Anti-Tuberculosis Medications: A Comprehensive Guide to Mechanism, Effects, Side Effects, and Usage

This article will provide detailed information on common anti-tuberculosis medications, including their mechanisms of action, pharmacokinetics, side effects, indications, and contraindications.

Isoniazid (INH):

• Characteristics: The number one drug in tuberculosis treatment, it has the ability to inhibit and destroy the multiplication of Mycobacterium tuberculosis both in and out of culture. INH’s effectiveness against tuberculosis is significantly higher than against other bacteria, requiring thousands of times the dose to affect other bacteria.

• Mechanism: INH is a prodrug, metabolized by the enzyme KatG into the nicotinoyl radical, which is the active form of INH. Subsequently, active INH forms a complex with bacterial enzymes, creating INH-A and kasa, which inhibit the synthesis of mycolic acid, a component of the Mycobacterium tuberculosis cell wall.

• Pharmacokinetic Characteristics: INH has a structure similar to vitamin B6, is rapidly absorbed through the gastrointestinal tract. Food and aluminum-containing medications reduce INH absorption, therefore it should be taken on an empty stomach. INH is widely distributed in the body, crosses the blood-brain barrier, the placenta, and enters breast milk.

• Metabolism and Excretion: INH is metabolized in the liver through acetylation, hydrolysis, and conjugation with glycine. Acetylation is controlled by the enzyme NAT2, which is genetically determined. Individuals with strong NAT2 activity have a shorter half-life (1.5 hours) than those with weak NAT2 activity (3-4 hours). INH is mainly excreted through the kidneys in the form of metabolites.

• Side Effects:

• Hepatitis: This is the most serious side effect, manifested as loss of appetite, nausea, vomiting, jaundice, and right upper quadrant pain. If not treated promptly, it can be fatal.

• Neurological Effects: Occurs in 10-20% of patients, including peripheral neuropathy, numbness in the hands and feet. The risk is higher in individuals with weak NAT2 activity, alcohol use, drug addiction, HIV infection, and anemia. Central nervous system effects are less common, including memory loss, mental disorders, and seizures.

• Allergic Reactions: Occurs in 2% of patients, manifested as rash and fever.

• Note: INH is similar to B6, so it can cause B6 deficiency. Supplement with 25-50mg of B6 per day during treatment.

• High-Risk Groups for Side Effects: People with weak NAT2, alcoholics, drug addicts, HIV-infected individuals, and anemic individuals.

• Effect on Metabolism: INH affects metabolism through the CYP450 enzyme system, inducing CYP2E1 and inhibiting other enzymes. Note that CYP2E1 is induced while others are inhibited.

• Overdose: Symptoms of INH overdose include seizures, metabolic acidosis, and coma.

• Overdose Management: Use pyridoxine (vitamin B6).

• Indications: Tuberculosis treatment and prevention:

• Treatment: Combined with other anti-tuberculosis drugs to treat all forms of tuberculosis.

• Prevention:

• Adults: Used alone, 9 months for children, 6 months for adults.

• All HIV-infected individuals who have been screened and are not diagnosed with tuberculosis.

• Children under 5 years old who are not HIV-infected and children aged 0-14 years old who are HIV-infected living with a tuberculosis patient, need to be confirmed to be tuberculosis-free.

• Those who have been in contact with someone with tuberculosis but have not yet developed the disease can be prevented.

• Contraindications:

• Allergy to INH.

• History of liver damage due to INH.

• Severe liver failure, severe hepatitis.

• Polyneuritis, epilepsy.

Rifampin (Rifamycin):

• Characteristics: Broad-spectrum antibacterial, kills Mycobacterium tuberculosis and leprosy, kills some gram-negative and gram-positive bacteria. Rifampin is the only drug that acts on all three populations of Mycobacterium tuberculosis A, B, and C. Rifampin is 5 times more potent in acidic environments.

• Mechanism: Rifampin binds to the beta subunit of bacterial RNA polymerase, forming a drug-enzyme complex and inhibiting RNA synthesis. Rifampin does not inhibit human and animal RNA polymerase.

• Pharmacokinetics: Rifampin is rapidly absorbed through the gastrointestinal tract, food reduces absorption. Bioavailability is about 68%. It should be taken on an empty stomach. Rifampin is widely distributed in the body, crosses the blood-brain barrier, the placenta, and enters breast milk. Rifampin is metabolized in the liver and excreted in the bile and feces. The half-life is about 2-5 hours. Rifampin self-induces the drug-oxidizing enzyme system in the liver, after about 14 days of treatment the drug’s half-life is shortened.

