Typical antipsychotic drugs from lippincot
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Typical (First-Generation) Antipsychotic Drugs
Source: Lippincott Illustrated Reviews - Pharmacology, Chapter 18
Overview
Typical antipsychotics are also called first-generation antipsychotics (FGAs), and historically referred to as conventional antipsychotics, neuroleptics, or major tranquilizers. They are primarily used for schizophrenia, mania, and other psychotic states. They are not curative - they reduce the intensity of hallucinations and delusions but do not eliminate chronic thought disorders.
Drug List (Figure 18.1, Lippincott Pharmacology)
Low Potency FGAs
| Drug | Brand |
|---|---|
| Chlorpromazine | Generic only |
| Thioridazine | Generic only |
High Potency FGAs
| Drug | Brand |
|---|---|
| Fluphenazine | Generic only |
| Haloperidol | Haldol |
| Loxapine | Generic only |
| Molindone | Generic only |
| Perphenazine | Generic only |
| Pimozide | Orap |
| Prochlorperazine | Compro, Procomp |
| Thiotixene | Generic only |
| Trifluoperazine | Generic only |
Note: "Low potency" vs "high potency" does NOT indicate clinical effectiveness. It refers to affinity for the D2 receptor, which influences the adverse effect profile.
Mechanism of Action
1. Dopamine D2 Receptor Blockade
All FGAs work as competitive inhibitors of dopamine D2 receptors. The antipsychotic effect comes from blocking D2 receptors in the mesolimbic pathway (reduces positive symptoms: hallucinations, delusions).
2. Four Key Dopaminergic Pathways (and consequences of D2 blockade)
| Pathway | Normal Function | Effect of D2 Blockade |
|---|---|---|
| Mesolimbic | Pleasure/reward; implicated in positive symptoms | Therapeutic - reduces positive symptoms |
| Mesocortical | Cognition, emotion; implicated in negative symptoms | May worsen negative symptoms |
| Nigrostriatal | Motor control | Extrapyramidal symptoms (EPS) |
| Tuberoinfundibular | Dopamine inhibits prolactin release | Hyperprolactinemia |
3. Other Receptor Actions
FGAs also block:
- Muscarinic (M1) receptors - dry mouth, urinary retention, constipation, blurred vision
- Alpha-1 adrenergic receptors - orthostatic hypotension, reflex tachycardia
- Histamine H1 receptors - sedation, weight gain
Pharmacokinetics
- Absorption: Oral absorption is highly variable; significant first-pass metabolism
- Distribution: Highly lipophilic; large volume of distribution; accumulate in the brain, lungs, and other tissues
- Metabolism: Hepatic via CYP enzymes; active metabolites possible (e.g., mesoridazine from thioridazine)
- Elimination: Long half-lives (18-40 hours); depot (long-acting injectable) formulations available (e.g., haloperidol decanoate, fluphenazine decanoate) for adherence
Adverse Effects
1. Extrapyramidal Symptoms (EPS) - Most Clinically Important
High-potency FGAs (e.g., haloperidol) cause more EPS; low-potency agents (e.g., chlorpromazine) cause fewer.
