Chemotherapy of Tuberculosis By Prof Azza ElMedany Tuberculosis

Chemotherapy of Tuberculosis By Prof. Azza El-Medany

Tuberculosis v Common sites of infections : v 1 -Apical areas of lung v 2 - Renal parenchyma v 3 - Growing ends of bones Where oxygen tension is high

Transmission v Through inanimate ﺟﺎﻣﺪﻩ objects v Through air ( air borne transmission )

Treatment Of Tuberculosis v Tuberculosis remains the primary cause of death due to infectious disease. v Periods of treatment ( minimum 6 months) ﻣﻬﻤﻪ v Drugs are divided into two groups: v First line v Second line

Antimycobacterial drugs v. First line of drugs: v Isoniazid (INH) v Rifampin v Ethambutol v Streptomycin v Pyrazinamide

Never use a single drug therapy v. Isoniazid –rifampin combination administered for 9 months will cure 95 -98% of cases. v. Addition of pyrazinamide for this combination for the first 2 months allows total duration to be reduced to 6 months.

ﺍﻭﻻ v. Bacteriostatic : Isoniazid for resting bacilli. v ﻣﻬﻤﻪ Bactericidal ﻗﺎﺗﻞ ﻟﻠﺒﻜﺘﻴﺮﻳﺎ for rapidly dividing bacilli. v. Is effective against intracellular as well as extracellular bacilli ﻻﻧﻬﺎ ﺗﺨﺘﺮﻕ ﺍﻟﻤﺎﻳﻜﺮﻭﻓﻴﺞ

Clinical uses ﻣﻬﻤﻪ v. Mycobacterial infections . v. Latent tuberculosis in patients with positive tuberculin skin test v Prophylaxis ﻭﻗﺎﺋﻲ against active TB in individuals who are in great risk.

Adverse effects v Peripheral neuritis ﺍﻻﻋﺼﺎﺏ ﺍﻟﺘﻬﺎﺏ ( ﺑﺎﻻﻃﺮﺍﻑ vitamine B 6) Pyridoxin v ﻳﺤﺪﺙ ﻫﺬﺍ ﺑﺴﺒﺐ ﻧﻘﺺ v Optic neuritis &atrophy. ﻧﻔﺲ ﺍﻟﺴﺒﺐ ﺍﻟﻌﻼﺝ (Pyridoxine should be given ) v Allergic reactions v systemic lupus erythematosus ( SLE) gondes v Hepatitis ( ) ﻋﻼﻣﺎﺗﻬﺎ ﻣﻬﻤﻪ ﻣﻦ

Cont. : ﺗﺤﺪﺙ ﺍﻻﻋﺮﺍﺽ ﺍﻟﺠﺎﻧﺒﻴﻪ ﻏﺎﻟﺒﺎ ﻟﻠﻤﺮﺿﻰ ﺍﻟﺬﻳﻦ It is more likely to occur in slow acetylators and patients with malnutrition, alcoholism, diabetes and AIDS Drug Interactions v Inhibits ﺩﻭﺍﺀ ﻳﺤﻈﺮ ﻋﻤﻞ ﺩﻭﺍﺀ ﺍﺧﺮ of INH the hepatic microsomal enzymes, cytochrome P 450. v ﻣﻤﺎ ﻳﻘﻠﻞ ﻋﻤﻠﻴﻪ. . metabolize of other drugs

ﺛﺎﻧﻴﺎ : Rifampin v Bactericidal ﻗﺎﺗﻞ ﻟﻠﺒﻜﺘﻴﺮﻳﺎ v MOA : ﻣﻬﻤﻪ Inhibits RNA synthesis. ﺑﺎﻟﺘﺎﺛﻴﺮ ﺑﺎﻻﺳﻔﻞ ﺍﻻﻧﺰﻳﻤﺎﺕ ﻛﻤﺎ ﺷﺮﺡ ﻋﻠﻰ v ﺷﺮﺡ : Rifampin binds to the β subunit of bacterial DNA – dependent RNA polymerase ﺍﻻﻧﺰﻳﻢ ﺍﺳﻢ and thereby inhibits RNA synthesis. v 2 nd chioce after INH and do not used alone

Site of Action v Intracellular bacilli v Extracellular bacilli

Clinical uses v Mycobacterial infections v Prophylaxis ﻭﻗﺎﺋﻲ of active tuberculosis. v Treatment of serious staphylococcal infections. v Meningitis ﻣﻬﻤﻪ by highly resistant penicillin pneumococci v. Atypical mycobacterial infections. v As alternative of isoniazid in prophylaxis of latent tuberculosis

Adverse effects v Harmless red-orange discoloration of body secretions. ﻣﺜﻞ ﺍﻟﺒﻮﻝ ﻭﺍﻟﺪﻡ v Hepatitis v Flu-like syndrome v Hemolytic anemia v Thrombocytopenia

Drug Interactions v Potent ﻗﻮﻱ inducer ﻋﻜﺲ ﺍﻟﺪﻭﺍﺀ ﺍﻟﺴﺎﺑﻖ – ﻣﻨﺸﻂ of hepatic microsomal enzymes ﻣﻬﻤﻪ ﺟﺪﺍ ( cytochrome P 450) v ﻣﻤﺎ ﻳﺰﻳﺪ ﻋﻤﻠﻴﻪ. . metabolize of other drugs ﻣﻤﺎ ﻳﻌﻄﻞ ﻋﻤﻠﻬﺎ Rimpfin excreted by ﻣﻬﻤﻪ Bile from live as fesses Liver >> bile >> fesses

Site Of Action v Intracellular & Extracellular bacilli

Clinical uses v Treatment of tuberculosis in combination with other drugs. ﺍﻻﺳﺘﺨﺪﺍﻡ ﺍﻟﻮﺣﻴﺪ ﻟﻪ

