Psychiatry: Pharmacology - Antipsychotics and mood stabilisers Flashcards
Define neuroleptic agent
Subtype of antipsychotic that produces high incidence of EPSE at clinically effective doses
Define atypical antipsychotic
Antipsychotic that dissociates antipsychotic actions from EPSEs
Explain the serotonin hypothesis of schizophrenia. What class of drugs supports this hypothesis?
5HT(2A) receptor blockade reduces psychotic symptoms
Main class of atypical antipsychotics (e.g. clozapine, quetiapine) act as inverse agonists at 5HT(2A) receptors
Explain the dopamine hypothesis of schizophrenia. What drugs support this hypothesis?
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
Explain the glutamate hypothesis of schizophrenia. What class of drugs supports this hypothesis?
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
Five structural classes of antipsychotic drugs with an example of each
- Phenothiazines (e.g. chlorpromazine, thioridazine, fluphenazine)
- Thioxanthenes (e.g. thiothexene)
- Butyrophenones (e.g. haloperidol)
- Miscellaneous (e.g. pimozide, molindone)
- Second-generation (atypical; e.g. clozapine, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole)
Adverse effects of phenothiazines
Produces weight gain and sedation
Describe the potency and side effect profile of butyrophenones (e.g. haloperidol)
Tend to be more potent
Fever autonomic effects but more EPSEs
Describe the mechanism of action of atypical antipsychotics
Alter 5HT2A activity more than D2 activity
Most are partial 5HT1A agonists, which produces synergistic effects with 5HT2A antagonism
Five important dopaminergic pathways involved in schizophrenia, and the role of each
- Mesolimb-mesocortical: related to behaviour and psychosis
- Nigrostriatal: coordination of voluntary movement (blockade of D2 receptors in this pathway causes EPSEs)
- Tuberoinfundibular: dopamine release from these neurons inhibits prolactin secretion (causes hyperprolactinaemia when antagonised by antipsychotics)
- Medullary-periventricular: may be involved in eating behaviour
- Incertohypothalamic: regulates anticipatory motivational stage of copulatory behaviour
Describe the mechanism of action of antipsychotics
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
Five examples of antipsychotics which antagonist a2-adrenoceptors
- Risperidone
- Olanzapine
- Quetiapine
- Clozapine
- Aripiprazole
What autonomic adverse effects are seen with antipsychotic use and what are the underlying mechanisms of these?
Muscarinic cholinoceptor blockade: loss of accommodation, dry mouth, difficulty urinating, constipation
a-adrenoceptor blockade: orthostatic hypotension, impotence, failure to ejaculate
What CNS adverse effects are seen with antipsychotic use and what are the underlying mechanisms of these?
Dopamine receptor blockade: Parkinson’s syndrome, akathisia, dystonias
Supersensitivity of dopamine receptors: tardive dyskinesia
Muscarinic blockade: toxic-confusional state
What endocrine adverse effects are seen with antipsychotic use and what are the underlying mechanisms of these?
Dopamine receptor blockade resulting in hyperprolactinaemia: menorrhoea-galactorrhoea, infertility, impotence
What is the mechanism of antipsychotic-associated weight gain?
Possibly combined H1 and 5HT2 blockade
What causes neuroleptic malignant syndrome?
Believed to be related to excessively rapid blockade of postsynaptic dopamine receptors
What is the clinical presentation of neuroleptic malignant syndrome?
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
What is the mortality of neuroleptic malignant syndrome?
> 10%
How is neuroleptic malignant syndrome managed?
Supportive care
Antiparkinsonism drugs to counter EPSEs
Muscle relaxants (e.g. diazepam)
Cooling
After recovery should be switched to an atypical drug
What 7 symptoms are seen in antipsychotic overdose? How commonly is antipsychotic overdose fatal?
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
Describe the general pharmacokinetics of antipsychotics
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
What is the oral bioavailability of chlorpromazine compared with haloperidol? What accounts for this difference?
Chlorpromazine 25%, haloperidol 65% due to lesser degree of first-pass metabolism
How long after last injection do depot antipsychotics continue to produce D2 blockade?
3-6 months
How long after last dose are metabolites of chlorpromazine found in the urine?
Weeks
What is the average time to relapse after discontinuation of antipsychotics in schizophrenia? What medication is the exception to this?
