What are the first-line indications and contraindications for promethazine, diazepam, and phenytoin?

Promethazine, Diazepam, and Phenytoin: First-Line Indications and Contraindications

Promethazine

First-Line Indications

Promethazine is NOT a first-line drug for any condition. It serves only as an adjunct sedative agent in specific procedural contexts.

• Adjunct sedation for endoscopic procedures: Promethazine (12.5-25 mg IV) can be used as an adjunct to benzodiazepines and opioids during gastrointestinal endoscopy, potentially reducing the required doses of primary sedatives 1
• The drug possesses antihistamine, sedative, antiemetic, and anticholinergic effects but is never recommended as monotherapy for any indication 1

Absolute Contraindications

Promethazine is absolutely contraindicated in the following conditions:

• Pediatric patients less than 2 years of age 2
• Comatose states 2
• Known hypersensitivity to promethazine or other phenothiazines 2
• Lower respiratory tract symptoms including asthma (antihistamines are contraindicated) 2

Critical Safety Warnings

• Serious limb-threatening adverse effects can occur with extravasation or inadvertent intra-arterial injection, including tissue necrosis and gangrene 1, 3
• Adverse effects include hypotension, respiratory depression, neuroleptic malignant syndrome, and extrapyramidal effects ranging from restlessness to oculogyric crises 1
• The FDA changed product labeling in December 2023 to recommend dilution and preferential intramuscular administration due to these risks 3

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Diazepam

First-Line Indications

Diazepam is a first-line drug for acute seizure management, though lorazepam is generally preferred.

• Status epilepticus (when IV access unavailable): Rectal diazepam is an alternative first-line treatment when IV lorazepam cannot be administered 4
• Emergency management of acute seizures: Diazepam is considered a first-line agent alongside lorazepam and clonazepam for acute seizure control 5
• Note: Lorazepam is superior to diazepam for status epilepticus (59.1% vs 42.6% seizure termination efficacy) and is the preferred benzodiazepine due to longer duration of action 6, 4

Absolute Contraindications

No specific absolute contraindications are listed in the provided evidence for diazepam. However, general benzodiazepine contraindications apply:

• Severe respiratory depression
• Acute narrow-angle glaucoma
• Known hypersensitivity to benzodiazepines

Critical Drug Interaction

• Phenytoin interaction: Diazepam can cause phenytoin toxicity by acting as an alternate substrate for CYP2C19, potentially increasing phenytoin levels to toxic ranges 7
• This interaction is clinically significant and requires monitoring when drugs are coadministered 7

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Phenytoin

First-Line Indications

Phenytoin (or fosphenytoin) is a first-line drug for specific seizure types and situations:

• Partial seizures and secondarily generalized tonic-clonic seizures (chronic management): Phenytoin is recommended as a first-choice drug alongside carbamazepine for single-drug therapy in adults 8
• Second-line treatment for status epilepticus: Phenytoin/fosphenytoin (20 mg/kg IV at maximum 50 mg/min) is the traditional and most widely available second-line agent after benzodiazepines fail, with 95% of neurologists recommending it for benzodiazepine-refractory seizures 6, 4
• Prevention and treatment of seizures during neurosurgery 9
• Generalized tonic-clonic status epilepticus 9

Absolute Contraindications

Phenytoin is absolutely contraindicated in:

• Hypersensitivity to phenytoin, its ingredients, or other hydantoins 9, 10
• Sinus bradycardia, sino-atrial block, second and third degree AV block, and Adams-Stokes syndrome 9
• History of prior acute hepatotoxicity attributable to phenytoin 9
• Coadministration with delavirdine 9

Critical Safety Warnings

• Cardiovascular monitoring required: Continuous ECG and blood pressure monitoring are essential due to 12% risk of hypotension and cardiac toxicity 6, 4
• Serious dermatologic reactions: Discontinue immediately at first sign of rash; if Stevens-Johnson syndrome/toxic epidermal necrolysis suspected, never resume phenytoin 9
• DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms): Evaluate immediately if hypersensitivity signs present 9
• Withdrawal-precipitated seizures: Never discontinue abruptly; may precipitate status epilepticus 9
• Teratogenicity: Prenatal exposure increases risk of congenital malformations 9
• HLA-B*1502 screening: Check in Asian patients before starting due to Stevens-Johnson syndrome risk 4

Important Clinical Considerations

• Alternative second-line agents may be superior: Valproate has 88% efficacy with 0% hypotension risk compared to phenytoin's 84% efficacy with 12% hypotension risk 6, 4
• Avoid as first-choice for long-term management: Due to sedative effects and cognitive/cerebellar dysfunction 4
• Maximum infusion rate: 50 mg/min for adults; 1-3 mg/kg/min or 50 mg/min (whichever slower) for pediatrics 9