Neuropharmacology Flashcards
What determines the absolute refractory period of a neuron?
Duration of Na+ channel inactivation
What determines the relative refractory period of a neuron?
Duration of after hyper-polarisation (AHP)
Describe the mechanism of an action potential.
1) RMP of ~-70mV by Na/K pump and selective permeability of membrane (K+ >Cl-»>Na+)
2) Depolarising stimulus → MP towards threshold
3) Beyond threshold
- voltage-gated Na+ channels open → Na+ influx → further depolarisation
- voltage-gated K+ channels slowly open
4) Peak (~35mV) → Na+ channels inactivated
- slower K+ channels open → K+ efflux → repolarisation
5) Slow closure of K+ channels → hyperpolarisation
6) RMP returned by Na/K pump
Describe a typical cholinergic synapse.
1) Synthesis of ACh
Acetyl-CoA → ACh (by ChAT)
2) ACh packaging by VAChT
3) Exocytosis of ACh
4) Post-synaptic uptake by mAChR (muscarinic/GPCR) or nAChR (nicotinic/ion channels)
5) Synaptic removal of ACh
i) Reuptake by mAChR
ii) Catabolism by AChE
iii) Reuptake of Ch by SDHACU (CH used to regenerate ACh)
How does AP propagation along a neuron differ when it is myelinated?
Unmyelinated → Wave of depolarisation by adjacent Na+ channels
Myelinated → Saltatory conduction via Nodes of Ranvier
How is neurotransmitter release initiated?
1) AP reaches axon terminal → voltage-gated Ca2+ channels open → Ca2+ influx
2) VAMPS (Ca2+ sensitive vesicle membrane proteins) release synaptic vesicles from cytoskeleton
3) VAMPS facilitates (i) docking and (ii) fusion of synaptic vesicles with membrane for exocytosis
How is synaptic transmission regulated?
1) By pre-synaptic APs
2) Presynaptic autoreceptors
- activated along with postsynaptic receptors for feedback inhibition
3) Post-synaptic desensitisation
- ligand-induced (GPCR) receptor internalisation
- requires AP-2 and ß-arrestin adaptor proteins → clathrin-coated pits
Glutamate is the major transmitter in (excitatory/inhibitory) synapses while GABA is the major transmitter in (excitatory/inhibitory) synapses.
Glutamate → Excitatory
GABA → Inhibitory
Glutamate is found in __________ and used in _______________.
Pyramidal neurons in neocortex
Learning and memory
Acetylcholine is found in __________ and used in _______________.
Nucleus basalis of Meynert
Learning, arousal, reward
Dopamine is found in __________ and used in _______________.
Substantia nigra
Motor system, reward
What are 3 symptoms of depression?
Emotional:
1) Misery, apathy and pessimism
2) Low self-esteem (guilt, inadequacy, ugliness)
3) Indecisiveness, loss of motivation (anhedonia)
Others:
4) Retardation of thought and action
5) Loss of libido
6) Sleep disturbance and loss of appetite
What are the 2 major types of depression?
1) Unipolar
- mood swings all in same direction
2) Bipolar depression/affective disorder
- alternating depression and mania
- strongly familial, in early childhood
What are 2 forms of unipolar depression?
1) Reactive (75%)
- non-familial
- a/w life-events
- a/w anxiety and agitation
2) Endogenous depression (25%)
- familial
- not directly related to external stress
What is the monoamine theory of depression?
Deficits in monoamine neurotransmitters (NA, 5-HT) cause depression
What are 3 limitations of the monoamine theory of depression?
1) Studies of monoamine markers in depressed px inconsistent results
2) Monoamine theory alone inadequate to explain all pharmacological actions
3) Originally formulated for NA, but emphasis later shifted to 5-HT
MOA-B selective inhibitors (eg. selegiline) are used in __________.
Parkinson’s disease
What is the moa of phenelzine?
Non-selective, irreversible MOA inhibitor
→ ↓Monoamine NT breakdown
→ ↑bioavailability
What are 2 AEs of MOAis?
1) Postural hypotension
- sympathetic block by accumulation of dopamine in cervical ganglia
2) Restlessness and insomnia
- CNS stimulation
MOAis should not be combined with ______________ drugs lest px experience ______________________.
Serotoninergic function enhancers (eg. pethidine)
- hyperexcitability, ↑tone, myoclonus, LOC
What are 3 examples of TCAs?
Non-selective for SERT/NET:
1) Imipramine
2) Amitriptyline
3) Nortriptyline
Selective for NET:
4) Desipramine
How is nortriptyline different from the other non-selective TCAs?
1) Second generation
2) Milder AEs
3) Improved compliance
What are 3 AEs of TCAs?
