Pharmacotherapy of Tuberculosis and Drug Interactions Ace Inhibitors and Thiazides

Pharmacotherapy of Tuberculosis and Drug interactions ACE inhibitors and Thiazides

1. Pharmacotherapy of Pulmonary Tuberculosis Drug Interaction: ACE inhibitors and Thiazides By-Junior Resident Department of Pharmacology and Therapeutics King George’s Medical University, Lucknow

2. Introduction Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis It primarily affects the lungs but can also affect other parts of the body It is a slow-growing, acid-fast bacillus with a complex cell wall that makes it resistant to many disinfectants and drying, contributing to its persistence in the environment

3. People living with HIV (18 times more likely to develop active TB) Individuals with compromised immune systems (e.g., diabetes, immunosuppressive treatments) M alnourished individuals Healthcare workers Smokers and those with chronic lung diseases Populations with higher risk of developing TB

4. Pathophysiology of Tuberculosis

5. Combination Therapy : Use of multiple drugs to prevent the development of drug resistance Phased Treatment : Consists of an intensive phase to rapidly reduce the bacterial load and a continuation phase to eliminate remaining bacteria Adherence to Treatment : Ensuring patients to complete the full course of therapy to prevent the relapse and the emergence of drug-resistant TB Principles of TB treatment :

6. Isoniazid (INH) Integral to all anti-TB regimens unless there’s intolerance or resistance MOA : INH targets mycolic acids unique to mycobacterial cell walls, and inhibits its synthesis ADME : Completely absorbed orally, penetrates tissues, tubercular cavities, placenta, and meninges. Metabolized in liver and excrete through urine

7. Adverse Effects: - Peripheral Neuritis - Hepatitis: More common in older individuals and alcoholics ,Lethargy, rashes, mild anaemia, and arthralgia Drug Interactions: - Aluminium hydroxide inhibits INH absorption - INH retards metabolism of phenytoin, carbamazepine, diazepam, theophylline, and warfarin

8. Rifampin (Rifampicin, R) Semisynthetic derivative of rifamycin B from Streptomyces mediterranei MOA : Binds to the β subunit of mycobacterial DNA-dependent RNA polymerase, blocking RNA synthesis ADME: Well absorbed orally, food reduces absorption. Widely distributed, reaches tubercular cavities, caseous masses, placenta. Metabolized in liver, excreted in bile/urine

9. Interactions : Induces CYP450, increasing metabolism of warfarin, contraceptives, sulfonylureas, NNRTIs, phenytoin Adverse Effects : Hepatitis, flushing, pruritus, rash, chills, fever , headache, bone pain, red-orange urine , purpura, hemolysis , shock, renal failure

10. Pyrazinamide (Z) MOA : Converted inside mycobacterial cells into active metabolite pyrazinoic acid. It inhibits mycolic acid synthesis ADME : Orally absorbed, widely distributed, good CSF penetration (useful in meningeal TB). Extensively metabolized in the liver and excreted in urine. Half-life : 6–10 hours

11. Adverse Effects: - Hepatotoxicity (contraindicated in liver disease) - Hyperuricaemia , potentially causing gout - Other Effects: Abdominal distress, arthralgia, Considered safe during pregnancy

12. Ethambutol (E) MOA : Inhibits arabinosyl transferases involved in arabinogalactan synthesis, interfering with mycolic acid incorporation in the mycobacterial cell wall ADME : Widely distributed, inconsistent meningeal penetration, better when meninges are inflamed. Excreted in urine and faeces; plasma half-life is ~4 hours

13. Adverse Effects: - Visual Toxicity (due to retrobulbar neuritis ) Side Effects: Nausea, rashes, fever, rarely peripheral neuritis. Generally well tolerated and safe during pregnancy

14. Streptomycin (S) Tuberculocidal but less effective than INH or Rifampin ; acts on extracellular bacilli with poor intracellular penetration & ineffective against intracellular bacilli ADME : Poor cellular penetration, reaches tubercular cavities, not CSF Administration : Intramuscular injections. 15 mg/kg once daily Toxicity : Lower safety margin. Restricted use (max. 2 months) due to toxicity risks. Ototoxic and Nephrotoxic

15. Second Line Anti-TB Drugs 1. Kanamycin (Km) and Amikacin (Am)Class: Aminoglycoside antibiotics. They have similar properties to streptomycin, with less vestibular toxicity but equal nephrotoxicity. The dosage is 0.75–1.0 g/day (10–15 mg/kg/day) IM 2. Capreomycin (Cm)Class: Cyclic peptide antibiotic, similar mycobactericidal activity but may cause ototoxicity, nephrotoxicity, and injection site pain. Dosage : 0.75–1.0 g/day IM .

16. 3. Fluoroquinolones (FQs) Ofloxacin , Levofloxacin, Ciprofloxacin, Moxifloxacin Order of Efficacy : Mfx > Lfx > Ofx > Cfx for TB MOA : Inhibit DNA gyrase and Topoisomerase; kills mycobacteria inside macrophages. Dosage : Levofloxacin: 500-1000 mg OD , Ofloxacin : 800 mg OD , Moxifloxacin : 400 mg OD

17. 4. Ethionamide ( Eto ) : Moderately effective against intra/extra-cellular bacilli and some atypical mycobacteria MOA : Inhibits mycolic acid synthesis, similar to INH ADME : Orally absorbed, crosses CSF, liver metabolism, 2-3 hour half-life; Dose : Start at 250 mg/day, increase to 750 mg/day over 5-6 days Uses : Drug-resistant TB, MDR-TB regimens. 5. Prothionamide ( Pto ) : Close congener of Eto .

