Psychopharmacology Flashcards
1
Q
What is the name given to the range of doses at which a medication appeared to be effective in clinical trials for a median of participants without unacceptable adverse effects?
A
Therapeutic Index/ Therapeutic ratio
2
Q
When does a drug have a narrow TI?
A
Less than 2x difference in minimum toxic conc, and minimum effective conc
3
Q
Pharmacodynamics vs pharmacokinetics:
A
Pharmacokinetics = how the body affects the drug:
ADME (Absorption, Distribution, Metabolism, Excretion)
Pharmacodynamics - how the drug affects the body (mechanism of action, physiological effects)
D - Dynamics - Drug (affecting body)
4
Q
Pharmacokinetic effects in elderly:
- Distribution
A
Increased body fat and decreased albumin and water = increased distribution of lipid sol drugs = prolonged half-life (prolonged side effects) PLUS increased conc of H2O sol drugs so lower doses needed
Increased VOL OF DISTRIBUTION for fat sol drugs
5
Q
Pharmacokinetic effects in elderly:
- Absorption
A
Reduced gastric acid secretion and gastric motility - no huge effect clinically
6
Q
Pharmacokinetic effects in elderly:
- Metabolism
A
Hepatic metabolism of drugs decreases with age as a consequence of reduced hepatic blood flow and reduced enzyme activity.
7
Q
Pharmacokinetic effects in elderly:
- Excretion
A
By 65, 35% of renal function is lost, and by 80, 50% is lost - smaller doses needed of drgs primarily excreted by the kidney e.g lithium, sulpride
NB: Serum creatinine and urea is often used to estimate renal function but can be misleading in the elderly as they have less muscle and so produce less creatinine.
8
Q
Pharmacodynamics in the elderly:
A
Increased receptor sensitivity = smaller doses required and more side effects
Reduced therapeutic response
9
Q
4 types of EPSE
What causes EPSEs?
A
Dystonias (young men)
Akathisia - most resistent to treat
Parkinsonism (older females)
Tardive Dyskinesia (older females, affective illness)
Caused by antagonism of dopaminergic D2 receptors in the basal ganglia.
Threshold of approx 80% receptor occupancy = EPSEs occur
10
Q
Tetrabenzine (a reversible inhibitor or vesicular monoamine transporter 2) is used to treat which EPSE?
A
Tardive Dyskinesia - happens down the line e.g months to years later
NB: Also discontinue anticholinergics (unlike the other ESPEs where these can be used as treatment)
Also, Ginkgo Bilboa
11
Q
A subjective sense of restlessness, along with such objective evidence of restlessness as pacing or rocking is known as:
What are the treatments?
A
Akathisia - most resistant EPSE to treat
Can use Mirtazapine/ Mianserin in low doses
Propranolol
Benzos - clonazepam, diazepam as longer 1/2 life
Anticholinergics
Cyproheptadine (a H1 receptor blocker, and 5HT-2 receptor antagonist)
Clonidine
12
Q
What is tardive dyskinesia?
Where?
When better or worse?
When does it happen?
A
Involuntary and repetitive body movements
Face affected in 75%
Limbs in 1/2
Trunk in 1/4
Fluctuates, worse with increased arousal and distraction, and anticholinergics
Better with sleep, relaxation and voluntary movements
Happen when pt has been on meds for long time
13
Q
5 types of dystonia:
A
1) torticollis - cervical muscles spasms, resulting in a twisted posturing of the neck
2) trismus (lock-jaw)
3) opisthotonus - arched posturing of the head, trunk, and extremities.
4) laryngeal dystonia - difficulty breathing
5) occulogyric crises - involuntary contraction of one or more of the extraocular muscles, which may result in a fixed gaze with diplopia
14
Q
Mechanism of action of Mirtazapine:
Mirtazapine acts by antagonism of these 5 receptors:
A
Noradrenaline and serotonin specific antidepressant (NaSSa)
5HT2
5HT3
H1 - most effective here at lower doses
Alpha 1
Alpha 2 - more effective at higher doses here, causes more wakefulness
(All of these enhance sleep except for alpha 2 which is a presynaptic receptor that inhibits the release of norepinephrine.)
15
Q
In the P450 system, which enzyme shows the largest phenotypic variation amongst the cytochromes?
A
CYP2D6 - it is inactive in 6-10% of white people, and 2% of Asians.
16
Q
How do tobacco and grapefruit juice affect clozapine?
A
Tobacco induces CYP1A2 and so lowers clozapine levels. Grapefruit juice inhibits CYP1A2 and therefore can increase clozapine levels.
(CYP1A2 = primarily responsible for clozapine metabolism)
17
Q
How do smoking, alcohol, barbiturates, carbamazepine, Phenytoin, and St John’s Wort affect the P450 system?
A
Inducers
18
Q
How do chlorpromazine, SSRI’s, and grapefruit juice affect the P450 system?
A
Inhibitors
19
Q
Which enzyme in the P450 system exhibits genetic polymorphism (it varies in its expression from person to person)?
A
CYP2D6 - Caucasians show less activity of CYP2D6 (6-10% poor metabolisers) than their Asian (2% poor metabolisers) counterparts.
20
Q
5 key features of NMS:
A
- mental status changes (first sign)
- muscular rigidity
- hyperthermia
- autonomic instability (typically tachycardia)
- elevated CK
21
Q
which drug is a recognised cause of hypercalcemia and hyperparathyroidism?
A
Lithium
22
Q
Suboxone vs Subutex
A
Suboxone = buprenorphine and naloxone (4:1)
Subutex = just buprenorphine
23
Q
Which ADHD drug is a prodrug?
A
Lisdexamphetamine is absorbed by GI tract, converted to dexamfetamine which inhibits the reuptake of NA and DA.
24
Q
What is the mechanism of action of dexamphetamine and methylphenidate?
A
Inhibit both DA and NA uptake - SODIUM-dependent
25
Naloxone vs Naltrexone:
Both opioid antagonists
Naloxone - pure (competitive) opioid antagonist at mu, delta, kappa - It reveals very high affinity for the opioid receptor sites and therefore displaces both opioid agonists and partial antagonists. Note: no mu efficacy, but high affinity.
