Chemotherapy of Tuberculosis

By

Prof. Azza El-Medany

Tuberculosis

Common sites of infections : 1-Apical areas of lung 2- Renal parenchyma 3- Growing ends of bones

Where oxygen tension is high

Transmission

Through inanimate جامده objects Through air ( air borne transmission )

Treatment Of Tuberculosis

Tuberculosis remains the primary cause of death due to infectious disease.

Periods of treatment ( minimum 6 months) مهمه

Drugs are divided into two groups:First lineSecond line

Antimycobacterial drugs

First line of drugs:Isoniazid (INH)RifampinEthambutolStreptomycinPyrazinamide

Never use a single drug therapy

Isoniazid –rifampin 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.

Isoniazidاوال :

Bacteriostatic for resting bacilli. مهمهBactericidal للبكتيريا قاتل

for rapidly dividing bacilli.Is effective against intracellular as

well as extracellular bacilli النهاالمايكروفيج تخترق

Mechanism Of Action

Is a prodrug التناول قبل نشط غير دواءبواسطه تنشيطه بعد النشط للشكل يحولالبكتيريا من او بالجسم بعضاالنزيماتactivated by mycobacterial enzyme ,نفسها

Inhibits synthesis of mycolic acid----

( component of mycobacterial cell wall). جدا جدا مهمه

Clinical uses مهمهMycobacterial infections .Latent tuberculosis in patients with positive

tuberculin skin test

Prophylaxis وقائي against active TB in individuals who are in great risk .

Adverse effectsPeripheral neuritis باالطراف االعصاب التهاب بسببنقص هذا يحدثOptic neuritis &atrophy. نفسالسبب

( Pyridoxine should be given)العالجAllergic reactionssystemic lupus erythematosus ( SLE)Hepatitis ( ) عالماتها جدا من مهمه

Pyridoxin (vitamine B6)

gondes

مرضالكبد عن ناتج صفار

Drug Interactions اخر دواء عمل يحظر of INH دواءInhibits the hepatic microsomal enzymes,

cytochrome P450 . .. عمليه يقلل metabolize of otherمما

drugs

Cont .الذين للمرضى غالبا االعراضالجانبيه : تحدث

It is more likely to occur in slow acetylators and patients with malnutrition, alcoholism, diabetes and AIDS

Rifampin : ثانيا

Bactericidal للبكتيريا قاتلMOA : مهمهInhibits RNA synthesis.

باالسفل شرح كما االنزيمات على بالتاثير : شرحRifampin binds to the β subunit of

bacterial DNA – dependent RNA polymerase االنزيم .and thereby inhibits RNA synthesis اسم

2nd chioce after INH and do not used alone

Site of Action

Intracellular bacilliExtracellular bacilli

Clinical usesMycobacterial infectionsProphylaxis وقائي of active tuberculosis.Treatment of serious staphylococcal infections.Meningitis مهمه by highly resistant penicillin

pneumococci. Atypical mycobacterial infections.As alternative of isoniazid in prophylaxis of latent

tuberculosis

Adverse effects

Harmless red-orange discoloration of body secretions . والدم البول مثل

HepatitisFlu-like syndromeHemolytic anemiaThrombocytopenia

Drug Interactions

Potent قوي inducer عكس – منشطالسابق of hepatic microsomal الدواء

enzymes جدا جدا cytochrome ) مهمهP450)

.. عمليه يزيد metabolize of otherمماdrugs عملها يعطل Rimpfin excreted byمما

Bile from live as fessesLiver >> bile >> fesses

مهمه

Ethambutol ثالثا :

Bacteriostatic – عكسالسابق جدا مهمهالبكتيريا تكاثر يقلل

جدا Inhibits mycobacterialمهمهarabinoglycan a component of mycobacterial cell wall تكوين يمنع لذلك

الخلوي الجدار

Site Of Action

Intracellular & Extracellular bacilli

Clinical uses

Treatment of tuberculosis in combination with other drugs. له الوحيد االستخدام

Adverse effects

Optic neuritis جدا causing loss of مهمهvisual acuity

red-green color blindness.(Relatively contraindicated in

children under 5 years).

