Antimycobacterials | Anti-TB Drugs

Introduction to Anti-Mycobacterial Drugs

In this section, the speaker introduces the topic of anti-mycobacterial drugs and emphasizes the importance of understanding their mechanism of action and clinical applications.

Mechanism of Action

• RNA polymerase is a key enzyme required for mycobacterial DNA replication and transcription.

• Rifamycins (e.g. rifampin, rifabutin) inhibit RNA polymerase, leading to reduced mRNA synthesis and protein production.

• Para-aminobenzoic acid is converted into dihydrofolate, which is essential for nucleotide synthesis in DNA and RNA.

• Dapsone inhibits enzymes involved in converting para-aminobenzoic acid into dihydrofolate, leading to reduced nucleotide incorporation into DNA and RNA.

Clinical Applications

• Anti-mycobacterial drugs are used to treat tuberculosis, MAC infections, and leprosy.

• Rifabutin may be preferred over rifampin in HIV-positive patients due to fewer drug interactions.

• Adverse effects of anti-mycobacterial drugs include hepatotoxicity, gastrointestinal disturbances, and skin reactions.

Antibiotics Mechanisms of Action

In this section, the speaker explains how different antibiotics work to inhibit bacterial growth.

Streptomycin

• Streptomycin inhibits the 30s ribosomal subunit from interacting with RNA and making proteins.

• This inhibition leads to a decrease in protein synthesis.

Rifampicin

• Rifampicin inhibits the RNA polymerase enzyme.

• This inhibition leads to a decrease in mRNA synthesis.

Dapsone

• Dapsone inhibits the para-amino benzoic acid pathway leading to less tetrahydrofolate and fewer nucleotides needed for DNA and RNA synthesis.

Isoniazid

• Isoniazid gets taken up into mycobacterial cells and is converted into an active metabolite by catalase peroxidase (cat G).

• The active metabolite binds with NAD and then inhibits enol reductase, which helps synthesize mycolic acid molecules that are integral to the cell wall.

• Inhibition of enol reductase reduces mycolic acid synthesis, leading to loss of an integral component of the cell wall and subsequent bacterial death.

Pyrazinamide

• Pyrazinamide works by inhibiting fatty acid synthase, which helps synthesize mycolic acid molecules that are integral to the cell wall.

Inhibitors of Mycobacterium tuberculosis Cell Wall Synthesis

This section discusses the inhibitors of Mycobacterium tuberculosis cell wall synthesis and their mechanisms of action.

Rifamycins

• Rifamycins inhibit RNA polymerases.

• Rifampin is a rifamycin used to treat tuberculosis.

Streptomycin

• Streptomycin inhibits the 30S ribosomal subunit.

• Streptomycin is used in combination with other drugs to treat tuberculosis.

Dapsone

• Dapsone inhibits the PABA pathway, which inhibits nucleotide formation.

• Dapsone is used in combination with other drugs to treat leprosy.

Isoniazid

• Isoniazid inhibits fatty acid synthesis, particularly of mycolic acid, by inhibiting enol reductase.

• Isoniazid is used in combination with other drugs to treat tuberculosis.

Pyrazinamide

• Pyrazinamide inhibits mycolic acid formation by inhibiting fatty acid synthase.

• Pyrazinamide is used in combination with other drugs to treat tuberculosis.

Ethambutol

• Ethambutol inhibits arabinoglactin formation by inhibiting arabinosol transferase.

• Ethambutol is used in combination with other drugs to treat tuberculosis.

Clinical Indications of Anti-Tuberculosis Drugs

This section discusses the clinical indications of anti-tuberculosis drugs.

Mycobacterium tuberculosis

• Mycobacterium tuberculosis causes tuberculosis, which primarily affects the lungs but can also spread to other organs.

• Latent tuberculosis infection is treated with isoniazid or rifampin, while active tuberculosis infection is treated with a combination of drugs including rifampin, isoniazid, pyrazinamide, and ethambutol.

Treatment of Tuberculosis and Leprosy

In this section, the speaker discusses the treatment of latent and active tuberculosis as well as leprosy.

Latent TB Treatment

• Latent TB patients who test positive or have a particular size of the tuberculin skin test can be put on one of two drugs for that time duration.

