The Typical Impressionist First Generation Antipsychotics

5.1 – “The Typical Impre Impressionist”: ssionist”: First generati generation on antip antipsychotics sychotics (hal (haloperidol, operidol, trifluoperazine, ffluphenazine, luphenazine, ch chlorproma lorproma lorpromazine, zine, thioridazine) Historical aside: Vincent van Gogh was a Dutch post-impressionist painter whose work is characterized by bold colors, expressive brushwork, and a variety of subjects, including landscapes, still life, portraits, and self-portraits. While highly influential on 20th century modern art, van Gogh was considered a madman and a failure during his lifetime, and only achieved fame & recognition after his death by suicide in 1890 at 37 yo. He suffered from psychotic episodes, depression, and delusions, and spent a period of his life in a psychiatric hospital in Saint-Rémy in southern France. In 1880s Paris, van Gogh ran in avant-garde art circles, where he apparently befriended Paul Gauguin; their friendship fell apart when van Gogh, angry at Gauguin following a fight, cut off his own ear. Van Gogh apparently had no recollection of this event afterward, suggesting an acute psychotic episode. Now on to the medical stuff. Physiology • Several NTs are involved in psychosis, including dopamine and serotonin. o FGAs target dopamine transmission, specifically bock D2 receptors in the mesolimbic & striatofrontal system (snapping double rope with D-rings) o 5HT-2A receptors are key in modulating release of both excitatory and inhibitory NTs, and are a main target of 2nd generation antipsychotics. • Antipsychotics are highly lipophilic, highly protein & tissue bound, and consequently have a large Vd, leading to long half-lives (long tapering flag). Typically have half-lives of 20-40 hours, and many have active metabolites as well. Indications • Antipsychotics are used in many condition with characteristics of psychosis. While schizophrenia is the primary indication, may also be used in psychotic mania in bipolar, MDD with psychotic features, delirium, psychosis associated with Alzheimer’s or Parkinson’s, and drug induced psychosis • Schizophrenia is the primary indication for antipsychotic drugs. o FGA are generally effective at treating positive symptoms (hallucination, delusions, disorganized thoughts, or behavior) (positive angel sitting on van Gogh’s shoulder next to his dead ear – i.e. angel is “blocked”) o Not so effective at treating negative symptoms (apathy, flat affect, lack of energy) (negative devil on opposite shoulder is still audible) • Acute psychotic episodes, regardless of etiology, are generally managed with antipsychotics (patient running up angled roof). • Can be used to treat acute aggression or anxiety. In particular, psychosis is often associated with increased motor activity, heightened emotional arousal, anxiety (angry patient not wanting to share roof). • Manage motor tics of Tourette’s (marionette), although has fallen out of favor for other dopamine depleting agents Rx • Can be classified as high- or low-potency drugs. • Note the -azine ending of many names (starry gazing) • High potency include trifluoperazine, fluphenazine (person on roof trying to fly), haloperidol (halo around moon in painting) o High clinical potency = greater dopamine receptor binding. o Associated with less sedation, weight gain and anticholinergic activity o Higher risk of extrapyramidal adverse effects • Low potency include thioridazine (color theory wheel) & chlorpromazine (Color-pro paints) o higher histaminic & muscarinic activity with corresponding sedation & antimuscarinic effects o Lower incidence of extrapyramidal effects • Adverse effects (for all antipsychotics) result from effects on multiple receptors and NTs. Most of these effects are more prominent with FGAs than SGAs, or in high- or low-potency drugs; however, any adverse effects may be seen in any antipsychotics o QT prolongation, increasing risk for torsades des pointes (twisted streamers) o Can lower seizure threshold (shaking escapee). Should be used with caution in patients on other seizure exacerbating meds. More prominent with high potency rx (characters high up on roof): o Extrapyramidal symptoms are the major limiting factor in FGA use, and the incidence of such symptoms is the defining difference between FGA & SGA (patient trying to fly is wearing pyramid shaped newspaper hat with “Extra”) . Occur d/t D2 dopamine blockade in the nigrostriatal tract, which is normally involved in the control of muscle movement. Will most often present with initiation of treatment or changes in dosing; may include: ▪ Acute dystonia (i.e. sudden onset sustained muscle contractions); may occur within hours of treatment (observer with cocked head & rigid back). More common in young men on high-potency FGAs. Depending on muscle group may involve • Spasmodic torticollis • Oculogyric crisis with forced sustained elevation of the eyes • Arching of back and neck ▪ Akathisia (subjective restlessness with inability to is still) (critic knocking over chair); may occur within days. ▪ Drug induced parkinsonism with cogwheel rigidity, bradykinesia, masked facies, tremor (cogged wheels). Usually occur within weeks. Cannot be managed with levodopa, which may precipitate psychosis; instead, ▪ Tardive dyskinesia; abnormal choreoathetoid movements following months to years of use (escapee in carriage with newspaper hat sticking out tongue). Advanced cases may be irreversible, so want to catch early and decrease dose or change to SGA. ▪ Tuberoinfundibular blockade → hyperprolactinemia (person laughing milk out nose). More common with high-potency. Downstream effects include inhibition of GnRH release, resulting in central hypogonadism (galactorrhea, amenorrhea, impotence, ↓libido) ▪ Neuroleptic malignant syndrome (“Now More Spicy” chicken bucket). Occurs in patients extra sensitive to dopaminergic effects (patient is sensitive to friend’s antics & is laughing). • Treatment: Dantrolene (mm relaxant) (trampoline). Blocks RyR and prevents further release of calcium into muscle fibers (adult blocking Ryan from getting on trampoline). ▪ More common with high-potency FGAs, but can be seen with any antipsychotic meds. • Lead pipe rigidity (person holding onto pipe) • Altered mental status, fever, autonomic instability (crazy, sweating, and tachycardic) • Rhabdomyolysis (eating chicken). Watch for elevated CK. ▪ Note D2 dopamine blockade in the nigrostriatal tract is often accompanied by excess cholinergic activity. So may coadminister with rx with M1 antagonism effects (e.g. benztropine, diphenhydramine) to reestablish dopaminergic/cholinergic balance. More prominent with low potency rx o Systemic effects are most prominent with low-potency rx (painting with Color-Pro paints) o Antimuscarinic action (tea party in Café Terrace at Night): dry mouth & constipation common; blurred vision, urinary retention less common. Results from inhibition of central and peripheral muscarinic blockade. Symptoms significantly less or entirely absent with higher potency drugs. o Orthostatic hypotension d/t blockade of α-1 receptors (Siesta painting; extinguished α candle). Often accompanied by tachycardia, especially in the first days of treatment or with increased dosing. o Block H1 activity (bees around Sunflowers); can be highly sedating (may be utilized clinically with aggressive or agitated patients) (Bedroom in Arles painting) o Chlorpromazine: gray deposits in cornea and lens (corn yellow paint) o Thioridazine: retinal deposits (deposits on retinal palette). May cause browning of vision; advanced cases may look like retinitis pigmentosa.