TUBERCULOSIS AND ANTI-TUBERCULAR DRUGS

G Vijay Narasimha KumarAsst. Professor,

Dept. of. PharmacologySri Padmavathi School of Pharmacy

INTRODUCTION◦DEFINTION : Tuberculosis is a chronic granulomatous disease caused by

Mycobacterium tuberculosis.

◦GRANULOMA : A nodule consisting of epithelioid macrophages and other

inflammatory and immune cells and matrix ( fibroblasts ) and the matrix form when

the immune system tends off and isolates an antigen.

◦TUBERCLE : A small round grey translucent granulomatous lesion usually with

central caseation.

Mycobacterium tuberculosis

M. Hominis M. bovis M. avium M. vertebrae M. africanum

Mostly in humans

TUBERCULOSIS

Atypical mycobacterium

M. Kansasii M. scrofulaceum M. ulcerans

Mycobacterium tuberculosis:◦Atypical – due to mycolic acid ,which are long chain β hydroxylated fatty

acids◦Rod shaped◦Aerobic – requires oxygen. Hence it will lies in areas where there is more

oxygen tension◦Intracellular – due to tubercle the bacteria will be present in the

macrophages

less reproduction but can resist to high temperature and other climatic conditions

WHY TB IS A DREADFUL DISEASE ?REASON FOR DREADFUL DISEASE:

• Presence of Mycolic acid (90’c’ atoms arranged in a ring like structure) in Mycobacterium species.

• Mycolic acids Prevents ,resists against

hydrophilic and lipophilic antibiotics, loss of water, transport of various substances

Helps in evading from immune system.

Mycolic acids

Mycolic acids:◦Prevents action of hydrophobic antibodies ◦Prevent bacterium from chemical damage or dehydration◦Evades mycobacterium from immune system◦Resistant to normal stains – even acid stains ( hence acid fast bacilli )◦Will provide favorable environment for the growth of bacteria in

macrophages

WHY IT CAN’T BE STAINED BY NORMAL STAINS?

Due to presence of mycolic acids and cross linked fatty acids and other lipids in the cell wall of organisms ,making it impermeable to usual stain.

M.tuberculi in Acid fast staining

Takes up stain by carbol fuschin.

Resists decolorisation by acids and alcohol.

Don’t acquire 20 stain methylene blue

These retain carbol fuschin hence they appear red.

WHY TB AFFECTS ONLY LUNGS ? M.tuberculi Enters Host cell Utilizes

Cholesterol in cell membrane (Highly oxygenases amount involved in metabolism of cholesterol into)

e-

◦The concentrations of oxygenases greater in alveoli of lungs.Hence Mycobacterium species majorly reside in alveoli of lungs.

◦And as it is strict aerobe strictly thrives best in tissues with high Oxygen tension such as in the apex of the lung.

ATP

SIGNS AND SYMPTOMS OF TB

DIAGNOSISPhysical examination – weight loss, sputum examinationChest X-raySputum test/ culture testBlood test Tuberculin skin test IFN-γ test ( Quantiferon TB-gold test )According to RNTCP(2014) GENE EXPERT test is performed to diagnose

between MDR-TB, XDR-TB, TDR-TB.

◦Tuberculin skin test:A dose of 5 TU (tuberculin units) of PPD (0.1 ml) is injected intra dermally and after 48-72 hours the induration(swelling) is observed.If the swelling is <5mm – no TBIf the swelling is >5mm – TB is presentThe results may be:• False positive – due to BCG, allergens• False negative – seen in immunocompromised patients

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Fig: Tuberculin test

Fig: Chest X-ray radiography

Showing cavity

Wheal

Prevention of TB

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◦Prevention strategies include BCG vaccination and treatment of persons with latent tuberculosis infection who are at high risk of developing active disease.

◦BCG was derived from an attenuated strain of M. bovis.

◦Efficacy is between 0-80%.

◦BCG vaccine is recommended for routine use at birth in countries with high tuberculosis prevalence.

◦Bacillus Calmette-Guérin (BCG)

Based on resistance

Susceptible MDR-TB XDR-TB Based on their ability to undergo division

Active TB Latent TB(may be active, slow acting, (bacteria in dormant) intermittent, dormant)

Types of TB

Based on type of tissue response and age

Primary TB or Ghon’s complex or childhood TB ( infection of an individual who has not been previously infected or immunised)Secondary TB or Post-primary or Reinfection, or Chronic TB(infection of an individual has been previously infected or sensitized).

