PHT P.13 Sulfonamides, Trimethoprim & Quinolones PDF

PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.13 SULFONAMIDES,TRIMETHOPRIM & QUINOLONES PHARMACOLOGY LECTURE LECTURER: Dr. Paul Tang DATE: February 18,2024 TOPIC OUTLINE I. ANTIFOLATE DRUGS a. Sulfonamides b. Trimethoprim & TrimethoprimSulfamethoxazole Mixtures II. DNA GYRASE INHIBITORS a. Fluoroquin...

PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.13 SULFONAMIDES,TRIMETHOPRIM & QUINOLONES PHARMACOLOGY LECTURE LECTURER: Dr. Paul Tang DATE: February 18,2024 TOPIC OUTLINE I. ANTIFOLATE DRUGS a. Sulfonamides b. Trimethoprim & TrimethoprimSulfamethoxazole Mixtures II. DNA GYRASE INHIBITORS a. Fluoroquinolones I. ANTIFOLATE DRUGS SULFONAMIDES Belongs to the group of anti-folate drugs Chemical structure similar to the paminobenzoic acid Sulfonamides differ from each other by attaching substituents to the amido group (-SO2 -NH -R) or the amino group(-NH2) of the sulfanilamide nucleus o Side chains are useful because the bacteria need PABA for the formation of folate which is required for protein synthesis o By substituting PABA with sulfonamide à once it enters the bacterial cell à will be mistakenly recognized as PABA folate or protein synthesis will now be able to detect this. Sulfonamides tend to be much more soluble at alkaline than at acid pH Most can be prepared as sodium salts, which are used for intravenous administration of cellular events initiated by osteoclastic bone resorption and followed by osteoblastic bone formation MECHANISM OF ACTION & ANTIMICROBIAL ACTIVITY Sulfonamide-susceptible organisms, cannot use exogenous folate but must synthesize it from PABA which is essential for production of purines and nucleic acid synthesis Sulfonamides inhibit dihydropteroate synthase and folate production Sulfonamides inhibit both gram-positive bacteria, and gram-negative enteric bacteria, as well as Nocardia Species, Chlamydia Trachomatis, and some protozoa Activity is poor against anaerobes Pseudomonas aeruginosa is intrinsically resistant to sulfonamide antibiotics Combination of a sulfonamide with an inhibitor of dihydrofolate reductase (trimethoprim or pyrimethamine) provides synergistic activity because of sequential inhibition of folate synthesis Actions of Sulfonamides and Trimethoprim RESISTANCE Sulfonamide resistance may also occur as a result of mutations that: 1. Cause overproduction of PABA 2. Cause production of a folic acid synthesizing enzyme that has low affinity for sulfonamides 3. Impair permeability to the sulfonamide Structure of sulfonamide and p-aminobenzoic acid PHARMACOKINETICS 3 Major Groups: 1. Oral absorbable Oral absorbable sulfonamides are absorbed from the stomach N OT E TA K E R : A B U L E N C I A , B A C W A D E N , B A L D O S , A F R I L , C U TAY, F E R R E R , S A N G D A A N Page 1|6 PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.13 SULFONAMIDES,TRIMETHOPRIM & QUINOLONES and small intestine and distributed widely to tissues and body fluids, placenta and fetus 2. Oral non-absorbable 3. Topical Protein binding varies from 20% to over 90% Blood levels generally peak 2-6 hours A portion of absorbed drug is acetylated or glucuronidated in the liver Sulfonamides and inactive metabolites are then excreted in the urine, mainly by glomerular filtration CLINICAL USE Regardless of the preparation Rarely used as a single agent The fixed-drug combination of Trimethoprim Sulfamethoxazole is the drug of choice for infections such as Pneumocystis jiroveci (formerly P carinii) pneumonia, Toxoplasmosis, and Nocardiosis A. ORAL ABSORBABLE AGENTS Administration of Sulfadiazine + Pyrimethamine is 1st line therapy for treatment of Acute Toxoplasmosis o By combining with Pyrimethamine, a potent inhibitor of dihydrofolate reductase, they block sequential steps in the folate synthesis pathway Sulfadoxine is a long-acting sulfonamide that is co-formulated with pyrimethamine (Fansidar) which is used as 2nd line of treatment for Malaria B. ORAL NON-ABSORBABLE