Pharmacology of Anti- Tubercular Drugs

Pharmacology of Anti- Tubercular Drugs

• 1.
  PHARMACOLOGY ANTI-TUBERCULAR DRUGS Nem KumarJain MS (Pharm.) Pharmacology & Toxicology Assistant Professor, School of Pharmacy ITM University Gwalior
• 2.
  TUBERCULOSIS(TB) Chronic granulomatous inflammatory diseaseand a major health problem in developing countries. Primarily affects lungs, other organs such as brain, liver, kidney, spleen, bone etc. As per WHO reports(2010), approx. 9.4 million active TB cases globally India: 2.3 million cases Other common names included “wasting disease” and the “white plague”. Etiology: TB is caused by Mycobacterium species mainly by Mycobacterium tuberculosis which is aerobic atypical slender, rod shaped bacteria. • Other strains which causes TB are  M. Avium Complex (MAC): M. avium & M. intracellulare • Less common strains which causes TB are  M. africanum  M. microti  M. pinnipeddi  M. cannetti • Less pathogenic strains are  M. abscessus  M. fortuitum  M. chelonae  M. ulcerans • Non pathogenic strains are M. smegmatis • M.tuberculi also called as Koch’s bacilli or Acid Fast bacilli (with lipid-rich cell walls that stain poorly with the Gram stain, but once stained, the walls cannot be easily decolorized by treatment with acidified organic solvents). – Stained by carbofuscine
• 3.
  TYPES AND SOMEFACTS OF TUBERCULOSIS • Based on anatomical side: Pulmunary TB (lungs) Milliary (Spleen, kidney, liver, brain etc) • Based on presence of signs and symptom:  Active TB (only shows signs and symptoms).  Latent TB (Signs and symptoms absent, Dormant) • Based on type of tissue response  Primary TB: First time, Childhood TB No Immunization or infection Secondary TB: Re-infection sp. which makes resultant disease Chronic and necessitates prolong treatment  Slow growing Intracellular infection Formation of slow growing granuloma results in destruction of host tissue • Biology of Mycobacterium: distinct populations Rapidly growing with high bacillary load Slow growing Spurters Dormant
• 4.
  UNIQUE CELL WALL Mycobacterialcell wall • Presence of Mycolic acid (90’c’ atoms arranged in a ring like structure) in Mycobacterium species. • Mycolic acids  Prevents ,resists against hydrophilic and lipophilic antibiotics, loss of water, transport of various substances  Helps in evading from immune system. • High potential to become Resistant
• 5.
  PREVENTION OF TB 22 •Prevention strategies include BCG vaccination and treatment of persons with latent tuberculosis infection who are at high risk of developing active disease. • BCG was derived from an attenuated strain of M. bovis. • Efficacy is between 0-80%. • BCG vaccine is recommended for routine use at birth in countries with high tuberculosis prevalence. • Bacillus Calmette-Guérin (BCG)
• 6.
  • Mycobacteria areintrinsically resistant to most antibiotics – Grows more slowly than other bacteria – antibiotics active against rapidly growing cells – lipid-rich mycobacterial cell wall is impermeable to many agents – It grows inside macrophage – poorly penetrated by drugs – Excellent ability to develop resistance – Multiple Drug Resistant (MDR) • Combinations of two or more drugs – to overcome these obstacles – to prevent emergence of resistance during the course of therapy • The response of mycobacterial infections to chemotherapy is slow - treatment must be administered for months to years, depending on which drugs are used
• 7.
