IN THE NAME OF ALLAH

THE MOST GRACIOUS,THE MOST MERCIFUL

 ANTITUBERCULOSIS
DRUGS

DR MUHAMMAD FAROOQUE
MB BS DTCD
CHEST & FEVER HOSPITAL NAJRAN KSA
drfarooq_malik@yahoo.com
WHAT IS TUBERCULOSIS?
 Chronic,
 granulomatous,
 infectious,
 communicable,
 Multisystem,
 curable disease.
 Global burden of
tuberculosis
• 1 out of 3 infected with MTB
• 2 billions in total
• 7th Rank in causes of deaths
• 1 Death every 15 secs.
• 1 Person infected every 1 sec.
• 1 Untreated AFB +ve pt infects 10-15 people
in a year.
• 75% Pts in age group 15-54
• 95% cases in developing world
• 99% of all TB deaths in dvlping world
• Males>>>>females
 History of TB treatment
• PRE-CHEMOTHERAPY • CHEMOTHERAPY
ERA prior to 1950s
ERA
 Controversial and
Dangerous Treatments
• PNEUMOTHORAX treatments
In 1890, the Italian physician
FORLANINI created the lung-collapse therapy.

• THORACOPLASTY. Ribs from one

side of the thorax were removed
• GOLD THERAPY. 1925 by Holger
Mollgaard in Copenhagen
 Safer and Acceptable
Methods
• SANATORIUMS
Hermann Brehmer (1826-
1889) In 1854, he presented
his medical dissertation
Tuberculosis is a Curable
Disease.
• Developing
Vaccines
BCG First
administered to
humans in 1921
• CHEMOTHERAPY
 The study of tuberculosis dates back to
The Canon of Medicine written by Ibn Sina

(Avicenna) in the 1020s

• He was the first physician to

identify pulmonary
tuberculosis as a
contagious disease, the first
to recognise the association
with diabetes, and the first to
suggest that it could spread
through contact with soil and
water.[86][87] He developed
the method of quarantine in
order to limit the spread of
tuberculosis.[88]
 1921 BCG

1943 STREPTOMYCIN

1944 PASA

Late 40s S/M+ PAS

FIRST EDINBURGH
S/M+ PAS MULTIDRUG METHOD
1950 MONO V/S COMBINED TREATMENT

1952 INH SYNTH IN 1912 MADRAS STUDY

SIMILAR RESULTS ACHIEVED IN
BOTH GROUPS SUCCESS
1952 S/M + PAS + INH
CLAIMED UPTO 90%

1954 PZA

PAS+INH
1956 SANATORIUM V/S HOME RX
 1955 CYCLOSERINE

1956 ETHIONAMIDE

1962 ETHUMBUTOL

SM+INH+E
1962 18 M RX
(PAS REPLACED BY E)

1963 RIFAMPICIN

1970s R ADDED TO ATT 9 M RX

1980 PZA ADDED TO ATT 6 M RX

SINCE1970 NO NEW EFFECTIVE DRUG RESISTANT TB ON RISE

 Antituberculosis Drugs
First-Line Drugs Second-Line Drugs
• ISONIAZID • CYCLOSERINE
• RIFAMPIN • P-AMINOSALICYLIC
• PYRAZINAMIDE ACID

• ETHAMBUTOL • ETHIONAMIDE

• STREPTOMYCIN • AMIKACIN OR
KANAMYCIN*
• RIFABUTIN*
• CAPREOMYCIN
• RIFAPENTINE
• LEVOFLOXACIN*
• MOXIFLOXACIN*
• GATIFLOXACIN*
* Not approved by the U.S. Food and Drug Administration for use in the
treatment of TB
 NEW Antituberculosis
Drugs
• ETHUMBUTOL ANALOGUES NIH 241
and SQ109
• ISONIAZID ANALOGUES & DERIVATIVES
• RIFAMYCIN DERIVATIVES RIFABUTIN
Rifalazil
• Quinolones Gatifloxacin Moxifloxacin
New molecules in clinical
trials
• DARQ
• TMC207
• Nitroimidazoles PA-824
•?
•?
•?
•?
 VALIDITY PERIOD & DRUG
PREPARATIONS AVAILABLE
• H--5 YEARS • TABLETS,ELIXIR,AQ;INJ: IM IV
• TABLETS,
• E--5 YEARS
• TABLETS,POWDER
• R--3 YEARS SUSPENSION ,AQ;INJ: IM IV

