ANTIMYCOBACTERIALAHMAD ALJIFRI

OUTLINES• Introduction• Classifications

–Structures –MOA–SAR–Uses–Side effects

Definition• An antimycobacterial is a

type of drug used to treat mycobacteria infections.

• Types include:1. Tuberculosis

treatments2. Leprostatic agents

TB• is a common, and in many cases

lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis.

• Tuberculosis usually attacks the lungs but can also affect other parts of the body.

TB

• It is spread through the air when people who have an active MTB infection cough, sneeze, or otherwise transmit their saliva through the air.

Symptomschest pain, coughing up blood,

and a productive, prolonged cough for more than three weeks. Systemic symptoms include fever, chills, nigh sweats, appetite loss, weight loss, pallor, and fatigue.

First line• All first-line anti-tuberculous drug

names have a standard three-letter and a single-letter abbreviation:– Ethambutol is EMB or E,– isoniazid is INH or H,–pyrazinamide is PZA or Z,– rifampicin is RMP or R,– Streptomycin

Never use a single drug therapy

– Isoniazid –rifampicin combination administered for 9 months will cure 95-98% of cases .–Addition of pyrazinamide for this

combination for the first 2 months allows total duration to be reduced to 6 months.

isoniazid

MOA–Bacteriostatic at low conc. &

bacteriocidal at high conc. Especially against actively growing bacteria.– Inhibits synthesis of mycolic

acid is an essential components of mycobacterial cell wall.–Readily absorbed from GIT.

MOA–Diffuse into all body fluids and

tissues –Penetrates caseous material

and macrophages so it is effective against intra and extracellular organisms.–Metabolized in liver by

acetylation–Excreted mainly in urine

SAR1-Substitutionof hydrazine portion of INH with alkyl and ar-alkyl substitution resulted in a series of active and inactive derivatives.

SAR

2-Substitution on the N2 position (R 1,R2=alkyl,R3=H)----active compounds.

SAR

2-Substitution on the N2 position (R 1,R2=alkyl,R3=H)----active compounds.

SAR

3-Any Substitution at N1-hydrogen(R3=alkyl)------------destroy the activity.

SAR

4-Any Substitution---not superior than INH.

Uses–Mycobacterial infections (it is

recommended to be given with pyridoxine to avoid neuropathy).– Latent tuberculosis in patients

with positive tuberculin skin test–Prophylaxis against active TB in

individuals who are in great risk as very young or immunocompromised individuals.

Side effects–Peripheral neuritis–Optic neuritis.–Allergic reactions ( fever,skin

rash,systemic lupus erythematosus )–Hepatitis–Gastric upset–Haemolytic anaemia– Enzyme inhibitor–CNS toxicity.

Ethambutol

MOA– Inhibits mycobacterial cell wall

synthesis by inhibiting arabinosyl transferase .–Bacteriostatic–Active against intra&extracellular

bacilli .–Well absorbed from gut.–20% excreted in feces and 50% in

urine in unchanged form.–Crosses BBB in meningitis

SAR

– Ethylene diamine chain --↑this chain length --↓or destroy.

– Replacement of either N--↓or destroy.– Increasing the size of Nitrogen substituents--↓or

destroy.– Moving the location of alcohol groups--↓or

destroy.

Uses

–Used only in mycobacterial infections.

Side effects–Retrobulbar (optic) neuritis

causing loss of visual acuity and red-green colour blindness.– It is relatively contraindicated in

children.–GIT .upset .–Hyperuricemia

2nd line• Indication of 2nd line treatment :–Resistance to the drugs of 1st

line.– Failure of clinical response– Increase of risky effects.–Patient is not tolerating the

drugs first line drugs.

– Ethionamide–Capreomycin–Amikacin–Ciprofloxacin & levofloxacin–Rifapentine–Aminosalicylic Acid (PAS)

Ethionamide

MOA–As isoniazid blocks synthesis of mycolic

acid .–Available only in oral form.–Metabolized by the liver ,excreted by

kidney.– It is poorly tolerated because of :• intense gastric irritation• neurologic symptoms• hepatotoxicity

Uses

Used in TB & leprosy.

Fluoroquinolones

CIPROFLOXACIN LEVOFLOXACIN

MOA–Broad

spectrum,antibacterial,but also active for M.tuberculosis,– binding to DNA gyrase-DNA

complex (gyrA and gyrB )– inhibiting bacterial DNA

replication and transcription, bactericidal.

SAR–Non fluorinated quinolones are

inactive against mycobacteria.–Different substitution in

quinolones improve activity toward Mycobacterium avium intracellular complex(MAC – MAI) known as biophores.

• A cyclopropyl ring at N1position.• F atom at position C-6 and C-8• A C-7 heterocyclic substituents

SAR

– Excessive lipophillicity atN1 can↓activity.–The N-7 substituents with greatest

activity against mycobacteria include substituted piperazines and pyrrolidines.

Leprosy• Leprosy or Hansen's disease (HD) is a

chronic disease caused by the bacteria Mycobacterium leprae and Mycobacterium lepromatosis.

• granulomatous disease of the peripheral nerves and mucosa of the upper respiratory tract; skin lesions are the primary external sign.

Leprosy• Secondary infections, in turn, can

result in tissue loss causing fingers and toes to become shortened and deformed, as cartilage is absorbed into the body

• usually spread from person to person in respiratory droplets

Drugs used in leprosy

• Dapsone• Clofazimine

Dapsone

MOAInhibits folate synthesis.–Well absorbed orally,widely

distributed .– Half-life 1-2 days,tends to be retained

in skin,muscle,liver and kidney.– Excreted into bile and reabsorbed in

the intestine.– Excreted in urine as acetylated.– It is well tolerated.

SAR

– Relpcemnet of 1 benzene ring results in thiazosulfones—less active than DDS

– Substitution on benzene ring results in acetosulphone--↓ activity, ↓g.i.t irritation(bz increase solubility)

– Substitution by methanesulfinate (CH2SO2)-gives sulfoxone Na, which is water soluble, ↓g.i.t irritation(bz increase solubility) –this drug is preferred who can’t tolerate DDS-but given 3times of DDS bz of its hydrolysis.

Uses– Tuberculoid leprosy.– Lepromatous leprosy in

combination with rifampin & clofazimine.

– To prevent & treat Pneumocystis pneumonia in AIDS caused by Pneumocystis jiroveci ( Pneumocystis carinii).

Side effects

– Haemolytic anaemia–Methemoglobinemia– Gastrointestinal intolerance– Fever,pruritus,rashes.– Erythema nodosum leprosum

Clofazimine

MOA– It is a phenazine dye.–Unknown mechanism of

action ,may be DNA binding.

– Antiinflammatory effect.– Absorption from the gut is

variable.– Given orally , once daily.

MOA– Excreted mainly in feces.– Stored mainly in

reticuloendothelial tissues and skin.

– Half-life 2 months.– Delayed onset of action (6

weeks).

SAR

– Basic nucleus –phenazine – Halogen substitution at P-

position of two phenyls at C-3, and C-10-enhance activity but are not essential for activity.

– Br > Cl > CH3 >C2H5OH > H >F

Uses–Multidrug resistance TB.– Lepromatous leprosy – Tuberculoid leprosy in :• patients intolerant to

sulfones– dapsone-resistant bacilli.– Chronic skin ulcers caused by

M.ulcerans.

Side effects– Skin discoloration ranging from

red-brown to black.– Gastrointestinal intolerance.– Red colour urine.– Eosinophilic enteritis

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