18. 6. Cycloserine (Cs) : MOA : Inhibits bacterial cell wall synthesis;tuberculostatic . ADME : Well absorbed, wide distribution, good CSF penetration Adverse Effects: Drowsiness, headache, tremor, slurred speech, altered behavior , psychosis, seizures. Dosing: Start 250 mg BD, up to 750 mg/day for >45 kg. 7. Terizidone : Contains 2 molecules of cycloserine

19. 8. Para-amino Salicylic Acid (PAS) : Inhibits folate synthase; tuberculostatic . Delays resistance development 9 . Rifabutin : Less active against M. tuberculosis, more active against MAC. Dose : 300 mg/day 10. Rifapentine : Rifampin congener, used in the continuation phase of TB treatment. Dose: 600 mg once or twice weekly

20. 11. Bedaquiline (BDQ) Mechanism: Inhibits mycobacterial ATP synthase Pharmacokinetics: Well absorbed orally, enhanced by fatty meals; highly protein-bound, extensive tissue distribution; metabolized by CYP3A4, with a 160-day half-life Max 24 weeks: 400 mg/day for 2 weeks, then 200 mg 3 times/week for 22 weeks Not for drug-sensitive TB, extrapulmonary TB

21. Treatment of Drug Sensitive TB Standard Treatment Regimen: Intensive Phase : Typically lasts 2 months and includes all four first-line drugs (HRZE). Continuation Phase : Lasts 4-6 months and usually includes isoniazid,rifampicin and ethambutol (HRE). Type of TB case Treatment regimen in Intensive Phase Treatment regimen in Continuous Phase New or Previously Treated Cases (2) HRZE (4) HRE

22. The drugs are given daily and doses are calculated according to body weight FDC tablets are used Isoniazid 75mg (H) , Rifampicin 150mg (R) Pyrazinamide 400 mg (Z) , Ethambutol 275 mg (E)

23. Special Considerations: HIV Co-infection: Requires careful management due to potential drug interactions and overlapping toxicities. Co-treatment with antiretroviral therapy (ART) is crucial. Pregnancy: Some TB drugs are contraindicated or require dose adjustments. EMB and INH are generally considered safe. Paediatrics: Dosing is adjusted based on weight, and drug formulations suitable for children are used.

24. Drug-Resistant Tuberculosis Mono-Resistant TB : Resistant to one first-line drug Poly-Resistant TB : Resistant to multiple first-line drugs, but not both isoniazid and rifampicin Multidrug-Resistant TB (MDR-TB) : Resistant to both isoniazid and rifampicin Extensively Drug-Resistant TB (XDR-TB) : MDR-TB resistant to any fluoroquinolone & at least one second-line injectable drug (amikacin, kanamycin, or capreomycin )

25. Shorter Regimen: ( 9-11 months of treatment ) Suitable for patients without resistance to fluoroquinolones or second-line injectable drugs Longer Regimen: This regimen lasts 18-20 months and includes drugs such as bedaquiline , levofloxacin (or moxifloxacin), linezolid, clofazimine , cycloserine , pyrazinamide , and ethambutol MDR-TB Treatment

26. XDR-TB Treatment Individualized Treatment: XDR-TB treatment is based on Drug Susceptibility Testing (DST), often including bedaquiline , delamanid , linezolid, clofazimine , cycloserine , & other susceptible drugs Duration: Typically 20-24 months, adjusted based on response and tolerance Monitoring: Monthly sputum cultures & regular DST recommended to track progress & adjust treatment

27. National Tuberculosis Elimination Programme (NTEP) The National Tuberculosis Elimination Programme (NTEP) in India aims to eliminate TB by 2025 through comprehensive strategies and interventions. Formerly known as the Revised National Tuberculosis Control Programme (RNTCP)

28. Mechanism of ACE Inhibitors: ACE inhibitors block the conversion of angiotensin I to angiotensin II , a potent vasoconstrictor. Reduced angiotensin II levels lead to vasodilation, decreased blood pressure, and reduced aldosterone secretion . Reduced Aldosterone Secretion: Lower aldosterone levels decrease sodium and water reabsorption in the kidneys, leading to diuresis and decreased blood volume. This further contributes to lowering blood pressure . Drug Interaction: ACE inhibitors and Thiazides

29. Mechanism of Thiazides : (Inhibition of Sodium-Chloride Symporter ) Thiazide diuretics inhibit the sodium-chloride symporter in the distal convoluted tubule of the nephron. This leads to increased excretion of sodium and chloride, and consequently water, resulting in diuresis The diuretic effect reduces blood volume, which helps lower blood pressure .

30. Combined Mechanism and Interaction : Additive Effect on Blood Pressure: The combination of ACE inhibitors and thiazides has an additive effect on lowering blood pressure . Therapeutic Use: The combination is commonly used in treating hypertension, especially in patients who do not achieve adequate blood pressure control with a single agent .

31. References Tripathi KD. Essentials of Medical Pharmacology. 9th ed. New Delhi: Jaypee Brothers Medical Publishers; 2023. Papadakis MA, McPhee SJ, Rabow MW, editors. Current Medical Diagnosis and Treatment 2024. 63rd ed. New York: McGraw Hill; 2024. National guidelines for programmatic management of Tuberculosis Preventive Treatment in India 2021

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