Adverse effects v Optic neuritis ﻣﻬﻤﻪ ﺟﺪﺍ causing loss of visual acuity v red-green color blindness. (Relatively contraindicated in children under 5 years). v Hyperuricemia

Contraindication ﺍﻻﺳﺘﺨﺪﺍﻡ v It ﻣﻮﺍﻧﻊ is relatively contraindicated in children too young to permit assessment of visual acuity and red green color discrimination

v Prodrug Pyrazinamide ﻳﺘﺤﻮﻝ ﻟﻠﺸﻜﻞ ﺍﻟﻨﺸﻂ ﻋﻨﺪ ﺩﺭﺟﻪ ﺣﺎﻣﻀﻴﻪ ﻣﻨﺨﻔﻀﻪ v : ﻳﺘﺤﻮﻝ ﻟﻠﺸﻜﻞ ﺍﻟﻨﺸﻂ ﻛﻤﺎ ﻳﻠﻲ v Pyrazinamide >> ﻳﺘﺤﻮﻝ ﺍﻟﻰ pyrizenic acid at PH= 5. 5 v Bactericidal v Mechanism of action is unknown. Pharmacodinamic : Half time = 1 - widley disturputed 8 -11 H 2 - orally and well absorbed in GIT 3 - pass through 1 st pass metabolism in liver then excreted through kidney

Site Of Action v Active against Intracellular Bacilli

Clinical uses v Mycobacterial infections mainly in multidrug resistance cases. v It is important in short –course (6 months) regimen. v Prophylaxis ﻭﻗﺎﺋﻲ of TB.

Adverse effects v Hepatotoxicity v Hyperuricemia >> cause GOUTY ﻧﻘﺮﺱ ARTHRIETS ( ﻣﻬﻤﻪ ﺟﺪﺍ ) ﺳﺆﺎﻝ v Drug fever & skin rash

ﺭﺍﺑﻌﺎ : Streptomycin v Bactericidal v Inhibitors of protein synthesis by binding to 30 S ribosomal subunits. v Active mainly on extracellular bacilli erythrobutile ﺍﻟﻌﻼﺟﻴﻪ ﺍﻟﺨﻄﻪ ﻓﻲ ﻳﻌﺘﺒﺮ ﻛﺒﺪﻳﻞ ﻟﻞ given by injection ﺍﻟﻮﺣﻴﺪ ﺍﻟﺬﻱ ﻳﻌﻄﻰ ﻋﺒﺮ ﺍﻟﺤﻘﻦ ﻋﻜﺲ ﻛﻞ ﺍﻟﺴﺎﺑﻖ ﺍﻟﺬﻱ ﻳﻌﻄﻰ ﻋﺒﺮ ﺍﻟﻔﻢ

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

Adverse Effects v Ototoxicity ﻣﻬﻤﻪ v Nephrotoxicity ﺗﺴﻤﻢ ﺍﻟﻜﻠﻴﻪ v Neuromuscular block

Indication of 2 nd line treatment v Resistance to the drugs of 1 st line. v Failure of clinical response v There is contraindication for first line drugs. v Patient is not tolerating the drugs first line drugs.

Clinical uses v As a secondary line agent.

Adverse Effects Poorly tolerated Because of : ﻣﻬﻤﻪ v Severe gastric irritation & v Neurological manifestations

ﺛﺎﻟﺜﺎ : Cycloserine v Inhibitor of cell wall synthesis by inhipite formation of peptiesdoglycan v The most serious side effects are peripheral neuropathy and CNS dysfunction ﻣﻬﻤﻪ. v Pyridoxine should be given. v Contraindicated in epileptic ﺻﺮﻉ patients.

ﺭﺍﺑﻌﺎ : Fluoroquinolones (Ciprofloxacin &Levofloxacin ) v Effective against multidrug- resistant tuberculosis. v Block DNA bacterial synthesis v ﻳﺴﺘﺨﺪﻡ ﺿﺪ ﺍﻟﺠﺮﺍﻡ ﺍﻟﺴﺎﻟﺒﻪ

Adverse effects v Nausea , vomiting , diarrhea v Prolong QT interval v Damage growing cartilage ( arthropathy) ﻣﻬﻤﻪ ﻟﺬﻟﻚ ﻟﻼﻃﻔﺎﻝ ﻭﺍﻟﺤﻮﺍﻣﻞ ﻭﺍﻟﻤﺮﺿﻌﺎﺕ ﻻ ﻳﻌﻄﻰ

ﺧﺎﻣﺴﺎ : Rifabutin RNA inhibitor. rifampin ﺷﺒﻴﻪ ﺍﻝ v. Cross –resistance with rifampin is complete. v. Enzyme inducer for P 450 (hepatic enzymes). v

Clinical uses v Effective in prevention &treatment of T. B. in AIDS patients.

Adverse Effects v GIT intolerance v Orange-red secretions. discoloration of body

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

Adverse effects v GIT upset ( anorexia, nausea, diarrhea, epigastric pain ). v Hypersensitivity v Crystalluria reactions

TB & Pregnancy v Untreated TB represents a great risk to the pregnant woman & her fetus than the treatment itself. v First line drugs are given for 9 months in normal doses v Streptomycin is the last alternative in treatment

TB & Breast Feeding v It is not a contraindication to receive drugs , but caution is recommended ﺷﻜﺮ ﺧﺎﺍﺍﺍﺹ ﻟـ ﻏﺎﻟﻲ ﻋﺒﺪ ﺍﻟﺮﺣﻤﻦ ﻓﻬﺪ ﺍﻟﻤﻄﻴﺮﻱ ﻧﺎﺻﺮ ﺍﻟﻌﺒﻴﺪﺍﺀ