Chapter 45 antituberculous drugs

and antileprosy drugs

Pharmacology department guofang Wang

acid-fast staining:

The mycobacteria
are classified on the
basis of their staining
properties.
 Paul Ehrlich

 acid-fast staining is one of standard methods to diagnose

tuberculosis.

 Paul Ehrlich won Nobel prize

in1908, for achievement
of immunology and
microbiology
 The modern era of tuberculosis therapy began with
the introduction of streptomycin, isoniazid, and p-
aminosalicylic acid and so on.
 The number of cases of tuberculosis waned and
there was hope of complete eradication. However,
in the past decade, tuberculosis cases have
significantly increased, chief reason is the
increasing of AIDS patients and multiple drug
resistance.
 Today tuberculosis is still the leading cause of
death by infectious disease throughout the world.
 Objectives

 understanding classification of antituberculous

drugs;
 understanding the mechanisms of action of the fist-
line agents;
 mastering the major pharmacological effects and
the major adverse reactions of the fist-line agents.
 Classification of drugs

 A. antituberculous drugs

 1. first-line agents
The first-line agents included isoniazid(1952),
rifampin(1963) (rifampicin), ethambutol(1962),
streptomycin(1944) and pyrazinamide(1954).

 2.second-line agents
Sodium para-aminosalicylate(1949), ethionamide,
cycloserine(1955), and thioacetazone.
B. antileprosy drugs

 Commonly used antileprosy agents included

Dapsone, clofazimine, rifampin, etc..
 isoniazid (INH)

 pharmacological properties

 Isoniazid is bacteriostatic for resting M. tuberculosis

but bactericidal for producing tubercle bacillus.
 Isoniazid is active against both extracellular and
intracellular tubercle bacillus
 mechanisms of isoniazid
inhibiting the synthesis of mycolic acids, important
constituents of the mycobacterial cell wall;
mycobacterial catalase-peroxidase, covalent complex

 inhibiting the synthesis of DNA in tubercle bacillus;

 combining with certain susceptible enzyme in
isoniazid-susceptible strains of M. tuberculosis.
 pharmacokinetics
 absorbed from gastrointestinal tract
 diffuses into all of the body fluids and tissues ,cells
 Metabolism of isoniazid: N-acetylation and hydrolysis

acetylation by liver N-acetyltransferase, is under genetic

control, the fast and the slow acetylation types.
 Isoniazid metabolites and a small amount of unchanged
drug are excreted mainly in the urine.
 Isoniazid can inhibite the hepatic microsomal enzymes,
leading to a lengthened half-life of other agents
 therapeutic applications
 Isoniazid is the primary drug for the treatment of all types
of tuberculosis
 it can be used alone for prophylaxis or the early
pulmonary tuberculosis with slight symptom.
 Isoniazid should be used concurrently with other agents
 adverse reactions
 reactions on nervous system
 peripheral neuritis (hand and foot thrill, numbness)
 toxic encephalopathy and mental abnormalities
a relative pyridoxine (VitamineB6) deficiency ,
prophylactic application with pyridoxine
 hepatotoxicity
 jaundice, hepatic injury, even lethal injury
 others :allergic reactions
 Skin rash ,fever, agranulocytosis, thrombocytopenia,
arthritic symptoms, etc
 rifampin

 Rifampin is a large, complex semisynthetic

derivative of rifamycin, an antibiotic produced by
streptomyces mediterranei.

 Rifampin has a broader antimicrobial activity than

isoniazid and has found application in the treatment
of other bacterial infections.
 rifampin

 pharmacological properties
 Rifampin has a broad antimicrobial spectrum
 gram-positive and gram-negative
 resting and producing M. tuberculosis
 bacteriostatic and the bactericidal effects
 Intracellular and extracellular mycobacteria
 Leprosy bacillus
 mechanisms of Rifampin
β subunit of DNA-dependent RNA polymerase
 inhibiting RNA synthesis
 no effect on the RNA polymerase in mammalian cells
 Pharmacokinetics
 well absorbed after oral administration
 distributed widely in body fluids and tissues, cells
 excreted mainly through the liver into bile.

It then undergoes enterohepatic circulation, with the bulk

excreted as a deacylated metabolite in feces and a small
amount in the urine.
 Rifampin can induce the hepatic microsomal enzymes,
leading to a shortened half-life of other agents
 Urine, feces and other secretions have an orange-red
color, patients should be forewarned.
 therapeutic application
 all types of tuberculosis , an alternative to isoniazid
prophylaxis for patients
 other serious infectious diseases

It can eliminate meningococcal carriage and can

eradicate staphylococcal carriage
 leprosy
 adverse reactions
 gastrointestinal disturbances
 Hepatotoxicity : jaundice and hepatic dysfunction
 A flu-like syndrome : if administered less often than
twice weekly. Fever, chills, myalgias,
 an inducer of hepatic microsomal enzymes ,
decrease half-life , including digitoxin, quinidine,
propranolol, verapamil, and corticosteroids.
 secretion appear in a harmless orange color.
 ethambutol

 pharmacological properties
 Ethambutol suppresses the growth of tubercle
bacillus, is bacteriostatic and specific for most strains
of M.tuberculosis,
 mechanisms :
Ethambutol is an inhibitor of mycobacterial
arabinosyl transferases. Arabinosyl transferases
are involved in the polymerization reaction , inhibit
the incorporation of mycolic acid into the
mycobacterial cell wall
 inhibit RNA synthesis in bacteria by combining
with divalent metal ions, such as magnesium.
 Pharmacokinetics
 Well absorbed on oral administration.
 Well distributed throughout the body.

