Antipsychotics 1st Generation
- 카테고리 없음
- 2020. 7. 27.
Indications: Schizophrenia another psychotic disorders
Schizophrenia [the classic-psychotic disorder]
- Cause of schizophrenia [조현병] is not clearly known; Primarily related to altered levels of dopamine and glutamine and includes altered brain structure and chemistry
- Ranges: Mild - Moderate - Severe
- Clinical S/Sx
| DSM-5 Diagnostic Criteria For Schizophrenia: delusions, hallucinations or disorganized speech must be present | |
| NEGATIVE S/Sx | POSITIVE S/SX |
| Loss of interest in everyday activities | Hallucinations: auditory, visual, somatic |
| Lack of emotions=Flat Affect (Apathy) | Delusions: beliefs held by the patient that are without a basis in reality |
| Inability to plan or carry out activities | Disorganized thinking/behavior, incoherent speech, often on unrelated topics, purposeless behavior, or difficulty speaking an organizing thoughts, such as stopping in mid-sentence or jumbling together meaning-less words. |
| Poor hygiene | Difficulty paying attention |
| Social withdrawal | |
| Loss of motivation | |
| Lack of speech (Alogia [실어증]) | |
Pathophysiology: hypothesis → schizophrenia results from increased dopaminergic neurotransmission
- DOPAMINE PATHWAYs ← this dopaminergic model is now added to supply with a more recent understanding of the role of the glutaminergic NMDA (N-methyl-D-aspartate) receptor
- Mesolimbic pathway - controls motivations and desire; High levels of DA which lead to + symptoms of schizo
- Mesocortical pathway - controls emotions; Low levels of DA which lead to - symptoms of schizo
- Nigrostriatal pathway - controls motor neurons that Bypass the medullary pyramids and involuntary movements and coordination; may cause side effects such as EPS (abnormal movements)
- Tuberoinfundibular pathway - releases dopamine to limit the secretion of prolactin; may cause oligomenorrhea, galactorrhea, gynecomastia for side effects
- Chemoreceptor trigger zone - controls vomiting reflex
- Medullary periventricular pathway - controls eating behavior
In schizophrenia, altered levels of dopamine mainly affect affected mesolimbic and mesocortical pathways
Drugs
Typical antipsychotics - blocks DA (dopamine) receptor, blocks 5HT2a receptor minimally; CYP450 liver metabolism
- Beneficial for POSITIVE S/Sx
- Take longer time to respond for cognitive and functional impairment and motivation deficiency
1st Generation Antipsychotics
| LOW [Aliphatic Phenothiazine] | LOW [Piperidine-like Phenothiazine] | MID | HIGH [Piperazine Phenothiazines] |
| Chlopromazine (Thorazine): 300-1000 mg/day; divided Triflupromazine (Vesprin) Chlorprothixine (Tractan) |
Thioridazine (Mellaril): 300-800 mg/day; divided **BBW → QTc Prolongation Piperacetazine (Quide) Mesoridazine (Serentil) |
|
Fluphenazine (Modecate) |
Dr. Moniri @Mercer University College of Pharmacy
Dr. Moniri @Mercer University College of Pharmacy
Prephenazine (Trilafon)
- Side Effects
- Sedation (by blocking H1 receptor), seizures, CV effects (orthostatic hypotension - by blocking a1-receptor), tachycardia, QTc prolongation-IV Haldol has high risk), sexual dysfunction, EPS (extrapyramidal symptoms), muscarinic receptor blocking effects (anticholinergic "atropine-like" side effects: dry mouth, blurred vision, urinary retention, constipation.
- EPS = dystonia, akathisia, pseudo-parkinsonism, tardive dyskinesias, and dyskinesias
- Dystonia (few hours to days) = higher risk for younger males - diphenhydramine, benztropine may be used for prophylaxis. Can occur within a few hours to day of the treatment. Muscle spasms of the tongue, face neck and back. And also causes oculogyric crisis (spasm of extraocular muscles; eyes moving upwards involuntarily) .
- Akathisia (days to months) = may be treated with anticholinergics (diphenhydramine, benztropine) and BZDs, or propranolol. Characterized by restlessness, urge to move the limbs
- Parkinsonism (days to months) = EPS looks similar to parkinson disease - tremors, unstable gait, bradykinesia. Can be treated with anticholinergics or propranolol. Characterized by muscle (facial muscle usually rigidity, bradykinesia, and tremors.