1) Sedation
- H1 receptor antagonism
- tolerance to sedation within 1-2 weeks
2) Postural hypotension
- α-adrenoceptor sympathetic block
3) Xerostomia, blurred vision, constipation
- muscarinic receptor antagonism
How are TCAs metabolised?
Hepatic
What are 2 examples of SSRIs?
1) Fluoxetine
2) Citalopram
What are 4 advantages of SSRIs?
Specific for 5-HT:
1) ↓sedation (↓histamine receptor antagonism)
2) ↓CVS effects and safer in OD (↓α-adrenoceptor antagonism)
3) Minimal anticholinergic (xerostomia, constipation) AEs
4) Better compliance + Safer in OD
How does MOA-A differ from MOA-B?
MOA-B: break down NA and dopamine
MOA-A: also break down 5-HT
What are 4 AEs of SSRIs?
1) Nausea
2) Insomnia
3) Sexual dysfunction (anorgasmia due to ↑5HT2 receptors)
4) Serotonin syndrome (CVS collapse, tremor, hyperthermia)
- from DDI with drugs ↑serotoninergic activity
Which SSRI can lead to sedation?
Citalopram
What is given for a px on SSRIs experiencing SSRI-induced sexual dysfunction?
Cyproheptadine
Which of the NARIs causes seizures, sedation and postural hypotension?
Maprotiline
What is an example of an NARI?
Reboxetine
True or false:
MOAis are given regularly for px diagnosed with clinical depression.
False.
What are 3 AEs of reboxetine (NARI)?
1) Xerostomia, constipation (anticholinergic effects)
2) Insomnia
- ↑NA activity in CNS
3) Tachycardia
- ↑NA at sympathetic synapses
What are 3 examples of SNRIs?
1) Venlafaxine
2) Desvenlafaxine
3) Duloxetine
What are 3 advantages of SNRIs?
1) Fewer AEs
2) Faster than other antidepressants
3) Better in treatment-resistant px
What are 3 AEs of SNRIs?
Serotoninergic AEs (eg. SSRIs):
1) Nausea
2) Insomnia
3) sexual dysfunctions
4) Serotonin syndrome
5) Withdrawal effects more common and stronger than SSRIs and TCAs
What is Mirtazapine?
Norepinephrine and specific serotonin antidepressant (NASSA)
What is Bupropion?
Norepinephrine-dopamine reuptake inhibitor (NDRI)
What is agomelatine?
Melatonin MT1/2 receptor agonists
- less TCA/SSRI AEs
- helps in sleep disorders
What is ketamine?
Glutamate NMDA receptor antagonist
- anaesthetic
- rapid-onset antidepressant
What is the moa of vortioxetine?
1) 5-HT1A receptor agonist
2) 5-HT1A receptor partial agonist
3) 5-HT1D, 5-HT7, 5-HT3 receptor antagonist
What are 4 ways in which vortioxetine differs from other antidepressants?
1) Effective in px resistant to other antidepressants
2) Procognitive effects
3) AEs similar to other antidepressants but + risk of suicidal thoughts
4) Multimodal serotoninergic antidepressant
How does the mechanism of postural hypotension differ in MOAis and TCAs?
How does ketamine differ from other antidepressants?
Only one that has very fast onset
(the rest take weeks to months to show subtle effects)
What defines a psychiatric state of anxiety?
Interferes with ADLs, work and relationship
What are 5 manifestations of anxiety stress?
Psychological:
1) Negative emotions (worry, nervousness, unease)
2) Arousal
3) Lack of concentration
4) Insomnia
Physical:
5) Tachycardia
6) Nausea
7) Gastric acid hypersecretion
8) Trembling
What is the biochemical basis of anxiety stress?
1) CNS/PNS NA/A activation → sympathetic response
2) Stress → HPA axis → cortisol
What are 5 examples of anxiety disorders?
1) Generalised anxiety disorder
2) Post-traumatic stress disorder
3) Phobias
4) Panic disorder
5) Obsessive compulsive disorders
How do CNS depressants help with anxiety?
1) Sedation + relaxation
2) Hypnotic (drowsiness, amnestic)
3) Anxiolytic
How does the effect of CNS depressants vary with dose?
Low: anxiolytic + sedative
Higher: Hypnotic
Very high: Anesthesia
What are 4 uses of benzodiazepines?
1) Anxiolytics/sedatives (eg. diazepam, lorazepam)
2) Hypnotic (eg. diazepam, triazolam, temazepam)
3) Pre-anaesthetics (eg. diazepam, midazolam)
4) Anti-convulsants (eg. diazepam)
What are 4 examples of benodiazepines?
1) Diazepam
2) Lorazepam
3) Triazolam
4) Temazepam
5) Midazolam
What are 4 examples of non-benzodiazepines used in anxiety disorders?
