1469CHAPTER 124 Adverse Drug Reactions and Drug Drug Interactions Many medications used in pediatric patients have been affiliated with myocyte injury and subsequent cardiac damage leading to heart fa[.]
CHAPTER 124 Adverse Drug Reactions and Drug-Drug Interactions • BOX 124.2 Drugs Commonly Associated With QT Interval Prolongation Antiarrhythmics Antipsychotics Amiodaronea Flecainide Procainamidea Propafenoneb Quinidinea Sotalola Aripiprazole Haloperidolb Quetiapine Risperidone Ziprasidone Antidepressants Isradipine Nicardipine Verapamil Amitriptylineb Citalopram (doses 40 mg)a Escitalopram Fluoxetine Sertraline Venlafaxine Antiinfectives Ciprofloxacin Clarithromycinb Erythromycinb Fluconazole Levofloxacin Moxifloxacina Pentamidineb Quinidineb Quinineb Trimethoprim-sulfamethoxazole Voriconazole Cardiovascular Agents Gastrointestinal Agents Cisapridec Droperidolb Ondansetrona Miscellaneous Methadone Tacrolimus All unmarked medications are considered low risk; however, they have a documented or theoretical association with QT prolongation For a complete list, see www.crediblemeds.org Medications highly associated with QT prolongation b Medications moderately associated with QT prolongation c Cisapride, though removed from the US market, has been approved for limited compassionate use in some pediatric disease states a magnesium sulfate is the drug of choice to treat TdP Magnesium stabilizes the myocyte and prevents early depolarization, which may disrupt an unstable rhythm.72 Owing to alterations in extracellular levels of potassium, the risk of medication-induced TdP increases with decreased heart rate Known as reverse-use dependence, the inhibition of potassium ion channels is enhanced in the setting of both hypokalemia and bradycardia For this indication, it has been suggested that the use of vasoactive medications to increase heart rate, such as isoproterenol, may potentially minimize the effects of drug-induced LQTS.72,73 Medication-induced heart failure may be caused by a reduction in myocardial contractility, increase in preload, direct myocyte toxicity, or development of cardiovascular risk factors Dexmedetomidine, non-DHP CCBs (nifedipine, verapamil, diltiazem), b-blockers, and some antiarrhythmics (dronedarone, flecainide, ivabradine, and sotalol) exert a negative inotropic effect, decreasing contractility, which may lead to acute heart failure.74 Medications that increase fluid and sodium retention, such as NSAIDs and corticosteroids, can slowly or dramatically increase preload precipitating heart failure with chronic use.75–77 NSAIDs are considered to be contraindicated in patients with or at risk of heart failure due to increased preload and decreased response to diuretics If treatment with NSAIDs is necessary in patients with heart failure, lower doses and shorter durations are recommended 1469 Many medications used in pediatric patients have been affiliated with myocyte injury and subsequent cardiac damage leading to heart failure.78–81 Amphotericin B has been associated with cardiomyopathy in multiple case reports; however, patients generally recover within months after stopping therapy.74 Rheumatologic agents—such as infliximab, etanercept, and adalimumab, used to treat rheumatoid arthritis and Crohn disease—have been associated with increased risk of heart failure However, this has mostly been seen in adults, with limited case reports in pediatric patients.74 Chemotherapeutic agents are commonly associated with cardiotoxicity Anthracyclines—such as doxorubicin, daunorubicin, epirubicin, idarubicin, and mitoxantrone—may lead to acute cardiotoxicity or cardiomyopathy, which is related to cumulative lifetime dose The rate of heart failure related to anthracyclines in pediatric patients has been reported to be as high as 16%.74 However, it is important to note that the development of cardiotoxicity may not be seen for many years There are reports in the literature of patients who received anthracycline therapy as children who developed cardiac symptoms between and 20 years after exposure.82 Severe anthracycline toxicity is irreversible; therefore, it is associated with poor prognosis and increased risk of mortality.82 In adults, strategies to minimize anthracycline toxicity include limiting total lifetime dose (goal ,550 mg/m2), use of liposomal anthracyclines, prolonged infusion times, initiation of ACE inhibitors in high-risk patients, and dexrazoxane Dexrazoxane, a derivative of the chelating agent ethylenediaminetetraacetic acid, binds free radicals produced by anthracyclines, preventing oxidative damage to the myocyte Its use is reserved for patients whose diagnoses typically require higher cumulative lifetime doses of anthracyclines.83 More recent data suggest that pediatric patients treated with anthracyclines may be at greater lifetime risk of developing heart failure than patients first treated with anthracyclines as adults In a study of pediatric anthracycline recipients, there was a higher rate of heart failure with increased time from first dose and