Pharmacology (Dr.

Albatross)
Anti-TB and Anti-Leprosy

8-10 January 2008

DRUGS USED IN TUBERCULOSIS • Less effective against atypical mycobacterial

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
species
• Ca penetrate into phagocytic cells
• Active both intra and extracellular organisms
MOA
• 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 N-
acetyltransferase) 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

Sexy & Babe  + MR 1 of 3

 Pharmacology – Antimycobacterial Drugs by Dra Alabastro Page 2 of 3

Adverse Reactions • Not given to children below 6 years old because of

• 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
difficult to assess visual acuity
Streptomycin
• Only with parenteral preparation (IM)
• MOA: irreversible inhibitors of protein synthesis
• Resistance & features of aminoglycoside

• Active in-vitro against Gr(-) and (+) cocci, some

• Poor penetration into cells, active against
extracellular tubercle bacilli only
enteric bacteria, Mycobacteria and Chlamydia
• Serum concentration achieved in 30-60 min after IM
• MOA: inhibit RNA synthesis • OTOTOXIC and NEPHROTOXIC
• Acts on intra and extracellular bacillary • Monitor renal fcn & reduce dose if decrease in renal
populations output
• Resistance due to mutations preventing binding
of ripamfin to RNA
• Well-absorbed after oral administration and in DIRECT OBSERVED THERAPY SHORT COURSE (DOTS) – 6 mos
fasting states therapy
• Induces hepatic enzymes therefore there is • political comitment
drug interaction • case detection by sputum smear microscopy (3
• Excreted mainly through the liver into bile, smears)
recirculated and excreted in urine and feces • standardized short course therapy with direct
• No adjustment of dose in renal insufficiency observation of drug intake
• regular & uninterrupted supply of all essential
Clinical Uses antiTB drugs
• TB in combination with INH • standardized recording & reporting system
• Atypical mycobacterial infection
• Leprosy with sulfone DOSAGE REGIMEN FOR TB (WHO)
Dose
• Meningococcal carriage Regimen Patient
adjustment
• H. influenzae type B prophylaxis
New
• Staphylococcal carriage with anti staph pulmonary
• Pneumococcal meningitis combine with smear (+)
streptomycin, rifmpicin cases
New seriously Add 1 tab INH,
Pyrazinamide ill, smear (-) 100 mg PZA, 400
Regimen I:
cases with mg each patient
2 HRZE → 4
• MOA: unknown extensive with >50 kg
HR
• Relative of nicotinamide; stable, parenchymal body wt before
• Weakly bactericidal involvement initiation of tx
• Acts on intracellular organisms within acidic New severely
environment ill
extrapulmonar
• Resistance due to mutations in pncA (impair y TB cases
conversion of pyrazinamide to its active form) or
Previously
impaired uptake of pyrazinamide; no cross-
treated smear
resistance with INH or other antiTB
Regimen II: (+)
• Rapidly absorbed from the GIT; Widely distributed in 2 HRZE/ 1 PTB with -
body fluids; peak concentration in 1-2 hrs HRZE → 5 HRE relapsed tx
• T1/2=8-12 hrs Failure, return
to default
Ethambutol New smear
Add 1 tab INH,
• BACTERIOSTATIC; Bactericidal at higher dose (but Smear (-) PTB
100 mg PZA, 500
toxic) other than
Regimen III: mg each patient
• MOA: inhibitor of mycobacterial arabinosyl cat1
2 HRZ → 4 HR with >50 kg
transferases, encoded by the emb-CAB Extrapulmonar body wt before
• Acts on both extra- & intracellular bacillary y TB, less initiation of tx
populations severely ill
• Resistance due to mutations of emb gene; 1,2,4,5 – denotes mos of therapy
resistance when given alone *PZA only for two months
• Well absorbed from the GIT, peak concentration in 4
MINOR SIDE EFFECTS
hrs
Side Effect Drug(s) What to do
• T /2=4
Give medication at
• Excretion: feces & urine GI intolerance R
bedtime
• Accumulates in renal failure, reduce dose Mild skin rxn Any Drug Give anti-histamines
Orange-red urine R Reassurance
 Pharmacology – Antimycobacterial Drugs by Dra Alabastro Page 3 of 3

