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[Pharmacology](https://durgical.com/en/pharmacology/) · Class

# First-generation antipsychotics

The older «typical» antipsychotics: they block dopamine D2 receptors, calm psychosis and often cause movement side effects.

Updated 2026-11-01

## What they are

Antipsychotics developed from the 1950s on (phenothiazines such as chlorpromazine and fluphenazine, butyrophenones such as haloperidol). They are grouped by potency: high-potency drugs cause more extrapyramidal effects; low-potency drugs cause more sedation, hypotension and anticholinergic effects.

## Mechanism of action

They block D2 receptors. In the mesolimbic pathway this reduces positive symptoms (hallucinations, delusions). The same blockade in the nigrostriatal pathway causes extrapyramidal effects, and in the tuberoinfundibular pathway it raises prolactin. Many also block H1, α1 and muscarinic receptors, which explains sedation, orthostatic hypotension and dry mouth.

Target: Dopamine D2 receptor

## Key points

- Extrapyramidal effects follow a rough timeline: acute dystonia (hours to days), akathisia and parkinsonism (days to weeks), tardive dyskinesia (months to years).
- Acute dystonia responds to an anticholinergic (benztropine) or diphenhydramine; akathisia often responds to propranolol; anticholinergics worsen tardive dyskinesia, which is treated with VMAT2 inhibitors (valbenazine, deutetrabenazine).
- Neuroleptic malignant syndrome: fever, rigidity, altered mental status and autonomic instability, with high creatine kinase. The antipsychotic is stopped at once; care is supportive, with dantrolene or bromocriptine in some cases.
- Several prolong the QT interval (thioridazine most, and intravenous haloperidol); low potassium and magnesium add to the risk.
- All antipsychotics carry a warning of higher mortality in older people with dementia-related psychosis.

## Drugs in this class

- [**Haloperidol** A high-potency classic antipsychotic that strongly blocks dopamine D2 receptors. Used for psychosis, agitation and… Dopamine D2 receptor](https://durgical.com/en/pharmacology/haloperidol/)
- [**Chlorpromazine** The first antipsychotic, a low-potency phenothiazine: very sedating, lowers blood pressure, also controls nausea and… Dopamine D2 receptor](https://durgical.com/en/pharmacology/chlorpromazine/)

## Others in the class

- Fluphenazine
- Perphenazine
- Thioridazine
- Levomepromazine
- Zuclopenthixol
- Pimozide

## Test yourself

Think of the answer, then tap the question to see it.

## Why do high-potency first-generation antipsychotics cause more extrapyramidal effects than low-potency ones?

They block striatal D2 receptors strongly and have little anticholinergic action; low-potency drugs block muscarinic receptors, which partly offsets the movement effects.

## Which dopamine pathway explains galactorrhoea and amenorrhoea with antipsychotics?

The tuberoinfundibular pathway: dopamine normally inhibits prolactin release, so D2 blockade raises prolactin.

## A patient on haloperidol has fever, rigidity, confusion and labile blood pressure. What is suspected and what is the first step?

Neuroleptic malignant syndrome; the antipsychotic is stopped immediately and supportive care is started.

## Why are anticholinergics avoided in tardive dyskinesia?

They can worsen it; tardive dyskinesia is linked to supersensitive D2 receptors and is treated with VMAT2 inhibitors.

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Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: [DailyMed - HALOPERIDOL tablet](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=31e33656-2f53-49e6-9816-261ea2e6961a) (DailyMed (U.S. National Library of Medicine), 2026); [DailyMed - CHLORPROMAZINE HYDROCHLORIDE tablet, film coated](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2bd42d3a-bf89-4d74-a252-9b914106a570) (DailyMed (U.S. National Library of Medicine), 2026); Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th ed., ch. 19 (McGraw Hill, 2023).

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