SULFONAMIDES Dr Rajendra Nath Professor SULFONAMIDES First effective

SULFONAMIDES Dr. Rajendra Nath Professor

SULFONAMIDES First effective chemotherapeutic agents to be employed systemically for the prevention & cure of bact. Infections in humans. The discovery of Penicillin & subsequ. of other antib. s has diminished the usefulness of the sulfonamides.

SULFONAMIDES -Presently sulf. occupy small place in therapeutic armamentarium of the physician. -In 1970 s however the combination of Trimethoprim &Sulfmethoxazole has increased the use of sulf. s for the Tt. & prophylaxis of specific microbial

SULFONAMIDES diseases. History – Domagk tested the new comp. Azodye ( Prontosil ) & observed that mice with Streptococcal & other inf. s could be protected by prontosil ( active metabolite was sulf. ) & was very useful

SULFONAMIDES in puerperal sepsis & in Meningococ. Infection. Subsequently Carbonic anhydrase inhi. type of diuretics & Sulfonylurea hypoglycemic agents followed from observ. made with sulf. antibiotics. For the discovery of therapeutic

SULFONAMIDES value of prontosil Domagk was awarded Nobel prize in medicine in 1938. Chemistry : Sulf. is a generic name for derivatives of Para – aminobenzene sulf. ( Sulfanilamide )

SULFONAMIDES -Insoluble in water but sodium salts are soluble. -The para. NH 2 gp. is essential for activity. H 2 N SO 2 NH 2

SULFONAMIDES Effect on Microbes: -Wide range of AM activity against both G+ve & G- ve bacteria. - But now resist. strains have become common & usefulness of these agents has diminished. - The Sulf. exert only bacteriostatic action. - Cellular & humoral defense mech. of the

SULFONAMIDES host are essential for final eradication of the Infection. Anti bact. Spectrum : - Resistance is increasingly a problem Still sensitive strains are-Most of the Strept. pyogenes , Haemophilus ducrei & influenzae , Vibrio cholerae & Calymmatobacterium granulomatis.

SULFONAMIDES Few strains of Staph. aureus , pneumococci, Meningococci & gonococci , E. coli & shigella are sensitive ( most of the strains are resistant ). - Anaerobes are not sensitive - Chlamydiae (causing trachoma , lymphogranul. venereum , inclusion conjunctivitis), Actinomyces, Nocardia & Toxoplasma are sensitive -

SULFONAMIDES Mech. of action : Sulf. s are structural analogue & competit. antagonists of Para- aminobenzoic acid ( PABA).

SULFONAMIDES - Prevent normal bact. utilization of PABA for the synthesis of folic acid (Pterylgluta mic acid). - Specifically Sulf. s are competitive inhibitor of dihydropteroate synthase ( bact. enz. responsible for incorporation of PABA into dihydropteroic acid ( immed. precursor of folic acid )

SULFONAMIDES - Sensitive org. s are those that must synthesize their own folic acid & bact. s that utilize preformed folate are not affected. - PABA competitively counteract Sulf. ’ s bacteriostatic action. (Sulf. s do not affect mammalian cells because they require preformed folic acid

SULFONAMIDES and can not synthesize it ). Pteridine + PABA Dihydropteroate synth. X SULF. Dihydropteroic acid Dihydrofolic acid NADPH Glutamate x DHFR NADP Tetrahydrofolic acid Trimethoprim

SULFONAMIDES Synergists : Most active agent that exerts a synergistic effect with Sulf. is Trimethoprim It is a potent & selective competitive inhibitor of microbial dihydrofolate reductase ( enz that reduces dihydrofol. to tetrahydrofolate ). Simultaneous administ. of Sulf. & Trimeth. thus introduces Sequential Block in the

SULFONAMIDES pathway & kill the bact. Acquired bact. resist. to Sulf. : - Originate by random mutation & selection or by transfer of resist. by Plasmids ( this type of resist. is persistent & irreversible) May be due toi) Lower affinity for Sulf. by dihydropteroate synthase.

SULFONAMIDES ii) ↓ bact. permeability or active efflux of the drug. iii) Alternate metabolic pathway for synthesis of essential metabolite. iv) ↑ production of essen. metabolite or drug antagonists. ↑ prod. of PABA is not a constant finding in sulf. resist. . Bacteria & resist. mutants may

SULFONAMIDES posses enz. s that are less readily inhibited by sulfonamides Pharmacokinetics: -They are absorbed rapidly from GIT except locally acting sulf. s. - Peak plasma levels are achieved in 2 -6 hrs depending on the drug (100 -200 µg / ml ). - Small intestine is the major site of abs. but

SULFONAMIDES Some of the drug absorbed through stomach. - Abs. from other site e. g. –vagina, resp. tract or abraded skin is variable & cause toxic reaction in susceptible person. - All sulf. s are bound to plasma protein esp. albumin & distributed throughout all tissues of the body.

