Drugs Masterlist Flashcards
What are MAOIs and how do they work
monoamine oxidase inhibitors - prevent the metabolism of common neurotransmitters (dopamine -> noradrenaline)
What is an example of a MAOI
iproniazid
What are TCAs and how do they work
Tricyclic antidepressants - block neurotransmitter uptake in the synapse (in particular noradrenaline and serotonin)
What is an example of a TCA
imipramine
How well does fluoxetine get into the brain
almost completely absorbed by oral administration and readily crosses the BBB
What is fluoxetine metabolised into
norfluoxetine (an active SSRI)
How was fluoxetine efficacy tested
Forced swim test
What did human clinical trials for fluoxetine show
more than 50% of clinical studies failed to show elevated 5-HT level - suggests that the mechanism of action for Fluoxetine cannot be attributed to an increase in 5-HT alone
What condition is CPPene developed for
Epilepsy and stroke
What receptor does CPPene act on
NMDA antagonist
How was selectivity of CPPene determined
22Na+ efflux assay - CPPene blocked the response of NMDARs but not of AMPARs or Kainate receptors
What type of antagonist is CPPene
competitive - could be overcome by large concentrations of NMDA agonist
How was the type of antagonism exhibited by CPPene determined
Rat cortical wedge preparations
What toxin induces excitotoxicity through activation of NMDA receptors
quinolinic acid (QUIN)
Why did CPPene fail in human clinical trials
Inhibition of normal NMDAR function
Patients were more sensitive to the side effects than healthy volunteers
NMDARs are not the only receptors involved in neuronal cell death
What drug affects ACh reuptake
hemicholinium
What drug affect ACh release into the synapse
botulinum toxin
tetanus toxin
What are non-depolarising blockers
competitive antagonists which act post-synaptically to inhibit neuromuscular transmission
What are some non-depolarising blockers
alpha-bungarotoxin
tubocurarine
gallamine
What is the onset and duration of action of tubocurarine
slow onset (>5min) and long duration of action (1-2h)
What are some adverse effects of tubocurarine
hypotension, bronchoconstriction
What are depolarising blockers
agonists which act post-synaptically
What is an example of a depolarising blocker
suxamethonium
How long is the onset of action for suxamethonium
fast (1-2min)
How long is the duration of action of suxamethonium
about 10min
How is suxamethonium cleared
hydrolysed by plasma cholinesterases
How is tubocurarine cleared
reversible by anticholinesterase drugs
What is the key difference between non-depolarising and depolarising blockers
depolarising blockers produce initial fasciculations and often postoperative pain
Are anticholinesterases depolarising or non-depolarising blockers
depolarising blockers
What drug is used in the diagnosis of myasthenia gravis
edrophonium
What drugs are used in the reversal of non-depolarising blocks
neostigmine
What drugs are used in the treatment of myasthenia gravis
pyridostigmine
physostigmine
What are some organophosphate compounds which act as anticholinesterases
insecticides (e.g. malathion), nerve gases (e.g. dysflos)
What are some effects of anticholinesterase intoxication on the NMJ
convulsions, followed by flaccid paralysis
How is anticholinesterase intoxication at the NMJ treated
cholinesterase reactivation - pralidoxime
How do benzodiazepines bind to GABAA receptors
at the alpha-gamma interface
What condition is L-DOPA used in
Parkinson’s Disease
What does L-DOPA target
target synthesis
What condition is reserpine used in
hypertension - disruption of noradrenaline vesicular storage
What condition is amphetamine used in
ADHD
How does amphetamine work
re-uptake inhibitor
What receptors does mirtazapine work on
alpha2-adrenoceptor antagonist and 5-HT antagonist
What is mirtazapine
antidepressant
What condition is atomoxetine used in
ADHD
What is clonidine used for
antihypertensive, epidural anaesthetic
What receptor does clonidine act on
alpha2-adrenoceptor
How does L-DOPA work
bypasses rate limiting synthetic enzyme -> more dopamine produced
What is haloperidol
antipsychotic
