Chemotherapy of Tuberculosis

Medically important mycobacteriaMycobacterium TuberculosisA typical MycobacteriumMycobacterium Leprae

Treatment Of Tuberculosis

Tuberculosis remains the primary cause of death due to infectious disease.

Organs involved --------- primarily lungsDrugs are divided into two groups:First lineSecond line

Antimycobacterial drugs

First line of drugs:Isoniazid (INH)RifampicinEthambutolStreptomycinPyrazinamide

Never use a single drug therapy

Isoniazid –rifampicin combination administered for 9 months will cure 95-98% of cases .

Addition of pyrazinamide for this combination for the first 2 months allows total duration to be reduced to 6 months.

Isoniazid

Bacteriostatic for resting bacilli.Bactericidal for rapidly

dividing bacilli.Is effective against intracellular

as well as extracellular bacilli

Mechanism Of Action

Is a prodrugCell wall synthesis inhibitorInhibits synthesis of Mycolic acids----Which are essential components of Mycobacterial cell walls.

Pharmacokinetics

Readily absorbed when given either orally or parenterally.

Aluminum containing antacids interfere with absorption.

Distribution

Diffuse rapidly into all body fluids and cells.

Detected in significant concentrations in pleural & ascitic fluids.

Its concentration in CSF is significant in inflammed meninges.

Penetrates well into caseous material.

Metabolism & Excretion

75% to 95% of a dose of INH is excreted in urine within 24 hours.

Mostly as metabolities.The main excretory products in

human result from enzymatic acetylation.

Clinical usesMycobacterial infections (it is recommended

to be given with pyridoxine to avoid neuropathy).Latent tuberculosis in patients with

positive tuberculin skin test Prophylaxis against active TB in individuals

who are in great risk as very young or immunocompromised individuals.

Adverse effects

Peripheral neuritisOptic neuritis &atrophy.Allergic reactions ( fever,skin

rash,systemic lupus erythematosus )Hepatitis

Adverse effects (cont.)

Hematological reactionsVasculitisArthritic symptoms

Adverse effects (cont.)

CNS toxicity include ;Lack of mental concentration , memory

loss.Excitability & seizuresPsychosis( Respond to pyridoxine)

Drug Interactions of INH

Inhibits the hepatic microsomal enzymes, cytochrome P450 & decrease metabolism of other drugs ( especially , Phenytoin )and increase their toxicity .

Rifampicin

BactericidalInhibits RNA synthesis----- by binding to

the beta –subunit of bacterial DNA dependent RNA polymerase.

Site of Action

Intracellular bacilliExtracellular bacilliBacilli in caseous lesions

Pharmacokinetics

Well absorbed orally.Aminosalicylic acid delay the absorption

of rifampicin, (They should be given separately at an interval of 8-12 hour ).

Metabolism & Excretion

Metabolized in liver by acetylation & enters enterohepatic circulation.

Half-life 1.5-5 hours & increased in hepatic dysfunction.

Eliminated in bile & feces( 60-65% ) & 30% in urine.

Distribution

Distributed throughout the body organs & fluids including CSF in effective concentration.

Clinical uses

Mycobacterial infectionsProphylaxis of active tuberculosis.Treatment of serious staphylococcal

infections as osteomyelitis and endocarditis.

Meningitis by highly resistant penicillin pneumococci

Adverse effects

Harmless red-orange discoloration of body secretions( urine, sweat, tears) & contact lenses ( soft lenses may be permanently stained ).

Skin rashFever

Adverse Effects ( cont.)

Nausea & vomiting Hepatotoxicity ( Hepatitis, cholestatic jaundice) If administered less than twice weekly causes a

flu-like syndrome( fever , chills, myalgias, hemolytic anemia, thrombocytopenia & acute tubular necrosis.

