1474 SECTION XII I Pediatric Critical Care Pharmacology and Toxicology of the magnesium is resorbed 128 In addition, hypomagnesemia is often closely associated with hypocalcemia and hypokalemia; cor r[.]
1474 S E C T I O N X I I I Pediatric Critical Care: Pharmacology and Toxicology of the magnesium is resorbed.128 In addition, hypomagnesemia is often closely associated with hypocalcemia and hypokalemia; correcting serum magnesium may be required to normalize potassium and calcium levels.133 Hypocalcemia is another common abnormality in critically ill patients Calcium is critical for cell function, neural transmission, membrane stability, bone health, and intracellular signaling Calcium homeostasis is maintained through regulatory mechanisms via parathyroid hormone (PTH) and vitamin D but disruptions can cause calcium to shift from the extracellular fluid in greater quantities than it can be replaced.134 Overall, hypocalcemia typically occurs as a result of PTH deficiency, vitamin D deficiency, calcium chelation, or bone resorption dysfunction For example, some antiepileptic agents (e.g., phenytoin, phenobarbital, carbamazepine) cause vitamin D deficiency/resistance, whereas several chemotherapeutic agents and bisphosphonates inhibit bone resorption (see Table 124.3).121,128,134 Drug-induced hypercalcemia is also secondary to disruptions in calcium homeostasis that involve PTH and vitamin D Overall, the rate of calcium influx extracellularly exceeds the kidney’s ability to eliminate it.128 The most common drugs associated with hypercalcemia include vitamin D toxicity, thiazide diuretics, lithium, and calcium supplementation (e.g., calcium carbonate).121,128 In summary, electrolyte abnormalities are a common ADR that can complicate therapy The cause is often multifactorial; however, medications are a known cause of electrolyte disorders As a result, critically ill patients may require frequent electrolyte monitoring, especially if on multiple-drug therapy Electrolyte abnormalities have been noted with the use of amiodarone; however, it is most commonly known for its adverse effects on the thyroid gland Due to the large amount of iodine in amiodarone (3 mg iodine/100 mg drug is released into circulation), it has a counter-regulatory effect on the production of thyroid hormones.121 In patients in more developed countries, where iodine deficiency is rare, use of amiodarone is associated with hypothyroidism In contrast, in countries where iodine deficiency is more common, amiodarone can cause hyperthyroidism.121 Therefore, it is recommended to obtain baseline thyroid studies prior to starting therapy and to periodically monitor them throughout treatment Other drugs associated with thyroid dysfunction can be found in Table 124.3.121,135–137 Sodium nitroprusside (SNP), a potent vasodilator, has been used to control blood pressure in the ICU for many years However, SNP is metabolized to cyanide and thiocyanate; thus, cyanide toxicity should be considered when SNP is given at higher doses and with prolonged use.138,139 Overall, SNP is considered safe to use in pediatric patients at lower doses and for short durations The pediatric literature has demonstrated that cyanide toxicity is uncommon.138–140 Risk factors for developing toxicity include renal or liver dysfunction, prolonged infusion duration (24 hours), and/or higher doses (.2 mg/kg per minute).139,140 Propofol is widely used for procedural sedation in the ICU, although its use as a continuous infusion is limited owing to the possibility of developing propofol-related infusion syndrome (PRIS) Although rare, the hallmark signs of PRIS include severe metabolic acidosis, acute refractory bradycardia, rhabdomyolysis, and hyperlipidemia that can lead to cardiovascular collapse and death.141 In 2001, the FDA issued a warning against off-label use of propofol for sedation in the PICU after reviewing data from a randomized controlled trial The trial evaluated the safety and efficacy of propofol versus standard sedation in pediatric patients Approximately 10% of patients treated with propofol died compared with 4% of children receiving standard treatment.142 In general, PRIS appears to be dose dependent and is associated with propofol infusion rates greater than mg/kg per hour for at least 48 hours, although there are reports of PRIS occurring at shorter durations and lower infusion rates.141,143 Other risk factors for developing PRIS include younger age, severe critical illness, exogenous catecholamine or glucocorticoid administration, low carbohydrate supplies (especially in children), and subclinical mitochondrial disease (such as defects in lipid metabolism).141,143,144 Overall, the use of propofol infusions in the PICU remains controversial If