What receptor does haloperidol act on
D2-receptor antagonist
What condition does amantadine treat and how does it work
Parkinson’s Disease - DA releasing agent
How does bupropion work
DA/NA re-uptake inhibitor
What receptor does aripiprazole act on
D2 partial agonist
What is risperidone
atypical antipsychotic
what receptors does risperidone act on
5-HT2 and D2 antagonist
What receptor does buspirone
5-HT1A partial agonist
What is scopolamine
muscarinic antagonist (amnesic)
What is morphine
selective (partial) agonist for mu receptors
What is naloxone
mu, delta and kappa antagonist - antidote to opiate overdose
What is pentazocine
mu antagonist and kappa agonist
What are some opioid drugs
morphine
heroin
codeine
oxycodone
methadone
fentanyl
What opioid drug is used in anaesthesia
fentanyl
What makes benzocaine different to other local anaesthetics
no use-dependence
ester group, no amine group (0% ionised)
works via hydrophobic pathways only
What makes QX-314 different from other local anaesthetics
100% ionised
blocks Na channels only if introduced into cells (experimental tool)
What is lidocaine
local anaesthetic
What is the half life of lidocaine
2h
How is lidocaine metabolised
metabolised in the liver by N-dealkylation
How long is the onset and duration of action of lidocaine
rapid onset (5-10min), moderate duration of action
What are the atypical local anaesthetics
benzocaine and QX-314
How are ester-linked local anaesthetics metabolised
metabolised by plasma esterases
How are amide-linked local anaesthetics metabolised
metabolised in the liver
How do vasodilator properties of local anaesthetic affect their pharmacokinetics
leads to more rapid vascular uptake and shorter duration of activity
How can vasodilator properties of local anaesthetics be overcome
give a vasoconstrictor to prolong anaesthesia (usually adrenaline)
What are adverse effects of local anaesthetics
respiratory depression
decreased blood pressure
hypersensitivity reactions
toxic metabolites produced from pilocarpine, articaine, benzocaine
What are the ways of general anaesthetic drug administration
inhalation, injection
What general anaesthetics are administered by inhalation
nitrous oxide
halogenated ethers
What general anaesthetics are administered by injection
propofol
thiopental
ketamine
What are the pharmacokinetics of propofol (induction, distribution, metabolism)
rapid
What is propofol used for
maintaining anaesthesia
What receptors does propofol act on
GABAA and Glycine receptor potentiation
What are adverse effects of propofol
can cause burning pain at injection site
cardiovascular depressant
What is thiopental
A bartbiturate (GABAA receptor potentiator)
What are the pharmacokinetics of thiopental
rapid induction, rapid recovery from single dose and high lipid solubility (rapid distribution)
What are adverse effects of thiopental
may depress respiratory centres of brain
How long does it take for thiopental to clear
‘Hangover effect’ - drug remains in body for prolonged time
What is an example of a dissociative anaesthetic
ketamine
What are advantages of dissociative anaesthetics
high therapeutic index
no cardiovascular or respiratory depression
analgesic
What are disadvantages of dissociative anaesthetics
psychic disturbances
involuntary movements
What are advantages of injectable anaesthetics
easy to administer
rapid induction
What are disadvantages of injectable anaesthetics
complex pharmacokinetics
slow elimination
side effects
What is minimum alveolar concentration (MAC)
a measure of potency - alveolar concentration giving surgical anaesthesia in 50% of patients
How is blood solubility related to induction speed
lower blood solubility -> faster induction
Are nitrous oxides sedative or anaesthetic
sedative - they are unable to give surgical anaesthesia on their own
What is nitrous oxides given with to become a good analgesic
O2 (entonox)
What receptors to nitrous oxides act on
NMDA antagonist, potassium channel activator
What are some halogenated ethers
desflurane, isoflurane, sevoflurane, enflurane
What receptors do halogenated ethers act on
GABAA receptor potentiator, glycine receptor potentiator, potassium channel activator