• The two drugs used to treat latent TB are rifampin and isoniazid.

• Patients on isoniazid may develop B6 deficiency, which can cause neuropathy, anemia, and increase the risk of seizures. Therefore, B6 supplements are given to prevent B6 deficiency.

Active TB Treatment

• Active TB patients are treated with what's called a "ripe regimen" consisting of rifampin, isoniazid, piracinamide, and ethambutol for at least two months.

• After two months, patients move into the second part of the regimen which utilizes rifampin and isoniazid for four months.

• If a patient has active tuberculosis that is spreading (miliary tb or tb meningitis), streptomycin may be added as a second-line agent.

• The most important things to remember about treating active TB are the ripe regimen for the first two months followed by rifampin and inh for four months. Additionally, B6 should be added to prevent adverse effects from isoniazid.

Leprosy Treatment

• Leprosy typically involves the skin and may cause hypopigmented skin lesions and nerve palsies.

• The two drugs used to treat leprosy are dapsone and rifampin. Sometimes, clefazamine is added if the patient has the tuberculoid form of leprosy.

• Patients with leprosy are isolated for six to nine months.

Mycobacterium Avium Intracellular Complex Infections

• These infections generally cause fibrocavitary pneumonia and may disseminate in immunosuppressed individuals.

Treatment of Mycobacterium Avium Intracellular Complex Infections

This section discusses the primary agents used to treat Mycobacterium Avium Intracellular Complex infections and potential additional agents that may be added in severe cases.

Primary Agents for Treatment

• Ethambutol, rifampin, and a macrolide are the primary agents used to treat Mycobacterium Avium Intracellular Complex infections.

• Rifampin can interact with the CYP 450 system, so if a patient is HIV positive and taking nrtis or protease inhibitors, it may decrease the concentration of those drugs. In this case, rifabutin should be used instead.

Additional Agents for Severe Cases

• Aminoglycosides or fluoroquinolones may be added in severe or refractory cases.

Adverse Effects of Antibacterial Drugs

This section discusses adverse effects associated with specific antibacterial drugs.

Rifampin

• Red-orange urine is a harmless but common adverse effect of rifampin. Patients should be informed about this before leaving the hospital.

• Rifampin can cause false-positive urine opiate tests.

• Rifampin acts as an inducer on the CYP 450 system and can decrease drug concentrations when taken with other medications such as nrtis or protease inhibitors. Careful monitoring is necessary when using these drugs together.

Pyrazinamide

• Pyrazinamide can cause hepatotoxicity, so liver function tests should be monitored regularly during treatment.

• Pyrazinamide may reduce uric acid in urine and increase it in the blood, causing hyperuricemia.

Isoniazid

• Isoniazid can cause hepatotoxicity, so liver function tests should be monitored regularly during treatment.

Important Considerations for Antitubercular Drugs

In this section, the speaker discusses important considerations for antitubercular drugs.

Rifampin

• Rifampin is a CYP450 inducer.

• It can cause false-positive urine screens.

• It can cause hepatotoxicity and hyperuricemia.

Pyrazinamide

• Pyrazinamide can cause hyperuricemia and hepatotoxicity.

Ethambutol

• Ethambutol can cause optic neuritis.

• Patients on ethambutol should be monitored by an ophthalmologist or optometrist.

Dapsone

• Dapsone can cause methemoglobinemia, which leads to hypoxia.

• Patients with G6PD deficiency may experience acute hemolytic events when taking dapsone.

• Dapsone may suppress the production of white blood cells, leading to neutropenia.

Isoniazid

• Isoniazid can cause liver injury and increase LFT levels.

• It can also cause anion gap metabolic acidosis through increased beta-hydroxybutyrate and lactate levels.

• Isoniazid is one of the drugs that can cause drug-induced lupus. Remember the mnemonic "SHIPP" (Sulfa drugs, Hydralazine, Isoniazid, Procainamide, Phenytoin).

• Isoniazid can cause B6 deficiency, leading to peripheral neuropathy and anemia. It can also reduce the seizure threshold, causing refractory seizures.

Conclusion

In this section, the speaker concludes the discussion on antitubercular drugs.