Active TB Latent TBSigns and symptoms + _Tuberculin skin test + +Blood test + +Sputum + _Chest X-ray + _Treatment + +Transmission + +

ANTI TUBERCULAR DRUGS FRIST LINE AGENTS

ISONIAZID(H)RIFAMPICIN(R)PYRAZINAMIDE(Z)ETHAMBUTOL(E)STREPTOMYCIN(S)

SECOND LINE AGENTS*Aminoglycosides *BEDAQUILINE KANAMYCIN *CYCLOSERINE AMIKACIN *ETHIONAMIDES*Macrolides *CAPREOMYCIN AZITHROMYCIN *THIACETAMIDE CLARITHROMYCIN*Fluoro quinolones LEVOFLOXACIN MOXIFLOXACIN*PARA AMINO SALICYLIC ACID

Based on Anti – TB activity

Tuberculocidal

Tuberculostatic

◦Isoniazid◦Streptomycin◦Capromycin◦Ciprofloxacin◦Rifampicin◦Pyrazinamide◦Kanamycin ◦Ethambutol◦Thiacetazone◦PAS◦Ethionamide◦Cycloserine

◦First line drugs:- kill active bacteria, important in the early stages of infection.

◦Second line drugs:- hinder bacterial growth.- Strengthen treatment in the case of resistant bacteria.- Less efficient and generally more toxic than first line drugs.

Isoniazid (INH)◦Most effective and cheapest primary anti

tubercular drug.

◦Effective in both acidic and alkaline medium

◦Tuberculocidal for rapidly multiplying bacilli

◦Tuberculostatic for resting bacilli

FIRST LINE AGENTS:

ISONIAZID (H) or ISONICOTINIC ACID HYDRAZIDE:It is a prodrug and is converted into active form inside mycobacterium cell

MOA: ISONIAZID(pro drug)

mycobacterial catalase peroxidase(Kat G)

Active form

forms complexes with

NADP NAD+ co-enzyme for DHFR

acyl carrier β-keto acyl

protein reductase ACP synthase Thus inhibition of DNA synthesis

(Inh A) (Kas A)

Inhibition of mycolic acid synthesis Destruction of cell wall(Tuberculocidal)

RESISTANCE:Due to mutations in Kat G gene Inh A gene Kas A geneISONIAZID can kill intracellular organisms can penetrate into caseous necrotic material (abscess) highly active in rapidly dividing bacteriaPHARMACOKINETICS AND ADRs:Taken orallyAbsorption - good but limited when taken with high fatty dietDistribution – very well distributed and can cross BBB and placental barrierMetabolism – ISONIAZID N-acetyl transferase Acetyl ISONIAZID

Acetyl ISONIAZID

Urine Liver excretion can accumulate & forms free radicals hepatotoxicity Slow acylators – T1/2=90 minN-Acetyl transferase hence dose adjustment is done Fast acylators – T1/2=3 to 4 hours

DRUG INTERACTIONS:It is enzyme inhibitor and inhibits cyp450 enzymes alters metabolism of PHENYTOIN CARBAMAZEPINE increases their effectsCan enhance excretion of PYRIDOXINE(Vitamin B6) peripheral neuritis, numbness hence pyridoxine supplements(25-50mg) must be given

As it is hepatotoxic LIVER FUNCTION TESTS should be performed regularly to monitor transaminase levels.DOSE:5mg/kg OD

Rifampicin

◦Semisynthetic derivative of rifamycin ,

an anitibiotic obtained from streptomyces mediterranei.

◦Highly effective tuberculocidal

◦Acts on both intra and extracellular organisms.

◦It is called a sterilizing agent.

Mechanism of actionRifampicin

Binds with Beta subunit of DNA dependent RNA polymerase

Inhibition of m.R.N.A synthesis

Tuberculocidal effect

It cannot bind to human RNA polymerase, thus selectively destroying the bacteria.

oRIFAMPICIN acts on gram +ve gram –ve non tubercular bacteria like M. kansasii, M. avium complexoUsed to treat MENINGITIS, LEPROSY, TB.oRIFAMPICIN acquires resistance due to mutations in DNA dependent RNA polymerase.PHARMACOKINETICS: Taken orally Food decreases absorption of RIFAMPICINVery well distributed (even in macrophages)Only 10-20% of drug reaches CSFRIFAMPICIN is a potent enzyme inducer(cyp450) It causes hepatotoxicity but not as ISONIAZID and it is not teratogenic.

RIFAMPICIN can increase the metabolism of: HIV protease inhibitors NNRTIs Sulfonyl ureas their T1/2 increases and hence dose Anti epileptic drugs should be increased QUINIDINE WARFARIN PROPRONOLOLHence in HIV patients RIFABUTIN is used which is not as potent enzyme inducer as

RIFAMPICINRIFAMPICIN contains metals and it undergoes enterohepatic recycling. Hence excreted

into bile and feces. As a result the urine, feces, tears and tongue turns orange red in color.