What are advantages of inhalation anaesthetics
quick introduction
rapid recovery
easily change depth of anaesthesia
What are disadvantages of inhalation anaesthetics
need specialist equipment to administer
What are the drug combinations for general anaesthesia
premedication
rapid induction
maintenance of anaesthesia
analgesic supplement
muscle relaxant
muscarinic antagonist
antiemetic
What premedications are given in general anaesthetics
sedatives
What rapid induction drugs are given in general anaesthetics
propofol
thiopental
What drugs are given for maintenance of general anaesthesia
desflurane
What analgesic supplements are given in general anaesthetics
opiate
What muscle relaxants are given in general anaesthetics
NMJ blocking agent e.g. atracurium
What antiemetics are given in general anaesthesia
ondasetron
What is the mechanism of action of NSAIDS
competitively inhibit cyclooxygenase, inhibiting production of prostaglandins
What are some examples of NSAIDS
ibuprofen, aspirin, naproxen, diclofenac, celecoxib
What are side effects of NSAIDS
GI disturbances: abdominal pain, diarrhoea, damage to stomach lining, ulcers
Is paracetamol a NSAID
no - no anti-inflammatory action and no GI disturbances
What is paracetamol
weak cyclooxygenase inhibitor
How does paracetamol reduce pain
metabolites activate TRPA1 receptor -> reduces voltage-gated sodium and calcium channels -> reduces action potential firing
What is ziconotide
N-type calcium channel inhibitor - a synthetic derivative of snail toxin w-conotoxin MVIIA (from Conus Magnus)
How is ziconotide administered
intrathecal pump (large molecule - not orally active)
What are examples of endogenous cannabinoids
anandamine and 2-AG
What receptor does bradykinin act on
B2 receptor -> stimulates prostaglandin synthesis
What drug is licensed to treat ALS
Riluzole
What is the mechanism of action of Riluzole
Activates potassium channels and blocks VG Na+ channels
Inhibits glutamate release and may inhibit non-NMDA glutamate receptors
Enhances activity of GLT1
What are drugs which potentiate GABA action at GABAA receptors
benzodiazepines
valproate
phenobarbitone
felbamate
What are drugs which inhibit GABA-transaminase
vigabatrin
What are drugs which inhibit SSA dehydrogenase
valproate
What are drugs which inhibit GABA transporter
tiagabine
What are some uses of benzodiazepines
emergency/rescue medication
acute/short-term medication
adjunctive therapy
When are benzodiazepines used as emergency medication
tonic-clonic seizures lasting >5mins
What are examples of benzodiazepines used in emergency medications
diazepam, midazolam (paediatric)
What is acute/short-term medication in epilepsy
reducing the effects of a cycle of seizures
What are examples of benzodiazepines used as acute/short-term medication
clonazepam, clobazam
When is adjunctive therapy used in epilepsy
Adjunctive therapy is the principal mode of drug treatment for refactory epilepsy
What drugs are used in adjunctive therapy in epilepsy
clonazepam, clobazam
What AMPAR antagonist is licensed for epilepsy
perampanel - negative allosteric modulator (licensed for the treatment of partial seizures)
What NMDA receptor antagonist is used to treat epilepsy
felbamate (is also a GABAA receptor potentiator)
How is glutamate release reduced
metabotropic glutamate receptor agonists
What are examples of drugs used to block voltage-gated sodium channels in epilepsy
carbamazepine, valproate, phenytoin, lamotrigine
How does gabapentin and pregabalin work
bind to alpha2-delta (P/Q) subunit and prevents trafficking to plasma membrane
How does levetiracetam work
binds to the synaptic vesicle glycoprotein SV2A
also inhibits presynaptic VGCC -> reduction in transmitter release
How does retigabine work
activates K+ channels -> hyperpolarises neurons -> reduces seizure activity
licensed for partial seizures
How does valproate work
increases brain GABA concentration
- potentiates GABAA receptors
- inhibits Na+ channels
- inhibits T-type Ca2+ channels
What is topiramate
a broad spectrum convulsant
What is Epidyolex licensed to treat
Dravet syndrome and Lennox-Gastaut Syndrome