• Z--3 YEARS • TABLETS,ELIXIR

• S--3 YEARS • ,AQ;INJ: IM

FDCs AVAILABLE

HRZ HR HE HRZE
 STEPWISE APPROACH TO THE
MANAGEMENT OF TB

• SELF ADMINISTERED ATT WITH

MONTHLY F/U
• DOTS
• VOLUNTARY HOSPITALIZATION
• COMPULSORY HOSPITALIZATION
 PATIENT`S NON-
COMPLIANCE/ADHERENCE TO ATT
• A SERIOUS ISSUE
CAUSES
• POVERTY
• HOMELESSNESS
• ALCOHOLISM
• DRUG ADDICTION
• HIV-RELATED ILLNESSES
• LINGUISTIC/ETHNIC DIFFICULTIES
• ILLITERACY
 FACTORS INCREASING
DRUG COMPLIANCE
• DISEASE SYMPTOMS
• KNOWLEDGE ABOUT DISEASE
• FAMILY HISTORY OF TUBERCULOSIS
• HOSPITALIZATION
PROBLEM ON DR`S SIDE
 WHO SHOULD BE
HOSPITALIZED
• PULM SMEAR POSITIVE PT. DURING
INTENSIVE PHASE
• CRITICAL CASE
• COMPLICATED CASES
• OTHERS
 DOTS
• DIRECTLY OBSERVED TREATMENT,SHORT
COURSE
• OPTIMAL WAY TO TREAT TB
• SHORT DURATION ----ADHERENCE TO
TYREATMENT
• RAPID SPUTUM CONVERSION
• HIGH CURE RATE COMPARED WITH LOW COST
• DECREASED COMPLICATIONS OF TB
• DECREASING CHANCE OF EMERGENCE OF DRUG
RESISTANT TB
• DECREASING MORTALITY RATE
: Number of countries implementing DOTS (out of a
total of 211 countries), 1991-
2004.
ADEQUATE SUPPLY OF DRUGS DIAGNOSIS BY M/SCOPY

DIRECTLY OBSERVED TTT

COMMITMENT AT ALL LEVELS

RECORDING AND REPORTING

RATIONALE OF SHORT-COURSE
CHEMOTHERAPY

•WHY MUTIPLE DRUGS?

?WHY NOT MONOTHERAPY?

1. SELECTION OF DRUG RESISTANT
BACILLI
2. FAILURE TO ELIMINATE DISEASE
3. DIFFERENT POPULATION OF AFBs
EACH ONE WITH
DIFFERENT SUSCEPTIBILITY
 AFB
LOW O2
TENSION
INGESTED BY MACROPHAGE NEUTRAL PH
AFB POPULATION IN
ACIDIC PH DON’T
TUBERCULOUS
FAVOUR
LESIONS
RAPID
DIVISION OF
AFB RELEASED
AFB
SLOW
GROWING
PROCESS AFB,<100000/
CONTINUES DVLPMT OF CASEATION
TISSUE

RAPID
FURTHER CASEATION GROWTH OF
CAVITY FORMATION AFB
NEUTRAL PH POP ALMOST
DOUBLES
MUTANT RESISTANT TO S, MUTANT RESISTANT TO
H & E=1/0.1MILLION-10 BILLIONS R =1/10000000