SULFONAMIDES - They readily enter pleural , peritoneal , synovial , ocular & similar body fluids. - After systemic abs. of adequate doses , Sulfadiazine & Sulfisoxazole attain conc. in CSF which may be effective in meningeal infection. - They reach the fetal circulation in placenta in preg. mothers & can cause toxic

SULFONAMIDES as well as antibacterial effect. - They undergo metabolic alteration in vivo esp. in liver. Major metabolite is N 4 acetylated sulfonamide. - Excreted from the body partly unchanched & partly as metabolic prod. s. The largest fraction excreted in urine. - In acidic urine the older Sulf. s are insol. &

SULFONAMIDES form crystalline deposits that can cause urinary obstruction. - Small fractions are eliminated in the feces bile , milk etc. Pharmacological properties: They are classified into four gps on the basis of the rapidity with which they are absorbed & excreted.

SULFONAMIDES CLASS SULFONAMIDE 1. Absorbed & Excreted rapidly SERUM H-½ in Hrs Sulfisoxazole Sulfamethoxazole Sulfadiazine 5 -6 11 10 Sulfasalazine --- 3. Topically used Sulfacetamide Silver sulfadiazine ----- 4. Long acting Sulfadoxine 100 - 230 2. Poorly absorbed. Active in bowel lumen

SULFONAMIDES 1. Agents that are absorbed & excreted rapidly: e. g. Sulfisoxazole & Sulfadiazine Sulfisoxazole: - having excellent AM activity - high solubility eliminates much of the renal toxicity. - It is highly protein bound. approx. 95% of

SULFONAMIDES a single dose is excreted by the kidney in 24 hrs. , conc. in urine thus exceeds than in blood & may be bactericidal. - 1/3 rd of the blood conc. reaches. CSF Sulfamethoxazole : cong. of sulfisoxazole. Enteric abs. & renal excrt. is slower. Given orally & employed for both systemic & urinary tract inf. s. Precaution must be taken

SULFONAMIDES to avoid crystalluria (i. e. take plenty of water) -Also marketed in fixed dose combination with Trimethoprim. Sulfadiazine : Given orally , absorbed rapidly from GI tract & peak conc. reaches in 3 -6 hrs after single dose. Fluid intake is must so that

SULFONAMIDES 1200 ml. urine output is maintained ( to avoid crystalluria) 2. Poorly absorbed Sulf. s : Sulfasalazine - poorly abs. from the GI tract therefore used in therapy of Ulcerative colitis & Reigional Ileitis , but relapses occurs ( Corticosteroids are better but in mild to mod. form Sulfasalaz. is preferred.

SULFONAMIDES -It is broken down by int. bact. s into Sulfapyridine an active Sulf. + 5 -aminosalicylic acid which reaches high levels in feces -5 -aminosal. is the effective agent in inflammatory bowel disease. Whereas Sulfapyridine is respons. for toxicity e. g. – Heinz body anemia , acute hemolysis in pts of G 6 PO 4 dehyd. enz. deficiency

SULFONAMIDES (G 6 PD enzyme is required for regeneration of NADPH & Which is required for reduction of oxidized glutathione. Reduced glutathione protects –SH dependent enzyme & other proteins against oxidation. Thus in presence of pro-oxidants ( e. g. - Aspirin , Nitrofurantoin, Primaquine, Chloroquine , Quinine , Sulfonamide, Vit. K etc. ) in a pt. with deficiency of G 6 PD , there is no protection to RBCs & so hemolysis occurs. )

SULFONAMIDES agranulocytosis & may cause rev. infertility in males. 3. Sulf. For Topical use : Sulfacetamide – Sod. Salt of drug is extensively employed in ophthalmic inf. s. Advantages –high aquous conc. not irritating to eyes. - the drug penetrates in high

SULFONAMIDES conc. into ocular fluids & tissues. - Sensitivity react. s are rare Silver Sulfadiazine; the comp. is used topically to reduce microbial coloniz. & the incidence of wounds from burns( one of the agents of choice for the prev. of burn inf. ). other is Mafenide.

