First-Generation Antipsychotics

Antipsychotics, also called neuroleptics, are used to treat psychotic disorders and alleviate agitation, mania, and aggression. Antipsychotics are notable for their use in treating schizophrenia and bipolar disorder and are divided into 1st-generation antipsychotics (FGAs) and atypical or 2nd-generation antipsychotics. Drugs from both classes act on dopamine receptors. Notable side effects from antipsychotic agents include movement disorders, dose-related sedation, and metabolic syndrome. A serious long-term side effect to be cautious of is tardive dyskinesia, which is characterized by repetitive involuntary movements.

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Chemistry and Pharmacodynamics

Neurotransmitters that may be modulated by antipsychotics for a therapeutic effect include dopamine, serotonin (also called 5-hydroxytryptamine (5-HT)), and norepinephrine (NE).

Mechanism of action

  • Blockade of postsynaptic dopamine D2 receptors in the mesolimbic pathway → relief of psychotic symptoms
  • Blockade in mesocortical, nigrostriatal, and tuberoinfundibular pathways → adverse effects
  • Low-potency agents have a greater affinity for:
    • Alpha-adrenergic receptors
    • Histaminergic receptors
    • Muscarinic receptors

Physiologic effects

  • Dopaminergic receptors:
    • Subtypes D1 and D2 are pharmacologic targets.
    • D1-like receptors are excitatory.
    • D2-like receptors are inhibitory.
    • D2 receptors are expressed on dopaminergic neurons as presynaptic and postsynaptic receptors.
  • Dopamine hypothesis of schizophrenia:
    • Dopamine hyperfunction in the striatum (mesolimbic tract) → “positive symptoms”; 1st-generation antipsychotics (FGAs) reduce:
      • Delusions
      • Hallucinations
      • Paranoia
      • Mania
      • Aggressiveness
    • Dopamine hypofunction in the prefrontal cortex (mesocortical tract) → negative and cognitive symptoms:
      • Blunted affect, anhedonia, avolition, social withdrawal
      • Impairment of attention, working memory, and executive function
    • High doses of psychostimulants can cause psychosis.
  • Effects of increasing dopamine in the other 2 dopaminergic tracts in the brain:
    • In the nigrostriatal tract: improves extrapyramidal function such as symptoms of Parkinson’s disease
    • In the chemoreceptor zone (vomiting center of the brain): anorexia, nausea/vomiting
  • Serotonergic (5-HT) receptors:
    • Major serotonin-producing neurons are located in the raphe nuclei in the brainstem.
    • 5-HT is synthesized in serotonergic nerve terminals:
      • Upon the propagation of an action potential down the neuron → storage vesicles fuse with the presynaptic membrane → release neurotransmitters into the synaptic cleft 
      • 5-HT activity is terminated by the serotonin transporter → reuptake of 5-HT into the serotonergic nerve terminal
      • 5-HT can then be reloaded into vesicles or metabolized on the outer mitochondrial membrane in nerve terminals.
  • Serotonin hypothesis of schizophrenia: Hyperactivation of cortical 5-HT2A receptors on glutamatergic pyramidal neurons → ↑ glutamate release in the ventral tegmental area (VTA) → overactivation of the mesolimbic pathway → ↑ dopamine release in the striatum

Pharmacokinetics and Classification

Pharmacokinetics

There are numerous medications with unique pharmacokinetics.

  • FGAs act at the D2 receptor.
  • Well absorbed:
    • Cross the blood-brain barrier easily
    • Have long half-lives:
      • Half-lives of orally administered drugs vary from 2 hours (chlorpromazine) to 55 hours (pimozide).
      • IM dosing of some FGAs (e.g., the half-life of IM haloperidol decanoate is 3 weeks; dosed monthly)
    • Cytochrome P450 (CYP) inhibitors will prolong the action of FGAs:
      • Different FGAs use any or all of the CYP2D6, 3A4, and 1A2 pathways.
      • Other medications that are substrates for these pathways may cause overdose symptoms.
  • FGAs need 1–2 weeks for full effect.
  • All FGAs except haloperidol block the H1 histamine receptor.
  • Highly lipid-soluble compounds, some of which can be used as a long-acting injection (every 2–4 weeks)
  • Elimination: excreted in the urine and feces