• Side Effects:

• Common manifestation: Orange urine, sweat, tears, rash, nausea, vomiting.

• Rare: Hepatitis, death due to liver failure. Caution in the elderly, alcoholics, and those with chronic liver disease.

• High dose: Causes influenza-like syndrome: fever, chills, muscle aches, can lead to acute renal failure, hemolytic anemia, shock.

• Drug Interactions: Rifampin induces CYP450, reducing the half-life of some drugs such as methadone, anticoagulants, cyclosporine, anticonvulsants, protease inhibitors, and contraceptives.

• Indications:

• Tuberculosis treatment: Combined with other anti-tuberculosis drugs to treat all forms of tuberculosis, prevent drug resistance mutations.

• Tuberculosis prevention: Replace INH in patients with contraindications to INH. Those who have been in contact with tuberculosis patients resistant to INH but sensitive to Rifampin.

• Other indications:

• Infections caused by bacteria still susceptible to Rifampin.

• Combined treatment for leprosy.

• Meningitis caused by Haemophilus influenzae,…

• Contraindications:

• Liver failure.

• Concomitant use with saquinavir, ritonavir (increases liver toxicity).

Ethambutol:

• Characteristics: Water-soluble, heat-stable, strongly inhibits the growth of Mycobacterium tuberculosis, especially when the bacteria are in the multiplication phase. It has no effect on other bacteria.

• Mechanism: Ethambutol inhibits the enzyme arabinosyl transferase, inhibiting the polymerization of arabinoglycan, thereby inhibiting the formation of the bacterial cell wall.

• Pharmacokinetics: Ethambutol is well absorbed through the gastrointestinal tract. Ethambutol concentrates in tissues, especially the kidneys, lungs, saliva, visual nervous system, liver, and pancreas. Ethambutol only crosses the blood-brain barrier when the meninges are inflamed. Ethambutol crosses the placenta and is excreted in breast milk. Ethambutol is metabolized in the liver into aldehyde and dicarboxylic acid. Ethambutol is excreted in the urine.

• Side Effects:

• Decreased Visual Acuity: This is the most common side effect, manifested as loss of red-green color discrimination. The severity of the side effect depends on the dose.

• Cause of decreased visual acuity: Because Ethambutol concentrates in the visual nervous system, it forms a chelate with zinc, causing inflammation of the visual nervous system.

• Other side effects: Allergies, mental disorders, abdominal pain, joint pain, fatigue, headache, hallucinations. Reduced uric acid excretion in the kidneys, increased uric acid in the blood.

• Indications: Combined with other anti-tuberculosis drugs to treat tuberculosis.

• Other indications:

• Mycobacterium avium complex (MAC).

• Contraindications:

• Hypersensitivity to Ethambutol.

• Optic neuritis, decreased visual acuity, unless the benefits outweigh the risks.

Pyrazinamide (PZA):

• Properties: PZA is synthetically derived, is a nicotinamide derivative, and is poorly soluble in water. PZA is highly effective in acidic environments, killing Mycobacterium tuberculosis in macrophages, B cells, lungs, and acid.

• Mechanism:

• Inhibits fatty acid synthase type 1, interfering with mycolic acid synthesis.

• Reduces intracellular pH.

• Disrupts the transport function of the cell membrane.

• Pharmacokinetics: PZA is well absorbed through the gastrointestinal tract, widely distributed in the body, and crosses the blood-brain barrier when inflamed. PZA is metabolized in the liver into PZA, POA, and 5-hydro POA. PZA is excreted through the kidneys.

• Side Effects:

• Liver damage: This is the most serious side effect, seen after taking PZA for more than 2 months. Manifestation as jaundice, increased serum transaminases, meaning increased liver enzymes. Liver function should be assessed before and periodically during treatment.

• Causes acute gout attacks: Due to reduced uric acid secretion in the renal tubules.

• Other side effects: Joint pain, loss of appetite, nausea, vomiting,…

• Indications: Combined with other anti-tuberculosis drugs to treat tuberculosis, often used in short-term treatment regimens (6 months), usually discontinued after 2 months.