SULFONAMIDES 4. Long acting Sulf. s : e. g. – Sulfadoxine – having long half life ≈ 7 -9 days. - It is used in comb. with Pyrimethamine ( 500 mg Sulfadoxine + 25 mg Pyrimeth. ) as Fansidar in prophylaxis & Tt of Malaria caused by resist strains of Plasmodium falciparum.

SULFONAMIDES Sulfonamide Therapy : - Various conditions for which the sulf. s are therapeutically useful & constitute DOC has been reduced sharply. - The development of more effective AM agents & gradual increase in resist. of no. of bact. species to this class of drugs leads to rare use of these agents - The introduction of Trimethoprim &

SULFONAMIDES Sulfamethoxazole combinations has revived the use of sulf. s. 1. Urinary Tract Inf. s : Sulf. s are no longer a therapeutic choice in UTI. Preferred agents are –Trimethop. + Sulfamethoxazole , Quinolones , Trimethop. alone , Fosfomycin , Ampicillin & Cephalosporins Sulfisoxazole may be used effectively

SULFONAMIDES 2. Nocardiosis – good response with Sulf. s e. g. - Sulfisoxazole & Sulfadiazine Dose – 6 - 8 Gm. / day continued for several months. second antb. along with sulf. is recomme. in advanced cases e. g. - Ampicillin & Erythromycin.

SULFONAMIDES 3. Toxoplasmosis : Sulfadiazine( 1 Gm. ) + Pyrimethamine (75 mg loading & 25 mg later on) is given 6 hrly x 3 -6 weeks with folic acid 10 mg orally. 4. Treatment & Prophy. of resist. Malaria : Sulfadoxine + Pyrimethamine( Fansidar)

SULFONAMIDES 5. Use of Sulf. s for Prophylaxis : They are as efficacious as Penicil. s in prev. Streptococcal inf. s & recurrence of Rheumatic fever. 6. Ophthalmic inf. s : topical –e. g. Sulfacetamide. 7. Infection of Burns : e. g. - topical Silver sulfadiazine.

SULFONAMIDES Adverse reactions : 1. Disturbance of urinary tract – risk of crystalluria – high with older less sol. Sulf. s but very less with more sol. agents e. g. - Sulfisoxazole -Fluid intake should be sufficient – daily ensure urine out put of 1200 ml. - Alkalinization of urine is desirable.

SULFONAMIDES 2. Disorders of Hematopoietic system : - Acute hemolytic anemia- sometimes sensitization phenomenon & in others erythrocytic def. of G 6 PO 4 dehydrogenase - Agranulocytosis – most pts recovered spontaneously with supportive care - Aplastic anemia –complete supp. of bone marrow activity with anemia ,

SULFONAMIDES granulocytopenia & thrombocytopenia. 3. Hypersensitivity reactions : Skin & mucous memb. manifestationsurticarial rash , pemphigoid , perpurial & petechial rashes , erythema nodosum multiforme of Stevenson Jonhson’s type, Exfoliative derm. & photosensitivity. most often occurs after 1 st wk. of therapy

SULFONAMIDES It can occur with fever , malaise & pruritis - Focal or diffuse necrosis of liver, fever, headach , hepatomegaly, jaundice – leading to yellow atrophy of liver & death Misce. : Anorexia , nausia & vomiting -1 -2% in new borns – free bilirubin can deposit in the basal ganglia & ant thalamic nuclei

SULFONAMIDES of the brain causing encephalopathy called Kern- icterus. ( Sulf. s are not given to pregnant women near term because these drugs pass through placenta & secret. in milk ). Drug interaction : with oral anticoagulant , sulfonylurea hypoglycemic agents & hydantoin --

SULFONAMIDES In each case sulf. s can potentiate the effect of the other drugs by inhibition of metabolis. & possibly displacement from albumin.

SULFONAMIDES TRIMETHOPRIM &SULFAMETHOXA. • Constitutes important advance in the dev. of clinically effective AM agents. • If the drugs act on sequential steps in the pathway of an obligatory enzymatic reac. in bact. , the result of their combination -

SULFONAMIDES will be synergistic. This comb. is known popularly as Cotrimoxazole. - Trimethoprim also comes in single entity prepration. Chemistry : Trimethoprim is Di-aminopyrimidine

SULFONAMIDES Spectrum : is equivalent to Sulfamethoxazole , although Trimeth. is 20 -100 times more potent. - Most G+ve & G-ve micro-org. are sensitive ( resist. occurs when used alone ).