RESISTANT MUTANTS CAN BE SELECTED BY MONOTHERAPY

MULTIPLE DRUG THERAPY AVOIDS SELECTION OF RESISTANT STRAINS
 BASIS OF TREATMENT OF
TUBERCULOSIS
• COMBINATION TREATMENT
• CORRECT DOSAGE
• REGULAR RX.
• FOR A SUFFICIENT PERIOD
• EACH TB PT SHOULD BE TREATED
• FREE OF CHARGE TREATMENT
 AIMS /OBJECTIVES OF TREATMENT
1 2
• Bactericidal Action • Sterilization…of slowly
dividing “”PERSISTERS””
• Fast elimination of Large
AFBs. In cells & caseous
population of rapidly
tissues & closed lesions,
dividing AFBs.in cavities
and
• a need to rapidly kill those
• to kill semi-dormant bacilli
bacilli living extracellularly
living intracellularly in other
in lung cavities, which are
host tissues, otherwise
metabolically active and are
these bacilli may persist
dividing continuously; this is
and will be responsible for
required in order to attain
subsequent TB
the negativization of sputum
and therefore to Prevent Relapses.
further transmission of the
disease.
INH WITH HIGHEST R & Z WITH GREATEST
ACTIVITY STERILIZING ACTIVITY
 AIMS /OBJECTIVES OF TREATMENT
3
• PREVENTION OF DRUG RESISTANCE
AFB COLONY
1 NATURAL MUTATIONS
NATURAL MUTATIONS
RESISTANT MUTANTS MONO
2 SELECTION OF RESISTANT STRAINS BY INADEQUATE TREATMENT THER
APY
SECONDARY
(MULTIPLE)
DRUG –RESISTANT HIV INFECTION
TB INADEQUATE
3 TRANSMISSION IN DROPLETS INFECTION
CONTROL
PRIMARY
DIAGNOSTIC DELAY
(MULTIPLE)
DRUG –RESISTANT
TB DEVELOPMENT AND SPREAD OF MDR
 principals of current short course
chemotherapy

• Rapidly multiplying extra-cellular

AFBs-------KILLED by H>>>>>R & S
• Slowly growing AFBs in cells & caseous
lesions (( THE PERSISTERS)) are
STERILIZED by H + R + Z (E----
B` static )
• FAILURE TO ACHIEVE STERILIZATION
MEANS---------------------------RELAPSE
 PRINCIPLES OF MODERN CHEMOTHERAPY OF
TUBERCULOSIS
H-R-S R-H-Z

SLOWLY
MULTIPLYING
ACTIVELY
INTRACELLULAR
MULTIPLYING
INAD & IN CLOSED
EXTRACELLULAR
EQU CASEOUS *INADE
AFB
ATE LESIONS QUATE
RX: RX:
*LATE
ADEQUATE RX: ADEQ RX: GROWT
BACTERICIDAL ACTION STERILIZING H
ACTION OF
PERSIS
ELIMINATION ELIMINATION OF TERS
OF EC AFB PERSISTERS
RX:
LASTING
FAILURE
CURE OF
TB RELAPSE
 PHASES OF TREATMENT

•INITIAL INTENSIVE PHASE •CONTINUATION PHASE

• 2-4 MONTHS • 4-7 MONTHS

• 3 OR MORE DRUGS • 2-3 DRUGS
• HRZES • RHE
• RAPID KILLING OF AFB • DORMANT AFBs
• CONVERSION TARGETTED
ACHIEVED • PREVENTION OF
RECURRENCE
 HEALTH EDUCATION
• FOR PATIENTS
• FOR RELATIVES
 HEALTH EDUCATION
CONTD;
• NO INTERRUPTION IN TREATMENT
• SWALLOW MEDS EMPTY STOMACH
• REGULAR FOLLOW-UPS
• CONSULT PHYSICIAN IF YOU NEED TO USE OTHER MEDS
• NO SMOKING
• NO ADDICTION
• ENSURE AVAILABILITY OF SUFFICIENT AMOUNTS OF
DRUGS.
• VACCINATE YOUR CHILDREN
• CONTACT EXAMINATION
• GOOD HEALTHY LIVING CONDITIONS
• PERSONAL CLEANLINESS
• IFORM IF CHANGE ADDRESS
 TREATMENT CATEGORIES
CAT 1 CAT 2 CAT 3 CAT 4
2HRZS(S)E/ 2HRZSE/ 2HRZ/4HR SECOND
4HR 1HRZE/ OR LINE ATT
NEW SMEAR 5HRE 2HR/6HE CHRONIC
POS RELAPSE NEW SMEAR CASES
SEV PULM CASES NEG (NON- DRUG
NEG. TREATMENT SEV) RESISTANT
SEV EPTB FAILURE CASES
EPTB (NON
CRITICAL)
 DOSAGES OF 1st. LINE ATT / DAY
DRUGS ADULT DOSE PEDIA DOSE

