Neuropharmacology Flashcards
Perampanel
AMPA antagonist, antiepileptic (specifically for partial seizures)
Memantine
NMDA channel blocker for Alzheimer’s.
Ketamine
NMDA channel blocker, anaesthetic, has antidepressant action not currently used as antidepressant.
Baclofen
GABA(B) agonist, a muscle relaxant used to treat spasticity in MS patients
Bicuculline
GABA(A) antagonist, pro-epileptic
Picrotoxin
GABA(A) antagonist + glycine receptor antagonist, pro-epileptic
Thiopental
Short acting barbiturate, GABA(A) PAM: enhances the magnitude of GABA(A) currents.
Rarely used anaesthetic, used for lethal injection
Phenobarbital
Long acting barbiturate, GABA(A) PAM: enhances the magnitude of GABA(A) currents
Rarely used antiepileptic due to sedative side effect with overdose causing respiratory failure.
Activates PXR to upregulate CYP3A4.
Diazepam
Benzodiazepine, enhances GABA(A) response to GABA, used to treat anxiety and status epilepticus. Long acting drug so has issue of tolerance to the drug and dependence (abrupt withdrawal causes heightened anxiety). Sedative side effect.
Lorazepam
Short acting benzodiazepine, enhances GABA(A) response to GABA, used as sedative and status epilepticus. Lorazepam is 10 times more powerful than diazepam as a sedative so must be used with care.
Flumazenil
Benzodiazepine antagonist, used to treat benzodiazepine overdose.
Zolpidem
‘Z’ drug (NOT a benzodiazepine) acts at GABA(A) benzodiazepine site. Also enhances GABA(A) response to GABA (P.35 notes).
Sedative used in the treatment of insomnia but causes people to sleepwalk!
Less addictive than benzodiazepines. Short acting.
AP5
Competitive NMDA antagonist
ACET
Kainate receptor antagonist
CNBX, NBQX
Competitive AMPA antagonists
βCCE
Inverse agonist at GABA(A)
Vigabatrin
Irreversible GABA transaminase inhibitor, antiepileptic (all forms apart from absence seizures due to GABA reactivating T-type Cav channels)
Tiagabine
Inhibits GAT1, antiepileptic (all forms apart from absence seizures due to GABA reactivating T-type Cav channels)
Carbamazepine
Nav blocker, antiepileptic (all forms apart from absence seizures), used for neuropathic pain.
Prodrug activated by CYP enzymes to active epoxide, metabolised by microsomal EH.
Phenytoin
Nav blocker, antiepileptic (all forms apart from absence seizures).
(1) 80-90% bound to plasma albumin (so an increase in dose will cause a disproportionate increase in Cfree).
(2) Metabolised by CYP2C9 and CYP2C19, then by glucuronidation.
(3) Therapeutic doses saturate hydroxylation by CYP2C9 pathway so elimination follows zero order kinetics. So an increase in rate of infusion cause a massive increase in plasma concentration.
(4) Inhibits CYP2C9 (together with valproate). Inhibits glucuronidation (together with pentobarbital, issue for paracetamol overdose).
(5) CYP2C19 is highly polymorphic, especially in Asians.
(6) Overdose can increase seizure frequency
Lamotrigine
Nav blocker, antiepileptic (all forms including absence seizures), used for bipolar disorder and neuropathic pain.
Lacosamide
Inactivates Nav by enhancing slow inactivation, meaning Navs are less available for activation (involves structural rearrangement), antiepileptic (specifically for partial seizures).
Ethosuximide
T-type Cav blocker, antiepileptic (specifically for absence seizures)
Valproate (sodium valproate, valproic acid)
T-type Cav blocker, Nav blocker, weakly inhibits GABA transaminase, enhances GABA function, antiepileptic (treats all kinds) Inhibits microsomal EH (issue for carabamazepine metabolism) Inhibits CYP2C9 (issue for phenytoin metabolism)
Gabapentin + Pregabalin
Binds α2δ subunits so reduces Cav plasma membrane expression, antiepileptic (specifically for partial and absence seizures), used for neuropathic pain.
Topiramate
Blocks Nav, Cav, AMPA receptors, enhances GABA(A) function, antiepileptic (treats all kinds), anti-migraine.
Zonisamide
Blocks Nav, Cav, enhances GABA(A) function, antiepileptic (treats all kinds).
Retigabine
Kv7.2 channel opener, antiepileptic (specifically for partial seizures).
Levetiracetam
Binds SV2A (synaptic vesicle protein 2A), antiepileptic (treats all kinds).
Phenelzine
Irreversible, non-selective MAO inhibitor, antidepressant.
Moclobemide
Reversible MAO-A inhibitor, antidepressant.
