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MRCPsych Part A > 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
Types of antagonism
``` Competitive Noncompetitive Irreversible Pharmacological Physiological Chemical ```
26
What is competitive antagonist?
Can be reversed by increasing dose of agonist drug. | Reduce potency but not efficacy of agnoist.
27
What is potency?
Minimal dose needed to produce an efacy
28
Examples of competitive antagonism drugs?
Atropine - muscarinic receptors | Propranolol - beta-adrenergic receptors
29
How do noncompetitive antagonists work?
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.
30
E.g. of noncompetitive antagonists.
Ketamine and phencyclidine are noncompetitive NMDA antagonists.
31
Give e.g. of irreversible antagonists
MAOIs
32
What is pharmacological antagonism?
Opposing action of 2 molecules acting via same receptor
33
What is physiological antagonism?
Opposing action of 2 molecules by acting via different receptors
34
What is chemical antagonism?
Opposing action of 2 molecules acting via chemical reactions.
35
Give e.g. of chemical antagonism
Not seen in psychotropics | Heparin and protamine reaction
36
What is the law of mass action?
Reversible action of drugs on receptors leads to response that s proportional to the fraction of receptors occupied.
37
Which drugs cause down-regulation of receptor numbers?
Agonists
38
Which drugs may cause upregulation or hypersensitivity or receptor numbers?
Antagonists
39
What is the potency of a drug?
Amount of drug needed to produce particular effect compared to another standard drug with similar receptor profile (vigor)
40
What determines the potency of a drug?
Proportion of drug reaching receptor Affinity for receptor Efficacy
41
What is affinity?
Ability of drug to bind to appropriate receptor
42
What is efficacy?
How well drug produces expected response.
43
What does efficacy depend upon?
Affinity Potency Duration of receptor action Kinetic properties such as half-life
44
Mechanism of Amisulpride?
D2 and D3 antagonism Dose-dependent Limbic selectivity an 5HT7 activity
45
Mechanism of Aripiprazole?
Partial dopamine agonist at D2 5HT2A antagonist Goldilocks phenomenon
46
What is Goldilocks phenomenon?
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.
47
Which receptors does Aripiprazole act on?
Postsynaptic D2 receptors | Presynaptic autoreceptors
48
Mechanism of Asenapine
D2 antagonist and 5HT2A blocker | Alpha-2 blockage
49
Difference of Asenapine given sublingually?
Weight and prolactin-neutral
50
Mechanism of Chlorpromazine and promazine?
Moderate antimuscarinic effect D2 blockade Highly sedative
51
Mechanism of clozapine?
``` 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 ```
52
Profile of Clozapine?
Faster dissociation rate (such as Quetiapine)
53
Mechanism of Lurasidone?
``` 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) ```
54
What makes Lurasidone have a less orthostatic affect?
Minimal affinity for alpha-1
55
Mechanism of Olanzapine
High 5HT2/D2 blockade ratio. Potent D4 blockade and 5HT6 blockade Significant anticholinergic and antihistaminic effects
56
Mechanism of Quetiapine
Similar to clozapine - hit and run profile on D2. Less 5HT2A blockade compared to other antipsychotics. Significant anticholinergic effects.
57
Mechanism of Risperidone
Serotonin-Dopamine antagonist. High 5HT2A antagonist. Therapeutic doses: binds D2 similar to typicals -> EPSEs and prolactin SEs.
58
How does Risperidone lead to EPSEs?
At therapeutic doses binds D2 similar to typical antipsychotics
59
Mechanism of Sulpride?
Pure D2 antagonist. Low doses: presynaptic receptors blocked (helps with -ve symptoms). Above 800mg/day; affects postsynaptic D2 - reducing +ve symptoms.
60
Mechanism of Thioridazine, pericyazine
D2 antagonist Marked antimuscarinic effect Less EPSEs than other typicals
61
Mechanism of thioxanthenes
Exhibits stereoisomerism. | D2 antagonist - typical antipsychotic.