AGENTS Sulfasalazine (salicylazosulfapyridine) is widely used in ulcerative colitis, enteritis, and other inflammatory bowel disease o Because it is found that in these GI conditions, there may be an overwhelming colonization of the normal flora C. TOPICAL AGENTS Sodium sulfacetamide solution or ointment is effective in the treatment of bacterial conjunctivitis and as adjunctive therapy for trachoma Mafenide acetate is used topically but can be absorbed from burn sites Silver sulfadiazine is a less toxic topical sulfonamide o preferred to mafenide for prevention of infection of burn wounds o Most commonly used ORAL ORAL NONTOPICAL ABSORBABLE ABSORBABLE AGENTS AGENTS AGENTS - Sulfadiazine + -Sulfasalazine - Sodium Primethamine sulfacetamide - Sulfadoxine - Mefenide Acetate - Silver sulfadiazine ADVERSE REACTIONS The most common adverse effects are fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria, nausea, vomiting, diarrhea, and difficulties referable to the urinary tract Stevens-Johnson syndrome is a hypersensitivity reaction to sulfamethoxazole and pyrimethamine particularly serious and potentially fatal type of skin and mucous membrane eruption associated with sulfonamide use because it has a skin manifestation and at times it can affect kidney function causing kidney failure Urinary Tract Obstruction May precipitate in urine, especially at neutral or acid pH, producing crystalluria, hematuria, or even obstruction but rare with more soluble sulfonamide such as Sulfisoxazole Sulfadiazine and Sulfamethoxazole are relatively insoluble in acidic urine and can cause crystalluria but this reaction is dose related N OT E TA K E R : A B U L E N C I A , B A C W A D E N , B A L D O S , A F R I L , C U TAY, F E R R E R , S A N G D A A N Page 2|6 PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.13 SULFONAMIDES,TRIMETHOPRIM & QUINOLONES Crystalluria is treated by administration of sodium bicarbonate to alkalinize the urine and fluids to increase urine flow Hematopoietic Disturbances Sulfonamides can cause hemolytic or granulocytopenia, leukemoid reactions aplastic thrombocytopenia, or may provoke hemolytic reactions in patients with glucose-6- phosphate dehydrogenase deficiency Sulfonamides taken near the end of pregnancy increase the risk of kernicterus in newborns Other unwanted effects include stomatitis, conjunctivitis, arthritis, hematopoietic disturbances, hepatitis, and, rarely, polyarteritis nodosa and psychosis - TRIMETHOPRIM & TRIMETHOPRIMSULFAMETHOXAZOLE MIXTURES Trimethoprim, a trimethoxybenzylpyrimidine, selectively inhibits bacterial dihydrofolic acid reductase, which converts dihydrofolic acid to tetrahydrofolic acid, a step leading to the synthesis of purines and ultimately to DNA RESISTANCE 3 Mechanisms: 1. Reduced cell permeability 2. Overproduction of dihydrofolate reductase 3. Production of an altered reductase with reduced drug binding Made possible by mutation, but more commonly it is due to plasmid- encoded trimethoprim-resistant dihydrofolate reductases PHARMACOKINETICS Well absorbed from the gut and distributed widely in body fluids and tissues, including cerebrospinal fluid More lipid-soluble than sulfamethoxazole, it has a larger volume of distribution than the latter drug About 30-50% of the Sulfonamide and 50-60% of the Trimethoprim (or their respective metabolites) are excreted in the urine within 24 hours Dosage is reduced in presence of kidney diseases Because of the acidity of the sites, trimethoprim has better antibacterial activity in those areas than in plasma CLINICAL USES A. ORAL TRIMETHOPRIM Can be given alone (100 mg twice daily) in Acute Urinary Tract Infections B. ORAL TRIMETHOPRIMSULFAMETHOXAZOLE (TMP-SMZ) Treatment for a wide variety of infections including p jiroveci pneumonia, urinary tract infections, prostatitis, and some infections caused by susceptible strains of shigella, salmonella, and nontuberculous mycobacteria Commonly used for the treatment of uncomplicated skin and soft tissue