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Used for tx of SZ and for the tx of psychotic sx in manic states, major depression, dementia, delirium, and drug-induced psychoses
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Antipsychotic Drug Groups:
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➤ 1st generation antipsychotic agents (Typical)
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➤ 2nd generation (Atypical)
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Low Potency
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Chlorpromazine (1st antipsychotic discovered)
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Thioridazine
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Medium Potency
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Loxapine
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Perphenazine
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High Potency
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Haloperidol
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Droperidol
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Fluphenazine
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Pimozide
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Very 1st antipsychotic drug discovered
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Prototypic, low-potency drug (now, rarely used as an antipsychotic agent)
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Has Low affinity for D2 receptors
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Main Side Effects: orthostatic hypotension (alpha 1 receptor blockade), sedation (H1), and weight gain (H1 and 5-HT-2A)
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LOW incidence of EPS (low affinity for D2)
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Dermatological reactions (urticaria and photosensitivity resembling sunburn) and LFT abnormalities
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What is a measure of a drug's affinity for a receptor?
Ki - determined experimentally and is a measure of the affinity for a drug for a receptor (a measure of strength of the drug-receptor interaction)
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The lower the Ki value, the ________ (lower or higher) the affinity of the antagonist for the receptor.
Higher - On Exam: Ki values will be provided and we'll need to be able to determine the affinity of the antagonist for the receptor
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Prototypic high-potency antipsychotic agent
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High affinity for D2 receptors
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Side Effects: EPS and hyperprolactinemia
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30 to 50% of SZ pt's do NOT respond to these drugs
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Typical antipsychotic drugs improve positive sx, but only marginally improve negative sx and cognitive impairments of Sz
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High incidence of ADRs
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2nd gen (atypical) antipsychotics have been increasingly replacing them as the 1st-line tx of SZ
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Clozapine, Olanzapine, Risperidone, Paliperidone, Ziprasidone, Quetiapine, Iloperidone, Asenapine, Lurasidone
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Aripiprazole, Braxpiprazole, Cariprazine (Considered 3rd gen)
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More effective than 1st gens in treating negative symptoms and improving cognitive functioning
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Currently 1st line (except clozapine) due to fewer side effects than typical agents
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Atypicals have also been associated with a reduction in the incidence of suicide in SZ
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Block 5-HT 2A receptors (functionally, they are 5-HT-2A antagonists)
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Also block D2 receptors ⇨ D2 antagonism is still required to achieve antipsychotic effects
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Also block other receptors (*H1, M1, alpha-1) ⇨ Side effects
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Ziprasidone also inhibits 5-HT and NE uptake
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Chemistry
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Structure-Fxn relationships that were relied upon in the past have become less important
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Instead, receptor-fxn relationships and functional assays are more clinically relevant
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✽ Classification According to Potency ✽
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Low Potency
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Chlorpromazine
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Thioridazine
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Medium Potency
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Loxapine
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Perphenazine
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High Potency
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Haloperidol
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Droperidol
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Fluphenazine
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Pimozide
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✽ MOA ✽
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Block dopamine D2 receptors
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D2 receptor binding affinity (but not D1) strongly correlates with clinical potency of typical antipsychotic agents
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Blockade of postsynaptic D2 receptors
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⇨ Reduction of dopaminergic neurotransmission
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D2 receptor blockade in ALL dopaminergic pathways
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⇨ beneficial in the mesolimbic pathway
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⇨ alleviates positive sx of SZ
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⇨ It doesn't do really anything for the negative or cognitive sx
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Side Effects:
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• D2 receptor blockade in nigrostriatal pathway ⇨ extrapyramidal sx (EPS)
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• D2 receptor blockade in the tuberoinfundibular pathway ⇨ increased prolactin release from the anterior pituitary
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Blocks other receptors:
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5-HT2A blockade
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Contributes to antipsychotic effects
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Other receptor blockade
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Numerous additional side effect
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✽ SIDE EFFECTS ✽
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EPS
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Various movement disorders associated with antipsychotic therapy (occurs mostly with 1st gen)
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Occurs due to D2 receptor blockade in the nigrostriatal pathway
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• Akathisia: uncontrollable motor restlessness
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• Dystonias: muscular spasms of the neck, eyes, and tongue
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• Drug-Induced Parkinson's Syndrome: Resembles Parkinson's Syndrome
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• Tardive Dyskinesia (TD): occurs after months or years of tx; may become irreversible; repetitive, involuntary, purposeless movements (typically facial muscles are involved); mechanism: up-regulation and supersensitivity of D2 receptors (that can become permanent)
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Hyperprolactinemia
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D2 receptor blockade in the tuberoinfundibular pathway causes increased plasma prolactin levels (Hyperprolactinemia)
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Manifested as: Amenorrhea-galactorrhea in women, gynecomastia in men, Infertility in both men and women
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ADRs caused by Blockade of Non-Dopamine Receptors
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1st generation antipsychotic drugs also block 5-HT-2, alpha 1 adrenergic, muscarinic, and histamine H-1 receptors ⇨ More Side Effects
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Blockade of H1 Receptors
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Sedation
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Blockade of alpha 1 adrenergic receptors
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Orthostatic hypotension (could result in falls and injuries)
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Blockade of muscarinic receptors
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dry mouth, urinary retention, blurred vision, tachycardia, constipation, toxic-confusional state
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Blockade of both H1 and 5-HT-2A receptors
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Weight gain
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ADDITIONAL SIDE EFFECTS
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Typical antipsychotic agents affect hypothalamic function
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impaired ability to regulate body temperature
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Hypo or Hyperthermia may result, depending on the ambient temperature
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Thioridazine
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Cardiac toxicity: reflected in prolongation of QTc interval and abnormal configuration of ST segment and T wave (correlates to increased risk of ventricular arrhythmias)
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Retinal Tox: (pigmentary retinopathy): decreased vision and "browining" of vision
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Neuroleptic Malignant Syndrome (NMS)
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Rare, but life-threatening reaction to antipsychotic drugs
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Symptoms: extreme muscle rigidity (lead pipe), hyperreflecia, fever, unstable BP, tachycardia, sweating, rapid changes in mental status, confusion, and coma
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Lab: myoglobinemia and metabolic acidosis
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Cheatography n. The art of mapping complex subjects into clear, instantly navigable reference guides.
