Isoniazid (INH)

Overview

Isoniazid (INH) is an antimycobacterial agent used primarily for chemoprophylaxis of Mycobacterium bovis or Mycobacterium tuberculosis in small animal species. It may also be used in combination with other antimycobacterial drugs for selected mycobacterial infections, although treatment of active infections remains controversial because of the potential public health risks associated with zoonotic transmission.

Mechanism of Action (MOA): Isoniazid inhibits the synthesis of mycolic acids, an essential component of the mycobacterial cell wall. It is most active against dividing mycobacteria and affects both extracellular and intracellular organisms. It is bactericidal against actively dividing mycobacteria and bacteriostatic against dormant or semi-dormant organisms. Isoniazid is active against Mycobacterium tuberculosis, Mycobacterium bovis, and some strains of Mycobacterium kansasii. It also has an inhibitory effect on monoamine oxidase.

Indications

Isoniazid is used primarily for chemoprophylaxis of tuberculosis in small animals and, in selected cases, as part of combination therapy for mycobacterial infections. Treatment of active tuberculosis remains controversial because of the potential zoonotic risk.

• Tuberculosis chemoprophylaxis: Prevention of Mycobacterium tuberculosis or Mycobacterium bovis infection in dogs and cats living in households with a person diagnosed with tuberculosis.
• Mycobacterial infections (combination therapy): Used with other antimycobacterial drugs for selected Mycobacterium bovis or Mycobacterium tuberculosis infections in dogs and cats.

Dosage (Reference)

Dog

In dogs, published doses cover tuberculosis chemoprophylaxis and the treatment of mycobacterial infections, including a combination protocol with rifampin and ethambutol. Treatment of active Mycobacterium tuberculosis or Mycobacterium bovis infection is considered controversial because of the zoonotic risk.

Cat

In cats, isoniazid is reserved as a second-line antimycobacterial drug for resistant tuberculosis infections.

Warnings & Precautions

Isoniazid (INH) has a narrow therapeutic index, and toxicity is a significant concern. Careful patient selection and monitoring are recommended throughout therapy.

• Acute liver disease: Contraindicated in patients with acute liver disease.
• Previous isoniazid-induced hepatopathy: Do not use in patients that previously developed hepatopathy while receiving isoniazid.
• Hypersensitivity: Contraindicated in patients with known hypersensitivity to isoniazid.
• Hepatic impairment: Use cautiously in patients with decreased hepatic function because of the increased risk of toxicity.
• Severe renal disease: Use cautiously in patients with severe renal disease.
• Narrow therapeutic index: Hepatotoxicity and neurotoxicity are important concerns during treatment.
• Pregnancy and lactation: Isoniazid crosses the placenta and was embryocidal in some laboratory species, and it should only be used when the maternal benefits outweigh the potential risks to offspring; it is excreted in milk in low concentrations and is thought to be safe during nursing.
• Zoonotic risk: In cats, treatment is not advised where immunosuppressed people may be exposed, or when the cat has generalized disease, cavitating lesions in the respiratory tract, or extensive draining skin lesions, which may increase the risk of transmission.

Drug Interactions

The most clinically relevant interactions with isoniazid (INH) involve an increased risk of hepatotoxicity or neurotoxicity, altered metabolism of concomitant medications, and reduced absorption of INH. Careful monitoring is recommended when these drugs are administered together.

• Acetaminophen: May increase the risk of hepatotoxicity.
• Alfentanil: May prolong the duration of action of alfentanil.
• Amiodarone: May increase amiodarone exposure.
• Antacids (especially aluminum-containing products): May decrease the absorption of isoniazid.
• Benzodiazepines: Isoniazid may reduce benzodiazepine metabolism.
• Clopidogrel: Isoniazid may reduce the antiplatelet effect of clopidogrel.
• Corticosteroids (e.g., dexamethasone, prednisolone): May reduce the efficacy of isoniazid.
• Insulin: May decrease the hypoglycemic activity of insulin and increase insulin requirements.
• Ketoconazole and itraconazole: Isoniazid may reduce serum concentrations of ketoconazole and itraconazole but does not appear to affect other azole antifungals; itraconazole may decrease isoniazid metabolism.
• Leflunomide: In humans, isoniazid should not be given concomitantly with leflunomide.
• Meperidine: May enhance the adverse effects of isoniazid.
• Other hepatotoxic drugs (e.g., azole antifungals, methimazole, phenothiazines, sulfonamides, estrogens): May increase the risk of hepatotoxicity.
• Other neurotoxic drugs: May increase the risk of neurotoxicity.
• Pyridoxine (Vitamin B₆): Isoniazid may antagonize pyridoxine, increase its excretion, and reduce formation of its active form. Higher pyridoxine supplementation may be required, and peripheral neuritis may occur secondary to this interaction.
• Rifampin: May increase the risk of hepatotoxicity.
• Selective serotonin reuptake inhibitors (e.g., fluoxetine, paroxetine, sertraline): May increase the risk of serotonin syndrome.
• Theophylline: May increase the risk of theophylline toxicity.
• Warfarin: May increase the risk of bleeding.
• Food interactions: In humans, isoniazid may interfere with the metabolism of tyramine- and histamine-containing foods, including certain cheeses (e.g., Swiss, Cheshire) and fish (e.g., tuna, sardines), and food can decrease its absorption.

