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Nervous System > Neuropharmacology > Flashcards

Neuropharmacology Flashcards

1
Q

What determines the absolute refractory period of a neuron?

A

Duration of Na+ channel inactivation

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2
Q

What determines the relative refractory period of a neuron?

A

Duration of after hyper-polarisation (AHP)

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3
Q

Describe the mechanism of an action potential.

A

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

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4
Q

Describe a typical cholinergic synapse.

A

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)

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5
Q

How does AP propagation along a neuron differ when it is myelinated?

A

Unmyelinated → Wave of depolarisation by adjacent Na+ channels

Myelinated → Saltatory conduction via Nodes of Ranvier

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6
Q

How is neurotransmitter release initiated?

A

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

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7
Q

How is synaptic transmission regulated?

A

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

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8
Q

Glutamate is the major transmitter in (excitatory/inhibitory) synapses while GABA is the major transmitter in (excitatory/inhibitory) synapses.

A

Glutamate → Excitatory
GABA → Inhibitory

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9
Q

Glutamate is found in __________ and used in _______________.

A

Pyramidal neurons in neocortex

Learning and memory

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10
Q

Acetylcholine is found in __________ and used in _______________.

A

Nucleus basalis of Meynert

Learning, arousal, reward

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11
Q

Dopamine is found in __________ and used in _______________.

A

Substantia nigra

Motor system, reward

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12
Q

What are 3 symptoms of depression?

A

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

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13
Q

What are the 2 major types of depression?

A

1) Unipolar
- mood swings all in same direction

2) Bipolar depression/affective disorder
- alternating depression and mania
- strongly familial, in early childhood

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14
Q

What are 2 forms of unipolar depression?

A

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

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15
Q

What is the monoamine theory of depression?

A

Deficits in monoamine neurotransmitters (NA, 5-HT) cause depression

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16
Q

What are 3 limitations of the monoamine theory of depression?

A

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

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17
Q

MOA-B selective inhibitors (eg. selegiline) are used in __________.

A

Parkinson’s disease

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18
Q

What is the moa of phenelzine?

A

Non-selective, irreversible MOA inhibitor
→ ↓Monoamine NT breakdown
→ ↑bioavailability

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19
Q

What are 2 AEs of MOAis?

A

1) Postural hypotension
- sympathetic block by accumulation of dopamine in cervical ganglia

2) Restlessness and insomnia
- CNS stimulation

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20
Q

MOAis should not be combined with ______________ drugs lest px experience ______________________.

A

Serotoninergic function enhancers (eg. pethidine)

  • hyperexcitability, ↑tone, myoclonus, LOC
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21
Q

What are 3 examples of TCAs?

A

Non-selective for SERT/NET:
1) Imipramine
2) Amitriptyline
3) Nortriptyline

Selective for NET:
4) Desipramine

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22
Q

How is nortriptyline different from the other non-selective TCAs?

A

1) Second generation
2) Milder AEs
3) Improved compliance

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23
Q

What are 3 AEs of TCAs?

A

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

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24
Q

How are TCAs metabolised?

A

Hepatic

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25
Q

What are 2 examples of SSRIs?

A

1) Fluoxetine
2) Citalopram

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26
Q

What are 4 advantages of SSRIs?

A

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

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27
Q

How does MOA-A differ from MOA-B?

A

MOA-B: break down NA and dopamine
MOA-A: also break down 5-HT

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28
Q

What are 4 AEs of SSRIs?

A

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

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29
Q

Which SSRI can lead to sedation?

A

Citalopram

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30
Q

What is given for a px on SSRIs experiencing SSRI-induced sexual dysfunction?

A

Cyproheptadine

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31
Q

Which of the NARIs causes seizures, sedation and postural hypotension?

A

Maprotiline

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32
Q

What is an example of an NARI?

A

Reboxetine

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33
Q

True or false:
MOAis are given regularly for px diagnosed with clinical depression.

A

False.

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34
Q

What are 3 AEs of reboxetine (NARI)?

A

1) Xerostomia, constipation (anticholinergic effects)

2) Insomnia
- ↑NA activity in CNS

3) Tachycardia
- ↑NA at sympathetic synapses

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35
Q

What are 3 examples of SNRIs?

A

1) Venlafaxine
2) Desvenlafaxine
3) Duloxetine

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36
Q

What are 3 advantages of SNRIs?

A

1) Fewer AEs
2) Faster than other antidepressants
3) Better in treatment-resistant px

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37
Q

What are 3 AEs of SNRIs?

