Pathophysiology and clinical management of tuberculosis

Tuberculosis, pathophysiology, Pharmacotherapeutics, pharm.d

1. TUBERCULOSIS T. SOUJANYA 16DC1T0021 PHARM. D

2. CONTENT: Definition Epidemiology Etiology Types of tuberculosis Risk factors Mode of transmission Pathophysiology of tuberculosis Diagnostic tests Clinical features Signs and symptoms Management of tuberculosis

3. DEFINITION: Tuberculosis is a communicable chronic granulomatous disease caused by “Mycobacterium tuberculosis”. It usually involves the lungs but may affect any organ or tissue in the body. Typically the centres of tubercular granulomas undergo “causeous necrosis”.

4. EPIDEMIOLOGY: Inspite of great advances in chemotherapy and immunology, tuberculosis still continues to be worldwide in distribution, more common in poorer countries of Africa, Latin America and Asia. Other factors contributing to higher incidence of tuberculosis are malnutrition, inadequate medical care, poverty, crowding, chronic debilitating conditions like uncontrolled diabetes, alcoholism and immunocompromised states like AIDS.

5. ETIOLOGY: TB is caused by tubercle bacilli, which belong to the genus Mycobacterium. Mycobacterium species include: M.tuberculosis complex: M.tuberculosis, M.bovis, M.africanum. Mycobacteria other than tuberculosis: Around 15 are recognised as pathogenic to humans and some cause pulmonary disease resembling TB. They have been found in soil, milk and water. They are also referred to as “atypical mycobacteria”. Mycobacterium leprae, the cause of leprosy.

6. TYPES OF TUBERCULOSIS: 1. PULMONARY TUBERCULOSIS: It mainly involves in lungs and pleura (85% of all TB cases). It is again classified into: Primary tuberculosis Secondary tuberculosis 2. EXTRA-PULMONARY TUBERCULOSIS: It is classified into: Lymph node (peripheral) tuberculosis Genito-urinary tuberculosis Skeletal tuberculosis Meningeal tuberculosis Gastrointestinal tuberculosis Disseminated/miliary tuberculosis Pericardial tuberculosis

7. TYPES OF PULMONARY TUBERCULOSIS: Lungs are the main organs affected in tuberculosis. The infection with tubercle bacilli is of two main types: Primary tuberculosis Secondary tuberculosis

8. 1. PRIMARY TUBERCULOSIS: The infection of an individual who has not been previously infected or immunised is called “primary tuberculosis” or “Ghon‘s complex” or “childhood tuberculosis”. Primary complex or Ghon’s complex is the lesion produced at the portal of entry with foci in the draining lymphatic vessels and lymph nodes. The most commonly involved tissues for primary complex are lungs and hilar lymph nodes. The incidence of disseminated form of progressive primary tuberculosis is particularly high in immunocompromised host.

9. 2. SECONDARY TUBERCULOSIS: The infection of an individual who has been previously infected or sensitized is called “secondary or post-Primary or reinfection or chronic tuberculosis”. The infection may be aquired from: Endogenous source such as reactivation of dormant primary complex Exogenous source such as fresh dose of reinfection by tubercle bacilli.

10. RISK FACTORS: The following are some of the risk factors of tuberculosis: Low socio-economic status Crowded living conditions Disease that weakens immune system like HIV Person or immunosuppressants like steroid health care workers Migration from a country with high number of cases Alcoholism Recent tubercular infection (within last 2 years)

11. MODE OF TRANSMISSION: Human beings acquire infection with tubercle bacilli by one of the following routes: Inhalation Ingestion Inoculation of tissue Transplacental route

12. PATHOPHYSIOLOGY OF TUBERCULOSIS: The sequence of events from inhalation of the infectious inoculum to containment of primary focus can be stated as following: A) Primary pulmonary tuberculosis (0-3 weeks): The virulent strains of mycobacteria gain entry into the macrophage endosomes, the organisms are able to inhibit normal microbicidal response by manipulation of endosomal p H and arrest of endosomal maturation. The end result of this “endosomal manipulation” is impairment of effective phagolysosome formation and unhindered mycobacterial proliferation. Thus, the earliest phase of primary tuberculosis (<3 weeks) in the non-sensitized individual is characterised by bacillary proliferation within the pulmonary alveolar macrophages and air spaces, with resulting bacteremia and seeding of multiple sites. Most persons at this stage are asymptomatic or have a mild flu like illness.