SULFONAMIDES Pseudomonas aeruginosa , Bact. fragilis & Enterococci are resist. Efficacy of combination : Additional micro-org. covered by this combination – Klebsiella , S. typhi , Serratia , Yersinia enterocolitica , Enterobacter, Brucella

SULFONAMIDES abortus, Proteus mirabils , Pseudomonas , Klebsiella , Brucella abortus , Pneumocystis jiroveci. -Many sulfonamide resistant strains of S. pyogenes , Staph. aureus, Shigella, E. coli , H. influenzae , meningococci & gonococci becomes sensitive.

SULFONAMIDES Max. degree of synergism occurs when micro-org. are sensitive to both component. Mech. of action : Sequential block in Folic acid synthesis occurs. Trimeth. is selective inhibitor of DHFR enzym. of lower org. s, about 100, 000

SULFONAMIDES times more drug is required to↓ human reductase than bact. enz. ( Optimal synergy exhibited at a conc. ratio of sulfamethoxazole 20: Trimethoprim 1. This ratio is obtained in the plasma when the two are given in a dose ratio of 5 : 1 ). Bact. Resist. : It is a rapidly increasing problem but lower than the resistance to either drug

SULFONAMIDES alone. ( due to acquisition of a plasmid that codes for an altered DHFR enz. ). However, resist. to the combination has been slow to develop compared to either drug alone Absorption , Distribution &Excretion: Constant ratio of 20: 1 in their conc.

SULFONAMIDES in blood & tissues is not perfectly matched by the two drugs. The ratio in blood is often greater than 20: 1 & that in tissues is frequently less. -After single oral dose of the comb. prep. Trimeth. is absorbed more rapidly than Sulfamethoxazole.

SULFONAMIDES Half life of trimeth. & sulfmethox. is 11 & 10 hrs respectively. (800 mg. of Sulfamethox +160 mg. of Trimeth. is the comb. dose) dose. -The drug readily enters in CSF & sputum. - High conc. is also found in bile.

SULFONAMIDES -About 60% of administ. Trimeth. & 2550% of Sulfamethox. are excret. in urine. Uses : 1. UTI (uncomplic. ) – more efficac. in chronic & recurrent inf. of the UT. small doses / day or usual dose

SULFONAMIDES once or twice a wk. appears to be effective in reducing the no. of recurrt. UTI in adult female. ( Enterobacteriace surrounding the urethral orifice may be eliminated or markedly red. in no. . Thus diminishing the chance of ascending reinfection. )

SULFONAMIDES - Also effective in bact. prostatitis. 2. Resp. tract inf. : -effective in acute exacerbation of chr. bronchitis ( 1 tab. BD is sufficient to ↓ sputum , fever & purulence ). - Effective in acute otitis media in children & acute maxillary sinusitis in

SULFONAMIDES adults caused by H. influenzae & S. pneumoniae. 3. GIT : - Alternative to Fluoroquinolones for Shigellosis. - Second line drug for Typhoid fever (1 st line drug is Ceftriaxone or fluroq. )

SULFONAMIDES - Also effective in carriers of S. typhi. 4. Inf. by Pneumocystis jiroveci : high dose is effective for this severe inf. in pts of AIDS ≡ Pentamidine. 5. Prophy. in Neutropenic pts. 6. Miscellaneous : Nocardia , Brucellosis & Methicil.

SULFONAMIDES resist. Strains of S. aureus (MRSA). Adverse Effects : More or less same as Sulf. s -Folate def. in normal person may prod. megaloblastosis , leukopenia or thrombocytopenia. - 75% of ADRs involves skin –

SULFONAMIDES exf. dermatitis , Stevenson Johnson’s syndrome & toxic epidermal necrolysis ( Lyell’s syndrome). GIT-Nausea, vomiting , diarrhea is rare glossitis , stomatitis & aller. cholest. hepatitis ( Jaundice). CNS –headache , depression & halluci.

SULFONAMIDES Hematological – Aplastic , hemolytic & microcytic anem. coagul. disorder , granulocytopenia , agranulocytosis & perpura. -Pts with AIDS have increased chances of hypersensitivity reaction.

SULFONAMIDES ICLAPRIM ( a Trimethoprim analogue with improved activity ) - Recently introduced - Given I. V. - More effective & better tolerated than Trimethoprim - ≡ Linezolid - Effective in Pts. Suffering from skin & soft tissue infection caused by MRSA. - Highly effective against Vancomycin resist. Staph. Aureus (VRSA ) - In Streptococcal Pneumonia. (Phase III trials are going on for oral use )

QUINOLONES - First Quinolone , Nalidixic acid was isolated as a byproduct of the synth. of Chloroquine & mainly used for UTI. (Bactericidal against most G-ve organisms except Pseudomonas Less active against G+ ve organisms. There is rapid development of resistance. It acts by ↓ DNA gyrase & is bactericidal.