| EPS Type | Onset | Features | Treatment |
|---|---|---|---|
| Acute dystonia | Hours to days | Muscle spasms, torticollis, oculogyric crisis, opisthotonos | Benztropine or diphenhydramine (anticholinergics) |
| Akathisia | Days to weeks | Motor restlessness, inability to sit still | Beta-blockers, benzodiazepines |
| Parkinsonism | Weeks | Bradykinesia, rigidity, tremor | Reduce dose or anticholinergics |
| Tardive dyskinesia (TD) | Months to years | Repetitive, involuntary orofacial movements | Reduce dose; switch to SGA; valbenazine/deutetrabenazine |
2. Neuroleptic Malignant Syndrome (NMS)
A life-threatening emergency characterized by:
- Hyperthermia (>38°C)
- Muscle rigidity
- Autonomic instability (BP fluctuations, tachycardia, diaphoresis)
- Altered consciousness
- Elevated creatinine kinase (CK), leukocytosis
Treatment: Stop the drug immediately; supportive care; dantrolene (muscle relaxant) and bromocriptine (D2 agonist)
3. Metabolic and Endocrine Effects
- Hyperprolactinemia (due to tuberoinfundibular pathway blockade) → galactorrhea, amenorrhea, gynecomastia, sexual dysfunction
- Weight gain (particularly with low-potency agents)
4. Cardiovascular Effects
- Orthostatic hypotension (alpha-1 blockade) - most prominent with low-potency agents like chlorpromazine
- QTc prolongation - particularly thioridazine and pimozide (risk of torsades de pointes)
5. Anticholinergic Effects
- Dry mouth, constipation, urinary retention, blurred vision
- More prominent with low-potency agents
6. Sedation
- H1 blockade causes sedation; more common with low-potency FGAs (chlorpromazine, thioridazine)
7. Ophthalmologic Effects
- Chlorpromazine: pigment deposits in lens/cornea with prolonged use
- Thioridazine: irreversible pigmentary retinopathy - limits its use to patients who fail other agents
Specific Drug Notes
Chlorpromazine (Prototype low-potency FGA)
- Phenothiazine class
- Useful as antiemetic, for intractable hiccups
- High sedation, high anticholinergic effects, high alpha-1 blockade
- Low EPS relative to high-potency agents
Haloperidol (Prototype high-potency FGA)
- Butyrophenone class
- Available as oral, IM (acute agitation), and long-acting injectable decanoate (monthly)
- High EPS, low sedation, low anticholinergic effects
Pimozide
- Used specifically for Tourette disorder
- Risk of QTc prolongation; cardiac monitoring required
Prochlorperazine
- Also widely used as an antiemetic
Fluphenazine
- Available as decanoate depot injection (every 2-4 weeks) for adherence
Low Potency vs High Potency - Side Effect Comparison
| Adverse Effect | Low Potency (Chlorpromazine) | High Potency (Haloperidol) |
|---|---|---|
| EPS | Low | High |
| Sedation | High | Low |
| Anticholinergic | High | Low |
| Orthostatic hypotension | High | Low |
| Prolactin elevation | Moderate | High |
Key Clinical Points
- All FGAs are equally effective for positive symptoms - drug selection is based on tolerability and adverse effect profile.
- FGAs only treat positive symptoms (hallucinations, delusions) - they do not help and may worsen negative symptoms (avolition, flat affect, alogia).
- Second-generation antipsychotics (SGAs) are now preferred first-line because they have lower EPS risk, though they carry higher metabolic risks.
- Anticholinergic agents (benztropine) are used to treat acute EPS (dystonia, parkinsonism).
- FGAs lower the seizure threshold - use with caution in epileptic patients.
Source: Lippincott Illustrated Reviews: Pharmacology, Chapter 18 - Antipsychotic Drugs
Atypical antipsychotic
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Here is the full Lippincott chapter on Atypical (Second-Generation) Antipsychotics:
Atypical (Second-Generation) Antipsychotic Drugs
Source: Lippincott Illustrated Reviews - Pharmacology, Chapter 18
Overview
Second-generation antipsychotics (SGAs), also called atypical antipsychotics, are the first-line treatment for schizophrenia. They differ from typical (FGA) agents in two key ways:
- Lower risk of extrapyramidal symptoms (EPS)
- Higher risk of metabolic adverse effects (weight gain, diabetes, hypercholesterolemia)
Drug List
| Drug | Brand Name |
|---|---|
| Aripiprazole | Abilify, Aristada |
| Asenapine | Saphris, Secuado |
| Brexpiprazole | Rexulti |
| Cariprazine | Vraylar |
| Clozapine | Clozaril |
| Iloperidone | Fanapt |
| Lumateperone | Caplyta |
| Lurasidone | Latuda |
| Olanzapine | Zyprexa |
| Paliperidone | Invega |
| Pimavanserin | Nuplazid |
| Quetiapine | Seroquel |
| Risperidone | Perseris, Risperdal |
| Ziprasidone | Geodon |
Mechanism of Action
1. Dual Receptor Blockade (Core SGA Mechanism)
SGAs block both D2 (dopamine) AND 5-HT2A (serotonin) receptors. The serotonin blockade in the nigrostriatal pathway allows dopamine to be released, which counteracts the D2 blockade - this is why EPS is reduced compared to FGAs.
