Beach antipsychotics

Anti-Psychotic Agents

Overview of Anti-Psychotic Drugs

  • Anti-psychotics are drugs used primarily in the treatment of psychosis.

  • They act as antagonists at one or several types of receptors.

Typical Anti-Psychotic Agents

  • Phenothiazines (Typical Agents)

    • Mainly function by antagonizing dopamine receptors.

    • Exhibit additional actions such as:

    • Antihistamine activity

    • Anticholinergic activity

    • Anti-adrenergic activity

Atypical Anti-Psychotic Drugs

  • Newer agents primarily antagonize serotonin (5HT2) and dopamine (D2) receptors but exhibit less activity on other receptors.

  • Some atypical agents also have monoamine reuptake inhibitor activity (specifically serotonin).

  • Atypical agents are commonly preferred due to a favorable side effect profile that can be linked to the receptors they inhibit.

Therapeutic Index and Side Effects

  • Anti-psychotic drugs possess a high therapeutic index concerning mortality.

  • Side effects occur frequently even at therapeutic doses and are generally not life-threatening, except in overdose cases.

Common Adverse Reactions

  1. Behavioral Changes:

    • Sedation is a frequent side effect found in all anti-psychotic compounds.

    • Notably pronounced with high doses of low-potency phenothiazines (e.g., chlorpromazine).

  2. Extrapyramidal Reactions (Early Signs):

    • Acute Dystonia:

      • Symptoms include grimacing, blepharospasm, perioral spasms, tongue protrusion, and masseter spasms (chewing).

    • Akathisia:

      • Characterized by a feeling of restlessness, uncomfortable pacing, and agitation, often misdiagnosed as psychotic agitation.

    • Parkinsonism:

      • Symptoms consist of rigidity, bradykinesia, shuffling gait, and mask-like facial expressions.

  3. Extrapyramidal Reactions (Late Signs):

    • Tardive Dyskinesia:

      • Oro-buccal-lingual dyskinesia, choreiform movements affecting the jaw, tongue, face, trunk, and extremities.

Non-Central Side Effects

  • Autonomic side effects (mainly seen in low potency compounds include):

    • Anticholinergic and antiadrenergic effects.

Overview of Individual Anti-Psychotic Drugs

Chlorpromazine

  • The first antipsychotic marketed, serving as the prototype for aliphatic phenothiazines.

  • Characteristics:

    • Relatively low potency and the most sedative of antipsychotics; tolerance may develop.

    • Well tolerated by patients younger than 40 years old.

    • Primarily used as an antiemetic.

    • Less likely to cause extrapyramidal side effects than other phenothiazines, although parkinsonism and akathisia are more frequent than acute dystonia.

    • Notable side effects include:

    • Pronounced antiadrenergic and anticholinergic effects.

    • Common outcomes: orthostatic hypotension, dry mouth, blurred vision, urinary retention, and constipation.

  • Risk of agranulocytosis and cholestatic jaundice (rare incidence).

  • Frequent photosensitivity, with possible conjunctival melanosis and pigmentary opacities of the cornea and lens.

Thioridazine

  • A low potency agent with efficacy similar to chlorpromazine at equivalent doses.

  • Metabolizes into an active metabolite known as mesoridazine.

  • Side effects:

    • Similar sedation and orthostatic hypotension as seen in chlorpromazine.

    • Noteworthy anticholinergic activity and weak antidopaminergic action, resulting in a low incidence of extrapyramidal reactions, barring tardive dyskinesia.

    • EKG changes occur more frequently than with other phenothiazines, especially when combined with tricyclic antidepressants.

    • Risk of pigmentary retinopathy, particularly at dosages exceeding 800 mg/day, potentially irreversible; smaller doses may induce impaired vision without retinal changes.

Mesoridazine

  • A sulfoxide metabolite of thioridazine, also low potency.

  • Side effects and indications are the same as those for thioridazine.

  • Might be beneficial for patients resistant to thioridazine.

Trifluoperazine

  • A prototype of the piperazine type anti-psychotics.

  • Known for:

    • High potency in treating psychosis.

    • Anti-emetic activity and relatively less sedation compared to other phenothiazines.

    • Lesser autonomic side effects (antiadrenergic and anticholinergic).

  • Higher propensity for extrapyramidal effects, particularly in older patients.

  • Lower likelihood of blood dyscrasia or jaundice related issues and ocular changes; no notable EKG changes observed.

Acetophenazine

  • Less potent than trifluoperazine due to the weaker electron-withdrawing group at position 2.

  • Side effects are consistent with trifluoperazine.

Fluphenazine

  • Offers the highest potency of the phenothiazines on a milligram basis.

  • Maintenance dosing differs significantly:

    • 3 mg/day for fluphenazine compared to 15 mg/day for trifluoperazine.

    • The increased receptor affinity is attributed to the alcohol group.

  • Long-chain esters can be formed from the alcohol functionality for depot administration, hydrolyzed slowly over a two to three-week period.

    • Available forms include heptanoic (enantate) and decanoic esters for longer durations.

  • The HCl salt form can be administered IM for patients unable to take oral medication; high incidence of extrapyramidal effects may arise within the first week of therapy.

Loxapine

  • Classified as a typical agent with properties:

    • Anti-emetic and moderate sedation; characterized by high anticholinergic and low antiadrenergic effects.

