أسئلة_الـ_19_فارما_PPPM_قبل_التعديل_

• This lecture discusses anti-TB (Tuberculosis) treatment.

Mycobacterium Tuberculosis

• Rod-shaped, acid-fast bacilli resist decolorization by acidified solvents are the cause of tuberculosis
• It is an obligate aerobe, multiplying slowly (every 18-24 hours in vitro).
• Spread by aerosol droplets expelled by infected individuals through coughing or sneezing, leading to pulmonary alveoli infection.
• It invades macrophages, leading to the formation of granulomas and caseous lesions within connective tissue.
• These lesions protect the organism from the immune system and drugs.
• This leads to a dormant state and contributes to the chronic nature of the infection and the need for long-term treatment.

Aims of Anti-Tuberculosis Therapy

• Kill tubercle bacilli rapidly to cure the patient.
• Eliminate dormant and sequestered bacilli to prevent relapse.
• Prevent transmission of tuberculosis to others.
• Prevent the development of acquired resistance to treatment.
• Decrease mortality from tuberculosis.

Anti-Tuberculosis Therapy

• Combinations of 3 or more drugs are required for effective treatment.
• Treatment is continued for months to years, depending on the drugs used, because Mycobacteria:
  • Grow slowly
  • Have lipid-rich cell walls that are impermeable to many agents
  • Are intracellular pathogens
  • Can develop resistance to drugs

General Principles of Treatment

• Multidrug regimens suppress the emergence of resistant strains.
• Prolonged therapy (6-24 months) eradicates persistent organisms and prevents relapses:
  • Active drug-susceptible TB requires 6 months of treatment.
  • Active multidrug-resistant TB requires 24 months of treatment.
• Directly Observed Therapy (DOT) ensures patients take medications while monitored by a healthcare team member.
• This improves cure rates and decreases drug resistance.

Drugs for M. Tuberculosis

• First-line drugs (essential anti-TB) are used initially to treat most patients with TB:
  • Isoniazid (INH)
  • Rifampicin/Rifampin
  • Ethambutol
  • Pyrazinamide
• Second-line drugs (reserve anti-TB) are used to treat patients infected with organisms resistant to first-line drugs:
  • Rifabutin and rifapentine
  • Fluoroquinolones
  • Aminoglycosides (capreomycin, amikacin, kanamycin)
  • Ethionamide, cycloserine, bedaquiline, pretomanid, linezolid

Isoniazid (INH)

• Well absorbed from the gastrointestinal tract.
• Widely distributed throughout the body, including caseous material.
• It reaches high enough intracellular concentrations to be effective.
• Metabolism occurs through acetylation in the liver
  • Fast acetylators are more prone to INH-induced hepatotoxicity, especially in patients over 35.
  • Slow acetylators are more prone to INH-induced peripheral neuropathy.
• Excreted in urine, requiring dose adjustments in patients with renal failure.
• The slow phenotype predominates in some Middle Eastern populations.

Adverse Effects of Isoniazid

• Hepatotoxicity
• Peripheral neuropathy can cause numbness and tingling in fingers and toes and can be prevented with pyridoxine (Vitamin B6).
• Hypersensitivity reactions include skin rashes, fever, and arthralgia.
• CNS effects include toxic encephalopathy or seizures.
• Drug interactions can inhibit the metabolism of carbamazepine and phenytoin.

Indications for Isoniazid

• Part of the standard four-drug regimen for TB, killing rapidly growing and dormant bacilli
  • In combination with rifampin and pyrazinamide, it eradicates rapidly growing organisms during the first 2 months of therapy.
  • During the next 4 months, isoniazid and rifampin act against dormant bacteria.
• Can treat latent TB with a preferred duration of treatment of 9 months, or rifampin can be used if isoniazid is contraindicated.

Rifampicin (RMP)

• Administered orally
• Adequately distributes into tissues, pus, and CSF, making it useful in treating tubercular meningitis.
• Metabolized via hepatic microsomal induction.
• Excreted mainly into bile and undergoes enterohepatic circulation.

Adverse Effects of Rifampicin

• Hepatotoxicity is rare; avoid in older adults and those with chronic liver diseases, and monitor liver functions.
• A major cause of drug interactions due to hepatic microsomal induction, it shortens the half-life of many drugs like warfarin, theophylline, and oral contraceptives.
• Flu-like symptoms occur in 50% of patients, including fever, chills, and myalgia.
• High-dose intermittent therapy can cause hemolytic anemia, acute renal failure, leukopenia, and thrombocytopenia.
• Causes orange-red discoloration of saliva, urine, and tears.

Indications of Rifampicin

• Part of the standard four-drug regimen for TB.
• An alternative to INH for latent TB when INH resistance is present, administered for 4 months.

Ethambutol

• Most unsafe in renal failure
• Can cause optic neuritis and red-green color blindness.

Pyrizinamide

• More rapidly bactericidal compared to other agents used to treat TB.
• Adding pyrazinamide to TB treatment regimens reduces the treatment duration to 6 months.
• Reaches sufficient concentrations in acidic lesions and inside macrophages.

Anti-TB Drugs - Mechanisms, Routes, Sites, Metabolism, and Side Effects

• Isoniazid:
  • Mechanism: inhibits mycolic acid synthesis
  • Route: oral
  • Site: Intracellular and Extracellular
  • Cidal or Static: Bactericidal
  • Metabolism: Liver - Acetylation
  • Side Effects: Hepatotoxicity (Fast acetylators), Peripheral neuropathy (Slow Acetylators)
• Rifampicin:
  • Mechanism: Inhibits DNA-dependent RNA polymerase
  • Route: oral
  • Site: Intracellular and Extracellular
  • Cidal or Static: Bactericidal
  • Metabolism: Liver-CYP Inducer
  • Side Effects: Hepatotoxicity, Reddish Orange discoloration, Hyperurecemia (Gout)
• Ethambutol:
  • Mechanism: Inhibits Mycolic acid and Arabinosyl-transferase
  • Route: oral
  • Site: Intracellular and Extracellular
  • Cidal or Static: Bacteriostatic
  • Metabolism: Unchanged Urine
  • Side Effects: Retrobulbar neuritis (red-green color blindness), Hyperurecemia (Gout)
• Pyrazinamide:
  • Mechanism: Inhibits membrane transport function
  • Route: oral
  • Site: Intracellular only
  • Cidal or Static: Bactericidal
  • Metabolism: Liver
  • Side Effects: Hepatotoxicity, Hyperurecemia (Gout)

Second-Line Anti-Tuberculosis Drugs

• Bedaquiline:
  • Blocks ATP synthase in M. tuberculosis
  • Prolongs the QT interval, leading to arrhythmias and sudden death.
  • Metabolized by CYP3A4, causing drug-drug interactions
• Ethionamide and Cycloserine: inhibit mycolic acid synthesis.

Standard Short-Course Chemotherapy for Active Drug-Susceptible TB

• Intensive phase (2 months):
  • HRZ+/-E (Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol) daily and observed
• Continuation phase (4 months):
  • Isoniazid (H) and Rifampicin (R) daily and observed

Indications of Corticosteroids in TB

• TB meningitis
• TB pericarditis
• TB pleura
• Military TB
• Corticosteroids must be given under the umbrella of anti-TB drugs.