used, appropriate monitoring of arterial blood gases (pH), serum lactate, creatinine kinase, electrolytes, and liver and renal function is warranted PRIS can also be prevented by ensuring that patients maintain an adequate carbohydrate load, which will help avoid an increase in fatty acids.143 Although the safe use of propofol without adverse effects has been reported, high-dose, prolonged propofol infusions are not recommended in the pediatric ICU setting given the risk of death with PRIS.143 Dermatologic Drug-induced dermatologic reactions are the most common reported adverse events, affecting 2% to 3% of all hospitalized patients They include hypersensitivities, cutaneous eruptions or exacerbations, and severe cutaneous adverse reactions (SCARs) Drug-induced hypersensitivities describe both immunoglobulin (Ig)-mediated allergic reactions and pseudoallergies Urticaria, pruritus, angioedema, and facial flushing can occur with both types of hypersensitivity Though their clinical presentation is similar, true allergic reactions require a sensitization period (5–21 days after the first dose) due to the activation of antibodies Allergic reactions are often associated with antimicrobials, antivirals, and aromatic anticonvulsants, such as phenobarbital and phenytoin Coexisting conditions may also contribute to the development of allergic reactions For example, active infection with Epstein-Barr virus may increase the potential for a reaction to aminopenicillins.145 Though commonly described as true allergies, dermatologic reactions to vancomycin, radiocontrast, aspirin, and ACE inhibitors are usually pseudoallergic.145 Pseudoallergies include infusion-related reactions, skin flushing, and anaphylactoid reactions, which usually occur within minutes of administration “Red man syndrome,” facial and neck flushing associated with vancomycin, is an example of a pseudoallergy As with other pseudoallergies, reducing the infusion rate and premedicating with antihistamines are strategies to reduce the development of this adverse effect Many medications are associated with hypersensitivities and pseudoallergy Therefore, it is important to assess patients carefully when these types of reactions occur, as a falsely labeled “allergy” may limit future treatment options Maculopapular rashes are the most common types of druginduced skin eruptions Like hypersensitivity reactions, the rash usually develops to 14 days after initiation of the causative medication However, unlike urticaria, which is associated with IgE-mediated allergic reactions, maculopapular rashes are selflimiting and not typically lead to more severe symptoms, such as angioedema and anaphylaxis It is important to note that lesions located in the mucous membranes, palms, or soles of the feet are evident in approximately 90% of SCARs and may be a prelude to a more serious reaction After discontinuation of the suspected medication, most erythematous reactions can be treated with antihistamines and a low-dose steroid taper (if rash is diffuse) CHAPTER 124 Adverse Drug Reactions and Drug-Drug Interactions SCARs include drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and warfarin-induced necrosis Drug rash with eosinophilia and systemic symptoms (DRESS) is defined by a constellation of symptoms, including high fever, symmetric maculopapular rash, and internal organ involvement Often associated with anticonvulsants, specifically phenytoin and phenobarbital, allopurinol, and dapsone, symptoms may take to weeks to develop after the initiation of the causative medication Organ dysfunction may be severe and can lead to liver or kidney failure Treatment includes supportive care and high-dose steroids In patients receiving allopurinol, it is beneficial to adjust for renal dysfunction and avoid concurrent use of thiazide diuretics or ACE inhibitors SJS and TEN are similar SCARs that are considered dermatologic emergencies Often preceded by a viral-appearing prodrome, both conditions are associated with high fever and maculopapular skin eruptions that blister, leading to epidermal necrosis and detachment These symptoms often appear within to 14 days of drug exposure Though their presentations are similar, TEN is often considered a more severe presentation of SJS since patients with TEN develop epidermal detachment on greater than 30% of their body surface area (BSA) versus less than 10% of BSA in SJS Additionally, TEN is associated with acute renal failure, respiratory failure, and sepsis Medications commonly known to cause SJS and TEN include allopurinol, lamotrigine, penicillin, TMP-SMX, and voriconazole.146 Patients with SJS and TEN require admission to the ICU for supportive care, including extensive wound care and surgical debridement In smaller