A

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

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38
Q

What is Mirtazapine?

A

Norepinephrine and specific serotonin antidepressant (NASSA)

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39
Q

What is Bupropion?

A

Norepinephrine-dopamine reuptake inhibitor (NDRI)

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40
Q

What is agomelatine?

A

Melatonin MT1/2 receptor agonists
- less TCA/SSRI AEs
- helps in sleep disorders

41
Q

What is ketamine?

A

Glutamate NMDA receptor antagonist
- anaesthetic
- rapid-onset antidepressant

42
Q

What is the moa of vortioxetine?

A

1) 5-HT1A receptor agonist
2) 5-HT1A receptor partial agonist
3) 5-HT1D, 5-HT7, 5-HT3 receptor antagonist

43
Q

What are 4 ways in which vortioxetine differs from other antidepressants?

A

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

44
Q

How does the mechanism of postural hypotension differ in MOAis and TCAs?

A
45
Q

How does ketamine differ from other antidepressants?

A

Only one that has very fast onset
(the rest take weeks to months to show subtle effects)

46
Q

What defines a psychiatric state of anxiety?

A

Interferes with ADLs, work and relationship

47
Q

What are 5 manifestations of anxiety stress?

A

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

48
Q

What is the biochemical basis of anxiety stress?

A

1) CNS/PNS NA/A activation → sympathetic response

2) Stress → HPA axis → cortisol

49
Q

What are 5 examples of anxiety disorders?

A

1) Generalised anxiety disorder
2) Post-traumatic stress disorder
3) Phobias
4) Panic disorder
5) Obsessive compulsive disorders

50
Q

How do CNS depressants help with anxiety?

A

1) Sedation + relaxation
2) Hypnotic (drowsiness, amnestic)
3) Anxiolytic

51
Q

How does the effect of CNS depressants vary with dose?

A

Low: anxiolytic + sedative
Higher: Hypnotic
Very high: Anesthesia

52
Q

What are 4 uses of benzodiazepines?

A

1) Anxiolytics/sedatives (eg. diazepam, lorazepam)
2) Hypnotic (eg. diazepam, triazolam, temazepam)
3) Pre-anaesthetics (eg. diazepam, midazolam)
4) Anti-convulsants (eg. diazepam)

53
Q

What are 4 examples of benodiazepines?

A

1) Diazepam
2) Lorazepam
3) Triazolam
4) Temazepam
5) Midazolam

54
Q

What are 4 examples of non-benzodiazepines used in anxiety disorders?

A

1) Barbiturates (eg. phenobarbital)
2) Buspirone
3) Zolpidem
4) Propanolol

55
Q

What is the moa of benzodiazepines?

A

bind to allosteric site on GABA
→ ↑frequency of GABA-induced channel opening
→ greater Cl- influx
→ hyperpolarise cell
→ ↓neuronal excitability

56
Q

What are 4 AEs of benzodiazepines?

A

1) Drowsiness, confusion, amnesia
2) Impaired muscle coordination
3) Tolerance
4) Dependence (have to withdraw gradually)
5) OD: severe respiratory depression

57
Q

What are 2 examples of short acting and 3 examples of long acting benzodiazepines?

A

Short acting:
1) Midazolam
2) Triazolam
3) Oxazepam

Long acting:
1) Flurazepam
2) Diazepam
3) Chlordiazepoxide
4) Quazepam
5) Clorazepate

58
Q

Why should px on benzodiazepines avoid alcohol?

A

Can precipitate severe respiratory depression

59
Q

How is a benzodiazepine OD treated?

A

Flumazenil (benzodiazepine antagonist)

60
Q

What is the moa of Zolpidem?

A

Potentiates GABA-A mediated Cl- currents at benzodiazepine site

61
Q

What is the therapeutic use of Zolpidem?

A

Insomnia (good hypnotic)
- not effective as anxiolytic

62
Q

What is the moa of Buspirone?

A

Serotonin 5-HT1A receptor partial agonist + dopaminergic agonist

63
Q

What is the therapeutic use of Buspirone?

A

GAD but anxiolytic effect takes 1-2 weeks
- not effective as anticonvulsants, muscle relaxant properties

64
Q

What is the moa of barbiturates?

A

Binds to GABA-A at barbiturate site
→ potentiate GABA-mediated Cl- currents
→ Cl- influx
→ hyperpolarisation
→ ↓neuronal excitability

65
Q

What are the drawbacks of using barbiturates to treat anxiety?

