Anti-mycobacterial
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Pharmacology (Dr. Albatross) Anti-TB and Anti-Leprosy 8-10 January 2008 DRUGS USED IN TUBERCULOSIS
•
5 FIRST-LINE AGENTS for TB treatment (in order of preference): 1. Isoniazid – INH, H 2. Rifampicin / Rifampin – RIF, R 3. Pyrazinamide – PZA, Z 4. Ethambutol – E 5. Streptomycin – S
• •
Second line agents: Amikacin (Aminoglycoside) Aminosalicylic acid Ethionamide Fluoquinolones * Given when unresponsive to 1st line + INH, RIF
•
Isoniazid and Rifampin most active drugs, this combination administered for 9 months will cure 95-98% of TB Isoniazid and Rifampin and Pyrazinamide during the first 2 months allows total duration of therapy to be shortened to 6 months without loss of efficacy Isoniazid, Rifampin, Pyrazinamide and either Ethambutol or Streptomycin initial 4-drug therapy give until susceptibility of isolate has been determined; neither ethambutol nor streptomycin adds substantially reduce or duration of treatment regimen but provide additional coverage if the isolate is resistant to INH, R or both Characteristics of Mycobacterium Tuberculosis • Naturally occurring drug resistant mutants are present within large bacterial populations even before chemotherapy is started • Replicates slowly, can remain dormant for prolonged periods and can be eradicated only during replication • Bacilli live in several sites within the hosts and each site contains organisms with a different population size, metabolic activity and replication rate Principles of Treatment • Treatment of disease must contain multiple drugs to which the organisms are susceptible • Drugs must be taken regularly and treatment should continue for a sufficient length of time Isoniazid • • • • •
Most active drug Small simple molecule freely soluble in water With structure similar to Pyridoxine Inhibits most tubercle bacilli in a concentration of 0.2µg/mL or less Bactericidal for actively growing bacilli
Sexy & Babe + MR
MOA • •
•
Less effective against atypical mycobacterial species Ca penetrate into phagocytic cells Active both intra and extracellular organisms Inhibits synthesis of mycolic acids (essential component of cell wall) Bactericidal, prodrug activated by KatG, the mycobacterial catalase-peroxidase Activated form of INH forms a covalent complex with an acyl carrier protein (AcpM) and KasA. A beta-ketoacyl carrier protein synthetase blocks mycolic acid synthesis Acts on extra and intracellular bacilliary population
Resistance to INH • Overproducers of inhA express low-level INH resistance and cross-resistance to ethionamide • Mutation or deletion of KatG : high level of resistance • Due to mutations, resulting in overexpression of inhA, which encodes an NADH-depedent acyl carrier protein reductase • Overexpression ahpC, a presumed virulence gene involved in protection of the cell from oxidative stress • Mutation in kasA
• •
KatG mutants express high-level INH resiostance and usually not cross-resistant to ethionamide Single-drug therapy with IH and failure to use INH plus at least one other drug to which the infecting strain is susceptible led to isoniazid resistance
Pharmacokinetics • Readily absorbed from GIT and peak plasma concentration within 1-2 hours • Absorption is decreased by aluminum hydroxide (give H2 blockers instead) • Diffuses readily into all body fluids and tissues • Metabolisms of INH (i.e acetylation by liver Nacetyltransferase) is genetically determined • Average concentration of INH in the plasma of rapid acetylators is 1/3 to ½ of that in slow acetylators, average half-lives are 1 hour and 3 hours, respectively • Isoniazid metabolites and a small amount of unchanged drug are excreted mainly in the urine • No dose adjustment for renal failure but dose is reduced in hepatic insufficiency because it is metabolized in the liver • INH can reduce metabolism of phenytoin and carbamazepine which increases its blood level and toxicity • Should be protected from light
1 of 3
Pharmacology – Antimycobacterial Drugs by Dra Alabastro Adverse Reactions • Allergic reactions, hepatitis, peripheral neuropathy, CNS, tinnitus, GI discomfort • IH promotes excretion of Pyridoxine and this toxicity is reversed by administration of pyridoxine in a dosage as low as 10mg/d Rifampin/Rifampicin
