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ANTI-TUBERCULAR DRUGSTuberculosis (often called TB) is chronic bacterial infection caused by“MYCOBACTERIUM TUBERCULOSIS, M. Bovos.It contains unusual cell wall. The cell wall has a high lipid content,resultinghigh degree of hydrophobicity and resistance to alcohol,acids, alkaliesand some disinfefectants.This organism usually attacks or affects almost any tissue and lungs, butcan also affect the …1. CNS (meningitis),Circulatory system,Genitourinary system,Bones,joints.It is characterized by the formation of nodular bodies or tubercles( hencethe name tuberculosis)• It is one of the most deadly and common major infectious diseasetoday, more than 2 billion people have been suffering the world’spopulation.1000 people have been dieing daily in India by TB.TB spread person to person through the air.When people with TB in their lungs or throat cough, laugh, sneeze, sing oreven talk the germs that cause TB may be spread into the air, if anotherperson breaths in these germs there is a chance that they will becomeinfected with TB.(Anti mycobacterial drugs)
• Generally it spreads in crowded areas, elderlypersons AIDS patients, and severity of diseaseIncreased further in patients withDiabetes mellitusHodgkin’s lymphomaChronic lung diseaseChronic renal failureMalnutrition, and Immuno suppression.Symptoms of TB:• An unproductive cough.• Feeling tired all the time.• Weight loss, loss of appetite,Night time sweating.• Fever, Coughing up blood.• Fatigue, night sweats,constant tiredness.• Chest x-ray examination reveals changes like pleuraleffusion (increase volume of pleural space), diffuse infiltrates inlung parenchyma. Untreated cases may show systemicsecondary amyloidosis ( infiltration of liver, kidneys, spleen andother tissues with amyloid.
Chest X-Ray of Patient with ActivePulmonary Tuberculosis
• Tuberculosis Treatment:Because administration of a single drugOften leads to the development of a bacterialpopulation resistant to the drug.• Effective treatment of TB must containmultiple drugs to which the organisms aresusceptible.Definition:-Anti-tubercular drugs are the agents which areused to treatment of tuberculosis.
In 1938, Sulphanilamide was discovered and was found to possess bacteriostitacAction although weak in nature.Later Dapsone was developed, Although dapsone was effective it was notConsidered for clinical use because it demanded high doses which in turnwere associated with toxicity.Eventually, many potent anti-tubercular drugs were developed in to orderStreptomycinPASAIsoniazidEthambutolRifampicin etc.The discovery of Rifampicin was a major break through in the treatment ofTuberculosis.This is because combination of Isoniazid, ethambutol and Rifampicin requiredComparatively less time for producing effective results than the individual drugsUsed alone.Since then combination of the three drugs have acquired prime importance inThe treatment of tuberculosis.
First- line drugs are those which exhibit high efficacy and less toxicityAll first-line anti-tuberculous drug nameshave a standard three-letter and a single-letter abbreviation:* [[Ethambutol]] is EMB or E,* [[isoniazid]] is INH or H,* [[pyrazinamide]] is PZA or Z,* [[rifampicin]] is RMP or R,* [[streptomycin]] is STM or S.Second line drugs:Second-line drugs for tuberculosis are found to be more toxic but mayrequired with certain resistance problemsThere are six classes of second-line drugs (SLDs) used for the treatment of TB. Adrug may be classed as second-line instead of first-line for one of three possiblereasons: it may be less effective than the first-line drugs (e.g., p-aminosalicylic acid);or, it may have toxic side-effects (e.g., cycloserine); or it may be unavailable in manydeveloping countries (e.g., fluoroquinolones):Aminoglycosides: Amikacin(AMK) Kanamycin(KM)Fluroquinolones: Ciprofloxacin(CIP), Levofloxacin.Thioamines: thionamide.P-amino salicylic acid(PAS)Polypeptides: Viomycin, Enviomycin, Capreomyhcin.Cycloserine(The only antibiotic in its class)Classification :Anti-tubercular drugs are classified on the basis of efficacy and safety clinical utility
• Third line• Other drugs that may be useful, but are not on the WHO list .Thesedrugs may be considered "third-line drugs" and are listed here eitherbecause they are not very effective (e.g., clarithromycin) or becausetheir efficacy has not been proven (e.g., linezolid, R207910).Rifabutin is effective, but is not included on the WHO list becausefor most developing countries, it is impractically expensive.
