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isoniazid AND adverse effects

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CDC isoniazid treatment latent tuberculosis pyridoxine peripheral neuropathy hepatotoxicity

These slides describe isoniazid (INH), a first-line anti-tuberculosis drug.

1. Clinical uses

INH is used as part of a combination regimen for active tuberculosis. It should not be used alone for active TB because resistance can develop.
A traditional adult dose is 300 mg once daily, approximately 5 mg/kg/day.
It has also been used for latent TB infection (LTBI), traditionally for 6 or 9 months. Current practice often prefers shorter rifamycin-based regimens when suitable, rather than INH alone.

2. Why pyridoxine (vitamin B6) is given

INH interferes with vitamin B6 metabolism. B6 deficiency can injure peripheral nerves and cause peripheral neuropathy.

Symptoms of neuropathy

Tingling, burning, numbness, or pins-and-needles sensations
Usually begins in the feet or hands
May progress to pain or weakness if not addressed

Pyridoxine prophylaxis The slide means that pyridoxine is given to prevent, not cause, neuropathy. Typical preventive supplementation is 25-50 mg/day in people at higher risk, such as those with:

Diabetes
Alcohol use disorder
Malnutrition
HIV infection
Chronic kidney failure/uremia
Pregnancy or early postpartum period
Older age
Existing neuropathy

This is consistent with the CDC LTBI guide.

3. Adverse reactions

A. Immunologic reactions

These are allergic or immune-mediated reactions and are relatively uncommon:

Fever
Skin rash
Rarely, drug-induced lupus erythematosus, which may cause joint pain, fever, fatigue, and sometimes rash.

B. Direct toxicity: liver injury

The most important serious toxicity is hepatitis or drug-induced liver injury.

Warning symptoms

Loss of appetite
Nausea or vomiting
Unusual fatigue
Pain or discomfort in the right upper abdomen
Dark urine
Jaundice, meaning yellow eyes or skin

The practical point on the slide is correct: these symptoms require prompt medical assessment and withholding the medicine until reviewed, because continuing INH during clinically significant hepatitis can cause severe liver damage.

Risk is higher with:

Increasing age
Daily alcohol intake
Pre-existing liver disease or hepatitis B/C
Concomitant hepatotoxic drugs, including some TB medicines
Pregnancy and especially the early postpartum period

For LTBI, the latest Harrison text reports symptomatic hepatitis in fewer than 0.1% of people receiving INH alone, with risk rising in the groups above. Monitoring is particularly important when baseline liver tests are abnormal or liver-risk factors are present.

4. “Slow acetylators”

INH is metabolized in the liver by N-acetyltransferase-2 (NAT2). People who metabolize it slowly, called slow acetylators, can have higher INH exposure. This raises the likelihood of dose-related toxicity, particularly neuropathy.

Key exam summary

Isoniazid adverse effects:

Hepatitis/hepatotoxicity: most serious.
Peripheral neuropathy: due to functional B6 deficiency, prevented with pyridoxine.
Rash and fever: hypersensitivity reactions.
Drug-induced lupus: rare.

Memory aid:
INH = Injures Nerves and Hepatocytes
Give B6 to protect the nerves; watch for hepatitis symptoms.

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rifampin resistance rpoB

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CDC rifampin mechanism RNA polymerase rpoB resistance tuberculosis treatment latent tuberculosis

The image continues isoniazid adverse effects and introduces rifampin (rifampicin).

1. Remaining adverse effects of isoniazid

Relative pyridoxine (vitamin B6) deficiency

Isoniazid can cause a functional deficiency of vitamin B6 by interfering with its metabolism. This leads mainly to peripheral neuropathy.

Symptoms: tingling, numbness, burning pain, or pins-and-needles in hands and feet.
It is especially likely in slow acetylators and people with diabetes, alcohol dependence, malnutrition, HIV, kidney failure, pregnancy/postpartum state, or pre-existing nerve disease.
It can be prevented or treated with pyridoxine supplementation. The slide’s “as low as 10 mg/day” reflects older teaching; current preventive doses are commonly 25-50 mg/day in people at risk.

Central nervous system toxicity

This is less common than peripheral neuropathy. It may include:

Poor memory
Irritability or psychosis
Seizures

This is more likely with severe B6 deficiency, overdose, or predisposition to neurologic toxicity.

Other isoniazid adverse effects

Hematologic problems: rare anemia, including sideroblastic anemia due to impaired heme synthesis from B6 deficiency.
Tinnitus: ringing in the ears.
Gastrointestinal upset: nausea, anorexia, abdominal discomfort.
Phenytoin interaction: isoniazid inhibits phenytoin metabolism. Therefore phenytoin levels can rise, causing toxicity such as nystagmus, ataxia, slurred speech, and confusion.

Rifampin

2. What is rifampin?

Rifampin is a rifamycin antibiotic, originally derived from Streptomyces mediterranei and modified semisynthetically.

It is active against:

Mycobacterium tuberculosis
Some atypical or non-tuberculous mycobacteria
Mycobacterium leprae
Several Gram-positive organisms
Some Gram-negative organisms, including Neisseria meningitidis

3. Why rifampin must be given in combination for active TB

A few organisms may already carry spontaneous mutations that make them rifampin-resistant. If rifampin is used alone in active tuberculosis, those resistant organisms survive and multiply rapidly.

Therefore, active TB is treated with multiple drugs together, classically including rifampin, isoniazid, pyrazinamide, and ethambutol in the initial phase.

Rifampin resistance is a major concern because it is often used as a marker of serious drug-resistant TB.

4. Mechanism of action

Rifampin binds the beta subunit of bacterial DNA-dependent RNA polymerase.

Normally:

Bacterial DNA → RNA transcription → protein synthesis

Rifampin blocks the transcription step. Without RNA, the bacterium cannot make the proteins it needs to survive and replicate.

It is selectively toxic because human RNA polymerase does not bind rifampin in the same way.

5. Why it works well in TB

Rifampin penetrates:

Macrophages/phagocytic cells
Many tissues
Cavities and abscesses

This matters because TB bacilli can live inside macrophages and in relatively inaccessible sites. Rifampin can reach these intracellular bacilli.

6. Mechanism of resistance

Resistance usually results from a point mutation in the bacterial rpoB gene.

rpoB encodes the beta subunit of RNA polymerase.
Mutation changes the target site.
Rifampin can no longer bind effectively.
RNA synthesis continues, so the bacterium survives.

Exam line:
Rifampin resistance = rpoB mutation causing altered RNA polymerase beta subunit.

7. Clinical uses shown on the slide

Tuberculosis: used with other anti-TB drugs, not alone in active disease.
Atypical mycobacterial infections: used in selected multidrug regimens.
Leprosy: an important component of multidrug therapy.
Meningococcal carriage: rifampin can eradicate N. meningitidis from the nasopharynx of close contacts. This is prophylaxis for carriage, not treatment of meningococcal meningitis itself.

High-yield additional point

Rifampin is a powerful inducer of hepatic drug-metabolizing enzymes, especially CYP450 enzymes. It can reduce the effectiveness of many medicines, including:

Oral contraceptives
Warfarin
Some antiretroviral drugs
Antifungals
Antiseizure drugs

It also commonly causes harmless orange-red discoloration of urine, sweat, tears, and contact lenses.

One-line summary

Isoniazid: inhibits mycolic-acid synthesis; major concerns are hepatitis and B6-related neuropathy.
Rifampin: inhibits RNA polymerase; resistance is due to rpoB mutation, and it must be combined with other drugs for active TB.

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