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MRCPsych Part A - Al-Rashid Hospital > Pharmacodynamics > Flashcards

Pharmacodynamics Flashcards

1
Q

What is pharmacodynamics?

A

Study of mechanism of action of drugs

effect of drugs on the body

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2
Q

Which psychiatric drugs affect the synthesis of neurotransmitters?

A

L-dopa

L-tryptophan

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3
Q

Which psychiatric drugs affect the storage of neurotransmitters?

A

Reserpine depletes NA and DA

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4
Q

Which psychiatric drugs affect the release from storage of neurotransmitters?

A

SSRI
TCA
Cocaine - dopamine reuptake
Bupropion - dopamine and noradrenaline reuptake

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5
Q

Which psychiatric drugs affect the degradation of neurotransmitters?

A

MAOI

Acetylcholinesterase inhibitors e.g. donepezil

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6
Q

Which psychiatric drugs affect the pre synaptic receptors?

A

Clonidine

Lofexidine at alpha2

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7
Q

Which psychiatric drugs affect the postsynaptic receptors?

A

Most antipsychotics at D2

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8
Q

Which psychiatric drugs cause partial agonism?

A

Aripiprazole - D2
Buspirone - 5HT1A
Clonazepam - BDZ receptor
Buprenorphine - opioid receptor mu

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9
Q

Which receptor does Aripiprazole cause partial agonism at?

A

D2

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10
Q

Which receptor does Buspirone cause partial agonism at?

A

5HT1A

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11
Q

Which receptor does Clonazepam cause partial agonism at?

A

BDZ

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12
Q

Which receptor does Buprenorphine cause partial agonism at?

A

Opioid receptor mu

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13
Q

Which psychiatric drugs cause antagonism?

A

Flumazenil - benzos

Antipsychotics at D2

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14
Q

Which psychiatric drugs cause full agonism?

A

Benzos - GABA-A complex

Bromocriptine - dopamine

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15
Q

Which psychiatric drugs have an affect via second messengers?

A

Lithium

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16
Q

What does activation of ligand-gated ionotropic channels lead to?

A

Rapid and transient increase in membrane permeability to either positive cations (Na/Ca) or negative anions (Cl), causing axcitation/inhibition of postsynaptic membrane.

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17
Q

E.g. of ionotropic receptrs?

A

Aectylcholine
GABA-A
Glutamate
5HT-3

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18
Q

Describe how metabotropic receptors work

A

Produce slower responses involving G-proteins which bind to intracellular portion of receptor and activate second messenger.

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19
Q

What does altered second messenger levels in metabotropic receptors lead to?

A

Changes in phosphorylation state of key proteins rendering them active or inactive.

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20
Q

Examples of Metabotropic receptors?

A 
Dopamie - D1-5
Noradrenaline
5HT1-7 (except 5HT-3)
Muscarinic Acetylcholine receptors
Opioid receptors - mu
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21
Q

Which receptors do most antipsychotics work via?

A

Metabotropic

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22
Q

What is a ceiling effect?

A

Related to partial agonists; degree of response depends on availability of physiological neurotransmitter in the vicinity.

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23
Q

What is an inverse agonist

A

Agent that binds to same receptor but produces opposite pharmacological effect.

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24
Q

Give e.g. of clinical inverse agonist?

A

None

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25
Q

Types of antagonism

A 
Competitive
Noncompetitive
Irreversible
Pharmacological
Physiological
Chemical
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26
Q

What is competitive antagonist?

A

Can be reversed by increasing dose of agonist drug.

Reduce potency but not efficacy of agnoist.

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27
Q

What is potency?

A

Minimal dose needed to produce an efacy

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28
Q

Examples of competitive antagonism drugs?

A

Atropine - muscarinic receptors

Propranolol - beta-adrenergic receptors

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29
Q

How do noncompetitive antagonists work?

A

Alter receptor site so increasing dose of agonist drug can reverse effects on partially.
Reduces both potency and efficacy of agonists.
Shift curve to right.

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30
Q

E.g. of noncompetitive antagonists.

A

Ketamine and phencyclidine are noncompetitive NMDA antagonists.

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31
Q

Give e.g. of irreversible antagonists

A

MAOIs

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32
Q

What is pharmacological antagonism?

A

Opposing action of 2 molecules acting via same receptor

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33
Q

What is physiological antagonism?

A

Opposing action of 2 molecules by acting via different receptors

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34
Q

What is chemical antagonism?

A

Opposing action of 2 molecules acting via chemical reactions.

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35
Q

Give e.g. of chemical antagonism

A

Not seen in psychotropics

Heparin and protamine reaction

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36
Q

What is the law of mass action?