1) Barbiturates (eg. phenobarbital)
2) Buspirone
3) Zolpidem
4) Propanolol
What is the moa of benzodiazepines?
bind to allosteric site on GABA
→ ↑frequency of GABA-induced channel opening
→ greater Cl- influx
→ hyperpolarise cell
→ ↓neuronal excitability
What are 4 AEs of benzodiazepines?
1) Drowsiness, confusion, amnesia
2) Impaired muscle coordination
3) Tolerance
4) Dependence (have to withdraw gradually)
5) OD: severe respiratory depression
What are 2 examples of short acting and 3 examples of long acting benzodiazepines?
Short acting:
1) Midazolam
2) Triazolam
3) Oxazepam
Long acting:
1) Flurazepam
2) Diazepam
3) Chlordiazepoxide
4) Quazepam
5) Clorazepate
Why should px on benzodiazepines avoid alcohol?
Can precipitate severe respiratory depression
How is a benzodiazepine OD treated?
Flumazenil (benzodiazepine antagonist)
What is the moa of Zolpidem?
Potentiates GABA-A mediated Cl- currents at benzodiazepine site
What is the therapeutic use of Zolpidem?
Insomnia (good hypnotic)
- not effective as anxiolytic
What is the moa of Buspirone?
Serotonin 5-HT1A receptor partial agonist + dopaminergic agonist
What is the therapeutic use of Buspirone?
GAD but anxiolytic effect takes 1-2 weeks
- not effective as anticonvulsants, muscle relaxant properties
What is the moa of barbiturates?
Binds to GABA-A at barbiturate site
→ potentiate GABA-mediated Cl- currents
→ Cl- influx
→ hyperpolarisation
→ ↓neuronal excitability
What are the drawbacks of using barbiturates to treat anxiety?
1) high tendency to develop tolerance and dependence
2) Severe withdrawl symptoms
3) Flumazenil not effected in treating OD
At anaesthetic doses, barbiturates can ____________________.
1) Directly open Cl-
2) Block Na+ channel
What are 4 examples of barbiturates grouped by their duration of action?
Ultrashort (20mins): anaesthesia
1) Thiopental
Short (3-8hrs): sedative + hypnotic
2) Pentobarbital
3) Amobarbital
Long acting (1-2days): anticonvulsant
4) Phenobarbital
Which drug is indicated for a px who is not anxious but struggles with sleeping?
Zolpidem
How does the dose-dependent CNS depression differ between barbiturates and benzodiazepines?
CNS effects for ↑dose of benzodiazepines taper at medullary depression
(does not for barbiturates → can lead to coma)
What is the moa of pregabalin?
i) GABA analogue → ↑GABA-mediated Cl- currents → hyperpolarisation
ii) acts on voltage gated Ca2+ channels agonist
What is the therapeutic use of Pregabalin?
1) GAD
2) Anticonvulsant
Pregabalin may be a/w _________________.
Suicidal ideation
What is the moa of hydroxyzine?
Antihistamine
- serotonergic
- α-adrenergic receptor agonists
How does hydroxyzine differ from benzodiazepines and barbiturates?
1) Anxiolytic effect by 5-HT2 antagonism
2) Lower addictive potential
3) Also helps with itching
What is the moa of propanolol?
ß-adrenergic receptor antagonist
What is the therapeutic use of propanolol?
1) Performance anxiety and social phobia
2) ↓physical symptoms a/w adrenergic activation
When is propanolol contraindicated?
Px with asthma and heart conditions
What are 3 antidepressants that are also anxiolytics?
NaSSA:
1) Mirtazapine
TCA:
2) Clomipramine
SSRI:
3) Fluoxetine
4) Citalopram
5) Sertraline
6) Paroxetine
SNRI:
7) Velafaxine
8) Duloxetine
What are the 5 symptom domains of schizophrenia?
1) Positive symptoms
- abnormal behaviours added
- delusions, hallucinationos
- thought/behavioural disorders
2) Negative symptoms (#1)
- normal behaviours subtracted
- withdrawal from social contacts
- flattening of emotional responses
3) Anxiety/depression
4) Aggressive symptoms
5) Cognitive symptoms
- impairment of selective attention
- impairment of working memory
What are 2 possible aetiology of schizophrenia?
1) Genetic
- incomplete hereditary tendency
- some possible genes (DISC1, COMT, dysbindin-1, neuregulin-1)
2) Environment
- neurodevelopmental abnormalities
- eg. viral infections during pregnancy, obstetric complication
- abnormal myelination of cortico-cortical pathways
What are 3 neurochemical theories of schizophrenia?
1) Dopamine theory
- amphetamine produces similar acute schizophrenic symptoms
- all antipsychotic drugs are D2 antagonists
- dopamine is increased in acute schizophrenia
2) 5-HT theory
- LSD acts at 5-HT2 and produces similar acute schizophrenic symptoms
- newer atypical antipsychotics have 5-HT2 antagonism
3) Glutamate theory
- PCP/Ketamine block NMDA and produce symptoms similar to acute schizophrenia
What are 4 dopamine pathways of the brain?
