A FIGHT AGAINST DEADLY DISEASE

PRESENTED TO:PRESENTED TO:

Presented by:Presented by:

Ayesha MumtazAyesha Mumtaz Fatima ShababFatima Shabab Adeela AtiqAdeela Atiq Rizwana RaheelRizwana Raheel

DP 305-901DP 305-901 DP 305-902DP 305-902 DP305-903DP305-903 DP305-904DP305-904

Parameters to be discussedParameters to be discussed

Name of drugName of drug Chemical dataChemical data Administration dataAdministration data PharmacokineticsPharmacokinetics PharmacodynamicsPharmacodynamics IndicationsIndications ContraindicationsContraindications PrecautionsPrecautions

Contd……Contd……

InteractionsInteractions Adverse effects Company dataAdverse effects Company data Research dataResearch data Marketing informationMarketing information

TUBERCULOSISTUBERCULOSIS

History:

Tuberculosis was first formally described by Greek physician Hippocrates around 460 B.C.E.

Introduction.

TB, or tuberculosis, is a disease caused by bacteria called Mycobacterium tuberculosis. The bacteria can attack any part of your body, but they usually attack the lungs.

Site of infection of TBSite of infection of TB

Types of tuberculosis

Asymptomatic TBAlso known as LATENT TB

Symptomatic TBKnown as TB DISEASE

Symptoms:Symptoms:

Pain in the chest Pain in the chest Coughing up blood or sputum Coughing up blood or sputum

(phlegm from deep inside the lungs) (phlegm from deep inside the lungs) A bad cough that lasts longer than 2 A bad cough that lasts longer than 2

weeksweeksOther symptoms of TB disease are Other symptoms of TB disease are Weight loss Weight loss

Contd……….Contd……….

no appetite no appetite chills chills fever fever sweating at night sweating at night weakness or fatigueweakness or fatigue

Tests for identification of Tests for identification of TB:TB:

Chest x-rayChest x-ray Mantoux testMantoux test

Treatment strategies

ANTITUBERCULAR DRUGS

Isoniazid (INH)RifampinEthambutolPyrazinamide

Recommended Drugs for the Initial Treatment of Tuberculosis in Children and Adults

  Daily Dose\ *

Maximal

Daily Dose in Childre

n and

Adults

Twice Weekly Dose

Drug Children Adults Children

Adults

Isoniazid 10 to 20 mg/kg

PO or IM

5 mg/kg PO or IM

300 mg 20 to 40 mg/kg Max.

900 mg

15 mg/kg Max. 900 mg

Rifampin 10 to 20 mg/kg

PO

10 mg/kg PO

600 mg 10 to 20 mg/kg Max.

600 mg

10 mg/kg Max. 600 mg

Pyrazinamide 15 to 30 mg/kg

PO

15 to 30 mg/kg

PO

2 g 50 to 70 mg/kg

50 to 70 mg/kg

Ethambutol 15 to 25 mg/kg

PO

15 to 25 mg/kg

PO

2.5 g 50 mg/kg

50 mg/kg

Chemical structures of antitubercular drugs

Rifampin isoniazid

ethambutol pyrazinamide

Dosage form available

Capsule

Tablet

injections

Syrup

Powder for injections

Administration DataAdministration Data

IsoniazidIsoniazid RifampinRifampin PyrazinamidePyrazinamide EthambutolEthambutol

Oral, IM, IVOral, IM, IV Oral, IVOral, IV OralOral OralOral

Origin of antitubercular drugsOrigin of antitubercular drugs

All the four drugs are synthesized All the four drugs are synthesized chemicallychemically

Pharmacodynamics

Mechanism of action

catalase-peroxidase enzyme katG

INH

Isonicot-inic acyl anion

NADH radical or anion

isonicotinic acyl-NADH complex

ketoenoylreductase

enoyl-AcpM substrate

mycolic acid

Cell lysis

MOA of Isoniazid

Bacteria

Rifampin

translation

Cell deathtranscripti

on

prokaryotic DNA-dependent RNA polymerase

RNAPROTEIN

MOA of Rifampin

pyrazinamide

Pyrazinamidase

Pyrazinoic acid

fatty acid synthetase I

Short chain fatty acid precursors

MOA of Pyrazinamide

Arabinosyl transferase

Mycobacterial Arabinogalactan Cell Wall

ETB

Bacteria

Mycolic acid

Ethambutol

MOA of Ethambutol

IndicationsIndications

INH

Rifampicin

Ethambutol OR

Pulmonary extrapulmonarytuberculosis T.b prophylaxis

Pyrazinamide

Indications of IsoniazidIndications of Isoniazid

Pulmonary Tuberculosis LeprosyMeningitidisMRSAGram_,+veBacteriachlamydial activity Virusesbrucellosis.

