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ACEM Primary Written > Psychiatry: Pharmacology - Antipsychotics and mood stabilisers > Flashcards

Psychiatry: Pharmacology - Antipsychotics and mood stabilisers Flashcards

1
Q

Define neuroleptic agent

A

Subtype of antipsychotic that produces high incidence of EPSE at clinically effective doses

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2
Q

Define atypical antipsychotic

A

Antipsychotic that dissociates antipsychotic actions from EPSEs

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3
Q

Explain the serotonin hypothesis of schizophrenia. What class of drugs supports this hypothesis?

A

5HT(2A) receptor blockade reduces psychotic symptoms
Main class of atypical antipsychotics (e.g. clozapine, quetiapine) act as inverse agonists at 5HT(2A) receptors

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4
Q

Explain the dopamine hypothesis of schizophrenia. What drugs support this hypothesis?

A

Excessive limbic dopamine release is involved in schizophrenia (however this is no longer considered sufficient to explain all symptoms)
Antipsychotics antagonise D2 receptors
Drugs that increase dopamine (e.g. levadopa, amphetamines) can produce psychosis

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5
Q

Explain the glutamate hypothesis of schizophrenia. What class of drugs supports this hypothesis?

A

Hypofunction of NMDA receptors on inhibitory GABAergic interneurons leads to decreased inhibitory influences on neuronal function
Drugs that inhibit NMDA receptors (e.g. PCP, ketamine) exacerbate schizophrenia

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6
Q

Five structural classes of antipsychotic drugs with an example of each

A
  1. Phenothiazines (e.g. chlorpromazine, thioridazine, fluphenazine)
  2. Thioxanthenes (e.g. thiothexene)
  3. Butyrophenones (e.g. haloperidol)
  4. Miscellaneous (e.g. pimozide, molindone)
  5. Second-generation (atypical; e.g. clozapine, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole)
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7
Q

Adverse effects of phenothiazines

A

Produces weight gain and sedation

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8
Q

Describe the potency and side effect profile of butyrophenones (e.g. haloperidol)

A

Tend to be more potent
Fever autonomic effects but more EPSEs

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9
Q

Describe the mechanism of action of atypical antipsychotics

A

Alter 5HT2A activity more than D2 activity
Most are partial 5HT1A agonists, which produces synergistic effects with 5HT2A antagonism

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10
Q

Five important dopaminergic pathways involved in schizophrenia, and the role of each

A
  1. Mesolimb-mesocortical: related to behaviour and psychosis
  2. Nigrostriatal: coordination of voluntary movement (blockade of D2 receptors in this pathway causes EPSEs)
  3. Tuberoinfundibular: dopamine release from these neurons inhibits prolactin secretion (causes hyperprolactinaemia when antagonised by antipsychotics)
  4. Medullary-periventricular: may be involved in eating behaviour
  5. Incertohypothalamic: regulates anticipatory motivational stage of copulatory behaviour
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11
Q

Describe the mechanism of action of antipsychotics

A

Effect dose of typical antipsychotics correlates with D2 (but not D1) receptor affinity
Most are D2 antagonists but some are partial agonists (e.g. aripiprazole)
Atypical antipsychotics also act as 5HT2A receptor antagonists (and so have good efficacy despite lower D2 receptor occupancy than typical antipsychotics)
Some also antagonise a2-adrenoceptors

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12
Q

Five examples of antipsychotics which antagonist a2-adrenoceptors

A
  1. Risperidone
  2. Olanzapine
  3. Quetiapine
  4. Clozapine
  5. Aripiprazole
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13
Q

What autonomic adverse effects are seen with antipsychotic use and what are the underlying mechanisms of these?

A

Muscarinic cholinoceptor blockade: loss of accommodation, dry mouth, difficulty urinating, constipation

a-adrenoceptor blockade: orthostatic hypotension, impotence, failure to ejaculate

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14
Q

What CNS adverse effects are seen with antipsychotic use and what are the underlying mechanisms of these?

A

Dopamine receptor blockade: Parkinson’s syndrome, akathisia, dystonias
Supersensitivity of dopamine receptors: tardive dyskinesia
Muscarinic blockade: toxic-confusional state

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15
Q

What endocrine adverse effects are seen with antipsychotic use and what are the underlying mechanisms of these?

A

Dopamine receptor blockade resulting in hyperprolactinaemia: menorrhoea-galactorrhoea, infertility, impotence

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16
Q

What is the mechanism of antipsychotic-associated weight gain?

A

Possibly combined H1 and 5HT2 blockade

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17
Q

What causes neuroleptic malignant syndrome?

A

Believed to be related to excessively rapid blockade of postsynaptic dopamine receptors

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18
Q

What is the clinical presentation of neuroleptic malignant syndrome?

