Pharmacology of Tuberculosis Drugs

Tuberculosis is a bacterial infection caused by Mycobacterium tuberculosis (MTB). Here, we review the first-line drugs used to treat tuberculosis – their mechanism of action, side effect profiles and other clinical considerations.

This is not intended as a complete clinical guide on how to manage the infection. Here, our focus is on the first-line drugs and their underlying pharmacology that makes them effective treatment options for this serious infection.

So, what is tuberculosis?

Tuberculosis is a bacterial infection caused by Mycobacterium tuberculosis; an infection commonly characterised by pulmonary symptoms – such as chest pain and a productive cough (including blood). It is also associated with fever, night sweats, weight loss (hence its former name, “consumption”), loss of appetite and fatigue.

Infection is more likely in HIV patients and in those who smoke. Prevention involves early detection and screening, as well as vaccination via the bacillus Calmette-Guerin (BCG) vaccine. In 2016, TB infections resulted in approximately 1.5 million deaths.

Medicines used as first-line agents include the RIPE drugs:

  • Rifampicinknown as rifampin in the US
  • Isoniazid
  • Pyrazinamide
  • Ethambutol

In addition, streptomycin – an aminoglycoside – may also be used.

Treatment regimens for active TB infection typically involve more than one medicine.

For example – a standard treatment may involve using the RIPE drugs for the first two months of therapy, switching to isoniazid and rifampicin for the final four months – totalling six months of treatment.

Mechanism of action

Two of the medicines – namely, isoniazid and ethambutol – work to disrupt the mycolic cell wall.

Isoniazid is a prodrug activated by the mycolic enzyme, KatG; an enzyme that catalyses formation of an isonicotinic acyl radical; a radical which, through further transformation, inhibits synthesis of mycolic acid – an essential component of the cell wall.

Ethambutol obstructs formation of the mycolic cell wall; specifically, it inhibits the enzyme arabinosyl transferase. This enzyme inhibits the formation of the wider mycolyl-arabinogalactan-peptidoglycan complex; one of the principal backbones of the mycolic cell wall.

Rifampicin works by inhibiting DNA-dependent RNA polymerase, thereby inhibiting production of RNA synthesis.

The mechanism of pyrazinamide is not fully understood. It is known to be converted into its more active form, pyrazinoic acid, which accumulates inside the bacterium. It is not yet known how the accumulated active form achieves its therapeutic effects.

Streptomycin is an aminoglycoside, and, like all aminoglycosides, it works as a protein synthesis inhibitor. More specifically, streptomycin binds to the 16S element of the 30S ribosomal unit, disrupting the binding of formyl-methionyl-tRNA to the 30S unit.

Side effects

Side effects depend upon which drug is administered. Each medicine is, however, associated with their own range of distinct side effects.

These include:

  • Ethambutol – optic neuritis; red-green color blindness; arthralgia
  • Isoniazid – pyridoxine deficiency; peripheral neuropathy
  • Streptomycin – nephrotoxicity and ototoxicity; vertigo
  • Rifampicin – discolors urine-sweat-tears a red-orange hue; thrombocytopenia

Pyrazinamide, isoniazid and rifampicin are most associated with drug-induced hepatitis and hepatotoxicity generally.

Side effects are more likely in patients over the age of 60, who are females, who have HIV, and who belong to the Asian community.

Clinical considerations

When we talk about the clinical pharmacology of tuberculosis drugs, we need to think about the following factors:

  • That risk of peripheral neuropathy with isoniazid is reduced when taken with pyridoxal phosphate. Similarly, pyridoxine may be used as an antidote to isoniazid toxicity.
  • That the risk of developing TB increases when the patient has established alcoholic liver disease, or who have renal failure.
  • That, for the above reason, aminoglycosides – such as streptomycin – should be used with extreme caution in patients with renal damage due to the additional renal damage that the medicine may precipitate.
  • That isoniazid is associated with an increased risk of seizures.
  • That HIV therapy may be halted, or not commenced at all, until tuberculosis has been successfully treated. However, this depends upon the patient, their clinical state and on the advice and recommendation of their clinical team.
  • That rifampicin should be taken on an empty stomach with a full glass of water.
  • That isoniazid increases the risk of acetaminophen toxicity; decreases the metabolism of carbamazepine, phenytoin, valproate and phenytoin – decreasing clearance and increasing toxicity risk.

Treatment for active tuberculosis infection is long, often lasting for at least six months. The clinician should understand the implications of therapy – combining knowledge from the patient, their age, their current medical state, the medicines they are/have taken, and many other factors, to establish the most optimum path toward full health.

For even more facts and pharmacology quiz questions on tuberculosis drugs pharmacology, register with PharmaFactz today. Check back to our pharmacy blog soon for even more great facts on anti-TB medicines and how they work to eliminate both active and latent tuberculosis infections!