Sulfonamides, Trimethoprim and FluoroquinolonesFluoroquinolones

Dr. Deepak Kumar Gupta

Introduction

• 1st antimicrobial agent

• Effective against pyogenic bacterial infections

• Used extensively in past, but its avoide now due to increased side effect and resistantdue to increased side effect and resistant

• Limited used, except in the combination of trimethoprim (cotrimoxazole) or pyrimethamine (malaria)

Chemistry

• Derived from sulfanilamide –structural simialarity to -aminobenzoic acid (PABA)

• produced by - attaching substituents to the amidosubstituents to the amidogroup (–SO2 –NH–R) or the amino group (–NH2 ) tothe sulfanilamide nucleus

• soluble at alkaline than at acid pH

• sodium salts - intravenous administration

Classification

• Short acting (4-8 hr) : Sulfadiazine

• Intermediate acting ( 8-12 hrs) : Sulfamethoxazole

• Long Acting ( 7 day) : Sulfadoxine, • Long Acting ( 7 day) : Sulfadoxine, sulfamethopyrazine

• Special Purpose Sulfonamindes : Mafenide, Silver sulfadiazine, sulfasalazine

Mechanism of Action

• MCO susceptible to supfonamide – cannot use exogenous folate.

• So it utilizes PABA to form folate and subsequently purinespurines

• structural analogs of PABA – inhibit folate synthesis.

• Combination with an inhibitor of dihydrofolatereductase - trimethoprimor pyrimethamine -synergistic activity

Antibacterial Spectrum

• Both gram-positive and gram-negative bacteria

• Nocardia sp, Chlamydia trachomatis, Escherichia coli, Klebsiella pneumoniae, Salmonella , Shigella , and Enterobacter sp. and some protozoa.

• Activity is poor against anaerobes.

• Rickettsiae – not inhibited instead stimulated in their growth

• Pseudomonas aeruginosa is intrinsically resistant

Resistance

• Sulfonamide resistance may occur as a result of mutations that

– cause overproduction of PABA,

– cause production of a folic acid-synthesizing – cause production of a folic acid-synthesizing enzyme that has low affinity for sulfonamides,or

– impair permeability to the sulfonamide

Pharmacokinetics• Sulfonamides can be divided into three major groups– Oral absorbable; – Oral nonabsorbable; – topical.

• absorbed from the stomach and small intestine and distributed widely to tissues and body fluids, placenta, distributed widely to tissues and body fluids, placenta, and fetus

• Protein binding varies from 20% to over 90%• A portion of absorbed drug is acetylated or

glucuronidated in the liver. • Excreted into the urine, mainly by glomerular filtration.• In significant renal failure, the dosage of sulfonamide

must be reduced.

Clinical Use

• Sulfonamides are infrequently used as single agents.

• The fixed-drug combination of trimethoprim-sulfamethoxazole - drug of choice for sulfamethoxazole - drug of choice for infections such as pneumonia, toxoplasmosis, nocardiosis, and occasionally other bacterial infections.

Clinical Use : Oral Absorbable Agents

• Sulfisoxazole and sulfamethoxazole– urinary tract infections : adult dosage is 1 g of

sulfisoxazole four times daily or 1 g of sulfamethoxazole two or three times daily

• Sulfadiazine in combination with pyrimethamineis first-line therapy for treatment of acute

• Sulfadiazine in combination with pyrimethamineis first-line therapy for treatment of acute toxoplasmosis.– 1 g four times daily, with pyrimethamine given as a

75-mg loading dose followed by a 25-mg once-daily dose.

– Folinic acid, 10 mg orally each day, should also be administered to minimize bone marrow suppression

Clinical Use : Oral Absorbable Agents

• Sulfadoxine

– long-acting sulfonamide

– combination formulation with pyrimethamine

– a second-line agent in the treatment of malaria– a second-line agent in the treatment of malaria

Clinical Use : Oral NonabsorbableAgents

• Sulfasalazine (salicylazosulfapyridine)

– Ulcerative colitis,

– enteritis,

– other inflammatory bowel disease– other inflammatory bowel disease

Clinical Use : Topical Agents

• Sodium sulfacetamide ophthalmic solution or ointment

– effective in the treatment of bacterial conjunctivitis and as adjunctive therapy for conjunctivitis and as adjunctive therapy for trachoma.