Antitubercular drugs are also classified on the basis ofChemical moiety as:-1.Salicylic acid derivatives:Para amino salicylic acid.2.Pyridine derivatives:Isoniazid (Isonicotinic acid hydrazine) ,Ethionamide, Prothionamide.3.Pyrazine derivatives:Pyrazinamide4.Ethylenediaminobutanol derivatives:Ethambutol.5.Antibiotics:Streptomycin, Refampin (Refampicin), Kanamcin.6.Miscellaneous drugs:Fluoroquinolones: Ofloxacin ,Ciprofloxacin.Macrolides: Clarithromycin,,Azithromycin.
ISONICOTINIC ACID HYDRAZINE( ISONIAZID),INH:Isonicotinic acid hydrazine (INH) first synthesized in 1952.It is a first-line synthetic anti-tubercular drug having bacteriostatic action.It is also known as isoniazid,INH,Isonicotinohydrazine(Nydrazid,Lanizid)Although it is effective when used alone, combination of it with other drugsRefampicin is preferred firstly, to avoid the development of resistance to wordsthe drug by tubercle bacilli and to achieve good therapeutic effects and alsoAvoid high doses of isoniazid.Structure:It is a very simple derivative of pyridine, and also one of the cheapestAnti-tubercular drug.Pyridine-4-corboxylic acid hydrazide.
Mechanism of action/mode of action:-Exact mechanism of action of isoniazid is not known; although several mechanismsHave been reported.The mechanism of action might involve the displacement of nicotinamide by isoniazidIn an enzyme.Basically Isoniazid is a prodrug and is activated by oxidation to isonicotinaldehyde,Isonicotinic acid, iso nicotinamide.The enzymecomplex catalase peroxide responsible for oxidation which is found in bacilli..(present in mycobacterium)This inactive enzyme-drug complex try to change the metabolism of proteins,Nuclic acids, lipids and carbohydrates.INH is highly selective towards Mycobactera. These bacterial cell walls are made up ofMycolic acids. Mycolic acids is an important constituents of mycobacterial cell wallIf Mycolic acid synthesis inhibited, causing in loss of some areas of outermembrane and thinness of the cell wall.Isoniazid(INH) Isonicotinaldehyde Isonicotinic acid Isonicotinamidecatalyzed by an endogenousenzyme KatG
• Isoniazid specifically inhibits long-chain fatty acid synthesis(>26 carbon atoms) lipids having a short arm of 20-24 carbonatoms and a long arm of 50-60 carbons. It has been proposedthatINH is activated to an electrophilic species that acylates thefour position of the NADH.The acylation of unsaturated fattyacids which are essential for the synthesis of the mycolic acids.
SAR OF ISONIAZID:a. The N-1 nitrogen in hydrazine side chain should be unsubstituted.b. N-2 Nitrogen can be substituted with alkyl groups to get active compounds.c. Replacement of pyridine nucleus with other aromatic ring such asbenzine or piperidine or thiazole ring diminished the anti-tubertcular activity.d. Neumerous derivatives have been developed none of them haveexhibited activity superior to that of the parent drug.e. When isopropyl group is substituted at R2, the resultant was a N2isopropyl derivative named iproniazid. This drug apart fromantitubercular activity it was also found to exhibit psychomotor stimulantactivity.NO OHisonicotinic acidOHNNH2NisoniazidNCH34-methyl pyridineOxidation H2NNH2AnhydroushydrazineSynthesis of isoniazid:
• Metabolism of Isoniazid:• Isoniazid is metabolized in the liver via acetylation. There are two forms ofthe enzyme responsible for acetylation, so that some patients metabolizethe drug more quickly than others. Hence, the half-life is bimodal with peaksat 1 hour and 3 hours in the US population. The metabolites are excreted inthe urine. Doses do not usually have to be adjusted in case of renal failure.Metabolism of isoniazid
Physico-chemical properties:soniazid is a colorless, odourless,sweet to bitter, crystalline, easily soluble inAlcohol, water and partially insoluble in ether and benzene.Adverse effects:The most common side effects is peripheral neuritis, optic neuritis,hepatotoxicity,Anorexia,weakness,fever,fatigue,Nephrotocicity,prupra,urticaria,anaemia,eosinophiliaCoagulation,granulocytosis,nausea,vomiting,restlessness and dryness of mouth.Toxic doses may cause hyperglycemia,glycosuria,seizures and even coma.Therapeutic uses:1. Treatment of tuberculosis. Usually 2 or 3 agents together or alone for prophylaxisof TB.2.Pridoxine (Vit-B6) is given together with the isoniazid to correct theoxic reactions of INH.3.It is first line drug. It is generally used with the other anti-tubercular drugs inmultiple drug theoay to lower the doses of other active drug and achieve effectiveness.Adult dose: Each tablet contains:Isoniazid--------50mg.Rifampicin-----120mg.Pyrazinamide—300mg.This dose is to be taken on empty stomach. One hour prior or 2 hours after meals. for2 monthsContinuation phase: Isoniazid and rifampicin are to be used for next 4-months(2 times/week.4.It is used in the treatment of latent TB.
