oktober 2010pharmacology of antituberculosis drugs

7/25/2019 Oktober 2010Pharmacology of Antituberculosis Drugs

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Pharmacology of

Antituberculosis drugs

Dr.Datten Bangun MSc,SpFK

Dept.Farmakologi !erapeutikFak.Kedokteran

" # $


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General Considerations

!uberculosis is a chronic infection,!uberculosis is a chronic infection,

potentially of lifelong duration, causedpotentially of lifelong duration, caused

by t%o species of mycobacteriaby t%o species of mycobacteria

M.tuberculosis and, rarely, M.bo&isM.tuberculosis and, rarely, M.bo&is

't %as isolated by (obert Koch in )**+'t %as isolated by (obert Koch in )**+

!he morbidity and mortality of!he morbidity and mortality of

tuberculosis are high in de&elopingtuberculosis are high in de&elopingcountries.countries.


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!B Diagnosis

Symptoms persistent cough, fe&er, night

s%eats, %eight loss

(isk factors for e-posure to !B close

contact of case, residencetra&el in highpre&alence country, congregate li&ing %ith

other high risk indi&iduals

(isk factors for de&elopment of acti&e

disease if infected recent infection,

#'/A'DS, other underlying medical condition


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Etiology

!he tubercle bacillus!he tubercle bacillus0M.!uberculosis1 is0M.!uberculosis1 is

aerobie, non2motile,non2aerobie, non2motile,non2

spore2forming, highspore2forming, high

in lipid content, andin lipid content, and

acid and alcohol2fastacid and alcohol2fast

't gro%s slo%ly .'t gro%s slo%ly .

't can3t tolerate heat, but't can3t tolerate heat, but

't can li&e in humid or't can li&e in humid or

dry or colddry or cold

surroundings.surroundings.


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Treatment !he principles of antituberculous chemotherapy!he principles of antituberculous chemotherapy

in&ol&ein&ol&e 4 earlier,4 earlier,

4 combination,4 combination,

4 appropriate ,4 appropriate ,

4 regularly and4 regularly and

4 durations.4 durations.

!he critical issue in !B control is adopting the D5!S!he critical issue in !B control is adopting the D5!S0)6671 0 Directly 5bser&ed !reatment, Short2course0)6671 0 Directly 5bser&ed !reatment, Short2course

therapy8therapy8

D5!S Strategy is recommended by the 9#5 !BD5!S Strategy is recommended by the 9#5 !B

Program.Program.


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Antituberculosis Drugs :urrently in

"se in the "S

First2line Drugs

'sonia;id

(ifampin

(ifapentine

(ifabutin


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Antimycobacterial drugs

First line of drugs

'sonia;id 0'$#1

(ifampicin


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'sonia;id 0'$#1 first-line drug 'sonia;id is a principal agent used to treat'sonia;id is a principal agent used to treat

tuberculosistuberculosis

't is uni&ersally accepted for initial treatment't is uni&ersally accepted for initial treatment

$o% considered the best antituberculous drug$o% considered the best antituberculous drug

't should be included in all !B treatment't should be included in all !B treatmentregimens unless the organism is resistantregimens unless the organism is resistant

Bacteriostatic at lo% conc. bacteriocidal at high conc.


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Ad&antages included

'ne-pensi&e'ne-pensi&e

(eadily synthesi;ed(eadily synthesi;ed

A&ailabe %orld%ideA&ailabe %orld%ide

#ighly selecti&e for mycobacteria#ighly selecti&e for mycobacteria

9ell tolerated0about only 7? of patients9ell tolerated0about only 7? of patients

e-hibiting ad&erse effects1e-hibiting ad&erse effects1

Dosage

!uberculosis organi;ation ha&e recommended!uberculosis organi;ation ha&e recommended

4 7 mgkg daily for both groups4 7 mgkg daily for both groups

>enerally, a>enerally, a

4 @mg daily oral dose is adopted4 @mg daily oral dose is adopted


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Pharmacokinetics

(eadily absorbed from >'!.

Diffuse into all body fluids and tissues

Penetrates caseous material andmacrophages so it is effecti&e against

intra and e-tracellular organisms.

Metaboli;ed in li&er by acetylation


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Clinical uses

Mycobacterial infections 0it isrecommended to be gi&en %ithpyrido-ine to a&oid neuropathy1.

=atent tuberculosis in patients %ithpositi&e tuberculin skin test

Prophyla-is against acti&e !B in

indi&iduals %ho are in great risk as&ery young or immunocompromisedindi&iduals.


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Adverse effects

Peripheral neuritis

5ptic neuritis.