H 5mg/kg MAX:300mg 10-20mg/kg

MAX:300mg
E 15-25mg/kg 15-25mg/kg
MAX:2500mg MAX:2500mg
Not recmnd
<6yrs.
Z 15-30mg/kg 15-30mg/kg
MAX:2000mg MAX:2000mg
R 40-55kg:::450mg 10-20mg/kg
>55kg:::600mg MAX:600mg
S 15mg/kg 15mg/kg
 DOSAGES OF 2nd. LINE ATT / DAY
DRUGS ADULT DOSE PEDIA DOSE
THIACETAZONE
150mg 4mg/kg
PAS 10-20g 300mg/kg
ETHIONAMIDE <50 kg::750mg
>50kg::1g.
CYCLOSERINE 15-20mg/kg 10-20mg/kg
MAX:600mg
KANAMYCIN 15mg/kg 15-20mg/kg
 HOW TO ADMINISTER
ATT
• ALL DRUGS TAKEN IN FASTING 30
MIN. BEFORE BREAKFAST
• SWALLOWING OF ATT SHOULD BE
OBSERVED
 ATT

SYMPTOMS
ASSESS SIGNS
TREATMENT WEIGHT
RESPONSE CXR
BACTERIOLOGY

ADVERSE V/A
REACTIONS CBC
MONITORING UA
LFT
CLIN.EXAM
 RIFAMPICIN. {RIF} [R]
• Semi-synthetic, broad-spectrum bactericidal antibiotic.
• Activity against staph, strep, clostridium,coliforms, pseudomonas,
proteus, salmonella, shigella, bacteroids, legionella.
• Completey absorbed from GIT
• Partly deacylated in LIVER
• Taken on an empty stomach
• 75% protien bound
• Therapeutic conc; achieved CSF when meninges r inflammed
• Excretion entirely in BILE
• Enterohepatic circulation exists
• Some Rif appear in urine.
• DOSE 10 MG/KG/DAY
 RIFAMPICIN

MECHANISM OF ACTION

• Intra and extra-cellular bactericidal

activity
• Rifampicin inhibits DNA-dependent
RNA polymerase in bacterial cells by
binding its beta-subunit, thus
preventing transcription to RNA and
subsequent translation to proteins
 Adverse effects of
Rifampicin
• Orange-pink color of body fluids
• Nausea
• Anorexia
• Mild abdominal pain
• Vomiting
• Diarrhoea
• Transient rise in AST
• Hepatitis with jaundice
 Adverse effects of
Rifampicin contd:
• Cutaneous reactions
• Flushing with or without itching
• Rash
• Sev.conjunctivitis
• Ch;papular acneform reactions of head and neck
• Osteomalacia
• Pseudomembranous colitis
• Pseudoadrenal crisis
• Light chain proteinuria
• Renal failure
• Cutaneous vasculitis
 Adverse effects of Rifampicin
contd:
seen mostly with intermittent
therapy
• Flu syndrome
• Thrombocytopenic purpura
• Asthmatic And hypotensive
syndromes
• Acute hemolytic anemia
• Acute tubular necrosis
 RIFAMPICIN: ADVERSE
EFFECTS

Nothing to worry Reassure the pt;

 RIFAMPICIN
GIT REACTIONS
• Nausea
• Anorexia
• Mild abdominal pain
• Vomiting
• diarrhoea
•OCCURS IN < 5%.
•COMMON IN ELDERLY
•DRUG MAY BE ADMINISTERED AT NIGHT
•OR IF THIS FAILS DURING A MEAL
 RIFAMPICIN
ADVERSE EFFECTS WHICH NEED
INTERVENTION
PROBLEM SOLUTION

3x rise IN AST STOP R

Rise in bilirubin---------- STOP R

JAUNDICE
RESPIRATORY SYNDROME STOP R
CONSISTING OF
SOB,COLLAPSE,SHOCK
PURPURA STOP R
AC HAEMOLYTIC ANAEMIA
SHOCK
RENAL FAILURE
Reduced hepatic uptake of bilirubin