13. Contd... B) Primary pulmonary tuberculosis (>3 weeks): 1. The development of cell mediated immunity occurs approximately 3 weeks after exposure. Processed mycobacterial antigens reach the draining and are presented in a major histocompatibility class-II context by dendritic cell macrophages to CD 4 + T-cells. Under the influence of macrophage-secreted IL-12, CD 4 + T-cells of the T H 1 subset are generated, capable of secreting IFN-gamma.

14. Contd... 2. IFN-gamma released by the CD 4 + T-cells of the T H 1 subset is crucial in activating macrophages. Activated macrophages, in turn, release a variety of mediators with important down-stream effects, including: Secretion of TNF Expression of inducible nitric oxide synthase (iNOs) gene Generation of reactive oxygen species 3. Defects in any of the steps of a T H 1 response (including IL-12, IFN-gamma, TNF or nitric oxide production) result in poorly formed granulomas, absence of resistance and disease progression.

15. DIAGNOSTIC TESTS: The following are some of the tests used in the diagnosis of tuberculosis: Mantoux test/Tuberculin sensitivity test Acid fast bacilli (AFB) test Mycobacterial culture PCR (Polymerase chain reaction) test Radiographic procedures

16. CLINICAL FEATURES: Referable to lungs: such as productive cough, may be with haemoptysis, pleural effusion, dyspnoea, orthopnoea etc. Chest X-ray shows typical apical changes like pleural effusion, nodularity and miliary or diffuse infiltrates in the lung parenchyma. Systemic features: such as fever, night sweats, fatigue, loss of weight and appetite. Long-standing and untreated cases of tuberculosis may develop systemic secondary amyloidosis. Causes of death in primary tuberculosis are usually pulmonary insufficiency, pulmonary haemorrhage, sepsis due to disseminated miliary tuberculosis, cor pulmonale or secondary amyloidosis.

17. SIGNS AND SYMPTOMS: Cough for 3 weeks or more/productive cough Sputum usually mucopurulent/purulent Haemoptysis Fever with night sweats Tiredness Weight loss Anorexia Malaise

18. MANAGEMENT OF TUBERCULOSIS: In treating tuberculosis, a number of factors are important: Choice of drugs Length of treatment Co-morbidity especially HIV infection, liver and renal diseases Adherence to treatment by the patient Drug treatment: Treatment with anti-TB drugs has 2 main purposes: To cure people with TB, provided the bacilli are drug sensitive. To control TB, by either preventing the development of infectious forms or reducing the period of infectivity of people with infectious disease.

19. FIRST-LINE DRUGS: Isoniazid(H) Rifampicin(R) Pyrazinamide(Z) Ethambutol(E) Streptomycin(S)

20. 1. ISONIAZID: MOA: Isoniazid inhibits biosynthesis of mycolic acid, which is an essential component of mycobacterial cell wall and results in the death of bacteria (tuberculocidal). It is active against both intracellular and extracellular bacilli. ADRs: Peripheral neuropathy, hepatotoxicity, skin rashes, arthralgia, GI disturbances, psychosis and rarely convulsions. Dose: 5-10mg/kg or a maximum dose of 300mg/day