infections C. INTRAVENEOUS TRIMETHOPRIMSULFAMETHOXAZOLE Agent of choice for moderately severe to severe pneumocystis pneumonia May be an effective alternative for infections caused by some multidrug-resistant species such as Enterobacter and Serratia; Shigellosis or Typhoid D. ORAL PYRIMETHAMINE WITH SULFONAMIDE Used in the treatment of Toxoplasmosis N OT E TA K E R : A B U L E N C I A , B A C W A D E N , B A L D O S , A F R I L , C U TAY, F E R R E R , S A N G D A A N Page 3|6 PCC SOM 2026 - PHARMACOLOGY AND THERAPEUTICS P.13 SULFONAMIDES,TRIMETHOPRIM & QUINOLONES In Falciparum malaria, the combination of pyrimethamine with sulfadoxine (Fansidar) has been used TMP-SMX ADVERSE EFFECTS Trimethoprim produces the predictable adverse effects of an antifolate drug, especially megaloblastic anemia, leukopenia, and Granulocytopenia The combination trimethoprimsulfamethoxazole may cause all of the untoward reactions associated with sulfonamides Nausea and vomiting, drug fever, vasculitis, renal damage, and central nervous system disturbances occasionally occur Because trimethoprim inhibits secretion of creatinine at the distal renal tubule, mild elevation of serum creatinine without impairment of glomerular filtration rate may occur II. DNA GYRASE INHIBITOR FLUOROQUINOLONES CIPROFLOXACIN | GEMIFLOXACIN | LEVOFLOXACIN | MOXIFLOXACIN | NORFLOXACIN | OFLOXACIN Quinolones block bacterial DNA synthesis by inhibiting bacterial Topoisomerase II (DNA gyrase) and Topoisomerase IV Inhibition of DNA gyrase prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication Inhibition of topoisomerase IV interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division RESISTANCE Emerging resistance is due to one or more point mutations in the quinolone binding region of the target enzyme or to a change in the permeability of the organism Resistance to one fluoroquinolone, particularly if it is of high level, generally confers crossresistance to all other members of this class PHARMACOKINETICS After oral administration fluoroquinolones are well absorbed and distributed widely in body fluids and tissues Serum half-lives range from 3 to 10 hours. The relatively long half-lives of Levofloxacin, Gemifloxacin, and moxifloxacin permit oncedaily dosing Impaired by divalent and trivalent cations, including those in antacids, oral fluoroquinolones should be taken 2 hours before or 4 hours after any products containing these cations o Any cations such as magnesium and aluminum will humper the absorption of Fluoroquinolones, hence should be taken on empty stomach. Most fluoroquinolones, except Moxifloxacin, are eliminated by renal mechanisms, either tubular secretion or glomerular filtration Dosage adjustment is required for patients with creatinine clearances less than 50 mL/min Dosage adjustment for renal failure is not necessary for Moxifloxacin since it is metabolized in the liver, it should be used with caution in patients with hepatic failure CLINICAL USES Originally, they had excellent activity against gram-negative aerobic bacteria; but limited activity against gram-positive organisms Norfloxacin, is the least active of the fluoroquinolones against both gram negative and gram-positive organisms Ciprofloxacin, Enoxacin, Lomefloxacin, Levofloxacin, Ofloxacin, and Pefloxacin comprise a second group of similar agents possessing excellent gram-negative activity and N OT E TA K E R : A B U L E N C I A , B A C W A D E N , B A L D O S , A F R I L , C U TAY, F E R R E R , S A N G D A A N Page 4|6 PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.13 SULFONAMIDES,TRIMETHOPRIM & QUINOLONES moderate to good activity against gram-positive bacteria o Enoxacin & Lomefloxacin are not available in the Philippines When treating staphylococcal infections, fluoroquinolones are typically used in combination with a second active agent, such as Rifampin, to prevent emergence of resistance while on therapy Levofloxacin, the l-isomer of ofloxacin, has superior activity against gram-positive