Orkelax (Chlorpheniramine + Paracetamol) aka. Orphenadrine (Norgesic)

Drug Composition:

• Chlorpheniramine Maleate: 4 mg

• Paracetamol (Acetaminophen): 500 mg

• Orkelax is available in tablet form combining Chlorpheniramine 4 mg and Paracetamol 500 mg per tablet.
  

Mechanism of Action:

1. Chlorpheniramine Maleate:

   • Class: First-generation H1-antihistamine.

   • Mechanism: Chlorpheniramine works by competitively inhibiting H1-receptors, blocking the action of histamine, a primary mediator of allergic reactions. This action reduces symptoms such as sneezing, itching, rhinorrhea, and lacrimation commonly seen in allergic rhinitis and the common cold.

   • CNS Effects: As a first-generation antihistamine, chlorpheniramine crosses the blood-brain barrier, which can result in sedation, drowsiness, and sometimes paradoxical excitation, especially in pediatric and geriatric patients.

2. Paracetamol (Acetaminophen):

   • Class: Analgesic and antipyretic.

   • Mechanism: While its exact mechanism of action remains not fully understood, paracetamol primarily acts in the CNS by inhibiting cyclooxygenase (COX) enzymes, particularly COX-3, reducing the synthesis of prostaglandins involved in pain and fever. Unlike NSAIDs, paracetamol lacks significant anti-inflammatory effects, and its peripheral action is minimal.

   • Safety Profile: Paracetamol is generally safe at recommended doses, but its use is associated with hepatotoxicity at high doses due to the formation of a toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which is detoxified by glutathione in the liver. Overdose or chronic use in hepatic impairment can lead to glutathione depletion and subsequent liver damage.

Pharmacokinetics:

1. Chlorpheniramine:

   • Absorption: Well absorbed from the gastrointestinal tract, reaching peak plasma concentrations in 2-3 hours.

   • Distribution: Volume of distribution (Vd) is 0.25–0.58 L/kg. It crosses the placenta and is found in breast milk.

   • Metabolism: Extensively metabolized in the liver by cytochrome P450 (CYP2D6) enzymes.

   • Elimination Half-life: Ranges from 12 to 43 hours, with prolonged half-life in geriatric populations.

   • Excretion: Primarily excreted in the urine as both unchanged drug and metabolites.

2. Paracetamol:

   • Absorption: Rapidly absorbed from the gastrointestinal tract with peak plasma concentrations within 30 minutes to 2 hours.

   • Distribution: Widely distributed in body tissues, crosses the placenta, and is secreted in breast milk. The volume of distribution (Vd) is about 0.9 L/kg.

   • Metabolism: Primarily metabolized in the liver through conjugation reactions (glucuronidation and sulfation), with a small portion metabolized by the CYP450 (CYP2E1) pathway to form the toxic metabolite NAPQI.

   • Elimination Half-life: Approximately 2-3 hours in healthy individuals but may be prolonged in hepatic impairment or overdose.

   • Excretion: Excreted mainly in urine as conjugates (glucuronide and sulfate), with less than 5% excreted unchanged.

Indications:

1. Chlorpheniramine:

   • Allergic rhinitis (seasonal and perennial)

   • Urticaria

   • Common cold symptoms (e.g., sneezing, rhinorrhea)

   • Allergic conjunctivitis

2. Paracetamol:

   • Relief of mild to moderate pain (e.g., headache, myalgia, arthralgia)

   • Reduction of fever in conditions like viral infections or post-vaccination

Dosage and Administration:

1. For Adults:

   • Chlorpheniramine: 4 mg orally every 4-6 hours. Maximum dose: 24 mg/day.

   • Paracetamol: 500-1000 mg orally every 4-6 hours. Maximum dose: 4000 mg/day.

   • Caution: The combination should not exceed the recommended maximum daily doses for each component to avoid antihistamine toxicity and paracetamol-induced hepatotoxicity.

2. For Children (6-12 years):

   • Chlorpheniramine: 2 mg orally every 4-6 hours. Maximum dose: 12 mg/day.

   • Paracetamol: 250-500 mg orally every 4-6 hours. Maximum dose: 2000 mg/day.