A

Reversible action of drugs on receptors leads to response that s proportional to the fraction of receptors occupied.

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37
Q

Which drugs cause down-regulation of receptor numbers?

A

Agonists

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38
Q

Which drugs may cause upregulation or hypersensitivity or receptor numbers?

A

Antagonists

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39
Q

What is the potency of a drug?

A

Amount of drug needed to produce particular effect compared to another standard drug with similar receptor profile (vigor)

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40
Q

What determines the potency of a drug?

A

Proportion of drug reaching receptor
Affinity for receptor
Efficacy

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41
Q

What is affinity?

A

Ability of drug to bind to appropriate receptor

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42
Q

What is efficacy?

A

How well drug produces expected response.

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43
Q

What does efficacy depend upon?

A

Affinity
Potency
Duration of receptor action
Kinetic properties such as half-life

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44
Q

Mechanism of Amisulpride?

A

D2 and D3 antagonism
Dose-dependent
Limbic selectivity an 5HT7 activity

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45
Q

Mechanism of Aripiprazole?

A

Partial dopamine agonist at D2
5HT2A antagonist
Goldilocks phenomenon

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46
Q

What is Goldilocks phenomenon?

A

Stabilizing action wherein antagonising DA at sites of excessive dopamine such as mesolimbic zones while mimicking DA (agonism) at dopamine deficient zones such as mesocortical areas that are linked with negative symptoms.

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47
Q

Which receptors does Aripiprazole act on?

A

Postsynaptic D2 receptors

Presynaptic autoreceptors

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48
Q

Mechanism of Asenapine

A

D2 antagonist and 5HT2A blocker

Alpha-2 blockage

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49
Q

Difference of Asenapine given sublingually?

A

Weight and prolactin-neutral

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50
Q

Mechanism of Chlorpromazine and promazine?

A

Moderate antimuscarinic effect
D2 blockade
Highly sedative

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51
Q

Mechanism of clozapine?

A 
High ratio of 5HT2 to D2 blockade
Blocks D4 and 5HT5
Alpha 1 antagonism
Anticholinergic and antihistaminic properties
Weak D1 and D2 affinity
Binds 5HT3
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52
Q

Profile of Clozapine?

A

Faster dissociation rate (such as Quetiapine)

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53
Q

Mechanism of Lurasidone?

A 
D2 antagonist
5HT2A blocker 
High affinity for 5HT7
Partial agonist at 5HT1A receptors
Minimal affinity for alpha-1 (less orthostatic effect) and histamine receptors (perhaps weight neutral)
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54
Q

What makes Lurasidone have a less orthostatic affect?

A

Minimal affinity for alpha-1

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55
Q

Mechanism of Olanzapine

A

High 5HT2/D2 blockade ratio.
Potent D4 blockade and 5HT6 blockade
Significant anticholinergic and antihistaminic effects

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56
Q

Mechanism of Quetiapine

A

Similar to clozapine - hit and run profile on D2.
Less 5HT2A blockade compared to other antipsychotics.
Significant anticholinergic effects.

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57
Q

Mechanism of Risperidone

A

Serotonin-Dopamine antagonist.
High 5HT2A antagonist.
Therapeutic doses: binds D2 similar to typicals -> EPSEs and prolactin SEs.

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58
Q

How does Risperidone lead to EPSEs?

A

At therapeutic doses binds D2 similar to typical antipsychotics

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59
Q

Mechanism of Sulpride?

A

Pure D2 antagonist.
Low doses: presynaptic receptors blocked (helps with -ve symptoms).
Above 800mg/day; affects postsynaptic D2 - reducing +ve symptoms.

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60
Q

Mechanism of Thioridazine, pericyazine

A

D2 antagonist
Marked antimuscarinic effect
Less EPSEs than other typicals

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61
Q

Mechanism of thioxanthenes

A

Exhibits stereoisomerism.

D2 antagonist - typical antipsychotic.

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62
Q

Mechanism of Ziprasidone

A

Atypical antipsychotic
5HT2A and D2 blockade.
Antagonizes 5HT1D, 5HT2C, D3 and D4 receptors
Poor affinity for muscarinic effects.
Some antihistaminic property
Agonist at 5HT1A
Some serotonin and norepinephrine reuptake inhibition

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63
Q

Mechanism of Zotepine

A 
Atypical antipsychotic
5HT2A, 5HT2C, D1-D4 antagonism
Potent noradrenaline reuptake inhibitor
Potent antihistaminic activity
Some NMDA antagonism
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64
Q

Mechanism of action of Agomelatine as an antidepressant

A

Enhances norepinephrine and dopamine neutransmission through 5-HT2C antagonism.
Direct antagonist at melatonin (Mt1-2) receptors.
Norepinephrine and dopamine disinhibitor via 5HT2C inhibition
Sedative effects

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65
Q

How does Agomelatine cause inhibition of norepinephrine and dopamine via 5HT2C?

