Introduction to Typical Antipsychotic Drugs

“Typical” antipsychotic drugs are also known as first-generation antipsychotics. They were first developed in the 1950s to treat psychosis but have since gone on to treat conditions such as mania, agitation, bipolar disorder and as antiemetic drugs.

Typical antipsychotic drugs differ from later, atypical psychotics, in that the latter were thought to cause extrapyramidal side effects to a lesser degree.

Extrapyramidal side effects include:

  • Dystonia – muscle spasms
  • Akathisia – restlessness
  • Parkinsonism – tremors
  • Tardive dyskinesia – involuntary, repetitive movements

Recent research suggests that the two generations are more similar than previous thought. Atypical antipsychotics also cause extrapyramidal effects, more than it was originally thought they would. For this reason, many figures argue that the two generations should be done away with.

Even though atypical antipsychotics are less likely to cause extrapyramidal effects, they also come with their own downsides. For example – they are considerably more likely to cause weight gain and type 2 diabetes. In this regard, the distinction between both generations has become somewhat blurred in recent years.

Examples of typical antipsychotic drugs include:

  • Haloperidol
  • Droperidol
  • Chlorpromazine
  • Prochlorperazine
  • Pimozide

Haloperidol and droperidol belong to the butyrophenone class. Both chlorpromazine and prochlorperazine belong to the phenothiazine class. Pimozide belongs to the diphenylbutylpiperidine class.

Mechanism of action

Typical antipsychotic drugs work by blocking dopaminergic receptors.

More specifically, they are antagonists at dopamine, D2 receptors. Through antagonism of this receptor in the nigrostriatal pathway, extrapyramidal side effects manifest.

Antipsychotic effects are likely to result from D2 receptor antagonism in the mesolimbic/mesocortical pathway – the pathway that connects the midbrain to the limbic system.

D2 receptors are sited throughout the brain though. For example – they are also found in the chemoreceptor trigger zone (CTZ), which helps to explain their antiemetic properties.

Side effects

Side effects of typical antipsychotic drugs include extrapyramidal effects – side effects that manifest from D2 blockade in the nitrostriatal pathway:

  • Dystonia – muscle spasms
  • Akathisia – restlessness
  • Parkinsonism – tremors
  • Tardive dyskinesia – involuntary, repetitive movements

Taridive dyskinesia does not occur suddenly. It usually manifests after many months, or even years, of D2 blockade.

Other side effects of typical antipsychotics include:

  • QT prolongation
  • Drowsiness
  • Sedation
  • Hypotension
  • Erectile dysfunction

Anticholinergic-type effects – such as dry mouth, constipation and blurred vision – may also occur, particularly with haloperidol.

Clinical considerations

When we talk about the clinical pharmacology of typical antipsychotic drugs, we need to think about the following factors:

  • That dosage should be reduced in vulnerable populations, such as the elderly.
  • That antipsychotics increase the risk of death in patients with dementia.
  • That they should be avoided in patients with Parkinson’s disease due to their extrapyramidal side effect profile.
  • That antipsychotics should be avoided with other drugs that prolong the QT interval such as amiodarone, quinine, macrolides and SSRIs.
  • That haloperidol decreases the effects of levodopa.
  • That droperidol, chlorpromazine and prochlorperazine are used to treat serious nausea and vomiting. Droperidol is often used for post-operative nausea and vomiting. Prochlorperazine has been used for this purpose as well as chemotherapy induced nausea and vomiting (CIVN), amongst other causes.
  • That typical antipsychotics are linked to the rare, but life-threatening condition of neuroleptic malignant syndrome (NMS).

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