  • Drugs usedin the treatment of tuberculosis can be divided into two major categories - First Line : high antitubercular efficacy as well as low toxicity – routinely used: - HRZES Isoniazid (H) , Rifampin (R), Pyrazinamide (Z), Ethambutol (E), Streptomycin (S) – Second Line : low antitubercular efficacy or high toxicity • Paraminosalicylic Acid (PAS), Cycloserine, ethionamide, prothionamide, Rifabutin, thiacetazone • Flouroquinolones: Ciprofloxacin, Olfloxacin, levofloxacine, moxifloxacine Kanamycin, Amikacin, capreomycine • Macrolides:Clarithromycin,Azithromycin • First Line Drugs • Isoniazide • Synthetic analogue of pyridoxine • Primary tubercilocidal • bacteriostatic for resting bacilli, but is bactericidal for rapidly dividing microorganisms • inhibits synthesis of mycolic acids - essential components of mycobacterial cell walls, not active against other microorganism • Highly selective for mycobacterium • Resistance  Its prodrug – activated by enzyme catalase- peroxidase  Mutation causes inhibition of this enzyme  No cross resistance occurs with other antitubercular drug  Always given in combination
• 8.
  MECHANISM OF ACTIONAND RESISTANCE Resistance – Mycobacteria may develops resistance towards H due to change in genes coding for catalase peroxidase (katG). – Alteration in KasA and InhA and in structure of efflux pumps of bacteria. • Pharmacokinetics: – Orally well absorbed – Well distributed – Metabolized in Liver by N-acetylation (NAT2) – Based on acylation • Slow acetylators (Half life- 3h) • Fast acetylators( Half life-1h) – Excreted through urine • Adverse effects: – GI disturbances, – Hepatotoxicity – Peripheral Neuritis – Hypersensitivity reactions • Interaction: alluminium hydroxide inhibits absorption, Potent enzyme inhibitor (cyp2c19, cyp3a4) Isoniazide Mycobacterial Catalase peroxidase (katG) activates Aducts with NAD NADP Mycobacerial Dihydrofolate reductase Type II fatty acid synthase (FAS) system Inhibition of Mycolic acid Inhibition of DNA synthesis Bactericidal action Active metabolite beta-ketoacyl ACP synthase (kasA) Enoyl acyl carrier protein reductase (inhA)
• 9.
  RIFAMPICIN/ RIFAMPIN (R) •Derived from the soil mold Streptomyces mediterranei • Bactericidal to M. tuberculosis and other gram positive and gram negative bacteria including M. leprae • Both extracellular and intracellular organisms are affected • Against TB bacilli, it is as efficacious as INH and better than all other drugs • Mechanism of action: Rifampin inhibits DNA dependent RNA synthesis. Probably, the basis of selective toxicity is that mammalian RNA polymerase does not avidly bind rifampin • Resistance: nearly always due to subunit of RNA polymerase-the target of rifampin action) reducing its affinity for the drug. • No cross resistance with any other antitubercular drug has been noted. • Pharmacokinetics: well absorbed orally, • widely distributed in the body: penetrates cavities, caseous masses, placenta and meninges. • metabolized in liver to an active deacetylated metabolite which is excreted mainly in bile, some in urine also. • Rifampin and its desacetyl derivative undergo enterohepatic circulation. The t1/2 of rifampin is variable (2-5 hours).
• 10.
  • Interactions: microsomalenzyme inducer-increases several CYP450 isoenzymes, including CYP3A4, CYP2D6, CYP1A2 and CYP2C subfamily. • It thus enhances its own metabolism as well as that of many drugs including warfarin, oral contraceptives, corticosteroids, sulfonylureas, digitoxin, steroids, HIV protease inhibitors, non- nucleoside reverse transcriptase inhibitors (NNRTis), theophylline, metoprolol, fluconazole, ketoconazole, etc. • Contraceptive failures have occurred • Adverse Effects: similar to INH. • Hepatitis, a major adverse effect, generally occurs in patients with preexisting liver disease and is dose-related • 'Respiratory syndrome': breathlessness • Purpura, haemolysis, shock and renal failure. Minor reactions usually not requiring drug withdrawal are: • 'Cutaneous syndrome': flushing, pruritus + rash (especially on face and scalp), redness and watering of eyes • 'Flu syndrome': with chills, fever, headache, malaise and bone pain. • 'Abdominal syndrome': nausea, vomiting, abdominal cramps with or without diarrhoea. • Urine and secretions may become orange- redbut this is harmless.
• 11.