• Treatment of tuberculosis• Single drug therapy is resistance to TB,thats why 4 drugregimens are given genarally• Then treatment is started with• INH and• Refanpin.Pyrizinamide and Ethambutal also given.These two drugs should stop after 2 months and another4 months INH and Rifampin should be given.6-monthsMycobacteria are very-slow-growing organisms that grow both intracellularlyand extracellularly. Because of their growth,the treatment of mycobacterialinfections,especially tuberculosis,requires long-term treatment with a combinationof agents to effectively eradicate the disease and prevent resistance.
ETHAMBUTOL(Myambutol)• Ethambutol abbreviated as EMB.• The dextro enantiomer (+) is almost 200-500 times more potent than themeso(-) -enantiomer.• Levo isomer is pharmacologically inert.• Structurally it possesses aliphatic diamine and two butanol moieties.• Ethambutol is a water-soluble,bacteriostatic agent that is readily absorbed(75-80%) following oral administration.(Ethylenediaminobutanol derivatives)2,2’-(1,2-ethanediyldiamino)bis-1-butanol.
SAR:1. The presence of two amino moieties is essential for antimicrobial activity.Presence of small branched alkyl groups on the nitrogen atom also influencesthe activity2. When amino moieties were replaced by either acetyl,sulphonyl or nitrosylmoieties antimycobacterial activity was abolished.3.When heteroatoms such as oxygen, sulphur group were substituted inethylene moiety , inactive derivatives were obtained.4.when hydroxyl groups were replaced with -0CH3or 0C2H5 equipotentactivity as that of parent drug–OH groups .5 Replacement of by benzoyl,thiomethyl –NH2NHR results ininactive compounds.Ethambutol is bacteriostatic against actively growing TB bacilli. It works byobstructing the formation of cell wall. Mycolic acids attach to the 5-hydroxylgroups of D-arabinose residues of arabinogalactan and form mycolyl-arabinogalactan-peptidoglycan complex in the cell wall. It disruptsarabinogalactan synthesis by inhibiting the enzyme arabinosyl transferase.Disruption of the arabinogalactan synthesis inhibits the formation of thiscomplex and leads to increased permeability of the cell wallMechanism of action:
• Metabolism of ethambutol:The majority of the administered EMB is excreted nchanged (73%),withno more than 15% appearing in the urine as either motabolite A orMetabolite B.Both metabolites are devoid of biological activity.
Synthesis:Physicochemical properties:It is odorless, bitter,M.P=199-204oC., Freely soluble in the water and alcohol andSlightly soluble in chloroform.Adverse/toxic effects:-Optic neuritis resulting in decreased vision and loss of ability to differentiate red,Green colours.Nausea,anorexia,rashes,fever and hyperuricaemia.Therapeutic uses:It is first line drug used in the treatment of Pulmonary and extrapulmonary TB.It is use in the prophylactic treatment of TB at dose if 15mg/kg/dayIn the combination therapy of TB it is given along with Isoniazid,Pyrazinamide,Rifampicin for 48 days(initial phase therapy).It is prepared by first resolving resimic 2-aminobutanol via its tartrate and the (+)-Enantiomorph is condensed with 1,2- dichloroethane in a in a suitable dehydro-Chlorinating atmosphere, the resulting atmosphere is dissolved in appropriateSolvent and treated with Hcl to obtain the official compound.