21. 2. RIFAMPICIN: MOA: Rifampicin binds to the beta subunit of the DNA dependent RNA polymerase enzyme and inhibits m-RNA synthesis in the bacteria. It has bactericidal effect. It is active against both intracellular and extracellular bacilli. ADRs: Hepatotoxicity, GI disturbances, flu-like syndrome, headache, drowsiness, dizziness, nausea, vomiting, hypersensitivity reactions etc. Dose: 15-20mg/kg or a maximum dose of 450-600mg/day

22. 3. PYRAZINAMIDE: MOA: Pyrazinamide is converted to its active form/active metabolite pyrazinoic acid by the enzyme pyrazinamidase present in the mycobacteria. This metabolite may inhibit the synthesis of mycolic acid by the mycobacteria. It requires an acidic p H (5.5) for its tuberculocidal activity. ADRs: Dose dependent hepatotoxicity, anorexia, nausea, vomiting, fever, skin rashes, malaise, urticaria, arthralgia etc. Dose: 25-40mg/kg or a maximum dose of 3g/day

23. 4. ETHAMBUTOL: MOA: Ethambutol inhibits mycobacterial arabinosyl transferase (encoded by emb gene) enzyme, which is involved in the polymerization reaction of the arabinoglycan, an essential component of mycobacterial cell wall. It is tuberculostatic and acts on fast multiplying bacilli in the cavities. It is also effective against atypical mycobacteria (mutation of emb gene). ADRs: Optic neuritis, hypersensitivity reactions like skin rashes, itching etc., fever, arthralgia, GI disturbances, headache, mental disturbances etc. Dose: 15-25mg/kg or a maximum dose of 800-1200mg/day

24. 5. STREPTOMYCIN: MOA: It irreversibly inhibits bacterial protein synthesis in atleast 3 ways: Interference with the initiation complex of peptide formation. Misreading of m-RNA, which causes incorporation of incorrect amino acids into the peptide, resulting in a non-functional or toxic protein. Breakup of polysomes into non-functional monosomes. ADRs: Dose related ototoxicity, nephrotoxicity, ataxia, vertigo, rashes, fever, renal impairment etc. Dose: 15mg/kg or a maximum dose of 0.75-1gm/day

25. SECOND-LINE DRUGS: Ethionamide Cycloserine Para-amino salicylic acid Rifabutine and rifapentine Fluoroquinolones: ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin Injectable drugs: capreomycin, kanamycin, amikacin Newer drugs: bedaquiline, pretomanid

26. Contd... Consider second-line drugs, if: Resistance to first-line agents. Failure of clinical response to conventional therapy. Serious treatment-limiting ADR. Expert guidance available for toxic effects.

27. 1. ETHIONAMIDE: MOA: Ethionamide upon oxidation with catalase-peroxidase is converted to an active acylating agent, ethionamide sulfoxide, which inturn activate inhA enoyl reductase and hence inhibits the synthesis of mycolic acids. It is a tuberculostatic drug which is effective against both intracellular and extracellular organisms. ADRs: Intense gastric irritation, optic neuritis, hepatotoxicity. Dose: 15mg/kg or a maximum dose of 0.75-1g/day

28. 2. CYCLOSERINE: MOA: It inhibits the incorporation of D-alanine into peptidoglycan pentapeptide by inhibiting the enzyme alanine racemase, which converts L-alanine to D-alanine and finally inhibits mycobacterial cell wall synthesis (tuberculostatic). ADRs: CNS dysfunction including depression and psychosis, peripheral neuropathy, seizures, tremors etc. Dose: 15mg/kg or a maximum dose of 1g/day

29. 3. PARA-AMINO SALICYLIC ACID (PAS): MOA: It is structurally similar to P-amino benzoic acid (PABA) and sulfonamides. It shows similar action of sulphonamide. PAS inhibits folate synthase enzyme, which is essential for the conversion of PABA to dihydro folic acid (DHFA) and inhibits the synthesis of cell wall (tuberculostatic activity). ADRs: GI effects like nausea, anorexia, epigastric pain, diarrhoea, fever, joint pain, hepatospleenomegaly, hepatitis, granuloytopenia, adenopathy, peptic ulcers, gastric haemorrhage etc. Dose: 200mg/kg or a maximum dose of 10-12g/day

