Pharmacotherapy of pulmonary T.B. andDrug interaction ACE inhibitors + Thiazide.pptx

Will help you learn about pulmonary TB

1. Pharmacotherapy of Pulmonary Tuberculosis and Drug Interaction: ACE inhibitors + Thiazides Presenter: Dr. Hasan Abbas (JR2) Moderator: Dr. Ashish Dixit (SR) Peer support: Dr. Naim Akhtar(JR2) Department of Pharmacology and Therapeutics King George’s Medical University, Lucknow, UP, India- 226003 Email: [email protected]

2. Contents: I ntroduction P athophysiology of Pulmonary T.B. C linical manifestation D iagnosis M anagement of Pulmonary T.B. D rug interaction between ACE inhibitors and thiazides Summary

3. Specific learning objectives: By the end of this teaching learning session, the audience will be able to : Understand the pathophysiology of pulmonary T.B. Understand drug sensitive and drug resistance T.B. with their treatment regimens K now the drug interaction between ACE inhibitors and thiazides

4. Introduction: Tuberculosis (TB)- infectious disease caused by Mycobacterium tuberculosis It primarily affects the lungs but can also affect other parts of the body Discovered by Robert Koch in 1882

5. Impact of Tuberculosis in India : According to India TB report 2024 (National Tuberculosis Elimination Programme ) - Incidence rate is 179 / 100000 Total 2.4 million fell ill in 2023 India accounts for 26% of total global impact

6. Why National Tuberculosis Elimination Programme is made? Decrease duration of therapy Decrease number of drugs No injectables Promote oral drugs

7. Pathophysiology of Tuberculosis:

8. Bacilli Entry (lungs) Cont.. Bacilli are taken up by alveolar macrophages in the lungs (Bacilli are either killed or survive to cause infection) Spread to Lung Tissue Surviving bacilli enter lung tissue (parenchyma) and travel to nearby lymph nodes where T cells get activated (Primed T cells)

9. Granuloma Formation Cont … Primed T cells attract various immune cells (e.g., T cells, B cells, macrophages, fibroblasts) to form a granuloma that trap infected macrophages in the lung tissue Calcification Granulomas in the lung ( Ghon focus) and lymph nodes may calcify Chest X-Ray : These calcified areas (Ranke complex) are visible on X-rays

10. Ghon Focus + Calcified Hilar Nodes = Ranke complex

11. Clinical manifestations: Cough: persistent, productive > 2 weeks Hemoptysis : blood-stained sputum Chest Pain: may be pleuritic (worsens with breathing) Dyspnea : shortness of breath in advanced cases Fever, night sweats, and unexplained weight loss are common symptoms

12. Diagnosis : Presumptive pulmonary tuberculosis – refers to a person with any of the symptoms or signs suggestive of TB Cough > 2 weeks Fever > 2 weeks Weight loss Haemoptysis Abnormality in chest radiography

13. Classification of Antitubercular Drugs: Anti tubercular drugs First line drugs Isoniazid Rifampicin Ethambutol Pyrazinamide Second line drugs Ofloxacin Levofloxacin Moxifloxacin Ciprofloxacin Ethionamide Prothionamide Cycloserine Terizidone Para amino salicylic acid (PAS) Rifabutin Rifapentin Streptomycin Kanamycin Amikacin Capreomycin Fluoroquinolones Other oral drugs Injectables

14. Isoniazid (INH): Bactericidal: Kills rapidly multiplying TB organisms and inhibits inactive ones MOA: Inhibit mycolic acids synthesis unique to mycobacterial cell walls Adverse Effects: Peripheral Neuritis Hepatitis: more common in older individuals and alcoholics Drug Interactions: CYP enzyme inhibitor INH retards metabolism of phenytoin, carbamazepine, diazepam, theophylline, and warfarin