QUINOLONES It is mainly used as a urinary antiseptic as a second line Drug. Nitrofurantoin is not given simultaneously as antagonism Occurs. It is also given in diarrhea caused by Proteus , E. coli , Shigella & Salmonella infections.

FLUOROQUINOLONES Introduction of Fluorinated 4 - Quino lones e. g. - First generation FQs Ciprofloxacin , Norfloxacin , , Ofloxacin , Pefloxacin. Second generation FQs. Gatifloxacin, Lomefloxacin , Sparfloxacin, Levofloxacin etc.

FLUOROQUINOLONES Gemifloxacin , Moxifloxacin, Trovafloxacin , Alatrofloxacin & Finafloxacin (some books describe Gemiflox. , Gatifloxacin & Sparfloxacin as 3 rd generation & Rest as 4 th generation FQs )

FLUOROQUINOLONES

FLUOROQUINOLONES represents a particularly important therapeut. advancement because these agents have broad spectrum of AM activity & effective after oral administ. for the Tt of wide variety of infectious diseases. - Microbial resist. does not dev. rapidly.

FLUOROQUINOLONES Chemistry : Quinolones contain a carboxylic acid moiety at pos. -3 of the primary ring struct. Fluoroquinolones also contain a fluorine substituent at pos. 6 & piperazine moiety at pos. – 7 & this is a breakthrough which confers

FLUOROQUINOLONES High potency , expanded spectrum , slow development of resistance , better tissue penetration and good tolerability to these agents.

FLUOROQUINOLONES Structure: 7 N F (6) COOH ( 3 ) O

FLUOROQUINOLONES

FLUOROQUINOLONES

FLUOROQUINOLONES Mech. of action : -Target is Bact. DNA Gyrase & Topoisomerase IV enzyme. - For most of the G +ve bact. e. g. S. aureus , Topoisomerase IV is the primary enz. inhibited by the Quinol. s - In contrast many G-ve bact. DNA Gyr.

FLUOROQUINOLONES is the primary Quinol. target. -Individual strand of double helical DNA must be separated to permit DNA replication & transcription. -DNA Gyrase is respons. for combating mechanical obstacle prod. by overwind or excessive post. supercoiling of the

FLUOROQUINOLONES DNA in front of the point of separation by continuous introd. of negative super coils into DNA. - The DNA Gyrase of E. coli consists of two subunits A & B. The A subunit which carry out the strand cutting function of the gyrase is the site of

FLUOROQUINOLONES

FLUOROQUINOLONES

FLUOROQUINOLONES

FLUOROQUINOLONES

FLUOROQUINOLONES action of the quinolone. Mutation of the gene that encode subunit A polypeptide can cause resist. - Topoisomerase IV consists of 4 subut. they separates interlinked daughter DNA mol. s that are prod. of DNA repl. (Eukaryotic cells have similar type II

FLUOROQUINOLONES variant of Topoisomerase & quinol. s suppress it in comparatively much higher conc. s ). Spectrum : Bactericidal against E. coli , Salmonella Shigella , Enterobacter, Campylobact. and Neisseria, Klebsiella , V. cholera

FLUOROQUINOLONES (Ciproflox. is active against P. aereug. , Staphylococcus but not against Methicil resist. strains ). Some intracellular bact. s are also inhib. e. g. – Chlamydia , Mycoplasma, Legionella , Brucella & M. tuberculos.

FLUOROQUINOLONES Absorption , Fate & Excretion : • Quinolones are well abs. after oral administration & distributed widely in body tissues. (Metal cations e. g. - Al , Mg , Ca, Fe & Zn form insoluble salts with Fluoroquinolones & inhibit absorption ) the

FLUOROQUINOLONES ) Doses : First generation FQs - Norfloxacin – 400 mg BD. , Ciprofloxacin – 500 mg BD. , Ofloxacin - 200 -400 mg BD. Pefloxacin. Second generation FQs -( with additional fluoro substit. s further extending AM activity to Gram +ve cocci & anaerobes & having longer t ½) Levofloxacin - 500 mg OD. , Gatifloxacin -200 -400 mg OD , Lomifloxacin , Sparfloxacin -400 mg 1 st day then 200 mg OD , Moxifloxacin – 400 mg OD , Trovafloxacin, Alatrofloxacin ( Prodrug for Trovaflox. Given I. V. ) & Finafloxacin