How does epidyolex work
Potentiator of GABAA receptor activity
Antagonism of G-protein-coupled receptor 55 (GPR55)
Activation of TRPV1 channels
Inhibition of the equilibrium nucleoside transporter (ENT-1)
How are biologics used in epilepsy therapy
mAbs disrupt signalling pathways
Anti-HMGB1 shown to prevent/reduce status epilepticus and epileptogenesis
What are some cholinesterase inhibitors used in treating Alzheimer’s disease
donepezil
galantamine
rivastigmine
What are some partial NMDA antagonists used in treating Alzheimer’s Disease
memantine
How does memantine work in Alzheimer’s Disease
Low affinity uncompetitive NMDA receptor antagonist - enhances depolarisation-mediated glutamate release; inhibits glial glutamate uptake
What is tarenflurbil
gamma-secretase modulator - favours the production of smaller less toxic beta-amyloid fragments (over beta-amyloid42)
What is aducanumab
a high-affinity, fully human lgG1 monoclonal antibody against a conformational epitope found on beta-amyloid
How does Lithium help treat Alzheimer’s
inhibitor of GSK-3b (one of the key enzymes which hyperphosphorylates tau)
What is an example of a microtubule modifier used in Alzheimer’s Disease treatment
paclitaxel - chemical stabiliser of microtubules to compensate for the loss of function
What is an example of a tau aggregation inhibitors
Rember (TauRx)
How does TauRx work
Inhibits the formation of Tau oligomers and their conversion to paired helical filaments, also can dissolve tau aggregates in vitro
What are some examples of monoclonal Antibodies against amyloid-beta
aducanumab, lecanamab, donanemab
What is lecanamab
humanised lgG1 version of mouse monoclonal antibody (mAb158) against beta-amyloid protofibrils (which are soluble)
acts to stop formation/growth of plaques or breaks them down
What is donanemab
humanised lgG1 mAb development based on targeting plaques specifically
- amyloid plaques reduced to sub-clinical levels
What are the drug classes used in treating Parkinson’s Disease
dopaminergic agents
catechol-o-methyl transferase (COMT)
monoamine oxidase-B (MAO-B) inhibitors
anticholinergics
amantadine
memantine
What are some dopaminergic agents used in the treatment of Parkinson’s Disease
L-DOPA
bromocriptine
pergolide
pramipexole
ropinirole
how is levodopa transported across the gut-blood and BBB
Large neutral amino acid; requires active transport
How does L-DOPA work
L-DOPA is a precursor which is metabolised by DOPA decarboxylase into dopamine
Why does L-DOPA cause dyskinesias
result of excessive dopaminergic simulation
What are advantages of direct dopamine receptor agonists
no metabolic conversion; bypasses nigrostriatal neurons
longer half-life than L-DOPA
monotherapy or adjunct therapy
may delay or reduce motor fluctuations and dyskinesias associated with L-DOPA
may be neuroprotective
What are adverse side effects of direct dopamine receptor agonists
nausea, vomiting - activation of peripheral dopamine receptors
dizziness, postural hypotension
headache
drowsiness and somnolence
dyskinesias
confusion, hallucinations, paranoia
pulmonary and retroperitoneal fibrosis; pleural effusion and pleural thickening; Raynaud’s phenomenon
What is selegiline
irreversible MAO-B inhibitor
What are some side notes of selegiline
potential interactions with tricyclics and SSRI antidepressants
low tyramine diet necessary
What are anticholinergics used for in the treatment of Parkinson’s Disease
effective mainly for tremor and to lesser degree, rigidity
What are the side effects of using anticholinergics in Parkinson’s Disease
dry mouth, sedation, delirium, confusion, hallucinations, constipation, urinary retention
When is amantadine used
Parkinson’s Disease - last resort if dyskinesias cannot be controlled
What are the possible mechanisms of amantadine
- enhancing release of stored dopamine
- inhibiting presynaptic reuptake of catecholamines
- dopamine receptor agonism
- NMDA receptor blockade
What is memantine
NMDA receptor antagonist
What is memantine used for
used to treat cognitive defects in Alzheimer’s Disease and is beneficial for Parkinson’s related dementia
