Please enable JavaScript.
Coggle requires JavaScript to display documents.
ANTI TUBERCULAR DRUGS - Coggle Diagram
ANTI TUBERCULAR DRUGS
FIRST LINE DRUGS
ISONIAZID (H)
MOA :check:
- Inhibits synthesis of mycolic acids→ imp. components of mycobacterial cell wall.
- INH: prodrug → converted to active form by an enzyme (catalases-peroxidases: KatG) inside organism → covalently binds to certain enzymes→ inhibit mycolic acid synthesis
RESISTANCE :check:
- About 1 in 10⁶ bacilli is inherently resistant to clinical conc.
- INH given alone→ resistant infection by 2-3months
Mechanisms :recycle:
- Mutation of catalase-peroxidase(KatG) gene
○ Active metabolite not formed
○ This type of resistance can't be overcome
○ INH should be stopped
- Low level INH resistance: inhA gene mutation
○ Reversible by giving high dose INH
PHARMACOKINETICS :check:
- Completely oral abs
- Penetrates all body tissues, tubercular cavities, placenta & meninges
- Extensively metabolised in liver
○ N-acetylation by NAT2
- Acetylated metabolite excreted in urine
- Genetic variation in rate of INH acetylation
○ Fast acetylators
○ Slow acetylators
○ → biweekly regimens less eff. in fast acetylators
○ → peripheral neuritis ↑ in slow acetylators
INTERACTIONS :check:
- Al. hydroxide→ inhibits INH abs.
- INH retards phenytoin, carbamazepine, diazepam, theophylline & warfarin metabolism
○ Inhibit CYP2C19, CYP3A4
○ May raise their blood levels
- Rifampin→ enzyme inducer
○ Concurrent use counteracts inhibitory effect of INH
- Net effect on drug metabolism unpredictable
- PAS inhibits INH metabolism & prolongs T½
ADVERSE EFFECTS :check:
- INH well tolerated by most patients
- Peripheral neuritis & other neurological manifestations
○ Paraesthesias, numbness, mental disturbances, rarely convulsions
○ Dose dependent toxic effects
- D/t interference of pdn. of active coenzyme pyridoxal phosphate from pyridoxine & ↑ excr. in urine
- Pyridoxine given prophylactically 10mg/d
○ Prevents neurotoxicity even with higher doses
○ Prophylactic pyridoxine must be given in diabetics, c/c alcoholics, malnourished, pregnant, lactating, & HIV infected patients & when high dose INH is used.
- INH neurotoxicity treated with 100mg/d pyridoxine
- Hepatitis-more common in older people & alcoholics
○ C/c alcoholics induces CYP2E1
○ INH must be stopped at first sign of hepatotoxicity→ dose related damage to liver cells
○ Reversible on stopping drug
- Other S/E : lethargy, rashes, mild anemia, arthalgia
RIFAMPICIN (R)
- Semisynthetic derivative of Rifamycin B
- Obtained from Streptomyces mediterranei
- Bactericidal to M. tuberculosis
- Many other G+ & G- bacteria like Staph. aureus, N. meningitidis, H. influenzae, E.coli, Klebsiella, Pseudomonas, Proteus & Legionella
MOA :check:
- Bactericidal action
○ M. tuberculosis, M. leprae, atypical mycobacteria
- Antitubercular action
○ Only drug acting on persisters
○ Acts on both intra & extracellular organisms
○ Eff. against tubercle bacilli resistant to other drugs→ sterilizing agent
- Binds to ß-subunit of DNA dep. RNA polymerase→ inhibits RNA synthesis in bacteria
- Reaches cavities, caseous material & penetrates macrophages.