3. For Elderly or Hepatically Impaired Patients:

   • Chlorpheniramine: Use caution due to the risk of sedation, dizziness, and prolonged half-life. Lower doses or less frequent administration may be required.

   • Paracetamol: Maximum daily dose should be reduced to 2000-3000 mg/day to minimize the risk of hepatotoxicity, especially in chronic alcohol users or those with pre-existing liver disease.

Dosage Adjustments:

1. Renal Impairment:

   • Chlorpheniramine: Dosage should be reduced in moderate to severe renal impairment (creatinine clearance <30 mL/min) due to reduced clearance and prolonged half-life.

   • Paracetamol: No significant adjustment is necessary for mild renal impairment; however, in patients with severe renal impairment (GFR <30 mL/min), extend dosing intervals to 6-8 hours to avoid accumulation.

2. Hepatic Impairment:

   • Chlorpheniramine: Use with caution; consider dose reduction or avoid use in severe hepatic dysfunction.

   • Paracetamol: Reduce the total daily dose to 2000 mg/day in patients with significant liver impairment or chronic alcohol abuse due to the increased risk of hepatotoxicity.

Drug Interactions:

1. Chlorpheniramine:

   • CNS Depressants (e.g., opioids, benzodiazepines): Additive CNS depression may occur, increasing the risk of sedation, respiratory depression, or impaired motor function.

   • Monoamine Oxidase Inhibitors (MAOIs): Concomitant use may prolong and intensify the anticholinergic and CNS-depressant effects. Avoid using within 14 days of MAOI therapy.

2. Paracetamol:

   • Warfarin: Chronic, high-dose paracetamol (≥2 g/day) can enhance the anticoagulant effect of warfarin, increasing the risk of bleeding.

   • Alcohol: Chronic alcohol use can induce CYP2E1, increasing the formation of hepatotoxic NAPQI, thus potentiating the risk of liver damage.

   • CYP450 Enzyme Inducers (e.g., rifampin, carbamazepine): These may increase the conversion of paracetamol to its toxic metabolite, raising the risk of hepatotoxicity.

Adverse Effects:

1. Chlorpheniramine:

   • Common: Sedation, dry mouth, dizziness, urinary retention, and blurred vision (anticholinergic effects).

   • Severe: Tachycardia, arrhythmias, confusion, particularly in elderly patients.

2. Paracetamol:

   • Common: Rarely causes adverse effects when taken within the therapeutic range.

   • Severe: Hepatotoxicity, particularly in overdose situations. Symptoms of hepatotoxicity (nausea, vomiting, malaise) may appear after 24-72 hours of overdose.

Toxicity Management:

1. Chlorpheniramine:

   • Overdose may present with anticholinergic toxicity (dry mouth, dilated pupils, hyperthermia, hallucinations) or severe CNS depression (somnolence, coma). Management includes supportive care, activated charcoal if early, and in severe cases, physostigmine to reverse anticholinergic toxicity.

2. Paracetamol:

   • Overdose Management: The primary concern is hepatotoxicity. Administer N-acetylcysteine (NAC) as an antidote if ingestion exceeds toxic thresholds (≥150 mg/kg in children or ≥7.5 g in adults). NAC is most effective within 8-10 hours post-ingestion but can be beneficial even if administered later.

Special Considerations:

1. Pregnancy:

   • Chlorpheniramine: Classified as Category B by the FDA (animal studies have shown no risk, but no adequate human studies). Use cautiously, especially in the third trimester due to the risk of sedation in the neonate.

   • Paracetamol: Considered safe during pregnancy (Category B), but chronic high doses should be avoided to prevent fetal hepatotoxicity.

2. Breastfeeding:

   • Chlorpheniramine: Excreted in breast milk. It may cause sedation in the breastfed infant, so use with caution.

   • Paracetamol: Generally considered safe during breastfeeding at recommended doses.

Conclusion:

For Orkelax, careful consideration should be given to the patient’s age, renal and hepatic function, and potential drug interactions. Pharmacists should be vigilant about the risk of chlorpheniramine-induced sedation and paracetamol-induced hepatotoxicity, especially when recommending or dispensing this combination. Proper patient counseling, particularly in vulnerable populations such as the elderly or those with liver impairment, is crucial to prevent adverse outcomes.