D-119

Dosage for Antipyrine varies significantly based on the indication and the specific formulation being used.

Otic Administration (Ear Drops)

For the treatment of pain associated with acute otitis media or for the softening of earwax, the standard adult dosage is as follows:

• Acute Otitis Media: Instill enough drops to fill the ear canal every 1 to 2 hours until the pain and congestion are relieved. Healthcare providers typically recommend maintaining the position of the head (tilted to the side) for several minutes after application to ensure the medication stays in contact with the tympanic membrane.
• Cerumen Removal: Instill the drops into the affected ear(s) three times daily for 2 to 3 days to effectively soften the wax before a scheduled irrigation procedure.

Diagnostic Use (Antipyrine Clearance Test)

For diagnostic purposes, a single oral dose is typically administered.

• Standard Dose: 10 mg/kg to 15 mg/kg of body weight.
• Procedure: Following administration, multiple blood or saliva samples are collected over a 24-to-48-hour period to calculate the rate of clearance and the half-life of the drug.

Antipyrine otic solutions are frequently used in children, but they must be administered with caution and only under the direction of a pediatrician.

• Children (All Ages): The dosage is generally the same as the adult dosage—instilling enough drops to fill the ear canal. However, the frequency may be adjusted by the physician based on the child's age and the severity of the infection.
• Safety Note: Ensure the child remains still for at least 5 minutes after administration. Use a cotton plug moistened with the solution to keep the medication in the ear if directed by a doctor.

Renal Impairment

Since Antipyrine is primarily eliminated via the kidneys as metabolites, patients with severe renal impairment (CrCl < 30 mL/min) may require monitoring for systemic accumulation, although this is rare with topical otic use. For systemic diagnostic use, dose reduction is generally not required, but the clearance rate will be affected by the patient's underlying physiology.

Hepatic Impairment

In patients with liver cirrhosis or hepatitis, the metabolism of Antipyrine is significantly slowed. While this is the basis of the diagnostic test, therapeutic use (if systemic) would require substantial dose reductions. For otic use, no adjustment is typically necessary unless there is a risk of systemic absorption.

Elderly Patients

Elderly patients often exhibit a reduced rate of hepatic metabolism. When using Antipyrine for diagnostic purposes, clinicians must account for age-related declines in CYP450 activity. For ear drops, the standard adult dose is generally safe, provided the eardrum is intact.

1. 1Warm the Bottle: Hold the bottle in your hands for a few minutes to warm the solution. Cold ear drops can cause dizziness or nausea when instilled.
2. 2Positioning: Lie on your side or tilt your head so the affected ear faces upward.
3. 3Application: Gently pull the earlobe up and back (for adults) or down and back (for children) to straighten the ear canal. Drop the prescribed amount of liquid into the ear.
4. 4Stay Still: Keep the ear tilted upward for about 5 minutes to allow the medicine to coat the eardrum.
5. 5Cotton Plug: You may place a small piece of cotton in the ear to prevent the medicine from leaking out, but do not push it deep into the canal.
6. 6Storage: Store at room temperature (15°C to 30°C). Keep the bottle tightly closed and protect it from light and moisture.

If you miss a dose of Antipyrine ear drops, apply it as soon as you remember. If it is almost time for your next scheduled dose, skip the missed dose and return to your regular schedule. Do not double the dose to catch up.

Systemic overdose from otic use is extremely rare unless the eardrum is perforated. Signs of systemic Antipyrine toxicity include:

• Central Nervous System: Dizziness, confusion, seizures, or coma.
• Respiratory: Slowed breathing or respiratory arrest.
• Cardiovascular: Cyanosis (bluish skin due to lack of oxygen) or hypotension.
• Heme: Methemoglobinemia (a blood disorder where oxygen cannot be effectively released to tissues).

In case of suspected ingestion or systemic toxicity, contact a Poison Control Center or seek emergency medical attention immediately.

> Important: Follow your healthcare provider's dosing instructions. Do not adjust your dose or use the medication for longer than prescribed without medical guidance.

When used as an otic preparation, Antipyrine is generally well-tolerated. However, some patients may experience localized reactions:

• Stinging or Burning: A brief sensation of heat or stinging immediately after the drops are instilled. This typically lasts only a few seconds.
• Local Irritation: Redness or itching within the ear canal.
• Sensation of Fullness: A feeling of pressure or "clogged" ears due to the glycerin base of the drops.

• Dizziness or Vertigo: This usually occurs if the drops are instilled while cold. It is a transient vestibular response to the temperature change in the ear canal.
• Contact Dermatitis: A localized allergic rash around the ear or on the neck where the drops may have leaked.