Selegiline
Irreversible MAO-B inhibitor, used for Parkinson’s. Metabolised to amphetamine so can cause insomnia.
Imipramine to Desipramine
Both are TCAs, inhibit NET and SERT, antidepressant. Side effects of TCAs:
Block of histamine H1 receptors causes sedation.
Block of ACh muscarinic receptors causes a dry mouth, constipation and urinary retention.
Metabolised in the liver by CYP enzymes - affected by other drugs.
Potentiate the effects of both alcohol and anaesthetics
Amitriptyline to Nortriptyline
Both are TCAs, inhibit NET and SERT, antidepressant, used as a migraine prophylactic (mechanism unknown).
Saclofen
GABA(B) receptor antagonist, antiepileptic (specifically for absence seizures).
7-chlorokynurenic acid
NMDA antagonist, binds at the glycine binding site.
Ifenprodil
Blocks spermine’s (polyamine) modulatory site on NMDA receptor.
Fluoxetine
SSRI, 5-HT(2C) antagonist, antidepressant. Inhibits CYP2D6, reducing morphine formation from codeine.
Citalopram
SSRI, antidepressant, used to treat panic attacks.
Venlafaxine
SNRI, antidepressant
Duloxetine
SNRI, antidepressant, can cause hepatotoxicity.
Bupropion
Inhibits NET and DAT, antidepressant, treat nicotine dependence.
Mirtazapine
NASSA (i.e. alpha 2 adrenoceptor, 5HT(2A/C), 5HT(3) antagonists), antidepressant.
Note that blocking presynaptic alpha 2 enhances NA and serotonin release.
Fewer side effects than SSRI (less sexual dysfunction and less nausea) due to 5HT(2A) and 5HT(3) inhibition.
Can cause sedation via H1 receptor blockade (like TCAs).
Trazodone
5HT(2A/C) antagonist, weak SSRI, antidepressant, treats insomnia by antagonising the action of wake promoting serotonin neurons.
Agomelatine
MT1 and MT2 agonist, antidepressant by correcting disturbances in circadian rhythm.
Lithium
Inhibits inositol monophosphatase, inhibits GSK3, inhibits hormone-induced cAMP production.
Treats bipolar disorder.
Na+ depletion increases Li+ absorption in proximal tubule.
Olanzapine
Mesolimbic D2 and 5-HT(2A) antagonist, atypical antipsychotic, treats bipolar disorder (better at treating mania aspect).
Sertraline
SSRI, antidepressant, treats panic attacks and PTSD.
Buspirone
Partial agonist of 5-HT(1A), causes desensitisation over time leading to increased serotonin release. Used in generalised anxiety disorder.
Clozapine
5-HT2 antagonist, weak mesolimbic D2 antagonist. Atypical antipsychotic.
Side effects: H1 antagonist (cause sedation), mAChR1 antagonist, α1 adrenoceptor antagonist (orthostatic hypotension), agranulocytosis (clozapine only).
Blockade of mAChR1 receptors helps to reduce extrapyramidal side effects. Striatal cholinergic neurones express D2 receptors, with D2 activation (Gi) normally blocking their action (which is to inhibit ‘direct pathway’ in the basal ganglia). D2 blockade means striatal cholinergic neurones are no longer inhibited, direct pathway is inhibited, causing extrapyramidal motor side effects. So blockade of mAChR1 reduces action of striatal cholinergic neurones.
ALL antipsychotics can cause neuroleptic malignant syndrome where rigidity occurs with hyperthermia and
confusion, and can cause renal/cardiovascular failure.
Diphenhydramine
H1 antagonist, used for sedation. No tolerance issue (cf lorazepam)
Thioperamide
H3 antagonist promotes wakefulness.
Ramelteon
MT1 and MT2 agonist to treat insomnia.
Caffeine
Non-selective PDE inhibitor, A1 and A2 antagonist. Promotes wakefulness.
Dexamphetamine/Amphetamine
Sympathomimetic agent to increase NA release and promotes wakefulness. Treats ADHD via increased DA release. NET/DAT inhibitor.
Methylphenidate (Ritalin)
DAT inhibitor. Elevated DA levels used in the treatment of ADHD. Treats narcolepsy.
Modafinil
Weak DAT inhibitor + enhances 5-HT, glutamate, histamine release + inhibits GABA release. Treats narcolepsy.
Amantadine
Anti-viral, NMDA antagonist, weak DAT inhibitor, used in Parkinson’s disease, treats fatigue in MS patients.
Suvorexant
OX1 and OX2 antagonist, treats insomnia.
Bromocriptine
D1-3 agonist, treats hyperprolactinaemia, used for Parkinson’s, acromegaly (by causing receptor desensitisation).