• • • • • •
• •
Active in-vitro against Gr(-) and (+) cocci, some enteric bacteria, Mycobacteria and Chlamydia MOA: inhibit RNA synthesis Acts on intra and extracellular bacillary populations Resistance due to mutations preventing binding of ripamfin to RNA Well-absorbed after oral administration and in fasting states Induces hepatic enzymes therefore there is drug interaction Excreted mainly through the liver into bile, recirculated and excreted in urine and feces No adjustment of dose in renal insufficiency
Clinical Uses • TB in combination with INH
• •
Atypical mycobacterial infection Leprosy with sulfone Meningococcal carriage H. influenzae type B prophylaxis
• •
Staphylococcal carriage with anti staph Pneumococcal meningitis streptomycin, rifmpicin
•
• •
combine
with
MOA: unknown Relative of nicotinamide; stable, Weakly bactericidal Acts on intracellular organisms within acidic environment Resistance due to mutations in pncA (impair conversion of pyrazinamide to its active form) or impaired uptake of pyrazinamide; no crossresistance with INH or other antiTB Rapidly absorbed from the GIT; Widely distributed in body fluids; peak concentration in 1-2 hrs T1/2=8-12 hrs Ethambutol
• • • •
• •
• •
Not given to children below 6 years old because of difficult to assess visual acuity Streptomycin
• • •
• • • •
Only with parenteral preparation (IM) MOA: irreversible inhibitors of protein synthesis Resistance & features of aminoglycoside Poor penetration into cells, active against extracellular tubercle bacilli only Serum concentration achieved in 30-60 min after IM OTOTOXIC and NEPHROTOXIC Monitor renal fcn & reduce dose if decrease in renal output
DIRECT OBSERVED THERAPY SHORT COURSE (DOTS) – 6 mos therapy • political comitment • case detection by sputum smear microscopy (3 smears) • standardized short course therapy with direct observation of drug intake • regular & uninterrupted supply of all essential antiTB drugs • standardized recording & reporting system FOR
Regimen
Pyrazinamide • • • •
•
DOSAGE REGIMEN
• •
Page 2 of 3
BACTERIOSTATIC; Bactericidal at higher dose (but toxic) MOA: inhibitor of mycobacterial arabinosyl transferases, encoded by the emb-CAB Acts on both extra- & intracellular bacillary populations Resistance due to mutations of emb gene; resistance when given alone Well absorbed from the GIT, peak concentration in 4 hrs T /2=4
TB (WHO) Dose adjustment
Patient
New pulmonary smear (+) cases New seriously ill, smear (-) Regimen I: cases with 2 HRZE → 4 extensive HR parenchymal involvement New severely ill extrapulmonar y TB cases Previously treated smear (+) Regimen II: 2 HRZE/ 1 PTB with HRZE → 5 HRE relapsed tx Failure, return to default New smear Smear (-) PTB other than Regimen III: cat1 2 HRZ → 4 HR Extrapulmonar y TB, less severely ill 1,2,4,5 – denotes mos of therapy *PZA only for two months MINOR SIDE EFFECTS Side Effect
Excretion: feces & urine
GI intolerance
Accumulates in renal failure, reduce dose
Mild skin rxn Orange-red urine
Drug(s) R Any Drug R
Add 1 tab INH, 100 mg PZA, 400 mg each patient with >50 kg body wt before initiation of tx
-
Add 1 tab INH, 100 mg PZA, 500 mg each patient with >50 kg body wt before initiation of tx
What to do Give medication at bedtime Give anti-histamines Reassurance
Pharmacology – Antimycobacterial Drugs by Dra Alabastro
Pain at injection site Burning sensation at feet, neuropathy Anthralgia due to hyperuricemia Flu like symptoms MAJOR SIDE EFFECTS Side Effect Severe rash from hypersensitivity Jaundice 2° to hepatitis
S
Warm compress, rotate injection sites
Z
Give pyridoxine
Z
NSAIDS (aspirin)
R
Give anti pyretics
Drug(s) Any drug esp S Any drug esp INH, R, P
What to do Discontinue drug & refer to MHO/CHO Discontinue drug & refer to MHO/CHO; Resume to medication when it subsides & monitor clinically Discontinue drug & refer to ophthalmologist
Impairment of visual acuity & vision due E to neuritis Impaired hearing, ringing of the ear & Discontinue drug & S dizziness due to refer to MHO/CHO damage of CN 8 Oliguria, or albuminuria due to S, R renal disorder Psychosis & H convulsion Thrombocytopenia, R anemia, shock MHO-municipal heath office; CHO-city heath office
