Drug Therapy of Respiratory System 3 (Drug Therapy of Tuberculosis) PDF

Drug Therapy of Respiratory System 3 Management & Science University (Drug Therapy of Tuberculosis) A.P. Dr. Mahfoudh A.M. Abdulghani...

Drug Therapy of Respiratory System 3 Management & Science University (Drug Therapy of Tuberculosis) A.P. Dr. Mahfoudh A.M. Abdulghani Pharmacology Department, IMS, MSU, Shah Alam, Selangor 1  Topic Learning Outcomes (TLO) After the session students will be able to: 1. Describe the therapeutic objectives of the treatment of pulmonary Management & Science University tuberculosis. 2. Classify drugs used for the treatment of tuberculosis. 3. Describe the mechanism of action, significant pharmacokinetics, usefulness and untoward effects of first line antituberculosis drugs. 4. State the drugs used for the treatment of different categories of pulmonary tuberculosis. 5. Describe the rationale of combination antimicrobial therapy in the treatment of tuberculosis. 6. Define Directly observed treatment, short-course (DOTS) and describe the advantages of DOTS. 7. Describe the mechanism of resistance of 1st line antituberculosis drugs. 2  Terminologies Latent tuberculosis infection: A state of persistent immune response to stimulation by M. tuberculosis antigens with no evidence of clinically manifest TB disease. Management & Science University Multidrug-resistant tuberculosis is present when a strain is resistant to at least the first line drugs isoniazid and rifampin. Extensively drug-resistant tuberculosis is present when a strain is resistant to at least the first line drugs isoniazid and rifampin, a fluoroquinolone, and aminoglycoside. Directly observed treatment, short-course (DOTS, also known as TB-DOTS) is refer to the tuberculosis (TB) control strategy recommended by the World Health Organization. tuberculocidal activity tuberculostatic activity Combination therapy Monotherapy Adjuvant therapy 3  Introduction Tuberculosis (TB) is a transmissible bacterial infection. Management & Science University TB is transmitted by inhalation and not all people who are exposed develop active TB. TB is endemic in Malaysia and continues to be a major public health concern. TB usually caused by Mycobacterium tuberculosis (bacteria). The mainstay of treatment of TB is antituberculosis medications. Drug treatment for active TB is Combination therapy with 4 drugs Drug treatment for latent TB can be monotherapy (one drug) and is considered as prophylactic treatment. 4  TLO1. Therapeutic objectives of the treatment of pulmonary tuberculosis The general therapeutic objectives of the treatment of pulmonary tuberculosis are: Management & Science University 1. Decrease transmission 2. Prevent emergence of drug-resistant TB 3. Prevent relapse 4. Reduce morbidity 5. Reduce mortality The main therapeutic objective in treatment of latent tuberculosis: To prevent development of active tuberculosis. The main therapeutic objective in treatment of active tuberculosis: The objective is to eradicate infection in affected patient and prevent spread of disease to contacts. 5  TLO2: Drug classes used for the treatment of tuberculosis Drug classes used for the treatment of tuberculosis can be divided into: Management & Science University First line therapy: Isoniazid; Rifampin; Ethambutol; Pyrazinamide. Second line therapy: Fluoroquinolones; (moxifloxacin, levofloxacin); Amikacin; Capreomycin; Bedaquiline; Cycloserine; Ethionamide; Aminosalicylic acid; Rifapentine; Linezolid Adjuvant therapy: Pyridoxine (Vit. B6) 6  Management & Science University Classification of anti-TB 7  TLO3: The mechanism of action, significant Management & Science University pharmacokinetics, usefulness and untoward effects of first line antituberculosis drugs First line therapy: Isoniazid; Rifampin; Slide 8 - 18 Pyrazinamide Ethambutol; 8  Isoniazid pharmacodynamics Site of Action: synthesis of mycolic acids of mycobacterial cell walls MoA: Management & Science University The active form of isoniazid Inhibits synthesis of mycolic acids, an essential component of mycobacterial cell walls. Bactericidal activity against susceptible strains of M. tuberculosis. Pharmacological effects: (Therapeutic effects & Side and toxic effects) a. Therapeutic effects or use: Firstline agent for tuberculosis: treatment of latent infection; less active against other mycobacteria. b. Side and toxic effects: Toxicity (Adverse effects) of isoniazid include: 1. Hepatotoxic, 2. Gastrointestinal upset 3. dose-related neurologic side effects: neuropathy, ataxia & paresthesia (give pyridoxine to prevent). 