Dose :10mg/kg OD

Uses TB & atypical mycobacteria

l infectionsLeprosy

Prophylaxis in H.

influenza

Resistant staph

infectionsBrucello

sis Pneumococcal meningitis

To eradicate carrier state

DOSE:25mg/kg OD

Pyrazinamide ◦Analog of nicotinamide

◦Tuberculocidal◦Requires acidic pH for its activity

◦Mechanism of action not clearly known.

◦HEPATOTOXICITY is the most common adverse effect

PYRAZINAMIDE

pyrazinamidase

PYRAZINOIC ACID

inhibits mycolic acid synthesis

Alterations in pyrazinamidase enzyme leads to resistance.

CLINICAL USAGE◦Half life is 8-11 hrs.

◦DOSAGE :- 50-70 mg/kg/d for twice / thrice weekly treatment regmens.

◦ Bacteriocidal & bacteriostatic. Used in both Extrapulmonary and pulmonary TBAdverse Reactions

Hyperuricemia (precipitating gout)Metallic stateSulfurous eructation'sToxic hepatitis (Not dose related)Arthralgia, nausea, vomiting, anorexia, malaise, Rarely photosensitivity reaction

ETHAMBUTOL (E):MOA: Inhibits Arabinosyl transferase enzyme

Inhibits Arabinoglycan

Inhibits cell wall synthesis•It can prevent emergence of resistance and can kill resistant forms.

ADRS:It can cause optic neuritis – decrease visual acuity, no differentiation of red and green colors, but reversible

It is teratogenicDOSE:

15 mg/kg OD

Streptomycin ◦Tuberculocidal◦Acts only against extracellular organisms◦Has to be given IM◦When used alone resistance develops.◦Least preferred first line drug.DOSE:15 mg/kg OD

Relative activity of first line drugs◦INH: potent bactericidal◦Rifampicin: potent bactericidal

◦Pyrazinamide: weak bactericidal ◦Ethambutol: bacteriostatic◦Streptomycin: bactericidal

Synergistic effect

NEVER USE A SINGLE DRUG FOR CHEMOTHERAPY IN TUBERCULOSIS, A COMBINATION OF 2 OR MORE IS

ALWAYS BETTER

Second line drugs in TB◦Less effective◦More toxic◦Used only if organism is resistant to first line drugs◦Ethionamide , PAS, cycloserine : bacteriostatic◦Amikacin, capromycin, fluoroquinolones are used in Multi Drug Resistant TB

THIACETAZONE (Tzn)◦Bacteriostatic drug.

◦Does not add the therapeutic effect to the H,S& Z but delays resistance to these drugs.

◦Half life is 12 hrs.

◦No longer used due to major adverse effect is hepatitis, exfoliative dermatitis, Stevens-Jonson syndrome.

◦Tzn is not used in HIV patients due to incidence of serious toxicity.

◦Dosage :- 150 mg/d in adults & 2.5mg/kg in children.

ETHIONAMIDE (Etm)Blocks the synthesis of mycolic acids and it is a tuberculostatic drug.

Acts on both extra & intracellular organism.Resistance to Etm develops rapidly.Cross resistance with Tzm ia also seen.Half life is 2-3 hrs.Recommended dosage is 1g/d.Anorexia , nausea & abdominal complaints are common.

CYCLOSERINE (Cys)◦Obtained from S.ORCHIDACEUS.

◦It is D-alanine analogue and hence it replaces alanine which is essential for cell wall synthesis.

◦Bacteriostatic drug.

◦It is effective against tubercle bacilli resistant to H or S and against atypical mycobacterium.

◦Rarely used .

◦Dosage :- 250 mg /B.D if tolerated can be increased to 500 mg B.D

Macrolide antibiotics (CLARITHROMYCIN AND

AZITHROMYCN)

Fluoroquinolones(CIPROFLOXACIN and

OFLOXACIN):

Aminoglycosides

MANAGEMENT OF TBAims:1. To kill the dividing bacteria in the lung lesions.2. To kill the persisters so as to avoid relapse and ensure total cure3. To prevent emergence of drug resistance

And based on

PATIENT

NEWLY AFFECTED PATIENTS

ACTIVE TB

LATENT TB

PREVIOUSLY TREATED PATIENTS AND BASED ON DRUG SENSITIVITY TEST

LESS SENSITIVE

MORE SENSITIVE

Phases of chemotherapy

Phase I• 1-3 months

• Rapidly kills bacilli

• Symptomatic relief

Phase II• 4-6 months

• Eliminates remaining bacilli

• Prevents relapse

INITIAL PHASE (2months):• ISONIAZID (H)• RIFAMPICIN (R)• PYRAZINAMIDE (Z)• ETHAMBUTOL (E)• Pyridoxine (Vit.B6) (100mg/day)

