74. Antituberculotic drugs. Anti-leprosy drugs

Antituberculotic drugs

Treating mycobacteria is a challenge for the following reasons:

  • The mycobacterial cell wall is thick and less permeable for antibiotics, and it expresses several efflux transporters
  • Mycobacteria multiply slowly
  • Many mycobacteria are genetically resistant to many antibiotics

For these reasons there are many drugs which are available for treating TB, so that we have multiple options in case of resistance.

The first-line agents in treating TB are:

  • Isoniazid
  • Rifampin/rifampicin
  • Pyrazinamide
  • Ethambutol

The standard first-line treatment of TB is 2 months of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by 4 months of just isoniazid and rifampin.

There are several second-line agents as well, used in case of resistance to the first-line agents:

  • Streptomycin
  • PAS (para-aminosalicylic acid)
  • Ethionamide
  • Cycloserine
  • Fluoroquinolones
  • Bedaquiline
  • Delamanid

A person with TB should never receive monotherapy to prevent resistance. The patient should be observed taking the drugs to ensure correct treatment.

Adverse effects:

Many of the antituberculotic agents can cause hepatotoxicity, in fact three of the four first-line agents do. If significant hepatotoxicity is detected the therapy should be suspended and second-line agents should be used.

Pyrazinamide and ethambutol also cause hyperuricaemia, which can be a problem for people with or at risk for gout.

Isoniazid

Indications:

  • M. tuberculosis
  • M. kansasii

Mechanism of action:

Isoniazid inhibits the synthesis of mycolic acid, an important component of the mycobacterial cell wall. It does this by inhibiting the FAS 2-system.

It is a prodrug which is activated by mycobacterial catalase-peroxidase. It is bactericidal against dividing mycobacteria and bacteriostatic against resting mycobacteria.

Resistance:

1 in 1 000 000 mycobacteria are resistant to isoniazid. A granuloma usually contains billions of bacteria, so isoniazid monotherapy would just select out the resistant bacteria and create a resistant infection.

Decreased expression of catalase-peroxidase can me a mechanism of resistance.

Pharmacokinetics:

Isoniazid is orally absorbed and well distributed, even into the CNS and the intracellular space.

It is eliminated mainly by acetylation in the liver with small amounts being excreted unchanged by the kidneys. The half-life depends on the patient. In rapid acetylators the half-life is 1 hour, in slow acetylators it’s 3 – 5 hours. In slow acetylators the proportion of isoniazid which is excreted unchanged is increased.

Interactions:

Isoniazid is a CYP1A2 and CYP2C9 inhibitor. It can interact with many drugs, like propranolol, amitriptyline, warfarin, phenytoin and ibuprofen.

Side effects:

Three major side effects can occur in isoniazid treatment:

  • Hypersensitivity reactions
    • Rarely SLE
  • Neurotoxicity
    • Peripheral neuropathy
  • Hepatotoxicity
    • Liver enzyme increase (15%)
    • Hepatitis (1%)

All three side effects are more common in slow acetylators. The latter two side effects are dose dependent.

Neurotoxicity is mediated by vitamin B6 deficiency, which occurs during isoniazid treatment. Both the neurotoxicity and hepatotoxicity can be prevented by supplementing B6.

Pyrazinamide

Indications:

The only bacterium sensitive to pyrazinamide is m. tuberculosis. Pyrazinamide is part of the first-line treatment for TB.

Mechanism of action:

Pyrazinamide inhibits the synthesis of mycolic acid, just like isoniazid. However, while isoniazid inhibits FAS2, pyrazinamide inhibits FAS1, the step before FAS2 in mycolic acid synthesis.

Pyrazinamide is a prodrug which is activated inside mycobacteria by the enzyme pyrazinamidase.

This drug has pH-dependent activity, which makes it ineffective at physiological pH, but bactericidal at acidic pH, like in the lysosomes of macrophages and in necrotic tuberculotic cavities.

Pharmacokinetics:

It is orally absorbed and well distributed. It is eliminated by the kidney.

Side effects:

  • Hepatotoxicity
  • Hyperuricaemia
Rifamycins

The most important rifamycins are rifampin/rifampicin and rifabutin.

