Pharmacotherapy of tuberculosis(II) :Dr. Rajendra K. Panda, M.D Faculty, Deptt. Of Pharmacology, S.C.B. Medical College, Cuttack Pharmacotherapy of tuberculosis(II)


INH :INH Salient features: 1) Most active antitb drug 2)Important assets are -potency -infrequent toxicity -low cost 3)Bactericidal for rapid growers 4)Useful for tb meningitis 5)Effective for both extra cellular & intracellular tb 6)If combined with other drug it has good resistance preventing action


Structure of INH :Structure of INH Hydrazide of isonicotinic acid INH PYRIDOXINE It has structural similarity with Pyridoxine


Mechanism of Action :Mechanism of Action ISONIAZID Kat G(catalase peroxidase in mycobacteria) Active INH AcpM & Kas AcpM-Acyl Carrier protein KasA( ßketoAcyl Carrier protein synthetase) Block Mycolic Acid Synthesis


Pharmacokinetics :Pharmacokinetics Abs:complete orally. Oral dose=Parenteral dose Dist: penetrate all body tissue Placenta Meninges Caseous tb lesion Meta: in liver INH N acetyl transferase(NAT2) N-Acetyl Isoniazid Isonicotinic Acid Acetyl Hydrazine 1st ACETYLATION(PhaseII), then HYDROLYSIS (Phase I)


Acetylation of INH is genetically determined :Acetylation of INH is genetically determined FAST SLOW Eskimos, Egyptians, Japanese Mediterin Jews Indians(30-40%), Indians(60-70% HIGH N-Acetyl transferase LOW Autosomal Inherited as Autosomal Dominant Recessive 70 mins T½ 2-3 hrs Occurs Peripheral neuritis More frequent Also occurs Hepatitis More


P/K Contd :P/K Contd Excretion:-75-95% excreted in urine -Dose adjustment is not required in Renal Failure -INH & Acetyl Hydrazine are not bound to P.P, thus dialyzable C/I - KNOWN HYPERSENSITIVITY -ACUTE HEPATIC DISEASE


Drug interaction :Drug interaction Inhibits metabolism of PHT,CBZ,ETX -inhibits parahydroxylation of PHT -Signs, Symptoms, Toxicity—27% -plasma conc. to be monitered Inhibit metabolism of Warfarin,Diazepam,Disulfiram Abs.impaired by Al(OH)3 PAS inhibits the metabolism of INH


Clinical Use :Clinical Use Therapeutic: Essential component of all AntiTB Regimen Prophylactic: -Transmission to close contact -Baby born to inf.mother -Development of active TB in immunodeficient individuals Doses of INH 5mg/kg/day 10mg/kg/A.D 10mg/kg/day –in serious infection -If malabsorbtion is a problem IV. Prophylactic: 5mg/kg/day


Adverse Effect:- :Adverse Effect:- Rash Peripheral Neuropathy Hepatitis Transient loss of Memory Seizure Pleural effusion HEPATOTOXICITY -Acetyl Hydrazine cause the damage -↑in Serum Transaminase -Clinical Hepatitis -Can be fatal if not withdrawn promptly


Contd. :Contd. PERIPHERAL NEUROPATHY -Parasthesia,numbness -Due to relative def.of Pyridoxine Pyridoxine Kinase 1)Pyridoxine Pyridoxal phosphate INH having str.similarity with Pyridoxine competes with Pyridoxine 2)INH ↑ Pyridoxine excretion –Thus causing deficiency Prophylaxis:10mg once daily Malnourished patient Elderly, Pregnant & lactating mother, Diabetics &Alcoholics T/t of established neuropathy:100-200mg/once daily


RIFAMPIN(R) :RIFAMPIN(R) Semisynth. deri of Rifamycin B-from St.meditarranei Bactericidal ,affect all subpopulation of M.tb.acts best on Spurters &slow growing Acts both extra &intracellularly Good sterilising property &resistance preventing action Bactericidal efficacy ≈ INH &>any other 1st line drug Analogue of RIFAMPIN isRIFABUTIN obtained from Rifamycin S


Bactericidal Efficacy :Bactericidal Efficacy Inhibits - Gm+ve -Gm-ve -Mycobact.inf -M.tb,M.leprae,M.kansassi Important ones are -H.influenzae -N.meningitis -Legionella -Brucella -M.R.S.A