cumulative lifetime dose greater than 300 mg/m2, which is much lower than adult guidelines.74,84 In addition, higher weekly doses (.45 mg/m2) appear to be independently associated with increased risk of acute heart failure.74,85 Frequent, lifelong, and guideline-directed monitoring is required for pediatric patients after administration of anthracycline chemotherapy owing to the heightened risk of acute heart failure Cyclophosphamide, an alkylating agent used for induction prior to bone marrow transplantation, is also associated with myocarditis Up to 50% of patients receiving higher-dose induction regimens may experience left ventricular dysfunction, with 15% to 30% developing acute heart failure.86 Though fatalities have been reported, cyclophosphamide-associated heart failure typically resolves within to weeks of therapy.74 Other agents used to treat pediatric cancer have been implicated in the development of cardiotoxicity These include monoclonal antibodies, tyrosine kinase inhibitors, high-dose interleukin-2, and mitomycin C Often used as targeted therapy, these agents increase the risk of heart failure by direct myocyte damage that may be related to their underlying mechanisms of action.74 Many medications increase cardiovascular risk through the development of associated comorbidities Long-term use of oldergeneration protease inhibitors, such as indinavir and lopinavir/ ritonavir and atypical antipsychotics, can cause hyperlipidemia, glucose abnormalities, and weight gain This predisposes patients to long-term cardiovascular issues.87 The calcineurin inhibitors tacrolimus and cyclosporine are known to cause hypertension; they are also associated with left ventricular dysfunction and 1470 S E C T I O N X I I I Pediatric Critical Care: Pharmacology and Toxicology hyperlipidemia Owing to their required use in transplant patients, long-term cardiac sequelae may be unavoidable Cardiovascular death is one of the most common causes of death after organ transplantation.87 Gonadotropin-releasing hormone agents (goserelin, histrelin, and leuprolide) may also lead to weight gain and hypertriglyceridemia with continued use.88 It is important to recognize agents that may contribute to the development of cardiovascular disease and follow patients closely with guideline-directed care when chronic therapy is indicated Central Nervous System CNS adverse effects include cerebrovascular events, delirium, seizures, movement disorders, serotonin syndrome, neuroleptic malignant syndrome, and ototoxicity Cerebrovascular and cerebellar consequences can present as loss of coordination and balance Drugs causing these effects include phenytoin, lithium, carbamazepine, cytarabine, and aminoglycosides Most cases are reversible with discontinuation of the offending agent; higher doses and extended duration increase risk of irreversibility Delirium in critically ill patients is a common occurrence, which presents as fluctuations in cognition, mood, attention, and arousal Both the hypoactive and agitation/hyperactive types of delirium are associated with negative outcomes, longer ICU stays, and increased costs.86,87 The risk factors for ICU delirium are multifactorial and include sleep deprivation, chronic neurologic illnesses, psychiatric disease, mechanical ventilation, and analgesics and sedative administration.89 Evidence suggests that sedative practices may influence and contribute to the development of delirium, especially the use of benzodiazepines Lorazepam has been shown to be an independent risk factor for transition to delirium.89 Antipsychotic medications are used off-label for delirium, but no clinical trial has shown significant reduction in delirium or ICU stay Nonpharmacologic interventions and increasing awareness among pediatric intensivists should help to prevent or attenuate ICU delirium Seizure disorders affect millions of patients It can be difficult to distinguish between a seizure disorder and a drug-induced seizure Prescription medications are the most common cause of iatrogenic seizures.84 Drug-related factors that may contribute to seizures include the intrinsic epileptogenicity of the agent, serum levels (dose, schedule, and route dependent), and permeability into the CNS (lipid solubility, molecular weight, ionization of the drug, protein binding, transport by endogenous systems).85 Patient-related factors may influence the risk for drug-induced seizures, such as preexisting epilepsy, neurologic abnormality, decreased drug elimination capacity (renal, hepatic), and conditions that disrupt the blood-brain barrier.85 Several medications used within the ICU have been associated with seizures (Table 124.2) Meperidine may induce seizures, TABLE 124.2 Medications That Can Induce Seizures Medication Potential Mechanism of Action Comments Acyclovir90 Neurotoxicity Renal impairment and parenteral administration increase the incidence Antipsychotics91 Decrease seizure threshold Increased incidence with high doses and rapid dose adjustments Carbapenems92 Potentiate seizure activity