Adverse Reactions

• Hypersensitivity Reactions

  • Hypersensitivity reactions represent the most common category of adverse effects associated with sulfonamides.

    • Common Reactions

      • The most frequent manifestations are cutaneous, including morbilliform (maculopapular) rashes and urticaria (hives).¹  

        • Photosensitivity is also a well-documented effect, making it essential to counsel patients on avoiding excessive sun exposure and using sunscreen.^2,3

        • Mechanisms associated with phototoxicity may involve UV radiation causing drug molecule electrons to transition to an excited, chemically unstable state. The excited state participates in direct energy transferred oxygen creating a singlet oxygen which is the reactive oxygen species (ROS).

        • Oxidative stress associated with ROS formation as well as direct cellular damage caused by the free radical results in extreme sunburn--like reaction.⁴ 

    • Severe Cutaneous Adverse Reactions

      Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)

      • These reactions are considered rare but extremely serious hypersensitivity reactions which constitutes medical emergencies.

        • Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)

          • Stevens-Johnson Syndrome (SJS) & Toxic Epidermal Necrolysis (TEN) | A Clinical Medicine Brief

            Attribution: Urbina A Stevens-Johnson Syndrome (SJS) & Toxic Epidermal Necrolysis (TEN) | A Clinical Medicine Brief https://www.youtube.com/watch?v=XBlDW73NZS4 (Jan 21, 2025)

          • SJS and TEN represent a continuum of the same disease process, distinguished by the percentage of body surface area (BSA) affected by epidermal detachment: <10% BSA for SJS, >30% BSA for TEN, and 10-30% for SJS/TEN overlap.⁵

            • Pathophysiology^5,6  

              • The underlying mechanism is a delayed-type (Type IV) hypersensitivity reaction, not a classic IgE-mediated allergy. (There are other theories that have been proposed)

                • This delayed-type hypersensitivity reaction may be initiated when the drug or its reactive metabolites trigger a massive, targeted attack on the body's own skin cells (keratinocytes) by cytotoxic T-lymphocytes (CD8+) and Natural Killer (NK) cells.

                • Resulting cell death is mediated by the release of cytotoxic proteins, including granulysin (a key mediator), Fas-Fas Ligand interactions, and perforin/granzyme.

                • Genetic predisposition plays a major role, with risk being strongly associated with specific Human Leukocyte Antigen (HLA) alleles, although the specific alleles for sulfonamides are less well-defined than for other drugs like carbamazepine or allopurinol.^5,6

            • Clinical Presentation^6,7

              • The reaction typically begins 1 to 3 weeks after starting the offending drug.

                • An initial prodrome of fever, malaise, and flu-like symptoms is followed by the abrupt onset of a painful, dusky red or purpuric rash that rapidly progresses to form flaccid bullae and extensive sheets of epidermal sloughing.

                • Severe, painful involvement of mucous membranes (oral, ocular, and genital) is a hallmark feature.

                • A positive Nikolsky sign (gentle lateral pressure causes the epidermis to shear off) is characteristic.

            • Management^6,7

              • SJS/TEN is a medical emergency requiring immediate hospitalization, often in a burn unit or intensive care unit.

                • The single most critical intervention is the immediate withdrawal of the suspected causative drug.

                • Treatment is primarily supportive, focusing on wound care, fluid and electrolyte management, nutritional support, and pain control.

• Renal Toxicity

  • Two primary mechanisms for renal toxicity

    • Crystalluria and Obstructive Uropathy^8,9,10  

      • Sulfonamides and, more importantly, their acetylated metabolites, have low solubility, particularly in neutral or acidic urine.

      • Low solubility can lead to their precipitation within the renal tubules and collecting ducts, forming crystals.

        • These crystals (classically described as "shocks of wheat" for sulfadiazine) can aggregate to form stones or sludge, causing tubular obstruction, hematuria, and acute kidney injury.

        • This complication can be largely prevented by ensuring the patient maintains adequate hydration to produce a high urine output, and in some high-risk situations, by alkalinizing the urine with sodium bicarbonate to increase drug solubility.

      • N-acetyl sulfamethoxazole crystals. Representative crystals from patient's urine

        N-acetyl sulfamethoxazole crystals. Representative crystals from patient's urine Attribution Figure above corresponds to figure 4 from reference 10 Azencot R Saint-Jacques C Haymann J-P Frochol V Daudon M Letavernier E Sulfamethoxazole-induced Crystal nephropathy: characterization and prognosis and AK series. Scientific Reports. 14, Article number: 6078 (2024). https://www.nature.com/articles/s41598-024-56322-9

     

    • Acute Interstitial Nephritis (AIN)^11,12,13 

      • Acute Interstitial Nephritis

        Presentation (unusual) of Classic Idiopathic Polyarteritis Nodosa as Acute Interstitial Nephritis, in clinical medicine insights. Case report. Attribution Libertas Academica (citing Figure 2 of An Unusual Presentation of Classic Idiopathic Polyarteritis Nodosa as Acute Interstitial Nephritis, in Clinical Medicine Insights: Case Reports, first author Ravi Sunderkrishnan), CC BY 2.0 <https://creativecommons.org/licenses/by/2.0>, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:Acute_Interstitial_Nephritis.jpg

      • This is a non-dose-related, idiosyncratic hypersensitivity reaction that causes inflammation of the kidney interstitium and tubules.