30. 4. RIFABUTINE & RIFAPENTINE: MOA: They are derived from rifamycin and related to rifampicin & show similar mechanism of action of rifampicin i.e., bacterial RNA polymerase enzyme inhibitors. These are weak enzyme inducers of CYT P450 enzymes. ADRs: Hepatotoxicity, GI disturbances, flu-like syndrome, nausea, headache, vomiting, drowsiness, dizziness, hypersensitivity reactions etc. Dose: 300mg/day

31. 5. FLUOROQUINOLONES: MOA: They are active against typical and atypical mycobacteria. They inhibit inhibit the bacterial DNA synthesis by inhibiting bacterial topoisomerase-II (DNA gyrase) and topoisomerase-IV. They have tuberculocidal activity. ADRs: Nausea, vomiting, diarrhoea, headache, dizziness, skin rashes, photosensitivity, damage growing cartilage, tendon rupture, insomnia etc. Dose: Ciprofloxacin-750mg, BD, PO levofloxacin-500mg, OD, PO Moxifloxacin-400mg, OD, PO Ofloxacin-400mg, BD, PO

32. 6. INJECTABLE DRUGS: MOA: These are aminoglycosides and their mechanism of action is similar to streptomycin. ADRs: Ototoxicity, nephrotoxicity, fever, rashes etc. Dose: Capreomycin-15mg/kg or a maximum dose of 0.75-1g/day Kanamycin-15mg/kg or a maximum dose of 0.75-1g/day Amikacin-15mg/kg or a maximum dose of 1g/day

33. 7. NEWER DRUGS: a) BEDAQUILINE: MOA: Bedaquiline binds to oligomeric and proteolipid subunit-c of mycobacterial ATP synthase, leads to the inhibition of ATP synthesis and death of bacteria (tuberculocidal). ADRs: Increased QT interval, abnormal and fatal heart rhythm (increased risk of death), nausea, joint pain, headache and increased liver enzymes. Dose: 100mg oral

34. b) PRETOMANID: MOA: It is a bicyclic nitroimidazole-like molecule. It is active against both replicating and non-replicating organisms. It inibits mycolic acid synthesis through unknown molecular mechanisms and inhibits cell wall synthesis (like isoniazid). ADRs: No ADRs are noticed. It is relatively safe, well-tolerated and efficacious. Dose: 100-200mg/day

35. TREATMENT REGIMEN: The recommended standard regimen for respiratory and most other forms of tuberculosis in UK is: Rifampicin, Isoniazid, Pyrazinamide and Ethambutol for the initial 2 months (initial phase). A further 4 months of Rifampicin and Isoniazid (continuous phase).

36. Contd... INITIATION PHASE 2-3 months 4-5 drugs Rapidly kills bacilli Isoniazid Rifampicin Ethambutol Pyrazinamide CONTINUOUS PHASE 4-6 months 2-3 drugs Eliminates remaining bacilli Prevents relapse Isoniazid + pyridoxine Rifampicin

37. DIRECTLY OBSERVED THERAPY (DOT): DOT, where the patient is observed taking their anti-tuberculous medication by a health care professional. But it is not needed for more cases of active TB. A risk of assessment for treatment adherence should be undertaken in all patients and DOT regimens considered where non-adherence to treatment might be a problem. e.g. In street or shelter dwelling homeless people with active TB and in patients with a history of non-adherence (individuals with chronic alcohol or other social problems). Advantages: High cure rate, decreased drug resistance, ADRs can be monitored

38. REFERENCES/BIBLIOGRAPHY: Text book of pathology by Harsh Mohan Clinical Pharmacy and Therapeutics – Roger and Walker, Churchill Livingstone publication Pharmacotherapy: A Pathophysiologic approach – Joseph T. Dipiro