FLUOROQUINOLONES - Most quinolones are cleared predominantly by the kidney (doses must be adjusted for renal failure) except Pefloxacin &Moxiflox. which are mainly metabolized by liver. Therapeutic Uses : 1. UTI – Nalidixic acid only used in

FLUOROQUINOLONES susc. organism. Fluoroquinolones are more potent & having much broad spectrum of AM activity. 2. Prostatitis 3. Sexually Transmit. Disease (STD): ( e. g. -Gonorrhoea , L. venereum, Chancroid but FQs lack activity against T. pallidum causing syphilis) syphilis - single oral dose of a Fluorq. e. g. -

FLUOROQUINOLONES Ofloxacin , Ciprofloxacin is effective for sens. strains of N. gonorrhoeae (but resist. led to Ceftriaxone as 1 st choice) -Pelvic Inflammatory Disease ( PID) 4. Gastro- int & abdominal inf. s: - In Traveller’s diarrhoea (by E. coli )

FLUOROQUINOLONES - Shigellosis - Cholera ( Norflox. is better than Tetracycline in ↓duration of diarrh. ) - Enteric fever by S. typhi ( Cipro, Oflo & Levoflox. ). It also clears chr. fecal carriage. - Peritonitis (in pts on peritoneal dialy. )

FLUOROQUINOLONES 5. Resp. tract inf. s : Poor activity against comm. acquired pneumonia & bronchitis ( newer Flqnl. s e. g. - Gatifloxacin have excel. activity against S. pneumonia ≡ β lact. ) other sens. org. for RT inf. are H. infl. M. catarrh. , S. aureus , M. pneum.

FLUOROQUINOLONES & Legionella. 6. Bone , Joint & Soft tissue inf. s: -For chr. osteomylitis (Tt need wks to months ) prod. by S. aureus & G-ve rods. - Diabetic foot infection - In anaerobic inf. it is given along with

FLUOROQUINOLONES Metronidazole. 7. Other inf. s : Ciproflox. – prophylax. of Anthrax (It is in news for used as a weapon of Bioterrorism ) & Tt of Tularemia. - for MDR cases of Tuberculosis & for atypical mycobact. inf. s caused by Mycobact. Avium compl. in AIDS pts.

FLUOROQUINOLONES - Ciproflox + Amoxycil. + Clavulinic acid has been shown to be effective as oral therapy for fever in low sens. Pts with granulocytopenia. (Pefloxacin- methyl derivative of Norfloxacin, penetrates tissue better CSF conc. is better than other fluorq. s therefore preferred drug for meningeal inf. , also used for gonorrhea & typhoid ).

FLUOROQUINOLONES Ofloxacin - more potent than Ciprofloxacin for G +ve org. s, inhibits Mycobact. tuberculosis & M. leprae & used as alternative in MDR regimen. Levofloxacin – levo - isomer of Ofloxacin , better activity against S. pneumoniae , also used in pyelonephritis , ch. bronchitis , sinusitis & other related inf. s of soft tissues. Can be administered just once a day. Gatifloxacin -spectrum same as other fluoroq. s , Gatifloxacin ophthal. sol. is the first FDA approved fluoroq. Sparfloxacin – difluorinated quinolone effective against G +ve bact. , anaerobes & mycobacteria. Used in the treatment of pneumonia , ch. bronchitis , sinusitis etc. Causes QT –prolongation in ECG.

FLUOROQUINOLONES Moxifloxacin –having high activity against Strep. pneumoniae. & other G +ve org. s. Indicated mainly in bronchitis , pneumonia , sinusitis & otitis media , also used as eye drops. Trovafloxacin – It is more active than other fluoroq. s against strept. pneumoniae & other G +ve bacteria. But due to its hepatotoxicity it is recomm. only in life threatening inf. s. ) Alatrofloxacin – It is a pro-drug for Trovaflox. usually given I. V. , both have an extended spectrum against anaerobes. Finafloxacin – More efficacious in tissues & body compartments having acidic p. H with high safety profile & widest spectrum. Once daily dosing , oral / I. V. ( undergoing phase III clinical trial )

FLUOROQUINOLONES Adverse Effects : Quinol. s & Fluoroql. are generally well tolerated, most common GI adv. reac. are – mild nausea , vomiting and /or abd. discomfort. CNS-S/E –mild headache & dizziness. -Rarely halluc. , delirium & seizures can

FLUOROQUINOLONES occur predominantly in pts who also are taking theophylline or NSAIDs simultaneously. -Ciproflox. & Peflox. ↓ the metabol. of theophylline so toxicity can occur with elevated levels of theophylline. -Rashes can occur including phototox.