Domperidone
CTZ D2/3 receptor antagonist, used to limit levodopa-induced nausea and migraine associated nausea.
More peripherally selective than metoclopramide so produce less acute dystonia.
Safinamide
MAO-B and DAT inhibitor, used in PD.
Talcapone
COMT inhibitor. Centrally penetrant. Entacapone is peripherally restricted.
Chlorpromazine
Non-selective dopamine blocker, 5HT2 blocker (lots of types), typical antipsychotic. Also H1, M1, alpha-1 blocker (see clozapine).
LSD
Modulates numerous 5-HT receptors, agonist at 5-HT(2A) receptors causes psychosis.
Haloperidol
D1/2 and 5-HT(2A) receptor antagonist, typical antipsychotic.
Side effects common to antipsychotics that block D2:
(1) Extrapyramidal motor symptoms.
(2) Increased prolactin secretion due to tuberoinfundibular D2 blockade.
(3) Anhedonia (reduced pleasure) due to D2 blockade of reward pathway of mesolimbic system.
(4) D2 blockade in mesocortical system increases negative symptoms.
Extrapyramidal side effects include:
(1) Neurolepsis: reduced motor activity
(2) Acute dystonia: Abnormal fixed postures like protruding tongue, reversible, more common, appears early in treatment.
(3) Tardive dyskinesia: Jerky, dance-like involuntary movements, appears late in treatment, due to upregulation of D2 receptors in striatum to try to overcome the blockade, D2 receptor levels don’t reset so it’s irreversible.
Extrapyramidal side effects occur more with typical than atypical antipsychotics because:
(1) Typical ones have slower dissociation kinetics. See aripiprazol for more info.
(2) Usually atypical ones are 5-HT(2A) antagonists and typical ones are not. 5-HT(2A) receptor activation decreases striatal dopamine release, which is reversed by 5-HT(2A) antagonism.
Note that atypical antipsychotics are just as efficacious in treating positive symptoms as typical ones, thus 5-HT probably doesn’t decrease mesolimbic dopamine release (5-HT different effects on dopamine throughout the brain).
Note that 5-HT(2A) receptor activation also induces prolactin secretion so blocking it will decrease the hyperprolactinaemia caused by blocking D2 alone.
Aripiprazol
D2 partial agonist, 5-HT(1A) partial agonist, 5-HT(2A) antagonist - from Wikipedia. Atypical antipsychotic.
Atypical antipsychotics have faster dissociation kinetics than typical antipsychotics. Rapidly dissociating drugs actually enables dopaminergic signalling by encouraging a surge of DA to overcome to block.
Hence D2 partial agonists can both block dopaminergic signalling in mesolimbic pathway to counteract positive symptoms and stimulate dopaminergic signalling in mesocortical pathway to counteract negative symptoms.
Being a 5-HT(1A) partial agonist also helps to reduce extrapyramidal motor symptoms, since 5-HT(1A) activation reduces 5-HT release, reducing the inhibition of striatal dopamine release.
The combined effects at 5-HT(1A)/5-HT(2A) and D2 receptors enhances the therapeutic window between the dose required for efficacy and induction of extrapyramidal side effects. Note that a role of 5-HT in aetiology of schizophrenia is unlikely.
The following side effects are more common with atypical antipsychotics:
Weight gain, increased diabetes risk and cardiovascular disease.
Levodopa/L-DOPA + carbidopa + entacapone/talcapone
Converted to dopamine by central DDC. Carbidopa inhibits peripheral DDC to prevent dopamine being formed in the periphery where it’s not needed. Entacapone prevents L-DOPA metabolism in the periphery and talcapone prevents dopamine metabolism in the brain.
L-DOPA has a short half life so produces a fluctuating plasma concentration. This causes dyskinesia. Action of COMT inhibitors helps stabilise plasma concentrations.
Other side effects include nausea (prevented by domperidone), psychosis (dopamine overload).
Ropinirole
D2/3 agonist. Used for Parkinson’s. Can cause impulse control disorder.
Orphenadrine
Non-selective muscarinic antagonist. Treats Parkinsonism induced by antipsychotics.
Galantamine, rivastigmine
Covalent, reversible, medium acting anti-cholinesterases. Note that all other ones in that group are charged and can’t enter brain. Used for Alzheimer’s.
Aducanumab
Monoclonal antibody against Aβ aggregates. Recruits microglia phagocytosis of Aβ. Used for Alzheimer’s.
Propranolol
Non-selective β adrenoceptor antagonist. reduces the physical symptoms of anxiety (muscle tremor, tachycardia), preventing extracerebral vasodilation in migraine (migraine prophylactic).