Pain at injection site S

Warm compress, • ADR: hemolysis in patients with G6PD deficiency,
rotate injection sites methemoglobinemia, erythema nodosum leprosum
Burning sensation at (flaring of lepromatous lesions)
Z Give pyridoxine
feet, neuropathy
Anthralgia due to
Z NSAIDS (aspirin)
hyperuricemia Rifampin
Flu like symptoms R Give anti pyretics
• Very effective against lepromatous leprosy
MAJOR SIDE EFFECTS • 600 mg daily
Side Effect Drug(s) What to do • Given in combination w/ dapsone or another
Severe rash from Any drug Discontinue drug & antileprosy drug to prevent rifampin-resistant M.
hypersensitivity esp S refer to MHO/CHO leprae
Discontinue drug &
refer to MHO/CHO; Clofazimine
Any drug
Jaundice 2° to Resume to
esp INH, • Phenazine dye used as alternative to dapsone
hepatitis medication when it
R, P • MOA: unknown but may involve DNA binding
subsides & monitor
clinically • Variable absorption from the gut, excreted primarily
Impairment of visual Discontinue drug & by feces
acuity & vision due E refer to • Stored widely in reticuloendothelial tissues & Slowly
to neuritis ophthalmologist released, T1/2 = may be 2 mos
Impaired hearing, • Indicated for sulfone-resistant leprosy or sulfone
ringing of the ear & Discontinue drug &
S intolerance
dizziness due to refer to MHO/CHO
damage of CN 8 • ADR: skin discoloration (since it is stored in skin)
Oliguria, or ranging from red-brown to nearly black, GI
albuminuria due to S, R - intolerance
renal disorder
Psychosis & Prednisone
H -
convulsion
• Combined with other drug
Thrombocytopenia,
R -
anemia, shock
MHO-municipal heath office; CHO-city heath office Thalidomide

• MOA: Inhibits angiogenesis

ANTITB DRUGS DURING PREGNANCY AND LACTATION
• Anti-inflammatory, immunomodulatory
• INH, RIF & E: std drugs given bec they cross the • For multiple myeloma
placenta
• Removed from the market
• PAS: can be safely used but could be poorly
tolerated Amithiozone
• S & other aminoglycosides: shld be avoided;
effect on ear devt & fcn • hepatotoxic
• Capreomycin, cycloserine, ethionamide: not
recommended RECOMMENDED TREATMENT FOR LEPROSY
• PZA: avoid (teratogenic) Indeterminate
• Breastfeeding not discouraged; feed infants first ◦ Smear (-)
before taking medicine ◦ Flat, hyposthetic (no sensation) lesion usually in
• Drugs in breast milk not considered effective tx of the face, arms, legs
TB in infants ◦ Single dose of Rif + ofloxacin + minocycline
Paucibacillary
◦ Smear (-)
DRUGS USED IN LEPROSY ◦ Flat, hyposthetic, hyperpigmented lesions <5
◦ Rif 1x/month + dapsone 1x/day for 6 months
Multibacillary
• M. leprae never grown in vitro ◦ Smear (+)
◦ Multiple, erythematous, copper-colored plaques,
Dapsone & other Sulfones nodules with or without anesthesia
◦ Rif + dapsone + clofazimine 1x/month for 12
• Main drug months
• BACTERIOSTATIC
• MOA: inhibits folate synthesis Eto yung sa lecture lang talaga nya
• Resistance even if the dose is very low, combined
with other drugs Thanks kay ape sa record =p
• T1/2 (dapsone) = 1-2 days, tend to be retained in
skin, muscle, liver, kidney
• Dose must be adjusted in renal failure