Naltrexone - LONGER ACTING
Targets all receptors but mostly Mu
26
Which mood stabiliser has GABA modulation (increases GABA in the brain), sodium channel inhibition and NMDA antagonist?
Valproate
27
What is the mechanism of action of Carbamazepine and Phenytoin?
Stabilising Na channels - increases refractory period
28
Which mood stabiliser is a GABA modulator, NMDA antagonist, and Na channel stabiliser?
2 side effects to be aware of:
Topirimate
Increased GABA levels, inhibits socium channels therefore reducing action potentials
Can develop kidney stones
Weight loss and anorexia
29
Which mood stabiliser has NMDA receptor modulation, stabilises Na channels, blocks calcium channels, and has some GABA modulation?
What is it licenced for?
Lamotrigine
Epilepsy
Bipolar - prevention of depression in bipolar I - not licenced for acute treatment of manic or depressive episodes)
30
Which 2 mood stabilisers bind to the alpha-2-delta subunit of voltage-gated calcium channels, which reduces the release of certain neurotransmitters, including glutamate and substance P, and can help reduce neuronal excitability?
Gabapentin and Pregabalin
31
Which addictions drug is a pure opioid antagonist (will reverse mu, delta, and kappa)
1/2 life?
Naloxone
Short 1/2 life - 30-120 mins
32
Which addictions drug is a partial agonist at the mu-opioid receptor?
What affinity does it have?
Halflife?
Buprenorphine
5X HIGHER AFFINITY THAN MORPHINE
Half life 24-42 hours (oral)
Also partial kappa agonist and weak delta agonist
33
Which drug binds irreversibly to enzyme aldehyde dehydrogenase (ALDH) and causes acetaldehyde to accumulate following ingestion of alcohol
Disulfiram
34
Which addictions drug is an NMDA glutamate receptor antagonist and positive allosteric modulator of GABA-A receptors (effect on both receptors is indirect)?
Acamprosate - reduces the excitatory actions of *glutamate* in the central nervous system via the NMDA receptors. This modulation helps in reducing the withdrawal symptoms associated with alcohol dependence.
35
Type A vs Type B adverse drug reactions:
A: Pharmacological reactions
80% of ADRs
Predictable based on drug pharmacology
Dose dependent and reversible
B: idiosyncratic reactions
Unrelated to drug's intended pharmacological action
Includes allergic reactions (4 types)
36
Type 1 allergic reactions:
IgE-mediated
Immediate hypersensitivity reactions
e.g anaphylaxis
37
Type 2 allergic reactions:
Cytotoxic (TOTO = 2x = type 2)
involve the activation of complement proteins and destruction of cells by antibodies.
Examples include drug-induced haemolytic anaemia or thrombocytopenia.
38
Type 3 allergic reactions:
Immune Complex
Antigen-antibody aggregates (immune complexes), can form and deposit in tissues, leading to inflammation. This can manifest as conditions like serum sickness or drug-induced lupus. These usually occur 1 to 3 weeks after exposure.
39
Type 4 allergic reactions
Cell-mediated
These reactions are mediated by T cells and occur over a delayed period, often days to weeks after exposure to the drug. Contact dermatitis and some forms of drug-induced hepatitis are examples.
40
Mechanism of action of caffeine:
Caffeine primarily acts as an adenosine (an endogenous purine nucleoside) antagonist.
Antagonistic effect at all 4 g-protein coupled adenosine receptor subtypes, but mostly A2A - involved in wakefulness
Normally, when adenosine binds to its receptors, neural activity slows down and we feel sleepy. Caffeine blocks this.
NB: Inhibitor of CYP1A2 = clozapine levels can decrease by nearly half following a 5 day caffeine-free period in a regular user
41
4 secondary amines:
Protriptyline
Amoxapine
Nortriptyline
Desipramine
PAND
The PANDa is DESperate for AMOXicillin
So you know that Amoxapine (not Amitriptyline) and Desipramine (not dosulepin or doxepin)
42
What name is given to a compound that binds to a receptor and produces the biological response?
Agonist
43
What is a partial agonist vs a full agonist?
A partial agonist produces the biological response but cannot produce 100% of the response even at very high doses.
A full agonist displays full efficacy at a receptor
44
What does an antagonist do?
Antagonists block the effects of agonists. They have no effect on their own.
45
What is an inverse agonist?
Inverse agonists have opposite effects from those of full agonists. It binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist. They are not the same as antagonists, which block the effect of both agonists and inverse agonists.
46
What is a competitive antagonist?
Competitive antagonists bind to the receptor in a reversible way without affecting a biological response. They make the agonist look less potent.
47
What is a non-competitive antagonist?
These ALTER the receptor in some way to make binding harder and can only be reversed by increasing the dose of the agonist drug
These reduce the potency and efficacy of agonists
48
Which anticonvulsant/ mood stabiliser can cause Stevens-Johnson Syndrome?
Lamotrigine
49
Which antidepressants are licenced for nocturnal eneuresis in children: (3)
Amitriptyline, Imipramine, Nortriptyline
50
Which antidepressants are licenced for panic disorder and agorophobia: (5)
CEPSV
Citalopram, Escitalopram, Sertraline, Paroxetine, Venlafaxine
(Moclobemide = for social anxiety/ phobia, citalopram = for panic disorder/ agorophobia) - citAlopram = pAnic
51
Which antidepressants are licenced for social anxiety/ phobia: (5)
EMPSV
Escitalopram, Paroxetine, Sertraline, Moclobemide, Venlafaxine
(Moclobemide = for social anxiety/ phobia, citalopram = for panic disorder/ agorophobia) - MOCLO = SOcial, PHObia
52
Which antidepressants are licenced for generalised anxiety disorder: (4)
DEPV
Escitalopram, Paroxetine, Duloxetine, Venlafaxine
(NOT SERTRALINE or FLUOXETINE)
53
Which antidepressants are licenced for OCD: (6)
CEFFPS
Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Clomipramine
54
Clomiprimine is licenced for: (3)
On its own:
Phobic and obsessional states
Adjunctive treatment of cataplexy associated with narcolepsy
OCD (with other meds as well)
55
Which antidepressant is licenced for bulimia?
Fluoxetine
56
Which 2 antidepressants are licenced for PTSD?