A

GABA interneurons tonically inhibit noradrenergic circuits from locus coeruleus and dopaminergic ciriuts from ventral tegmentum, projecting to prefrontal cortex.
Serotonin via 5HT2C stimulation drives these GABA interneurons.

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66
Q

Structure of Amoxapine

A

Tetracyclic with dibenzoxazepine structure

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67
Q

Mechanism of Amoxapine

A

Both dopamine antagonistic and serotonin-noradrenaline reuptake inhibition effects.
Antipsychotic + antidepressant.
EPSEs.

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68
Q

Mechanism of Bupropion

A

Dopamine and noradrenaline reuptake inhibitor.
Increases efficiency of noradrenergic transmission and reduce total norepinephrine turnover.
Some degree of competitive nicotinic antagonism

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69
Q

What is Bupropion used in?

A

Depression

Smoking cessation

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70
Q

Mechanism of Buspirone?

A

Partial agonist on 5HT1A
Presynaptic - full agonist, inhibits release of serotonin which leads to antianxiety.
Postsynaptic - partial agonist to account for antidepressant acitivity.

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71
Q

Mechanism of Citalopram

A

Most selective of all SSRIs for serotonin reuptake.
Occurs in racemic mixture of which s isomer has pharmacological activity.
R-enantiomer inhibits action os s-enantiomer, hence is escitalopram is used (s-enantiomer), lesser dose used.

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72
Q

Mehcanism of Clomipramine

A

Tricyclic - most potent.

Higher SRI selectivity than other TCAs but less selectivity than SSRIs.

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73
Q

Mechanism of Desipramine

A

Tricyclic with least anticholinergic action but lethal on OD.

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74
Q

Mechanism of Duloxetine

A

SNRI

Better profile for psychosomatic and neuropathic pain

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75
Q

Mechanism of Levothyroxine

A

Levothyroxine -> T4
Liothyronine -> T3
Both suppress TSH and are adjuvants in resistant depression - possibly via neuroendocrine changes.

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76
Q

Mechanism of Lithium

A

Via second messenger system. Enhances serotonin transmission by increasing tryptophan uptake into neurons, enhancing serotonin release, downregulating 5HT1A, 1B and 2 receptor subtypes (on chronic administration), directly inhibiting glycogen synthase kinase-3 and competing with Mg directly at several regularly enzymes.

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77
Q

What causes therapeutic efficacy of lithium?

A

Inhibits inositol-monophosphatase which catalyzes inositol second messenger system. This reduces myoinositol and phosphoinositide phosphate.

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78
Q

How does lithium reduce dopamine synthesis?

A

Increases intracellular sodium, affecting NA+/K+ pump.

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79
Q

Mechanism of Milnacipran

A

SNRI

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80
Q

Mechanism of Mirtazapine

A

5HT2A antagonism
Alpha 2 antagonism
Antihistaminic
Anti 5HT3

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81
Q

Mechanism of Moclobemide

A

Reversible inhibitor of MAO-A electively.

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82
Q

Mechanism of Nefazadone

A

5HT2A antagonist with serotonin ruptake inhibition and mild norepinephrine reuptake inhibition.
Alpha 1 antagonism

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83
Q

What does Nefazadone produce as a metabolite?

A

MccP

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84
Q

Mechanism of Paroxetine

A

SSRI - most potent of all SSRIs in serotonin reuptake blockade but not specific.
Significant antimuscarinic action

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85
Q

Mechanism of Phenelzine

A

Monoamine Oxidase inhibitor - increased availability of monoamines including serotonin and noradrenaline may explain antidepressant action

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86
Q

Mechanism of Pindolol

A

Beta blocker with intrinsic symapthomimetic activity.

5HT1A antagonism - possibly enhances action of SSRI by this

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87
Q

Mechanism of action of Reboxetin

A

NARI

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88
Q

Mechanism of action of Selegiline

A

MAOI - selective for B at normal dose.

Selectivity lost when applied at higher doses.

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89
Q

Mechanism of action of SSRIs

A

Reuptake inhibition at somatodendritic areas soon after administration, leading to downregulation of somatic autoreceptors for serotonin and subsequent inhibitory tone on serotonergic transmission is lost .

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90
Q

Mechanism of action of Tranylcypromine

A

MAOI - irreversible, non-selective.

