Anti-tubercular drugs Prof. - PowerPoint Presentation

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Anti-tubercular drugs

Prof.

Anuradha

Nischal

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Deadly infectious disease caused by MYCOBACTERIUM TUBERCULOSIS

Affects the 

lungs but can also affect other parts of the body.

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It is currently estimated that 1/2 of the world's population (3.5 billion) is infected with Mycobacterium

tuberculosis.

Epidemiology

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Pulmonary

tuberculosis

Droplets

Patients with the active disease (bacilli) expel them into the air by:

coughing

sneezing

Transmission

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Signs & symptoms

A bad

cough

that lasts 3 weeks or longer

Coughing up

blood or sputum (phlegm from deep inside the lungs)Fever

Weakness or fatigue

Weight lossAnorexiamailaisePain in the chest

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Group 1/First line drugs include:

ISONIAZID RIFAMPICIN

PYRAZINAMIDE

ETHAMBUTOL

most potent and best tolerated oral drugs

HIGH EFFICACY AND LOW TOXICITY

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Group 2/

Injectable

ATDs

Streptomycin

Kanamycin Amikacin Capreomycin

potent, bactericidal, but injectable drugs

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Group 3/Flouroquinolones

Ofloxacin Levofloxacin Moxifloxacin

Ciprofloxacin(resistance) so removed

potent bactericidal well tolerated oral drugs.

MDR

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Group 4/Second line oral drugs include:

ETHIONAMIDE PROTHIONAMIDE

CYCLOSERINE

TERIZODONE

p-AMINOSALICYLIC ACID

less effective, bacteriostatic, more toxic drugs for resistant tuberculosis

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Group 5/Drugs with unclear efficacy

Thiacetazone Clarithromycin

Clofazimine

Linezolid Amoxicillin/clavulanate

Imipenem/

cilastin Drugs with uncertain efficacy, may be used for XDR

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ISONIAZID[H]

Cheapest ATD

Mycobactericidal

Bactericidal for rapidly growing bacilli

Quiscent

ones are only inhibitedExtra and intracellular bacilli

Equally active in acidic & alkaline medium.

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MOAInhibits

mycolic

acids synthesis (unique

component MBCW)

High

selectivity for mycobacteria

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MOA of INH:

ISONIAZID

Kat G(

catalase

peroxidase

in mycobacteria)

Reactive metabolite

Inh

A &

Kas

A

Inh

DHFR

Inh

DNA

syn

Inhibits the synthesis of Mycolic Acid

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Mechanism of Resistance

High level resistance is due to

mutation

in

catalase

peroxidase (Kat G) gene

Resistance may also develop due to

mutation in Kas

A & Inh A gene

Efflux Of INH

Loss of INH concentrating

ability of bacteria

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Absorption:

completely absorbed

orally

Distribution:

penetrate all body tissue tubercular cavities, placenta & meninges

Metabolism:

in liver Excretion

: in urine

C/I

known hypersensitivity

acute hepatic disease

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Peripheral Neuropathy

And neurological manifestations

Paresthesias

, numbness, mental disturbances most important dose dependent toxic effects.

Pyridoxine deficiency

Interference with activation of pyridoxine and its increased excretion in urine

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Q- Why Vitamin B6 is given with INH

Pyridoxine deficiency

Interference with activation of pyridoxine and its increased excretion in urine

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Pyridoxine given

prophylactically

(10mg/day) prevents neurotoxicity

INH

neurotoxicity

is treated by pyridoxine 100mg/day

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WHOM

Must

: Diabetics, Chr. Alcoholics, malnourished, pregnant, lactating & HIV infected patients

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Hepatitis

Common in older adults & alcoholics

Dose related damage to hepatic cells

reversible

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RIFAMPICIN[R]

Semi synthetic derivative of

Rifamycin

B from

St.

meditarranei

Bactericidal: Bactericidal efficacy ≈ INH

Extra & intracellular bacteria Good sterilising property & resistance preventing action. All sub populations; best on spurters

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MOA

Rifampicin

inhibits synthesis of R.N.A.

It binds to

β

subunit

of mycobacterial

DNA dependent RNA polymerase

& blocks its

polymerising

function

Resistance develop due to mutation in rpo B gene( codes for RNA polymerase);

X bind mammalian RNA polymerase (Basis for selectivity).

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Other bacteria

Activity against other

gram positive and

gram negative

bacteriaStaph

N. meningitidisH. influenzae

E.coli

KleibseillaPsuedomonasProteusLegionella

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M. leprae

is highly sensitive

MAC & other mycobacteria are moderately susceptible.

