update on anti tubercular drugs

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Update on anti tubercular drugs : 

Update on anti tubercular drugs

A Global Emergency : 

A Global Emergency The Tuberculosis in the beginning of the 21st Century - declared as Global Emergency (WHO)

Why Tuberculosis is a Important Disease. : 

Why Tuberculosis is a Important Disease. An Important communicable disease. A leading cause of morbidity and mortality in Developing world. Most common in Bangladesh, India, China, Indonesia, Africa, and Pakistan. But it is Curable Disease

Tuberculosis is a Global Problem : 

Tuberculosis is a Global Problem

Discovery of Mycobacteriumtuberculosis - A Tribute to Robert Koch : 

Discovery of Mycobacteriumtuberculosis - A Tribute to Robert Koch

Historical Background : 

Historical Background Neolithic Time 2400 BC - Egyptian mummies spinal columns 460 BC Hippocrates, Greece First clinical description: Phthisis / Consumption (I am wasting away) 500-1500 AD Roman occupation of Europe it spread to Britain 1650-1900 AD White plague of Europe, causing one in five deaths

Diagnostic discoveries : 

Diagnostic discoveries 24th March 1882 (Robert Koch) TB Day Discovery of staining technique that identified Tuberculosis bacillus Definite diagnosis made possible and thus treatment could begin 1890 (Robert Koch) Tuberculin discovered Diagnostic use when injected into skin 1895 (Roentgen) Discovery of X-rays Early diagnosis of pulmonary disease

Microscopy and Tuberculosis : 

Microscopy and Tuberculosis Microscopy with Ziehl – Neelsen’s staining A century old procedure

Smear showing Acid Fast Bacilli. : 

Smear showing Acid Fast Bacilli.

Transmission : 

Transmission Incubation period 4-12 weeks Latent infection may remain dormant for years Transmitted through droplet spread Undiagnosed / confirmed infected persons Breathing, coughing, sneezing, talking, or singing

Signs and symptoms : 

Signs and symptoms Early symptoms Common cold symptoms Listlessness, fatigue, fever, a minimally productive cough of yellow or green sputum and a general feeling of malaise. Later symptoms Night sweats, fever, cough with purulent secretions and haemoptysis, dyspnoea, chest pain, and hoarseness appear.

When to suspect Tuberculosis : 

When to suspect Tuberculosis Cough longer than 2 weeks, Fever for 1 month, or Both. Blood stained sputum, Night sweats, weight loss

Diagnosis : 

Diagnosis Sputum for AFB X-ray chest Sputum culture PPD

ANTI TUBERCULAR DRUGS : 

ANTI TUBERCULAR DRUGS FIRST LINE ESSENTIAL DRUGS Isoniazid Rifampicin Ethambutol Pyrazinamide FIRST LINE SUPPLEMENTARY DRUGS Streptomycin

ANTI TUBERCULAR DRUGSSECOND LINE DRUGS : 

ANTI TUBERCULAR DRUGSSECOND LINE DRUGS

INH : 

INH Most active anti TB drug Important assets are -potency -infrequent toxicity -low cost Bactericidal for rapid multipliers Bacterostatic for dormants Effective for both extra cellular & intracellular tb 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 A AcpM - Acyl Carrier protein KasA (ßketo Acyl Carrier protein synthetase) Block Mycolic Acid Synthesis

Pharmacokinetics : 

Pharmacokinetics Abs: Complete , Oral dose = Parenteral dose Dist: Penetrate all body tissues Placenta Meninges Caseous tb lesion Meta: Liver INH N acetyl transferase (NAT 2) N-Acetyl Isoniazid Isonicotinic Acid Acetyl hydrazine 1st ACETYLATION (Phase II), 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 --------- Peripheral neuritis More common More common Hepatitis ------------

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

Adverse Effect:- : 

Adverse Effect:- Rash Peripheral Neuropathy Hepatitis Transient loss of Memory Seizure Pleural effusion

Slide 26: 

HEPATOTOXICITY -Acetyl Hydrazine cause the damage -↑in Serum Transaminase -Clinical Hepatitis -Can be fatal if not withdrawn promptly 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

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

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 39: 