Positive enantiomer better MAOI, negative enantiomer = better reuptake inhibitor.

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91
Q

Mechanism of action of Trazadone

A 
5HT2A/2C antagonism
Alpha 2 blockade
Alpha 1 blockade
Antihistaminic
Mild reuptake inhibition of serotonin transporters
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92
Q

Mechanism of Tricyclics

A

MAOI
Mid noradrenaline and serotonin reuptake inhibition.
Secondary amines are more adrenergic.

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93
Q

Which TCA is most serotonin specific?

A

Clomipramine

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94
Q

Mechanism of action of Venlafaxine?

A

SNRI

Acts as SSRI in lower <150mg doses.

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95
Q

Mechanism of Vilazodone

A

Selective serotonin reuptake inhibition

Partial agonist at 5HT1A

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96
Q

Mechanism of Vortioxetine

A

SSRI-like effect
5HT3 antagonism
5HT1-A agonism

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97
Q

What is selectivity of an antidepressant?

A

Ratio of conc required to produce equivalent inhibitions of 5HT to noradrenalin.

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98
Q

Selectivity of Amitriptyline?

A

1:1

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99
Q

Selectivity of clomipramine?

A

1:7

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100
Q

Selectivity of Fluoxetine?

A

150:1

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101
Q

Selectivity of Citalopram?

A

> 2000:1

102
Q

Describe mechanism of TCA

A

Inhibition of nerve terminal NE neuronal uptake system
Increase in synaptic conc of NE
Desensitization of inhibitory alpha2 adrenoreceptors in terminal
Increase in neuronal NE release
Further increase in synaptic conc of NE
Desensitization of postsynaptic beta adrenoreceptors w/o affecting postsynaptic alpha1 adrenoreceptor sensitivity

103
Q

Mechanism of SSRI action

A

5HT reuptake inhibition at somatodenritic areas
Increase in local conc of 5HT
Desensitization of inhibitory 5HT1A autoreceptors in soma
Increase in neuronal 5HT release
Increase in synaptic conc of 5Ht
Desensitization of presynaptic 5HT1B receptors w/o affecting postsynaptic 5HT1A sensitivity

104
Q

Mechanism of Carbamazepine

A

Prolongs Na channel inactivation, so that ca channel inactivation is prolonged.
Reduces glutamate neurotransmission, adenosine A1 receptor antagonism and increase in brain catecholamine activity.
Inhibits peripheral benzo receptors and reduces limbic kindling.
Interferes with glial cell steroidogenesis.

105
Q

Structure of gabapentin

A

GABA analogue

106
Q

Mechanism of Gabapentin

A

Binds to alpha2delta subunit of voltage-dependent ca channel in CNS.
Acts on 1-aa transport and thereby increases GABA availability in brain.
No benzo-like actions
High affinity site in GABA-A complex

107
Q

How does gabapentin cross blood brain barrier?

A

1-aa transport

108
Q

Mechanism of Lamotrigine

A

Blockade of voltage-sensitive Na channels leads to modulation of glutamate and aspartate release.
Some effect on ca channels.
Some inhibition of Serotonin reuptake and weak inhibition of 5HT3 receptors.

109
Q

Mechanism of Levetiracetam

A

Indirectly enhances GABA system

Anticonvulsant with weak evidence against mania

110
Q

Mechanism of oxarbazepine

A

Metabolite of carbamazepine

111
Q

Structure of Pregabalin

A

GABA analogue

112
Q

Mechanism of Pregabalin

A

Binds to alpha2delta subunit of voltage-dependent ca channel in CNS - reduce release of certain neurotransmitters.
Influences GABAergic neurotransmission.
Anti-epileptic, analgesia (neuropathic) and anxiolytic effects.

113
Q

Comparison between pregabalin and gabapentin

A

Pregabalin is more potent, has a higher therapeutic index and fewer dose-related SEs.

114
Q

Mechanism of Tiagabine

A

Potent and selective reuptake inhibitor of GABA.

Mild antihistamine

115
Q

Mechanism of Topiramate

A

Fructose derivative.
Selective inhibitor of glutamate AMPA receptors, blocks Na receptors, indirect GABAergic activity by potentiating action of GABAa receptor.

116
Q

Mechanism of Valproic acid

A

Acts via increased GABA release, decreased GABA metabolism, increased neuronal responsibeness to GABA, increased GABA receptor density
Inhibition of phosphokinase C
Functional dopamine antagonism

117
Q

Function of Vigabatrin

A

Vi-GABA Transminase inhibitor

118
Q

Mechanism of Benzos

A

Act via omega site in GABA-A
all agonists (except clonazepam - partial)
Facilitate GABA action via GABA-A complex - facilitate inhibitory neurotransmission via Cl-.
No agonistic action in absence of GABA.