Allergic reactions 0 fe&er,skin rash,systemic

lupus erythematosus 1 #epatitis

>astric upset

#aemolytic anaemia


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#epatoto-ity

'sonia;id associated hepatitis is idiosyncratic'sonia;id associated hepatitis is idiosyncraticand increase in incidence %ith age."suallyand increase in incidence %ith age."sually

among the rapid acetylators1among the rapid acetylators1

9e must measure li&er en;ymes before9e must measure li&er en;ymes before

administrating and during treatmentadministrating and during treatment

periods0usually monthly measure1periods0usually monthly measure1

'f the li&er en;ymes le&el is higher than'f the li&er en;ymes le&el is higher than

normal,the drug must be discontinuednormal,the drug must be discontinued


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Peripheral neuritis

't3s associated %ith isoni;iad de&elops at a't3s associated %ith isoni;iad de&elops at a

dose2dependent rate of + to +? and probablydose2dependent rate of + to +? and probably

relates to interference %ith pyrido-ine metabolismrelates to interference %ith pyrido-ine metabolism

0slo% acetylators 10slo% acetylators 1

!his rate can be reduced to .+? %ith the!his rate can be reduced to .+? %ith theprophylactic administration of ) to 7 mg ofprophylactic administration of ) to 7 mg of

pyrido-ine dailypyrido-ine daily


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(esistance

't is associated %ith loss of pyra;inamidase't is associated %ith loss of pyra;inamidase

acti&ityacti&ity

Pyra;inamidase acti&ity is determined byPyra;inamidase acti&ity is determined by

P$:A gene, if P$:A gene is mutated, itsP$:A gene, if P$:A gene is mutated, its

acti&ity is lostacti&ity is lost


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(ifampin 0(FP1 first2line drug

't is also considered the most important and't is also considered the most important and potent antituberculose agentpotent antituberculose agent

=ike isonia;id it is bactericidal and highly=ike isonia;id it is bactericidal and highly

effecti&eeffecti&e "nlike isonia;id, it is also effecti&e against"nlike isonia;id, it is also effecti&e against

most other mycobacteria as %ell as othermost other mycobacteria as %ell as other

organismsorganisms

Bactericidal ,binds strongly to subunit

of bacterial D$A2dependent ($A polymerase

leading to inhibition of ($A synthesis .


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Pharmacokinetics

9ell absorbed orall.


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Clinical uses

Mycobacterial infections

Prophyla-is in contacts of children %ith

#aemophilus influen;ae type b disease.

!reatment of serious staphylococcal

infections as osteomyelitis and

endocarditis.

Meningitis by highly resistant penicillin

pneumococci


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Adverse effects

#armless red2orange colour to

urine,s%eat,tears,contact lenses.

(ashes

!hrombocytopenia

$ephritis

:holestatic aundice,hepatitis

Flu2like syndrome 'nduce cytochrome p2E7


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Ad&antage include

't is absorbed after either oral or't is absorbed after either oral or

intra&enous administrationintra&enous administration

't has both intracellular and e-tracellular't has both intracellular and e-tracellular

anti2bacterial acti&ityanti2bacterial acti&ity

Dosage ) mgkgB9,usually mg ,daily or t%ice %eekly

Ad&erse effects2 the most common effect8 gastrointestinal upsets

2 hepatitis


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(esistance

(esults from spontaneous point(esults from spontaneous pointmutations that alter themutations that alter the subunitsubunit

of the ($A polymeraseof the ($A polymerase


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Pyra;inamide 0PGA1 first2line drug

Pyra;inamide is a maor oral agentPyra;inamide is a maor oral agent

used against mycobacteriaused against mycobacteria 't is an important bactericidal drug't is an important bactericidal drug

used in short2course therapy forused in short2course therapy for

tuberculosistuberculosis


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Ad&antageAd&antage 't is %ell absorbed after oral administration't is %ell absorbed after oral administration

!he drug is used to kill intracellular tubercle!he drug is used to kill intracellular tuberclebacillusbacillus

't is distributed throughout the body,'t is distributed throughout the body,

e-cellent in :SFe-cellent in :SF

DosageDosage

-)7 to @ mgKgday)7 to @ mgKgday


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Ad&erse effectAd&erse effect

At the high dosages, hepatoto-ityAt the high dosages, hepatoto-ity

is a prominent side effectis a prominent side effect

(esistance(esistance Due to loss of pyra;inamidaseDue to loss of pyra;inamidase

acti&ityacti&ity


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Streptomycin 0SM1Streptomycin 0SM1 first2line drugfirst2line drug

It is frequently used in developing country for itsIt is frequently used in developing country for its

lower costlower cost

It is administered only parenterally, intramuscularIt is administered only parenterally, intramuscular

or intravenousor intravenous

A bactericidal

Dosage

4 !he usual adult dose is .72). g 0 ) to )7 mgkg1!he usual adult dose is .72). g 0 ) to )7 mgkg1

daily or fi&e times %eeklydaily or fi&e times %eekly

4 !he dosage must be lo%ered and the freCuency4 !he dosage must be lo%ered and the freCuency

of administtation reduced0to onlyof administtation reduced0to only

t%o or three times per %eek1 in most patientst%o or three times per %eek1 in most patients

o&er fifty years old and in any patient %itho&er fifty years old and in any patient %ith

renal impairmentrenal impairment


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Streptomycin

=ife threathening forms of !B 0 meningitis,

dissiminated disease1. (esistant cases 0Multidrug resistance tuberculosisat least to '$# rifampicin 1 .