(Unconjugated )
INDIRECT HYPERBILIRUBINEMIA
 RIFAMPICIN: ADVERSE
EFFECTS

CUTANEOUS VASCULITIS CONJUNCTIVITIS

RIFAMPICIN: ADVERSE
EFFECTS
THROMBOCYTOPENIC PURPURA
Rifampicin induced rashes
RIFAMPICIN: ADVERSE
EFFECTS
OSTEOMALACIA PSEUDOMEMBRANOUS COLITIS
 Rifampicin adverse effects & drug
interactions
• Potent liver enzyme inducer
• Increase metabolism of certain drugs
administered concurrently
• Decreases half lives of certain drugs
 RIFAMPICIN::DRUG INTERACTIONS
DRUGS AFFECTING RIF DRUGS AFFECTED BY RIF
• RITONAVIR::PI • PI
• EFAVIRENZ::ANTIRETR • NNRTI
OVIRAL • Atovaquone
• CLOFAZIMINE • azathioprine
• , chloramphenicol,
cyclosporine,
• cimetidine,
• clofibrate,
• corticosteroids,
coumarin
anticoagulants,
• dapsone,
 DRUGS AFFECTED BY RIF
• methadone, • diazepam
ondansetron, • and other
• oral hypoglycemics, benzodiazepines,
phenytoin, • doxycycline,
• quinine, fluconazole,
• rofecoxib, • haloperidol,
• statins, hexobarbital,
• sulphasalazine, itraconazole,
tacrolimus, • ketoconazole,
• the bronchodilator lamotrigine,
• theophylline,
•
 DRUGS AFFECTED BY RIF
• thyroid hormones, • antiarrhythmics such as
• and several disopyramide,
cardiovascular drugs • lorcainide,
including beta • mexiletine,
• blockers, • propafenone,
• digitalis • quinidine,
• alkaloids and • tocainide, and
• verapamil and
• other calciumchannel
• blockers
 Rifampicin drug interactions
INTERACTION Mech POTENTIAL Solution
WITH CONSEQUENCES
Warfarin INC METABOLISM THRU Clot formation MONITOR DRUG
ENZYME INDUCTION LEVELS
OCD INC METABOLISM THRU pregnancy MONITOR DRUG
ENZYME INDUCTION LEVELS
USE ALTERNATE
CYCLOSPORINE / INC METABOLISM THRU rejection
TACROLIMUS ENZYME INDUCTION

HIV-1 PROTEASE inc viral load resistance AVOID USE

INHIBITORS

NNRTI inc viral load resistance

GLUCOCORTICOI ACCELERATED POTENTIAL ADRENAL INC DOSE

DS METABOLISM CRISES
LOOS OF DTEROID
EFFECT
METHADONE withdrawal
DIGOXIN INC METABOLISM THRU subtherapeutic level MONITOR DRUG
ENZYME INDUCTION LEVELS
 Rifampicin drug interactions
interaction with mech Potential solution
consequences
itraconazole Inc metabolism Subtherapeutic
thru enzyme levels
induction

phenytoin Inc metabolism Loss of seizure

thru enzyme control
induction

statins Inc metabolism hypercholester

thru enzyme olemia
induction

diltiazim Inc metabolism Subtherapeutic

thru enzyme levels
induction

verapamil Inc metabolism Subtherapeutic

 RIFAMPICIN
RESISTANCE
• RESISTANCE RESULTS FROM
SPONTANEOUS POINT MUTATIONS
THAT ALTER BETA subunit OF RNA
POYMERASE GENE.
• RIFAMPIN-RESISTANT BACTERIA
PRODUCE RNA POLYMERASES WITH
SUBTLY DIFFERENT Β SUBUNIT
STRUCTURES WHICH ARE NOT
READILY INHIBITED BY THE DRUG
 INH
MECHANISM OF ACTION
• BACTERIOSTATIC AGAINST RESTING
AFBs.
• BACTERICIDAL AGAINST RAPIDLY
MULTIPLYING AFBs, BOTH
EXTRACELLULARLY AND
INTRACELLULARLY.
• IT INHIBITS MYCOLIC ACID-WALL
SYNTHESIS VIA O2-DEPENDENT
PATHWAY
 INH
PHARMACOLOGY
• ROUTE….PO, PARENTAL
• DOSE…….ADULTS-----5mg/kg/day.
CHILDREN------10-20mg/kg/day.
MAX:300mg/day
 INH
ADVERSE EFFECTS
• HEPATOTOXICITY
• PERIPHERAL NEUROPATHY
• RASH
• FEVER
• ANEMIA
• ACNE
• ARTHRITIC SYMPTOMS
• SLE-LIKE SYNDROME
• OPTIC ATROPHY
• SEIZURES
• PSYCHIATRIC SYMPTOMS
INH: ADVERSE EFFECTS