ANTITB DRUGS DURING PREGNANCY AND LACTATION • INH, RIF & E: std drugs given bec they cross the placenta • PAS: can be safely used but could be poorly tolerated • S & other aminoglycosides: shld be avoided; effect on ear devt & fcn • Capreomycin, cycloserine, ethionamide: not recommended • PZA: avoid (teratogenic) • Breastfeeding not discouraged; feed infants first before taking medicine • Drugs in breast milk not considered effective tx of TB in infants
DRUGS USED IN LEPROSY
•
M. leprae never grown in vitro Dapsone & other Sulfones
• • • •
• •
Main drug BACTERIOSTATIC MOA: inhibits folate synthesis Resistance even if the dose is very low, combined with other drugs T1/2 (dapsone) = 1-2 days, tend to be retained in skin, muscle, liver, kidney Dose must be adjusted in renal failure
Page 3 of 3
•
ADR: hemolysis in patients with G6PD deficiency, methemoglobinemia, erythema nodosum leprosum (flaring of lepromatous lesions)
Rifampin • •
Very effective against lepromatous leprosy 600 mg daily
•
Given in combination w/ dapsone or another antileprosy drug to prevent rifampin-resistant M. leprae Clofazimine
• • •
• •
•
Phenazine dye used as alternative to dapsone MOA: unknown but may involve DNA binding Variable absorption from the gut, excreted primarily by feces Stored widely in reticuloendothelial tissues & Slowly released, T1/2 = may be 2 mos Indicated for sulfone-resistant leprosy or sulfone intolerance ADR: skin discoloration (since it is stored in skin) ranging from red-brown to nearly black, GI intolerance Prednisone
•
Combined with other drug Thalidomide
• • • •
MOA: Inhibits angiogenesis Anti-inflammatory, immunomodulatory For multiple myeloma Removed from the market Amithiozone
•
hepatotoxic
RECOMMENDED TREATMENT FOR LEPROSY Indeterminate ◦ Smear (-) ◦ Flat, hyposthetic (no sensation) lesion usually in the face, arms, legs ◦ Single dose of Rif + ofloxacin + minocycline Paucibacillary ◦ Smear (-) ◦ Flat, hyposthetic, hyperpigmented lesions <5 ◦ Rif 1x/month + dapsone 1x/day for 6 months Multibacillary ◦ Smear (+) ◦ Multiple, erythematous, copper-colored plaques, nodules with or without anesthesia ◦ Rif + dapsone + clofazimine 1x/month for 12 months Eto yung sa lecture lang talaga nya Thanks kay ape sa record =p
•
5 FIRST-LINE AGENTS for TB treatment (in order of preference): 1. Isoniazid – INH, H 2. Rifampicin / Rifampin – RIF, R 3. Pyrazinamide – PZA, Z 4. Ethambutol – E 5. Streptomycin – S
• •
Second line agents: Amikacin (Aminoglycoside) Aminosalicylic acid Ethionamide Fluoquinolones * Given when unresponsive to 1st line + INH, RIF
•
Isoniazid and Rifampin most active drugs, this combination administered for 9 months will cure 95-98% of TB Isoniazid and Rifampin and Pyrazinamide during the first 2 months allows total duration of therapy to be shortened to 6 months without loss of efficacy Isoniazid, Rifampin, Pyrazinamide and either Ethambutol or Streptomycin initial 4-drug therapy give until susceptibility of isolate has been determined; neither ethambutol nor streptomycin adds substantially reduce or duration of treatment regimen but provide additional coverage if the isolate is resistant to INH, R or both Characteristics of Mycobacterium Tuberculosis • Naturally occurring drug resistant mutants are present within large bacterial populations even before chemotherapy is started • Replicates slowly, can remain dormant for prolonged periods and can be eradicated only during replication • Bacilli live in several sites within the hosts and each site contains organisms with a different population size, metabolic activity and replication rate Principles of Treatment • Treatment of disease must contain multiple drugs to which the organisms are susceptible • Drugs must be taken regularly and treatment should continue for a sufficient length of time Isoniazid • • • • •
Most active drug Small simple molecule freely soluble in water With structure similar to Pyridoxine Inhibits most tubercle bacilli in a concentration of 0.2µg/mL or less Bactericidal for actively growing bacilli
Sexy & Babe + MR
MOA • •
•
