Anti Tb Final

8/6/2019 Anti Tb Final

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ANTIMYCOBACTERIAL DRUGS

Frederick C. Loyola, M.D.

Department of Pharmacology

Therapeutics & Toxicology


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ANTI-MYCOBACTERIALS

(ANTI-TB)First line agents:

- Isoniazid (H)

- Rifampin (R)- Pyrazinamide (Z)

- Ethambutol (E)

- Streptomycin (S)

Second line agents: Amikacin; Aminosalicylic acid;Capreomycin; Ciprofloxacin; Moxifloxacin; Cycloserine;

Ethionamide; Kanamycin; Levofloxacin

H & R: 2 most active drugs


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CHARACTERISTICS OF

MYCOBACTERIUM TUBERCULOSIS

Naturally occurring drug resistant mutants arepresent within large bacterial populations evenbefore chemotherapy is started

Replicates slowly, can remain dormant forprolonged periods & can be eradicated onlyduring replication

Bacilli live in several sites within the host & each

site contains organisms with a differentpopulation size, metabolic activity & replicationrate


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PRINCIPLES ON TREATMENT

Treatment of disease must contain

multiple drugs to which the organisms are

susceptible

Drugs must be taken regularly

Drug therapy must continue for a sufficient

length of time


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Isoniazid (INH)

Inhibits mycolic acid synthesis. (bactericidal)

Acts on extra- & intra-cellular bacillary

populations A prodrug activated by KatG ( mycobacterialcatalase-peroxidase)

High level resistance- deletion of Cat K gene

(codes for catalase); low level (changed inhAgene).


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ISONIAZID Readily absorbed from GIT w/ peak concentration

w/in 1-2 hours; absorption decreased by aluminumhydroxide

Diffuses into all body fluids and tissues

Metabolism genetically determined : fast acetylators

(t1/2= 1 hr); slow acetylators (t1/2= 3 hrs) Excreted in urine but dose not adjusted in renal

failure but in hepatic insufficiency

Increases plasma conc.of phenytoin &

carbamazepine Adverse effects: hepatitis (age-dependent),peripheral neuritis (use B6), hemolysis in G6PDdeficiency, SLE in slow acetylators (rare)


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Rifampin

Inhibits DNA dependent RNA polymerase;

resistance (changed enzyme) emerges

rapidly if used alone Acts on extra- & intra-cellular bacillary

populations

Adverse effects: proteinuria, hepatitis, flu-

like syndrome, induction of P450,

thrombocytopenia, red-orange metabolites


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USES OF RIFAMPIN

Tuberculosis: in combination w/ INH etc.

Atypical mycobacterial infections

Leprosy: with sulfone

Meningococcal carriage

H. influenzae type b prophylaxis

Staphylococcal carriage: in combination

Penicillin-resistant pneumococcal meningitis:

combine with Ceftriaxone or Vancomycin


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Pyrazinamide

Mechanism unknown, but metabolicallyactivated-bacterial strains lacking bioactivatingenzymes are resistant

Relative of nicotinamide

Exerts activity against intracellular organisms inacidic environment; weakly bactericidal,sterilizing agent

No cross resistance

Adverse effects:polyarthralgia-myalgia, hepatitis, rash,hyperuricemia, phototoxicity, increase porphyrinsynthesis.


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Ethambutol

Blocks formation of Arabinoglycan, an essentialcomponent of mycobacterial cell wall by inhibitingArabinosyl transferases

Bacteriostatic but with some bactericidal action athigher doses

Acts on extra- & intra- cellular bacillary population Resistance due to mutations of emb gene;

resistance rapid when given alone

Accumulates in renal failure: dose reduced to half

Dose-dependent retrobulbar neuritis decreasevisual acuity. Not to be given in children below 6years because of unreliable monitoring of visualacuity


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STREPTOMYCIN

MOA: irreversible inhibitor of protein synthesis;

Resistance & features of aminoglycoside

Poor penetration into cells; active against extra-

cellular tubercle bacilli

Serum con. achieved 30-60 min. after IM

Do not give together with other nephrotoxic or

ototoxic drugs Monitor renal function & reduce dose to 50% if

with decrease urine output


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DIRECT OBSERVED THERAPY

SHORT-COURSE (D

OTS) Political commitment

Case detection by sputum smear

microscopy Standardized short course therapy with

direct observation of drug intake

Regular uninterrupted supply of allessential anti-TB drugs

Standardized recording and reporting

system


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TREATMENT REGIMEN FOR TB

Regimen Patient Dose adj. (kg)

Regimen I

2HRZE/ 4HR

New smear (+)