A

Marked muscle rigidity (“lead pipe”)
Fever if sweating impaired due to anticholinergic effect
Stress leukocytosis
Elevated CK
Autonomic instability with altered BP and HR

May progress to catatonia, cardiovascular lability, hypothermia and myoglobinaemia if untreated

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19
Q

What is the mortality of neuroleptic malignant syndrome?

A

> 10%

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20
Q

How is neuroleptic malignant syndrome managed?

A

Supportive care
Antiparkinsonism drugs to counter EPSEs
Muscle relaxants (e.g. diazepam)
Cooling

After recovery should be switched to an atypical drug

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21
Q

What 7 symptoms are seen in antipsychotic overdose? How commonly is antipsychotic overdose fatal?

A

Rarely fatal
1. Drowsiness -> intervening period of agitation -> coma
2. Neuromuscular excitability -> convulsions
3. Miosis
4. Decreased deep tendon reflexes
5. Hypotension
6. Hypothermia (fever may occur in later stage)
7. Risk of cardiac arrhythmias specific to thioridazine and mesoridazine

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22
Q

Describe the general pharmacokinetics of antipsychotics

A

Absorption: most readily but incompletely absorbed, undergo extensive first-pass metabolism
Distribution: most highly lipid soluble and protein bound with large Vd (>7L/kg), have a longer duration of action than estimated from t1/2
Metabolism: by oxidation or demethylation catalysed by CYP450 enzymes, with major isoforms involved including CYP2D6, CYP1A2 and CYP3A4

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23
Q

What is the oral bioavailability of chlorpromazine compared with haloperidol? What accounts for this difference?

A

Chlorpromazine 25%, haloperidol 65% due to lesser degree of first-pass metabolism

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24
Q

How long after last injection do depot antipsychotics continue to produce D2 blockade?

A

3-6 months

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25
Q

How long after last dose are metabolites of chlorpromazine found in the urine?

A

Weeks

26
Q

What is the average time to relapse after discontinuation of antipsychotics in schizophrenia? What medication is the exception to this?

A

6 months
Exception is clozapine in which relapse occurs rapidly

27
Q

Describe the differences in receptor affinities between chlorpromazine, haloperidol, clozapine, olanzapine, aripiprazole and quetiapine

A

Chlorpromazine: a1 = 5HT2A > D2 > D1
Haloperidol: D2 > a1 > D4 > 5HT2A > D1 > H1
Clozapine: D4 = a1 > 5HT2A > D2 = D1
Olanzapine: 5HT2A > H1 > D4 > D2 > a1 > D1
Aripiprazole: D2 = 5HT2A > D4 > a1 = H1&raquo_space; D1
Quetiapine: H1 > a1 > M1,3 > D2 > 5HT2A

28
Q

Advantages and disadvantages of chlorpromazine as an antipsychotic

A

Advantages: generic, cheap
Disadvantages: many adverse effects (especially autonomic)

29
Q

Advantages and disadvantages of haloperidol as an antipsychotic

A

Advantages: generic, available IM/IV
Disadvantages: severe EPSE

30
Q

Advantages and disadvantages of clozapine as an antipsychotic

A

Advantages: good for treatment resistance, little EPSEs
Disadvantages: risk of agranulocytosis (usually between weeks 6-18 of treatment), lowers seizure threshold

31
Q

Advantages and disadvantages of risperidone as an antipsychotic

A

Advantages: broad efficacy, little/no EPSE at low doses
Disadvantages: EPSE and hypotension at high doses

32
Q

Advantages and disadvantages of olanzapine as an antipsychotic

A

Advantages: effective against negative and positive symptoms of schizophrenia, little/no EPSE
Disadvantages: weight gain, lowers seizure threshold

33
Q

Advantages and disadvantages of quetiapine as an antipsychotic

A

Advantages: similar to olanzapine, less weight gain
Disadvantages: may require high doses if associated hypotension, short t1/2 necessitates twice-daily dosing

34
Q

Advantages and disadvantages of aripiprazole as an antipsychotic

A

Advantages: lower weight gain liability, long t1/2, novel mechanism
Disadvantages: uncertain

35
Q

Mechanism of action of chlorpromazine

A

Central dopaminergic blockade (D2 receptors)
Also antagonises 5HT, histamine, muscarinic and a-adrenergic receptors

36
Q

Describe the pharmacokinetics of chlorpromazine

A

Absorption: well-absorbed, extensive first-pass metabolism in liver and gut wall with bioavailability 30%
Distribution: highly lipid soluble and protein bound (95-98%), large Vd (20L/kg), accumulates in brain and lung
Metabolism: extensively metabolised in liver with numerous metabolites (some active)
Elimination: equal quantities urine and faeces