62
Mechanism of Ziprasidone
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
63
Mechanism of Zotepine
``` Atypical antipsychotic 5HT2A, 5HT2C, D1-D4 antagonism Potent noradrenaline reuptake inhibitor Potent antihistaminic activity Some NMDA antagonism ```
64
Mechanism of action of Agomelatine as an antidepressant
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
65
How does Agomelatine cause inhibition of norepinephrine and dopamine via 5HT2C?
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.
66
Structure of Amoxapine
Tetracyclic with dibenzoxazepine structure
67
Mechanism of Amoxapine
Both dopamine antagonistic and serotonin-noradrenaline reuptake inhibition effects. Antipsychotic + antidepressant. EPSEs.
68
Mechanism of Bupropion
Dopamine and noradrenaline reuptake inhibitor. Increases efficiency of noradrenergic transmission and reduce total norepinephrine turnover. Some degree of competitive nicotinic antagonism
69
What is Bupropion used in?
Depression | Smoking cessation
70
Mechanism of Buspirone?
Partial agonist on 5HT1A Presynaptic - full agonist, inhibits release of serotonin which leads to antianxiety. Postsynaptic - partial agonist to account for antidepressant acitivity.
71
Mechanism of Citalopram
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.
72
Mehcanism of Clomipramine
Tricyclic - most potent. | Higher SRI selectivity than other TCAs but less selectivity than SSRIs.
73
Mechanism of Desipramine
Tricyclic with least anticholinergic action but lethal on OD.
74
Mechanism of Duloxetine
SNRI | Better profile for psychosomatic and neuropathic pain
75
Mechanism of Levothyroxine
Levothyroxine -> T4 Liothyronine -> T3 Both suppress TSH and are adjuvants in resistant depression - possibly via neuroendocrine changes.
76
Mechanism of Lithium
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.
77
What causes therapeutic efficacy of lithium?
Inhibits inositol-monophosphatase which catalyzes inositol second messenger system. This reduces myoinositol and phosphoinositide phosphate.
78
How does lithium reduce dopamine synthesis?
Increases intracellular sodium, affecting NA+/K+ pump.
79
Mechanism of Milnacipran
SNRI
80
Mechanism of Mirtazapine
5HT2A antagonism Alpha 2 antagonism Antihistaminic Anti 5HT3
81
Mechanism of Moclobemide
Reversible inhibitor of MAO-A electively.
82
Mechanism of Nefazadone
5HT2A antagonist with serotonin ruptake inhibition and mild norepinephrine reuptake inhibition. Alpha 1 antagonism
83
What does Nefazadone produce as a metabolite?
MccP
84
Mechanism of Paroxetine
SSRI - most potent of all SSRIs in serotonin reuptake blockade but not specific. Significant antimuscarinic action
85
Mechanism of Phenelzine
Monoamine Oxidase inhibitor - increased availability of monoamines including serotonin and noradrenaline may explain antidepressant action
86
Mechanism of Pindolol
Beta blocker with intrinsic symapthomimetic activity. | 5HT1A antagonism - possibly enhances action of SSRI by this
87
Mechanism of action of Reboxetin
NARI
88
Mechanism of action of Selegiline
MAOI - selective for B at normal dose. | Selectivity lost when applied at higher doses.
89
Mechanism of action of SSRIs
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 .
90
Mechanism of action of Tranylcypromine
MAOI - irreversible, non-selective. | Positive enantiomer better MAOI, negative enantiomer = better reuptake inhibitor.
91
Mechanism of action of Trazadone
``` 5HT2A/2C antagonism Alpha 2 blockade Alpha 1 blockade Antihistaminic Mild reuptake inhibition of serotonin transporters ```
92
Mechanism of Tricyclics
MAOI Mid noradrenaline and serotonin reuptake inhibition. Secondary amines are more adrenergic.
93
Which TCA is most serotonin specific?
Clomipramine
94
Mechanism of action of Venlafaxine?
SNRI | Acts as SSRI in lower <150mg doses.