Rifampin

isoniazid rifampin

Ethambutol rifampin

isoniazid, ethambutol rifampin

Indications of RifampinIndications of Rifampin

Pyrazinamide

Active tuberculosis

isoniazid, rifampin pyrazinamide

2 Month regimen

4 Month regimen

isoniazid and rifampin

6 Month regimen

Indications of PyrazinamideIndications of Pyrazinamide

Ethambutol

continuation phase of tuberculosis

Ethambutol

Isoniazid

TabletCategory I

category III

Indications of EthambutolIndications of Ethambutol

Contraindications of Antitubercular Contraindications of Antitubercular drugsdrugs

pregnancy

Contd….Contd….

PharmacokineticsPharmacokinetics

PharmacokineticPharmacokineticNAME OF DRUG

BIOAVAILABILITY

HALF LIFE

METABOLISM

PROTEIN BINDING

VOL D EXCRETION

ISONIAZID _

0.5-1.6 hours

liver 0-10% 0.57-0.76 L/kg

Urine &Feces

RIFAMPIN 90-95% 6-7 hours

Hepatic and Intestinal wall

_ 1.6 L/kg Renal & Faecal

ETHAMBUTOL

Absorbed from GIT

3-4 hours

Liver 20-30% 1.6 L/kg Renal

PYRAZINAMIDE

>90% 9-10 hours

Hepatic _ 0.57-0.74 L/kg

Renal

Drug InteractionsDrug Interactions

Interactions of Isoniazid

Enflurane

Warfarin

Antacids

Benzodiazipine

Rifampin

Phenytoin

ISONIAZID

Interactions of Pyrazinamide

ProbenecidProbenecid

AcetestKetostix

test

AcetestKetostix

test

AllopurinolAllopurinolOfloxacinlevofloxacinOfloxacin

levofloxacin

Urinary ketone Deamination

test

Urinary ketone Deamination

test PYRAZINAMIDEPYRAZINAMIDE

warfarin steroids

Digoxin

RIFAMPIN

Interactions of Rifampin

RifampinUricosuric

agents

Antacids

ETHAMBUTOL

Interactions of Ethambutol

ADVERSE EFFECTSADVERSE EFFECTS

Blurred vision hepatotoxic seizuresBlurred vision hepatotoxic seizures

decreased apetitedecreased apetite

PrecautionsPrecautions

Protect from light Protect from light and moisture. and moisture.

Concurrent use of Concurrent use of any chronically any chronically administered administered medication is medication is prohibited. prohibited.

Injection drug Injection drug should be carefully should be carefully usedused

Marketing informationMarketing information

Marketing informationMarketing information

Tb is distributed throughout the worldTb is distributed throughout the world But is more frequent in underdeveloped But is more frequent in underdeveloped

countries due to lack of awareness.countries due to lack of awareness. In Pakistan it was abolished in mid 19s, but due In Pakistan it was abolished in mid 19s, but due

to development of multidrug resistant bacterias to development of multidrug resistant bacterias it has reoccured in Pakistan.it has reoccured in Pakistan.

So, these drugs are used worldwide. So, these drugs are used worldwide. It is It is INTERNATIONALLY RECOMMENDED TO INTERNATIONALLY RECOMMENDED TO

USE THESE DRUGS IN COMBINTIONS.USE THESE DRUGS IN COMBINTIONS.

Contd….Contd….

In Pakistan these drugs are produced by:In Pakistan these drugs are produced by:

SANDOZ PHARMACEUTICAL COMPANYSANDOZ PHARMACEUTICAL COMPANY Wilsons pharmaceutical companyWilsons pharmaceutical company

Worldwide, these drugs are distributed byWorldwide, these drugs are distributed by LARK LABORTARIES INDIA.LARK LABORTARIES INDIA.

