First-Generation Antipsychotics

In this article, we’ll describe “First-Generation Antipsychotics”, classification of antipsychotics, first-generation antipsychotics, effects of first-generation antipsychotics on the four dopamine pathways, side-effects and adverse drug reactions, drug interactions and withdrawal symptoms.


Psychotropic drugs are the drugs that have primary effects on the psyche (mental processes) and are generally used in order to treat psychiatric disorders.

These include drugs such as Chlorpromazine, Haloperidol, Fluphenazine, etc. 

Antipsychotic drugs have a salutary therapeutic effect on psychosis. Antipsychotics are also known as neuroleptics and are a class of medication that is used to manage psychosis (including delusions, hallucinations, paranoia or thought disorders), which majorly have been seen in schizophrenia and bipolar disorder.

Antipsychotics are usually effective in relieving symptoms of psychosis in the short term.

What is psychosis?

Psychosis is known as the severe psychiatric Illness with serious distortion of thought, behavior, capacity to recognize reality and of perception (delusions and hallucinations). 

The patient suffers from the extreme conditions of the misperception and misevaluation, the patient is unable to meet the ordinary demands of life and even are incapable of doing activities of daily living.

Symptoms of psychosis-

People may experience –

Behavioral: disorganized behavior, aggression, agitation, hostility, hyperactivity, hypervigilance, nonsense word repetition, repetitive movements, restlessness, self-harm, social isolation, lack of restraint, or persistent repetition of words or actions, etc.

Cognitive: thought disorder, confusion, belief that an ordinary event has a special and personal meaning, belief that thoughts aren’t one’s own, disorientation, memory loss, racing thoughts, slowness in activity, thoughts of suicide, unwanted thoughts, difficulty thinking, and understanding, or false belief of superiority, etc.

Mood: anger, anxiety, apathy, excitement, feeling detached from self, general discontent, limited range of emotions, loneliness, or nervousness, etc.

Psychological: fear, hearing voices, depression, manic episodes, paranoia, persecutory delusion, religious delusion, or visual hallucinations, etc.

Speech: deficiency of speech, excessive wordiness, incoherent speech, or rapid and frenzied speaking, etc.


Antipsychotic drugs are classified into-

  • Typical (First-generation antipsychotics) 
  • Atypical (Second-generation antipsychotics) 

First-generation antipsychotics include-

  1. Phenothiazines- (Chlorpromazine, trifluoperazine, perphenazine, prochlorperazine, acetophenazine, triflupromazine, mesoridazine),
  2. Butyrophenones- (haloperidol,penfluridol, trifluperidol)
  3. Thioxanthenes – (flupenthixol, thiothixene, chlorprothixene)
  4. Other heterocyclics- (loxapine, pimozide).

Second-generation antipsychotics include-

  1. risperidone,
  2. olanzapine, 
  3. quetiapine, 
  4. ziprasidone, 
  5. aripiprazole, 
  6. paliperidone, 
  7. asenapine, 
  8. lurasidone,
  9. iloperidone, 
  10. cariprazine, 
  11. brexpiprazole, 
  12. clozapine.


Mechanism of action:

First-generation antipsychotics are dopamine receptor antagonists (DRA).

Dopamine was discovered and categorized as a neurotransmitter in the late 1950s.

There are five pathways, or systems, of dopaminergic receptors in the central nervous system. 

These systems or pathways include:

  • Mesolimbic-mesocortical pathway
  • Nigrostriatal pathway
  • Medullary-periventricular pathway
  • Incertohypothalamic pathway
  • Tuberoinfundibular pathway

These pathways affect thinking, cognitive behavior, learning, sexual and pleasure feelings, and the coordination of voluntary movement.

Extra firing (production of this neurotransmitter) of dopamine in these pathways produces many of the symptoms of schizophrenia.

According to the dopamine theory of schizophrenia, positive symptoms are the result of overactivity in the mesolimbic dopamine pathway.

This is in part based on the observation that drugs that increase dopaminergic availability (L-DOPA, amphetamines) can trigger psychotomimetic effects in individuals not affected by schizophrenia.

As a result, they reduce dopaminergic neurotransmission in the four dopamine pathways.


Mesocortical pathway:

The pathophysiology of schizophrenia suggests that if there is dysfunction in this pathway then it may lead to cognitive impairments and sudden disturbances in emotions and affect would be prominent, these symptoms also known as negative symptoms in schizophrenia.