6 months
Exception is clozapine in which relapse occurs rapidly
Describe the differences in receptor affinities between chlorpromazine, haloperidol, clozapine, olanzapine, aripiprazole and quetiapine
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»_space; D1
Quetiapine: H1 > a1 > M1,3 > D2 > 5HT2A
Advantages and disadvantages of chlorpromazine as an antipsychotic
Advantages: generic, cheap
Disadvantages: many adverse effects (especially autonomic)
Advantages and disadvantages of haloperidol as an antipsychotic
Advantages: generic, available IM/IV
Disadvantages: severe EPSE
Advantages and disadvantages of clozapine as an antipsychotic
Advantages: good for treatment resistance, little EPSEs
Disadvantages: risk of agranulocytosis (usually between weeks 6-18 of treatment), lowers seizure threshold
Advantages and disadvantages of risperidone as an antipsychotic
Advantages: broad efficacy, little/no EPSE at low doses
Disadvantages: EPSE and hypotension at high doses
Advantages and disadvantages of olanzapine as an antipsychotic
Advantages: effective against negative and positive symptoms of schizophrenia, little/no EPSE
Disadvantages: weight gain, lowers seizure threshold
Advantages and disadvantages of quetiapine as an antipsychotic
Advantages: similar to olanzapine, less weight gain
Disadvantages: may require high doses if associated hypotension, short t1/2 necessitates twice-daily dosing
Advantages and disadvantages of aripiprazole as an antipsychotic
Advantages: lower weight gain liability, long t1/2, novel mechanism
Disadvantages: uncertain
Mechanism of action of chlorpromazine
Central dopaminergic blockade (D2 receptors)
Also antagonises 5HT, histamine, muscarinic and a-adrenergic receptors
Describe the pharmacokinetics of chlorpromazine
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
Three CNS effects of chlorpromazine
- Neurolepsis
- Anxiolysis
- Sedation
Three CVS effects of chlorpromazine
- Decreased contractility
- Decreased TPR (due to a-blockade): postural hypotension with reflex tachycardia
- May produce ECG changes including prolonged PR and QT intervals
Two respiratory system effects of chlorpromazine
- Respiratory depression
- Decreased upper respiratory tract secretions
GIT effect of chlorpromazine
Increased appetite (may cause weight gain)
Three GUT effects of chlorpromazine
- Weak diuretic
- Impaired ejaculation*
- Urinary retention*
*anticholinergic effect
Five metabolic effects of chlorpromazine
- Poor temperature regulation
- Increased prolactin secretion
- Decreased ACTH release
- Decreased ADH release
- May release insulin
Three toxic effects of chlorpromazine
- EPSE (including NMS)
- Anticholinergic effects
- Allergic phenomena
Four clinical applications of chlorpromazine
- Schizophrenia and related psychoses
- Agitation
- Nausea and vomiting (especially in terminal illness)
- Intractable hiccup
Mechanism of action of haloperidol
Central dopaminergic blockade via D2 receptors
Post-synaptic GABA antagonism
Describe the structure of lithium
Small monovalent cation (Li+)
Five proposed mechanisms of action of lithium
- 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)
- Substitute for Na+ in action potentials
- Decreased NA-sensitive adenylyl cyclase activity
- G protein uncoupling
- 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
What is the clinical significance of lithium’s uncoupling effect on GPCR in terms of its adverse effects?
Likely responsible for nephrogenic diabetes insipidus (via action on vasopressin receptor) and subclinical hypothyroidism (via action on TSH receptor)
Describe the pharmacokinetics of lithium
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
What is the target concentration of lithium? What is the typical dosage?
Target concentration: 0.6-1.4mEq/L
Dosage: 0.5mEq/kg/day in divided doses
At what level is lithium toxicity typically seen?
> 2mmol/L
What effect do diuretics have on renal clearance of lithium? What other drugs also have this effect?
Reduced renal clearance by 25% (dose should be reduced by similar amount)
Similar effect with newer NSAIDs
How do neuroleptics interact with lithium when co-administered? What are the exceptions?
Increased incidence of EPSE
Except with clozapine and newer atypicals
Seven CNS adverse effects of lithium
Tremor
Choreoathetosis
Motor hyperactivity
Ataxia
Dysarthria
Aphasia
Confusion
How is tremor caused by lithium treated?
Propranol or atenolol
What effect does lithium have on thyroid function?
Decreases but rarely causes frank hyperthyroidism
Changes in thyroid function are reversible and non-progressive
Three renal adverse effects of lithium
- Nephrogenic diabetes insipidus: polyuria, polydipsia
- Chronic interstitial nephritis
- Minimal change glomerulopathy with nephrotic syndrome
What cardiovascular side effect is caused by lithium? In what condition is lithium absolutely contraindicated for this reason?
SA node suppression
Absolutely contraindicated in sick sinus syndrome
What dermatological adverse effects are seen with lithium?
Transient acneiform eruptions
Folliculitis
What haematological adverse effects are seen with lithium?
Leukocytosis (may be therapeutic effect in leukopaenic patients)
What pregnancy-related adverse effects are seen with lithium?
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