organisms, especially Streptococcus pneumoniae o Levofloxacin is used for Pneumonia caused by S. pneumoniae Gatifloxacin, Gemifloxacin, and Moxifloxacin make up a third group (latest) of fluoroquinolones with improved activity against gram positive organisms, particularly S. pneumoniae and some Staphylococci o Ofloxacin is the cheapest available in 200mg and 400mg usually used for the treatment of UTI, Prostatitis & Vaginitis. o Levofloxacin comes in 500mg and 750mg, because of its superior strength against gram- positive organisms- given in high dose in a short course. Fluoroquinolones also are active against agents of Atypical Pneumonia (mycoplasma and chlamydiae) and against intracellular pathogens such as Legionella and some Mycobacteria, including Mycobacterium tuberculosis and Mycobacterium avium complex o Levofloxacin IV is considered the Drug of choice in multi-drug resistant TB Fluoroquinolones (other than moxifloxacin) are effective in urinary tract infections caused by many organisms, including P. aeruginosa Fluoroquinolones (except norfloxacin) are used in infections of soft tissues, bones, and joints and in intra-abdominal and respiratory tract infections Ciprofloxacin is a drug of choice for prophylaxis and treatment of Anthrax Levofloxacin and Ofloxacin are recommended as alternative treatment options for Chlamydial Urethritis or Cervicitis With their enhanced gram-positive activity and activity against atypical pneumonia agents (chlamydiae, mycoplasma, and legionella), Levofloxacin, Gemifloxacin, and Moxifloxacin (Respiratory Fluoroquinolones) which are effective for treatment of lower respiratory tract infections ADVERSE EFFECTS Fluoroquinolones are generally well tolerated. The most common effects are nausea, vomiting, and diarrhea. Occasionally, headache, dizziness, insomnia, skin rash, or abnormal liver function tests develop Prolongation of the QTC interval may occur with Gatifloxacin, Levofloxacin, Gemifloxacin, and Moxifloxacin; these drugs should be avoided or used with caution in patients with known QTC interval prolongation or uncorrected hypokalemia Risk factors for tendinitis include advanced age, renal insufficiency and concurrent steroid use Fluoroquinolones should be avoided during pregnancy in the absence of specific data Oral or intravenously administered fluoroquinolones have also been associated with peripheral neuropathy CHECKPOINT! 1.T/F. The fixed-drug combination of Trimethoprim Sulfamethoxazole is the drug of choice for infections such as Pneumocystis jiroveci ,pneumonia, Toxoplasmosis, and Nocardiosis 2.T/F. Agent of choice for moderately severe to severe pneumocystis pneumonia is oral Trimethoprim-Sulfamethoxazole 3. T/F. Quinolones block bacterial DNA synthesis by inhibiting bacterial Topoisomerase III and Topoisomerase IV 4. T/F. ORAL PYRIMETHAMINE WITH SULFONAMIDE is Used in the treatment of Toxoplasmosis 5.T/F. Administration of Sulfadiazine + Pyrimethamine is 2nd line therapy for treatment of Acute Toxoplasmosis 6. Agent of choice for moderately severe to severe pneumocystis pneumonia a. IV TMP- SMZ c. Oral TMP-SMZ b. Oral TMP d. Oral Pyrimethamine w/ Sulfonamide 7. Sulfonamides tend to be much more soluble at what pH? a. Acidic c. Neutral b. Alkaline 8. This is a hypersensitivity reaction to sulfamethoxazole and pyrimethamine? a. RA c. Arthus Reaction b. Steven Johnsons Syndrome d. Serum Sickness 9. Quinolones that can cause prolongation of the QTC interval except? a. Gatifloxacin c. Moxifloxacin b. Levofloxacin d.Ciprofloxacin 10. Sulfonamide drug that is the 2nd line of treatment for Malaria? a. Fansidar c. Sulfasalazine b. Sulfisoxazole d. NOTA N OT E TA K E R : A B U L E N C I A , B A C W A D E N , B A L D O S , A F R I L , C U TAY, F E R R E R , S A N G D A A N Page 5|6 PCC SOM 2026 PHARMACOLOGY AND THERAPEUTICS P.13 SULFONAMIDES,TRIMETHOPRIM & QUINOLONES TTFTFABBDA N OT E TA K E R : A B U L E N C I A , B A C W A D E N , B A L D O S , A F R I L , C U TAY, F E R R E R , S A N G D A A N Page 6|6