• Contraindications:

• Hypersensitivity to PZA.

• Liver failure.

• Hyperuricemia, gouty arthritis.

• Porphyria.

• Breastfeeding women.

• Not contraindicated in pregnant women.

• Use in patients with renal dialysis: PZA can be used.

Streptomycin:

• Characteristics: Aminoglycoside antibacterial, strongly kills Mycobacterium tuberculosis, especially tuberculosis bacteria in cavities. Kills some gram-negative and gram-positive bacteria.

• Pharmacokinetics: Streptomycin is injected, not absorbed through the gastrointestinal tract. It should be injected once a day. Drug levels in fetal blood are half the plasma level. Streptomycin enters cells poorly, does not kill Mycobacterium tuberculosis in macrophages like INH. Does not cross the blood-brain barrier. Streptomycin is excreted through glomerular filtration.

• Indications: Combined with other anti-tuberculosis drugs, intramuscular injection.

• Contraindications:

• Hypersensitivity to streptomycin.

• Myasthenia gravis.

• Patients on renal dialysis.

Tuberculosis Treatment Strategy:

• Principles:

• Direct: Directly treating the site of infection.

• Right Drug: Using the right drug for each type of tuberculosis.

• Right Dose: Dosage of the drug suitable for each patient, each form of tuberculosis.

• Regular: Taking medication regularly every day, avoiding missing doses.

• Sufficient Time: Ensuring sufficient treatment duration to eradicate Mycobacterium tuberculosis, preventing recurrence.

• Drug Combination:

• Must combine multiple drugs because each drug has a different mechanism of action, increasing treatment effectiveness and reducing the risk of drug resistance.

• Two main principles in tuberculosis treatment:

• Combining multiple drugs.

• Using the right dose.

• Content of principle 1: Each drug has a different effect, so multiple drugs must be combined to increase treatment effectiveness.

• Content of principle 2:

• Using the right dose: Drugs have synergistic effects.

• Low doses are ineffective and prone to generating drug-resistant strains.

• High doses are prone to side effects.

• Need to synergize drugs so that each drug is within a certain concentration range.

• Principle of regular medication:

• Medications should be taken all at once at a specific time each day.

• Taken away from meals to increase absorption.

• Principle of sufficient medication duration:

• Attack phase: 2-3 months, the goal is to quickly eliminate a large amount of Mycobacterium tuberculosis in affected areas, preventing drug resistance mutations.

• Maintenance phase: 4-6 months, the goal is to completely eliminate Mycobacterium tuberculosis in affected areas, preventing recurrence.

• Multidrug-resistant phase: To avoid multidrug-resistant tuberculosis, the attack phase is 8 months, total treatment duration is 20 months.

• Principle of time in multidrug-resistant tuberculosis treatment: Attack 8 months, total duration 20 months.

Drug-Resistant Tuberculosis:

• Drug resistance: The ability of Mycobacterium tuberculosis to resist the effects of drugs, leading to ineffective drug use in killing bacteria.

• Types of drug-resistant tuberculosis:

• Monoresistance: Resistance to one drug (except rifampicin).

• Polyresistance: Resistance to 2 drugs, but not the combination of isoniazid and rifampicin.

• Multidrug resistance: Resistance to at least both isoniazid and rifampicin, may be resistant to other drugs.

• Stages of drug-resistant tuberculosis:

• Pre-extensively drug-resistant: Multidrug-resistant tuberculosis, resistant to at least one fluoroquinolone or at least one of the three second-line drugs (capreomycin, kanamycin, amikacin).

• Extensively drug-resistant: Multidrug-resistant tuberculosis, resistant to at least one fluoroquinolone and at least one of the three drugs (capreomycin, kanamycin, amikacin).

• Totally drug-resistant: Resistance to all anti-tuberculosis drugs.

• Rifampicin-resistant tuberculosis: Resistance to rifampicin, may be resistant to other tuberculosis drugs. 90% of cases of rifampicin resistance are accompanied by isoniazid resistance. Therefore, patients with rifampicin resistance are considered multidrug-resistant and need to be treated according to regimen 4.

Conclusion:

This article provides knowledge about anti-tuberculosis drugs, including their mechanisms of action, pharmacokinetics, side effects, indications, and contraindications. Tuberculosis treatment should follow the principles of being direct, using the right drug, the right dose, regularly, and for a sufficient duration.