  PYRIZINAMIDE (Z) • Chemicallysimilar to INH • It is weakly tuberculocidal but more active in acidic medium • It is more lethal to Slow Growing, intracellularly located bacilli and to those at sites showing an inflammatory response (pH is acidic at both these locations. • highly effective during the first 2 months of therapy • PHARMACOKINETICS: – Rapidly absorbed from GI tract – It is widely distributed in the body and achieves a concentration in the CSF equal to the plasma levels. – Deaminated in the liver. – Degradation products and he free drug are eliminated in urine • ADVERSE EFFECTS: – Hyperuricemia (precipitating gout) – Hepatotoxicity – Arthralgia, nausea,vomiting, anorexia, malaise, – Rarely photosensitivity reaction – Loss of diabetes control • Used in both Extrapulmonary and pulmonary TB • Resistance: mutation of pncA geneMECHANISM OF ACTION PYRAZINAMIDE PYRAZINOIC ACID mycolic acid synthesis Disrupts cell membrane integrity Tuberculocidal effect Pyrizinamidase (pncA gene)
• 12.
  ETHAMBUTOL • Ethambutol isselectively tuberculostatic • Active against MAC as well as other mycobacteria but not other types of bacteria • Fast multiplying bacilli are more susceptible • Added to three drug regimen RHZ, primarily to prevent resistance development • Mechanism of Action: inhibits embAB gene encoded Arabinoacyl transferase Resistance: mutation of embAB gene • PHARMACOKINETICS: – 70% is absorbed – Penetrates into erythrocytes, gets deposited, and released into circulation – 50% of oral dose excreted unchanged in urine with in 24h – 15% excreted in the form of two metabolites – Accumulates in presence of renal damage • ADVERSE EFFECTS: – Retrobulbular optic neuritis on prolonged therapy which results in decrease visual acuity. – Others are Nausea,headache,anorexia,allergic reactions,and confusion – Hyperuricimia and Gout (Urate excretion decreased) • If any visual disturbances are seen in the patient,Ethambutol should be removed from patient’s regimen • Safe in pregnancy Ethambutol Inhibits Arabinosyl transferase Inhibits Synthesis of ARABINO GLYCANS Inhibits cell wall synthesis
• 13.
  STREPTOMYCIN • First anti-tuberculardrug • Tuberocidal but less effective than isoniazide or rifampicine • Acts only on extracellular bacilli Pharmacokinetics: – Not absorbed orally and must be given in IM. Well absorbed when instilled in intrapleurally – It doesn’t cross BBB. However, high concentrations are seen in CSF during meningeal inflammation. – It is mainly concentrated in kidneys, liver, and skeletal tissues. – It crosses Placental barrier, – Excreted unchanged by GFR. And approximately 50-60% of drug is eliminated in urine in active form within 24h. • ADVERSE EFFECTS: – Pain at the site of injection – 8th cranial nerve damage – Neuromuscular blockade – Nephrotoxicity and ototoxicity – Super infections with Staphylococcus aureus and candida Contraindication: Elderly and in those with impaired renal functions MECHANISM OF ACTION STREPTOMYCIN Binds to 30S subuint of ribosomes Which results in production Abnormal proteins Accumulates in mycobacterium Destruction of mycobacterium
• 14.
  SECOND LINE DRUGS •These are less effective and/or less well tolerated • Used only in case the bacilli are resistant to one or more first line drugs or when they are not well tolerated and/or contraindicated 1. Kanamycin and Amikacin: • Tuberculocidal aminoglycosides • Pharmacological profile similar to Streptomycin • Part of Regimen for S-resistant or MDR-TB • AM is less toxic • Cross resistance common • Equally nephrotoxic 2. Capreomycin: • Cyclic peptide antibiotic • Chemically different from aminoglycode but similar anti- tb effect and ototoxicity and nephrotoxicity • Used against Aminoglycosides resistant and MDR –TB strains 3. Flouroquinolones: useful new addition to the antitubercular drugs • Ofloxacin(Ofx), levofloxacin (Lfx),ciprofloxacin (Cfx)and moxifloxacin (Mfx) • Alternative to first line drugs • Active against MAC, M. fortuitum, other atypical mycobacteria • Anti- mycobacterial tuberculosis Activity Mfx> Lfx> Ofx & Cfx • Anti atypical mycobacteria activity Cfx> Lfx • FQs penetrate macrophages too • Cfx not used now because of its extensive use against other bacteria too • Primary indication is for treatment of MDR-TB • Resistance against Mfx is slow to develop
• 15.