119
Q

Mechanism of chloral hydrate. paraldehyde and meprobamate

A

Barbituate-like
Potentiate GABAergic neurotransmission
Paraldehyde if cyclic ether Poor safety profile - not in clinical use

120
Q

Mechanism of Flumazenil

A

Benzo antagonist

121
Q

Mechanism of Ramelteon

A

Melatonin receptor full agonist with high affinity and selectivity for human melatonin MT1 + 2.
Decreases sleep latency, increases sleep time.
No significant difference in efficacy between 16-64mg

122
Q

Mechanism of Thiopental

A

Directly on GABA-A complex
Facilitate GABA transmission by opening Cl- channels and enhancing hyperpolarisation.
Lower doses: enhance GABA by decreasing rate of GABA dissociation and increasing duration of GABA-activated Cl- channel opening.
Higher conc: directly activate Cl- channel opening even in absence of GABA

123
Q

Mechanism of Zolpidem, Zaleplon, Zopiclone, Eszopiclone

A

Via GABA-A complex.
Unlike benzos, only occupy certain subunits; zolpidem and zopiclone acts on w1 receptors so no muscle relaxant, anxiolytic or anticonvulstant effects.
Slow wave sleep unaffected.

124
Q

Which receptors does Zaleplon occupy?

A

All 3 q receptors

125
Q

Structure of Zopiclone vs eszopiclone

A

Zopiclone: racemic mixture, which only s-isomer is active - eszopiclone

126
Q

Why are Z-hypnotics less likely to impact sleep stages and lower risk of tolerance?

A

Selective on BDZ-receptor subunits

127
Q

Which z-hypnotic is least selective?

A

Zopiclone

128
Q

Mechanism of alcohol

A 
Intercalates into fluid cell membrane
Decreases NMDA sensitivity
Increases GABA sensitivity
Down-regulates ca chanels
Up-regulates nicotine receptor gated Na channels
129
Q

Mechanism of amphetamine

A

Acts via releasing stored monoamines - noradrenaline and dopamine.
Central sympathomimetic

130
Q

Mechanism of buprenorphine

A

Partial opioid agonist.
Lower doses - mild agonism.
Higher doses - antagonist.

131
Q

Mechanism of cannabis

A

Via cannabinoid receptors. CB1 is central, activated by 11OH tetra hydro cannabinoid - this inhibits GABA tone in substantia nigra and other areas - may be related to increase dopamine activity at reward centres.
CB2 - peripheral, immune-related, seen in spleen and thymus.

132
Q

Mechanism of clonidine and lofexidine

A

Presynaptic alpha 2 agonist - reduces central sympathetic tone.
Opioid receptors on locus coeruleus projections reduce noradrenergic tone on long-term use.
Cellular machinery compensates via up-regulation of adenylate cyclase and maintains sympathetic tone in chronic user.

133
Q

Mechanism of sudden withdrawl of clonidine or lofexidine?

A

Leads to increased adrenergic firing rate (withdrawl symptoms) - hence alpha 2 autoreceptor stimulation which reduces central sympathetic tone helps in opioid withdrawl.

134
Q

Mechanism of dexfenfluramine and fenfluramine

A

Produces serotonin release from nerve endings.

135
Q

SE of dexfenfluramine and fenfluramine?

A

Irreversible serotonergic damage, valvular regurgitation and pulmonary fibrosis

136
Q

Mechanism of disulfiram

A

Inhibits aldehyde dehydrogenase

Leads to accumulation of acetaldehyde if alcohol is consumed.

137
Q

Mehcanism of levomethadyl acetate

A

Long-acting opioid agonist
Pure mu agonist
(similar to methadone)

138
Q

Why was levomethadyl acetate withdrawn?

A

Prolonged QT and torsades de pointes.

139
Q

Mechanism of LSD

A

5HT2A partial agonism - produces hallucinogenic effect

140
Q

Mechanism of MDMA

A

2 isomers:
R (-) isomer produces LSD-like effects
S (+) isomer has amphetamine-like properties
LSD action mediated via serotonin release from presynaptic neurons.

141
Q

Long term effect of NMMA

A

Irreversible damage of serotonergic tracts

142
Q

Mechanism of methadone

A

Opioid receptor agonist
Longer acting than heroin
Pure mu agonist

143
Q

Mechanism of naloxone

A

Short-acting opioid mu antagonist

144
Q

Mechanism of naltrexone

A

Longer acting opioid mu antagonist

145
Q

Mechanism of phencyclidine

A

Noncompetitive NMDA antagonist

Binds to sigma receptors

146
Q

Mechanism of varenicline

A

Partial agonist at alpha2beta2 unit of nicotinic acetylcholine receptor

147
Q

When is varenicline used?