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Pk

Absorption

Well absorbed from

g.i

tract

Food also interferes with abs; empty stomach

Distribution

widely distributed. Penetration

intracellularly & enters • tubercular cavities

•

Caseous

masses

• Placenta

Metabolism

Chiefly

in liver to an active

deacetylated

metabolite. Which is excreted mainly in bile some in urine also. (30-70%). R and its metabolite undergoes enterohepatic circulation

T

1/2

varies from 2-5 hrs

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Adverse effects:

HEPATITIS a major adverse effect

Urine

and secretions become

orange-red

in colourCutaneous syndromeFlu syndrome

Abdominal syndrome

SERIOUS BUT RARERespiratory syndrome: breathlessnessPurpura, haemolysis, shock and renal failure

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INTERACTIONS

Rifampicin is a

microsomal

enzyme inducer

It induces several CYP 450

iso enzymesThus enhances its own metabolism as well as of other drugs including:

Warfarin, OCPs, Corticosteroids, Anti-fungal drugs, Digitoxin, Protease inhibitors, NRTIs, etc.Increase dose; alternative method

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Why should Rifampicin not given with OCP?

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Other uses

Leprosy

Prophylaxis of meningococcal & H.

influenzae

meningitis & carrier state

MRSA

Brucellosis.

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PYRAZINAMIDE

Weakly

tuberculocidal

More active in

acidic

medium

More lethal to intracellular bacteria

& bacteria at the site of

inflammation Highly effective during 1st 2 months

By killing the residual intracellular bacteria it has good sterilizing activity

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Its inclusion has enabled duration of treatment to be

shortened

& reduced risk of relapse

One third reduction in the duration of anti-TB therapy & a two third reduction in TB relapse

This led to reduction in duration of therapy to 6

mths

, producing the short course

ctx

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MOA

Pyrazinamide

Mycobacterial Pyrazinamidase

Pyrazinoic

Acid (gets accumulated in acidic medium)

Inhibits Mycolic Acid Synthesis

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+

Pyrazinoic

acid also disrupts mycobacterial cell membrane and its transport function

Resistance develops rapidly if used alone &

is due to mutation of gene

pncA

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Absorption

: Well absorbed orally

Distribution

: good penetration to all body

tissue & CSF

Metabolism

: extensively in liver

Excreted in urine

T1/2 

6-10hrs

Dose: 25-30mg/kg/

day

Adverse

effects:

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Hepatotoxicity (dose dependent); occurs at 40mg/kg/day; hepatic disease in 15%. Regimens employed currently 15-30 mg/kg/day are much safer.

Hyperuricemia

;

inhibits excretion of

urates

. In nearly all patients. May ppt acute episodes of gout.

Arthralgia

, nausea, vomiting, dysuria, malaise and fever, loss of diabetes control

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ETHAMBUTOL[E]

Only

Tuberculostatic

drug among 1

st

line drugs.

Added to RHZ hastens the rate of sputum conversion and prevents the development of resistance.

Primarily added for this reason.

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MOA

E

Inhibits

Mycobact

. Arabinosyl Transferase

III 

Arabinogalactan

synthesis



Essential component of

Myco

. Cell wall;

disrupts the assembly of mycobacterial cell wall.

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PK

Absorption: Well absorbed from g.i.t.

Distribution : Widely distributedT

1/2

~

4hrsExcretion: Glomerular filtration & tubular secretion

Dose to be reduced in Renal failure

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Side effects:

Loss of visual acuity

(reversible)

loss of color vision

Field Defect due to optic neuritis

Dose & duration dependent toxicity.

Pt should be instructed to stop the drug at first indication of visual impairment. Visual toxicity: reversible

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Contra-indication; In children <6yrs and Creatinine clearance <50ml/min

Hyperuricaemia

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FQs

Ofloxacin

LevofloxacinCiprofloxacin

Moxifloxacin

New potent oral

mycobactericidal drugs

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Primary indication Drug resistant TB

key component of all regimens for MDR TB

Alternative to first line Substitution of

Ethambutol

with Mfx

has been found to enhance rate of bacterial killing & cause faster sputum conversion Possibility of decreasing the duration of treatment to

less than 6 months

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Mfx is the most active FQ against M. TBLvx

is more active than

Ofx & Cfx

Dose

:

Ofloxacin: 800mg ODLevofloxacin 750 mg ODMoxifloxacin 400mg OD

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Goal of AT CTx

Kill dividing bacilli

Kill persisting bacilliPrevent emergence of resistance.

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Goal of AT CTx

Kill dividing bacilli

Reduce bacillary loadAchieve quick sputum negativity

Patient non-contagious

Transmission interupted

Quick symptomatic reliefKill persisting bacilliEffect cure & prevent relapse

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Goal of AT CTx

Prevent emergence of resistance

.So that bacteria remain susceptible to the drugs

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Short Course Chemotherapy

Who has introduced 6-8 months multidrug “short course” regimens under DOTS

programme

.