Company DataCompany Data

Brand NamesBrand Names

DRUGSDRUGS BRAND BRAND NAMENAME

DOSEDOSE DOSAGEDOSAGE

FORMFORMCOMPANYCOMPANY

ISONIAZISONIAZIDID

I.N.HI.N.H

SONOREXSONOREX100m100mgg

5mg/5mg/5ml5ml

TABLETTABLET

SYRUPSYRUPIRZAIRZA

REXREX

RIFAMPIRIFAMPINN

RIFAMPRIFAMP 150m150mgg

CAPS.CAPS. LISKOLISKO

PYRAZINPYRAZINAMIDEAMIDE

PYRAZINAPYRAZINAMIDEMIDE

500m500mgg

TABLETTABLET WYETHWYETH

LISKOLISKO

ETHAMUETHAMUTOLTOL

U-BUTOLU-BUTOL 400m400mgg

TABLETTABLET UNEXOUNEXO

Combination of ATT-DrugsCombination of ATT-DrugsDRUGSDRUGS BRAND BRAND

NAMENAMEDOSEDOSE DOSAGE DOSAGE

FORMFORMCOMPANYCOMPANY

INH&RIFINH&RIFAMPINAMPIN

RIFAMATERIFAMATE-INH-INH

450m450mgg

TABLETTABLET WILSHIREWILSHIRE

RIAMPIN, RIAMPIN, INH&PYRINH&PYRAZINMIDAZINMIDEE

PYRATARPYRATAR -- TABLETTABLET UNEXOUNEXO

ETB.INH-ETB.INH-RIFAMYCRIFAMYCININ

CYREXCYREX

MYRINMYRIN - -

--TABLETTABLET

TABLETTABLETREXREX

WYETHWYETH

Research DataResearch Data

Clinical trialsClinical trials

CLINICAL TRIALS

• Objective:

To assess the severity and frequency of hepatotoxicity caused by different antituberculosis (ATT) drugs and to evaluate whether concurrence of risk factors influence the antituberculosis drug induced hepatotoxicity.

Hepatotoxicity:

Normalization of liver function after withdrawal of all anti-tuberculosis drugs, and the presence of at least one of the following criteria:

appearance of jaundice a rise in the level of serum total

bilirubin > 1.5mg/dl.

Reported risk factors for hepatotoxicity include:

older age, female sex, poor nutritional status, high alcohol intake, advanced tuberculosis,inappropriate use of drugs and acetylator status

Patient Selection

This prospective cohort study was conducted in:

Medical Unit-V and Out Patient Department of Civil Hospital,

Karachi, from 15 July 2004 to 14 July 2005

Total 393 patients selected males were 183 (53.98%) and female 156 (46.02%) included

who were prescribed to receive anti tuberculosis drugs for pulmonary or extra pulmonary tuberculosis.

393 PTS.With

Active TBInfection and

with:

Normal liver clinical

And Biochemical

tests

ExperimentExperiment

ISONIAZID5mg/kg/day

RIFAMPIN10mg/kg/day

PYRAZINMIDE20-25mg/kg/day

67 Pts. Developed hepatitis

Concomitant use ofAlcohol

Paracetamol

ATT-INDUCED

LIVER

INJURY

Conclusion:Conclusion:

ATT-induced hepatitis is significantly more ATT-induced hepatitis is significantly more frequent and more severe in patients with frequent and more severe in patients with hepatotoxicity risk factors.hepatotoxicity risk factors.

ReferencesReferences

http://www.doctorslounge.com/infections/http://www.doctorslounge.com/infections/drugs/antibiotics/antitubercular/drugs/antibiotics/antitubercular/

http://www.thesynapticleap.org/node/118http://www.thesynapticleap.org/node/118http://gateway.nlm.nih.gov/http://gateway.nlm.nih.gov/

MeetingAbstracts/ma?f=102265766.htmlMeetingAbstracts/ma?f=102265766.htmlhttp://www.liebertonline.com/doi/abs/http://www.liebertonline.com/doi/abs/

10.1089/1096620026039820610.1089/10966200260398206http://www.freepatentsonline.com/http://www.freepatentsonline.com/

7001893.html7001893.html