    • Risk of prolonged QTc interval and extrapyramidal reactions between the efficacy of aliphatic and piperazine phenothiazines.

Clozapine

  • An atypical antipsychotic structurally related to loxapine, lacking chlorine and including NH replacement.

  • Notable characteristics:

    • Acts moderately at the D receptor and interacts with various others:

    • a1, a2, 5HT1a, 5HT2a, 5HT2c, M, H, and more.

    • Minimal risk of extrapyramidal effects; no cases of tardive dyskinesia reported over ten years of use.

    • Useful in patients who cannot tolerate other agents due to extrapyramidal side effects.

    • Significant risk of agranulocytosis necessitating regular weekly or biweekly white blood cell count monitoring.

    • High sedation, anticholinergic, and anti-adrenergic effects.

    • Metabolized by 1A2 and inhibits 2D6.

Olanzapine

  • Classified as an atypical agent.

  • Interaction includes:

    • 5HT2a, 5HT2c, D, M, H, a1 interactions.

    • Metabolizes by 1A2 and is a weak inhibitor of various Cytochrome P450 enzymes.

    • Sedative effects are moderate to high, with low extrapyramidal symptoms and moderate anticholinergic and antiadrenergic effects.

    • Used in combination with fluoxetine for depressive episodes in bipolar disorder.

Quetiapine

  • Another atypical agent acting as an antagonist at D, 5HT, M, α, and H receptors.

  • Metabolism is predominantly through 3A4 and 2D6 with a minor metabolic pathway.

  • Characterized by moderate to high sedation, low extrapyramidal risk, and moderate levels of antiadrenergic and anticholinergic effects.

Haloperidol

  • A typical agent closely related to fentanyl and meperidine.

  • High affinity for D receptors with additional activity on some 5HT and α receptors.

  • Notable for low sedation and high extrapyramidal risks, along with low anticholinergic and antiadrenergic effects.

  • Indicated for schizophrenia and Tourette's syndrome.

  • Metabolized by 2D6 and 3A4, having a moderate inhibitory effect on both enzymes.

Pimozide

  • Connected to haloperidol and droperidol; indicates moderate sedation with a high risk of extrapyramidal reactions due to moderate anticholinergic and low anti-adrenergic effects.

  • Used for Tourette's syndrome in patients not responsive to standard therapies.

Risperidone

  • An atypical agent showing high affinity for 5HT2 and some affinity for D2 receptors (20:1), also acts as an antagonist at H1 and α1 and α2 adrenergic receptors.

  • Exhibits low to moderate sedation with low extrapyramidal symptoms and moderate anticholinergic and low antiadrenergic effects.

  • Metabolized by 2D6 to yield active metabolite, 9-OH risperidone, which contributes mainly to the activity.

Paliperidone

  • An atypical agent serving as the active metabolite of risperidone (9-OH risperidone).

  • Features a relatively long half-life (23 hours) and is primarily excreted unchanged through an osmotic delivery device.

  • Essentially has the same effects as risperidone.

Ziprasidone

  • Another atypical agent with high affinity (antagonist) for 5HT2 and D2 receptors.

  • Displays low to moderate sedation levels, low extrapyramidal risk, very low anticholinergic activity, and moderate antiadrenergic effects.

  • Notable for causing an increase in QTc interval.

Lurasidone

  • An atypical agent with high antagonist affinity for 5HT2 (5HT2a and 5HT7) and D2 receptors.

  • Exhibits some antagonism on a2c and a2a, with partial agonist characteristics at 5HT1a.

  • Lacks antihistamine or anticholinergic effects, predominantly features low to moderate sedation, and shows low extrapyramidal symptoms and antiadrenergic impact.

Aripiprazole

  • Classified as an atypical agent functioning as a D2 partial agonist and 5HT1 partial agonist, while antagonizing 5HT2 receptors and exhibiting some monoamine reuptake inhibition.

  • Known for low sedation and very low extrapyramidal, anticholinergic, and antiadrenergic effects.

  • Metabolized by 2D6 and 3A4, converting into its active metabolite dehydro aripiprazole.

  • Particularly useful for patients with bipolar disorder due to its unique pharmacology.

Aripiprazole Lauroxil

  • A prodrug intended for IM administration.

  • The onset of aripiprazole effect occurs 5-6 days post IM injection, maintaining effects for an additional 36 days.

Cariprazine (Vraylar®)

  • Structurally similar to aripiprazole and used for both schizophrenia and bipolar disorder.

  • Acts as a partial agonist at D2 and D3 (with preferential affinity for D3) and 5HT1a, and as an antagonist at 5HT2a.

  • Metabolized mainly by 3A4, with some 2D6 involvement, resulting in two active metabolites.

Brexpiprazole (Rexulti®)

  • Shares structural similarities with aripiprazole.

  • Indicated for schizophrenia and major depressive disorder as an adjunct therapy.

  • Functions as a partial agonist at D2 and 5HT1a, while antagonizing 5HT2a.

    • Metabolized by 3A4 and 2D6; higher plasma levels observed in patients who are poor metabolizers or treated with inhibitors of 3A4 and 2D6.

Additional Atypicals

  • Asenapine (SAPHRIS®).

  • Iloperidone (FANAPT®).