Paroxetine and Sertraline
P(t)S(d)
57
Side effects at which receptors cause:
Galactorrhoea, gynecomastia, menstrual disturbance, lowered sperm count, reduced libido, Parkinsonism, dystonia, akathisia, tardive dyskinesia
Dopaminergic
58
Side effects at which receptors cause:
Drowsiness
Histaminergic
59
Side effects at which receptors cause:
Postural (orthostatic) hypotension and ejaculatory failure, priapism, sedation
Antiandrenergic (Alpha 1)
60
Side effects at which receptors cause:
Dry mouth, blurred vision, urinary retention, constipation, narrow angle glaucoma, ataxia
Anticholinergic (antimuscarinic PERIPHERAL M1 blockade)
61
Antagonism at which receptors cause:
Agitation, delirium, memory impairment, confusion, seizures?
Muscarinic CENTRAL M1 blockade
62
5 criteria (Barrter and Schwartz) for SIADH:
Euvolemia
Decreased serum osmolality (<275 mOsm/kg)
Increased urine osmolality (>100 mOsm/kg) and urine sodium (>20 mmol/L)
No other cause for hyponatraemia (no diuretic use and no suspicion of hypothyroidism, cortisol deficiency, marked hyperproteinaemia, hyperlipidaemia or hyperglycaemia).
63
Benzos vs Barbiturates mechanism of action:
GABA-A drugs:
Benzodiazipines increase the frequency of chloride channels
Barbiturates increase the duration of chloride channel opening
64
4 sedatives recommended in hepatic impairment:
Lorazepam
Oxazepam
Temazepam
Zopiclone
65
Teratogenic effects of Valproate vs Carbamazepine:
V: spina bifida, hypospadias, cleft lip/ palate (1-10%). developmental delay (31-40%), autism, congenital heart abnormalities
C: fingernail hypoplasia, cranialfacial defects
IMPORTANT: They can synergistically increase the teratogenic effects from each other
66
67
5 facts about tricyclics (pharmacokinetics):
Highly protein bound
Highly lipid soluble
Smoking facilitates metabolism so reduces levels by 25-50%
May reduce own absorption as anticholinergic effects
Extensive hepatic breakdown
68
Mechanism of Lithium-Induced DI:
Lithium causes dysregulation of cells of collecting duct. Cells of collecting duct are less responsive to ADH = induces expression of water transport proteins in the late distal tubule and collecting duct to increase water reabsorption.
69
Treatment options for Lithium-induced DI include (4 main ones):
1) stop lithium
2) keep levels 0.4-0.8
3) Once daily dosing at bedtime - lower trough levels allows for renal repair
4) amiloride (K+ sparing diuretic
OTHER:
Thiazide diuretics, indomethacin, desmopressin
70
Absorption of controlled release drugs and depot anhtipsychotics follow which type of kinetics?
Zero Order - i.e constant AMOUNT rather than constant FRACTION
71
First Order vs Zero Order kinetics:
ZOC FLaP
Rate of reaction dependent on concentration of substance?
FO: Y
ZO: N
1/2 life:
FO: Constant
ZO: Decreases with decreased concentration i.e no fixed 1/2 life
Most drugs follow First Order Kinetics - rate of elimination proportional to level of drug in body
72
73
How long do benzos take to reach peak serum levels?
What is the protein binding level?
30mins-2hrs
High - 70-99%
74
What is the volume of distribution?
Quantity of drug divided by plasma concentration, at zero time
It is a theoretical volume that a drug would occupy if it were uniformly distributed throughout the body and is proportionate to the dose given
(Larger VoD in lipid sol drugs. Higher VoD = drug in tissues, more than plasma)
75
Steady-state plasma levels are usually achieved after how many half lives?
4-5
76
What receptors does Clozapine have effects at?
Antagonist at 5-HT2A, D1, D3, D4
(D4 = most effect, cortical and limbic dopamine pathways, less at striatal)
Also potent antagonist of M1, H1, Alpha-1
Low potency antagonist of D2 (occupies 40-50% D2 receptors = fewer EPS)
Partial agonist at 5HT1A = beneficial in reducing negative symptoms
Agonism at M4 = hypersalivation
(Also 5-HT2C = receptor responsible for weight gain)
77
D1-like vs D2-like receptors:
D1-like: D1, D5 - high density in striatum, NA, olfactory bulb, SN
D1 and D5 receptors couple to G stimulatory sites and activate adenylyl cyclase. The activation of adenylyl cyclase leads to the production of the second messenger cAMP, which leads to the production of protein kinase A (PKA), which leads to further transcription in the nucleus.
D2-like: D2, D3, D4 - high density in striatum, external GP, NA, hippocampus and cortex
D2 through D4 receptors couple to G inhibitory sites, which inhibit adenylyl cyclase and activate K+ channels
78
Ammonium chloride can be used for urinary acidification for overdose of which drug?
Amphetamines
79
Drug tolerance vs Drug sensitisation:
Opposites.
Tolerance = reduced response with repeated exposure
Sensitisation = increased response with repeated exposure
80
How is Amisulpride excreted?
Through the urine - 50% is excreted unchanged (compared to 95% of lithium)
Also excreted in urine = gabapentin, amisulpride, acamprosate, amantadine
81
What is the half life of lithium?
What is the protein binding?
How does sodium affect the renal clearance?
10-24 hours
Low protein binding
Clearance reduced when low sodium
82
Which SSRI exhhibits autoinhibition?
Paroxetine i.e doses can x2 when increased by 50% - non linear dosing
83
What is the 1/2 life of quetiapine?
Around 7 hours = short = may require multiple x per day dosing
84
Define clearance:
Volume of blood plasma cleared of drug per unit time (NOT AMOUNT OF DRUG)
Determines 1/2 life
Specific for each drug and does NOT depend on drug conc in plasma
Depends on renal and non-renal clearance e.g sweat, bile
Involves metabolism and excretion
85
What is the Steady State?
Once the drug intake equals the clearance it is referred to as a steady state. Steady state is usually achieved by 4.5 half lives. The time taken to reach steady state therefore depends on the half life.