95
Mechanism of Vilazodone
Selective serotonin reuptake inhibition | Partial agonist at 5HT1A
96
Mechanism of Vortioxetine
SSRI-like effect 5HT3 antagonism 5HT1-A agonism
97
What is selectivity of an antidepressant?
Ratio of conc required to produce equivalent inhibitions of 5HT to noradrenalin.
98
Selectivity of Amitriptyline?
1:1
99
Selectivity of clomipramine?
1:7
100
Selectivity of Fluoxetine?
150:1
101
Selectivity of Citalopram?
>2000:1
102
Describe mechanism of TCA
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
Mechanism of SSRI action
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
Mechanism of Carbamazepine
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
Structure of gabapentin
GABA analogue
106
Mechanism of Gabapentin
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
How does gabapentin cross blood brain barrier?
1-aa transport
108
Mechanism of Lamotrigine
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
Mechanism of Levetiracetam
Indirectly enhances GABA system | Anticonvulsant with weak evidence against mania
110
Mechanism of oxarbazepine
Metabolite of carbamazepine
111
Structure of Pregabalin
GABA analogue
112
Mechanism of Pregabalin
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
Comparison between pregabalin and gabapentin
Pregabalin is more potent, has a higher therapeutic index and fewer dose-related SEs.
114
Mechanism of Tiagabine
Potent and selective reuptake inhibitor of GABA. | Mild antihistamine
115
Mechanism of Topiramate
Fructose derivative. Selective inhibitor of glutamate AMPA receptors, blocks Na receptors, indirect GABAergic activity by potentiating action of GABAa receptor.
116
Mechanism of Valproic acid
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
Function of Vigabatrin
Vi-GABA Transminase inhibitor
118
Mechanism of Benzos
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
Mechanism of chloral hydrate. paraldehyde and meprobamate
Barbituate-like Potentiate GABAergic neurotransmission Paraldehyde if cyclic ether Poor safety profile - not in clinical use
120
Mechanism of Flumazenil
Benzo antagonist
121
Mechanism of Ramelteon
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
Mechanism of Thiopental
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
Mechanism of Zolpidem, Zaleplon, Zopiclone, Eszopiclone
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
Which receptors does Zaleplon occupy?
All 3 q receptors
125
Structure of Zopiclone vs eszopiclone
Zopiclone: racemic mixture, which only s-isomer is active - eszopiclone
126
Why are Z-hypnotics less likely to impact sleep stages and lower risk of tolerance?
Selective on BDZ-receptor subunits
127
Which z-hypnotic is least selective?
Zopiclone
128
Mechanism of alcohol
``` Intercalates into fluid cell membrane Decreases NMDA sensitivity Increases GABA sensitivity Down-regulates ca chanels Up-regulates nicotine receptor gated Na channels ```
129
Mechanism of amphetamine
Acts via releasing stored monoamines - noradrenaline and dopamine. Central sympathomimetic
130
Mechanism of buprenorphine
Partial opioid agonist. Lower doses - mild agonism. Higher doses - antagonist.
131
Mechanism of cannabis
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
Mechanism of clonidine and lofexidine
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
Mechanism of sudden withdrawl of clonidine or lofexidine?
Leads to increased adrenergic firing rate (withdrawl symptoms) - hence alpha 2 autoreceptor stimulation which reduces central sympathetic tone helps in opioid withdrawl.
134
Mechanism of dexfenfluramine and fenfluramine
Produces serotonin release from nerve endings.
135
SE of dexfenfluramine and fenfluramine?
Irreversible serotonergic damage, valvular regurgitation and pulmonary fibrosis
136
Mechanism of disulfiram
Inhibits aldehyde dehydrogenase | Leads to accumulation of acetaldehyde if alcohol is consumed.
137
Mehcanism of levomethadyl acetate
Long-acting opioid agonist Pure mu agonist (similar to methadone)
138
Why was levomethadyl acetate withdrawn?
Prolonged QT and torsades de pointes.
139
Mechanism of LSD
5HT2A partial agonism - produces hallucinogenic effect
140
Mechanism of MDMA
2 isomers: R (-) isomer produces LSD-like effects S (+) isomer has amphetamine-like properties LSD action mediated via serotonin release from presynaptic neurons.