Hyperuricemia

Contraindication االستخدام موانع It is relatively contraindicated in children too

young to permit assessment of visual acuity and red green color discrimination

PyrazinamideProdrug درجه عند النشط للشكل يتحول حامضيه

منخفضه يلي كما النشط للشكل : يتحول Pyrazinamide >> الى pyrizenic acid at PH= 5.5 يتحول

Bactericidal Mechanism of action is unknown .

Pharmacodinamic : 1- widley disturputed 2- orally and well absorbed in GIT3- pass through 1st pass metabolism in liver then excreted through kidney

Half time = 8-11 H

Site Of Action

Active against Intracellular Bacilli

Clinical uses

Mycobacterial infections mainly in multidrug resistance cases.

It is important in short –course (6 months) regimen.

Prophylaxis وقائي of TB .

Adverse effects

Hepatotoxicity

Hyperuricemia >> cause GOUTY نقرس ARTHRIETS ( ) سؤال جدا مهمه

Drug fever & skin rash

Streptomycin رابعا :

BactericidalInhibitors of protein synthesis by binding to 30 S

ribosomal subunits. Active mainly on extracellular bacilli

العالجيه الخطه في لل كبديل يعتبر given by injection عبر يعطى الذي الوحيدعبر يعطى الذي السابق عكسكل الحقنالفم

erythrobutile

Clinical uses

Severe , life-threating form of T.B. as meningitis مهمه, disseminated disease.

Adverse Effects

Ototoxicityمهمه Nephrotoxicity الكليه تسممNeuromuscular block

Indication of 2nd line treatment

Resistance to the drugs of 1st line.Failure of clinical responseThere is contraindication for first line

drugs.Patient is not tolerating the drugs first

line drugs.

Ethionamide اوال

Inhibits the synthesis of mycolic acid

نفسميكانيكيه له الدواء هذا INH

له شبيه ويعتبر

Clinical uses

As a secondary line agent.

Adverse Effects

Poorly tolerated

Because of : مهمهSevere gastric irritation &Neurological manifestations

CAPREOMYCIN : ثانيا

الجانبيه اعراضه من ولذلك العضل عبر يعطى Local pain & sterile abscesses due to injection. الجانبيه اثاره : ومن Nepherotoxicity

Cycloserine ثالثا :

Inhibitor of cell wall synthesis by inhipite formation of peptiesdoglycan

The most serious side effects are peripheral

neuropathy and CNS dysfunction مهمه.

Pyridoxine should be given. Contraindicated in epileptic صرع patients.

Fluoroquinolones رابعا : (Ciprofloxacin &Levofloxacin )

Effective against multidrug- resistant tuberculosis.

Block DNA bacterial synthesis السالبه الجرام ضد يستخدم

Adverse effects

Nausea , vomiting , diarrhea Prolong QT interval Damage growing cartilage ( arthropathy) مهمه

والمرضعات والحوامل لالطفال يعطى ال لذلك

Rifabutin : خامسا

RNA inhibitor. ال شبيهCross –resistance with rifampin is

complete.Enzyme inducer for P450 (hepatic

enzymes).

rifampin

Clinical uses

Effective in prevention &treatment of T.B. in AIDS patients.

Adverse Effects

GIT intolerance

Orange-red discoloration of body secretions.

Aminosalicylic Acid : سادسا(PAS).

كثره بسبب االيام هذه االستخدام قليل االعراضالجانبيه

Bacteriostatic

Inhibits Folic acid synthesis.

Clinical uses

AS a second line agent is used in the treatment of pulmonary & other forms of tuberculosis.

Adverse effects

GIT upset ( anorexia, nausea, diarrhea, epigastric pain ).

Hypersensitivity reactions

Crystalluria

TB & Pregnancy

Untreated TB represents a great risk to the pregnant woman & her fetus than the treatment itself.

First line drugs are given for 9 months in normal doses

Streptomycin is the last alternative in treatment

TB & Breast Feeding

It is not a contraindication to receive drugs , but caution is recommended

خااااصلـ شكرالرحمن عبد غالي

المطيري فهدالعبيداء ناصر