DRUGS ANTITUBERCULOSIS

ANTITUBERCULOSIS

DRUGS

Prof. Zeynep Ateş-Alagöz

Ankara University Faculty of Pharmacy

Department of Pharmaceutical Chemistry

Tuberculosis

• a chronic granulomatous disease

• In developing countries it is a major health problem

• ≈ 30% of world population is infected with Myc. Tuberculosis infection

• In India > 2 million people develop active disease every year & half million die. • Typical growth characteristics

• Peculiar cell wall structure (waxy appearance ) due to mycolic acid. • Resistance to infection emerges quickly.

Mycobacterium tuberculosis

Mycobacterium Infections

Common infection sites

• Lung (primary site) - Intestines

• Brain - Lymph nodes

• Bone

• Liver

• Kidney

• Aerobic bacillus

• Passed from infected:

– Humans

– Cows (bovine) and birds (avian)

• Much less common

Tuberculosis - Pathophysiology

• M. tuberculosis

–

gram-positive, acid-fast bacillus

• Spread from person to person via airborne

droplets

– Coughing, sneezing, speaking – disperse organism and

can be inhaled

– Not highly infectious – requires close, frequent, and

prolonged exposure

– Cannot be spread by hands, books, glasses, dishes, or

Tuberculosis – Diagnostic Studies

• Tuberculin Skin Testing

-- + reaction 2-12 weeks after the initial

infection

– PPD

– Purified protein derivative – used to detect delayed

hypersensitivity response

• Two-step testing – health care workers

• 5mm > induration – Immunosuppressed patients

• 10 mm> “at risk” populations & health care workers

• 15 mm> Low risk people

– Chest X-ray

-- used in conjunction with skin testing

• Multinodular lymph node involvement with cavitation in the upper

lobes of the lungs

• Calcification – within several years after infection

– Bacteriologic Studies

–

• Sputum, gastric washings –early morning specimens for acid-fast

bacillus -- three consecutive cultures on different days

Antitubercular Agents

• Now there is emergence of multidrug resistant ( MDR ) TB . More than 0.4

million cases globally.

History

• First successful drug for treating TB was

PAS (Para- aminosalicylic acid)

developed by

Lehman in 1943.

• Dramatic success came when

Waksman & Schutz

discovered

Streptomycin

which has made remarkable progress.

• Followed by

Thiacetazone

by

Domagk

in 1946

• In 1952

Isoniazid

came into being

• Pyrazinamide

by

Kushner & colleagues

in 1952 & later on

Rifampicin

in 1957

by

S. Margalith

has totally changed the strategy in the chemotherapy.

• Ethambutol

came in 1961 by

Lederle -laboratories

• Fluoroquinolones, newer macrolides & congener of Rifampicin →Rifabutin are

recent addition in antimycobacterial drugs

Antitubercular Agents

First line drugs:

Essential component of all anti TB regimen (except intolerance or resistance)

-Interferes with mycolic acid synthesis (unique to mycobacterial cell wall)

-It is tuberculocidal , kills fast multiplying organism & inhibit slow acting organism -Acts both on intracellular ( present in macrophages ) & extracellular bacilli

-It is the cheapest agent

N C O N H N H₂ 4 -p irid in k a rb o k s ilik a s it h id ra z it is o n ik o tin ik a s it h id ra z it h id r a z it 2 v e y a 3 . k o n u m d a _{e tk i d ü ş e r} d iğ e r k a r b o n il tr v . e tk i k a y b o lu r

İPRONİAZİD

N O _NH N H N C H 3 N C O O H N N C O C H 3 N C₂H₅ N C O O H N C O O E t N C O N H N H 2 H₂S O₄ H 2N - N H2 o x id . iz o n ik o t in ik a c . a ) b ) A c C l / Z n C l₂ o x id . r e d . E t O H - E t O H

N N O N H 2 N N O O H d e a m in a z p ir a z in o ik a c . ( a k t if m e t a b o lit ) p ir a z in k a r b o k s a m id

Pyrazinamide

bactericidal hepatotoxic, Anorexia N H₂ N H₂ N N N N C O O H C O O H K M n O₄ O O H H - C O₂ N H 3 N N C O O H N N C O N H₂ g lio k s a l +

MORPHAZINAMIDE (Morphozide)

Turning Pyrazineamide to show effect.

Side effects less

tuberculocides

N N O N H C H 2 N O a m in o m e t ila s y o n ile e . e .