OPTIC NEURITIS LUPUS REACTION SEC TO INH

INH: ADVERSE EFFECTS

AGRANULOCYTOSIS HEMOLYTIC ANEMIA IN G6PD DEF

 INH CAUSES
PELLAGRA-LIKE
SYNDROME IN
NICOTINE-DEFICIENT PTS
 INH
ADVERSE EFFECTS CONTD;
INH-ASSOCIATED HEPATITIS
• IDIOSYNCRATIC
• INCREASES WITH AGE
• RISK INCREASED BY
DAILY ALCOHOL CONSUMPTION,
CONCOMITANT USE OF RIFAMPICIN
SLOW INH ACETYLATION
• MONITOR LIVR ENZYMES
 INH
ADVERSE EFFECTS CONTD;
PERIPHERAL NEUROPATHY
• DOSE-DEPENDENT
• INTERFERENCE WITH PYRIDOXINE
METABOLISM
• CAN BE REDUCED WITH
PROPHYLACTIC USE OF 10-50mg/day
OF PYRIDOXINE
 INH
RESISTANCE
• AMINO ACID CHANGES IN THE CATALASE-
PEROXIDASE GENE (katG) OR A TWO-
GENE LOCUS KNOWN AS inhA
• MISSENSE MUTATIONS OR DELETION OF
katG ALSO ASS WITH REDUCED
PEROXIDASE AND CATALASE ACTIVITY
• PRIMARY RESISTANCE EXISTS >>>>7%
INH DRUG INTERACTIONS
DRUGS AFFECTING INH DRUGS AFFECTED BY INH