M.O.A OF Rifampin :M.O.A OF Rifampin D.N.A   DNA dependent R.N.A.polymerase R.N.A  Protein Syn.  Cell multiplication Rifampin bind to β S.U of D.D.R.P  Drug –Enz Complex  Supression of chain initiation RIFAMPIN


Pharmacokinetics :Pharmacokinetics Abs: -Well absorbed from g.i tract -PAS interferes with abs. -Food also interferes with abs. Dist: -wide. Penetration to •Cavities •Meninges •Caseous Mass •Placenta Rifampicin causes an orange red coloration of body secretion due to various aspect of Rifampin metabolism


P/K Contd.Metabolism :P/K Contd.Metabolism Following abs. from G.I. Tract  Eliminated rapidly in the bile &undergoes Enterohepatic Circulation  Rifampin is progressively deacetylated  This metabolite is bactericidal T1/2 varies from 1.5-5 hrs EXCRETION: Urine-30% Faeces 60-65% Recycling through liver by excretion in bile, reabsorption from intestines into portal circulation, passage back into liver, and re-excretion in bile.


Doses of Rifampin :Doses of Rifampin Doses- 10mg/kg/day 10mg/kg/Alt.day C/I –k/c/o history of h/s to Rifamycin -Hepatic Dysfunction Precaution –Careful monitoring of L.F.T. -In elderly - In alcoholics -Pts. having hepatic disease


Side Effects: :Side Effects: 1)Hepatitis: i)Mod - bilirubin -S.G.O.T/S.G.P.T which are common at the outset ii)Transient 2)Haemolytic Syn:Purpura,Haemolysis,Shock &Renal failure 3)Exfoliative Dermatitis in H.I.V +ve 4)Temp.oliguria,Dysnoea,Haemolytic anemia-Thrice/wk 5)Flu like Syndrome –Twice/ wk


Drug Interactions of RIFAMPIN :Drug Interactions of RIFAMPIN Strongly induces CYTP450 isoforms CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4 Own metabolism &also other drugs like OCPill –contraceptive failure,Estrogen to be / nonhormonal methods to accept Oral anticoagulant Oral hypoglycaemic drugs Corticosteroid drugs Antiarrythmic drugs -Digitoxin,Quinidine Antiretroviral drugs –PI &NNRTI except EFAVIRENZ Antifungal Drugs –Ketoconazole


USES OF RIFAMPIN :USES OF RIFAMPIN 1)Mycobacterial infection ☻M.tb ☻M.leprae ☻Atypical mycobacteria -M.kansassi -M.intracellulare -M.marinum


2)Other indications :2)Other indications a)meningococcal meningitis-carrier state 600mg B.D for 2 days b)H.influenzae meningitis –close contact 20mg/kg/dayfor 4days c)Legionella infection -Along wiyh Erythromycin d) Serious staphylococcal infection like - osteomylitis -prosthetic Valve Surgery e)Brucellosis –Along with Doxycycline f)MRSA g)T/t of meningitis caused by highly penicillin resistant strain


PYRAZINAMIDE(Z) :PYRAZINAMIDE(Z) Synthetic analogue of Nicotinamide Though weakly tuberculocidal  More active in acidic medium Highly effective during 1st 2months More effective against Slow Growing Active both intra&extracellularly Including Z in combination tharapy -duration of t/t is ↓ -It has potent sterilising action -Risk of relapse is reduced


Slide 23:Pyrazinamide is essential for the first two months of 6/8-month treatment Relapses


Slide 24:Pyrazinamide does not give any additional benefit if given beyond two months in short-course treatment Cure Rate (%)


MOA OF Z :MOA OF Z Pyrazinamide Mycobacterial Pyrazinamidase Pyrazinoic Acid Inhibits Mycolic Acid Synthesis Resistance due to mutation of gene pncA


Pharmacokinetics :Pharmacokinetics Abs:Well absorbed from g.i.tract Dist:good penetration to all body tissue&CSF Meta: Pyrazinamide Pyrazinoic Acid 5-OH pyrazinoic Acid T1/2  6-10hrs Dose: 25mg/D 35mg/A.D


