DRUGS USED IN TUBERCULOSIS • Less effective against atypical mycobacterial
species 5 FIRST-LINE AGENTS for TB treatment (in order of • Ca penetrate into phagocytic cells preference): • Active both intra and extracellular organisms 1. Isoniazid – INH, H 2. Rifampicin / Rifampin – RIF, R MOA 3. Pyrazinamide – PZA, Z • Inhibits synthesis of mycolic acids (essential 4. Ethambutol – E component of cell wall) 5. Streptomycin – S • Bactericidal, prodrug activated by KatG, the mycobacterial catalase-peroxidase Second line agents: • Activated form of INH forms a covalent complex Amikacin (Aminoglycoside) with an acyl carrier protein (AcpM) and KasA. A Aminosalicylic acid beta-ketoacyl carrier protein synthetase Ethionamide blocks mycolic acid synthesis Fluoquinolones * Given when unresponsive to 1st line + INH, RIF • Acts on extra and intracellular bacilliary population Isoniazid and Rifampin - most active drugs, this combination Resistance to INH administered for 9 months will cure 95-98% • Overproducers of inhA express low-level INH of TB resistance and cross-resistance to ethionamide • Mutation or deletion of KatG : high level of Isoniazid and Rifampin and Pyrazinamide resistance - during the first 2 months allows total duration of therapy to be shortened to 6 • Due to mutations, resulting in overexpression months without loss of efficacy of inhA, which encodes an NADH-depedent acyl carrier protein reductase Isoniazid, Rifampin, Pyrazinamide and either • Overexpression ahpC, a presumed virulence Ethambutol or Streptomycin gene involved in protection of the cell from - initial 4-drug therapy give until susceptibility oxidative stress of isolate has been determined; neither • Mutation in kasA ethambutol nor streptomycin adds substantially reduce or duration of • KatG mutants express high-level INH treatment regimen but provide additional resiostance and usually not cross-resistant to coverage if the isolate is resistant to INH, R ethionamide or both • Single-drug therapy with IH and failure to use INH plus at least one other drug to which the Characteristics of Mycobacterium Tuberculosis infecting strain is susceptible led to isoniazid • Naturally occurring drug resistant mutants are resistance present within large bacterial populations even before chemotherapy is started Pharmacokinetics • Replicates slowly, can remain dormant for prolonged • Readily absorbed from GIT and peak plasma periods and can be eradicated only during concentration within 1-2 hours replication • Absorption is decreased by aluminum • Bacilli live in several sites within the hosts and each hydroxide (give H2 blockers instead) site contains organisms with a different population size, metabolic activity and replication rate • Diffuses readily into all body fluids and tissues • Metabolisms of INH (i.e acetylation by liver N- Principles of Treatment acetyltransferase) is genetically determined • Treatment of disease must contain multiple drugs to • Average concentration of INH in the plasma of which the organisms are susceptible rapid acetylators is 1/3 to ½ of that in slow acetylators, average half-lives are 1 hour and 3 • Drugs must be taken regularly and treatment should hours, respectively continue for a sufficient length of time • Isoniazid metabolites and a small amount of unchanged drug are excreted mainly in the Isoniazid urine • Most active drug • No dose adjustment for renal failure but dose is • Small simple molecule freely soluble in water reduced in hepatic insufficiency because it is metabolized in the liver • With structure similar to Pyridoxine • Inhibits most tubercle bacilli in a concentration • INH can reduce metabolism of phenytoin and of 0.2µg/mL or less carbamazepine which increases its blood level • Bactericidal for actively growing bacilli and toxicity • Should be protected from light
Sexy & Babe + MR 1 of 3
Pharmacology – Antimycobacterial Drugs by Dra Alabastro Page 2 of 3
Adverse Reactions • Not given to children below 6 years old because of
• Allergic reactions, hepatitis, peripheral neuropathy, difficult to assess visual acuity CNS, tinnitus, GI discomfort • IH promotes excretion of Pyridoxine and this toxicity Streptomycin is reversed by administration of pyridoxine in a dosage as low as 10mg/d • Only with parenteral preparation (IM) • MOA: irreversible inhibitors of protein synthesis Rifampin/Rifampicin • Resistance & features of aminoglycoside
• Active in-vitro against Gr(-) and (+) cocci, some
• Poor penetration into cells, active against extracellular tubercle bacilli only enteric bacteria, Mycobacteria and Chlamydia • Serum concentration achieved in 30-60 min after IM • MOA: inhibit RNA synthesis • OTOTOXIC and NEPHROTOXIC • Acts on intra and extracellular bacillary • Monitor renal fcn & reduce dose if decrease in renal populations output • Resistance due to mutations preventing binding of ripamfin to RNA • Well-absorbed after oral administration and in DIRECT OBSERVED THERAPY SHORT COURSE (DOTS) – 6 mos fasting states therapy • Induces hepatic enzymes therefore there is • political comitment drug interaction • case detection by sputum smear microscopy (3 • Excreted mainly through the liver into bile, smears) recirculated and excreted in urine and feces • standardized short course therapy with direct • No adjustment of dose in renal insufficiency observation of drug intake • regular & uninterrupted