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4 drugs

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Multidrug therapy

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4 drugs/Multidrug therapy

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Why?????Use of single drug in tuberculosis results in the emergence of resistant organisms and relapse in almost 3/4

th

of patients. Combination:H & R

most potent bactericidal

Combination synergistic

Duration of therapy shortened from >12 months to 9 months

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Z acts on intracellular bacteria

It has very good sterilizing activity

Addition of Pyrizinamide further reduces duration from 9 to 6 months

E

is bacteriostatic mainly serves to prevent resistance and may hasten sputum conversion

Single daily doseAKT-4

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Cost

Convenience

FeasibilityDecreased resistance

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TREATMENT CATEGORIES

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Category I

New case

Sputum positive for Mycobacterium TB

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Category II

Smear positive TB patients

Exposed to ATT in the pastDid not complete the courseOr took irregular medication

Or

relapsed after responding

Failed to respond; failuresHigher risk of harbouring

DR bacilli

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Intensive phase

4-5 drugs

2-3 monthsRapidly kill the bacilli

Bring about sputum conversion

Afford symptomatic relief

Continuation phase

2-3 drugs

4-5 months Remaining (few) bacilli eliminated So that relapse does not occur

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Category

Intensive phase

Continuous phase

Duration

(months)

Comment

I

2 HRZE daily4 HR daily6Optimal

2 HRZE daily4 HR thrice weekly

6Acceptable if DOT ensured

2 HRZE thrice weekly

4 HR thrice weekly

6

Acceptable if DOT ensured

II

2 HRZE

S

daily

+

1

HRZE daily

5

HR

E

daily

8

For patient with low/medium

risk of MDR-TB.Emperical (Standardized) MDR regimenEmperical(Standardized)MDR regimen18-24Till DSTFor patient with high risk of MDR-TB.Failures, 2nd default, contact of MDRTt

of TB Guidelines, 4th edition (2010), WHO , Geneva.

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Category twoThrice weekly option not available for retreatment categories

Assess risk of MDR-TB (DST)

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Recommended doses

Drug

Daily dose

mg/kg maximum

3 times per week dose

mg/kg maximum

Isoniazid

5(4-6)

300 mg10(8-12) 900 mgRifamin

10(8-12) 600 mg10(8-12) 600mg

Pyrazinamide

25(20-30)

35(30-40)

Ethambutol

15(15-20)

30(25-35)

Streptomycin

15(12-18)

15(12-18) 1000mg

Tt

of TB Guidelines, 4

th

edition (2010), WHO , Geneva.

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Multiple Drug Resistance(MDR)

Defined as Resistance to both

Isoniazid and

Rifampin

(compulsorily) and number of other(1st

line drugs)Rapid course

With worse outcomes

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2.8% of all new cases12-17% of retreatment cases

Treatment is

difficult as second line drugs are less

efficacious, less convenient,

more expensive and toxic for longer duration

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General principles

MDR Regimen

At least 4 drugsInclude drugs from group I to group IV Gp

I drugs (except H;R) 2

+ one injectable

; Gp II 1 One FQ; Gp

III 1

One/two Gp IV drugs 2

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General principles

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Standardized RNTCP regimen for MDR-TB

Intensive phase

6 drugs; 6-9 months;

Kanamycin

Ofloxacin

Ethionamide

Cycloserine

PyrazinamideEthambutol Continuous Phase

4 drugs; 18 monthsOfloxacinEthionamide

CycloserineEthambutol

+ Pyridoxine 100 mg/day

RNTCP DOT plus guidelines;2010.

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Extensively Drug Resistant(XDR)

This term is applied to bacilli that are

resistant to at least four most effective

cidal

drugs

, i.e. Cases resistant to INH

Rifampicin

Flouroquinolone and one of Kanamycin/Amikacin/Capreomycin

Virtually untreatableMortality is very high, particularly among HIV positive patients.

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detected or diagnosedStandardized MDR regimen must be

stopped

immediatelyExpert panel may decide on instituting treatment with group v drugs

Uncertain efficacy

Expensive

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Chemoprophylaxis

INH

: 300mg daily X 6 months Children : 10 mg /Kg

INH resistance

H(5 mg/kg)+R(10 mg/kg; max: 600 mg)X 3 months

If INH cannot be used : R X 4 months

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Whom

Contacts of open cases

Children with Mx positive & TB pt in the family

Neonate of TB mother

Pt of leukemia

DiabetesSilicosisHIV positiveC. steroid therapy; who show +ve

Montoux

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Pregnancy

S contraindicated

;

ototoxicity

USA

Z not recommendedINDIA

Avoid Z

2HRE+7HR

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Treatment should not be withheld or delayed

because of pregnancy

All pregnant women being treated with INH should receive pyridoxine 10-25 mg/day

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Lactation

All ATDs compatible with breast feeding

Full course should be given to mother

Infant

: BCG vaccination

6 month INH prophylaxis after ruling out active TB.

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Thanks for your attention