studies, higher doses of intravenous immunoglobulin (IVIG) have been shown to decrease disease progression and improve outcomes Warfarin-induced skin necrosis (WISN) is a severe cutaneous reaction that typically occurs within the first 10 days after the initiation of warfarin therapy A dramatic drop in protein C, compared with other coagulation factors, creates a hypercoagulable state in which areas with higher amounts of adipose tissue can develop blistering plaques eventually leading to necrosis Treatment includes discontinuation of warfarin, anticoagulation with heparin to prevent further microthrombi from developing, freshfrozen plasma or protein C concentrate to restore protein C levels, and surgical debridement with or without skin grafting Strategies to prevent WISN include initiation with lower doses of warfarin and bridging with heparin or low-molecular-weight heparin for at least days when starting warfarin therapy Drug-Drug Interactions The pediatric intensive care physician is confronted daily with potentially hazardous DDIs in the critical care setting A DDI has been defined as “the possibility that one drug may alter the intensity or pharmacological effects of another drug given concurrently The net result may be enhanced or diminished effects of one or both of the drugs or the appearance of a new effect that is not seen with either drug alone.”147 Given the extent of polypharmacy in the PICU, the risk may be significant However, of the thousands of documented DDIs, only a small fraction is clinically significant.148 The ability to differentiate between clinically significant and insignificant interactions requires an understanding of their mechanisms of action In most cases, DDIs are predictable and preventable with appropriate dose modifications or avoidance of combinations Medications with narrow therapeutic indices are especially susceptible to DDIs, as small alterations in exposure can lead to 1475 large changes in response Typically, drugs with large therapeutic indices are at minimal risk for clinically significant DDIs DDIs can occur by three different mechanisms: pharmacokinetic, pharmacodynamic, and pharmaceutical Pharmacokinetic DDIs have been defined as “interactions which affect a target drug through alterations in their absorption, distribution, metabolism, or excretion; the result may be an increase or decrease in the concentration of drug at the site of action.”147 Pharmacodynamic interactions are defined as interactions at a common receptor site or that have additive or inhibitory effects as a result of actions at different sites.147 Pharmaceutical interactions or incompatibilities “occur when drugs interact in vitro so that one or both are inactivated.”149 Pharmacokinetic Drug-Drug Interactions The most common and well-studied etiology of DDIs is through pharmacokinetic interactions Pharmacokinetic interactions can occur throughout the entire pharmacologic spectrum and can affect the absorption, distribution, metabolism, or elimination of the compound of interest However, DDIs are important only when they impact the resulting drug exposure to such an extent that the patient experiences an alteration in the expected drug effect, either through diminution of drug effect (when drug exposure is decreased) or through predisposition to adverse effects (when drug exposure is increased) Interactions Affecting Drug Absorption (Enteral Absorption) Several factors determine the rate and extent of oral absorption of drug products DDIs affecting enteral absorption occur through several mechanisms with a common result: alteration of availability of the drug at its primary site of absorption The most common mechanisms include adsorption or complexation of the target drug by other drugs or food; alterations in the ionization of the drug through pH changes; and perturbation of normal GI function (e.g., motility, bacterial colonization, and mesenteric blood flow) In the critical care setting, adsorption and complex formation are the most likely causes of decreased enteral drug absorption Commonly prescribed medications, such as sucralfate, are implicated in causing decreased absorption of other drugs by adsorbing target drugs and rendering them unavailable for absorption across the GI barrier.150–152 Food, especially enteral formula, is capable of causing adsorption of drugs Phenytoin, levothyroxine, flecainide, and warfarin all have known interactions with enteral formulations.153–155 Although less commonly prescribed in the pediatric setting, tetracycline and quinolone antibiotics have long been known to cause drug complexes with metallic cations such as iron and calcium, resulting in a decreased effect of both the supplement and the antibiotic.156,157 Interactions Affecting