86
What happens to drugs that move from first order to zero order kinetics in supratherapeutic doses? (e.g fluoxetine)
Saturation of enzymes
Switch to ZO kinetics - regardless of how much drug in body, fixed amount cleared = no real 1/2 life any more and clearance becomes DEPENDENT on the dose
87
The active metabolite of
a) imipramine
b) amitriptyline
Desipramine
Nortriptyline
88
Mechanism of action of clonidine and guanfacine (ADHD meds)
Pre-synaptic alpha-2 receptor agonists = cause vasodilation of blood vessels, and reduce amount of norepinephrine released from presynaptic nerve terminals
Can cause orthostatic hypotension
89
What is the mechanism of mebolism of lorazepanm, temazepam and oxazepam?
metabolised by non CYP-450 pathways i.e phase 2 metabolism directly without undergoing phase 1 reactions
90
Which SSRIs are most selective for serotonin uptake?
Citalopram and escitalopram
91
High D2 affinity/ high 5HT2 activity is characteristic of:
Risperidone, olanzapine, loxapine
NB: Haloperidol = high D2, LOW 5-HT2
Risperidone = higher for 5-HT2A than D2
92
Most of the body's dopamine is metabolised by:
MAO-B and COMT
93
MAO-A preferentially deaminates:
Serotonin and norepinephrine
94
Two drugs metabolised by both MAO A and MAO B:
Dopamine
Tyramine
95
What is the mechanism of action of methadone?
Full agonist at mu opioid receptors
Long 1/2 life (15-22 hours)
(some action against kappa and delta)
M = Most = Mu = Methadone
Compared to bupernorphine which is a PARTIAL agonist at mu opioid receptors
96
Mechanism of action of galantamine: (2)
Competitive, reversible ACh-i
Also binds allosterically to the nicotinic acetylcholine receptor (agonist)
97
Mechanism of action of mamantine
NMDA receptor antagonist (non-competitive) - may protect neurones from glutamate-mediated excitotoxicity
Also 5-HT3 receptor antagonist
98
How does DisulfIram work?
Irreversible inhibitor of ALDEHYDE DEHYDROGENASE = accumulation of acetaldehyde
Dose dependent
99
Which TCA has the most evidence for use in ADHD due to its stimulant effect?
Desipramine
100
Which receptor is implicated in the weight gain caused by clozapine?
5HT2-C
101
Which channels are blocked by antidepressants e.g TCAs?
Catacholamine reuptake channels - how tyramine enters the presynaptic neurones
102
What is the mechanism of action of buspirone?
5HT1A partial agonist - chemically distinct from other psychotropic agents
103
Mechanism of action of Varenecycline:
What is its metabolism?
Partial, selective nicotinic receptor agonist
= reduces dopaminergic reward if patient smokes (competes with nicotine)
but also reduces withdrawal symptoms by stimulating some neurotransmission
High affinity for Alpha 4 Beta 2 nicotinic receptor
Only undergoes 10% hepatic metabolism = safe in liver dysfunction
104
Mechanism of action of trazodone:
Mixed serotonin agonist/ antagonist (SARI - serotonin antagonist and reuptake inhibitor) - blocks SERT (serotonin reuptake pump) and antagonist at 5HT2A and 5HT2C - these are the receptors that cause the most side effects, so antagonism here is helpful
105
Sedation, increased appetite, dry mouth with Mirtazapine are caused by effects at which receptor?
H1 blockade - NB: lower doses only. Noradrenergic (alpha-2 blockade) effect is higher at higher doses = stimulating effect
106
Which antidepressants are effective for patients with premature ejaculation?
Fluoxetine, sertraline - anorgasmic effects
107
Mechanism of action of Reboxetine:
NA reuptake inhibitor (NARI)
It has little or no affinity for 5-HT, dopamine, histamine, muscarinic and alpha-adrenergic receptors. This makes it unique among antidepressants as it specifically targets the reuptake of noradrenaline.
108
Mechanism of action of aripiprazole:
1/2 life:
Partial D2 **agonist**, also 5HT1A agonist and 5HT2A (high affinity) antagonist. NO anticholinergic effect, but low/mod affinity antagonist for H1 and Alpha 1
75hrs 1/2 life - 2 weeks to steady state
109
Mechanism of action of bupropion (Zyban):
NDRI (norepinephrine-dopamine reuptake inhibitor) and nicotinic receptor antagonist
Licenced outside UK for smoking cessation
Note: dose-related risk of seizures
110
Bupropion vs Varenicline mechanism of action:
Both used as smoking cessation
Bupropion is a norepinephrine-dopamine reuptake inhibitor and a nicotinic receptor antagonist
Varenicline is a partial agonist at nicotinic acetylcholine receptors, specifically binding to the alpha4-beta2 subunit. This action helps reduce cravings and withdrawal symptoms associated with smoking cessation by partially stimulating these receptors, but with a lower intrinsic activity compared to nicotine.
111
What does the ASEX scale measure?
Arizona Sexual Experiences Scale - sexual side effects of psychotropic medications
112
Which 2 antipsychotics cause the most sexual side effects?
Risperidone and Haloperidol - 70%
Both cause ++ prolactin
NB: amisulpride and sulpride also cause increased prolactin
113
6 contraindications for lithium treatment:
- Addison's disease
- Brugada syndrome
- Cardiac disease associated with rhythm disorders
- Clinically significant renal impairment
- Untreated or untreatable hypothyroidism
- Low sodium levels, including people that are dehydrated and those on low-sodium diets
114
What drug is first line to treat Lithium-induced DI?
Amiloride - K-sparing diuretic
Can also use indomethacin or desmopressin
115
What is the rating scale for Lithium toxicity?
AMDISEN (0-3 SCALE)
116
Lithium monitoring requirements:
Levels weekly until stable then 3-monthly
(12 hours post-dose) - NICE (6 months, Maudsley)
TFTs and U&Es every 6 months
117
Which antidepressants can be given IV?
Citalopram
Escitalopram
Amitriptyline
Clomipramine
(Ketamine and allopregnanolone)
118
Which FGA is most effective in preventing relapses?
Zuclopentixol
119
3 atypical antipsychotics available in depot form:
Aripiprazole
Risperidone
Olanzapine
120
Who discovered lithium's beneficial effect in Mania? (1949)
Cade
121
Who discovered the antidepressant effects of imipramine? (1957)
Kuhn
NB: Clozapine first synthesised from imipramine in 1958
122
Who discovered the use of iproniazid (MAOI) in 1951?