FLUOROQUINOLONES reactions. -Achilles tendon rupture & tendinitis can occur rarely. -All these agents can prod. arthropathy (joint erosions) erosions & reversible arthralgia in several sp. of animals & especial. in children (therefore the use of quinol. s has been C/I in developing age & preg. )

FLUOROQUINOLONES - In some cases can be used where benefits may overweighs the risk of quinol. therapy in children. - Leukopenia , Eosinophilia & mild elevation in Transaminases enz. s which occur rarely. - QT prolongation can occur with Sparfloxacin & to a lesser extent

FLUOROQUINOLONES with Gatifloxacin & Moxifloxacin therefore quinol. s should be used with caution in pts on class III (Amiodarone) & class IA ( Quinidine, Procainamide) antiarrhythmics.

ANTISEPTIC & ANALGESIC AGENTS FOR UTI • The urinary tract antiseptics ↓ the growth of many species of bacteria. • They can not be used to treat syst. inf. s because effective conc. s are not reached in plasma with safe doses. • However because they are concen. in the renal tubules they can be

ANTISEPTIC & ANALGESIC AGENTS FOR UTI administered orally to Tt inf. s of U. tract • Tt with these agents is effective as a local therapy only in the kidney , ureter & bladder inf. s. 1. Methenamine: Methenamine Urinary tract antisep. & a prodrug that owes its activity to generate formaldehyde.

ANTISEPTIC & ANALGESIC AGENTS FOR UTI - Acidification of the urine promotes the formald. dependent antibacterial action NH 4 (CH 2)6 + 6 H 2 O + 4 H+ → 4 NH 4 + 6 HCHO. -React. is slow &≈ 3 hr. are required to reach 90% completion.

ANTISEPTIC & ANALGESIC AGENTS FOR UTI AM activity – all bacteria are sensitive to free formald. at conc. of about 20μg/ml ( Proteus sp. raise the p. H of the urine & thus ↓ the release of formald. ). formald Microbial org. do not develop resist. to formald.

ANTISEPTIC & ANALGESIC AGENTS FOR UTI Pharmacology : Absorbed orally (10 -30% decompose in gastric juice unless drug is given as enteric coated tabs ) - Ammonia is prod. so C/I in hepatic insufficiency. -Excreted in urine ( when urinary p. H is 6

ANTISEPTIC & ANALGESIC AGENTS FOR UTI & daily urine output is 1 to 1. 5 L , a daily dose of 2 G will yield 16 -60 μg/ml of formalde. sufficient to kill micro-org). micro-org -Bacteriostatic only at low p. H , along with acids act as bactericidal (acids used are Mandelic acid & Hippuric acid). • GI disturbance if dose > 500 mg QID

ANTISEPTIC & ANALGESIC AGENTS FOR UTI • Painful micturition , hematuria, albuminuria & rashes occur at 4 -8 gm /day doses for 5 wks or more. • Renal insuffic. does not constitute a C/I for Methenamine alone but the acid given concurrent. is detrimental • Crystalluria ( from mandelic moiety) can occur

ANTISEPTIC & ANALGESIC AGENTS FOR UTI • With Sulf. s mutual antagonism can occur. Therapeutic Uses : -Not a primary drug for acute UTI (Value in chronic suppressive Tt. ) - most effective when org. is E. coli (also against other common G+ve org. s

ANTISEPTIC & ANALGESIC AGENTS FOR UTI e. g. -S. aureus & S. epidermidis. ) 2. Nitrofurantoin ( Furadantin ) : Synthetic nitrofuran that is used for the prev. & Tt of UTI. (Nitrofurazone -used in burns & skin grafts , Furazolidone – used in diarrhea , Giardiasis ) AM activity : Enz capable of reducing NF appear to be crucial for its activation

ANTISEPTIC & ANALGESIC AGENTS FOR UTI → highly reactive intermediates are formed→ damage DNA of bact. ( It also blocks bact. carbohydrate metabol. by ↓ Acetyl. Co- A synthesis ) • • Bact. reduces NF more rapidly than mammalian cells & this is the cause of selective AMA. Bact. s which are susceptible rarely become resist.