Indications:

Rifampin is part of the first-line therapy for TB. Rifabutin is used in rifampin-resistant mycobacteria and to treat people with HIV and TB.

These drugs can also be used to treat H. influenzae type b and leprosy.

Mechanism of action:

These drugs inhibit RNA polymerase, making them bactericidal.

Pharmacokinetics:

Rifamycins are orally absorbed and well distributed.

They’re partially metabolized in the liver by CYP3A4 and mainly excreted by bile. Rifampin is a strong CYP inducer, also for CYP3A4, thereby inducing its own elimination.

Interactions:

Rifampin is a strong CYP inducer for many of the isozymes, including the isozyme which is most involved in metabolism of drugs (CYP3A4). This causes it to interact with a large number of drugs. The maybe most clinically relevant is that it interacts with anti-HIV drugs.

Rifabutin is not a CYP inducer. For this reason, it’s preferred over rifampin in people who take anti-HIV drugs.

Side effects:

  • Hepatotoxicity
  • Harmless orange discoloration of body fluids (urine, tears)
    • Due to the strong red-orange colour of these drugs
Ethambutol

Indications:

M. tuberculosis and m. avium-intracellulare are sensitive to ethambutol. This drug is part of the first-line treatment for TB.

Mechanism of action:

Ethambutol inhibits the synthesis of arabinogalactan, a component of the mycobacterial cell wall.

Pharmacokinetics:

Ethambutol is orally absorbed and well distributed. It’s mostly excreted by the kidney in unchanged form.

Side effects:

  • Optic neuritis
    • Diminished visual acuity
    • Blindness
  • Hyperuricaemia
PAS

PAS (para-aminosalicylic acid) is not the same as the PAS-stain in histology.

Indications:

Only m. tuberculosis is sensitive. PAS is a second-line agent for TB.

Mechanism of action:

PAS inhibits folic acid synthesis.

Pharmacokinetics:

Orally absorbed. Doesn’t enter the CNS. Excreted by the kidney partly in unchanged form and partially as an acetylated metabolite.

Side effects:

  • GI symptoms
  • Hypersensitivity
Ethionamide

Ethionamide is a derivative of isoniazid.

Indication:

Second-line drug for TB.

Mechanism of action:

Inhibits mycolic acid synthesis.

Pharmacokinetics:

Orally absorbed and well distributed. Eliminated by biotransformation.

Side effects:

  • GI symptoms
  • Hepatotoxicity
  • CNS effects
    • Depression
  • Hypersensitivity reaction
Cycloserine

Indication:

Second-line drug for TB.

Mechanism of action:

Inhibits peptidoglycan synthesis.

Pharmacokinetics:

Orally absorbed and distributed. Excreted by the kidney.

Side effects:

  • CNS toxicity
    • Headache
    • Convulsions
Bedaquiline and delamanid

Bedaquiline and delamanid are new (2012 and 2014, respectively) antituberculotic drugs. They’re used exclusively for multi-drug resistant TB.

Both these drugs cause prolongation of the QT interval, so the patient’s ECG must be closely monitored.

Anti-leprosy drugs

There are two types of leprosy: the tuberculoid type and the lepromatous type.

The therapy for the tuberculoid type is 6 months of dapsone and rifampin. The therapy for the lepromatous type is 12 – 24 months of dapsone, rifampin and clofazimine. Thalidomide is a second-line agent.

Rifampin was described above. Only dapsone and clofazimine will be discussed here.

Mechanism of action:

Dapsone inhibits folic acid synthesis. Dapsone is related to the sulphonamides.

Clofazimine inhibits DNA replication and transcription.

Pharmacokinetics:

Dapsone is orally absorbed and widely distributed. It’s metabolized in the liver and excreted by the kidney.

Clofazimine is orally absorbed. It accumulates in several tissues, giving it a tissue half-life of many weeks. It’s partially metabolized in the liver and partially excreted in bile in unchanged form.

Side effects:

Dapsone:

  • GI symptoms
  • Haemolysis
    • Cannot be given to people with malaria or G6PD deficiency
  • Methaemoglobinaemia

Clofazimine:

  • GI symptoms
  • Reddish discoloration of body fluids, skin and conjunctiva
  • Blue-black discoloration of skin and mucous membrane

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