Kline
First antidepressant
123
Who Introduced chlorpromazine as a treatment for schizophrenia and coined the term 'neuroleptic'? (1952)
Delay and Deniker
Charpentier
124
First described the 'cheese effect' seen in MAOI use in the 1960s?
Blackwell
125
Who reintroduced clozapine into clinical practice in 1988?
Kane
Was removed from markets in 1975 due to agranulocytosis deaths
126
127
Who synthesised chlorpromazine in 1950?
Charpentier
Note: Delay and Deniker first demonstrated its effectiveness in 1952
128
Which lab synthesised Haloperidol from pethidine in 1958 and then risperidone in 1989?
Janssen
129
3 risk factors for developing neutropenia on clozapine:
Afrocarribean ethnicity
Low WCC to start with
Younger age
(NOT DOSE DEPENDENT)
130
What was the first SSRI synthesised?
Why was this discontinued?
Zimelidine - 1972
(Carlsson)
Caused demyelinating disease, and hypersensitivity syndrome
131
What did Kline study in the 1950's?
Iproniazid - for TB
An MAOI
132
Mechanism of action of cariprazine
Partial D2/D3 agonist
D3 activity = particularly useful to treat neg symptoms of schizophrenia
133
Which Alzheimer's drug is neuroprotective?
Memantine
134
Mechanism of action of memantine:
Non-Competitive NMDA antagonist
Reduces NMDA receptor sensitivity to gutamate
135
What class of drugs are:
Diphenhydramine
Cetirizine
Chlorpheniramine
Cyclizine
Hydroxyzine
H1 receptor blockers - used for sedation and allergies
136
What class of drugs are:
Cimetidine
Ranitidine
H2 receptor blockers - used for excess stomach acid
137
What class of drugs:
Diphenhydramine
Promethazine
Hydroxyzine
Chlorpheniramine
Cyproheptadine
Cyclizine
Ketotifen
First generation antihistamines
138
What class of drugs:
Loratadine
Cetirizine
Fexofenadine
Acrivastine
Second generation antihistamines - less sedating as don't cross BBB as much.
Receptor-specific and don't show anticholinergic effects
139
3 contraindications to first gen antihistamines:
Benign prostatic hyperplasia
Angle-closure glaucoma
Pyloric stenosis (in infants)
140
3 reasons for First gen antihistamines use in psychiatry
Cross the BBB
Sedating
Anticholinergic properties
141
Mechanism of action of atomoxetine:
Selective NA reuptake inhibitor - used in ADHD
142
How do guanfacine and clonidine work in ADHD?
Agonists of alpha-2 adrenergic receptors, mimicking NA
143
2 active metabolites of clozapine:
N-desmethylclozapine (norclozapine)
clozapine N-oxide
144
Why was Pemoline removed from the market for ADHD?
Severe liver disease
Note: still used in Japan
145
Which antidepressant is most associated with priapism and can prolong the QTc interval in normal doses?
Which antipsychotics?
Trazodone - AD
Chlorpromazine and thioradazine - AP
146
3 types of opioid receptors and effects at each: (all G-protein coupled)
Mu - analgesia, euphoria, constipation, resp depression, dependence
Kappa - analgesia, diuresis, dysphoria
Delta - analgesia, anxiolysis
(MU = MOST
All = Analgesia)
147
Serotonin syndrome:
Mechanism
Symptoms
Caused by
Excess serotonergic activity in the CNS
- The symptoms of hyperreflexia, rigidity, and clonus tend to be more prominent in the lower extremities (clonus is nearly always present)
Rapid onset, within 24hrs
Often due to multiple agents but CAN be caused by single agent
(antidepressants (main group)
lithium
opioids
olanzapine
risperidone)
Triad to remember: neuromuscular abnormalities, altered mental state, autonomic dysfunction
148
Differentiating NMS from SS:
SS: hyper-reflexia, clonus, occular clonus, tremors
NMS: lead-pipe rigidity and hypo-reflexia
(NMS = bradykinesic, SS = "faster", aggitation)
SS: faster onset but also faster recovery
Both (4):
Hyperthermia
Tachycardia
Tachypnoea
Hypertension
149
1/2 life of: (5)
Aripiprazole
Olanzapine
Risperidone
Clozapine
Quetiapine
A - 75hrs - 2 weeks to SS
O - 30hrs - 1 week to SS
R - 20hrs
C - 12hrs
Q - 6hrs
RCQ = 2-3 days to SS
150
Drug interactions:
Pharmacokinetic vs Pharmacodynamic:
Pharmacokinetic drug interactions take place when one drug interacts with another at the level of metabolism, absorption or excretion.
Pharmacodynamic interactions occur when one drug directly alters the effect of another
151
5 examples of pharmacokinetic drug interactions:
Enzyme induction/ inhibition (interference with metabolism)
Changes in gastrointestinal tract motility and pH (interference with absorption)
Chelation
Competition for renal tubular transport (interference with excretion)
Changes in protein binding
152
3 examples of pharmacodynamic drug interactions:
Synergism
Antagonism
Interaction at receptors (allosteric modulation)
153
Phenothiazines:
3 types of side chain
Examples for each (1, 2, 2)
1) Aliphatic side chain - Chlorpromazine
2) Piperidine side chain - Thioridazine, pipothiazine
3) Piperizine side chaine - Trifluoperazine, fluphenazine
Notes:
(AliphatiChlorpromazine)
DINE with Thio and Pip
FLU...zine - FLU-Z
154
What class of antipsychotics?
Haloperidol
Butyrophenones
155
What class of antipsychotics?
Flupentixol, Zuclopenthixol
ThioXanthines
(X)
156
What class of antipsychotics?
Pimozide
DiPhenylbutylPiPeridines
All the "P"s
157
What class of antipsychotics?
Clozapine
Dibenzodiazepines
Call DIBs on Clozapine
(Diaz, not THIAZ - DibenzoTHIAZEPINE = Quetiapine)
158
What class of antipsychotics?
Risperidone
Benzoxasoles
159
What class of antipsychotics?