Systemic side effects are rare with topical use but can be severe if the drug enters the bloodstream:

• Agranulocytosis: A dangerous drop in white blood cell count. While this was the primary reason systemic Antipyrine fell out of favor, it remains a theoretical risk if large amounts are absorbed systemically.
• Methemoglobinemia: A condition where the blood's ability to carry oxygen is impaired. Symptoms include bluish skin, headache, and fatigue.
• Fixed Drug Eruption: A unique allergic skin reaction that recurs in the same location whenever the drug is taken.

> Warning: Stop taking Antipyrine and call your doctor immediately if you experience any of these serious symptoms.

• Anaphylaxis: Signs include hives, difficulty breathing, swelling of the face, lips, tongue, or throat. This is a medical emergency.
• Severe Skin Reactions: Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN). Watch for skin peeling, blisters, or a painful red rash that spreads.
• Ototoxicity: Sudden hearing loss, severe ringing in the ears (tinnitus), or intense dizziness. This may indicate the medication has reached the inner ear through an undiagnosed perforation.
• Severe Hematologic Changes: Unusual bruising, bleeding, fever, or persistent sore throat (potential signs of agranulocytosis).

Prolonged use of Antipyrine ear drops (beyond the recommended 2-3 days for wax removal or the acute phase of an infection) can lead to:

• Secondary Infections: Overgrowth of non-susceptible organisms, including fungi (otomycosis).
• Maceration of the Ear Canal: Softening and breakdown of the skin in the ear canal due to chronic moisture and chemical exposure.
• Chronic Hypersensitivity: Increased risk of developing a permanent allergy to pyrazolone medications.

No FDA black box warnings currently exist for Antipyrine otic preparations. However, the FDA has historically issued warnings regarding the systemic use of pyrazolone derivatives due to the risk of fatal agranulocytosis. Patients should be aware that while the topical ear drop is considered safe when used as directed, the chemical family has a history of serious hematologic risks.

Report any unusual symptoms or persistent irritation to your healthcare provider. If symptoms do not improve within 48 to 72 hours of starting treatment, a re-evaluation by a physician is necessary to rule out a worsening infection or a perforated eardrum.

Antipyrine must be used with caution and only for its intended purpose. The most critical safety consideration is the integrity of the tympanic membrane (eardrum). Using Antipyrine in an ear with a hole or tear can lead to severe complications, including middle ear damage and systemic absorption of the drug. If you experience fluid drainage, pus, or blood coming from the ear, do not use this medication and consult a doctor immediately.

No FDA black box warnings for Antipyrine are currently in effect for the otic formulations. However, clinicians are advised to remain vigilant for signs of hypersensitivity and hematologic changes, which are class-wide concerns for pyrazolones.

Allergic Reactions / Anaphylaxis Risk

Patients with a known sensitivity to Antipyrine, Benzocaine, or other pyrazolone derivatives (such as phenylbutazone or metamizole) must avoid this medication. Cross-sensitivity is common. Anaphylactic reactions, though rare with topical use, can be life-threatening.

Hematologic Toxicity

Although the risk is primarily associated with oral administration, Antipyrine has been linked to agranulocytosis and hemolytic anemia. Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency may be at a higher risk for hemolysis if systemic absorption occurs.

Methemoglobinemia

This is a significant risk, particularly when Antipyrine is combined with Benzocaine. It is a condition where an abnormal amount of methemoglobin is produced, reducing the blood's ability to release oxygen to tissues. This risk is highest in infants and the elderly.

For short-term otic use, routine lab monitoring is generally not required. However, for patients undergoing the Antipyrine Clearance Test or those using the medication systemically in a research setting, the following may be monitored:

• Complete Blood Count (CBC): To check for white blood cell and platelet levels.
• Liver Function Tests (LFTs): To assess baseline hepatic health before diagnostic testing.
• Physical Exam: Periodic inspection of the ear canal and eardrum by a healthcare professional.

Antipyrine ear drops may cause temporary dizziness or blurred vision (if the head is tilted for a long period). Patients should ensure their balance has returned to normal before driving or operating heavy machinery. Systemic Antipyrine may cause drowsiness or confusion.

Alcohol is a known inducer of certain hepatic enzymes and a suppressor of others. Consuming alcohol can significantly alter the results of an Antipyrine clearance test. For therapeutic otic use, there is no known direct interaction with alcohol, but alcohol should be avoided if the patient is experiencing dizziness or vertigo.

Antipyrine otic drops should be discontinued once the ear pain has subsided or the earwax has been successfully removed. There is no risk of withdrawal syndrome, and tapering is not required. If symptoms return after discontinuation, it may indicate a persistent infection that requires antibiotics.