Less effective against atypical mycobacterial species Ca penetrate into phagocytic cells Active both intra and extracellular organisms Inhibits synthesis of mycolic acids (essential component of cell wall) Bactericidal, prodrug activated by KatG, the mycobacterial catalase-peroxidase Activated form of INH forms a covalent complex with an acyl carrier protein (AcpM) and KasA. A beta-ketoacyl carrier protein synthetase blocks mycolic acid synthesis Acts on extra and intracellular bacilliary population
Resistance to INH • Overproducers of inhA express low-level INH resistance and cross-resistance to ethionamide • Mutation or deletion of KatG : high level of resistance • Due to mutations, resulting in overexpression of inhA, which encodes an NADH-depedent acyl carrier protein reductase • Overexpression ahpC, a presumed virulence gene involved in protection of the cell from oxidative stress • Mutation in kasA
• •
KatG mutants express high-level INH resiostance and usually not cross-resistant to ethionamide Single-drug therapy with IH and failure to use INH plus at least one other drug to which the infecting strain is susceptible led to isoniazid resistance
Pharmacokinetics • Readily absorbed from GIT and peak plasma concentration within 1-2 hours • Absorption is decreased by aluminum hydroxide (give H2 blockers instead) • Diffuses readily into all body fluids and tissues • Metabolisms of INH (i.e acetylation by liver Nacetyltransferase) is genetically determined • Average concentration of INH in the plasma of rapid acetylators is 1/3 to ½ of that in slow acetylators, average half-lives are 1 hour and 3 hours, respectively • Isoniazid metabolites and a small amount of unchanged drug are excreted mainly in the urine • No dose adjustment for renal failure but dose is reduced in hepatic insufficiency because it is metabolized in the liver • INH can reduce metabolism of phenytoin and carbamazepine which increases its blood level and toxicity • Should be protected from light
1 of 3
Pharmacology – Antimycobacterial Drugs by Dra Alabastro Adverse Reactions • Allergic reactions, hepatitis, peripheral neuropathy, CNS, tinnitus, GI discomfort • IH promotes excretion of Pyridoxine and this toxicity is reversed by administration of pyridoxine in a dosage as low as 10mg/d Rifampin/Rifampicin
• • • • • •
• •
Active in-vitro against Gr(-) and (+) cocci, some enteric bacteria, Mycobacteria and Chlamydia MOA: inhibit RNA synthesis Acts on intra and extracellular bacillary populations Resistance due to mutations preventing binding of ripamfin to RNA Well-absorbed after oral administration and in fasting states Induces hepatic enzymes therefore there is drug interaction Excreted mainly through the liver into bile, recirculated and excreted in urine and feces No adjustment of dose in renal insufficiency
Clinical Uses • TB in combination with INH
• •
Atypical mycobacterial infection Leprosy with sulfone Meningococcal carriage H. influenzae type B prophylaxis
• •
Staphylococcal carriage with anti staph Pneumococcal meningitis streptomycin, rifmpicin
•
• •
combine
with
MOA: unknown Relative of nicotinamide; stable, Weakly bactericidal Acts on intracellular organisms within acidic environment Resistance due to mutations in pncA (impair conversion of pyrazinamide to its active form) or impaired uptake of pyrazinamide; no crossresistance with INH or other antiTB Rapidly absorbed from the GIT; Widely distributed in body fluids; peak concentration in 1-2 hrs T1/2=8-12 hrs Ethambutol
• • • •
• •
• •
Not given to children below 6 years old because of difficult to assess visual acuity Streptomycin
• • •
• • • •
Only with parenteral preparation (IM) MOA: irreversible inhibitors of protein synthesis Resistance & features of aminoglycoside Poor penetration into cells, active against extracellular tubercle bacilli only Serum concentration achieved in 30-60 min after IM OTOTOXIC and NEPHROTOXIC Monitor renal fcn & reduce dose if decrease in renal output
DIRECT OBSERVED THERAPY SHORT COURSE (DOTS) – 6 mos therapy • political comitment • case detection by sputum smear microscopy (3 smears) • standardized short course therapy with direct observation of drug intake • regular & uninterrupted supply of all essential antiTB drugs • standardized recording & reporting system FOR
Regimen
Pyrazinamide • • • •
•
DOSAGE REGIMEN
• •
Page 2 of 3