Olanzapine
Thienobenzodiazepines
ThienOLANZAPINE
160
What class of antipsychotics?
Quetiapine
Dibenzothiazepines
2 x benzos makes a Quetiapine
(THIAZ not DIAZ
DibenziDIAZEPINE = clozapine)
161
Which 2 antipsychotics are substituted benzamides?
Sulpride and Amisulpride
162
What class of antipsychotics?
Aripiprazole
Arylpiperidylindole (quinolone)
Ar = Ar
163
Who coined the term psychopharmacology?
Macht and Mora - 1915, while studying opioid alkaloids on rats
164
Sen and Bose in 1931 in India discovered what?
Linked to which drug in 1954?
Antipsychotic properties of Rouwolfia Serpentine
Klein - Reserpine
165
What did Cerletti and Bini do in 1930?
Induced elective seizures - antidepressant effects
166
Who first undertook frontal lobotomy?
Moniz (1937)
167
Librium (chlordiazapoxide) was discovered in 1954 by:
Leo Sternbach
168
Which drugs are known as:
a) major
b) minor
tranquilisers?
Major: antipsychotics
Minor: Benzos and barbituates
169
Who discovered the use of Carbamazepine to treat mania in 1971?
Takezaki and Hanaka
170
What was the RCT done by Kane in 1988?
Clozapine vs Chlorpromazine for TR schizophrenia
30% responded to Cloz
4% to chlorpromazine
171
Who discovered the use of Valproate in Mania?
Bowden in 1994
172
What causes erectile dysfunction in antipsychotic use?
Cholinergic receptor antagonism
173
Which drug is licenced for narcolepsy, obstructive sleep apnoea, and chronic shift work, and is also suggested as an adjunctive treatment for depression (in the Maudsley)
Modafenil - a psychostimulant which enhances wakefulness, attention, and vigilance. It is similar to amphetamines apart from that it tends to lack the euphoric effects, does NOT seem to be associated with dependence or tolerance, and does not tend to precipitate psychosis.
174
5 examples of drugs that undergo significant first pass effect:
imipramine
fluphenazine
morphine
diazepam
buprenorphine
175
2 examples of drugs that do not undergo significant first pass effect:
Lithium
Pregabalin
176
Which TCAs are associated with discontinuation syndrome?
Amitriptyline
Imipramine
177
What are 3 symptoms of TCA discontinuation syndrome?
Flu-like symptoms
Insomnia
Excessive dreaming
178
Which mechanism of action is most associated with psychedelic hallucinogens?
5HT2A agonism
Psilocybin, LSD, DMT are potent agonists of serotonergic receptors, in particular 5HT2A
Note: only DMT and LSD have potent effects at 5HT1A as well, NOT psilocybin
179
What is the mechanism of action of:
Amphetamine, ecstasy, cocaine
Target monoamine transporters
180
What is the mechanism of action of:
Dissociatives - ketamine, PCP (phencyclidine, angel dust), dextromethorphan (DXM), nitrous oxide (N2O
NMDA antagonists - impacting glutamate system
181
Which drug has the following side effects:
Liver injury
Vomiting / diarrhoea
Gingival hyperplasia
Memory impairment / confusional state
Somnolence
Weight gain
Anaemia / thrombocytopenia
Alopecia (with curly regrowth)
Valproate
NB:
Increased liver enzymes are common, particularly at the beginning of therapy, and are usually transient.
V&D Tend to occur at start of treatment and remit after a few days
SEVERE LIVER IMPAIRMENT IS RARE but most cases occur in first 6 months of therapy (max risk 2-12 weeks) - risk also declines with advancing age
182
What is the prevalence of:
Dystonia
Pseudoparkinsonism
Akathisia
Tardive Dyskinesia
D: 10%
P: 20%
A: 25%
TD: 5%
183
Why do atypical antipsychotics have a lower risk of ESPEs and a better reduction of negative symptoms than typicals?
5-HT2A serotonin receptor antagonism
Also, their lower affinity for D2 receptors (antagonism)
184
Why does Clozapine have a reduced incidence of ESPEs?
It appears more active at the limbic than at striatal dopamine receptors
185
Which cytochrome P450 enzymes metabolise benzodiazepines?
Most benzodiazepines are metabolized extensively by hepatic CYP3A4 and CYP2C19
NB: Not lorazepam - so more suitable with liver impairment
186
1/2 life of different benzos:
DCNCTLAOZZZT
Diazepam 20-100
Clonazepam 18-50
Nitrazepam 15-38
Chlordiazepoxide 5-30
Temazepam 8-22
Lorazepam 10-20
Alprazolam 10-15
Oxazepam 6-10
Zopiclone 5-6
Zolpidem 2
Zaleplon 2
Triazolam 2
187
188
Approximate equivalent doses of other benzos to diazepam 10mg:
LLNTCO
Lorazepam 1mg
Lormetazepam 1mg
Nitrazepam 10mg
Temazepam 20mg
Chlordiazepoxide 25mg
Oxazepam 30mg
189
2 contraindications for carbamazepine therapy:
Hx of bone marrow depression
Combination with MAOIs
190
What is the most common side effect of discontinuing benzos?
Insomnia
Also: stiffness, weakness, GI sx, flu-like sx, anxiety, delusions
191
Use and mechanism of action of lofexidine:
Alpha-2 agonist, used to help withdrawal sx in opioid discontinuation. Not available in UK since 2018.
192
3 main medication causes of cleft lip and palate in babies:
Benzodiazepines, steroids, anticonvulsants
193
What is a biogenic amine?
A compound derived from amino acids.
Neurotransmitters in this class include:
Catecholamines (adrenaline, noradrenaline, dopamine)
Serotonin
Histamine
(HANDS)
194
What is the treatment for SIADH?
Fluid restriction
Democlocycline
195
How long do the following drugs take to reach steady state?
Lithium
Aripiprazole
Carbamazapine
Olanzapine
Risperidone depot
Paliperidone depot
L: 4-5 days
A: 14-16 days (2 weeks approx)
C: 14 days
O: 7 days (1 week)
RD: 6-8 weeks
PD: 2 months
196
How does Lurasidone work?