ANTISEPTIC & ANALGESIC AGENTS FOR UTI - Active against many strains of E. coli, Enterococci ( most sp. of proteus , Pseudomonas , enterobacter & Klebsiella are resistant ). • NF is bacteriostatic for most suscep. micro-org at conc. of 30μg/ ml. or less & bactericidal at conc. of

ANTISEPTIC & ANALGESIC AGENTS FOR UTI 100μg/ml. • Antibact. activity is more in acidic urine. Pharmacology : • It is abs. rapidly & completely from GIT. • Anti bact. conc. are not achieved in

ANTISEPTIC & ANALGESIC AGENTS FOR UTI plasma at recomm. doses as drug is eliminated rapidly. • Plasma half life is 0. 3 -1 hrs • In pts of impaired renal func. the effi. of drug is↓ & syst. toxicity ↑. • It colors the urine brown.

ANTISEPTIC & ANALGESIC AGENTS FOR UTI S/E – Nausea , vomiting & diarrhoea. - H/senst. react. e. g. - chills , fever leucopenia , granulocytopenia , hemolytic anemia ( ass. with G 6 PO 4 dehyd. enz deficiency ) -Cholestatic jaundice & hepatic cell. damage can occur.

ANTISEPTIC & ANALGESIC AGENTS FOR UTI - Acute pneumonitis with fever , chills cough & dyspnea can occur( more in elderly ). - Headache , vertigo , dizziness , musc. aches & nystagmus are readily reversible. - Neuropathies are more in pts having ↓ renal function.

ANTISEPTIC & ANALGESIC AGENTS FOR UTI Doses : adults- 50 -100 mg QID. with meals & at bed time. A single 50 -100 mg dose at bed time is sufficient to prev. recurr. ( children- 5 -7 mg/kg ). - only approved for Tt of UTI susc. to this drug (also not recommended for

ANTISEPTIC & ANALGESIC AGENTS FOR UTI prostatitis & pyelonephritis. ) but effective for prophyl. of recurrent UTI. 3. Phenazopyridine : Phenaz. HCl ( Pyridium) is not a urinary antiseptic but has analgesic action on the urinary tract & reduces

ANTISEPTIC & ANALGESIC AGENTS FOR UTI sympt. s of dysuria , frequency , burning & urgency ). Dose – 200 mg TDS daily. It is an Azo –dye which colors urine red / orange. GI upset can be reduced by giving it with meals.

URINARY TRACT INFECTION • In active UTI , there are more than 100, 000 bact. / ml i. e. more than 10 / hpf. • It may be acute or chronic , acute inf. is usually by one organism while in chronic inf. there may be two or more organisms.

URINARY TRACT INFECTION • Common infective org. s in UTI are E. coli , Proteus , Pseudomonas , Klebsiella & enterococci. • Recurrence with same org. is referred as relapse & with other org. / with long interval is referred as reinfection. (Renal inf. not treated properly may lead to loss of renal

URINARY TRACT INFECTION function. For soft tissue inf. e. g. – pyelonephritis , & prostatitis Tt is usually required for 3 -4 wks , whereas for mucosal inf. e. g. cystitis require 1 -3 days treatment. Furthermore urine lacks natural defense like lysozymes & immunoglobulins which are protective in tears & saliva. Organisms reach urinary tract by ascending inf. from urethra. In women , urethra is short & vagina is colonized with org. s. Free flow , large urinary volume , complete emptying & acidic p. H are anti bacterial defense.

URINARY TRACT INFECTION Manifestations : Lower urinary tract involvement leads - Frequency - Urgency - Dysuria -Lower abdominal discomfort. Upper tract involvement leads to -

URINARY TRACT INFECTION Headache Malaise Vomiting Fever with chills Abdominal pain. -Presence of pus cells/ bacteria / RBCs in plain urine & +ve urine culture

URINARY TRACT INFECTION confirms the diagnosis. -Untreated inf. may progress to ch. pyelonephritis , hypertension & renal failure. General management : - Prophylaxis for recurrent infection. - High fluid intake

URINARY TRACT INFECTION - Analgesic for brief period , urinary analgesic e. g. Phenazopyridine. - Urinary antiseptic e. g. –Nitrofurantoin or Methenamine. - Systemic antimicrobials

Bibliography 1. Goodman & Gilman’s , The Pharmacological Basis of Therapeutics (12 th Edition). 2. Clinical Pharmacology by Lawrence (Latest edition) 3. Pharmacology by G. M. Brenner & C. W. Stevens ( Latest Edition )

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