2. Partial Agonists (Unique subgroup)
Aripiprazole, Brexpiprazole, and Cariprazine are partial agonists at D2 and 5-HT1A receptors, AND antagonists at 5-HT2A receptors.
- Under low dopamine conditions → act as agonists (stimulate the receptor)
- Under high dopamine conditions → act as antagonists (block the receptor)
- This "dopamine stabilizer" effect gives minimal EPS and very low prolactin elevation
3. Special Mechanisms
| Drug | Special Mechanism |
|---|---|
| Clozapine | High affinity for D1, D4, 5-HT2, muscarinic, alpha-adrenergic; weak D2 antagonist |
| Quetiapine | Weak D2 and 5-HT2A blockade; rapidly dissociates from D2 (explains low EPS) |
| Pimavanserin | Inverse agonist/antagonist at 5-HT2A and 5-HT2C receptors; NO dopamine receptor affinity |
| Risperidone | Blocks 5-HT2A > D2 |
| Olanzapine | Blocks 5-HT2A > D2 |
Pharmacokinetics
- Oral absorption: Variable; food increases absorption of ziprasidone, lurasidone, and paliperidone (take with food)
- Distribution: Highly lipophilic, large volume of distribution
- Metabolism: Hepatic; CYP enzymes
- Long-acting injectables (LAIs): Available for adherence - risperidone (Perseris), aripiprazole (Aristada), paliperidone (Invega Sustenna/Trinza)
Therapeutic Uses
| Indication | Agents Used |
|---|---|
| Schizophrenia (first-line) | All SGAs |
| Refractory schizophrenia | Clozapine only |
| Bipolar disorder (mania/mixed) | Most SGAs (aripiprazole, olanzapine, quetiapine, risperidone, etc.) |
| Bipolar depression | Lurasidone, cariprazine, quetiapine |
| Adjunctive antidepressant | Aripiprazole, brexpiprazole, quetiapine |
| Schizoaffective disorder | Paliperidone |
| Autism irritability/disruptive behavior | Risperidone, aripiprazole |
| Parkinson disease psychosis | Pimavanserin (only agent approved - no D2 block so no motor worsening) |
| Chemotherapy-induced nausea | Olanzapine |
SGAs can help with both positive symptoms (hallucinations, delusions) AND negative symptoms (blunted affect, apathy, avolition) - unlike FGAs which mainly address positive symptoms only.
Adverse Effects
1. Metabolic Syndrome (Most Clinically Important for SGAs)
| Effect | Most Prominent Agents |
|---|---|
| Weight gain | Clozapine > Olanzapine > Quetiapine > Risperidone |
| Hyperglycemia / Diabetes | Clozapine, Olanzapine |
| Hyperlipidemia | Clozapine, Olanzapine |
Monitor: fasting glucose, lipids, and weight at baseline and regularly thereafter.
2. Extrapyramidal Symptoms (EPS)
- Much lower than FGAs, but not zero
- Risperidone - highest EPS risk among SGAs (especially at higher doses)
- Clozapine, quetiapine - lowest EPS risk
- Tardive dyskinesia is rare but can still occur
3. Prolactin Elevation
- Less than FGAs overall
- Risperidone and paliperidone still cause significant hyperprolactinemia
- Aripiprazole, clozapine, quetiapine - minimal or no prolactin elevation (aripiprazole may actually lower prolactin)
4. QTc Prolongation
- Ziprasidone and iloperidone carry the highest QTc risk among SGAs
- Avoid in patients with pre-existing cardiac conditions or on other QTc-prolonging drugs
5. Sedation
- Most sedating: Clozapine > Olanzapine > Quetiapine
- Least sedating: Aripiprazole, lurasidone
6. Orthostatic Hypotension
- Due to alpha-1 adrenergic blockade
- Most prominent with clozapine, iloperidone
Clozapine - Special Considerations
Clozapine is reserved for treatment-refractory schizophrenia (failed 2+ adequate antipsychotic trials) or patients with high suicide risk.