Drug Distribution (Protein or Tissue Binding) Since the majority of drugs are bound to plasma proteins or tissue-binding sites, the most commonly cited mechanisms for DDIs affecting distribution are those that involve protein or tissue binding Many factors affect protein or tissue binding, including pH, temperature, renal function, and low serum albumin Several examples exist in which one drug displaces an object drug through competitive inhibition at a protein- or tissue-binding site However, in most cases, the impact of the DDI is minimal The amount of free (active) drug may increase temporarily, but the free level falls back to its previous equilibrium as the clearance 1476 S E C T I O N X I I I Pediatric Critical Care: Pharmacology and Toxicology of drug subsequently increases Most cases of increased free drug concentrations secondary to protein-binding displacement occur when the displacing drug also inhibits the metabolism or excretion of the displaced drug Alterations in Total Body Water An important mechanism for DDIs affecting drug distribution that often is overlooked is alteration of body fluid composition Severe dehydration can be caused iatrogenically, either through fluid restriction or overzealous diuretic use In these cases, drug concentrations can be increased severalfold, resulting in adverse effects Conversely, the volume of distribution of drugs can be increased significantly by increasing total body water This can have the effect of decreasing drug concentrations to subtherapeutic levels Drugs that distribute primarily in total body water, such as aminoglycosides, are particularly susceptible to these types of effects.158 Interactions Affecting Drug Metabolism Most clinically relevant DDIs can be linked to an alteration in drug metabolism The two major pathways for drug metabolism in humans are the phase I oxidative pathway and the phase II conjugation reactions Inhibition or induction of the phase I pathway is the most studied mechanism of DDIs, especially in relation to the cytochrome P450 system of enzymes Table 124.4 lists the drugs that affect cytochrome P450 enzymes and those metabolized by the various clinically relevant isoforms The relative lack of formal pediatric studies makes predicting the impact of a particular interaction difficult in a given child Factors that must be considered include the state of maturation of the isoform and the presence of compensatory pathways In general, it is reasonable to assume that a reaction that occurs in adults will also occur in children; therefore, proper adjustments should be made if necessary One important consideration is the timing of DDIs secondary to P450 enzyme inhibition and/or induction In general, enzyme inhibition results from competitive inhibition at the enzyme binding site and therefore becomes clinically relevant as soon as the offending drug reaches sufficient concentrations in the liver Consequently, upon discontinuation of the offending drug, enzyme inhibition abates as the drug concentration falls In contrast, enzyme induction results from an increase in the amount of enzyme synthesized by hepatic cells Thus, there is a lag between the time that an inducer is introduced and the onset of induction effect As expected, the offset of effect also is somewhat prolonged Phase II reactions are rarely rate limiting, which makes their potential to be the cause of clinically significant DDIs low Interactions Affecting Drug Excretion The primary means for elimination of drugs or their metabolites is through renal excretion The process of renal excretion involves three mechanisms: glomerular filtration rate (GFR), active tubular secretion, and tubular reabsorption All three mechanisms can be affected by DDIs Alterations in GFR secondary to DDIs most often result from fluctuation in renal blood flow Drugs that act to reduce renal blood flow, such as cyclosporine or NSAIDs, can reduce GFR and increase the blood concentration of drugs eliminated by this route.159–163 Conversely, drugs that improve renal blood flow could increase GFR and decrease plasma concentrations of drugs eliminated through the kidneys As its name implies, active tubular secretion is a process during which drugs bind to receptors and are transported across the tubular cells to be excreted Drugs that compete for these binding sites may inhibit the secretion of other drugs and increase concentrations The two most commonly cited inhibitors of active tubular secretion are probenecid and cimetidine These reactions are rarely of clinical significance Tubular reabsorption is a passive process in which drugs are reabsorbed into the systemic circulation from the lumen of the distal tubules As with enteral absorption, only un-ionized molecules are available