> Important: Discuss all your medical conditions, especially any history of ear surgery or blood disorders, with your healthcare provider before starting Antipyrine.

While Antipyrine is used topically, the following interactions are critical if the drug is absorbed systemically or used in diagnostic testing:

• None Absolute for Otic Use: There are no medications that are strictly contraindicated for use with Antipyrine ear drops, provided the eardrum is intact.
• Systemic Contraindications: If used systemically, Antipyrine should not be used with other drugs that cause agranulocytosis (e.g., clozapine) due to the additive risk of bone marrow suppression.

Antipyrine is a "probe" drug for CYP450 enzymes. Therefore, drugs that strongly induce or inhibit these enzymes will interact with it:

• Enzyme Inducers (e.g., Rifampin, Phenobarbital, Phenytoin, Carbamazepine): These drugs increase the metabolism of Antipyrine, significantly shortening its half-life and reducing its concentration. This is a major concern during diagnostic testing.
• Enzyme Inhibitors (e.g., Cimetidine, Erythromycin, Ketoconazole, Disulfiram): These medications slow the metabolism of Antipyrine, leading to higher blood levels and an increased risk of toxicity.

• Oral Contraceptives: Estrogen-containing contraceptives can inhibit the metabolism of Antipyrine, potentially increasing its effects.
• Theophylline: Antipyrine and theophylline share similar metabolic pathways (CYP1A2). Taking them together may lead to altered clearance rates for both drugs.
• Warfarin: While not a direct anticoagulant interaction, changes in hepatic metabolism caused by Antipyrine (if used systemically) could theoretically affect the metabolism of warfarin.

• Caffeine: Caffeine is metabolized by CYP1A2, the same enzyme that handles a portion of Antipyrine metabolism. High caffeine intake can competitively inhibit Antipyrine clearance.
• Charbroiled Foods: Compounds found in heavily charred meats can induce CYP1A2, potentially speeding up the metabolism of Antipyrine.
• Grapefruit Juice: While primarily known for its effect on CYP3A4, grapefruit juice may have a minor inhibitory effect on the systemic metabolism of Antipyrine.

• St. John's Wort: This herbal supplement is a potent inducer of CYP3A4 and other enzymes. It will significantly increase the clearance of Antipyrine, rendering diagnostic tests inaccurate.
• Ginkgo Biloba: May have antiplatelet effects that could theoretically increase the risk of bleeding if systemic Antipyrine is present.

Antipyrine can interfere with certain laboratory tests:

• Liver Function Tests: As it is used to measure liver function, its presence is intended to "interact" with the assessment of metabolic capacity.
• Urinary Glucose Tests: High systemic levels of Antipyrine may cause false-positive results in certain copper reduction tests (e.g., Benedict's solution).

For each major interaction, the management strategy usually involves adjusting the timing of the diagnostic test or monitoring for signs of increased drug effect. In the case of ear drops, the risk is minimal unless the patient has a perforated eardrum.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking, especially if you are scheduled for a liver function or metabolic study.

Antipyrine must NEVER be used in the following circumstances:

1. 1Perforated Tympanic Membrane: If the eardrum has a hole or tear, the medication can enter the middle and inner ear, causing severe pain, ototoxicity (hearing damage), and systemic absorption. This is the most critical contraindication for otic use.
2. 2Hypersensitivity to Pyrazolones: Patients with a known allergy to Antipyrine, phenazone, or related drugs (like phenylbutazone) must avoid this medication. The risk of anaphylaxis or severe skin reactions is high.
3. 3Hypersensitivity to Benzocaine: Since most Antipyrine products are combination formulas, an allergy to ester-type local anesthetics (like benzocaine or procaine) is an absolute contraindication.

Conditions requiring a careful risk-benefit analysis include:

• G6PD Deficiency: These patients are at a higher risk for hemolytic anemia if the drug is absorbed systemically.
• History of Agranulocytosis: Even if the previous episode was caused by a different drug, the patient may be more susceptible to bone marrow suppression.
• Pregnancy and Lactation: Use only if clearly needed and if the eardrum is confirmed to be intact.
• Infants under 1 year: The risk of methemoglobinemia is significantly higher in this age group.

Patients who are allergic to aspirin or other NSAIDs may occasionally exhibit cross-sensitivity to Antipyrine, although this is less common than cross-sensitivity within the pyrazolone class itself. There is also a known cross-sensitivity between benzocaine (often found in Antipyrine ear drops) and other "caine" anesthetics or certain hair dyes (paraphenylenediamine).

> Important: Your healthcare provider will evaluate your complete medical history, including any history of ear tubes (tympanostomy tubes), before prescribing Antipyrine.

