Antituberculosis medications

Definitions & Key takeaways

Anti-tuberculosis (TB) medications are drugs used to treat tuberculosis. Common TB medications include Isoniazid (INH), Rifampin (RIF) Pyrazinamide (PZA), and Ethambutol (EMB). Other TB drugs include Streptomycin, Capreomycin, Amikacin, and Levofloxacin. TB drugs are typically administered in combination, which helps minimize resistance to one of the drugs.

Side effects of TB drugs include vitamin B6 deficiency for isoniazid. This is prevented by taking isoniazid with vitamin B6 supplements (pyridoxine). Other side effects include hepatotoxicity for isoniazid, ethambutol, and pyrazinamide; and thrombocytopenia and neutropenia for Rifampin.

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Introduction0:00–1:12

Anti-tuberculosis medications are agents used to treat tuberculosis, a disease caused by the bacteria Mycobacterium tuberculosis.
These include 4 1st line agents isoniazid, rifampin, ethabutal, and pyrazinamide, as well as several second line agents like streptomycin, which is an amino glycoside.
Anti-tuberculosis medications are also used to treat infections caused by other mycobacteria like Mycobacterium avium and Mycobacterium laprae.
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.
Several anti-tuberculosis medications like isoniazid and etambutal act mainly by preventing the production of mycolic acid and the synthesis of this cell wall.
Although about 2 billion people worldwide are infected with tuberculosis, or simply TB, the vast majority, about 90 to 95%, don't develop symptoms.

Pathology1:12–3:38

This is because usually the immune system can contain it. So Mycobacterium tuberculosis is usually transmitted by 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 to a lysosome, which has hydrolytic enzymes that can pretty much break down any biochemical molecule.
TB is tricky though, and once inside the macrophage, they produce a protein that inhibits this fusion and 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 the TB infection, creating a granuloma.
The tissue inside the middle dies as a result, a process referred to as caceous necrosis. This is also known as a go focus.
In some cases, the mycobacteria is killed off by the immune system, and that's the end of that. In other cases though, 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 go focus can be reactivated.
T cells quickly release cytokines to try and control the new outbreak, which forms more areas of caceous 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 through 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're often used together in case the bacteria is resistant to one or more of the drugs.

Isoniazid3:38–5:37

Let's start with isoniazid. It can be used on its own to treat latent infections and as prophylaxis for people at risk for TB.
Isomiazid 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.
Ironiazide inactivates enzymes associated with mycolic acid synthesis, and mycolic acid is needed to build mycobacterial cell walls.
It also inhibits mycobacterial peroxidase, preventing the bacteria from metabolizing hydrogen peroxide, which accumulates inside the cell and causes serious damage.
Side effects though, include rash, fever, and systemic lupus erythematosis, also called drug-induced SLE. It can also cause vitamin B6 deficiency, which leads tosideoblastic anemia, where there's a build-up of iron in the red blood cells in the body, causing them to be immature and dysfunctional.
Vitamin B6 deficiency also leads to 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.

Rifampin5:37–6:53

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 the urine, saliva, tears, feces, and sweat, which turns them orange.
Although this may alarm the patient, it is harmless. 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 a higher risk.
Rifampin also causes other side effects like rash, fever, and gastrointestinal symptoms like abdominal pain, diarrhea, nausea, and vomiting.
Now, an important fact is that rifampin is a strong CYP 450 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. Eambutal is up next.

Ethambutol6:53–7:39

This medication is administered orally. It exerts its effect by blocking arabinosyl transferase, which synthesizes the arabioglactin that's used in the bacterial cell wall.
The main side effect of the fambutal is optic neuritis, which decreases visual acuity and the ability to differentiate between red and green.
Because of this, regular vision checks are necessary while taking aambutal, and any color blindness will resolve when the treatment is discontinued.
Since it's difficult to do this in children under 5, aambital should not be given to them. Finally, this medication can decrease the renal excretion of uric acid, raising its levels in the blood and leading to gout.
Next we have pyrazinamide, which is a prodrug that gets converted to pyrizinoic acid, which is the active form. Although its exact mechanism is still uncertain, pyrazinamide most probably acts by disrupting cell membrane function, protein synthesis, and other cellular processes.

Pyrazinamide7:39–8:23

It's administered orally, like aambutal, pyrazinamide also inhibits the excretion of uric acid, almost always causing hyperuricemia, which can cause acute episodes of gout.
Other side effects include arthralgias, anorexia, nausea, and vomiting. But the most important is liver damage.
So pyrozinamide should be avoided in people with liver disease. The last medication is streptomycin, which is an amino glycoside that acts on the 30S subunit of the mycobacterial ribosome, which blocks protein synthesis.