141
Long term effect of NMMA
Irreversible damage of serotonergic tracts
142
Mechanism of methadone
Opioid receptor agonist Longer acting than heroin Pure mu agonist
143
Mechanism of naloxone
Short-acting opioid mu antagonist
144
Mechanism of naltrexone
Longer acting opioid mu antagonist
145
Mechanism of phencyclidine
Noncompetitive NMDA antagonist | Binds to sigma receptors
146
Mechanism of varenicline
Partial agonist at alpha2beta2 unit of nicotinic acetylcholine receptor
147
When is varenicline used?
Smoking cessation - relieves nicotine withdrawl symptoms and reduces rewarding properties of nicotine
148
Mechanism of donepezil, galantamine and rivastigmine
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
Mechanism of memantine
Blocks NMDA receptors. | Non-competitive with low affinity - only binds to actively open NMDA receptors (Ketamine is high affinity)
150
What inactivates Acetylcholine?
Acetylcholinesterase | Butyryllcholinesterase
151
Which drugs act on the ionic site of acetylcholinesterase?
Tacrine | Donepezil
152
Which drugs act on the catalytic esteratic subsite of acetylcholinesterase?
Physiostigmine | Rivastigmine
153
Which drugs are non-selective inhibitors of both acetylcholinesterase and butyl-cholinesterase?
Tacrine | Rivastigmine
154
Which drug leads to CNS specific inhibition of acetylcholinesterase?
Donepezil
155
Structure of acetylcholinesterase
Tetramer - G4, located on presynaptic membranes while monomer - G1 is on postsynaptic.
156
What happens to Acetylcholeinesterase in Alzheimers?
G4 decreased along with neuronal loss
157
Which drugs are selective for G1 on Ache?
Rivastigmine | Galantamine
158
Which drug is approved for use in MND?
Riluzole
159
What does Riluzole do for MND?
Prolongs survival by 10% for more than a year of treatment
160
Riluzole's mechanism of action?
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
Mechanism of amntadine
Used in Parkinsons | augments dopaminergic neurotransmission
162
Mechanism of dextroamphetamine and methylphenidate
Indirectly acting sympathomimetics - induce release of dopamine and noradrenaline from presynaptic neurons. Weak inhibitors of catecholamine reuptake and inhibitors of monoamine oxidase.
163
Mechanism of atomoxetine
Tricyclic like structure. | Selective inhibitor of presynaptic noradrenaline reuptake
164
Mechanism of benztropine, biperiden, orphenadrine, procycline
Anticholinergic drugs | Used to treat EPSEs from antipsychotics
165
Which drugs are used to treat EPSEs from antipsychotics?
benztropine, biperiden, orphenadrine, procycline
166
Mechanism of Carbidopa?
Inhibits aromatic L-aa decarboxylase (DOPA Decarboxylase) | Administered with l-dopa as sinemet to reduce peripheral conversion of dopa to dopamine.
167
What form of dopamine cannot cross the blood brain barrier?
Carbidopa
168
Mechanism of dantrolene?
Directly affects formation of actin-myosin complexes in skeletal muscle through ryanodine ca channel inhibition
169
Mechanism of diphenydramine, hydroxyzine, promethazine, cryproheptadine
Antihistaminic - against central H1. Cyproheptadine - antihistamince and 5HT2 antagonist. All have antimuscarinic properties.
170
What was Cyproheptadine used as?
Anti-anorexic | Treat delayed ejaculation associated with SSRI use
171
Mechanism of Levodopa?
Dopamine precursor used in Parkinsons; combined with carbidopa to reduce peripheral conversion to dopamine
172
Mechanism of Modafinil
Activates hypocretin-producing neurons through alpha 2 and alpha 1 adrenergic agonist properties and noradrenaline reuptake blocking effects.
173
How can stimulating effects of Modafinil be attenuated?
With Prazosin
174
Mechanism of Pemoline?