for reabsorption Therefore, drugs that alter the pH of the urine have the potential to alter tubular reabsorption of other drugs A common example is phenobarbital, which is a weakly acidic drug In overdose situations, sodium bicarbonate is administered to alkalinize the urine in the hopes that phenobarbital will become more ionized in urine, resulting in reduced tubular reabsorption and more rapid excretion.164 Interactions Affecting P-Glycoprotein Receptors Research in the oncology field has led to the identification of an important drug transporter that is ubiquitous throughout the human body: PgP PgP can be found in renal tubule cells; hepatic cells; in the blood-brain barrier; and in mucosal cells of the intestines, pancreas, and adrenal glands Table 124.4 lists drugs that are inhibitors and/or substrates for PgP In general, PgP is believed to serve a protective function by transporting molecules out of the body or, in the case of the blood-brain barrier, out of the CNS Drugs that inhibit PgP are expected to increase the concentrations of substrates (either in plasma or the CNS) Clinicians should be cautious when coadministering PgP substrates or inhibitors and should consider dose adjustments or alternative treatments when administering drugs with narrow therapeutic windows Pharmacodynamic Drug-Drug Interactions A pharmacodynamic DDI can be defined as the combination of two or more drugs with additive, synergistic, or antagonistic pharmacodynamic effects Additive pharmacodynamic interactions occur routinely when two or more drugs of the same class are given in combination, as in the case of antihypertensive medications or anticonvulsants A synergistic interaction occurs when the combination of two drugs has an effect greater than the sum of their individual effects One example of a clinically relevant synergistic interaction is the use of aminoglycosides in combination with b-lactam antibiotics In theory, combining a cell-wall active agent (b-lactam antibiotic) with an agent that inhibits bacterial protein synthesis (aminoglycoside) can achieve a greater antibiotic effect than the sum of the two individual effects Although difficult to prove clinically, in vitro and animal studies have validated this theory.165–167 Most antagonistic DDIs are more appropriately defined as pharmacokinetic interactions because they result from some alteration in drug concentrations, either in plasma or at the site of action Antagonistic interactions that are truly pharmacodynamic in nature most often result from competitive inhibition at the receptor site for drug activity Use of flumazenil to reverse benzodiazepine-induced sedation is an example of an antagonistic pharmacodynamic DDI used clinically.168–170 Drug-Drug Interactions by Therapeutic Class Cardiovascular Agents As opposed to many other classes of drugs, alterations in pharmacodynamics are the most common mechanism of cardiovascular CHAPTER 124 Adverse Drug Reactions and Drug-Drug Interactions 1477 TABLE 124.4 P-Glycoprotein and Cytochrome P450 Substrates, Inhibitors, and Inducers Substrates Inhibitors Inducers PgPa Amiodarone Apixaban Cimetidine Ciprofloxacin Cortisol Cyclosporine Dabigatran Dexamethasone Digoxin Diltiazem Edoxaban Erythromycin Everolimus Fentanyl Hydrocortisone Itraconazole Levofloxacin Lidocaine Methylprednisolone Morphine Nadolol Octreotide Ondansetron Phenytoin Ranitidine Rivaroxaban Sirolimus Verapamil Amiodarone Carvedilol Clarithromycin Cortisol Cyclosporine Diltiazem Erythromycin Everolimus Haloperidol Midazolam Nicardipine Nifedipine Ofloxacin Posaconazole Propranolol Quinidine Quinine Sirolimus Spironolactone Tacrolimus Verapamil Amiodarone Cyclosporine Dexamethasone Diltiazem Erythromycin Insulin Midazolam Morphine Nicardipine Nifedipine Phenobarbital Phenytoin Probenecid Rifampin Tacrolimus Verapamil CYP1A2 Acetaminophen Caffeine Carvedilol Cisapride Diazepam Haloperidol Levofloxacin Lidocaine Naproxen Nicardipine Ondansetron Ranitidine R-warfarin Verapamil Caffeine Cimetidine Ciprofloxacin Clarithromycin Diltiazem Erythromycin Grapefruit juice Lidocaine Nifedipine Omeprazole Ondansetron Propofol Propranolol Ranitidine Carbamazepine Pantoprazole Insulin Lansoprazole Nafcillin Omeprazole Phenobarbital Phenytoin Rifampin CYP2C9 Bosentan Caffeine Carvedilol Dextromethorphan Diazepam Diltiazem Fluconazole Indomethacin Lansoprazole Montelukast Naproxen Nicotine Omeprazole Ondansetron Pantoprazole Phenobarbital Phenytoin Propofol Quinidine S-warfarin Valproic acid Verapamil Voriconazole Zafirlukast Chloramphenicol Cimetidine Diltiazem Fluconazole Ibuprofen Itraconazole Lansoprazole Metronidazole Nifedipine Omeprazole Phenobarbital Phenytoin Probenecid Propofol Propranolol Sulfonamides Trimethoprim Verapamil Voriconazole