Rifampicin (Rifampin)•Refamycins are a group of macrocyclic antibiotics which areProduced by Streptomyces mediterranei.Refamycins inhibit the enzyme RNA polymerase and preventRNA synthesis.Than in turn prevent protein synthesis.•So they are useful in treating tuberculosis, leprosy,Mycobacterium avium complex (MAC) infection, andStaphylococcus infections.•Eventually 7, rifamycins were developed they areRifamycin A,B,C,D,E,S,SV.•Refampicin is a semi-synthetic rifamycin made fromRifamycin-B isolated from streptomyces mediterranei in 1957•Among the various rifamycins, rifamycin-B was the firstCommercial product.
Mechanism/mode of action:Refampin is bactericidal at 0.005-0.2micrograms/ml vsMicobacterium tuberculosis.Rifampicin inhibits Grampositive bacteria and works byBinding non-covalently to DNA-dependent RNA polymeraseand inhibiting the start of RNA synthesisThe DNA-dependent RNA polymerases in eukaryotic cellsare unaffected, since the drug binds to a peptide chain notPresent in the mamalian RNA polymerase. Therefore it ishighlyselective..It acts by inhibiting DNA-dependent RNA polymerase(DDRP)of mycobacteria and other microorganismsby binding strongly to their β-subunits viz ( α, α1, β, β1And sigma) and there by supression of inhibiting the m-RNA synthesis
•Intact macrocyclic molecule is required for antimycobacterial activity.•Double bonds in macrocyclic ring should not be redcuced ,or opening of the macro ringresults in compounds have decreased activity.• Free hydroxyl groups should be present at c-1,c-8,c-21,c-23 all lie in a plane and play arole in acting as binding groups for attachment to DDRP.• When –OH groups at c-21 and c-23 were completely removed or substituted theformation of derivatives are devoid of anti-mycrobial activity were obtained.•Activity of the compounds get diminished when the –OH groups at c21 and c23 areacetylated.• The maintenance of drug activity relies on the presence of either –OH or carbonylgroupboth of which should be unsubstituted.•Refampicin compound is formed by substitution of [(4-methyl-1piperazinyl)imino)methyl]rdFlat naphthalene ring andSeveral of the –OH groupsAre essential for activity.It is a zwitterion, and has goodSolubility both lipids and aqueous acid.
Uses:-1.Refampicin is used as a first line drug in the treatment of tuberculosis. As most of thetubercle bacilli develop resistance to rifampicin. It is used in combination with otheranti-tubercular drugs in the multiple drug therapy to minimize the problum.It is also used the treatment of leprosy.For prophylaxis in people exposed to meningococcemia or H. influenzae typeB meningitis.Adult dose: Each tablet containsGenarally the following dosage regimen is givenRifampicin----120mg.Isoniazid ------50mg.Pyrimethamine-300mg.4 tablets/day for patients ≤ 44kg.6 tablets /day for patients ≥ 55kg.child dose:- 100mg/kg of body weight as a single dose.Continuation phase:-Two drugs i.e. Rifampicin and isoniazid are to be used for a time period of the next4months. (2 times/week)Isoniazid---15mg/kg(orally),Rifampicin—10mg/kg (upto60mg/dose).It is used in the first-line therapy of brucellosis in combination with doxycline.
• The drug is bactericidal and is mainly used in the treatment oftuberculosis and staphylococci infections.• It is also used in combination with dapsone in Treating leprosy.• It is a very useful antibiotic, showing a high degre of selectivityagainst bacterial cells over mammalian cells.Unfortunately, it is so expensive, which discourages its use againsta wide range of infections.
