
therefore potentiates NA signalling in the synaptic cleft
How do MAOi work?
e.g. moclobemide reduced NA catabolism more NA recycled and packaged into nascent vesicles potentiates adrenergic transmission used as anti-depressant
How does a-methyltyrosine impact adrenergic transmission?
blocks NA synthesis in pre-synaptic terminal
How does guanethidine work on adrenergic transmission?
prevents release of NA vesicles
How do alpha-1 modulators work on adrenergic transmission?
Agonists:
NA > Adrenaline
Phenylephrine
stimulate vascular SNS smooth muscle
Antagonists:
prazosin (anti-hypertensive)
What are examples of beta 1 receptor modulators?
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
What are examples of alpha 2 receptor modulators?
agonists inhibit adrenergic transmission
- clonidine
antagonists allow adrenergic transmission (no inhibition)
- yohimbine
What are e.g. of adrenergic reuptake inhibitors?
cocaine
tricyclic anti-depressant
amphetamine
What are e.g. of beta 2 receptors modulators in adrenergic transmission?
agonists increase transmission in airways:
- adrenaline = noradrenaline (activity)
- salbutamol
antagonists inhibit transmission
- butoxamine
- propanolol
How does tetanus toxin work?
prevents release of glycine in the CNS
inhibitory NT
How does ketamine work?
NMDA antagonist
How does nalonxone work?
opioid antagonist
works on post-synaptic receptors