Ethambutol

• Inhibits arabinosyl transferases involved in cell wall biosynthesis

• Bacteriostatic to M.tuberculosis

• Resistance develops rapidly if used alone

C 2H5 C H 2O H H O H 2C H 5C2 C H - N H - C H₂- C H₂- N H - C H

( d ) N , N '- b is ( 1 - h id r o k s im e t il- 1 - p r o p il) e t ile n d ia m in ( d ) 2 , 2 '- ( e t ile n d ia m in o ) - d ib u t a n - 1 - o l

Rifampicin

-Semisynthetic derivative of Rifamycin B from Streptomyces mediterranei -Inhibits bacterial DNA-dependent RNA polymerase

-bactericidal

-Gram positive and negative -kill intracellular organism

Streptomycin

-Aminoglycoside - Inhibits protein synthesis -Bactericidal

-Poorly absorbed from GIT - given IM. -CSF penetration: poor

-Renal elimination Adverse effects

Ototoxicity, vestibular toxicity, nephrotoxicity Uses

very ill patients

Multi- drug resistance

Second line drugs:

N C 2H5 S N H 2

2 - e til- tiy o - is o n ik o tin a m id 2 - e til- 4 - p ir id in k a r b o tiy o a m id 2 - e til- is o n ik o tin il- tiy o a m id

Ethionamide :

-Tuberculostatic , having moderate efficacy

-Inhibits dehydrogenases enzymes .... inhibits peptide synthesis. -The effect is up to 10% of isoniazid, more toxic

-Behaves like pyridoxine antagonist ... peripheral neurite (pyridoxine) teratogenic

-Resistance develop readily & some cross resistance to TZN -Absorbed orally ,distributed all over including CSF

PROTİYONAMİDE

-At high concentration ... bactericide - CSF penetration: enough

-Oral abs.fast

-Some metabolites are also effective -Also used in Lepra

-pyridoxine -combined N CS N H ₂ C₃H ₇ 2-Propyl-4-piridinkarbotiyoamit

Cycloserine

NH O O N H 2 D (+) 4-amino-3-isoxazolidinone

- Obtained from S. archidacces -↓ Bacterial cell wall synthesis

-Tuberculostatic & ↓ other G -ve organisms ( E. coli , Chlamydia)

-Resistance develop slowly , no cross resist.

Broad spectrum antibiotic Reaches the CSF well Causes CNS side effects Use in drug resistant TB

PAS – Paraaminosalicylic acid:

O H N H₂ C O O H e s te r o la b ilir C O O H a g ö r e - o , - m o la b ilir S H , N H₂ , e te r o la m a z s e r b e s t o lm a lı a s e t il

-Related to sulfonamides chemically as well as in mech. of action. -Tuberculostatic , not add to therapeutic value , only delay resistance -Interfere with absorption of Rifampicin

S/E - Acceptability is poor due to frequent anorexia , nausea & epigastric pain

Thiazethazone (Citazone)

N H C H = N - N H C - N H₂ S C H 3 O p - a s e t il a m in o b e n z a ld e h it t iy o s e m ik a r b a z o n -Oral use.

-Also use in Lepra.

-There is no cross resistance with isoniazid ... the mechanisms of action are different (not completely known)

-Combined with isoniazid + streptomycin Anemia

leukopenia

Capreomycin

It is another alternative when resistance develops in first class compounds. Obtained from Streptomyces

Mycobacterium leprae (Hansen basil, Gram-positive)

Infection ability is low

Slowly developing

deformations

mutilation

In mild leprosy reactions ... aspirin,

prednisone, thalidomide, clofazimine use in some cases

The WHO recommendation is the use of Dapson + clofazimine + rifampin

for 2 years

DRUGS USED IN LEPRA

TREATMENT

Primer Drugs

- Dapson

- Rifampicin

- Clofazimine

- Ethionamide or Protionamid

Secondary Drugs

- Tiasetazone

- Tiambutazon

- Long acting sulfonamides

- Aminoglycosides

1- Sulphones

DAPSON

S O 2 N H 2 N H2 - N H S O₃H 4 , 4 '- d ia m in o d if e n il s ü lf o n ( D D S ) s ü lf a t g lu k u r o n a t 1 ) 2 ) 3 ) m o n o a s e t il d a p s o n - N H - g lu k u r o n a t