New smear (-) w/

extensive parenchymal

involvementNew extra-pulmonary

Add 1 tab INH (100

mg), PZA (500 mg),

Etham (400 mg) for

> 50 kg body wtbefore treatment

Regimen II

2 HRZES/

1HREZ/ 5HRE

Previously treated

smear (+) PTB w/

relapse, treatment

failure, treatment afterinterruption

Regimen III

2HRZ/ 4HR

New Smear (-) PTB

other than Cat 1

Extra-pulmonary TB

less severely ill

Add one tab of INH

(100 mg), PZA (500

mg) each for >50 kg

before treatment


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MAJOR SIDE-EFFECTS OF DRUGS

SIDE EFFECTS DRUG (S) WHAT TO DO?Severe skin rash from

hypersensitivity

Any drug esp Strep. Discontinue drug & refer to

MHO/CHO

Jaundice 2ry to hepatitis Any drug esp. INH,

Rifam. & PZA

Discontinue drugs & refer to

MHO/CHO

If Sx subside, resume Rx &

monitor clinicallyImpairment of visual acuity

& color vision due to optic

neuritis

Ethambutol Discontinue drug

Refer to ophthalmologist

Hearing impairment, ringing

of the ear & dizziness due

to damage of CN VIII

Streptomycin Discontinue & refer to

MHO/CHO

Oliguria or albuminuria due

to renal disorder

Streptomycin

Rifampicin

Psychosis & convulsion Isoniazid

Thrombocytopenia, anemia,

shock

Rifampicin


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MINOR SIDE-EFFECTS OF DRUGS

SIDE EFFECTS DRUG (S) WHAT TODO?

Gastrointestinal intolerance Rifampicin Give meds at bedtime

Mild skin reactions Any drug Give anti-histamines

Orange-red colored urine Rifampicin Reassure patient

Pain at injection site Streptomycin Apply warm compress

Rotate sites of

injection

Burning sensation in the feetfrom peripheral neuropathy

Isoniazid Give Pyridoxine 100-200 mg daily for Rx; 10

mg daily for prevention

Arthralgia due to

hyperuricemia

Pyrazinamide Give aspirin or NSAID

Flu-like symptoms Rifampicin Give antipyretics


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ANTI-TB DRUGS ON

PREGNANCY AN

DLACTATION

INH, rifampin & ethambutol cross placenta; standarddrugs given to pregnant women

PAS can be safely used but could be poorly tolerated

Streptomycin & other aminoglycosides should beavoided; effect on ear development & function

Capreomycin, ethiomide, quinolones & cycloserine notrecommended

PZA avoided; inadequate data on teratogenicity

Breastfeeding not discouraged; feed infants first beforetaking meds

Drugs in breast milk not considered effective treatmentof tuberculosis in infants


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M. avium-intracellulare (MAC)

Prophylaxis: Azithromycin or Clarithromycin

Treatment: Clarithromycin or Azithromycin +

Ethambutol +/- Rifabutin or Ciprofloxacin

M. kansasii

Rifamicin, Ethambutol, Isoniazid( )


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ANTI-MYCOBACTERIALS(ANTI-LEPROSY)

Dapsone & other sulfones (anti-folate);bacteriostatic

Resistance if very low doses are given;

combination recommended for initial therapy t1/2= 1-2 days; tends to be retained in skin,

muscle, liver, kidney

Dose adjusted in renal failure

ADR: hemolysis if w/ G6PD deficiency;methemoglobinemia;GI intolerance; fever;pruritus; erythema nodosum leprosum


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ANTI-LEPROSY

Rifampin : effective in lepromatous leprosy

Clofazimine: unknown MOA (DNA binding)

- stored in reticuloendothelial tissue &

skin; slow release; t1/2= 2 months- for sulfone-resistant leprosy

- ADR: skin discoloration (red-brown to black)

Prednisone

Thalidomide- inhibits angiogenesis; anti-inflammatory; immunomodulatory; for multiplemyeloma


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MARAMING SALAMAT PO!


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ISONIAZID

MOA: Inhibits mycolic acid synthesis (essentialcomponent of mycobacterial cell wall); bactericidal

A prodrug activated by KatG ( mycobacterial catalase-peroxidase)

Acts on extra- & intra-cellular bacillary populations Resistance due to:

- overexpression of inhA: low-level res; cross

resistance to ethionamide

- mutation or deletion of katG: high-level res

no cross resistance to ethionamide- overexpression of ahpC

- mutation in kasA


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RIFAMPICIN

Active against gram (+) and gram (-) cocci, some enteric bacteria,mycobacteria and chlamydia; bactericidal

MOA: inhibits RNA synthesis

Acts on extra- & intra-cellular bacillary populations

Resistance: mutations prevent binding of rifampin to RNA

polymerase Well-absorbed orally in the fasting state; distributed widely; highly

protein-bound; t1/2=1.5-5 hrs.

CSF conc. achieved in inflammation

Induces hepatic enzymes

Excreted through liver into bile; re-circulated and excreted in feces

and urine No dose adjustment for renal insufficiency

Protect drug from light


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ETHAMBUTOL

MOA: inhibitor of mycobacterial arabinosyl transferases

Bacteriostatic but with some bactericidal action at higherdoses

Acts on extra- & intra- cellular bacillary population

Resistance due to mutations of emb gene; resistancerapid when given alone

Well-absorbed in GIT; conc. reached in 2-4 hours

t1/2= 3-4 hours

Excretion: feces & urine

Accumulates in renal failure: dose reduced to half Not to be given in children below 6 years because of

unreliable monitoring of visual acuity


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RECOMMENDED TREATMENT

FOR LEPROSY

Indeterminate- smear (-), flat hyposthetic lesionusually in face, arms, legs

- single dose Rif + Oflo + Minocycline

Paucibacillary- smear (-), flat hyposthetic,hyperpigmented lesions no more than 5

- Rif once a month + Dapsone OD x 6 mos.

Multibacillary- smear (+) which are multiple,erythematous, copper-colored plaques, nodulesw/ or w/o anesthesia

- Rifam + Dapsone + Clofazimine once a

month x 12 months

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