Full D2 and 5-HT2A ANTAGONIST
High affinity at 5HT-7 (antagonist) - unique to Lurasidone
Partial agonist at 5-HT1
High affinity for D2
Minimal to no effect at H1 or N1 = better side effect profile, less metabolic syndrome
Food increases its absorption
197
What causes sexual side effects in SSRIs?
5-HT2 agonism
Note: can be reversed by 5-HT2 antagonists like cyproheptadine, or 5-HT1A agonists like buspirone
198
Which 2 antipsychotics have the highest risk of postural hypotension?
Clozapine
Quetiapine
199
Contraindications for chlorpromazine include: (5)
Bone marrow depression
Myasthenia gravis
History of agranulocytosis
Dopaminergic antiparkinsonism agents
Citalopram, escitalopram
NB: risk of photosensitivity
200
Which 2 TCAs have the most toxicity in OD (MOST SEDATING)?
Which has a lower incidence?
Highest - Dothiepin (Dosulepin) and then Amitriptyline
Lowest: lofepramine
201
Define bioavailability:
The fraction of an administered dose of unchanged drug that reaches the systemic circulation when given intravenously
202
Which drug is licenced for:
Generalised anxiety disorder
Diabetic neuropathy
Stress urinary incontinence
Depression?
Duloxetine
203
MAOIs examples:
Reversible (RIMA) x1
Irreversible x 4
RIMA: Moclobemide
Irreversible:
Selegiline
Tranylcypromine
Phenelzine
Isocarboxazid
204
Which Alzheimer's drug is a butyrylcholinesterase inhibitor?
(it also undergoes no hepatic breakdown)
Rivastigmine
205
A drug which is inactive until converted to its active metabolite is known as what?
Prodrug
206
What term describes the process by which a drug moves from its administration site to the systemic circulation?
Absorption
207
Methylphenidate vs amfetamine:
Both result in increased synaptic levels of monoamines (principally dopamine and noradrenaline)
Both block the reuptake of the monoamines from the synapse back into the presynaptic neurone (blocking DAT and NAT)
Amfetamine only:
- promotes release of monoamines from the presynaptic neurone into the synapse by disrupting the function of VMAT
- Blocks SERT
Methylphenidate only:
- binds to α-adrenergic receptors linked to cognitive effects and increased peripheral resistance (α1 agonism)
- agonist at 5-HT1A
208
How does Sidenafil work?
Inhibits cGMP-specific phosphodiesterase type 5 (PDE5) i.e prolongs effects of cGMP (phosphodiesterase would terminate it)
209
Which 2 antipsychotics were removed from the UK market due to their effect on the QTc interval and risk of sudden death?
Thioridazine and droperidol
210
What were Phase 1 and Phase 2 of the CATIE study?
Phase I compared typical and atypical antipsychotics - compared 4 new meds (OQRZ) to each other, and an older medication (perphenazine)
Phase II sought to provide guidance on which antipsychotic to try next if the first failed (either due to ineffectiveness or intolerability).
211
Opioids, cannabinoids and GHB (gamma hydroxybutyrate) interfere with which type of receptors? (ionotropic or g-protein coupled?)
G-protein coupled
212
Alcohol, benzos, nicotine and ketamine interfere with which type of receptors? (ionotropic or g-protein coupled?)
Ionotropic
213
Mechanism of action of agomelantine:
Agomelatine is a relatively new drug used for treating depression. It acts as an agonist at melatonin M1 and M2 receptors and as an antagonist at 5HT2C receptors.
NOTE: Not associated with discontinuation syndrome
214
What is torsades du point?
A type of polymorphic ventricular tachycardia, often transient, associated with prolonged QTc, often asymptomatic but associated with syncope and death (deteriorates into VF)
215
What is the issue with the Bazett formula for QTc?
The Bazett formula over-corrects at heart rates > 100 bpm and under-corrects at heart rates < 60 bpm, but provides an adequate correction for heart rates ranging from 60 - 100 bpm.
216
5 independent risk factors for prolonged QTc:
Female sex
Hypokalemia
Hypomagnesaemia
Hypocalcemia
Anorexia nervosa
217
Which cytochrome P450 subfamily is most abundant in the human liver?
The CYP3A subfamily is the most abundant in the human liver, accounting for nearly 30% of the total cytochrome P450 content.
218
What is the main difference between Phase I and phase II biotransformation reactions?
Phase I metabolism converts a parent drug to polar, water soluble ACTIVE metabolites while phase II metabolism converts a parent drug to polar INACTIVE metabolites.
219
3 processes involved in Phase I biotransformation reactions:
- Oxidation with cytochrome P450 (most common) - membrane-bound enzymes primarily found within the endoplasmic reticulum of hepatocytes
- Reduction
- Hydrolysis
220
3 antipsychotics LEAST likely to cause orthostatic hypotension:
Lurasadone, Asenapine, Amisulpride
Also Haloperidol, Sulpride, Aripiprazole. Trifluoperazine
221
Which D2/D3 antagonist is preferentially used in PET scans?
Raclopride - it can be radiolabelled, binds reversibly, is relatively selective for D2, shows low internalisation (does not induce internalisation / degradation of the D2 receptors), and has limited therapeutic effects.
222
Of the commonly used antipsychotics, which has the most and the least effect on EEG?
Most: Clozapine - 47.1%
Least: Quetiapine - 0%
223
5 types of medication that can precipitate mood changes, particularly in the elderly:
- Centrally-acting antihypertensives (e.g. methyldopa, reserpine, and clonidine) can cause depressive symptoms.
- Interferon-a is capable of inducing depressive symptoms.
- Digoxin is capable of inducing depressive symptoms.
- Corticosteroids can cause depressive, manic, and mixed symptoms with or without psychosis.
- Antidepressants can precipitate mania.
224
Which Alzheimer's drug is best for those with liver disease or those on multiple medications?
Rivastigmine - undergoes minimal metabolism through P450 system, primarily being metabolised through hydrolysis by esterases = fewer drug interactions
225
Nandrolone, Stanozolol, Oxandrolone, Trenbolone are examples of:
What psychiatric disorders are associated (4)?
