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Antituberculosis medications

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Antituberculosis medications

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Antituberculosis medications

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Macrolides are a type of antibiotic that (induce/inhibit) CYP450 enzymes.

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A 56-year-old man of Nepalese origin attends the clinic complaining of skin rashes which have been troubling him for years. On examination, there are numerous poorly demarcated skin lesions present on all parts of the body. There is also evidence of significant facial thickening, eyebrow loss, and symmetrical sensory neuropathy in a 'glove and stocking' distribution. An examination of the hands reveals bilateral weakness. A skin biopsy is taken from one of the lesions and the culture is positive for acid-fast bacilli. Which of the following pharmacological therapies is involved in the treatment of this condition?

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Antituberculosis medications are agents used to treat tuberculosis, a disease caused by the bacteria Mycobacterium tuberculosis.

Mycobacteria are an interesting bunch, they’re slender, rod-shaped, and need oxygen to survive, in other words, they’re “strict aerobes.”

They’ve got an unusually waxy cell wall, which is mainly a result of the production of mycolic acid.

This waxy cell wall makes them incredibly hardy, and allows them to resist weak disinfectants and survive on dry surfaces for months at a time.

Antituberculosis medications act mainly by preventing the production of mycolic acid and the synthesis of this cell wall.

Although about two billion people worldwide are infected with tuberculosis, or simply ‘TB, the vast majority, about 90-95%, don’t develop symptoms. And this is because usually the immune system can contain it.

So Mycobacterium tuberculosis is usually transmitted via inhalation, which is how they gain entry into the lungs.

TB can avoid the mucus traps and make its way to the deep airways and alveoli where we have macrophages which eat up foreign cells, digest, and destroy them.

With TB, they recognize foreign proteins on their cell surface, and phagocytize them, or essentially package them into a space called a phagosome.

With most cases, the macrophage then fuses the phagosome with a lysosome, which has hydrolytic enzymes that can pretty much break down any biochemical molecule.

TB’s tricky though, and once inside the macrophage, they produce a protein that inhibits this fusion, which allows the mycobacterium to survive.

It doesn’t just survive, though, it proliferates, and creates a localized infection.

Three weeks after initial infection, cell-mediated immunity kicks in, and immune cells surround the site of TB infection, creating a granuloma.

The tissue inside the middle dies as a result, a process referred to as caseous necrosis. This area is known as a “Ghon focus”.

In some cases, the mycobacteria is killed off by the immune system, and that’s the end of that.

In other cases, even though they were walled off, they remain viable, and are therefore still alive, but they’re just dormant. This stage of the disease is called latent TB.

When a person’s immune system becomes compromised, like with AIDS or with aging, the Ghon focus can be reactivated.

T cells quickly release cytokines to try and control the new outbreak, which forms more areas of caseous necrosis.

This time though, it tends to cavitate, or form cavities, which can allow the bacteria to disseminate.

The bacteria can cause bronchopneumonia; but it can also spread via the vascular system and infect almost every other tissue in the body, called systemic miliary TB.

Fortunately, there are many medications that can treat tuberculosis and they are often used together, in case the bacteria is resistant to one or more of the drugs.

Let’s start with isoniazid. It can be used on its own to treat latent infections and as prophylaxis for people traveling to regions where tuberculosis is common.

Isoniazid can be administered orally or parenterally.

In order to work, it’s first converted by a mycobacterial enzyme called peroxidase, into its active metabolite, iproniazid.

A mutation in the gene that codes for this enzyme helps the bacteria develop resistance, because the mutated enzyme won’t activate the medication.

Iproniazid inactivates enzymes associated with mycolic acid synthesis, and mycolic acid is needed to build bacterial cell walls.

It also inhibits mycobacterial peroxidase, preventing the bacteria from metabolizing hydrogen peroxide, which accumulates inside the cell causing serious damage.

Side effects include rash, fever, and systemic lupus erythematosus, called drug-induced SLE.

It can also cause vitamin B6 deficiency, which leads to anemia and neurological symptoms like dizziness, ataxia, or encephalopathy, but the most common is peripheral neuropathy.

Fortunately, these side effects can be prevented with the administration of pyridoxine, or vitamin B6.

Pyridoxine is also useful as an antidote in case of overdose with isoniazid, which can cause seizures, anion gap metabolic acidosis, and coma.

Last, but not least, patients who receive isoniazid should be assessed monthly for symptoms of hepatitis and jaundice in order to detect this serious potential side effect.

If liver damage is present, the medication should be discontinued right away.

Rifampin is the next medication. It can be administered orally or parenterally and acts by inhibiting mycobacterial RNA polymerase, and therefore, the synthesis of RNA.

A mutation in the gene that codes for this enzyme helps the bacteria develop resistance.

Since rifampin gets widely distributed throughout the body, it can get into urine, saliva, tears, feces and sweat, which turns them orange!

But, the most important side effect is hepatitis, which is more severe at high doses.

Luckily, it’s pretty uncommon, but elderly or alcoholic patients, or those who already have liver disease, are at higher risk.

Rifampin also causes other side effects such as rash, fever, and gastrointestinal symptoms like abdominal pain, diarrhea, nausea, and vomiting.

Now, an important fact is that rifampin is a strong CYP450 enzyme inducer, which means it increases the metabolism of many medications, like ritonavir and other HIV antivirals.

This can be problematic since these people with HIV are at a higher risk of developing active tuberculosis.

Sources
  1. "Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition" McGraw-Hill Education / Medical (2018)
  2. "Rang and Dale's Pharmacology" Elsevier (2019)
  3. "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition" McGraw-Hill Education / Medical (2017)
  4. "Treatment of Latent Tuberculosis Infection" Annals of Internal Medicine (2017)
  5. "Multidrug-Resistant Tuberculosis and Extensively Drug-Resistant Tuberculosis" Cold Spring Harbor Perspectives in Medicine (2015)
  6. "Molecular mechanism of the synergistic activity of ethambutol and isoniazid against Mycobacterium tuberculosis" Journal of Biological Chemistry (2018)