• ALCOHOL • CARBAMAZEPINE,
• ALLUMINIUM • ETHOSUXIMIDE
CONTAING • AND PHENYTOIN,
ANTACIDS • BENZODIAZEPINES,
• FOODS SUCH AS AND
FISH CHEESE RED • CHLORZOXAZONE.
WINE MAY
INCREASE INH S/E
 PYRAZINAMIDE
PHARMACOLOGY
• BACTERICIDAL
• WELL ABSORBED ORALLY
• GOOD CSF PENETRATION
 PYRAZINAMIDE
MECH; OF ACTION
• IT INHIBITS MYCOLIC ACID-WALL
SYNTHESIS VIA O2-DEPENDENT PATHWAY
• BACTERICIDAL TO SLOWLY METABOLIZING
ORGANISM LOCATED WITH IN THE ACIDIC
ENVIRONMENT OF PHAGOCYTES OR
CASEOUS GRANULOMA
• ACTIVE ONLY AT A pH OF<6.0
• IT’S A PRODRUG AND CONVERTED BY
AFBs TO PYRAZINOIC ACID …
PYRAZINAMIDE ADVERSE EFFECTS
• HEPATOTOXICITY
• HYPERURICEMIA
• GOUT
• POLYARTHRALGIA
• SKIN RASHES
PZA INDUCED DERMATITIS
PZA
A/E
 PYRAZINAMIDE
RESISTANCE
• ASS; WITH LOSS OF
PYRAZINAMIDASE ACTIVITY
• SO NO MORE CONVERSION OF PZA
TO PYRAZINOIC ACID
PZA DRUG INTERACTION
• PROBENECID MAY BLOCK
EXCRETION OF PZA & URATE
EXCRETION AFFECTED
• ZIDOVUDINE DEC: PZA LEVELS
 ETHUMBUTOL
MECH; OF ACTION
• BACTERIOSTATIC AGAINST RAPIDLY
GROWING AFBs
• IT INHIBITS
ARABINOSYLTRANSFERASES THAT
MEDIATE THE POLYMERIZATION OF
ARABINOSE INTO ARABINOGALACTAN
WITHIN CELL WALL.
• PRIMARY USE IS TO PREVENT
EMERGENCE OF RESISTANCE
 ETHUMBUTOL
PHARMACOLOGY
• AFTER ORAL ADMN; 75-80% OF DOSE IS
ABSORBED FROM GIT.
• LOW CSF PENETRATION
• EXCRETION BY KIDNEYS
• DOSE:15-25mg/kg/day
• BE CAUTIOUS!!!!! IN RENAL INSUFFICIENCY
….DECREASE THE DOSE
• AVOID IN CHILDREN AND MENTALLY
HANDICAPPED
 ETHUMBUTOL
ADVERSE EFFECTS
• RETROBULBAR NEURITIS-------AXIAL OR
CENTRAL IT INVOLVES
PAPPULOMACULAR BUNDLE OF FIBRES
AND RESULTS IN
REDUCED V/A
CENTRAL SCOTOMA
LOSS OF ABILITY TO SEE GREEN
• HYPERURICEMIA
OPTIC NEURITIS
ETHUMBUTOL INDUCED RASHES
 ETHUMBUTOL
RESISTANCE
• RELATED WITH MISSENSE MUTATIONS
IN THE embB GENE THAT ENCODES
FOR ARABINOSYLTRANSFERASE.
 ETHUMBUTOL
DRUG INTERACTION
• ALUMINUM HYDROXIDE-CONTAINING
ANTACIDS may reduce the
absorption of EMB up to a 20 %.
These compounds should be taken at
least two hours after the ingestion of
EMB to avoid interaction.
 STREPTOMYCIN
• In 1946, Dr Selman Abraham
Waksman announced his
discovery of streptomycin, the
first specific antibiotic effective
against tuberculosis. In 1943,
he had isolated streptomycin
from a mold he had known and
studied early in his life. For this
work, he was awarded the 1952
Nobel Prize.«
 STREPTOMYCIN
PHARMACOLOGY
• BACTERICIDAL FOR RAPIDLYDIVIDING
EXTRACELLULAR MYCOBACTERIA
• ITS INEFFECTIVE IN ACIDIC ENVIRONMENT
WITHIN MACROPHAGES
• DIFFUSE POORLY INTO THE MENINGES IN
MENINGITIS REACHES 20%OFSERUM LEVELS
• Dose10-15mg/Kg/Day (0.5-1.0 grams)
• CAUTION IN OLD AGE AND RENAL IMPAIREMENT
 STREPTOMUCIN
MECHANISM OF ACTION
• INHIBITS PROTEIN SYNTHESIS BY
DISRUPTION OF RIBOSOMAL
FUNCTION.
 STREPTOMYCIN
ADVERSE EFFECTS
OTOTOXICITY
• V111 CN DAMAGE
• VESTIBULAR COMMON
THAN AUDITORY
DAMAGE
• GIDDINESS
• LOSS OF BALANCE
• VERTIGO
• TINNITUS
• HEARING LOSS
• NYSTAGMUS
• OTOTOXIC TO FETUS
 STREPTOMYCIN
ADVERSE EFFECTS
NEPHROTOXICITY
• RENAL TUBULAR
DAMAGE
• NEPHROTOXICITY
NONOLIGURIC
RENAL FAILURE
 STREPTOMYCIN
ADVERSE EFFECTS
BLOOD DYSCRASIAS
• HAEMOLYTIC ANAEMIA
• APLASTIC ANAEMIA
• AGRANULOCYTOSIS
• THROMBOCTOPENIA
 STREPTOMYCIN
ADVERSE EFFECTS
CONTD:
• ANAPHYLAXIS
• PERIORAL PARESTHESIA
• EOSINOPHILIA
• RASH
• DRUG FEVER
• POTENTIATES N-M BLOCKING EFFECT OF
CURARE……
CONTRAINDICATED IN MYSTHENIA GRAVIS
AGRANULOCYTOSIS EOSINOPHILIA

