Chapter

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.

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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 paminosalicylic 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 fistline 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

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Isoniazid is bacteriostatic for resting M. tuberculosis but bactericidal for producing tubercle bacillus. Isoniazid is active against both extracellular and intracellular tubercle bacillus

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mechanisms of isoniazid inhibiting the synthesis of mycolic acids, important constituents of the mycobacterial cell wall; mycobacterial catalase-peroxidase, covalent complex 

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inhibiting the synthesis of DNA in tubercle bacillus; combining with certain susceptible enzyme in isoniazid-susceptible strains of M. tuberculosis.

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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 

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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 

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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,

 others  Skin

hepatic injury, even lethal injury

:allergic reactions

rash ,fever, agranulocytosis, thrombocytopenia, arthritic symptoms, etc

rifampin 

Rifampin is a large, complex semisynthetic derivative of rifamycin, an antibiotic produced by streptomyces mediterranei.

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Rifampin has a broader antimicrobial activity than isoniazid and has found application in the treatment of other bacterial infections.

rifampin  pharmacological  Rifampin     

properties

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 β

of Rifampin

subunit of DNA-dependent RNA polymerase  inhibiting RNA synthesis  no effect on the RNA polymerase in mammalian cells

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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. 

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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

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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.

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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.

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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.

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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 

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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.

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Adverse reactions  It has ototoxic and nephrotoxic vertigo and hearing loss  Dose must be adjusted according to renal function.

Second-line agents

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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. 

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Pharmacokinetics Absorbed from the gastrointestinal tract  Widely distributed in tissues and body fluids except the cerebrospinal fluid  Rapidly excreted in the urine 

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therapeutic applications 

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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, paraaminosalicylate 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 

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therapeutic applications used concurrently with other drugs in TB chemotherapy. Poorly-tolerated

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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. 

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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