A

Smoking cessation - relieves nicotine withdrawl symptoms and reduces rewarding properties of nicotine

148
Q

Mechanism of donepezil, galantamine and rivastigmine

A

Cholinesterase inhibitors.
Inhibit acetyl cholinesterase enzyme that breaks down acetylcholine centrally.
Rivastigmine inhibits both acetyl and butyl-cholinesterase.
Donepezil and galantamine - acetyl specific
Galantamine - nicotine agonist

149
Q

Mechanism of memantine

A

Blocks NMDA receptors.

Non-competitive with low affinity - only binds to actively open NMDA receptors (Ketamine is high affinity)

150
Q

What inactivates Acetylcholine?

A

Acetylcholinesterase

Butyryllcholinesterase

151
Q

Which drugs act on the ionic site of acetylcholinesterase?

A

Tacrine

Donepezil

152
Q

Which drugs act on the catalytic esteratic subsite of acetylcholinesterase?

A

Physiostigmine

Rivastigmine

153
Q

Which drugs are non-selective inhibitors of both acetylcholinesterase and butyl-cholinesterase?

A

Tacrine

Rivastigmine

154
Q

Which drug leads to CNS specific inhibition of acetylcholinesterase?

A

Donepezil

155
Q

Structure of acetylcholinesterase

A

Tetramer - G4, located on presynaptic membranes while monomer - G1 is on postsynaptic.

156
Q

What happens to Acetylcholeinesterase in Alzheimers?

A

G4 decreased along with neuronal loss

157
Q

Which drugs are selective for G1 on Ache?

A

Rivastigmine

Galantamine

158
Q

Which drug is approved for use in MND?

A

Riluzole

159
Q

What does Riluzole do for MND?

A

Prolongs survival by 10% for more than a year of treatment

160
Q

Riluzole’s mechanism of action?

A

Na channel blockade
High voltage Ca channel blockade
NMDA glutamate receptor antagonism
Blocks Na channels in damaged neurons, reducing ca flow and indirectly preventing excitotoxic damage

161
Q

Mechanism of amntadine

A

Used in Parkinsons

augments dopaminergic neurotransmission

162
Q

Mechanism of dextroamphetamine and methylphenidate

A

Indirectly acting sympathomimetics - induce release of dopamine and noradrenaline from presynaptic neurons.
Weak inhibitors of catecholamine reuptake and inhibitors of monoamine oxidase.

163
Q

Mechanism of atomoxetine

A

Tricyclic like structure.

Selective inhibitor of presynaptic noradrenaline reuptake

164
Q

Mechanism of benztropine, biperiden, orphenadrine, procycline

A

Anticholinergic drugs

Used to treat EPSEs from antipsychotics

165
Q

Which drugs are used to treat EPSEs from antipsychotics?

A

benztropine, biperiden, orphenadrine, procycline

166
Q

Mechanism of Carbidopa?

A

Inhibits aromatic L-aa decarboxylase (DOPA Decarboxylase)

Administered with l-dopa as sinemet to reduce peripheral conversion of dopa to dopamine.

167
Q

What form of dopamine cannot cross the blood brain barrier?

A

Carbidopa

168
Q

Mechanism of dantrolene?

A

Directly affects formation of actin-myosin complexes in skeletal muscle through ryanodine ca channel inhibition

169
Q

Mechanism of diphenydramine, hydroxyzine, promethazine, cryproheptadine

A

Antihistaminic - against central H1.
Cyproheptadine - antihistamince and 5HT2 antagonist.
All have antimuscarinic properties.

170
Q

What was Cyproheptadine used as?

A

Anti-anorexic

Treat delayed ejaculation associated with SSRI use

171
Q

Mechanism of Levodopa?

A

Dopamine precursor used in Parkinsons; combined with carbidopa to reduce peripheral conversion to dopamine

172
Q

Mechanism of Modafinil

A

Activates hypocretin-producing neurons through alpha 2 and alpha 1 adrenergic agonist properties and noradrenaline reuptake blocking effects.

173
Q

How can stimulating effects of Modafinil be attenuated?

A

With Prazosin

174
Q

Mechanism of Pemoline?

A

Indirectly stimulates dopaminergic activity.

175
Q

Why was Pemoline withdrawn?

A

Hepatotoxicity

176
Q

Mechanism of Reserpine?