• Silver sulfadiazine• infection of burn wounds

Adverse Reactions

• Allergenic– Fever– Skin rashes, – exfoliative dermatitis, – photosensitivity, – urticaria, – urticaria, – Nausea & vomiting, – diarrhea,– difficulties referable to the urinary tract– In extreme case it may cause - Stevens-Johnson syndrome

• It may also cause• stomatitis, conjunctivitis, arthritis, hematopoietic disturbances,

hepatitis, rarely polyarteritis nodosa and psychosis

Adverse Reactions• Urinary Tract Disturbances– Crystalluria (large doses), hematuria, or even

obstruction.

– nephrosis and in allergic nephritis

• Hematopoietic Disturbances– hemolytic or aplastic anemia, granulocytopenia, – hemolytic or aplastic anemia, granulocytopenia,

thrombocytopenia, or leukemoid reactions

– provoke hemolytic reactions in patients with glucose-6- phosphate dehydrogenase deficiency

– End of pregnancy increase the risk of kernicterus in newborns

Trimethoprim, Pyrimethamine• Selectively inhibits

bacterial dihydrofolic acid reductase - converts dihydrofolic acid to tetrahydrofolic acid.

• 50,000 times less efficient • 50,000 times less efficient - inhibition of mammalian dihydrofolic acid reductase.

• Pyrimethamine -selectively inhibits dihydrofolic acid reductase of protozoa.

Resistance

• reduced cell permeability

• overproduction of dihydrofolatedihydrofolatereductase

• production of an altered reductase with reduced drug binding

• mutation

Pharmacokinetics

• Usually given orally alone or in combinationwith sulfamethoxazole

• Can also be given intravenously• Well absorbed from the gut - distributed widely in

body fluids and tissues, including cerebrospinal fluidbody fluids and tissues, including cerebrospinal fluid• Trimethoprim is more lipid-soluble than

sulfamethoxazole– 1 part of trimethoprim is given with 5 parts of

sulfamethoxazole

• Concentrates in prostatic fluid and in vaginal fluid -more antibacterial activity in prostatic and vaginal fluids

Clinical Uses• Oral Trimethoprim– Given alone (100 mg twice daily– Acute urinary tract infections

• Oral Trimethoprim-Sulfamethoxazole– Wide variety of infectionsWide variety of infections– Empiric therapy of upper urinary tract infections or

pneumonia.– One double-strength tablet : trimethoprim 160 mg

plus sulfamethoxazole 800 mg - every 12 hours• effective treatment for urinary tract infections and

prostatitis

– One single-strength tablet : ½ of former dose• prophylaxis in recurrent urinary tract infections - women

Clinical Uses• Intravenous Trimethoprim-Sulfamethoxazole– Solution - 80 mg trimethoprim plus 400 mg

sulfamethoxazole per 5 mL– intravenous infusion over 60–90 minutes– moderately severe to severe pneumocystis pneumonia– gramnegative bacterial sepsis– gramnegative bacterial sepsis– multidrugresistant species - shigellosis; typhoid fever;

or urinary tract infection– leishmaniasis and toxoplasmosis

• Oral Pyrimethamine with Sulfonamide– leishmaniasis and toxoplasmosis– falciparum malaria

Adverse Effects

• Untoward reactions associated with sulfonamides

• Nausea and vomiting,

• Drug fever• Drug fever

• Vasculitis,

• Renal damage, and central nervous system

FLUOROQUINOLONES

Introduction• Quinolone structure• Active primarily against gram-

negative bacteria - excellent for lower UTI only

• Addition of Fluorine -Fluoroquinolones– active against gram positive

bacteriaactive against gram positive bacteria

– High potency– Expanded spectrum.– Better tissue penetration– Good tolerability

• Ex: Nalidixic acid,• 1st gen: Norfloxacin, Ciprofloxacin,

Ofloxacin

• 2nd gen: Lomefloxacinm, Gatifloxacin, Moxifloxacin

Mechanism of Action• block bacterial DNA synthesis by inhibiting– Bacterial topoisomerase II (DNA gyrase)