Why it's unique:
- Most effective antipsychotic known
- Lowest EPS of all antipsychotics
- Effective for negative symptoms and cognitive impairment
Why it's restricted:
| Serious Adverse Effect | Detail |
|---|---|
| Agranulocytosis | ~1-2% risk; life-threatening; mandatory ANC monitoring (Clozapine REMS program) |
| Seizures | Dose-dependent; risk increases at higher doses |
| Myocarditis/Cardiomyopathy | Rare but potentially fatal |
| Hypersalivation (sialorrhea) | Very common; paradoxical (despite muscarinic blockade) |
| Severe constipation | Can progress to bowel obstruction/perforation - monitor carefully |
| Metabolic syndrome | Highest weight gain and diabetes risk of all antipsychotics |
| Orthostatic hypotension | Prominent |
REMS = Risk Evaluation and Mitigation Strategy. Clozapine requires ANC (absolute neutrophil count) monitoring before dispensing each prescription.
Individual Drug Highlights
| Drug | Key Feature |
|---|---|
| Aripiprazole | D2/5-HT1A partial agonist; low metabolic risk; low sedation; can lower prolactin; used as adjunct antidepressant |
| Brexpiprazole | Similar to aripiprazole; adjunct for MDD and schizophrenia |
| Cariprazine | D2/D3 partial agonist (preferential D3); used in bipolar depression; may help negative symptoms |
| Clozapine | Most effective; reserved for refractory cases; risk of agranulocytosis |
| Lumateperone | Newer agent; modulates serotonin, dopamine, glutamate; low metabolic risk |
| Lurasidone | Must take with food (≥350 kcal); approved for bipolar depression; low metabolic risk |
| Olanzapine | Highly effective; highest metabolic risk (weight gain, diabetes) |
| Paliperidone | Active metabolite of risperidone; long-acting injection formulations; approved for schizoaffective disorder |
| Pimavanserin | Pure 5-HT2A inverse agonist; no D2 activity; only for Parkinson disease psychosis |
| Quetiapine | Wide uses (schizophrenia, bipolar, adjunct depression); sedating; low EPS; low prolactin |
| Risperidone | Highest EPS among SGAs at higher doses; significant prolactin elevation; LAI available |
| Ziprasidone | QTc prolongation risk; must take with food; low weight gain |
SGA Side Effect Comparison Table
| Drug | Weight Gain | EPS | Sedation | QTc | Prolactin |
|---|---|---|---|---|---|
| Clozapine | +++ | 0 | +++ | + | 0 |
| Olanzapine | +++ | + | ++ | + | + |
| Quetiapine | ++ | 0/+ | +++ | + | 0 |
| Risperidone | ++ | ++ | + | + | +++ |
| Aripiprazole | 0/+ | + | 0/+ | 0 | 0 |
| Ziprasidone | 0 | + | + | +++ | + |
| Lurasidone | 0/+ | + | + | 0 | + |
| Cariprazine | + | + | 0/+ | 0 | 0 |
| Paliperidone | ++ | ++ | + | + | +++ |
(0 = minimal/none; + = mild; ++ = moderate; +++ = high)
Key Exam Points
- SGAs are first-line for schizophrenia due to lower EPS risk compared to FGAs.
- SGAs help both positive AND negative symptoms; FGAs help mainly positive symptoms.
- Clozapine = most effective antipsychotic; reserved for refractory cases due to agranulocytosis risk.
- Aripiprazole/Brexpiprazole/Cariprazine = D2 partial agonists - unique "dopamine stabilizer" mechanism.
- Pimavanserin = only antipsychotic with no dopamine receptor activity; used exclusively in Parkinson disease psychosis.
- Risperidone = most EPS among SGAs; significant prolactin elevation (similar to FGAs).
- Ziprasidone/Iloperidone = highest QTc prolongation among SGAs.
- Olanzapine/Clozapine = highest metabolic risk (weight gain, diabetes, dyslipidemia).
- Lurasidone, ziprasidone, paliperidone absorption is increased with food - must be taken with food.
- Adjunctive use for treatment-resistant depression: aripiprazole, brexpiprazole, quetiapine.
Source: Lippincott Illustrated Reviews: Pharmacology, Chapter 18 - Antipsychotic Drugs
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