15. Rifampin (Rifampicin, R): Bactericidal MOA : Inhibit DNA-dependent RNA polymerase of Mycobacteria TB Adverse Effects : R ed-orange urine, hepatotoxicity, hypersensitivity and respiratory syndrome (dyspnea, cyanosis and shock) Interactions: Induces CYP450, increasing metabolism of warfarin, contraceptives, sulfonylureas, NNRTIs, phenytoin

16. Pyrazinamide (Z): Bactericidal MOA: Inhibits mycolic acid synthesis Adverse Effects: Hepatotoxicity (most common) Acute gout (Hyperuricaemia)

17. Ethambutol (E): Bactereostatic MOA : Inhibits arabino asyl transferases involved in arabinogalactan synthesis , interfering with mycolic acid incorporation in the mycobacterial cell wall Adverse Effects: Red green colour blindness , scotoma, retrobulbar optic neuritis Acute gout (hyperuricemia)

18. Newer Anti-Tubercular Drugs: 1. Bedaquiline : MOA - ATP synthase inhibitor Strong bactericidal Side effects - QT prolongation , hepatotoxic, electrolyte imbalance Formulation - 100 mg Tablet

19. Newer Anti-Tubercular Drugs: 2. Pretomanid : MOA - Inhibit cell wall synthesis by inhibiting mycolic acid synthesis Side effects - QT prolongation, hepatotoxic, electrolyte imbalance Formulation - 200 mg Tablet 3. Delamanid : MOA - Inhibit cell wall synthesis by inhibiting mycolic acid synthesis Side effects - QT prolongation, hepatotoxic, electrolyte imbalance Formulation - 50 mg Tablet

20. Dose(mg/kg) Mechanism of action Cidal /Static Hepatotoxicity Pregnancy H (5) Inhibit mycolic acid synthesis Cidal + Safe R (10) Inhibit DNA dependent RNA polymerase Cidal + Safe Z (25) Inhibit fatty acid synthesis that inhibit mycolic acid synthesis Cidal +++ (max.) Avoid E (15) Inhibit arabino acyl transferase Static + Safe S (15) Inhibit protein synthesis (bind 30S ribosomal subunit) Cidal toxic to kidney Avoid

21. Treatment of Drug Sensitive TB : Sensitive to H & R Duration- 6 months Drugs are given daily, doses of drugs are according to body weight FDC tablets are used CP can be extended by 12-24 weeks in certain forms like CNS, Bone TB Type Intensive Phase (IP) Continuous Phase (CP) Newly or Previously Treated 2 H R Z E 4 H R E

22. Treatment of TB-Adult : Intensive phase Continuous phase HRZE 75/150/400/275 HRE 75/150/275 25-34 Kg 2 2 35-49 kg 3 3 50-64 Kg 4 4 65-75 Kg 5 5 > 75 Kg 6 6 Weight Category Number of Tablets

23. Drug Resistant Tuberculosis: Monodrug resistant Resistance to anyone of 1 st line drug (HZE) except ‘R’ Classification of drug resistant TB Polydrug resistant Resistance to more than one drug from 1 st line drug or in combination (H+E/H+Z/H+Z+E) except ‘R’ Rifampicin resistant Resistance to ‘R’ but sensitive to ‘H’ Multi drug resistant (MDR) Resistance to (H+R) Pre XDR (extensive drug resistant) Resistance to (H+R) with any one of Fluoroquinolones XDR (extensive drug resistant) Resistance to (H+R) + (FQs)anyone + ( Bedaquiline or Linezolid)

24. Causes of Drug Resistance: Genetic Mutation Inadequate Drug Intake Inadequate Supply of drug Inadequate Regimen

25. Drugs Used for MDR-TB & XDR TB : Group A Levofloxacin ( Lfx ) , Moxifloxacin ( Mfx ), Bedaquiline ( Bdq ), Linezolid ( Lzd ) Group B (Take a ny one from both of them) Clofazimine ( Cfz ), Cycloserin (Cs)/Terizidone ( Trd ) Group C (I f agent from A and B can not be used , group C added to complete the regimen) Ethambutol (E), Delamanid ( Dlm ), Pyrazinamide (Z), Meropenem ( Mpm ), Amikacin (Am), Ethionamide ( Eto ) PAS ( p-amino salicylic acid )