Classification

The FGAs can be classified based on their potency:

  • High-potency FGAs:
    • Low activity at the histaminic and muscarinic receptors
    • Minimally associated with the following adverse effects:
      • Sedation
      • Weight gain
      • Anticholinergic activity
    • High risk for extrapyramidal side effects (EPS) with all of the high-potency FGAs:
      • Dystonia
      • Bradykinesia
      • Akathisia
    • Examples:
      • Fluphenazine (Prolixin)
      • Haloperidol (Haldol)
      • Loxapine (Loxitane)
      • Perphenazine (generic)
      • Pimozide (Orap)
      • Thiothixene (Navane)
      • Trifluoperazine (Stelazine)
  • Low-potency FGAs:
    • Lower affinity for dopamine receptors; thus, higher doses are needed
    • Higher incidence of anticholinergic and antihistamine side effects
    • Lower incidence of EPS and neuroleptic malignant syndrome (NMS)
    • Examples:
      • Chlorpromazine (Thorazine)
      • Thioridazine (formerly Mellaril, the branded product was withdrawn worldwide in 2005 because it caused severe cardiac arrhythmias. However, generic versions are still available in the US.)

Indications

  • Conditions treated using high-potency antipsychotics: 
    • Schizophrenia:
      • Reduces the “positive” symptoms (e.g., delusions, aggressiveness)
      • FGAs have few effects on the “negative” symptoms (e.g., anhedonia, social withdrawal).
      • 2nd-generation antipsychotics: more effective at reducing neurocognitive impairment
    • Psychosis
    • Mania associated with bipolar disorder:
      • Used in conjunction with mood stabilizers (e.g., lithium, valproic acid, and lamotrigine)
      • FGAs act rapidly → antimanic effect (mood stabilizers have a latency period before they take effect)
    • Tic disorder (Tourette syndrome)
    • Treatment-resistant depression: adjuvant therapy in combination with an antidepressant
    • Dementia:
      • Used cautiously in individuals with severe dementia
      • Used in individuals who are aggressive or pose danger to themselves or others
  • Low-potency antipsychotics: chlorpromazine (Thorazine)
    • Used for the same conditions listed above
      • Used to relieve prolonged hiccups
      • Used to treat severe behavioral problems in children
    • Reduces aggressive behavior, hallucinations, suicidal/homicidal thoughts

Adverse Effects

The adverse effects of FGAs are due to dopamine blockade.

  • Low-potency FGAs (chlorpromazine and thioridazine) can cause:
    • Sedation
    • Hypotension
    • Anticholinergic side effects:
      • Dry mouth
      • Dizziness
      • Blurred vision
      • Tachycardia
      • Delirium
      • Hallucinations
  • High-potency FGAs have a high risk of EPS:
    • Acute dystonia: prolonged tonic muscle spasms of rapid onset upon initiating (1st 4 days) or increasing the dose of antipsychotics
    • Bradykinesia (Parkinsonian symptom)
    • Akathisia (feeling of restlessness)
    • Perphenazine (generic): associated with a lower rate of extrapyramidal symptoms than that with high-potency FGA haloperidol; comparable with risperidone
  • Weight gain
  • Elevated liver enzymes
  • Ophthalmologic problems:
    • Retinitis pigmentosa (rare)
    • Worsened glaucoma
  • “Anti-HAM” symptoms:
    • H: Anti-Histamine symptoms:
      • Sedation
      • Seizures
      • Dizziness
      • Dry mouth
    • A: Anti-Alpha-adrenergic symptoms:
      • Orthostatic hypotension
      • Arrhythmias
      • Sexual dysfunction
    • M: Anti-Muscarinic symptoms:
      • Dry mouth
      • Tachycardia
      • Urinary retention
      • Blurred vision
      • Constipation
  • Tardive dyskinesia:
    • Due to postsynaptic dopamine receptor hypersensitivity
    • May take years or decades to appear
    • Usually permanent and distressing to affected individuals
    • Manifestations:
      • Abnormal, involuntary, hyperkinetic movements
      • Usually affects the mouth and tongue, but can also affect the trunk
      • Irreversible facial disfiguration
  • NMS:
    • Life-threatening reaction to FGAs
    • Causes hyperthermia (very high fever)
    • Other symptoms:
      • Confusion
      • Muscle rigidity
      • Diaphoresis
      • Tachycardia
  • Hyperprolactinemia (and galactorrhea in both women and men)