1) Nigrostriatal
- extrapyramidal motor system
- substantia nigra → dorsal striatum
2) Mesolimbic
- reward, emotion
- ventral tegmental area → limbic system
3) Mesocortical
- cognition, attention
- ventral tegmental area → prefrontal cortex
4) Tuberoinfundibular
- regulate prolactin secretion
- hypothalamus → anterior pituitary
What are 4 examples of antipsychotics?
1) Chlorpromazine
2) Fluphenazine
3) Haloperidol
4) Trifluoperazine
What are 4 examples of atypical antipsychotics?
1) Amisulpride
2) Clozapine
3) Olanzapine
4) Resperidone
What are 4 AEs of typical antipsychotics?
1) Parasympatholytic (xerostomia, constipation, blurred vision)
- M1 antagonism
2) Sedation + Weight gain
- H1 antagonism
3) Postural hypotension + Dizziness
- α1 antagonism
4) Extrapyramidal
- acute dystonia (2° parkinsonism, D2 antagonism in nigrostriatal pathway)
- tardive dyskinesia and akathisia
What is the moa of typical antipsychotics?
D2 antagonism
Why does haloperidol have less side effects than chlorpromazine?
Haloperidol only α1 and D2 antagonism → less than chlorpromazine → less side effect
How do the extrapyramidal AEs of typical antipsychotics differ?
1) Parkinsonism-like symptoms
- occur within weeks
- reversible when drug is stopped
- cogwheel rigidity, resting tremor
2) Tardive dyskinesia and akathisia
- occur over months-years (tardive)
- irreversible
- Repetitive and stereotyped involuntary movements of face, tongue, and limbs (dyskinesia)
- Involuntary movements and compulsion to act associated with restlessness, anxiety and agitation (akathisia)
What is the main difference between typical and atypical antipsychotics?
1) Serotonin-dopamine antagonism (5-HT2 + D2)
2) Atypical produces less severe extrapyramidal side effects
3) greater affinity at 5-HT2, D4, α-1, H1, muscarinic receptors
What is the main concern of px on clozapine?
Agranulocytosis
What are 4 AEs of atypical antipsychotics?
1) Parasympatholytic (xerostomia, constipation, blurred vision)
- M1 antagonism
- esp. clozapine, olanzapine
2) Sedation
- H1 antagonism
- esp. clozapine, olanzapine
3) Postural hypotension + reflex tachycadia
- α1 antagonism
- esp. risperidone
4) Hyperglycemia and DM
5) Agranulocytosis
- just clozapine
6) Mammary glands and tissues
- amisulpride
How does the AEs of amisulpride differ from other atypical antipsychotics?
1) Less AEs (↑selectivity for D2/3)
2) No α-adrenoceptor block, antihistaminergic, anticholinergic
3) AEs on mammary gland and tissues
- breast swelling, pain, lactation (F) gynaecomastia (M)
- ↑ prolactin secretion by blocking D2/3 receptors in AP gland
How do atypical antipsychotics induce hyperglycemia and DM?
Mechanism unknown
- 5-HT3 in hypothalamus and ß-cells
→ Irreversible DM
- strong for clozapine, olanzapine, risperidone (except amisulpride)
Why are D partial agonists as useful as antagonists?
Functional antagonism (competitive) → Reduce Vmax
How do atypical antipsychotics induce weight gain?
1) H1-mediated sedation → sedentary lifestyle
2) α + 5-HT2 antagonism on hypothalamus → ↑feeding behaviours
- esp clozapine, olanzapine, risperidone
Why could olanzapine be used to treat anorexia nervousa?
α + 5-HT2 antagonism on hypothalamus → ↑feeding behaviours
Why do atypical antipsychotics produces less extrapyramidal symptoms?
↓D2 antagonism → ↓nigrostriatal activation:
1) Potent 5-HT2A receptor antagonism vs. weak D2 antagonism → ↓EPS
- clozapine, olanzapine
2) High D3 to D2 antagonism ratio →
nucleus accumbens > striatum
- amisulpride
3) High D4 to D2 antagonism ratio →
prefrontal cortex > striatum.
- clozapine
4) High D2 to D1 antagonism ratio → ↓striatal antagonism (presynaptic D2 → autoregulation → ↓ complete blockage → ↑dopamine release)
- amisulpride, risperidone
Apart from less AEs, what 3 additional benefits do atypical antipsychotics have over typical antipsychotics?
1) More effective against negative symptoms
- clozapine, olanzapine, risperidone
2) More effective in ameliorating cognitive dysfunction
- clozapine, risperidone
3) Better at mood stabilisation
- clozapine, olanzapine, risperidone