through the inhibition of GABA receptor Use caution in patients with CNS disorders and renal dysfunction Imipenem has higher incidence compared with meropenem, ertapenem, doripenem Cephalosporins93 Inhibition of GABA receptor Ceftazidime ceftriaxone cefuroxime and cefotaxime Unknown but may involve the release of the potent vasoconstrictor endothelin from endothelial cells that induce microvascular damage and/or changes in permeability of the blood-brain barrier More common with high doses Increased incidence with hypercholesterolemia and hypomagnesemia Cerebral dysfunction Increased incidence with intrathecal administration Unknown but may involve inhibition of GABA receptor History of seizures and use of NSAIDs associated with increased risk of seizures Flumazenil97 May precipitate benzodiazepine withdrawal; inhibition with seizure medications Use caution in patients with underlying seizure disorder Meperidine91 CNS excitation from toxic metabolite (normeperidine); blockade of serotonin Common reaction with renal impairment and high doses Metronidazole93 Penetrates the blood-brain barrier Occurs with cumulative high dose and prolonged use Irritation of nervous system Use in caution with infants, rapid IV infusions, and renal impairment Neurotoxicity May be secondary to local vasoconstriction mediated by endothelin; elevated levels and hepatic impairment may increase the risk of neurotoxicity CNS toxicity Serum concentrations 25 µg/mL have been noted to induce seizures 94 Cyclosporine Cytarabine95 Fluoroquinolones Penicillins 98 Tacrolimus 99–101 Theophylline91 96 CNS, Central nervous system; GABA, g-aminobutyric acid; IV, intravenous; NSAIDs, nonsteroidal antiinflammatory drugs CHAPTER 124 Adverse Drug Reactions and Drug-Drug Interactions especially in patients with renal insufficiency, owing to accumulation of its metabolites This is why its use in ICU patients is often restricted to specific clinical indications.84 Multiple antiinfective and immunosuppressive medications—including b-lactam antibiotics, high-dose metronidazole, isoniazid, and cyclosporine— induce seizures.84 Many of the antiepileptic drugs can be implicated in worsening seizure activity, which usually occurs when higher than normal concentrations are used Seizures also may be precipitated by medication withdrawal Withdrawal of antiepileptic agents may cause seizures due to either subtherapeutic levels or excessively rapid removal of the agent.84 Owing to the complexity of care needed for intensive care patients, increasing awareness of these medications and their mechanisms of action should allow practitioners to recognize and diagnose drug-induced seizures more effectively Drug-induced movement disorders often present in patients taking a variety of drugs concurrently These movement disorders impose challenges for patients in resuming their activities of daily life after critical illness.102 First-generation antipsychotics (e.g., haloperidol) and GI agents (e.g., metoclopramide) are frequently used in the ICU and may induce extrapyramidal side effects (EPSs) Second-generation antipsychotics, such as risperidone, are thought to induce less EPSs; however, they are still possible.102 EPSs, particularly tardive dyskinesia, can be permanent; therefore, it is important to identify symptoms early and treat them appropriately.102 Another movement disorder commonly seen in the ICU is critical illness myopathy (CIM) It is associated with inability to wean from ventilatory support and is the most common cause of neuromuscular weakness in the ICU.103 Risk factors include vasopressor administration, renal replacement therapy, aminoglycosides, steroids, and neuromuscular blockade Combinations of these medications may further exacerbate CIM CIM is often underdiagnosed but has a mortality rate of up to 55%.103 Pediatric intensivists should consider the need for these medications carefully in patients at risk for CIM If unavoidable, every attempt should be made to limit combinations of offending agents and duration of therapy A potentially life-threatening drug-induced adverse event is serotonin syndrome Serotonin syndrome often presents as mental status changes, autonomic hyperactivity, hyperthermia, and neuromuscular abnormalities, specifically myoclonus.104 Although it is a relatively rare disease, use of multiple combinations of serotoninergic drugs greatly increases the risk Some of the drugs associated with serotonin syndrome and often used in the ICU include SSRIs, monoamine oxidase inhibitors (MAOIs), fentanyl, ondansetron, linezolid (partial MAOI), and valproate.104 The disease will persist as long as precipitating agents continue to be administered or the drug’s activity is present Fluoxetine, an SSRI, has a half-life of approximately week, which could cause prolonged duration of serotonin syndrome.104 Early diagnosis is critical; treatment involves supportive care There have been reports of effective use of cyproheptadine, a serotonin antagonist, to treat serotonin syndrome; however, this remains controversial.105 