First-Generation Antipsychotic Agent (Conventional or Typical)

First-Generation Antipsychotic Agent: Chemical Classification

• Chlorpromazine

• Haloperidol

Drugs in all groups equivalent with respect to antipsychotic actions

What is the primary indication for antipsychotic drugs?

Schizophrenia is the primary indication for antipsychotic drugs

What do antipsychotic drugs do?

• These drugs suppress symptoms during acute psychotic episodes

• Continue use reduces the risk of relapse

Antipsychotic drugs: Mechanism of Action

• Conventional antipsychotic drugs lock a variety of receptors within and outside of the CNS

• Suppress symptoms of psychosis by blocking dopamine₂ receptors in the brain

Antipsychotic drugs: What are adverse effects a result of?

adverse effects are a result of blocking receptors for dopamine, acetylcholine, histamine, and norepinephrine

Antipsychotic drugs: Adverse Effects

• Extrapyramidal Symptoms (EPS)

  • Same neuronal network as Parkinson’s - blockade of D2 receptors

  • Acute dystonia (involuntary muscle contractions), parkinsonism, and akathisia (early in therapy)

  • Tardive dyskinesia (late-onset, involuntary movement disorder) (late in therapy)

What is acute dystonia?

involuntary muscle contractions, twisting of body parts, repetitive movements, increased muscular tone; rhythmic jerks

Treatment: removal of drug or anticholinergic: benztropine or diphenhydramine

Acute dystonia: Treatment

• Removal of drug

• Anticholinergic: benztropine or diphenhydramine

Early Therapy Adverse Effects (EPS): Parkinsonism

• Bradykinesia

• Mask-like face

• Drooling

• Tremor

• Cogwheel rigidity

• Shuffling gait

• Stooped posture

Parkinsonism: Bradykinesia

(brady = slow, kenesia = movement) extreme slowness of movement

Parkinsonism: Treatment

Anticholinergics

• Benztropine

• Diphenhydramine

• Amantadine

Early Therapy Adverse Effects (EPS): Akathisia

Akathisia (a = without, kathis = sitting)

• Intolerance of inactivity

• Motor restlessness

• Pacing and squirming brought on by an uncontrollable need to be in motion

Akathisia: Treatment

• Beta-blocker

• Benzodiazepines

• Anticholinergics

• Or switch to a low potency FGA

Late Therapy Adverse Effects (EPS): Tardive dyskinesia

• Twisting, worm-like movements of the tongue and face

• Lip-smacking movements

• Tongue flicks out in a “fly-catching motion

• Slow, worm-like movement of the tongue

• Involuntary movements of the limbs, toes, fingers, and trunk

What does Tardive dyskinesia interfere with/result in?

• Interfere with chewing, swallowing, speaking

• Result in malnutrition and weight loss

Tardive dyskinesia: Treatment

• Reduce dose or drug withdrawal

• Switch to an SGA

• Valbenazine

Adverse Effects: Neuroleptic malignant syndrome

• Rare but serious reaction

• Risk of death without treatment

• “Lead pipe” muscle rigidity, sudden high fever, altered LOC, sweating, autonomic instability (tachycardia, dysrhythmias, fluctuations in BP), and seizures or coma may develop, rhabdomyolysis & acute kidney failure

• Death can result from respiratory, cardiovascular collapse dysrhythmias

Neuroleptic Malignant Syndrome: Treatment

• Immediate withdrawal of antipsychotic meds

• Supportive measures

  • Hyperthermia: cooling blankets & antipyretics

  • Hydration: fluid

  • Benzodiazepines: muscle relaxant, reduces rigidity, & hyperthermia

  • Bromocriptine: dopamine receptor agonist relieves CNS toxicity

What does dopamine agonist do?

dopamine agonist stimulate the brain influenced by dopamine

Antipsychotic medications: Anticholinergic effects

• Dry mouth

• Blurred vision

• Photophobia

• Urinary hesitancy

• Constipation

• Tachycardia

Antipsychotic medications: Orthostatic hypotension

• Antipsychotic drugs promote orthostatic hypotension by blocking alpha₁-adrenergic receptors on blood vessels

• This blockage prevents compensatory vasoconstriction upon standing and causes BP to fall

• Teach signs of hypotension: lightheaded, dizziness; instructed to sit or lie down if symptoms occur; teach to get up slowly

Antipsychotic medications: More Side Effects

• Sedation - results from histamine blocking in CNS; given at bedtime

• Neuroendocrine effects - increased prolactin = gynecomastia

• Sexual dysfunction - leads to poor adherence

• Dermatologic effects - phenothiazines (chlorpromazine) = photosensitivity

  • Contact dermatitis

• Agranulocytosis - risk for infection; monitor WBC and withdraw medication to reverse

• Severe dysrhythmias - FGAs prolong QT interval; check ECG and potassium

What is neuroendocrine?

Neuroendocrine - dopamine inhibits prolactin, antipsychotics block dopamine and therefore increase levels of prolactin promoting gynecomastia (benign enlargement of male breast tissue)

Antipsychotic Medication: Physical and Psychological Dependence

• Development of physical and psychological dependence is rare

• Abrupt withdrawal of antipsychotics can precipitate a mild abstinence syndrome

• Do not stop abruptly unless there is a medical emergency (NMS)

Antipsychotic Medication: Drug Interactions

• Anticholinergic drugs

  • Intensity the anticholinergic effect (can’t see, can’t pee, can’t spit, can’t shit)

• CNS depressants

  • Can intensify the CNS depressant effect; avoid alcohol

• Levodopa and direct dopamine receptor agonists

  • May counteract the antipsychotic effects of neuroleptics

Antipsychotic Medication: Toxicity

• Conventional (FGAs) antipsychotic drugs are very safe

• Death by overdose is extremely rare

• Overdose produces hypotension, CNS depression, and EPS

• Treatment

  • Hypotension: Intravenous fluids, alpha-adrengergic agonists

  • Gastric lavage to remove drug from stomach

  • Treats EPS with antiparkinsonian drugs