26. Treatment of drug resistant TB: 1. Treatment of Isoniazide Resistant TB: Levofloxacin , Pyrazinamide, Rifampicin , Ethambutol for 6-9months 2. Treatment of RR/MDR TB: 1- Shorter oral MDR/RR –TB Regime 2 - Longer oral M/XDR-TB Regime

27. 1- Shorter oral Bedaquiline -containing MDR/RR-TB regimen: H resistant due to either InhA mutation or KatG mutation only (not both) No FQs resistance No history of exposure to previous treatment with 2 nd line drugs in the regimen ( Bdq,Lfx,Eto or Cfz ) for more than 1 month Above 5 years of age No extensive TB disease No severe extra pulmonary TB Not in pregnant or lactating Intensive phase Continuation phase 4-6 Bdq , Lfx , Cfz , Z, E, Hh , Eto 5 Lfx , Cfz , Z, E Total duration- 9-11 months

28. 2- Longer oral MDR/XDR-TB Regimen: All group A and B agents are used Bedaquiline is stopped after 6 months No Intensive and Continuation phase 18-20 Bedq , Lf , Lzd , Clf /Cs Total duration- 18-20 months

29. Why to choose longer regimen? History of more than 1 month of 2 nd line drug intake and discontinued If resistance to FQs In pregnancy & pediatrics (<6 years) If extensive TB is diagnosed (bilateral cavitation) or extensive lung parenchyma involved In severe extra pulmonary TB

30. BPaLM Regimen : (6 th September 2024) BPaLM regimen must be the first choice of treatment in eligible patients > 14 years age with MDR/RR-TB regardless of their FQ resistance status or HIV status Inclusion criteria: Person with age 14 years & above With new microbiologically confirmed MDR/RRTB Probable MDR-TB who failed H mono/poly DR-TB treatment

31. BPaLM Regimen : Dosage Drugs Regimen Bedaquiline Weeks 1-2 : 400mg once daily Weeks 3 to 26/39 : 200mg 3 times a week Pretomanid Weeks 1 to 26/39 : 200mg once daily Linezolid Weeks 1 to 26/39 : 600mg once daily Moxifloxacin Weeks 1 to 26/39 : 400mg once daily

32. BPaLM Regimen : Pyridoxine dosage In case of intolerance to FQ, drop Mfx , complete the rest of the regimen as BPaL and extend the treatment up to 39 weeks. Drugs Regimen Pyridoxine 16-19 Kg 50 mg 30 or > 30 kg 100 mg

33. Special Considerations: 1. T.B. in HIV: 1 st start ATT and after 8 weeks continue ART (Anti retroviral therapy ) Rifampicin is CYP enzyme inducer, increases metabolism of HIV drugs Anti retroviral therapy (ART) includes NRTI- Zidovudine NNRTI- Efavarine and Nevirapine Protease inhibitors- Ritonavir Nevirapine and Ritonavir- Not to be given with Rifampicin, but can be given with Rifabutin

34. Special Considerations: 2. T.B. in Pregnancy: C/I: HER X 9 months Vit. B6 is mandatory Streptomycin > Pyrazinamide

35. Drug Interaction: ACE inhibitors and Thiazides

36. 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

37. 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

38. 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

39. 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

40. Summary Pulmonary TB is t ransmitted through inhalation of droplet nuclei containing Mycobacterium tuberculosis Types of regimens based on drug sensitive and drug resistance TB bacteria Drug interaction between ACE inhibitors and thiazide shows additive effects to decrease blood pressure

41. 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 TB Elimination Programme , Central TB Division. National guidelines for programmatic management of Tuberculosis Preventive Treatment in India. New Delhi: Ministry of Health and Family Welfare, Government of India; 2021. National TB Elimination Programme , Central TB Division. National guidelines for management of drug-resistant TB. New Delhi: Ministry of Health and Family Welfare, Government of India; 2024 Nov. p. 5-84.

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