supply of all essential Clinical Uses antiTB drugs • TB in combination with INH • standardized recording & reporting system • Atypical mycobacterial infection • Leprosy with sulfone DOSAGE REGIMEN FOR TB (WHO) Dose • Meningococcal carriage Regimen Patient adjustment • H. influenzae type B prophylaxis New • Staphylococcal carriage with anti staph pulmonary • Pneumococcal meningitis combine with smear (+) streptomycin, rifmpicin cases New seriously Add 1 tab INH, Pyrazinamide ill, smear (-) 100 mg PZA, 400 Regimen I: cases with mg each patient 2 HRZE → 4 • MOA: unknown extensive with >50 kg HR • Relative of nicotinamide; stable, parenchymal body wt before • Weakly bactericidal involvement initiation of tx • Acts on intracellular organisms within acidic New severely environment ill extrapulmonar • Resistance due to mutations in pncA (impair y TB cases conversion of pyrazinamide to its active form) or Previously impaired uptake of pyrazinamide; no cross- treated smear resistance with INH or other antiTB Regimen II: (+) • Rapidly absorbed from the GIT; Widely distributed in 2 HRZE/ 1 PTB with - body fluids; peak concentration in 1-2 hrs HRZE → 5 HRE relapsed tx • T1/2=8-12 hrs Failure, return to default Ethambutol New smear Add 1 tab INH, • BACTERIOSTATIC; Bactericidal at higher dose (but Smear (-) PTB 100 mg PZA, 500 toxic) other than Regimen III: mg each patient • MOA: inhibitor of mycobacterial arabinosyl cat1 2 HRZ → 4 HR with >50 kg transferases, encoded by the emb-CAB Extrapulmonar body wt before • Acts on both extra- & intracellular bacillary y TB, less initiation of tx populations severely ill • Resistance due to mutations of emb gene; 1,2,4,5 – denotes mos of therapy resistance when given alone *PZA only for two months • Well absorbed from the GIT, peak concentration in 4 MINOR SIDE EFFECTS hrs Side Effect Drug(s) What to do • T /2=4 Give medication at • Excretion: feces & urine GI intolerance R bedtime • Accumulates in renal failure, reduce dose Mild skin rxn Any Drug Give anti-histamines Orange-red urine R Reassurance Pharmacology – Antimycobacterial Drugs by Dra Alabastro Page 3 of 3
Pain at injection site S
Warm compress, • ADR: hemolysis in patients with G6PD deficiency, rotate injection sites methemoglobinemia, erythema nodosum leprosum Burning sensation at (flaring of lepromatous lesions) Z Give pyridoxine feet, neuropathy Anthralgia due to Z NSAIDS (aspirin) hyperuricemia Rifampin Flu like symptoms R Give anti pyretics • Very effective against lepromatous leprosy MAJOR SIDE EFFECTS • 600 mg daily Side Effect Drug(s) What to do • Given in combination w/ dapsone or another Severe rash from Any drug Discontinue drug & antileprosy drug to prevent rifampin-resistant M. hypersensitivity esp S refer to MHO/CHO leprae Discontinue drug & refer to MHO/CHO; Clofazimine Any drug Jaundice 2° to Resume to esp INH, • Phenazine dye used as alternative to dapsone hepatitis medication when it R, P • MOA: unknown but may involve DNA binding subsides & monitor clinically • Variable absorption from the gut, excreted primarily Impairment of visual Discontinue drug & by feces acuity & vision due E refer to • Stored widely in reticuloendothelial tissues & Slowly to neuritis ophthalmologist released, T1/2 = may be 2 mos Impaired hearing, • Indicated for sulfone-resistant leprosy or sulfone ringing of the ear & Discontinue drug & S intolerance dizziness due to refer to MHO/CHO damage of CN 8 • ADR: skin discoloration (since it is stored in skin) Oliguria, or ranging from red-brown to nearly black, GI albuminuria due to S, R - intolerance renal disorder Psychosis & Prednisone H - convulsion • Combined with other drug Thrombocytopenia, R - anemia, shock MHO-municipal heath office; CHO-city heath office Thalidomide
• MOA: Inhibits angiogenesis
ANTITB DRUGS DURING PREGNANCY AND LACTATION • Anti-inflammatory, immunomodulatory • INH, RIF & E: std drugs given bec they cross the • For multiple myeloma placenta • Removed from the market • PAS: can be safely used but could be poorly tolerated Amithiozone • S & other aminoglycosides: shld be avoided; effect on ear devt & fcn • hepatotoxic • Capreomycin, cycloserine, ethionamide: not recommended RECOMMENDED TREATMENT FOR LEPROSY • PZA: avoid (teratogenic) Indeterminate • Breastfeeding not discouraged; feed infants first ◦ Smear (-) before taking medicine ◦ Flat, hyposthetic (no sensation) lesion usually in • Drugs in breast milk not considered effective tx of the face, arms, legs TB in infants ◦ Single dose of Rif + ofloxacin + minocycline Paucibacillary ◦ Smear (-) DRUGS USED IN LEPROSY ◦ Flat, hyposthetic, hyperpigmented lesions <5 ◦ Rif 1x/month + dapsone 1x/day for 6 months Multibacillary • M. leprae never grown in vitro ◦ Smear (+) ◦ Multiple, erythematous, copper-colored plaques, Dapsone & other Sulfones nodules with or without anesthesia ◦ Rif + dapsone + clofazimine 1x/month for 12 • Main drug months • BACTERIOSTATIC • MOA: inhibits folate synthesis Eto yung sa lecture lang talaga nya • Resistance even if the dose is very low, combined with other drugs Thanks kay ape sa record =p • T1/2 (dapsone) = 1-2 days, tend to be retained in skin, muscle, liver, kidney • Dose must be adjusted in renal failure
(Autism and Child Psychopathology Series) Johnny L. Matson - Comorbid Conditions Among Children With Autism Spectrum Disorders-Springer International Publishing (2016)