37
Q

Three CNS effects of chlorpromazine

A
  1. Neurolepsis
  2. Anxiolysis
  3. Sedation
38
Q

Three CVS effects of chlorpromazine

A
  1. Decreased contractility
  2. Decreased TPR (due to a-blockade): postural hypotension with reflex tachycardia
  3. May produce ECG changes including prolonged PR and QT intervals
39
Q

Two respiratory system effects of chlorpromazine

A
  1. Respiratory depression
  2. Decreased upper respiratory tract secretions
40
Q

GIT effect of chlorpromazine

A

Increased appetite (may cause weight gain)

41
Q

Three GUT effects of chlorpromazine

A
  1. Weak diuretic
  2. Impaired ejaculation*
  3. Urinary retention*

*anticholinergic effect

42
Q

Five metabolic effects of chlorpromazine

A
  1. Poor temperature regulation
  2. Increased prolactin secretion
  3. Decreased ACTH release
  4. Decreased ADH release
  5. May release insulin
43
Q

Three toxic effects of chlorpromazine

A
  1. EPSE (including NMS)
  2. Anticholinergic effects
  3. Allergic phenomena
44
Q

Four clinical applications of chlorpromazine

A
  1. Schizophrenia and related psychoses
  2. Agitation
  3. Nausea and vomiting (especially in terminal illness)
  4. Intractable hiccup
45
Q

Mechanism of action of haloperidol

A

Central dopaminergic blockade via D2 receptors
Post-synaptic GABA antagonism

46
Q

Describe the structure of lithium

A

Small monovalent cation (Li+)

47
Q

Five proposed mechanisms of action of lithium

A
  1. Decreased IP3 signalling by depletion of inositol (with inhibition of IMPase): IP3/DAG important second messengers for a-adrenergic and muscarinic transmission (increased in mania)
  2. Substitute for Na+ in action potentials
  3. Decreased NA-sensitive adenylyl cyclase activity
  4. G protein uncoupling
  5. Decreased glycogen synthase kinase-3 (GSK-3) activity: results in increased B-catenin which acts as transcription factor for proteins which modulate energy metabolism, neuroprotection and neuroplasticity
48
Q

What is the clinical significance of lithium’s uncoupling effect on GPCR in terms of its adverse effects?

A

Likely responsible for nephrogenic diabetes insipidus (via action on vasopressin receptor) and subclinical hypothyroidism (via action on TSH receptor)

49
Q

Describe the pharmacokinetics of lithium

A

Absorption: complete within 6-8hrs, peak levels of 30mins to 2hrs
Distribution: in TBW (no protein binding) with slow entry into intracellular compartment, initial Vd 0.5L/kg -> 0.7-0.9L/kg, some sequestration in bone
Metabolism: none
Elimination: entirely in urine (clearance ~20% of creatinine), can be removed by dialysis, t1/2 = 20hrs

50
Q

What is the target concentration of lithium? What is the typical dosage?

A

Target concentration: 0.6-1.4mEq/L
Dosage: 0.5mEq/kg/day in divided doses

51
Q

At what level is lithium toxicity typically seen?

A

> 2mmol/L

52
Q

What effect do diuretics have on renal clearance of lithium? What other drugs also have this effect?

A

Reduced renal clearance by 25% (dose should be reduced by similar amount)
Similar effect with newer NSAIDs

53
Q

How do neuroleptics interact with lithium when co-administered? What are the exceptions?

A

Increased incidence of EPSE
Except with clozapine and newer atypicals

54
Q

Seven CNS adverse effects of lithium

A

Tremor
Choreoathetosis
Motor hyperactivity
Ataxia
Dysarthria
Aphasia
Confusion

55
Q

How is tremor caused by lithium treated?

A

Propranol or atenolol

56
Q

What effect does lithium have on thyroid function?

A

Decreases but rarely causes frank hyperthyroidism
Changes in thyroid function are reversible and non-progressive

57
Q

Three renal adverse effects of lithium

A
  1. Nephrogenic diabetes insipidus: polyuria, polydipsia
  2. Chronic interstitial nephritis
  3. Minimal change glomerulopathy with nephrotic syndrome
58
Q

What cardiovascular side effect is caused by lithium? In what condition is lithium absolutely contraindicated for this reason?

A

SA node suppression
Absolutely contraindicated in sick sinus syndrome

59
Q

What dermatological adverse effects are seen with lithium?

A

Transient acneiform eruptions
Folliculitis

60
Q

What haematological adverse effects are seen with lithium?

A

Leukocytosis (may be therapeutic effect in leukopaenic patients)

61
Q

What pregnancy-related adverse effects are seen with lithium?

A

Increased renal clearance during pregnancy which resolves immediately post delivery: risk of postpartum toxicity
Can cause toxicity in newborns (found in breastmilk): lethargy, cyanosis, poor suck and Moro reflex

ACEM Primary Written (150 decks)

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