4. Rash, 9  Isoniazid significant of Pharmacokinetics, and Interactions Isoniazid is a prodrug and must be activated by bacterial catalase. Management & Science University Readily absorbed following oral administration; however, may undergo significant first pass metabolism. Absorption and bioavailability are reduced when isoniazid is administered with food. Metabolism of isoniazid occurs by acetylation and may be affected by genetic differences in slow and fast acetylators. Currently there are no recommendations in testing for genetic differences that affect treatment. Caution should be used with this agent in patients with liver disease. 10  Hepatotoxicity caused by isoniazid Hepatotoxicity symptoms: transaminases exceed five times the upper limit of normal or Management & Science University bilirubin is significantly elevated with nausea, vomiting, and jaundice. INH-induced hepatotoxicity is related to metabolites of INH (monoacetylhydrazine) and is not correlated with serum concentrations of the parent compound. Isoniazid is metabolized by N -acetyl transferase. Monoacetylhydrazine is associated with hepatotoxicity via formation of a reactive intermediate metabolite when N-hydroxylated by the cytochrome P450 mixed oxidase system. The toxic metabolite of INH producing due to genetic polymorphisms that affect the metabolic rates of drug enzymes. 11  Food-isoniazid interactions Administer vitamin supplements. Vitamin B6 (pyridoxine) should be given with isoniazid to Management & Science University prevent the side effect of INH administration. Avoid alcohol. Consuming alcohol may also increase the risk of isoniazid induced hepatitis and neuropathy. Avoid chocolate. Chocolate contains caffeine, which should be limited during isoniazid therapy. Because caffeine reduce the effectiveness of INH. Avoid histamine-containing foods and supplements. Histamine-containing foods (e.g., skipjack, tuna, other tropical fish) can cause headaches, sweating, palpitations, flushing, and hypotension. Avoid tyramine-containing foods and supplements. Tyramine-containing foods include cheese, red wine, fava beans, pickled food, cured food, and alcoholic beverages. Take on an empty stomach. Take at least 1 hour before or 2 hours after meals. Take separate from antacids. Taking this medication with antacids can reduce absorption. 12  Isoniazid drug interactions Drug interactions — Isoniazid is an inhibitor of several drug-metabolizing enzymes, which Management & Science University can lead to: 1. Isoniazid may diminish the therapeutic effect and therapeutic failure of other drugs. a. Levodopa; Patient Management Monitor for reduced levodopa effectiveness and worsening of Parkinson disease symptoms if combined with isoniazid. 2. Increase drug toxicity by reducing its metabolism. a. Isoniazid may enhance the hepatotoxic effect of acetaminophen. b. Using phenytoin together with isoniazid may increase the effects of phenytoin through inhibition of phenytoin metabolism. 13  Rifampin (Rifamycin) The rifamycins include rifampin, rifapentine, and rifabutin. rifampin is most used, Management & Science University either as first-line therapy Site of Action: DNA dependent RNA polymerase MoA: Inhibition of DNA-dependent RNA polymerase results in the blocking of RNA production, which exhibits bactericidal activity against mycobacteria. Resistance rapidly emerges when used as a single drug in the treatment of active infection. Pharmacological effects: (Therapeutic effects & toxicity) a. Therapeutic effects: Firstline agent for tuberculosis atypical mycobacterial infections b. Toxicity (side effects): see next slide 14  Rifampin side effects 1. Gastrointestinal effects (nausea, vomiting, diarrhea), Management & Science University 2. Central nervous system effects (headache, fever), 3. Dermatologic effects (rash, itching, flushing), 4. Hematologic effects (thrombocytopenia, neutropenia, and acute hemolytic anemia), and 5. pulmonary toxicity. 6. Hepatitis is more commonly observed in patients with predisposing factors, including administration of concomitant hepatotoxins (such as isoniazid), HIV coinfection, history of liver disease, regular alcohol consumption. 7. Rifampin typically causes an orange or red-orange discoloration of body fluids (including urine, sweat, saliva, and tears). 15  Pharmacokinetics rifamycins (rifampin) Management & Science University The rifamycins include rifampin, rifapentine, and rifabutin. rifampin is most commonly used, as first-line therapy. Rifampin rapid and complete absorption after oral administration. Rifampin undergoes wide distribution into most body tissues and fluids. Rifampin undergoes extensive hepatic metabolism to less active metabolites. Oral, IV hepatic clearance (half-life 3.5h) Renal elimination of unchanged drug is minimal (