- TD (months to years; Can be Irreversible) = higher risk for elderly females; abnormal facial movements - primarily in the tongue or mouth. If TD occurs during treatment, drug should be stopped right away then switch to second generation antipsychotics with low EPS risk (quetiapine, clozapine). Characterized by constant, involuntary, rhythmic movements (Perioral muscles smack or purse lips)
- Approved tx for TD = Valbenazine (Ingrezza) 40 mg PO QD ➡︎ 1wk after inc to 80 mg PO QD
- SEs: somnolence, QTc prolongation
- Dose adjustment is needed in M-S hepatic impaired patients
- Drug interaction: Avoid use with MAO inhibitors, Ingreazza is a strong 2D6 and 3A4 inhibitors, and P-gp inhibitor
- 2D6: paroxetine, fluoxetine
- 3A4: itraconazole, clarithromycin
- P-gp inhibitor: increases digoxin concentration - dose adjustment of digoxin is required
- NMS - Neuroleptic malignant syndrome (weeks to months; most SEVERE symptoms): Characterized by confusion, coma, agitation, muscle rigidity, seizures, and hyperthermia. These symptoms are very similar to SEROTONIN SYNDROME except SS has hyperreflexia and dilated pupils but NMS has hyporeflexia, and normal pupils. If NMS persists, it could lead to rhabdomyolysis. However, it can be treated by "Dantrolene" a muscle relaxant. And quickly taper off AP. *NMS is more common with EGAs than SGAs*
- Lab results: increased creatine phosphokinase and increased white blood cells
- LOW potency agents = ⬆︎ EPS ⬇︎ Sedation
- HIGH potency agents = ⬇︎ EPS ⬆︎ Sedation
- TYPICAL ANTIPSYCHOTICS = HIGH RISK of EPS than SGAs. *EPS symptoms usually stop with DC drug*
- Drug specific SEs:
- IV haloperidol = QTc prolongation
- Loxapine = dysgeusia-bad, bitter, metallic taste in mouth
- Chlorpromazine = corneal deposits
- Thioridazine = retinal deposits
- Safety [ BBW ]
- AVOID in order patients with dementia-related psychosis due to increased risk of death
- Most deaths occur due to CV (e.g., HF, sudden death) or infectious in nature
- NOT approved for Tx of dementia-related psychosis
- Relative Potency
| Receptor affinity | Activities: HIGH LOWEST |
| DA (D2) receptors | Piperazine > Piperidines > Aliphatics |
| Physiological Effect | |
| Antipsychotic Potency | Piperazine > Piperidines > Aliphatics |
| EPS | Piperazine > Aliphatics > Piperidines |
| Sexual dysfunction | Aliphatics = Piperidines > Piperazine |
| Hypotension | Aliphatics = Piperidines > Piperazine |
| Sedation | Aliphatics = Piperidines > Piperazine |
Esterified phenothiazine = long acting phenothiazine (IM injection)
- Adding ester (esterification): longer duration
- Drug goes to DEPOT (storage site): drug will leave out of DEPOT in the muscle and hydrolyze into active phenothiazine durg.
- Benefit: longer duration of treatment (weekly administration), better compliance
- Fluphenazine Enanthate (Flunanthate) = 7 carbons; 1-2wks
- Fluphenazine Dexanoate (Modecate) = 10 carbons. ⬅︎ longest duration due to more carbon chain 2-3wks
- Perphenazine Enanthate (Trilafon Depot) = 7 carbons; 1-2 wks
Haloperidol and Droperidol: Butyrophenon Antipsychotic Agents
- Butyrophenone is an analog of meperidine (opioid analgesic (Demerol)
- Bind to D2, 5HT2 and Sigma-2 receptors
- Produces high degree of EPS, and dyskinesia BUT less sedation, less histaminergic and less adrenergic effects.
Haloperidol Decanoate
- Binds to D2 receptor and act as antagonist in nigrostriatal pathway
- Contains 10 carbons - extend treatment duration - aids in compliance
- IM injection
- Have high degree of EPS