A

1) high tendency to develop tolerance and dependence
2) Severe withdrawl symptoms
3) Flumazenil not effected in treating OD

66
Q

At anaesthetic doses, barbiturates can ____________________.

A

1) Directly open Cl-
2) Block Na+ channel

67
Q

What are 4 examples of barbiturates grouped by their duration of action?

A

Ultrashort (20mins): anaesthesia
1) Thiopental

Short (3-8hrs): sedative + hypnotic
2) Pentobarbital
3) Amobarbital

Long acting (1-2days): anticonvulsant
4) Phenobarbital

68
Q

Which drug is indicated for a px who is not anxious but struggles with sleeping?

A

Zolpidem

69
Q

How does the dose-dependent CNS depression differ between barbiturates and benzodiazepines?

A

CNS effects for ↑dose of benzodiazepines taper at medullary depression

(does not for barbiturates → can lead to coma)

70
Q

What is the moa of pregabalin?

A

i) GABA analogue → ↑GABA-mediated Cl- currents → hyperpolarisation

ii) acts on voltage gated Ca2+ channels agonist

71
Q

What is the therapeutic use of Pregabalin?

A

1) GAD
2) Anticonvulsant

72
Q

Pregabalin may be a/w _________________.

A

Suicidal ideation

73
Q

What is the moa of hydroxyzine?

A

Antihistamine
- serotonergic
- α-adrenergic receptor agonists

74
Q

How does hydroxyzine differ from benzodiazepines and barbiturates?

A

1) Anxiolytic effect by 5-HT2 antagonism
2) Lower addictive potential
3) Also helps with itching

75
Q

What is the moa of propanolol?

A

ß-adrenergic receptor antagonist

76
Q

What is the therapeutic use of propanolol?

A

1) Performance anxiety and social phobia
2) ↓physical symptoms a/w adrenergic activation

77
Q

When is propanolol contraindicated?

A

Px with asthma and heart conditions

78
Q

What are 3 antidepressants that are also anxiolytics?

A

NaSSA:
1) Mirtazapine

TCA:
2) Clomipramine

SSRI:
3) Fluoxetine
4) Citalopram
5) Sertraline
6) Paroxetine

SNRI:
7) Velafaxine
8) Duloxetine

79
Q

What are the 5 symptom domains of schizophrenia?

A

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

80
Q

What are 2 possible aetiology of schizophrenia?

A

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

81
Q

What are 3 neurochemical theories of schizophrenia?

A

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

82
Q

What are 4 dopamine pathways of the brain?

A

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

83
Q

What are 4 examples of antipsychotics?

A

1) Chlorpromazine
2) Fluphenazine
3) Haloperidol
4) Trifluoperazine

84
Q

What are 4 examples of atypical antipsychotics?

A

1) Amisulpride
2) Clozapine
3) Olanzapine
4) Resperidone

85
Q

What are 4 AEs of typical antipsychotics?

A

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

86
Q

What is the moa of typical antipsychotics?

A

D2 antagonism

87
Q

Why does haloperidol have less side effects than chlorpromazine?

A

Haloperidol only α1 and D2 antagonism → less than chlorpromazine → less side effect

88
Q

How do the extrapyramidal AEs of typical antipsychotics differ?

A

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)

89
Q

What is the main difference between typical and atypical antipsychotics?

A

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

90
Q

What is the main concern of px on clozapine?

A

Agranulocytosis

91
Q

What are 4 AEs of atypical antipsychotics?

A

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

92
Q

How does the AEs of amisulpride differ from other atypical antipsychotics?

A

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

93
Q

How do atypical antipsychotics induce hyperglycemia and DM?

A

Mechanism unknown
- 5-HT3 in hypothalamus and ß-cells
→ Irreversible DM
- strong for clozapine, olanzapine, risperidone (except amisulpride)

94
Q

Why are D partial agonists as useful as antagonists?

A

Functional antagonism (competitive) → Reduce Vmax

95
Q

How do atypical antipsychotics induce weight gain?

A

1) H1-mediated sedation → sedentary lifestyle
2) α + 5-HT2 antagonism on hypothalamus → ↑feeding behaviours

  • esp clozapine, olanzapine, risperidone
96
Q

Why could olanzapine be used to treat anorexia nervousa?

A

α + 5-HT2 antagonism on hypothalamus → ↑feeding behaviours

97
Q

Why do atypical antipsychotics produces less extrapyramidal symptoms?

A

↓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

98
Q

Apart from less AEs, what 3 additional benefits do atypical antipsychotics have over typical antipsychotics?

A

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

Nervous System (14 decks)

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