A

Depletes stored dopamine and monoamines from vesicles.

Can lead to depression and suicide.

177
Q

Mechanism of Sildenafil?

A

Phosphodiesterase-5 inhibitor

178
Q

Mechanism of propranolol

A

Beta-adrenergic antagonist.

Lipophilic - passes through blood brain barrier and have central actions.

179
Q

Clinical effects and uses of propranolol

A

Reduces akathisia and peripheral signs of sympathetic overdrive seen in anxiety

180
Q

Mechanism of pramipexole, ropinirole, aopmorphine

A

Dopamine agonists - bind 20x more selectively to D3 than D2.

Pramipexole - nonergot dopamine agonist.

181
Q

Structure of bromocriptine

A

Selective 2:1 to D3:D2

Ergotamine derivatives

182
Q

Mechanism of sumatriptan

A

5HT1D and 1F agonist

183
Q

Mechanism of yohimbe

A

Alpha 2 antagonist

Used to treat erectile dysfunction

184
Q

Drug treatments for obesity

A

Lorcaserin, phentermine-topiramate combinatino and

Naltrexone-bupropion combination

185
Q

Mechanism of Lorcaserin

A

Serotonin 2C receptor agonist

186
Q

Affect of lorcaserin in diabetes?

A

Hypoglycaemia

187
Q

Mechanism of phentermine?

A

Sympathomimetic amine

188
Q

Side effect of lorcaserin

A

Headache

189
Q

Side efect of Phentermine and topiramate combination?

A

Parasthesia
Dysguesia
Dizziness

190
Q

What is kindling?

A

Repeated subconvulsive electrical stimulation in animals leading to reduced seizure threshold

191
Q

Relationship between ect and kindly?

A

ECT is anti-kindling

192
Q

What leads to kindling?

A

Hippocampal neuronal loss

193
Q

How does ECT lead to neurogenesis?

A

Mediated by increased expression of brain-derived neurotrophic factor and its receptor

194
Q

What happens to blood brain barrier permeability in ect?

A

Acutely increases, returns to normal within 24 hours

195
Q

EEG activity in ECG?

A

Delta and theta activity afterwards - returns to normal after 3 months.

196
Q

Impact of ECFT on neurotrophic factors

A

Increase in NGF, BDNF, NF3

197
Q

Impact of ECT on cell growth and synaptic connectivity

A

Increased in hippocampus

198
Q

Impact of ECT on hormones

A

Increased cortisol, prolactin and TSH coincides with good response.
Vasopressin, ACTH, Oxytocin and opioid endorphins can also increase.

199
Q

Impact of ECT on neurotransmitters

A

5HT, NA, cholinergic and glutaminergic and GABAergic systems, adenosine, A1-receptor and 5HT2A all decrease in sensitivity.
Activation of DA transmission and stimulation of 5HT in hippocampus and amygdala.

200
Q

Impact of ECT on 5HT2 receptors?

A

Increase

201
Q

Impact of ECT on alpha 2 receptors and beta noradrenergic receptors?

A

Reduced

202
Q

Impact of ECT on noradrenaline?

A

Increases turnover

203
Q

What is psychopharmacogenetics?

A

Focuses on how polymorphisms in genes affecting mechanism of action of a drugs effect or metabolism can influence individuals clinical response to a drug

204
Q

Biological substitute leading to differing response to nictotine replacement

A

Dopamine receptor DRD2 variant

205
Q

Which polymorphisms are associated with response to Clozapine?

A

5HT2A, 2C, 5HT transporter linked polymorphic region

206
Q

Which polymorphisms are associated with response to methylphenidate?

A

Homozygosity for 10-repeat allele at DAT1

207
Q

Which polymorphisms are associated with agranulocytosis with clozapine?

A

HLA loci variants

208
Q

Which polymorphisms are associated with response to typical antipsychotics?

A

DRD3 Ser9Gly

5HT2A receptor

209
Q

Which polymorphisms are associated with EPSEs, postural hypotension and sedation with typical antipsychotics?

A

Poor metabolizers of CYP2D6

210
Q

Which polymorphisms are associated with acute akathisia in typical antipsychotics?

A

Polymorphisms in DRD3 and DRD2

211
Q

Which polymorphisms are associated with tardive dyskinesia with typical antipsychotics?

A

DAT polymorphism
5-HTTLPR and tryptophan hydroxylase polymorphism
CYP1A2

212
Q

Which polymorphisms are associated with hyperprolactinaemia and NMS with typical antipsychotics?

A

DRD2 polymorphism

213
Q

What does 5HTT do?

