What are the major side effects of phenothiazine antipsychotics?

  • Anti-cholinergic:
    • dry mouth,
    • dry eyes,
    •  urinary retention,
    • constipation;
    • Extra-pyramidal:
      • dystonia,
      • Parkinson-like effects,
      • akathisia,
      • tardive dyskinesia;
      • Hypotension;
      • Neuroleptic malignant syndrome
      • Sedation;
      • Weight gain;

What mechanisms of drug action are responsible for these side effects?

  • Anti-muscarinic;
  • Alpha blockade;
  • D2 antagonism;
  • Serotonin receptor antagonism;
  • Anti-histamine (H1)

How could the extra-pyramidal side effects be managed?

  • Lower dose;
  • Switch to an atypical drug (lower incidence of extra-pyramidal effects);
  •  Administer benztropine or diazepam;
  • No effective treatment for tardive dyskinesia: prevention vital; monitor for early signs and reduce or cease anti-psychotic asap


What are the proposed mechanisms of action of valproate?

  • Blocks Na channels
    • thereby blocking sustained high frequency firing of neurones.
    • Blockade of NMDA receptor mediated excitation.
      • Increase GABA levels

Describe the toxic effects of valproate.

  • Hepatotoxicity,
    • Mostly within 4 months of initiation of treatment,
    • Treat with intravenous L-carnitine.
    • GI,
    • tremor,
    • weight gain, appetite,
    • sedation,
    • allergy
    • Malformations in pregnancy

What interactions does valproate have with other anti-seizure drugs?

  • Phenytoin
    • inhibits metabolism and displaces from plasma proteins
    • Phenobarbitone
      • inhibits metabolism
      • Carbamazapine
        • inhibits metabolism
        • Lamotrigine
          • decreases clearance



What are the pharmacokinetics of tricyclic anti-depressants?

  • Bioavaility = 40-50%,
    • high first pass metabolism
    • long half-time,
    •  large VOD,
      • high tissue protein binding,
      • high lipid solubility,
      • metabolised in liver, active metabolites

What are the toxic effects of tricyclics in overdose?

  • Sedation
  • Seizures
  • Na channel blocker,
    • arrhythmias
    • Alpha-blocker,
      • hypotension,
      • Psychiatric- psychosis, agitation, withdrawal
      • Sympathomimetic tremor, insomnia,
      • Antimuscarinic
        • blurred vision, constipation, urinary, confusion, tachycardia cardiovascular-
        • Weight gain

What drugs could be used in the treatment of tricyclic toxicity in overdose?

  • Sodium bicarb 50-100 mEq IV
  • Dopamine/NA for hypotension


Describe the pharmacokinetics of Lithium.

  • Absorption;
    • rapid and near complete.
    • peak levels in 30-120min
    • Distribution;
      • total body water Vol.D 0.5 to 0.9L/kg
      • Slow distribution into and out of CNS.
      • T 1/2; @20 hours.
      • Metabolism = none
      • Elimination = renal excretion

What are some of the drug interactions with lithium?

  • Thiazide diuretics- 25% reduction in lithium clearance
  • Newer NSAID’s – similar reductions in clearance
  • Neuroleptics (except clozapine) and antipsychotics-
    • enhancement of extrapyramidal syndromes

What are some of the side effects of lithium?

  • Neurological;
    • tremor, confusion, ataxia, dysarthria, new psychiatric symptoms
    • Hypothyroidism
    • Nephrogenic diabetes insipidis

– loss of responsiveness to ADH.

  • Oedema
  • Skin reactions; acneiform eruptions


Name some antiemetics used in the Emergency Department.

  • Ondansetron (or Granisetron or Tropisetron)
  • Metoclopramide
  • Prochlorperazine
  • Chlorpromazine.
  • Droperidol
  • Diphenhydramine (or other antihistamines).
  • Meclizine.
  • Hyoscine.
  • Benzodiazepines.


Compare the mechanisms of action of ondansetron and metoclopramide.

  • Act at different receptors:
    • Ondansetron:
      • Peripheral 5HT3 blockade (vagal and spinal afferents, Reduces sensory visceral output)
      • Central 5HT3 blockade (vomiting centre and CTZ)
      • Metoclopramide:
        • D2 blockade (CTZ). Increases oesophageal motility. Increases LOS pressure. Increase gastric emptying

Describe the potential adverse effects of metoclopramide.

  • CNS:
    • Restlessness,
    • drowsiness,
    • insomnia,
    • anxiety,
    • agitation – common (20%), esp. elderly
    • Extrapyramidal effects:
      • acute dystonia,
      • akathisia,
      • parkinsonian effects – more likely with higher doses
      • Tardive dyskinesia with chronic dosing

Pass Criteria: Bold


List the drug classes which are used in management of acute agitation in the ED.

  • Benzodiazepenes
    • Midazolam
    • Diazepam
    • Antipsychotics –
      • Phenothiazines eg chlorpromazine
      • Butyrophenones eg haloperiodol, droperidol
      • Atypicals
        • olanzapine ,
        • risperadone
        • Barbiturates –
          • phenobarbital

What is the predominant mechanism of action of the atypical antipsychotics.