  SECOND LINE DRUGS 3.Ethionamide: chemically resembles Isoniazid • MECHANISM OF ACTION: Blocks the synthesis of mycolic acids and it is a tuberculostatic drug. • PHARMACOKINETICS: ABSORPTION is similar to H, Metabolized in liver and only 1% excreted unchanged in urine • Because of its Intense gastric irritation and neurological toxicity(optic and peripheral neuritis) and hepatotoxicity, it is rarely used, • Used only for Drug Resistant TB, MDR-TB regimen. MAC infection in AIDS • Also reserved drug for Leprosy. 4. Prothionamide: congener of Ethionamide and resembles pharmacologically in all aspects to ethionamide Interchangiable to Ethionamide in use 5. Cycloserine: MECHANISM OF ACTION :It is D-alanine analogue and hence inhibits bacterial cell wall synthesis by inactivating the enzyme which racimize the L-alanine and link two D-alanine residues. tuberculostatic • PHARMACOKINETICS: Rapidly absorbed from gut,distributed through out the body (csf and plasma concentrations are equal in meningitis condition).50% of orally administered dose gets excreted in urine in unchanged form and 65% is excreted by kidneys within 72h. • Broad spectrum antibiotic and it is tuberculostatic. • It is effective against tubercle bacilli resistant to H or S and against atypical mycobacterium. • ADVERSE EFFECTS: – Peripheral neuropathy, – Delusions, Nervousness etc. – Contanindicated in patients with seizures Uses: MDR-TB NO cross resistance with any anti-TB drugs. 6. Terizidone: contains two molecules of Cycloserine • properties MOA similar to cycloserine • less Neurotoxic • interchangeable in use
• 16.
  7. Para aminosalicylic acid (PAS) • Sulphonamide derivative • Inhibits Folate synthase • Selective Mycobacterial Folate synthase inhibitor • Tuberculostatic • Resistance poor to develop • Adverse effects: Epigastric Pain, anorexia, nausea, rashes, goiter, liver dysfuction etc. poor patient tolerability • Uses: only in resistant TB, MDR-TB 8. Thiacetazone: not used nowadays due to questionable efficacy 9. Rifabutin: • chemically and pharmacologically similar to Rifampicine • Less active against M. Tuberculosis • R-resistant strains exhibit cross resistance • Rifabutin is weak enzyme inducer • Specially used in HIV –TB Infection who receive protease inhibitors and NNRTI • Prophylaxis and treatment of MAC-TB
• 17.
  TREATMENT REGIMEN FORTB FOR NEWLY INFECTED PATIENTS FOR PREVIOUSLY TREATED PATIENTS WITHLOW RESISTANCE TO DRUGS INTENSIVE PHASE (2months) H,R,Z,E+VitB6 CONTINUOUS PHASE (4months) H,R+VIT B6 INTENSIVE PHASE (3months) HRZES HRZE + Pyridoxine 100mg/day CONTINUOUS PHASE (5months) HRZ + Pyridoxine 100mg/day
• 18.
  MULTI DRUG RESISTANTOR HIGHLY RESISTANT CONTINUOUS PHASE (12-18months) E OFLOXACIN/LEVOFLOXA CIN CYCLOSERINE ETHIONAMIDE+ PYRIDOXINE • INTENSIVE PHASE • (6months) Z •E AMIKACIN/KANAMYCIN • OFLOXACIN/ • LEVOFLOXACIN • CYCLOSERINE ETHIONAMIDE+ • PYRIDOXINE For H resistance: R+Z+E for 12Months For R resistance: H+Z+E for 12Months For both H+R resistance: Z+E+S(Et)+CIROFLOXACIN(OR OFLOXAC OR LEVOFLOXACIN),for 12-18 Months