A

It is a transporter protein that is the primary mechanism for removing serotonin from synaptic cleft.

214
Q

What are the two polymorphisms identified with 5HTT?

A
  1. Insertion/deletion in promoter region (5-HTTLPER) resulting in short and long variant
  2. VNTR polymorphism in intron
215
Q

Define ethnicity

A

Self-ascribed belongingness to group with common geographical origins, race, language, religion which transcends kinship and neighbourhood

216
Q

Define race

A

Perceived by appearance and attributed to biological and genetic traits

217
Q

Absorption and availability of drugs in Caucasians?

A

Caucasians have lower plasma levels of TCAs and attain plasma peaks later compared to asians
Likely due to slow hydroxylation among asians

218
Q

Rapid tranq in Caucasians vs Asians

A

Maximumal haloperidol conc in plasma after rapid tranq is high for asians compared to caucasians

219
Q

What is the CYP2D6 variation called?

A

Debrisoquine/sparteine polymorphism

220
Q

Groups of CYP2D6 variation?

A

Poor metabolizers
Intermediate metabolizers
Extensive metabolizers
Ultrarapid metabolizers

221
Q

What are poor metabolizers of CYP2D6?

A

Develop SEs quickly.

222
Q

Which ethnicity are poor metabolizers of CYP2D6?

A

Caucasians - 7%
East asians - 1%
These lack this enzyme so are poor metabolizers of TCAs and risperidone

223
Q

Etnicity with intermediate metabolization of CYP2D6?

A

Higher in asians - higher SE but good drug efficacy

224
Q

Clinical effect of those who have ultrarapid metabolization of CYP2D6?

A

Need high doses of risperidone.

225
Q

Which ethnicity are ultrarapid metabolizers of CYP 2D6?

A

33% of north africans - they have multiple copies of CYP 2D6
5% cauccasians
1% east asians
25% indians

226
Q

What drugs does CYP2C19 metabolise?

A 
Omeprazole
Propranolol
Hexobarbital
Diazepam
Citalopram
Imipramine
Clomipramine
Sertraline
Amitriptyline
227
Q

Ethnicity with poor metabolizers of CYP2C19?

A

Asians - 15-30%

Caucasians 3-6%

228
Q

What is CYP2C19 polymorphism related to?

A

Mephenytoin

229
Q

What are variations in CYP3A4 influenced by?

A

Environment

230
Q

What ethnicities lack the aldehyde dehydrogenase enzyme?

A

40% asians

60% south american native indians

231
Q

Impact of long form seretonin transporter polymorphism in caucasians?

A

Associated with better SSRI response and tolerance

Opposite true for east asians

232
Q

Who is Low COMT varian seen in?

A

<20% of asians and africans

Nearly 50% of caucasians

233
Q

Ethnicity involved with Isoniazid?

A

East asians are more likely to be rapid acetylators and therefore suffer from hepatotoxicity.

234
Q

Which ethnicity have higher EPSEs with haloperidol?

A

Chinese

235
Q

Which ethnicity have higher prolactin levels from antipsychotics?

A

Asians compared to caucasians

236
Q

Which ethnicity have more SE from Lithium and TCAs?

A

African americans

237
Q

Which ethnicity have higher tardive dyskinesia from antipsychotics?

A

African americans

238
Q

Which group have better response to TCAs and lorazepam than fluoxetine?

A

African americans

239
Q

Psychiatric medication dosing in Asians?

A

Best to start at half dosage

240
Q

Impact of clozapine on asians?

A

Better effect at lower range

Higher incidence of agranulocytosis

241
Q

Which ethnicity have lower required therapeutic level of lithium?

A

Taiwanese

242
Q

Which ethnicity metabolise TCAs slowly?

A

Asians

243
Q

Which gender is antipsychotic response shown to be superior?

A

Women

244
Q

Antipsychotic plasma levels in men vs women?

A

Higher in women after receiving same dose

245
Q

Which enzyme is less active in women which leads to higher blood conc of olanzapine and clozapine in women?

A

CYP1A2

246
Q

Which type of drugs are have a higher volume of distribution in women?

A

Lipophilic - antipsychotics

247
Q

Why do women have higher volume of distribution of lipophilic drugs?

A

Smaller blood volume

Larger lipid compartments - this prolongs half-life of antipsychotics in body, leading to accumulation over time.

248
Q

Dosing intervals in men vs women?

A

Longer in women

249
Q

Is acute dystonia more common in men or women?

A

Women

250
Q

What is PE a side effect from?

A

Drugs that have affinity for 5HT2A

MRCPsych Part A - Al-Rashid Hospital (22 decks)

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