  • Serotonin (5HT2A) receptor antagonism
  • Dopamine (D2) receptor antagonism (weaker effect)

Describe adverse effects of the atypical antipsychotics.

  • Extrapyramidal reactions(less common than with older typical antipsychotics)
    • Tardive dyskinesia
    • Antimuscarinic effects – dry mouth, urinary retention etc Orthostatic hypotension
      • Weight gain
      • Hyperglycemia
      • Hyperprolactinemia
      • Agranulocytosis ( clozapine)
      • Neuroleptic malignant syndrome


Outline the clinical uses of carbamazepine.

  • Anticonvulsant; partial and generalised tonic-clonic seizures
  • Treatment of bipolar mood disorder
  • Trigeminal neuralgia

Describe the mechanism of its anticonvulsant activity.

  • Blocks sodium channels Inhibits high-frequency repetitive firing of neurons
  • Presynaptic blocker of synaptic transmission

Outline some of the side effects of carbamazepine.

  • Ataxia and diplopia,
  • Sedation
  • GI upsets and hepatic dysfunction
  • Erythematous skin rash
  • Hyponatraemia and water intoxication
    • Blood dyscrasias, including leukopenia common), and rarely aplastic anaemia and agranulocytosis.

Can you name some drug interactions involving carbamazepine?

  • Enzyme induction (all anticonvulsants including itself).
  • Valproic acid + phenytoin may inhibit carbamazepine elimination


Why is levodopa used in combination with carbidopa?

Carbidopa is a peripheral dopa decarboxylase inhibitor. Because it doesn’t penetrate the blood brain barrier, it reduces the peripheral metabolism of levodopa -> increased levodopa levels, increased half-life resulting in more dopa being available for entry into brain to exert its effects.

What are the adverse affects of levodopa?

GIT: Anorexia, nausea and vomiting in up to 80% of patients. Due to stimulation of emetic centre in brainstem.

Incidence decreased to < 20% if a peripheral decarboxylase inhibitor is added.

CVS: Arrhythmias-tachycardia, ventricular ectopics, AF. Due to increased catecholamine formation peripherally.

Postural hypotension

Dyskinesias: Up to 80% of those receiving levodopa for long periods.

Behavioural effects: Depression, anxiety, agitation, insomnia, nightmares, euphoria and mood changes. More common if taking a levodopa with a decarboxylase inhibitor. Due to higher levels presenting to the brain.

Fluctuations in clinical response occurs with increasing frequency as treatment continues.

Miscellaneous: Mydriasis, acute glaucoma, Coombs positive haemolytic anaemia, gout, abnormalities of taste and smell,

Brownish discolouration of saliva, urine or vaginal secretions, priapism, abn urea, LFTs.

Drug Interactions: Pyridoxine enhances metabolism of levodopa. Hence effect decreased.

3 systems to pass


What are the advantages of olanzapine over the older antipsychotics?
Prompt with: How does Olanzapine compare with haloperidol in terms of sedation, hypotensive effect and extrapyramidal toxicity? 2 out of 3, prompts allowed.

Can be given as tablet, wafer or injection (widerLess unwanted dopamine effects, eg tardive dyskinesia, NMSDrug            Usual   Sedation   Postural        AntichoHne     Extrapyrami   Weightdaily                     hypotension rgic                 dal                 gainoraldose range(mg)
haloperidol   1-7.5     +               +                   +                     +++                 ++ 
Otanzapine     5-20    +++           +                         ++                   +                            ÷++
Like clozapine, olanzapine has a wide range of receptor affinities. It is relatively well tolerated but drowsiness and dizziness can occur. Excessive weight gain may precipitate type 2 diabetes.
Transient elevation of liver enzymes has been associated with olanzapine, but this does not appear to be of clinical significance.


What are the clinical conditions Olanzapine is prescribed for?

Wide Spectrum of use:

Autism spectrum disorders. Behavioural emergencies

Delirium: mood and behavioural disturbances; palliative care; AIDS

Dementia: General; Sleep disorder in patients with dementia (palliative care)

Acute treatment of mania: Olanzapine


2 of list


Describe the mechanism by which Serotonin Syndrome occurs.
Prompt: What receptors are involved in SS?

Excessive stimulation of serotonin receptors in the CNS due to overdose of single drug or concurrent use of several drugs. Predictable, not idiosyncratic.

Pass: Must get bold items

How do drugs cause excessive stimulation of serotonin receptors?

Prompt: Can you give an example

Inhibition of serotonin metabolism: meclobemide, amphetamines

Prevention of serotonin reuptake in nerve terminals: fluoxetine, paroxetine, sertraline, venlafaxine, tramadol, TCA

Serotonin release or increased intake of serotonin precursors: tryptophan, lithium,

Pass: Must identify at least 1 mechanisms with corresponding example

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