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

Slide 40: 

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

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

Tuberculosis in the era ofHIV / AIDS. : 

Tuberculosis in the era ofHIV / AIDS. HIV / AIDS epidemic led to large increase of Smear negative pulmonary tuberculosis which in turn has led to poor treatment out comes, and early mortality

IMPACT OF HIV ON TB : 

IMPACT OF HIV ON TB Nearly 8% of the global TB is attributable to HIV One third increase in TB in last five years is attributable to HIV Health services struggle to cope with the large and rising numbers of TB patients. TB accelerates the progression to AIDS TB shortens the survival of patients with HIV infection TB is the cause of death for one out of three people with AIDS worldwide

Patterns of HIV-related TBPulmonary TB : 

Patterns of HIV-related TBPulmonary TB

Several reasons identified for resistance : 

Several reasons identified for resistance Deficient or deteriorating TB control programmes resulting in inadequate administration of effective treatment; poor case holding, administration of sub-standard drugs, inadequate or irregular drug supply and lack of supervision; ignorance of health care workers in epidemiology, treatment and control; improper prescription of regimens; interruption of chemotherapy due to side effects; non-adherence of patients to the prescribed drug therapy;

Several reasons identified for resistance : 

Several reasons identified for resistance availability of anti-TB drugs across the counter, without prescription; massive bacillary load; illiteracy and low socio-economic status of the patients; the epidemic of HIV infection; laboratory delays in identification and susceptibility testing of M. tuberculosis isolates; use of non standardized laboratory techniques, poor quality drug powders and lack of quality control measures; and use of anti-TB drugs for indications other than tuberculosis

What is MDR TB / XDR TB? : 

What is MDR TB / XDR TB? MDR-TB (Multidrug Resistant TB) describes strains of tuberculosis that are resistant to at least the two main first-line TB drugs - isoniazid and rifampicin. XDR-TB, or Extensive Drug Resistant TB (also referred to as Extreme Drug Resistance) is MDR-TB that is also resistant to three or more of the six classes of second-line drugs.

Mechanisms of Drug Resistance in Tuberculosis : 

Mechanisms of Drug Resistance in Tuberculosis

Impact of Drug Resistance : 

Impact of Drug Resistance

When to suspect MDR TB : 

When to suspect MDR TB Re-treatment patients who’s sputum smear remains positive after three months’ of intensive therapy Treatment failure and interruption cases Close contacts of MDR tuberculosis cases Positive diagnoses with; TB culture and susceptibility testing

TREATMENT OF MDR/XDR TB : 

TREATMENT OF MDR/XDR TB 4 months of intensive phase (5 drugs) Kanamycins Ethionamide Pyrazinamide Ofloxacin Cycloserine or Ethambutol 18 months of continuation phase (3 drugs) Ethionamide Ofloxacin Cycloserine or Ethambutol

DOTS-Plus : 

DOTS-Plus A comprehensive strategy of the WHO Stop TB Partnership, developed for the diagnosis and management of MDR-TB and other forms of drug resistant TB.

Slide 80: 

1. Sustained Political commitment 5. Recording and reporting system designed for DOTS-Plus programs. 4. Uninterrupted supply of quality assured second-line anti-tuberculosis drugs. 3. Appropriate treatment strategies that utilize second line drugs under proper management conditions. 2. Diagnosis of MDR-TB through quality-assured culture and drug susceptibility testing (DST). THE DOTS-Plus Framework

Monitoring Schedule for MDR-TB Treatment Response : 

Monitoring Schedule for MDR-TB Treatment Response Daily symptom check during DOT for signs of disease activity Monthly clinical evaluation by MD: symptoms, weight, disease site-specific exam Monthly bacteriological evaluation until sustained conversion then bimonthly Chest x-rays: end of continuation phase, end of treatment

A WORLD FREE OF TB : 

A WORLD FREE OF TB WHO is working to dramatically reduce the burden of TB, and halve TB deaths and prevalence by 2015, through its Stop TB Strategy and supporting the Global Plan to Stop TB.

World Tuberculosis Day (March 24) : 

World Tuberculosis Day (March 24)

Slide 85: 

Thank You