Drug-Drug Interactions and Contraindications

Drug-drug interactions

  • Antacids ↓ absorption of fluphenazine and trifluoperazine
  • Avoid the use of FGAs with all QT-prolonging agents.
  • CYP3A4 inducers interact with pimozide:
    • Carbamazepine
    • Drug-food interaction with grapefruit juice
  • CYP1A2 inhibitors interact with thiothixene and trifluoperazine.
  • CYP2D6 inhibitors interact with perphenazine and chlorpromazine:
    • Fluoxetine
    • Paroxetine
    • Bupropion

Contraindications

  • Beers list: a list of potentially inappropriate medications for use in the elderly
    • Originally published in 1991 and updated regularly
    • All antipsychotics are listed in the Beers list.
  • General black-box warning: All antipsychotics increase the risk of death in older individuals with dementia-related psychosis.
  • CNS:
    • Individuals who are in a coma or with CNS depression
    • Concomitant high-dose hypnotics
    • Parkinson’s disease
  • Cardiovascular:
    • Arrhythmias
    • Congenital long QT syndrome
  • Hematologic:
    • Blood dyscrasias
    • Bone marrow depression

References

  1. Meyer, J.M. (2018). Pharmacotherapy of Psychosis and Mania. In Brunton, L.L., Hilal-Dandan, R., Knollmann, B.C. (Eds.) Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13e. New York, NY: McGraw-Hill. 
  2. Nelson, L.S., et al. (2019). Neurotransmitters and Neuromodulators. In Goldfrank’s Toxicologic Emergencies, 11e. New York, NY: McGraw-Hill.
  3. Schatzberg, A.F., DeBattista, C. (2019). Schatzberg’s Manual of Clinical Psychopharmacology, 9e. Washington, DC: American Psychiatric Association Publishing.
  4. Kaar, S.J., et al. (2020). Antipsychotics: Mechanisms underlying clinical response and side effects and novel treatment approaches based on pathophysiology. Neuropharmacology. 172, 107704. https://doi.org/10.1016/j.neuropharm.2019.107704 
  5. Mandrioli, R., et al. (2015). Evaluation of the pharmacokinetics, safety, and clinical efficacy of ziprasidone for the treatment of schizophrenia and bipolar disorder. Expert Opinion on Drug Metabolism and Toxicology. 11, 149–174. https://doi.org/10.1517/17425255.2015.991713 
  6. Citrome, L. (2015). The ABCs of dopamine receptor partial agonists — aripiprazole, brexpiprazole, and cariprazine: the 15-min challenge to sort these agents out. The International Journal of Clinical Practice. 69, 1211–1220. https://doi.org/10.1111/ijcp.12752 
  7. American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Arlington, VA, American Psychiatric Association.
  8. Hasin, D.S., et al. (2005). Epidemiology of major depressive disorder: Results from the national epidemiologic survey on alcoholism and related conditions. Archives of General Psychiatry. 62, 1097–1106. https://doi.org/10.1001/archpsyc.62.10.1097 
  9. American Geriatrics Society. (2019). 2019 Updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults. Journal of the American Geriatric Society. 67, 674–694. https://doi.org/10.1111/jgs.15767 
  10. Jibson, M.D. (2020). First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects. UpToDate. Retrieved August 13, 2021, from https://www.uptodate.com/contents/first-generation-antipsychotic-medications-pharmacology-administration-and-comparative-side-effects
  11. Lexicomp, Inc. (2021). Pimozide: Drug information. UpToDate. Retrieved August 14, 2021, from https://www.uptodate.com/contents/pimozide-drug-information

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