RESISTANCE :check:
- Genetic mutation in rpoB gene→ ↓ binding of rifampicin to RNA polymerase
PHARMACOKINETICS :check:
- Oral BA~70%
- Food ↓ abs., taken on empty stomach
- Widely distributed in body
○ Penetrates intracellularly, tubercular cavities, caseous masses, placenta
○ Crosses meninges→ but pumped out from CNS via P-glycoprotein
- Metabolised in liver to an active deacetylated metabolite→ excreted mainly in bile & urine
- Rifampin & is desacetyl derivative→ enterohepatic circulation
- T½ variable
INTERACTIONS :check:
- Microsomal enzyme inducer
○ ↑ CYP3A4, CYP2D6, CYP1A2, CYP2C subfamily
- Enhances its own metabolism + other drugs
○ Warfarins
○ OCP, corticosteroids
○ Sulfonylureas
○ HIV PIs, NNRTIs, theophylline
○ Metoprolol
○ Fluconazole, ketoconazole
○ Clarithromycin, phenytoin, etc
- Contraceptive failures occur
○ Switch over to OCP higher dose of estrogen 50μg or use alt. methods
ADVERSE EFFECTS :check:
- Hepatitis
○ In preexisting liver disease→ dose related
○ Infrequent with ≤ 600mg/d dose
○ DIscontinuation→ reversible
- Cutaneous→ flushing, pruritis + rash, redness, watering of eyes
- Flu-like symptoms→ chills, fever, headache, malaise & bone pain
- Abdominal cramps, nausea, vomiting, diarrhea
- Staining of secretions→ tears, saliva, urine: orange red
- Serious but rare→ purpura, hemolysis, shock, renal failure
Other uses of Rifampicin :check:
- Leprosy
- Prophylaxis: meningococcal & H.influenzae meningitis & carrier state
- 2nd/ 3rd choice for MRSA, diphtheroids, legionella
- Doxy + rifampicin→ 1st line fo brucellosis
PYRAZINAMIDE (Z)
- Tuberculocidal, more active in acidic medium
- More action on intracellular bacilli & at sites showing infl. response
- Highly eff. in first 2 months when inflammatory changes are present
- Good sterilizing activity
- Duration of treatment shortened & risk of relapse reduced
MOA :check:
- Intracellularly converted to active metabolite Pyrazinoic acid by pyrazinamidase (encoded by pncA gene)
- Accumulates in acidic medium & inhibits mycolic acid synthesis
- Disrupt bacterial cell membrane & transport fn.
RESISTANCE :check: When used alone
PHARMACOKINETICS :check:
- Oral abs, wide distribution
- Good CSF penetration
○ → used in meningeal TB
- Metabolized in liver
- T½= 6-10hrs
ADVERSE EFFECTS :check:
- Hepatotoxicity
○ C/I in liver disease
○ Now considered safe in pregnancy
- Common: hyperuricemia
○ Gout can occur
- Abdominal distress, arthralgia
- Flushing, rashes, fever
- Loss of diabetes control
○ Repeated blood glucose monitoring required
ETHAMBUTOL (E)
- Selectively tuberculostatic
- Active against MAC & other mycobacteria
- Fast multiplying bacteria more susceptible
- Added to triple regimen of RHZ
○ Hastens rate of sputum conversion
○ Prevent resistance
MOA :check:
- Inhibit Arabinosyl transferases (encoded by embAB genes)
○ arabinogalactan synthesis blocked
○ Interfere with mycolic acid incorporation into cell wall.
PHARMACOKINETICS :check:
- About ¾ of oral dose absorbed
- Distributed widely
- Penetrates meninges inconsistently→ more when they are inflamed
- Less than ½ metabolized
- Excreted in urine by glomerular filtration & tubular secretion & feces
- Better patient acceptability
ADVERSE EFFECTS :check:
- Loss of visual acuity, color vision, field defects
○ D/t retrobulbar neuritis
○ Dose & duration dependent toxicity
○ Stop drug at first indication of visual impairment
○ Reversible
- Nausea, rashes, fever, peripheral neuritis
- Safe in pregnancy
STREPTOMYCIN (S)
- 1st clinically used
- Tuberculocidal
- Acts only on extracellular bacilli
- Penetrates tubercular cavities
- Does not cross CSF, poor action on acidic medium
- Rapid resistance when used alone
- Non tubercular mycobacteria unaffected by S.
- Need for IM injections & low margin of safety
○ Ototoxicity
○ Elderly & patients with impaired renal fn.
- Used in addition to 1st line anti-TB drugs or reserve
- Supplemental 1st line drug
-