The blockade of the mesocortical pathway by high doses of first-generation antipsychotics can start and increase secondary negative symptoms and cognitive effects as well

Mesolimbic pathway: 

Overactivity in this pathway is said to be responsible for the positive symptoms of schizophrenia.

The blockade of D2 receptors in the mesolimbic pathway has been the reason for the possible mechanism of antipsychotic action of first-generation agents.

Nigrostriatal pathway: 

Antagonism of D2 receptors in the nigrostriatal pathway is responsible for the increase in the risk of extrapyramidal symptoms.

Tuberoinfundibular pathway: 

Dopamine acts as a prolactin-inhibiting factor, D2 blockade increases prolactin levels by promoting its release in the pituitary gland.


People who take first-generation antipsychotic medications may experience negative side effects, such as:

Extrapyramidal Effects: 

Dystonias, akathisia, tardive dyskinesia, Parkinson’s-like symptoms, unwanted movements, ataxia, muscle breakdown, rigidity, tremors, and seizures are some major effects of this category of drugs.

The neuroleptic malignant syndrome may occur as well.

Effects on the Central Nervous System: 

Drowsiness, sedation, and hypnosis occur.

Confusion, vertigo, syncope, disturbed sleep, nightmares, and agitation are also reported by various studies.

Dementia, amnesia, and loss of memory are some adverse effects.

Suicidal ideation in old and young people with increased mania, anxiety, agitation, violent behavior, and depression can also be seen in people taking these drugs.

Effects on the Cardiovascular System: 

Cardiomyopathy is noted in nine out of every 100,000 people using clozapine.

Alteration in electrocardiogram (ECG) readings, chest pain, angina, myocarditis, palpitation, tachycardia, edema, phlebitis, and arrhythmias are serious adverse effects.

Myocardial infarction (heart attack) occurs in only 1% of people using this category of drug.

Orthostatic hypotension—the medical name for the fuzzy feeling you get when standing up to quickly—is very common.

Hepatic (Liver) Effects: 

These agents increase the serum concentration of alkaline aminotransferase.

Reversible liver cell hyperplasia, increase in bilirubin, jaundice, drug-induced hepatitis, and necrosis have been recorded in studies.

Gastrointestinal Effects: Constipation, dry mouth, anorexia, weight gain, increases in pancreatic enzymes, epigastric distress, abdominal cramps, dyspepsia, heartburn, and nausea are some common adverse effects.

Genitourinary (Urinary and Reproductive) Effects: Impotence, delayed and premature discharge, testicular swelling, priapism, increased or decreased libido, virginal itching, enuresis, polyuria, breast engorgement, galactorrhea, and anorgasmia have been reported.

Other Effects: 

Cases of blurred vision, hot flashes, dry throat, nasal congestion, severe hyperglycemia, numbness, chills, glaucoma, leukopenia, neutropenia, hyperlipidemia, agranulocytosis, and respiratory depression have been reported.

Pregnancy and Lactation: 

Antipsychotic drugs can be used in pregnant females since they have shown no teratogenic (development of the fetus or embryo) effects in animal studies.

Drugs like clozapine and olanzapine have shown no harm to the fetus.

However, during lactation, the metabolites may be disturbed in the milk and could harm the newborn.


First-Generation Antipsychotics cannot be used with the following substances:

  • Anti-anxiety drugs and other central nervous system depressants
  • Antidepressants
  • Hypotensive agents
  • Anticholinergic agents
  • Anticoagulants
  • Levodopa
  • Carbidopa
  • Alcohol
  • Valproic acid
  • Lithium
  • Drugs affecting seizure threshold
  • Smoking


Withdrawal from first-generation antipsychotics should be slow and gradual.

A period of at least 15–30 days should be considered for this purpose.

Nausea, vomiting, psychotic symptoms, hypertension, and sleep disturbances might come back if the sudden discontinuation of therapy occurs.


In this blog, we’ve described “First-Generation Antipsychotics”, classification of antipsychotics, first-generation antipsychotics, effects of first-generation antipsychotics on the four dopamine pathways, side-effects and adverse drug reactions, drug interactions and withdrawal symptoms.

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Essentials of pharmacology- KD Tripathi

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