Anti-leprotic drugs• The drugs which are used in the treatment of leprosy are termedantileprotic drugs.• Leprosy is an infectious disease caused by a bacillus,Mycobacterium leprae.M. Leprae multiplies very slowly the incubation period for thedisease is about 5 years.• Leprosy is not highly infectious. It is transmitted via droplets, fromthe nose and mouth during close and frequent contact with thoseinfected who are not on treatment of multi drug therapy.• Leprosy mainly affects the skin and peripheral nerves.Signs of leprosy:-A leprosy patient is someone who has a skin patch or patches with adefinite loss of sensation and who has not completed a full course oftreatment with Multidrug therapy.Leprosy patches:-• Can be pale or reddish or copper-colored• Can be flat or raised• Donot itch,usually don’t hurt, lack sensations to heat, touch or pain• Can appear anywhere.
Discovered by GerhardArmauer Hansen in 1873Global Project on the History of Leprosyhttp://www.leprosyhistory.org/graphics/gallery/hansen.jpgThe bacteria that causes Leprosy, (mycrobacteriumLeprae) was discovered by Gerhard Hansen in 1873Leprosy was known since ancient times, but noone knew what it was or what caused it.ArmadilloSome types ofmonkeys Rabits MicesTransmissionNasal/oral DropletsDermal Inoculations
• Diagnosis of leprosy:-Leprosy can be easily diagnosed on clinical signsalone. The main diagnostic sign is loss of feeling inthe affected skin and unique to the disease. Thediagnosis can be made by gently touching theaffected areas with a pointed object like a pen.Comparison can then be made with the sensation innormal skin.In earlier times, chaulmoogra oil was found to beeffective in the treatment of leprosy.Next this herbal remedy was replaced by sulphones.The prototype drug of these sulphones is dapsonewhich is still using as an antileprotic drug.Other drugs which find their use in the treatment ofleprosy are Clofazimine, certain tuberculars(rifampicin, ethionamide) and antibiotics.
How the Human Body isAffected by leprosyNerve isdamaged andbroken byleprosyinfection.Large bumps (legions)on the skin that do notheel and cannot feelpain.NerveLeprosy infection
classification:• 1.Sulfones: Dapsone,solapsone,Acedapsone.• 2.Phenazines: Clofazimine.• 3.Thiosemi carbazones: Amithiazone.• 4.Antitubercular drugs: Rifampicin,Ethionamide.• Antibiotics:Ofloxacin,Clarithromycin,Minocycline.• Natural oils: Chaulmoogra oil,Hydnocarpus oil.Drug for the treatment of leprosy:Sulfones: Most widely used sulphone is Dapsone.Sulphones were fist used in the treatment of leprosyIn 1941.4,4-Diaminodiphenylsulfone(Dapsone)
Mechanism of action of Dapsone• Dapsone acts by the same mechanism of action as that of sulfonamides. i.e.completely antagonizing PABA.(inhibited by PABA incorporation in to folicacid).It acts by inhibiting the enzyme dihydropteroate synthase or folic acid synthetaseduring the bacterial synthesis of tetrahydrofolic acid.Inhibition of tetrahydrofolic acid production leads to decreased levels of purinesand nucleic acid which is necessary for the synthesis of proteins by thebacteria.Hence dapsone exerts a bacteriostatic action on M.leprae and acts as antileprotic.Moreover dapsone exhibits the same antibacterial activity as that ofsulfonamides.Both dapsone and clofazimine have significant anti-inflammatory actionsMetabolism of Dapsone:The major metabolic product ofdapsone results from N-acetylationin liver by N-acetyl transferase.It also undergoes N-hydroxylationto hydroxylamine derivate.These metabolic reactions arecatalyzed by CYP3A4 isoforms.Neither of these compoundspossesses leprostatic activity.