Bosentan Carbamazepine Phenobarbital Phenytoin Rifampin CYP2C19 Cisapride Diazepam Fluconazole Ibuprofen Indomethacin Lansoprazole Metoprolol Omeprazole Pantoprazole Phenobarbital Phenytoin Propofol Propranolol Ranitidine R-warfarin Verapamil Voriconazole Cimetidine Diazepam Fluconazole Lansoprazole Omeprazole Voriconazole Carbamazepine Phenobarbital Phenytoin Prednisone Rifampin CYP2D6 Acetaminophen Amphetamine Caffeine Captopril Carvedilol Chlorpheniramine Codeine Dextromethorphan Diltiazem Fentanyl Hydrocodone Lidocaine Loratadine Meperidine Methadone Methamphetamine Metoprolol Morphine Nelfinavir Nevirapine Omeprazole Ondansetron Oxycodone Propofol Propranolol Ranitidine Amiodarone Chlorpheniramine Cimetidine Cisapride Codeine Dextromethorphan Diltiazem Haloperidol Lansoprazole Lidocaine Methylphenidate Metoprolol Nicardipine Omeprazole Ondansetron Oxybutynin Propofol Propranolol Quinidine Ranitidine Verapamil Carbamazepine Dexamethasone Ethanol Phenobarbital Phenytoin Rifampin 1478 S E C T I O N X I I I Pediatric Critical Care: Pharmacology and Toxicology TABLE 124.4 P-Glycoprotein and Cytochrome P450 Substrates, Inhibitors, and Inducers—cont’d Substrates CYP3A4 a Alprazolam Amiodarone Amlodipine Apixaban Atorvastatin Bosentan Carbamazepine Clarithromycin Cisapride Citalopram Cyclophosphamide Cyclosporine Dapsone Dexamethasone Diazepam Diltiazem Dofetilide Doxorubicin Edoxaban Erythromycin Ethinyl estradiol Etoposide Everolimus Fentanyl Fluconazole Imatinib Ifosfamide Itraconazole Lidocaine Loratadine Inhibitors Everolimus Losartan Methadone Methylprednisolone Miconazole Midazolam Montelukast Nefazodone Nimodipine Nisoldipine Pioglitazone Prednisolone Quetiapine Rivaroxaban Sertraline Sildenafil Simvastatin Sirolimus Tacrolimus Testosterone Verapamil Vinblastine Vincristine Voriconazole R-warfarin Zolpidem Inducers Isavuconazonium Methylprednisolone Metronidazole Nefazodone Norethindrone Prednisone Posaconazole Verapamil Voriconazole Clarithromycin Cyclosporine Diltiazem Erythromycin Ethinyl estradiol Fluvoxamine Grapefruit juice Isoniazid Itraconazole Barbiturates Bosentan Carbamazepine Dexamethasone Griseofulvin Phenytoin Primidone Rifabutin Rifampin Several drugs are listed as both P-glycoprotein (Pgp) inhibitors and inducers because their effects on Pgp expression can be concentration or duration related DDIs The potential for two drugs to act on the same receptor subtype sets the stage for pharmacodynamic interactions, which can be antagonistic, additive, or synergistic in nature TABLE 124.5 b-Blocker Receptor Selectivity Intrinsic Sympathomimetic Activity a-Blockade Metoprolol None None Atenolol None None Esmolol None None Sotalol None None Nebivolol None None Propranolol None None Nadolol None None Labetalol Yes Yes Carvedilol None Yes Vasopressors Vasoactive agents that increase sympathomimetic activity via a- or b-receptor stimulation are particularly susceptible to pharmacodynamic DDIs The extent and significance of these interactions depend on the physiochemical properties of the medications Vasopressors—including epinephrine, norepinephrine, phenylephrine, dopamine, dobutamine, ephedrine, and isoproterenol— are particularly susceptible to pharmacodynamic DDIs b-Blockers generally antagonize the cardiac and bronchodilating effects of the sympathomimetics.171 However, propranolol and other nonspecific b-blockers (Table 124.5) may enhance vasoconstriction produced with epinephrine via the reflex increase in systemic vascular resistance associated with lower heart rates However, labetalol possesses both a- and b-blocking activity, which increases diastolic blood pressure while decreasing heart rate when given during an epinephrine infusion.66,67 As a result, the patient may experience hypertension and bradycardia.66,67 Noncardiac medications can interact with vasopressors as well Linezolid, an antibiotic often reserved for methicillin-resistant Staphylococcus aureus (MRSA) infections, inhibits monoamine oxidase, which can b1 Selective b Nonselective Modified from Barres V, Taglialatela M New advances in beta-blocker therapy in heart failure Front Physiol 2013;4(323):1–9 ... Methylprednisolone Metronidazole Nefazodone Norethindrone Prednisone Posaconazole Verapamil Voriconazole Clarithromycin Cyclosporine Diltiazem Erythromycin Ethinyl estradiol Fluvoxamine Grapefruit juice... eruptions that blister, leading to epidermal necrosis and detachment These symptoms often appear within to 14 days of drug exposure Though their presentations are similar, TEN is often considered... outcomes Warfarin-induced skin necrosis (WISN) is a severe cutaneous reaction that typically occurs within the first 10 days after the initiation of warfarin therapy A dramatic drop in protein C, compared