Side Effects: :Side Effects: 1)Hepatotoxicity: Most hepatotoxic  SGOT &SGPT Serum Bilirubin C/I-Not to be given with any degree of hepatic dysfn 2)Inhibits the excren of ureates  Hyperuracemia  Acute episodes of Gout 3)Joint pain ,Athralgia


Management of ATT induced Hepatitis :Management of ATT induced Hepatitis Pt .developing hepatitis during t/t of T.B Rule out any probable cause of jaundice If the diagnosis is ATT induced hepatitis: Drugs prone for hepatitis must be stopped T/t must be withheld until LFT is normal Wait for 2 wks after disappearance of jaundice Seriously ill TB pt.with ATT induced hepatitis may die without t/t T/t- { 2SHE/10HE} (WHO Guidelines,2003) As hepatitis is resolved, usual Anti TB to be started


ETHAMBUTOL(E) :ETHAMBUTOL(E) Tuberculostatic ,active against M.tb M.A.C M.intracellularae Rapid Growers are more susceptible Hastens the rate of sputum conversion Prevent the emergence of Resistant bacilli


M.O.A of Ethambutol :M.O.A of Ethambutol Ethambutol   Mycobact. Arabinosyl Transferase   Polymerisation reaction of Arabinoglycan  Essential component of Myco.Cellwall E inhibits the enz.Myco. Arabin. Trans., which is required for polymerisation reaction of Arabinoglycan


Pharmacokinetics :Pharmacokinetics Abs:Well absorbed from g.i.t. Dist:Wide,penetrates the meninges T1/2 ~ 4hrs Excretion :-unchanged in urine(3/4th) -Excreted by G.F& T.S -Dose to be reduced in Renal failure C/I ; Cr. Clearance <50ml/min Doses of Ethambutol : 15mg/kg/day 30mg/kg/A.D


Side Effects: :Side Effects: 1)RETROBULBAR NEURITIS :causing -Loss of V.A - Red Green Color blindness -Field Defect Early recognition &stoppage of drug- visual toxicities is largely reversible Contra-indication ;In children <6yrs a) they are unable to report early. b) may not permit the assessment of V.A &red green color blindness discrimination 2) Renal uric acid excretion Hyperuricemia 3)Pruritus,Joint Pain


STREPTOMYCIN(S) :STREPTOMYCIN(S) Aminoglycoside from Str.griseus 1st clinically active against Mycobact. Limitation of its use i)dose related toxicity ii)devlopment of resistant org. iii)pt compliance is poor due to i.m Present status: -Least used 1st line A.T.D -More active against extracellular bacilli -Inactive against intracellular bacilii


Mechanism of Action: :Mechanism of Action: -Drug actively transported across Cell membrane by O2 dependent process -It binds with specific 30s S.U of ribo protein(s12) -Protein Syn . Is hampered *Interferes with chain initiation *Induce misreading of mRNA * Incorporation of incorrect A.A into peptide  Formation of Nonfunctional /toxic protein *Cause break up of polysomes into monosomes IRREVERSIBLE &LETHAL FOR CELL


Pharmacokinetics: :Pharmacokinetics: Neither absorbed / destroyed in G.I.Tract. Absorption from inj site is rapid (30-60min) Distributed to Extracellular TB cavities. Not metabolised,Excreted unchanged in urine


Side Effects: :Side Effects: i)OTOTOXICITY-drugs get conc. In labrynthine fluid,both vestibular & cochlear damage ii)NEPHROTOXICITY iii)N.M PARALYSIS -Ach release, sensitivity of post.syn. receptors. iv)Sterile abscess at the inj. site Contra Indication: - Not to be given in pregnancy -Avoid use with other ototoxic drug eg;High ceiling diuretics,Minocycline,Cisplatin -Avoid use of other nephrotoxic drug eg;Amphotericin B, Vancomycin,Cyclosporin,Cisplatin -Pts with renal disease. -Cautious use with muscle relaxant.


Uses :Uses Sensitive to M.tb M.A.C M.kansassi Remains as an imp drug when inj.form is needed- -espcially with severe &life threatening condn. -TB meningitis -Miliary TB Other uses: - Tularemia - Plague Dose:15mg/kg/D 15mg/kg/A.D


Slide 38:Thank You