• Antitubercular drugs have various side effects that need to be monitored.

• Ethambutol can cause optic neuritis, and patients should be monitored by an ophthalmologist or optometrist.

• Dapsone can cause methemoglobinemia and G6PD deficiency-related acute hemolytic events.

• Isoniazid can cause liver injury, anion gap metabolic acidosis, drug-induced lupus, B6 deficiency-related peripheral neuropathy and anemia, and refractory seizures.

Tryptamines and Practice Problems

In this section, the speaker discusses the use of tryptamines in treating TB meningitis. They also highlight the potential side effects of using these drugs, including nephrotoxicity and ototoxicity. The speaker then goes on to provide practice problems to help learners understand the mechanism of action of different drugs used in treating TB.

Tryptamines for TB Meningitis

• Tryptamines are used to treat TB meningitis.

• These drugs can cause nephrotoxicity and ototoxicity, so it's important to monitor renal function and watch for any changes in hearing.

• Tryptamines are teratogenic, so they should not be given to pregnant patients.

• Patients with myasthenia gravis should not be given tryptamines as it alters their antibody response.

Practice Problems

• The speaker provides a series of practice problems to help learners understand the mechanism of action of different drugs used in treating TB.

• Rifamycins inhibit RNA polymerase.

• Streptomycin inhibits 30S ribosomal subunit, which is needed for protein synthesis in bacteria.

• Ethambutol inhibits arabinosyl transferase, which is involved in making arabinoglactin - an important component of cell wall structure.

• Paraxinamide inhibits fatty acid synthase that helps make mycolic acid - another important component of cell wall structure.

• Dapsone inhibits enzyme that converts perimenobenzoic acid into dihydrofolate and subsequently tetrahydrofolate, which is needed to make nucleotides for DNA synthesis.

• Isoniazid is taken up by fungal cells and inhibits enol reductase, decreasing mycolic acid synthesis in the cell wall.

Overall, this section covers the use of tryptamines in treating TB meningitis and provides practice problems to help learners understand the mechanism of action of different drugs used in treating TB.

Treatment of Mycobacterial Infections

This section discusses the treatment options for different types of mycobacterial infections.

Rifampin and Rifabutin

• Rifampin is a CYP450 inducer that decreases the concentration of drugs metabolized by the CYP450 system.

• Rifabutin is used instead of rifampin in patients taking HIV medications to avoid decreasing drug efficacy.

• For latent TB, use isoniazid for 6-9 months or rifampin for 4 months. For active TB, use RIPE (rifampin, isoniazid, pyrazinamide, ethambutol) for 2 months followed by rifampin and isoniazid for 4 months. Add B6 if needed.

Mycobacterium Avium Intracellular and Streptomycin

• Treat with rifampin or rifabutin if patient has HIV. Consider adding ethambutol and a macrolide like azithromycin.

• Add streptomycin in refractory or miliary types of TB.

Mycobacterium Leprae

• Treat with dapsone and rifampin. Add clofazimine for tuberculoid leprosy.

Adverse Drug Reactions

This section discusses adverse drug reactions associated with different treatments.

Rifamycins

• Can cause red-orange urine and false positive urine opiates.

• CYP450 inducer that increases activity of cytochrome P450 metabolism, which decreases drug concentration.

Isoniazid

• Hepatotoxic and can cause metabolic acidosis, bone marrow suppression, drug-induced lupus, seizures, and neuropathy.

• Monitor LFTs.

Pyrazinamide

• No specific adverse reactions mentioned in the transcript.

Dapsone and Streptomycin

In this section, the speaker discusses the use of dapsone and streptomycin as anti-microbacterials.

Dapsone

• Dapsone is used to treat leprosy.

• It can cause methemoglobinemia and acute hemolytic crisis in patients with G6PDH deficiency.

• Patients taking dapsone should be monitored for neutropenia.

Streptomycin

• Streptomycin belongs to the aminoglycoside category of antibiotics.

• Aminoglycosides are nephrotoxic, ototoxic, and teratogenic.

• Streptomycin can worsen myasthenia gravis and is contraindicated in patients with this condition.

Conclusion

The speaker concludes the video.

• The speaker hopes that the information provided was helpful.

• The video ends with music.