Streptomycin8:23–9:08

It's administered intramuscularly or intravenously. Currently, this is only used in combination with other medications to treat miliary tuberculosis, where the bacteria is widely disseminated throughout the body, and for TB meningitis.
The side effects of streptomycin include rash and fever, as well as other side effects caused by damage to the 8th cranial nerve, which causes impaired hearing and balance.
Like with other amino glycosides, nephrotoxicity is also a problem with streptomycin. The treatment is different for latent and active infection.

Latent infection9:08–10:25

In fact, latent TB should only be treated when the patient is at risk of developing the active infection. An important aspect here is the tuberculin skin test, also known as the Mantu test, where a component of the mycobacteria called tuberculin is injected into the skin.
If a person has previously been exposed to TB, the immune system reacts to the tuberculin and produces an area of induration and redness within 48 to 72 hours.
If this area is greater than 15 millimeters, the patient is at risk of developing the active infection. This is also the case when the reaction is greater than 10 millimeters and the patient is an intravenous drug user, a child younger than 4 years old, or who's been in contact with other people with TB.
Finally, when the immune system is compromised, like with AIDS, a tuberculin test reaction of 5 millimeters is enough to indicate treatment.
So, in all of these cases, it's important to stay ahead of the game and do prophylaxis, which typically involves taking isoniazid daily or twice a week for 6 months.
Alternatives include rifampin alone or rifampin plus isoniazide daily for 4 months. On the other hand, for active infection, the treatment is a bit more complex.

Active infection10:25–11:32

The main issue here is bacterial resistance. So, to avoid it, it's mandatory to use a combination of antibiotics.
Also, a directly observed therapy, or DOT seems to be useful in order to make sure the patient is taking their medications and to decrease the risk of resistance.
Therapy is done in two phases. The initial phase consists of a daily dose of isoniazid, rifampin, pyrazinamide, and etambutal for 2 months.
Then there's the continuation phase, which consists only of rifampin and isoniazid for 4 months. For HIV positive patients, the only change that has to be made is to replace rifampin for rifabutyinn during the whole therapy.
It's also important to keep in mind that pyridoxine should be given to patients at risk of developing neuropathy due to isoniazid.
Now for patients with drug resistant TB, second line agents such as streptomycin and fluoroquinolones are used. Now, we wanna make a simple and fun mnemonic that'll help you efficiently memorize and retain all these farm facts.

Memory palace11:32–13:34

So, let's set the scene in a sewer pipe, which is like a tube for tuberculosis. The first drug we'll put in here is isoniazid, which is represented by a hermit who likes to be isolated, and that's why he lives in the sewers.
The sewer is not a very healthy place to live, so he's very pale, like a vampire, which represents anemia, and his arms are wrapped in bandages to represent peripheral neuropathy.
Since he doesn't get a lot of fresh veggies down in the sewers, he takes a lot of vitamins, and you can see that he's holding a big bottle of vitamin B6, which will hopefully fix the anemia and neuropathy.
He has a big pet wolf living with him, which represents the drug-induced SLE. The wolf is gnawing on a big liver, since isoniazid is hepatotoxic.
The wolf's eyes are yellow to help you remember that the liver damage can lead to jaundice. OK, so in the sewage, we'll have the hermit's raft, which represents rifampin.
The raft is leaking orange fluid from the hull, which will help you remember that it turns body fluids orange. Inside the raft, there's a pile of livers for the wolf, since rifampin also causes liver damage.
Tucked amongst the livers is a happy little chrome colored cell to help you remember this drug is a cytochrome P450 inducer.
OK, next, the hermit's prized possession is a globe of the Earth, representing Eambuttal. There's a pair of eyes on the globe colored red and green to help you remember it causes optic neuritis and red-green color blindness.
There's uric crystals growing out of the top of the globe to help you remember it increases the risk of developing gout.
The next drug is pyrazinamide, so let's have an Asian pirate represent this drug. He snuck down into the sewer to steal from the hermit.
He's carrying a big chunk of uric acid crystal and one of the livers, since it causes gout and liver damage. Finally, running away from the pirate is a giant mouse with stripes which represents streptomycin.

Mind map13:34–14:02

The fact that it's running away into the sewer should help you remember that it's used to treat TB that's spread to other parts of the body, like the brain, where it could cause meningitis.
The mouse is wearing kidney-shaped headphones to help you remember it's nephrotoxic and can also cause hearing loss. All right, as a quick recap.

Review14:02–14:50

There are 4 1st line anti-tuberculosis medications isoniazid, rifampin, ethambutal, and pyrazinamide. They should be used together to treat active TB since this prevents the development of resistance.
Isoniazid and less commonly, rifampin can be given as prophylaxis when there's a high risk of developing an active infection.
Second line agents like streptomycin can be used for drug resistant TB. Finally, streptomycin can also be given along with the other medications if there's miliary TB or TB meningitis.
But wait, there's more. Here's a mind map with all of the mnemonics.
Go ahead and pause the video so you can test yourself to see what you remember. Stay tuned for the answers after the credits.