– Topoisomerase IV

– prevents the relaxation of positively supercoiled DNA

– required for normal transcription and replication

Antibacterial Activity• Since quinolones were 1 of the best drug for gram(-) bacteria

– there was a need to increase its spectrum –FLUOROQUINOLONES

• Norfloxacin – least effective fluoroquinolones• Ciprofloxacin, enoxacin, lomefloxacin, levofloxacin,

ofloxacin, and pefloxacin– Methicillin-susceptible strains of S aureu - susceptible– Methicillin-susceptible strains of S aureu - susceptible– methicillin-resistant strains of staphylococci - resistant– most active agent of this group against gram-negative organisms,

P aeruginosa in particular– Atypical pneumonia (eg, mycoplasmas and chlamydiae)– Legionellapneumophila– mycobacteria, (Mycobacterium tuberculosis and Mycobacterium

avium complex)

Resistance

• one of every 107 –109 organisms.

• staphylococci, P aeruginosa , and Serratiamarcescens

• Point mutations in the quinolone binding • Point mutations in the quinolone binding region of the target enzyme

• permeability of the organism.

• Resistance to one fluoroquinolone - cross-resistance to all other members of this class

Pharmacokinetics

• oral administration– well absorbed : bioavailability of 80–95%

– distributed widely in body fluids

– Serum half-lives : 3 to 10 hour

– long half-lives of levofloxacin, gemifloxacin, – long half-lives of levofloxacin, gemifloxacin, gatifloxacin, and moxifloxacin - once-daily dosing

– impaired by divalent and trivalent cations, including those in antacids – 2 hours before or 4 hours

– eliminated by renal mechanisms - either tubular secretion or glomerular filtration

Clinical Use

• Fluoroquinolones (other than moxifloxacin): urinary tract infections including P. aeruginosa

• bacterial diarrhea caused by Shigella, Salmonella, toxigenic E coli and Campylobacter.toxigenic E coli and Campylobacter.

• Fluoroquinolones (except norfloxacin)

– Infections of soft tissues, bones, and joints

– Intra-abdominal infection

– Respiratory tract infections,

Clinical Use

• Effective against multidrug-resistant (MDR) organisms such as Pseudomonas and Enterobacter.

• Ciprofloxacin - drug of choice for prophylaxis• Ciprofloxacin - drug of choice for prophylaxisand treatment of anthrax

• Gonococcal infection

• Chlamydial urethritis or cervicitis

• Ciprofloxacin, levofloxacin or moxifloxacin : treatment of tuberculosis.

Clinical Use

• Eradication of meningococci

• Prophylaxis of infection in neutropenic cancer patients

• Respiratory fluoroquinolones : levofloxacin, • Respiratory fluoroquinolones : levofloxacin, gatifloxacin, gemifloxacin, and moxifloxacin– upper and lower respiratory tract infections

– enhanced gram-positive activity and activity against atypical pneumonia agents (chlamydiae, Mycoplasma and Legionella )

Adverse Effects

• generally well tolerated

• most common effects are nausea, vomiting, and diarrhea.

• Occasionally, headache, dizziness, insomnia, skin rash, or abnormal liver function tests.

• Occasionally, headache, dizziness, insomnia, skin rash, or abnormal liver function tests.

• May damage growing cartilage and cause anarthropathy - not routinely recommended for patients under 18 years of age.

• Tendonitis - a rare but serious complication

Summary

Summary

References

• Basic & Clinical Pharmacology Bertram G. Katzung, Twelfth Edition

• Essential of Medical Pharmacology, K.D. Tripathi, 6th edition

• Basic Principles of Pharmacology with Dental • Basic Principles of Pharmacology with Dental Hygiene Applications

• Rang and Dales Pharmacology 6th Ed 2007

• Color Atlas Of Pharmacology, 2Nd Ed (Lüllmann, Thieme 2000)