When benzene rings of dapsone wasreplaced with thiazole ringThiazolsulfone was obtained which isless activity when compared withDDS( Dapsone)When the phenyl rings(aromatic ring) ofdapsone were substituted with suitablegroups the derivatives possessed lessactivity than the parent drug. Exception:Aceto sulfoneAcedapsone, a prodrug ofdapsone. R= -COCH3. Thisderivative is used as a depotinj. Which is released veryslowly than parent drug.acetosulfone reduced activitywhile increasing watersolubility and decreasingGI irritation.•Infact none of the obtained derivativesproved to be superior than dapsone.Substitution of –CH2SO2Na(methanesulfinate)for R gave sulfoxoneSodium forms Solapsone(a prodrug of dapsone).The amount required forsulfoxone is thrice that ofdapsone.This can givepatients who are unable totolerate dapsone inducedGIT irritation..SAR OF DAPSONE:
Synthesis of DapsoneNa2sKmno4[ O ]ReductionMethod-1Method-2(Diamino diphenyl sulphone)(DDS)4,4’-
Physico chemical properties• It is a white or creamy white,odourless,slightly bitter crystalline,sparingly soluble in alcohol, slightly soluble in water.Adverse/toxic effects:Same adverse effects as those exhibited by sulfonamides.Nausea,vomiting anoroxia,Dermatitis,drug fever ,Hepatitis,psychosis.USES:-1. Dapsone is used for the treatment of Multibacillary leprosy.Dapsone100mg+Clofazimine-50mg for 12 months.2. Paucibacillary leprosy:100mg/day for 6months.3. Dermatitis herpetiformis (itching, lesions (similar tourticaria)4. Treatment of pneumonia in AIDS. In this case co-administredwith trimethoprim.5 Together with pyrimethamine + dapsone is used asprophylactic measure against malaria.6. Treatment of inflammatory disorders, polychondritis andleishmaniasis.
Clofazimine(Lamprene):It is classified as a secondary drug for the treatment of leprosy and commonlyused as a component of multidrug therapy.The chemical, a phenazine derivative,is a water-insolubledye(dark-red crystals) that leads to pigmentation of the skin.In addition,discoloration (pink,red or brownish-black)of the feces,eyelidlininig,sputum,sweat,tears and urine is seen.Mechanism of action:The mechanism of action remains unclear at the present time.It has been shown that clofazimine increases prostaglandin synthesis and thegeneration of antimicrobial reactive oxidants from neutrophils,which may playa role in the antileprosy effects.The host cell defense may be stimulated by clofazimine,resulting in the generationof oxidants,such as the super oxide anion,which in turn could have a lethal effecton the organism.
• SAR of CLOFAZIMINE:substituents on the imino groupat position 2 is essential.imino group is substituted withalkyl and cycloalkyl groupsactivity is increased.Halogensubstitution on para position of the2 phenyls at C-3 and N-10 enhance activity.The following order of activity has beenreported Br>Cl>CH3>Eto>H or F.213107The chemical phenazinenucleus is essential forantimycobacterial and immuno-suppressive properties.Clofazimine was first usedto treat advanced leprosyunresponsive to dapsoneor STM in 1966.
• Metabolism of clofazimine:• Various metabolites of clofazimine have been identified but these accountfor these account for less than 1% of the administered dose.• The elimination of the clofazimine from the body is very slow(estimatedhalf life of from 8.8 to 69 days).• The liphophilic nature of clofazimine results in distribution and storage ofdrug in fat tissue.• clofazimine undergo hydroxylic dehalogenation on the 3-chloroanilinefollowed by sulfate conjugation and 4-hydroxylation followed by glucuronicacid conjugation.Human metabolic products ofClofazimine.
• Side effects:The medication treats a common form of leprosy known as lepromatous leprosy,and it works best when used in conjunction with another leprosy drug such asdapsone. Clofazimine produces few serious side effects in most patients, butthe medications gastrointestinal effects can become life-threatening.Taking clofazimine frequently changes patients skin color, making it redder orbrowner.• Other common side effects patients have reported include dry and flaky skin,itching skin, rash, eye irritation, darkening of the whites of the eyes, highblood sugar and darkening of the bodys excretions (urine, sweat, feces).Uses of clofazimine:• clofazimine – an antibiotic drug that was originally designed to treat TB butdidn’t work, and is now used to treat leprosy – could bring benefits to peoplewith multiple sclerosis and other immune diseases, such as psoriasis and type1 diabetes.• Because clofazimine has already been used to treat leprosy, and isrelatively safe, it’s likely that it will be fast-tracked into clinical trials forautoimmune diseases in the future.