Antipyrine is classified as Pregnancy Category C by the FDA. There are no adequate and well-controlled studies in pregnant women. Animal reproduction studies have not been conducted with Antipyrine.

• First and Second Trimester: Use should be limited to cases where the potential benefit justifies the potential risk to the fetus.
• Third Trimester: Like other NSAIDs, there is a theoretical risk that systemic absorption of Antipyrine could cause premature closure of the ductus arteriosus in the fetus. While absorption from the ear is low, caution is advised.
• Clinical Recommendation: Healthcare providers typically avoid systemic Antipyrine in pregnancy. Otic use is generally considered safe only if the eardrum is confirmed to be intact.

Antipyrine is known to be excreted into human breast milk.

• Risk Summary: While the amount of drug a nursing infant would receive from the mother's otic use is likely negligible, systemic use for diagnostic purposes can result in measurable levels in milk.
• Effect on Infant: There have been rare reports of sedation or rash in nursing infants whose mothers took pyrazolones.
• Recommendation: A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Antipyrine/Benzocaine otic drops are commonly used in children for ear pain.

• Approved Use: It is often used for acute otitis media in children as young as 6 months.
• Special Dosing: Dosage is based on filling the ear canal rather than body weight for topical use.
• Warning: Infants are at a higher risk for methemoglobinemia. Symptoms such as pale, gray, or blue-colored skin, lips, or fingernails require immediate emergency care.

• Pharmacokinetics: Older adults often have a reduced volume of total body water and decreased hepatic enzyme activity. This leads to a longer half-life for Antipyrine (often exceeding 15-20 hours).
• Polypharmacy: The elderly are more likely to be on medications that interact with the CYP450 system, making the results of an Antipyrine clearance test more complex to interpret.
• Safety: For otic use, the standard precautions regarding eardrum integrity apply. There is no evidence that the elderly are at a higher risk for local side effects.

In patients with kidney disease, the excretion of Antipyrine metabolites is delayed. While the parent drug is mostly metabolized by the liver, the accumulation of metabolites in renal failure could theoretically lead to toxicity if the drug is used systemically. No specific dose adjustment is required for ear drops.

Antipyrine clearance is a direct measure of hepatic metabolic function. In patients with cirrhosis, the half-life of Antipyrine can be extended to 40 hours or more. While this makes it a useful diagnostic tool, it also means that these patients are at a much higher risk of toxicity if given systemic doses of any pyrazolone drug.

> Important: Special populations require individualized medical assessment. Always inform your doctor if you are pregnant, nursing, or have underlying organ dysfunction.

Antipyrine is a pyrazolone derivative that exerts its effects through several pathways. Its primary mechanism is the non-selective inhibition of cyclooxygenase (COX-1 and COX-2) enzymes. By blocking these enzymes, Antipyrine prevents the synthesis of prostaglandins from arachidonic acid. Prostaglandins are the primary mediators of the inflammatory response, sensitizing peripheral pain receptors and acting on the hypothalamus to increase body temperature.

In addition to its COX inhibition, Antipyrine may have effects on the central nervous system, potentially modulating the perception of pain through pathways involving the periaqueductal gray matter. In otic applications, its osmotic properties (when formulated in glycerin) help to draw fluid out of the inflamed tissues of the middle ear, reducing pressure and pain.

• Onset of Action: When applied to the ear, the analgesic effect of the Antipyrine/Benzocaine combination is rapid, often occurring within 5 to 15 minutes.
• Duration: The local effect typically lasts for 1 to 2 hours, necessitating frequent re-application in acute cases.
• Tolerance: There is no evidence of pharmacological tolerance developing with short-term use of Antipyrine.

| Parameter | Value |

|---|---|

| Bioavailability | ~100% (Oral); Negligible (Otic - Intact Eardrum) |

| Protein Binding | < 10% |

| Half-life | 10 - 15 hours (Adults); 20+ hours (Cirrhosis) |

| Tmax | 1 - 2 hours (Oral) |

| Metabolism | Hepatic (CYP1A2, 2C9, 2C19, 3A4) |

| Excretion | Renal (>95% as metabolites, <5% unchanged) |

• Molecular Formula: C11H12N2O
• Molecular Weight: 188.23 g/mol
• Solubility: Highly soluble in water, ethanol, and chloroform.
• Structure: A five-membered pyrazole ring with two nitrogen atoms, a carbonyl group at the 5-position, and phenyl and methyl substituents.

Antipyrine is classified as a Pyrazolone NSAID. It is the parent compound of the pyrazolone class, which also includes medications like metamizole (dipyrone) and propyphenazone. While many members of this class have been restricted due to hematologic risks, Antipyrine's continued use in otic and diagnostic medicine highlights its specific utility where systemic exposure is controlled or intentional.