Drug Interactions

Potent inducer of hepatic microsomal enzymes ( cytochrome P450)

Increase elimination of other drugs including :

AnticoagulantsAnticonvulsantsContraceptives

Ethambutol

BacteriostaticInhibits mycobacterial arabinosyl

transferase ( inhibits polymerization reaction of arabinoglycan an essential component of mycobacterial cell wall )

Site Of Action

Intracellular & Extracellular bacilli

Phrmacokinetics

Well absorbed orallyHalf-life 3-4 hours75% of the drug is excreted unchanged in

the urine, 15% as metabolities.

Clinical uses

Treatment of tuberculosis in combination with other drugs.

Adverse effects

Retrobulbar (optic) neuritis causing loss of visual acuity and red-green color blindness.

Relatively contraindicated in children( under 5 years).

GIT .upset .Hyperuricemia

Pyrazinamide

Prodrug( converted to pyrazinoic acid ,the active form .

BactericidalActing on mycobacterial fatty acid

synthase I gene involved in mycolic acid biosynthesis.

Site Of Action

Intracellular Bacilli

Phrmacokinetics

Well absorbed from GITWidely distributed including CSFHalf-life 9-10 hoursExcreted primarily by renal route.

Clinical uses

Mycobacterial infections (TB) mainly in multidrug resistance cases.

It is important in short –course (6 months) regimens with isoniazid and rifampicin.

Prophylaxis of TB in combination with ciprofloxacin.

Adverse effects

HepatotoxicHyperuricemia( provoke acute gouty

arthritis )Nausea & vomitingDrug fever & skin rash

Streptomycin & Amikacin

BactericidalInhibitors of protein synthesis by biding to

30 S ribosomal subunits.Acting on extracellular bacilli

Clinical uses

Severe , life-threating form of T.B. as meningitis, disseminated disease, infections resistant to other drugs( Multidrug resistance tuberculosis).

In aerobic gram –ve bacterial infections.

Adverse Effects

OtotoxicityNephrotoxicityNeuromuscular block

Contraindications

Myasthenia gravisPregnancy

Indication of 2nd line treatment

Resistance to the drugs of 1st line.Failure of clinical responseThere is contraindication for first line

drugs.Patient is not tolerating the drugs first

line drugs.

Ethionamide

Blocks synthesis of mycolic acid .

ProdrugIs converted to active form (sulfoxide ).

Pharmacokinetics

Absorbed from GIT, Given only orallyRapidly & widely distributed Half-life 2 hoursMetabolized in liver, less than 1% is

excreted in active form in urineInhibits the acetylation of INH

Clinical uses

Is a secondary agent , to be used concurrently with other drugs when therapy with primary agents is ineffective or contraindicated.

Adverse Effects

Anorexia, nausea, vomiting, gastric irritation.

About 50% of patients are unable to tolerate a single dose more than 500mg.

Adverse Effects (cont.)

CNS symptoms include :Mental depressionDrowsinessConvulsions & peripheral neuropathyHeadache( Pyridoxine relieves the neurologic

symptoms)

Adverse Effects(cont.)

Severe hypotensionAllergic skin reactionsHepatitisAlopeciaMetallic taste

Capreomycin

AminoglycosidesIt is an important injectable agent for

treatment of drug-resistant tuberculosis.It is nephrotoxic and ototoxic.Local pain & sterile abscesses may occur.

Cycloserine

Inhibitor of cell wall synthesis Cleared renally The most serious side effects are peripheral

neuropathy and CNS dysfunction, including depression & psychotic reaction.

Pyridoxine should be given. Contraindicated in epileptic patients.

Amikacin

Used as alternative to streptomycin.Used in multidrug- resistance tuberculosis.No cross resistance between streptomycin

and amikacin.

Ciprofloxacin & levofloxacin

Effective against typical and atypical mycobacteria.

Used against multidrug- resistant tuberculosis.

Used in combination with other drugs.

Rifabutin

As rifampicin , it is RNA polymerase inhibitor.

Cross resistance with rifampicin but not to all microorganisms.

Enzyme inducer of cytochrome p450.Effective against typical and atypical

mycobacteria.