Amikacin can be used as alternati&e to streptomycin.

Both acti&e mainly against e-tracellular bacilli.

Ad&erse effects of SMAd&erse effects of SM

4 5toto-ity4 5toto-ity 4 (enal to-icity4 (enal to-icity

(esistance(esistance

44 >ene mutation>ene mutation


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'ndication of +ndline treatment

(esistance to the drugs of )stline.

Failure of clinical response

'ncrease of risky effects. Patient is not tolerating the drugs first

line drugs.


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Ethambutol

'nhibits mycobacterial cell %all synthesis byinhibiting arabinosyl transferase .

Bacteriostatic

Acti&e against intrae-tracellular bacilli . 9ell absorbed from gut.

+? e-creted in feces and 7? in urine inunchanged form.

:rosses BBB in meningitis

"sed only in mycobacterial infections.


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Adverse effects

Retrobulbar (otic! neuritis causing loss of

visual acuity and red-green colour

blindness.

"t is relatively contraindicated in children.

#"$ .uset .

%yeruricemia

Ethambutol


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Ethionamide

As isonia;id blocks synthesis of mycolic acid.

A&ailable only in oral form.

Metaboli;ed by the li&er ,e-creted by kidney. 't is poorly tolerated because of

2intense gastric irritation

2neurologic symptoms

2hepatoto-icity

"sed in !B leprosy.


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Careomycin

"t is an imortant in&ectable agent for

treatment of drug-resistant tuberculosis.

"t is nehroto'ic and ototo'ic.

ocal ain ) sterile abscesses may occur.


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Cycloserine

"nhibitor of cell *all synthesis

Cleared renally

$he most serious side effects areeriheral neuroathy and C+,

dysfunction including deression )

sychotic reaction.

Pyrido'ine should be given.

Contraindicated in eiletic atients.


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Amikacin

sed as alternative to stretomycin.

sed in multidrug- resistance tuberculosis.

+o cross resistance bet*een stretomycinand amikacin.


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Ciroflo'acin ) levoflo'acin

Effective against tyical and atyical

mycobacteria.

sed against resistant strains.

sed in combination *ith other drugs.


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Rifaentine

As rifamicin it is R+A olymerase

inhibitor.

Cross resistance *ith rifamicin.

Potent inducer of cytochrome /01.

Effective against tyical and atyical

mycobacteria.


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Aminosalicylic Acid 0PAS1.

Similar in structure to sulfonamide and p2aminoben;oic acid.

Folate synthesis inhibitor.

9ell absorbed from >'!.

9idely distributed in tissues e-cept :SF.


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Retreatment of Tuberculosis

Surgical 'nter&ention ca&ity,Surgical 'nter&ention ca&ity,

!uberculoma, empyema,!uberculoma, empyema,se&ere hemoptysis, ects.se&ere hemoptysis, ects.


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!reatment of !B Disease

!he first rules of !B treatment are


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(egimens of chemotherapy 2 3 4

'$# and (FP are the central agent'$# and (FP are the central agent

of any regimen based on their superiorof any regimen based on their superior

bactericidal acti&ity and lo% to-icitybactericidal acti&ity and lo% to-icity

PGA has special utility in promotingPGA has special utility in promoting rapid, early reduction in bacillaryrapid, early reduction in bacillary

burden8 in drug2susceptible casesburden8 in drug2susceptible cases

PGA need be gi&en only for the initial +PGA need be gi&en only for the initial +

months to produce this effectmonths to produce this effect


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(egimens of chemotherapy 2 3 4


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(egimens of chemotherapy 2 34

Streptomycin 0SM1, parenteral agent,Streptomycin 0SM1, parenteral agent,

has found a diminishing role in modernhas found a diminishing role in modern

therapy due to problems %ith regularlytherapy due to problems %ith regularly

administering intramuscular inectionsadministering intramuscular inections

#o%e&er, for patients %ith &ery#o%e&er, for patients %ith &ery

e-tensi&e tuberculosis, SM maye-tensi&e tuberculosis, SM may

accelerate initial bactericidal acti&ity.accelerate initial bactericidal acti&ity.


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Prevention

Pre&ention of !uberculosis /accination

B:> /accination can obtain immunity

acCuired for tubercle bacillus. !herefore, it is

one of the most important tuberculosispre&ention

/accination target infants children and

youngster of tuberculin negati&e 0&accination

is of course of no use in tuberculin2positi&e

persons1


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5anagement of severe hemotysis

>eneral measures eliminate patient3san-iety, rest in bed

Maintain the air%ays"se of medicines of hemastatic, antitussi&e,

ects.Supporti&e measures keep %ater,

electrolytes and acid2base balance.


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oktober 2010pharmacology of antituberculosis drugs

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