Anabolic steroids - Class C controlled drug
Aggression / irritability / moods swings ('roid rage' refers to frenzied violent behaviour during the high-dose cycles of steroid use)
Psychosis, Mania/hypomania, Depression / anxiety
226
Compare the mechanism of action of amphetamines and cocaine:
Amphetamines act primarily by inducing the release of dopamine, a neurotransmitter associated with pleasure and reward, from presynaptic neurons into the synaptic cleft. This results in increased concentrations of dopamine in the synapse and prolonged stimulation of post-synaptic neurons.
Cocaine DOES NOT STIMULATE the release of dopamine but instead works by blocking the reuptake of dopamine at the synaptic cleft (competes at DAT). By inhibiting its reuptake, cocaine increases the concentration of dopamine in the synapse, resulting in an enhanced and prolonged stimulatory effect on post-synaptic neurons.
227
Which drug is known to increase lamotrigine levels?
How does the use of oestrogen in the COCP affect lamotrigine?
2 MAJOR side effects of lamotrigine to be aware of:
Valproate
Decreased lamotrigine - lamotrigine doses may need to be doubled
SJS - in first 8 weeks
suicidal ideation
228
Which TCA is considered the LEAST cardiotoxic?
Lofepramine
229
Which TCA has a stimulant effect and can be used in ADHD?
Desipramine
230
4 types of drugs that can cause porphyria:
Barbiturates
Benzodiazepines
Sulpiride
Certain mood stabilizers
231
Which mood stabilizer causes hypospadias, neural tube defects, cleft lip/palate when used during pregnancy?
Valproate
Also can cause: cardiovascular abnormalities, developmental delay, endocrinological disorders, limb defects, and autism
232
The reduction in drug concentration that occurs when a drug is absorbed before it reaches the systemic circulation is termed:
First Pass Effect
233
Most sedating SSRI:
SSRI with most activation:
SSRI most likely to cause sexual side effects:
SSRI least likely to cause sexual side effects:
Most protein bound SSRI:
Paroxetine
Fluoxetine
Paroxetine - includes issues with lubrication
Vortioxetine
Sertraline
234
What is the mechanism of action of Iecanemab in the treatment of Alzheimer's Disease?
Binds to soluble amyloid-beta protofibrils. This facilitates their removal from the brain before they can accumulate into larger, insoluble plaques, which are characteristic features in Alzheimer’s disease pathology.
235
What receptor is responsible for the following side effect of psychotropic medications:
Weight gain caused by antipsychotics (2)
H1 and 5HT2C antagonism
236
What receptor is responsible for the following side effect of antipsychotics:
Hyperprolactinaemia
D2 blockade in the tuberoinfundibular pathway
237
What receptor is responsible for the following side effect of psychotropic medications:
Postural Hypotension:
Alpha 1 adrenergic receptors
238
What receptor is responsible for the following side effect of psychotropics:
Parkinsonism
D2 blockade in the nigrostriatal pathway
239
What receptor is responsible for the following side effect of psychotropic medication:
Gastrointestinal distress caused by SSRIs
5HT3 receptor stimulation
240
What receptors do Sulpride and Amisulpride work on?
Sulpride: Predominant D2 antagonist, minima D3 antagonist/partial agonist actions (known as a "pure D2 antagonist")
Amisulpride: D2/D3 antagonist - reduces positive symptoms by affecting dopamine in the limbic system
241
The chronic administration of tricyclics results in:
Down-regulation of beta adrenergic receptors
242
What effect does D2 blockade have at the:
1) mesocortical pathway
2) mesolimbic pathway
3) tuberoinfundibular pathway
4) nigrostriatal pathway
1) production or worsening of negative symptoms
2) improvement of positive symptoms
3) hyperprolactinaemia - pituitary stuff
4) EPSEs
243
What class of drugs can cause bruxism?
Stimulants
244
What is the treatment for amphetamine or PCP overdose?
Acidification of the urine
245
What is the treatment for severe lithium toxicity (>3)?
Haemodynamic dialysis
246
What is the treatment for the tyramine-induced Cheese Reaction caused by MAOIs?
Alpha-adrenergic agents e.g phentolamine or chlorpromazine
247
What is the range for target plasma levels for:
1) Lithium
2) Carbamazepine
3) Clozapine
4) Phenytoin
5) Amitriptyline
6) Valproate
1) 0.6-1 mmol/L
2) >7 mg/L
3) 350-500mg mg/L
4) 10-20 mg/L
5) 100-200 mcg/L
6) 50-150 mg/L
248
When would you see the following side effects:
Headache, halitosis, metalic taste in mouth, dermatitis, sedation
Disulfaram - in the ABSENCE of alcohol
249
What is the rate limiting step in Dopamine metabolism?
Tyrosine to DOPA (using tyrosine hydroxylase)
(DOPA is then converted into Dopamine)
250
When switching from MAOIs to SSRIs how long is the crossover?
Withdraw and wait 2 weeks (to prevent serotonin syndrome)
251
Which antidepressant has the same sexual side effects as the placebo?
Agomelantine
252
What is the annual risk of a patient on clozapine for developing agranulocytosis?
0.01% - usually seen in first 18 weeks of treatment
253
What are the risk factors for agranulocytosis on clozapine:
Female sex, being older, Asian or Ashkenazi Jewish
254
How do caffeine, acetazolomide and theophylline affect lithium levels?
Can reduce lithium levels
255
How do furosemide, NSAIDs, ACEi's and thiazides affect lithium levels?
They increase lithium levels
256
What is the most likely explanation for SSRI discontinuation syndrome?
Temporary deficiency in the brain of one or more essential neurotransmitters associated with mood
257
Clozapine can cause myocarditis - what ECG changes would be seen?
Saddled ST elevation
Diffuse T-wave inversion
Other non-specific ST changes
258
What is the main active metabolite of diazepam?
What are the 2 minor metabolites?
Major - desmethyldiazepam
Minor - oxazepam, temazepam
259
How does Vortioxetine work?
SERT inhibition
Antagonist at 5-HT3 and 5HT7
Agonist at 5-HT1A
(some weak action at 5-HT1B/D)
260
How does carbidopa work?
Inhibits DOPA-decarboxylase (which metabolises L-dopa into dopamine) outside the CNS = more L-DOPA is able to enter the CNS and become dopamine
It does not itself cross the BBB