Phrmacokinetics

Absorbed from GITLipophilic drug Excreted in urine & bileAdjustment of dosage is not necessary in

patients with impaired renal function.

Clinical uses

Treatment of T.B. in HIV- infected patients ( replaced rifampicin, because it is less potent enzyme inducer)

Prevention of tuberculosisPrevention & treatment of disseminated

atypical mycobacterial infections in AIDS patients

Adverse Effects

Skin rash(4%)GIT intolerance (3%)Neutropenia (2%)ArthralgiaOrange-red discoloration ( skin,urine, -----

as rifampicin ).

Drug Interactions

Enzyme inducer of cytochrome P450 enzymes.

Aminosalicylic Acid (PAS).

Similar in structure to sulfonamide and p-aminobenzoic acid.

BacteriostaticFolate synthesis inhibitor.

Pharmacokinetics Well absorbed from GIT Best given after meals Distributed throughout the total body water &

reaches high concentration in pleural fluid & caseous tissues.

CSF levels are low Half-life one hour 80% of the drug is excreted in urine as

metabolities.

Clinical uses

AS a second line agent is used in the treatment of pulmonary & other forms of tuberculosis.

Adverse effects

GIT upset ( anorexia, nausea, epigastric pain , diarrhea ).

Hypersensitivity reactionsHematological troubles ( leukopenia,

agranulocytosis, eosinophilia)Crystalluria

Clofazimine

Drug Regimens

6 months durationA) First 2 months:INH+ Rifampin + Pyrazinamide +

Ethambutol or StreptomycinB) Last 4 monthsINH + Rifampin

2- Drug Regimens

2- 9 months duration:A) First 2 months:INH + Rifampicin + Ethambutol

B) Last 7 months:INH + Rifampicin

Drug Regimens(cont.)

If there is possibility of drug resistance, Ethambutol or Streptomycin or even second line drugs is added

Depending on :Type of resistanceSensitivity of microorganisms

Drug Regimens (cont.)

We give drug combination to :1- Avoid the emergence of resistance2- Increase therapeutic efficacy3- Decrease : Dose, Frequency of dose

administration, adverse effects

Treatment Of Tuberculosis In Pregnant Women

AS previously mentioned , but streptomycin is contraindicated because it can cause congenital ototoxicity

Drugs used in leprosyDapsone

Inhibits folate synthesis. Well absorbed orally,widely distributed . Half-life 1-2 days,tends to be retained in

skin,muscle,liver and kidney. Excreted into bile and reabsorbed in the intestine. Excreted in urine as acetylated. It is well tolerated.

Clinical uses

Tuberculoid leprosy. Lepromatous leprosy in combination with rifampin

& clofazimine. To prevent & treat Pneumocystis pneumonia in

AIDS caused by Pneumocystis jiroveci ( Pneumocystis carinii).

Adverse effects

Haemolytic anaemia Methemoglobinemia Gastrointestinal intolerance Fever,pruritus,rashes. Erythema nodosum leprosum

Clofazimine It is a phenazine dye. Unknown mechanism of action ,may be DNA binding. Antiinflammatory effect. Absorption from the gut is variable. Given orally , once daily. Excreted mainly in feces. Stored mainly in reticuloendothelial tissues and skin. Half-life 2 months. Delayed onset of action (6 weeks).

Clinical uses

Multidrug resistance TB. Lepromatous leprosy Tuberculoid leprosy in :

patients intolerant to sulfones dapsone-resistant bacilli. Chronic skin ulcers caused by M.ulcerans.

Adverse effectsSkin discoloration ranging from red-brown to black.Gastrointestinal intolerance.Red colour urine.Eosinophilic enteritis

Treatment of TB in pregnant women

INH ( pyridoxine should be given ), Rifampicin , ethambutol Pyrazinamide is given only if : Resistant to other drugs is documented Streptomycin is contraindicated. Breast feeding is not contraindication to receive

drugs , but caution should be observed.