Pharmacology
Summary
The traditional first-line treatment for tuberculosis is known as RIPE therapy. RIPE therapy is composed of four drugs: rifampin, isoniazid, pyrazinamide, and ethambutol. Each drug has a unique mechanism of action to overcome obstacles presented by the slowly growing, resistant mycobacterial tuberculosis cell. Isoniazid is notable because it can be used alone for the treatment of latent tuberculosis, preventing its reactivation by inhibiting the synthesis of essential components of the mycobacterial cell wall, mycolic acids. Adverse effects commonly associated with isoniazid are neurologic side effects, such as peripheral neuropathy and hepatic toxicity.
On the other hand rifampin is active against both mycobacteria and certain gram-negative bacteria. It's the go-to for prophylactic coverage against certain types of meningitis, specifically from close contact exposure to Haemophilus influenzae or Neisseria meningitidis. Its method of action is inhibition of RNA synthesis in bacteria. Another member of the therapy, ethambutol, is a bacteriostatic agent that affects the mycobacterial cell wall by blocking the enzyme arabinosyl transferase. Lastly, pyrazinamide can increase uric acid, which can potentially lead to gout attacks. And a`ll four drugs are associated with hepatotoxicity.
Lesson Outline
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FAQs
The treatment for tuberculosis comprises two phases. The first phase lasts for two months and includes a combination of four drugs: rifampin (R), isoniazid (I), pyrazinamide (P), and ethambutol (E). This is often referred to as "RIPE therapy". The second phase lasts for four months and involves the continued use of just two of those drugs: isoniazid and rifampin. The goal of using this combination of drugs is to prevent the development of resistant strains of Mycobacterium tuberculosis.
Isoniazid, or INH, plays a crucial role in tuberculosis treatment by inhibiting the production of mycolic acids, essential components of the mycobacterial cell wall. Mycobacteria develop resistance to INH by downregulating a catalase-peroxidase called KatG, which is necessary for activating INH. INH can have side effects including peripheral neuropathy, hepatitis (shown as an asymptomatic rise in aminotransferases), seizures, and anion gap metabolic acidosis. These side effects can be exacerbated in slow acetylators, as INH is metabolized by the liver enzyme N-acetyltransferase. Additionally, coadministration of INH with pyridoxine (vitamin B6) can prevent peripheral neuropathy, a side effect caused by INH's promotion of pyridoxine excretion.
Rifampin is another drug used in RIPE therapy. It functions by binding to bacterial DNA-dependent RNA polymerase, thereby inhibiting protein synthesis essential for the bacteria's survival. Apart from its use in TB treatment, rifampin monotherapy can also be used as prophylaxis in close contacts exposed to Haemophilus influenzae or Neisseria meningitidis. Rifampin can cause hepatotoxicity, a common effect of all RIPE therapy drugs, and can turn body fluids an orange color. Significantly, it also activates cytochrome P450, thus it can increase the metabolism of other drugs.
Ethambutol is an essential component of the RIPE therapy used in the first phase of tuberculosis treatment. Its primary function involves blocking arabinosyl transferase, which inhibits carbohydrate formation at the cell wall of the mycobacteria. Despite being bacteriostatic, meaning it merely stops the bacteria from reproducing rather than killing them, ethambutol is crucial in the tuberculosis treatment regimen. Possible side effects of ethambutol can include optic neuritis and red-green color blindness.
Pyrazinamide is the fourth drug used in the RIPE therapy for tuberculosis treatment. Its mechanism of action is not fully understood, but it is thought to be active against mycobacteria. However, pyrazinamide can have potential side effects, including causing hyperuricemia (excess uric acid in the blood). Because of this, it may precipitate gout attacks in susceptible individuals.
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