Indirectly stimulates dopaminergic activity.
175
Why was Pemoline withdrawn?
Hepatotoxicity
176
Mechanism of Reserpine?
Depletes stored dopamine and monoamines from vesicles. | Can lead to depression and suicide.
177
Mechanism of Sildenafil?
Phosphodiesterase-5 inhibitor
178
Mechanism of propranolol
Beta-adrenergic antagonist. | Lipophilic - passes through blood brain barrier and have central actions.
179
Clinical effects and uses of propranolol
Reduces akathisia and peripheral signs of sympathetic overdrive seen in anxiety
180
Mechanism of pramipexole, ropinirole, aopmorphine
Dopamine agonists - bind 20x more selectively to D3 than D2. | Pramipexole - nonergot dopamine agonist.
181
Structure of bromocriptine
Selective 2:1 to D3:D2 | Ergotamine derivatives
182
Mechanism of sumatriptan
5HT1D and 1F agonist
183
Mechanism of yohimbe
Alpha 2 antagonist | Used to treat erectile dysfunction
184
Drug treatments for obesity
Lorcaserin, phentermine-topiramate combinatino and | Naltrexone-bupropion combination
185
Mechanism of Lorcaserin
Serotonin 2C receptor agonist
186
Affect of lorcaserin in diabetes?
Hypoglycaemia
187
Mechanism of phentermine?
Sympathomimetic amine
188
Side effect of lorcaserin
Headache
189
Side efect of Phentermine and topiramate combination?
Parasthesia Dysguesia Dizziness
190
What is kindling?
Repeated subconvulsive electrical stimulation in animals leading to reduced seizure threshold
191
Relationship between ect and kindly?
ECT is anti-kindling
192
What leads to kindling?
Hippocampal neuronal loss
193
How does ECT lead to neurogenesis?
Mediated by increased expression of brain-derived neurotrophic factor and its receptor
194
What happens to blood brain barrier permeability in ect?
Acutely increases, returns to normal within 24 hours
195
EEG activity in ECG?
Delta and theta activity afterwards - returns to normal after 3 months.
196
Impact of ECFT on neurotrophic factors
Increase in NGF, BDNF, NF3
197
Impact of ECT on cell growth and synaptic connectivity
Increased in hippocampus
198
Impact of ECT on hormones
Increased cortisol, prolactin and TSH coincides with good response. Vasopressin, ACTH, Oxytocin and opioid endorphins can also increase.
199
Impact of ECT on neurotransmitters
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.
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Impact of ECT on 5HT2 receptors?
Increase
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Impact of ECT on alpha 2 receptors and beta noradrenergic receptors?
Reduced
202
Impact of ECT on noradrenaline?
Increases turnover
203
What is psychopharmacogenetics?
Focuses on how polymorphisms in genes affecting mechanism of action of a drugs effect or metabolism can influence individuals clinical response to a drug
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Biological substitute leading to differing response to nictotine replacement
Dopamine receptor DRD2 variant
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Which polymorphisms are associated with response to Clozapine?
5HT2A, 2C, 5HT transporter linked polymorphic region
206
Which polymorphisms are associated with response to methylphenidate?
Homozygosity for 10-repeat allele at DAT1
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Which polymorphisms are associated with agranulocytosis with clozapine?
HLA loci variants
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Which polymorphisms are associated with response to typical antipsychotics?
DRD3 Ser9Gly | 5HT2A receptor
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Which polymorphisms are associated with EPSEs, postural hypotension and sedation with typical antipsychotics?
Poor metabolizers of CYP2D6
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Which polymorphisms are associated with acute akathisia in typical antipsychotics?
Polymorphisms in DRD3 and DRD2
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Which polymorphisms are associated with tardive dyskinesia with typical antipsychotics?
DAT polymorphism 5-HTTLPR and tryptophan hydroxylase polymorphism CYP1A2
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Which polymorphisms are associated with hyperprolactinaemia and NMS with typical antipsychotics?
DRD2 polymorphism
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What does 5HTT do?