THROMBOCYTOPENIA THROMBOCYTOPENIA
 STREPTOMYCIN
RESISTANCE
• MUTATIONS IN ONE OF THE TWO
TARGETS INVOLVED IN RIBOSOMAL
BINDINGS
• 16S rRNA GENE (rrs)
• GENE ENCODING RIBOSOMAL
PROTIEN S12 (rpsL)
 STREPTOMYCIN
DRUG INTERACTION
• The administration of SM with other
nephrotoxic drugs, including other
aminoglycosides, vancomycin, and
some of the cephalosporins, or
potentially ototoxic drugs such as
ethacrynic acid or frusemide should
be avoided since this could increase
the risk of toxicity.
 GENERALIZED REACTIONS TO ATT

• GENERALIZED HYPERSENSITIVITY REACTION

• COMMON IN 2nd TO 4th. WEEK OF ATT
• USUAL MANIFESTATIONS ARE
FEVER & RASH

ANAPHYLAXIS
ERYTHEMATOUS PERIORBITAL SWELLING
MACULAR GEN; LYMPHADEN
APULAR HEPATOSPLENO
ITCHY MEGALY
PROMINENT ON ENCEPHALITIS
EXPOED PARTS RIGORS
EXF; DERMATITIS HIGH FEVER
STEVENS-JOHNSON ACUTE MYOCARDITIS
SYND PULM EOSINOPHILIA
 GENERAL MANAGEMENT OF
GENERALIZED REACTIONS
REACTION ACTION ABOUT ATT
MINOR ANTIHISTAMIN CONT
RASHES E

RASHES NOT ANTIHISTAMIN STOP

SUBSIDING E+ CURRENT ATT
CALAMINE IF
LOTION NECCESSORY
START 2 NEW
DRUGS
 GENERAL MANAGEMENT OF
GENERALIZED REACTIONS CONTD:
REACTION ACTION ABOUT ATT

SEV;ILLNESS + ADD STEROIDS STOP ATT

HYPOTENSION OR
EXFOLIATIVE
DERMATITIS

•WAIT FOR THE REACTION TO SUBSIDE

•IDENTIFY OFFENDING DRUGS
•DESENSITIZE
ANTI TUBERCULOSIS
DRUGS IN SPECIAL
SITUATIONS
 Hepatic disease
• Isoniazid, Pyrazinamide and Rifampicin cause hepatotoxicity in
patients with liver disease.

• In patients with normal liver, if liver enzymes increase more than 2

folds and/or bilirubin increase above normal range you have to stop the
hepatotoxic drugs (INH, RMP, PZA).
• Then try to reintroduce one by one starting with INH with close
monitoring of liver function tests.
( 2 SHER / 6 HR )
• If major hepatotoxicity occur with short term chemotherapy regimens
used the following: - EMB + SM + PAS or INH for 3 months
- Followed by 15 months of 2 oral drugs (EMB +PAS or INH)
 Renal disease
(Uremia and End-Stage Renal Disease)

• Rifampicin (RMP) is the safest as it is excreted

entirely in bile in complete renal failure so it is
given in standard dosage.

• INH - in mild to moderate disease : give

standard dosage
- in severe renal disease : give 200 mg - B6 is
given in a dose of 100mg daily
• Pyrazinamide (PZA): Two schools
1- standard dosage
2- others: less dose 15-20 mg/kg

• Streptomycin (SM):
- If creatinine clearance is less than 50
ml/min, give SM 0.25gm for 3 days per
week.
- If on regular dialysis, give 0.75 gm. 4-6
hours before dialysis.
• Pyrazinamide (PZA): Two schools
1- standard dosage
2- others: less dose 15-20 mg/kg

• Streptomycin (SM):
- If creatinine clearance is less than 50
ml/min, give SM 0.25gm for 3 days per
week.
- If on regular dialysis, give 0.75 gm. 4-6
hours before dialysis.
 PREGNANCY AND TUBERCULOSIS

Considerations for the fetus and infant

• Congenital transmission of TB is rare and

occur when placenta is actively infected.

• TB confined to thorax or to lymphadenitis has

little risk to the fetus.
• Streptomycin is ototoxic to the fetus so avoid in
pregnancy.
• Treatment : Drug which are not teratogenic
are: INH, RMP, EMB.
Regimen is : INH + RMP + EMB for 2 months
INH + RMP for 7 months
• PZA can be used if there is drug resistance or
HIV.