Antipsychotics

Snapshot

• A 19-year-old male is brought into the ED by his parents.  The patient recently started college and was living in the dorms.  He struggled with school and friends and had some issues with his roommate so he moved back home.  His parents have noticed that he has become more reclusive and often stays in his room alone.  He no longer cares for himself, and has not showered in over a month.  The patient is often seen talking to himself, and when his parents ask him what he is doing he says, “It’s classified information.”

Overview

• 2 classes
  • typical
    • older
    • stronger D2 receptor antagonism
      • ↑ [cAMP]
  • atypical
    • newer
    • weaker D2 receptor antagonism and stronger 5-HT2, α, and H1 antagonism
• Targets
  • dopaminergic neurons
    • specific pathways affected include:
      • nigrostriatal (extrapyramidal motor)
      • mesolimbic (mood and reward)

• tuberoinfundibular (prolactin release)

Typical Antipsychotics Overview

Typical Antipsychotics
High Potency Antipsychotics (in Descending Order)	Advantages	Disadvantages	Unique Features
Haloperidol	Fewer side effects of sedation and hypotension	High association with extrapyramidal symptoms	Able to use as long-acting depot injectionsCan be given IM in acute situations
Fluphenazine
Perphenazine
Chlorpromazine	Lower frequency of extrapyramidal side effects	Greater incidence of anticholinergic side-effects, hypotension, sedation	Corneal deposits
Thioridazine	Retinal depositsQT prolongation

Typical Antipsychotics

• Overview
  • AKA neuroleptics
  • two types
    • high potency
    • low potency
  • highly fat soluble → stored for long time in body fat
• Drugs (“haloperidol + -azines”)
  • high potency – low dose needed (more movement side-effects)
    • haloperidol
    • trifluoperazine
    • fluphenazine
  • low potency – high dose needed (more anti-cholinergic side-effects)
    • thioridazine
    • chlorpromazine
• Clinical use
  • schizophrenia
    • primarily positive symptoms
  • psychosis
  • acute mania
    • temporary treatment because lithium has slow onset
  • Tourette’s syndrome
• Toxicity
  • high potency
    • ↑ extrapyramidal system (EPS) side effects
      • due to high affinity for D2 receptor
      • has characteristic time course
        • early onset/reversible symptoms
          • 4 hours = acute dystonia
            • spasm of face, neck, tongue, and extraocular muscles
        • intermediate-onset symptoms (days to weeks)
          • Parkinsonism
            • muscle rigidity, bradykinesia, tremor, and shuffling gait
          • akathisia
            • urge to move
        • late onset/irreversible symptoms 
          • 4 months = tardive dyskinesia  
            • involuntary, repetitive movements of facial, tongue, and neck muscles
            • likely caused by chronic D2 receptor antagonism 
            • anticholinergics worsen!
            • must reduce dose or switch to an atypical antipsychotic
      • can be treated with diphenhydramine or benztropine 
    • ↓ non-specific side effects (SE)
  • low potency
    • ↓ EPS SEs
    • ↑ non-specific SEs  
      • due to low affinity to D2 receptors and high concentrations needed to achieve effect
      • muscarinic receptor antagonism
        • dry mouth and constipation
        • vision problems
      • α receptor antagonism
        • orthostatic hypotension
        • sexual dysfunction
      • histamine receptor antagonism
        • sedation
      • chlorpromazine → corneal deposits 
      • thioridazine → retinal deposits 
  • endocrine side effects
    • dopamine normally inhibits prolactin secretion
      • antagonism of receptor may result in hyperprolactinemia→ galactorrhea
  • neuroleptic malignant syndrome (NMS) 

Extrapyramidal Side Effects of High Potency D2 Blockers (Haloperidol, Fluphenazine, Perphenazine)
3 Hours: Acute Dystonia	3 Days – Weeks: Bradykinesia (Pseudo-Parkinsonism)	3 Months: Akathisia	3 Years: Tardive Dyskinesia	Emergency: Neuroleptic Malignant Syndrome
Muscle spams (neck, eye, diffuse)Trouble swallowing	Symptoms of Parkinson’s disease: tremors, bradykinesia, rigidity	Sustained feeling of motion/restlessness	Uncontrollable repetitive, stereotypical writhing movements, usually of the tongue	High feverMuscle rigidityUnstable vitalsIncreased CK, K+, and WBC’s
Treatment of Side Effects
Anticholinergic medications:(benztropine, diphenhydramine, trihexyphenidyl)	β-blockersBenzodiazepines	Stop high potency D2 blockersSwitch to atypicals	Stop antipsychoticIV fluidsCoolingDantrolene

Atypical Antipsychotics – Overview

Medication	Unique features and side effects
Risperidone	High potencyUsually first lineHyperprolactinemiaWeight gain
Olanzapine	Severe weight gainVery sedating
Ziprasidone	Minimal to no weight gainIncreased QTc
Quetiapine	Low potencySedatingWeight gainUseful in bipolar depression and augmentation of major depression therapy
Lurasidone	Minimal weight gainUseful in biploar depression
Clozapine	Weight gainMost effective anti-psychoticDecreased suicide riskAgranulocytosisMyocarditisSialorrheaOrthostatic hypotensionIncreased seizures
Aripiprazole	D2 partial agonistAugmentation of major depression therapy

Atypical Antipsychotics

• Drugs 
  • olanzapine
  • clozapine
  • quetiapine
  • risperidone
  • aripiprazole
  • ziprasidone
• Mechanism
  • antagonist at 5-HT2, α, H1, and dopamine receptors
• Clinical use
  • schizophrenia
    • both positive and negative symptoms
  • olanzapine
    • OCD
    • anxiety disorder
    • depression
    • mania
    • Tourette’s syndrome
• Toxicity
  • less EPS and anticholinergic side effects as compared to traditional antipsychotics
  • olanzapine
    • weight gain/metabolic syndrome
  • clozapine 
    • agranulocytosis
      • requires patients to have weekly WBC monitoring 
    • weight gain/metabolic syndrome
  • ziprasidone
    • prolonged QT and possible resultant torsades 
  • risperidone
    • may result in hyperprolactinemia→ galactorrhea                                                   
    • EPS