It is a transporter protein that is the primary mechanism for removing serotonin from synaptic cleft.
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What are the two polymorphisms identified with 5HTT?
1. Insertion/deletion in promoter region (5-HTTLPER) resulting in short and long variant 2. VNTR polymorphism in intron
215
Define ethnicity
Self-ascribed belongingness to group with common geographical origins, race, language, religion which transcends kinship and neighbourhood
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Define race
Perceived by appearance and attributed to biological and genetic traits
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Absorption and availability of drugs in Caucasians?
Caucasians have lower plasma levels of TCAs and attain plasma peaks later compared to asians Likely due to slow hydroxylation among asians
218
Rapid tranq in Caucasians vs Asians
Maximumal haloperidol conc in plasma after rapid tranq is high for asians compared to caucasians
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What is the CYP2D6 variation called?
Debrisoquine/sparteine polymorphism
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Groups of CYP2D6 variation?
Poor metabolizers Intermediate metabolizers Extensive metabolizers Ultrarapid metabolizers
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What are poor metabolizers of CYP2D6?
Develop SEs quickly.
222
Which ethnicity are poor metabolizers of CYP2D6?
Caucasians - 7% East asians - 1% These lack this enzyme so are poor metabolizers of TCAs and risperidone
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Etnicity with intermediate metabolization of CYP2D6?
Higher in asians - higher SE but good drug efficacy
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Clinical effect of those who have ultrarapid metabolization of CYP2D6?
Need high doses of risperidone.
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Which ethnicity are ultrarapid metabolizers of CYP 2D6?
33% of north africans - they have multiple copies of CYP 2D6 5% cauccasians 1% east asians 25% indians
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What drugs does CYP2C19 metabolise?
``` Omeprazole Propranolol Hexobarbital Diazepam Citalopram Imipramine Clomipramine Sertraline Amitriptyline ```
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Ethnicity with poor metabolizers of CYP2C19?
Asians - 15-30% | Caucasians 3-6%
228
What is CYP2C19 polymorphism related to?
Mephenytoin
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What are variations in CYP3A4 influenced by?
Environment
230
What ethnicities lack the aldehyde dehydrogenase enzyme?
40% asians | 60% south american native indians
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Impact of long form seretonin transporter polymorphism in caucasians?
Associated with better SSRI response and tolerance | Opposite true for east asians
232
Who is Low COMT varian seen in?
<20% of asians and africans | Nearly 50% of caucasians
233
Ethnicity involved with Isoniazid?
East asians are more likely to be rapid acetylators and therefore suffer from hepatotoxicity.
234
Which ethnicity have higher EPSEs with haloperidol?
Chinese
235
Which ethnicity have higher prolactin levels from antipsychotics?
Asians compared to caucasians
236
Which ethnicity have more SE from Lithium and TCAs?
African americans
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Which ethnicity have higher tardive dyskinesia from antipsychotics?
African americans
238
Which group have better response to TCAs and lorazepam than fluoxetine?
African americans
239
Psychiatric medication dosing in Asians?
Best to start at half dosage
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Impact of clozapine on asians?
Better effect at lower range | Higher incidence of agranulocytosis
241
Which ethnicity have lower required therapeutic level of lithium?
Taiwanese
242
Which ethnicity metabolise TCAs slowly?
Asians
243
Which gender is antipsychotic response shown to be superior?
Women
244
Antipsychotic plasma levels in men vs women?
Higher in women after receiving same dose
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Which enzyme is less active in women which leads to higher blood conc of olanzapine and clozapine in women?
CYP1A2
246
Which type of drugs are have a higher volume of distribution in women?
Lipophilic - antipsychotics
247
Why do women have higher volume of distribution of lipophilic drugs?
Smaller blood volume | Larger lipid compartments - this prolongs half-life of antipsychotics in body, leading to accumulation over time.
248
Dosing intervals in men vs women?
Longer in women
249
Is acute dystonia more common in men or women?
Women
250
What is PE a side effect from?
Drugs that have affinity for 5HT2A

MRCPsych Part A (22 decks)

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