      • This hypersensitivity is a cell-mediated immune response, distinct from crystalluria.

        • The classic presentation includes fever, rash, and eosinophilia, accompanied by an acute decline in renal function.

        • The presence of eosinophils in the urine may be able marginally helpful diagnostic clue, though not always present.¹³

• Hematologic Toxicity

  • Agranulocytosis¹⁴

    • Agranulocytosis is a rare (<1%), unpredictable, but potentially fatal idiosyncratic reaction characterized by a profound decrease in the absolute neutrophil count to <0.5 x 10⁹/L, which results in the patient being patient at high risk for severe infections.

      • Mechanism

        • This reaction is believed to be immune-mediated.

          • The current hypothesis suggests that reactive metabolites of the sulfonamide, formed within neutrophils or their bone marrow precursors by enzymes like myeloperoxidase, act as haptens.

          • These sulfonamides reactive metabolites, acting as haptens, trigger an immune response that leads to mature neutrophils destruction and/or suppression of their production.

          • A strong association with certain HLA genotypes provides further evidence for an immunogenetic basis.

    • Hemolytic Anemia^15,16,17 

      • Sulfonamides are oxidizing agents and can induce acute hemolysis in patients with an inherited deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD).

        • In these individuals, red blood cells lack sufficient reducing power to protect themselves from oxidative stress, leading to their premature destruction.

    • Folate Deficiency¹⁸

      • While the affinity of trimethoprim for bacterial dihydrofolate reductase (DHFR) is many times greater than for human DHFR, prolonged use of TMP/SMX can still interfere with human folate metabolism.

        • Such interference can lead to megaloblastic anemia, leukopenia, and/or thrombocytopenia, particularly in patients with underlying risk factors such as malnutrition, alcoholism, or pregnancy.

      • The clinical importance of an interaction between trimethoprim-sulfamethoxazole and folic acid remains a topic for continued discussion, Noting the availability of folate in the diet^.19

    • Hyperkalemia²⁰

      • The trimethoprim component of TMP/SMX is structurally similar to the potassium-sparing diuretic amiloride.

        • Trimethoprim directly inhibits the epithelial sodium channel (ENaC) in the distal renal tubule, which reduces the excretion of potassium.

        • This effect may lead to clinically significant and potentially life-threatening hyperkalemia, especially in the elderly, patients with pre-existing renal insufficiency, and those taking concomitant medications that also raise potassium levels (e.g., ACE inhibitors, ARBs, spironolactone)

• Drug-Drug Interactions

  • Metabolic Interactions (CYP2C9 Inhibition): Sulfamethoxazole is a moderate inhibitor of the cytochrome P450 isoenzyme CYP2C9, which is responsible for the metabolism of many commonly used drugs.²¹

    • Warfarin²² 

      • The warfarin-sulfamethoxazole (SMX) interaction may be, arguably, the most clinically important.

        • SMX significantly inhibits the metabolism of S-warfarin, the more potent enantiomer of the anticoagulant.

          • This inhibition leads to a rapid and often unpredictable increase in the International Normalized Ratio (INR) and places the patient at a very high risk of serious or fatal bleeding.

            • If the combination cannot be avoided, extremely close monitoring of the INR (potentially daily) and proactive dose reduction of warfarin is required.

    • Sulfonylureas^20,23,24

      • SMX inhibits the metabolism of oral hypoglycemic agents like glyburide and glipizide.

        • Inhibition of metabolism of these oral hypoglycemic drugs potentiates their glucose-lowering effect and can precipitate severe, prolonged hypoglycemia.

        • Patients with diabetes taking these agents require frequent blood glucose monitoring and may need dose adjustments.

    • Phenytoin^20,25

      • Sulfamethoxazole  inhibits the metabolism of phenytoin, which can lead to elevated serum levels and an increased risk of dose-related toxicity (e.g., nystagmus, ataxia)

  • Protein-Binding and Renal Excretion Interactions

    • Methotrexate^26,27 

      • The combination of TMP/SMX and methotrexate is particularly hazardous and should generally be avoided.

        • The interaction is multi-faceted: SMX can displace methotrexate from its binding sites on plasma albumin, increasing the free, active fraction of the drug, while TMP competes with methotrexate for active tubular secretion in the kidneys, decreasing its clearance.

        • Both mechanisms lead to elevated methotrexate levels and a profound risk of toxicity, including severe myelosuppression, mucositis, and renal failure.

  • Pharmacodynamic Interactions

    • ACE Inhibitors and Angiotensin Receptor Blockers^28,29

      • The trimethoprim component has a potassium-sparing effect.

        • When used concurrently with other drugs that raise potassium levels, such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), there is an additive risk of developing hyperkalemia.

    • Digoxin³⁰

      • Sulfonamides have been reported to increase serum digoxin levels, potentially leading to toxicity.