Pharmacotherapy of Tuberculosis (II)

Category: Education

Presentation Description

This includes M.O.A, Pharmacokinatics,Adverse effects, C/I,Drug Interactions &Therapeutic uses of all the First line Antitubercular Drugs


Presentation Transcript

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) 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/ 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 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) 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

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

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


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) 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) 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

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