Side Effects & Overdose

Side Effects

The most important adverse effect associated with isoniazid (INH) is hepatotoxicity. Neurologic adverse effects have also been reported in dogs and cats, and hematologic adverse effects (thrombocytopenia) in dogs.

• Hepatotoxicity: The primary adverse effect in dogs, typically manifested by increased serum liver enzyme activity. Hepatotoxicity has also been reported in cats.
• CNS stimulation: Reported in dogs during therapy.
• Peripheral neuropathy / neuritis: Peripheral neuropathy has been reported in dogs, while peripheral neuritis has been reported in cats.
• Thrombocytopenia: Reported in dogs.
• Acute kidney injury: Isoniazid can cause acute renal failure, although less commonly than neurologic effects.

Overdose

Isoniazid overdose is a medical emergency and can result in severe neurologic, metabolic, and cardiovascular toxicity. In dogs, the reported LD50 is approximately 50 mg/kg, and ingestion of a single 300 mg tablet may cause serious poisoning.

• Neurologic effects: Ataxia, severe seizures, and other CNS signs may occur. Seizures can be difficult to control.
• Metabolic effects: Metabolic acidosis and rhabdomyolysis have been reported.
• Cardiovascular effects: Myocardial necrosis and cardiac arrhythmias may develop following overdose.
• Gastrointestinal signs: Salivation, vomiting, and diarrhea may occur.
• Initial management: Treatment may include enterogastric lavage, activated charcoal, intravenous fluids, and correction of acidemia.
• Seizure control: Benzodiazepines or phenobarbital may be used, although seizures may be difficult to control.
• Hemodialysis: May be indicated in severe intoxication.
• Pyridoxine (Vitamin B₆): May help treat seizures, other CNS effects, and metabolic acidosis. It has been suggested that pyridoxine be administered intravenously (preferably over 30–60 minutes) on a mg-per-mg basis equivalent to the amount of isoniazid ingested; if the amount ingested is unknown, 71 mg/kg can be given as a 5% to 10% IV infusion over 30–60 minutes, and injectable B-complex vitamins should not be used.
• Availability of pyridoxine: Pyridoxine is commercially available as a 100 mg/mL (1 mL) vial but may be difficult to obtain in an emergency; a local human hospital may stock it.

Key Notes

Practical clinical points that help optimize the safe and effective use of isoniazid (INH) in dogs and cats:

• Combination therapy: Isoniazid is generally used as part of a multidrug antimycobacterial protocol rather than as sole therapy to reduce the risk of resistance.
• Treatment duration: Antimycobacterial therapy is prolonged, and good client compliance is essential for successful treatment.
• Vitamin B₆ supplementation: Pyridoxine supplementation should be considered when prolonged therapy is used, particularly in patients at increased risk of neurologic toxicity.
• Tablet exposure: Even a single 300 mg tablet may cause severe intoxication in dogs, making prompt veterinary attention essential after accidental ingestion.
• Emergency antidote availability: Because injectable pyridoxine may not be readily available in veterinary practice, clinicians should know where it can be obtained rapidly in an emergency.
• Public health consideration: Cases of suspected mycobacterial infection should be managed with appropriate biosecurity measures because of the potential zoonotic implications of some mycobacterial species.
• Monitoring: Perform baseline and periodic physical examinations, CBCs, and chemistry profiles, monitoring liver enzymes and watching for signs of neurologic toxicity.