Sulphonamides PDF - Antimicrobial Drugs Notes
Download the comprehensive Sulphonamides PDF notes, an essential resource for understanding this important class of antimicrobial drugs. This document covers their unique mechanism of action (folic acid synthesis inhibition), spectrum of activity, common adverse effects, and therapeutic uses. Ideal for pharmacology and medicinal chemistry students. Available for free download or online viewing on Sildes By DuloMix.
Keywords: Sulphonamides PDF, Sulfonamide Antibiotics, Folic Acid Antagonists, Antibacterial Drugs, Sulfamethoxazole, Trimethoprim-Sulfamethoxazole, Adverse Reactions, Drug Resistance, DuloMix, Sildes By DuloMix, free PDF
Sulphonamides: Pioneering Antimicrobial Agents and Their Mechanism
Sulphonamides, commonly known as sulfa drugs, represent one of the earliest classes of effective antimicrobial agents. Their discovery in the 1930s revolutionized the treatment of bacterial infections, saving countless lives before the advent of penicillin. Although their use has somewhat declined due to the rise of resistance and the development of newer antibiotics, they remain important, particularly in combination therapies.
Chemical Structure and Classification
Sulphonamides are synthetic derivatives of para-aminobenzenesulfonamide. Their basic structure consists of a sulfonyl group (-SO2-) linked to an amine group (-NH2), and typically a substituted benzene ring. Variations in the substituent on the nitrogen atom of the sulfonamide group lead to different pharmacological properties, such as half-life, solubility, and antibacterial spectrum.
They can be classified based on their duration of action (short, intermediate, long-acting) or their primary use (e.g., systemic, intestinal, topical).
Mechanism of Action: Folic Acid Synthesis Inhibition
The antimicrobial action of sulphonamides is primarily bacteriostatic, meaning they inhibit bacterial growth rather than directly killing the bacteria. Their mechanism is centered on interfering with the synthesis of folic acid (folate), an essential coenzyme required for the synthesis of purines, pyrimidines, and amino acids—the building blocks of DNA, RNA, and proteins.
Bacteria, unlike humans, cannot absorb preformed folic acid from their environment and must synthesize it de novo. This process involves a series of enzymatic steps, beginning with the conversion of para-aminobenzoic acid (PABA) into dihydrofolic acid by the enzyme dihydropteroate synthase (DHPS). Subsequently, dihydrofolic acid is converted to tetrahydrofolic acid by dihydrofolate reductase (DHFR).
Sulphonamides are structural analogs of PABA. They competitively inhibit DHPS, thereby preventing the incorporation of PABA into dihydrofolic acid. This "antimetabolite" action halts bacterial folate synthesis, ultimately leading to a halt in bacterial DNA replication and cell division. Human cells are largely unaffected because they obtain folic acid from dietary sources, bypassing the need for de novo synthesis.
The combination of a sulphonamide (like sulfamethoxazole) with a dihydrofolate reductase inhibitor (like trimethoprim) results in a synergistic bactericidal effect. This combination, known as co-trimoxazole, blocks two sequential steps in the folic acid synthesis pathway, making it highly effective and reducing the likelihood of resistance developing.
Antimicrobial Spectrum
Sulphonamides have a broad spectrum of activity against many Gram-positive and Gram-negative bacteria. Historically, they were active against Streptococcus pyogenes, Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Escherichia coli, Klebsiella, Proteus, Salmonella, Shigella, and some protozoa (e.g., Toxoplasma gondii, Plasmodium falciparum). However, widespread resistance has significantly narrowed their clinical utility as monotherapy.
Pharmacokinetics (ADME)
- Absorption: Most sulphonamides are well absorbed orally.
- Distribution: They are widely distributed throughout body tissues and fluids, including the CSF, placenta, and fetal circulation.
- Metabolism: Primarily metabolized in the liver, mainly by N4-acetylation, which can produce inactive, less soluble metabolites that may crystallize in the urine.
- Excretion: Excreted primarily via the kidneys, both unchanged and as metabolites. Renal excretion is influenced by urine pH.
Adverse Drug Reactions (ADR)
While generally well-tolerated, sulphonamides can cause several adverse effects:
- Hypersensitivity Reactions: The most common and serious side effects, including skin rashes (mild to severe, e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis), fever, and photosensitivity.
- Urinary Tract Disturbances: Crystalluria (formation of crystals in urine), leading to renal damage, especially with older, less soluble sulphonamides or in dehydrated patients. Adequate hydration is crucial.
- Hematologic Reactions: Dose-related bone marrow suppression (anemia, leukopenia, thrombocytopenia), especially with co-trimoxazole. Hemolytic anemia can occur in patients with G6PD deficiency.
- Gastrointestinal Disturbances: Nausea, vomiting, diarrhea.
- Kernicterus: Sulphonamides can displace bilirubin from plasma proteins, increasing free bilirubin levels, which can lead to kernicterus in newborns. Therefore, they are contraindicated in late pregnancy, nursing mothers, and infants under 2 months.
- Drug Interactions: Can potentiate the effects of oral anticoagulants (e.g., warfarin), sulfonylurea hypoglycemics, and methotrexate due to protein binding displacement and/or enzyme inhibition.
Therapeutic Uses
Despite resistance, sulphonamides, especially in combination with trimethoprim (co-trimoxazole), remain valuable for:
- Urinary Tract Infections (UTIs): Co-trimoxazole is a common first-line agent for uncomplicated UTIs.
- Pneumocystis jirovecii Pneumonia (PCP): Co-trimoxazole is the drug of choice for treating and preventing PCP in immunocompromised patients (e.g., HIV/AIDS).
- Nocardiosis: A serious bacterial infection.
- Toxoplasmosis: Often used with pyrimethamine.
- Topical Use: Silver sulfadiazine is used for preventing infections in burn wounds.
- Inflammatory Bowel Disease: Sulfasalazine (a prodrug) is used for ulcerative colitis and Crohn's disease.
The continued relevance of sulphonamides, particularly in specific combinations, highlights their historical importance and ongoing utility in managing various infections, while underscoring the need for careful consideration of resistance patterns and adverse effects.
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