BACTERIOSTATIC; Bactericidal at higher dose (but toxic) MOA: inhibitor of mycobacterial arabinosyl transferases, encoded by the emb-CAB Acts on both extra- & intracellular bacillary populations Resistance due to mutations of emb gene; resistance when given alone Well absorbed from the GIT, peak concentration in 4 hrs T /2=4
TB (WHO) Dose adjustment
Patient
New pulmonary smear (+) cases New seriously ill, smear (-) Regimen I: cases with 2 HRZE → 4 extensive HR parenchymal involvement New severely ill extrapulmonar y TB cases Previously treated smear (+) Regimen II: 2 HRZE/ 1 PTB with HRZE → 5 HRE relapsed tx Failure, return to default New smear Smear (-) PTB other than Regimen III: cat1 2 HRZ → 4 HR Extrapulmonar y TB, less severely ill 1,2,4,5 – denotes mos of therapy *PZA only for two months MINOR SIDE EFFECTS Side Effect
Excretion: feces & urine
GI intolerance
Accumulates in renal failure, reduce dose
Mild skin rxn Orange-red urine
Drug(s) R Any Drug R
Add 1 tab INH, 100 mg PZA, 400 mg each patient with >50 kg body wt before initiation of tx
-
Add 1 tab INH, 100 mg PZA, 500 mg each patient with >50 kg body wt before initiation of tx
What to do Give medication at bedtime Give anti-histamines Reassurance
Pharmacology – Antimycobacterial Drugs by Dra Alabastro
Pain at injection site Burning sensation at feet, neuropathy Anthralgia due to hyperuricemia Flu like symptoms MAJOR SIDE EFFECTS Side Effect Severe rash from hypersensitivity Jaundice 2° to hepatitis
S
Warm compress, rotate injection sites
Z
Give pyridoxine
Z
NSAIDS (aspirin)
R
Give anti pyretics
Drug(s) Any drug esp S Any drug esp INH, R, P
What to do Discontinue drug & refer to MHO/CHO Discontinue drug & refer to MHO/CHO; Resume to medication when it subsides & monitor clinically Discontinue drug & refer to ophthalmologist
Impairment of visual acuity & vision due E to neuritis Impaired hearing, ringing of the ear & Discontinue drug & S dizziness due to refer to MHO/CHO damage of CN 8 Oliguria, or albuminuria due to S, R renal disorder Psychosis & H convulsion Thrombocytopenia, R anemia, shock MHO-municipal heath office; CHO-city heath office
ANTITB DRUGS DURING PREGNANCY AND LACTATION • INH, RIF & E: std drugs given bec they cross the placenta • PAS: can be safely used but could be poorly tolerated • S & other aminoglycosides: shld be avoided; effect on ear devt & fcn • Capreomycin, cycloserine, ethionamide: not recommended • PZA: avoid (teratogenic) • Breastfeeding not discouraged; feed infants first before taking medicine • Drugs in breast milk not considered effective tx of TB in infants
DRUGS USED IN LEPROSY
•
M. leprae never grown in vitro Dapsone & other Sulfones
• • • •
• •
Main drug BACTERIOSTATIC MOA: inhibits folate synthesis Resistance even if the dose is very low, combined with other drugs T1/2 (dapsone) = 1-2 days, tend to be retained in skin, muscle, liver, kidney Dose must be adjusted in renal failure
Page 3 of 3
•
ADR: hemolysis in patients with G6PD deficiency, methemoglobinemia, erythema nodosum leprosum (flaring of lepromatous lesions)
Rifampin • •
Very effective against lepromatous leprosy 600 mg daily
•
Given in combination w/ dapsone or another antileprosy drug to prevent rifampin-resistant M. leprae Clofazimine
• • •
• •
•
Phenazine dye used as alternative to dapsone MOA: unknown but may involve DNA binding Variable absorption from the gut, excreted primarily by feces Stored widely in reticuloendothelial tissues & Slowly released, T1/2 = may be 2 mos Indicated for sulfone-resistant leprosy or sulfone intolerance ADR: skin discoloration (since it is stored in skin) ranging from red-brown to nearly black, GI intolerance Prednisone
•
Combined with other drug Thalidomide
• • • •
MOA: Inhibits angiogenesis Anti-inflammatory, immunomodulatory For multiple myeloma Removed from the market Amithiozone
•
hepatotoxic
RECOMMENDED TREATMENT FOR LEPROSY Indeterminate ◦ Smear (-) ◦ Flat, hyposthetic (no sensation) lesion usually in the face, arms, legs ◦ Single dose of Rif + ofloxacin + minocycline Paucibacillary ◦ Smear (-) ◦ Flat, hyposthetic, hyperpigmented lesions <5 ◦ Rif 1x/month + dapsone 1x/day for 6 months Multibacillary ◦ Smear (+) ◦ Multiple, erythematous, copper-colored plaques, nodules with or without anesthesia ◦ Rif + dapsone + clofazimine 1x/month for 12 months Eto yung sa lecture lang talaga nya Thanks kay ape sa record =p