Approximately 70-80% of the dose is discarded as glucuronide or N-sulphate conjugates. N H2 H2N S O2 C H3C O N H S O2 N H2 _{H O N H S O2} N H2 M o n o a s e tild a p s o n M o n o -N -h id ro k s id a p s o n R -N H -g lü k u ro n it D a p s o n m o n o -N -g lü k u ro n it R N H S O3H D a p s o n m o n o s ü lfa t K o n ju g a tla ri K o n ju g a tla ri bacteriostatic

bactericide in high doses

Used safely in pregnancy, cheap

ASEDAPSON

Prodrug ... diacetyl derivative Prophylaxis + treatment

Structure-Activity Relations:

S O 2 N H 2 N H2 - N H S O 3H 4 , 4 '- d ia m in o d if e n il s ü lf o n ( D D S ) s ü lf a t g lu k u r o n a t 1 ) 2 ) 3 ) m o n o a s e t il d a p s o n - N H - g lu k u r o n a t

-Linked hydroxyl, amine, chlorine, methoxy and methyl groups to ring make it inactive. -Replacement of one of the amine groups with hydroxyl, nitro, or hydroxylamino groups reduces activity.

-When both amine groups are replaced by hydroxyl groups, inactive compounds form. -Reduction of the sulphone group to sulfoxide or conversion to thioether destroys the activity.

-As with sulfoxone sodium, aldehyde-bisulfite complexes of amine groups are the active compounds.

SULFOXONE SODIUM

S O 2 N a S O 2- C H2- N H N H - C H2- S O2 N a D is o d y u m [ s ü lf o n il b is ( 4 - f e n ila m in o ) ] d im e t a n s ü lf in a t Absorption variable N H₂ S O₂N H N N O M e SULFAMATEOXY PYRIDAZINE

2-Other Drugs

CLOFAZİMİNE

N N C l N N H C l

N , 5 - B is ( 4 - k lo r o f e n il) - 3 , 5 - d ih id r o - 3 - [ ( 1 - m e t ile t il) im in o ] - 2 - f e n a z in a m in

-The isozyme shows an equivalent potency to isoniazide -The only drug that does not develop resistance

-Cross resistance does not develop -70-95% unchanged with feces -bacteriostatic

THYAMBUTOSINAL

THALIDOMITE

N H N C H 3 C H 3 S N H O C₄H₉

1 - ( 4 - d im e t ila m in o f e n il) - 3 - ( 4 - b u t o k s if e n il) - 2 - t iy o ü r e

Resistance develops in 2-3 years ... dose is increased. N H N O O O O 3 - f t a lim id o g lu t a r im id

Hypnotic, Antiemetic, Antineoplastic Antilepra

Rifampin

The body secretions are reddish bactericidal

ethionamide Protiyonamid the Tiyasetazo isoniazid

Priority Order For Antimicrobial Therapy:

Initial treatment (for 2-3 months)

isoniazid rifampicin

Etambutol or Streptomyces., pyrazinamide

Stabilization treatment (for 4-7 months) isoniazid

Classic Combinations for Lepra

*Isoniazid + Procyanamide + Dapson (8-12 months treatment duration) * Dapson + Clofazimin (4-6 months duration of treatment)

* Dapson + Clofazimine + Rifampin (Rifampin every two days) * Clofazimine + Rifampin (2-3 months duration of treatment) * Dapson + Isoniazid + Thioacetazone (Sekonder combination)

NEW TREATMENT COMBINATIONS

Combinations made with the following drugs are the most common of the new generation drugs.

• Minocycline

• Ofloxacin, moxifloxacin, sparfloxacin ... bactericide • Clarithromycin

• Rifapenetin, rifabutin • Rifampicin

• Cefoxitin

• Sefoliprin i.v. and because it is expensive, it is not widely used in practice Rifampicin: 600 mg + ofloxacin: 400 mg + Minocycline: 100 mg

RIFAM + ofloxacin + clofazimine + minocycline 1 week Rifapenetin + Moxifloxacin + Minocycline

In our country, the multi-drug treatment protocol recommended by the world health organization is applied (1983).

According to this regulation, Lepra is a disease that must be recognized and declared by health personnel at all levels in our country.

Lepra is treated free of charge in our country.

WHO aims to launch multidrug therapy: - Increase treatment effectiveness

- Reduce the duration and frequency of treatment - Prevent the development of resistan bacilli

- Removing resistant strains from the center - reduce side effects most