Objectives of TB treatment:To kill actively dividing bacteria – relieve signs and symptoms ISONIAZIDTo kill slow dividing and persistent bacteria – eradicate the disease and prevent

relapse RIFAMPICIN, PYRAZINAMIDETo prevent emergence of drug resistance ETHAMBUTOL

CONTINUOUS PHASE (4months):• ISONIAZID (H)• RIFAMPICIN (R)• Pyridoxine (Vit.B6)

Drug-Resistant TB: Definitions◦Mono-resistant: Resistance to a single drug ◦Poly-resistant: Resistance to more than one drug, but not the combination of isoniazid and rifampicin

◦Multidrug-resistant (MDR): Resistance to at least isoniazid and rifampicin

◦Extensively drug-resistant (XDR): MDR plus resistance to fluoroquinolones and at least 1 of the 3 injectable drugs (amikacin, kanamycin, capreomycin)

GROUPS OF DRUGS FOR MDRGroup 1:first-line oral agents• pyrazinamide (Z)• ethambutol (e) • rifabutin (rfb)

Group 2:injectable agents• kanamycin (Km)• amikacin (Am)• capreomycin (cm) • streptomycin (S)

Group 3:fluoroquinolones• levofloxacin (lfx) • moxifloxacin (mfx) • ofloxacin (ofx)

Group 4:oral bacteriostatic second-line agents• para-aminosalicylic acid (pAS)• cycloserine (cs)• terizidone (Trd)• ethionamide (eto) • protionamide (pto)

GROUPS OF DRUGS FOR MDRGroup 5: Agents with unclear role in treatment of drug resistant-TB• clofazimine (cfz)• linezolid (lzd)• amoxicillin/clavulanate (Amx/clv)• thioacetazone (Thz)• imipenem/cilastatin (ipm/cln)• high-dose isoniazid (high-dose H)b• clarithromycin (clr)

Drug treatment for MDR-TB: According to RNTCP and WHO

Intensive phase Continuous phase (6-9 months) (18 months) Z – 25 mg/kg ETHIONAMIDE E – 15 mg/kg CYCLOSERINE AMIKACIN – 15 mg/kg OFLOXACIN/ LEVOFLOXACIN CYCLOSERINE – 10-20 mg/kg ETHAMBUTOL OFLOXACIN/ LEVOFLOXACIN ETHIONAMIDE – 10-20 mg/kg

Drug treatment for TB in pregnancy:• Category – I Intensive phase Continuous phase (2 months) (4 months) ISONIAZID ISONIAZID RIFAMPICIN RIFAMPICIN PYRAZINAMIDE• Category – II Intensive phase Continuous phase (2 months) (7 months) ISONIAZID ISONIAZID RIFAMPICIN RIFAMPICIN ETHAMBUTOL◦ E can be added during late but not early pregnancy. S is contraindicated.

Drug treatment for TB in lactating mothers: Category – I (Acute or latent) – 6 months Intensive phase Continuous phase (2 months) (4 months) H – 300 mg/day H R – 600 mg/day R Z – 25 mg/day E – 25 mg/day + Vitamin B6 – 25-50 mg

Category – II (MDR-TB) – 7 months Intensive phase Continuous phase Z KANAMYCIN E PAS FLUORO QUINOLONES CYCLOSERINE

All antiTB drugs are compatible with breastfeeding; full course should be given to the mother, but the baby should be watched. The infant should receive BCG vaccination and isoniazid prophylaxis

Drug treatment for TB in HIV patients: Intensive phase Continuous phase (2 months) (4-7 months) ISONIAZID ISONIAZID RIFABUTIN RIFABUTIN PYRAZINAMIDE ETHAMBUTOL ETHAMBUTOL

Drug treatment for MAC in HIV patients: Intensive phase Continuous phase (2-6 months) (6 months) If CD4 cells <100 cells/ϻl If CD4 cells >100 cells/ϻl CLARITHROMYCIN-500 mg OD/ CLARITHROMYCIN/AZITHROMYCIN AZITHROMYCIN-500 mg OD ETHAMBUTOL/RIFABUTIN ETHAMBUTOL-100 mg/day RIFABUTIN-300 mg/day + MOXI/CIPRO/LEVOFLOXACIN-500 mg BD

Drug treatment for TB with Meningitis: Intensive phase Continuous phase (2 months) (12 months) H-5 mg/kg/day H R-10 mg/kg/day R Z-25 mg/kg/day E-15 mg/kg/day CLARITHROMYCIN/ETHIONAMIDE – 15-20 mg/kg PREDNISOLONE – 20-40 mg/kg