Ethambutol crosses the BBB only if the meninges

are inflamed,
 Both parent drug and metabolites are excreted by
glomerular filtration and tubular secretion

ethambutol accumulates in renal failure, and the

dose should be reduced by half if creatinine
clearance is less than 10ml/min.
 therapeutic applications

 used for the treatment of all types of tuberculosis.

 Resistance is not a serious problem if the drug is
employed with other antituberculous agents.
 adverse reactions
 optic neuritis :decrease of visual acuity, red-green
blindness etc.
 In addition, urate excretion is decreased , thus gout
may be exacerbated.
 pyrazinamide

 pharmacological properties
 Pyrazinamide shows its bacteriacidal effect in vitro
only at a slightly acidic pH.
 At neutral pH, it is inactive in vitro, but at pH 5.5 it inhibits
tubercle bacillus and some other mycobacteria.
 Drug is taken up by macrophages and exerts its activity
against intracellular organisms residing within this acidic
environment.
 It is bactericidal to actively dividing mycobacteria

 Pyrazinamide must be enzymatically hydrolyzed to

pyrazinoic acid which is the active form of the drug.
 Pharmacokinetics
 Pyrazinamide is well absorbed from the gastrointestinal
tract
 It is widely distributed in body tissues, including inflamed
meninges.
 therapeutic applications
 pyrazinamide is used in the short-term (6-month)
regimens , as a “sterilizing “ agent active against residual
intracellular organisms that may cause relapse.
 Adverse reactions
 Hepatotoxicity, nausea, vomiting, drug fever, gout attacks
 Waksman

 1944, Waksman found

streptomycin, first
clinically effective
antituberculous drugs
 streptomycin

 pharmacological properties
 first clinically effective antituberculous drugs
 Streptomycin is bactericidal for the tubercle bacillus in vitro
but bacteriostatic only in vivo
 therapeutic applications
 Streptomycin is mainly used for severe life-threatening TB .
 It is employed principally in individuals with severe, possibly
life-threatening forms of tuberculosis, eg, meningitis and
disseminated disease, and in treatment of infections
resistant to other drugs.
 Other drugs are always given simultaneously to prevent
emergence of resistance.
 Adverse reactions
 It has ototoxic and nephrotoxic

vertigo and hearing loss

 Dose must be adjusted according to renal function.
 Second-line agents

 in case of resistance to the first-line agents

 in case of failure of conventional treatment
 sodium para-aminosalicylate

 pharmacological properties
 Sodium para-aminosalicylate exhibits bacteriostasis
only to extracellular M.tuberculosis with a narrow
antibacterial spectrum.
 The mechanism of action is very similar to that of
sulfonamides, which inhibit dihydropteroate synthase
and thus the biosynthesis of folic acid.
 Pharmacokinetics
 Absorbed from the gastrointestinal tract
 Widely distributed in tissues and body fluids except the
cerebrospinal fluid
 Rapidly excreted in the urine
 therapeutic applications
 administered mainly in combination with isoniazid and
streptomycin to delay the emergence of resistance and to
increase its therapeutic effects.
 Adverse reactions
 Gastrointestinal symptoms and hypersensitive reactions
 Because of inhibiting absorption of rifampin, para-
aminosalicylate cannot be combined with rifampin
 ethionamide

 Ethionamide is chemically related to isoniazid and

also blocks the synthesis of mycolic acids
 Pharmacokinetics
 oral administration
 Widely distributed throughout the body, including the
CSF
 Metabolized by the liver
 Urine is the main route of excretion
 inhibit the acetkylation of isoniazid
 therapeutic applications
 used concurrently with other drugs in TB chemotherapy.
Poorly-tolerated
 Adverse reactions
 gastrointestinal disorders
 the principle of application

 as early as possible
 Combination with other agents

Prevent the emergence of resistant stains

Increase curative effect

 regularly, sufficient application

 whole range

2HRZ/4HR
 bacille calmette-guerin(BCG)

 1900, Calmette-Guerin
use Mycobacterium bovis
to make vaccine,
 1921, use BCG to
prevent tuberculosis.
 Antileprosy drugs

 caused by M.leprae
 impairment of nerves and skin
 The world health organization recommends the
triple drug regimen, dapsone and clofazimine, and
rifampin for 6 to 24 mounths.
 Pharmacological properties
 Dapsone is bacteriostatic but not bactericidal for M.leprae
 mechanism of dapsone is considered similar to that of
sulfonamides, inhibit folate biosynthesis
 Therapeutic application
 Beginning from a small dose, the quantity shoule be
increased gradually to those recommended.
 Therapy shoule be continued for 1—3years, even for
lifetime
 adverse reactions
 hemolysis , especially in those with a glucose-6-phosphate
dehydrogenase (G-6-PD) deficiency
 Methemoglobinemia