Similar to serotonin syndrome, neuroleptic malignant syndrome (NMS) is also life-threatening and presents as mental status changes, autonomic hyperactivity, hyperthermia, and neuromuscular abnormalities, specifically muscle rigidity.106 The clinical characteristics of NMS also include abnormal laboratory findings, including elevated creatine kinase, liver function tests, and inflammatory markers.106 Medications associated with NMS include 1471 first- and second-generation antipsychotics and the antiemetic metoclopramide NMS is considered an emergency; therefore, treatment includes vigilant monitoring and significant supportive care as well as administration of higher doses of the intravenous skeletal muscle relaxant dantrolene to decrease associated muscle rigidity The dopamine agonists bromocriptine and amantadine may also be considered to help reverse symptoms of NMS.106 Several medications are associated with ototoxicity, which is usually iatrogenic.88 The main sites of action of ototoxic drugs are the cochlea, vestibulum, and stria vascularis.89 Salicylates and aminoglycosides are the most common agents associated with hearing loss.87,88 Other agents include cisplatin, loop diuretics, erythromycin, and vancomyin.89,102 The effect is usually dose and administration dependent, as with loop diuretics.88,89,102 Highdose and long-term therapy are common risk factors for aminoglycoside-induced ototoxicity, which is irreversible.89,102 Cisplatin is the most ototoxic of the antineoplastic agents, whereas etha crynic acid is the loop diuretic with the greatest potential for causing ototoxicity.102 Appropriate dosing and monitoring of agents associated with ototoxicity are important for prevention and early detection Hematologic Chemotherapy with cytotoxic agents is the most common cause of drug-induced bone marrow suppression and can lead to secondary morbidities For example, neutropenia predisposes a patient to opportunistic infections and sepsis Chemotherapy-induced thrombocytopenia may render a patient vulnerable to hemorrhage in the CNS or GI tract Severe anemia may lead to dizziness, fatigue, hypotension, and myocardial infarction.106a In addition to bone marrow suppression, some antineoplastics may produce thrombotic and hemorrhagic coagulation toxicities For example, l-asparaginase has been reported to induce changes in the von Willebrand factor multimer in children and, thereby, promote platelet aggregation.82 Drug-induced hematologic side effects have also been observed with several classes of antiinfectives, such as b-lactam antibiotics, linezolid, trimethoprim-sulfamethoxazole (TMP-SMX), dapsone, chloramphenicol, and antiviral agents.106b b-Lactam antibiotics have been reported to be associated with autoimmune hemolytic anemia, leukopenia, and thrombocytopenia.106b,106c Linezolid-induced thrombocytopenia and anemia are most commonly seen when therapy continues for more than weeks.106b,106c However, these effects are reversible upon discontinuation of therapy The manufacturer recommends weekly monitoring of complete blood counts, especially for patients who require treatment beyond weeks Neutropenia and thrombocytopenia are common side effects of TMP-SMX.107,108 Dapsone use has been associated with hemolytic anemia and methemoglobinemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.109–112 Therefore, patients should be screened for G6PD deficiency before initiating therapy and dapsone should be avoided in patients with this deficiency Ganciclovir and valganciclovir may cause neutropenia and are commonly used in immunosuppressed patients who are often on concurrent marrow suppressive agents Close monitoring of neutrophil counts in these patients is prudent to prevent neutropenia-associated complications These antiviral medications should be renally adjusted as appropriate to prevent neutropenia However, it is important to note that dose adjustments should not be made based on neutrophil counts, as it may lead to subtherapeutic drug levels and the potential for drug resistance 1472 S E C T I O N X I I I Pediatric Critical Care: Pharmacology and Toxicology Clozapine is an antipsychotic drug that has a risk of causing severe neutropenia in 3% of treated patients.109,113 The highest incidence occurs to 12 weeks after initiating therapy In the United States, dispensing of clozapine requires the prescriber, pharmacy, and patient to enroll in the Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program and comply with neutrophil monitoring and reporting requirements.34 Carbamazepine and valproic acid are anticonvulsants that have been associated with neutropenia, with reported incidences of 2.1% and 0.4%, respectively.114,115 Antithyroid medications, such as methimazole and propylthiouracil, are also commonly cited as causes for agranulocytosis.109,116 Heparin-induced thrombocytopenia (HIT) is an immunemediated ADR that develops when antibodies bind to heparin and platelet factor 4.117 This reaction results in a complex formation that leads to platelet activation and consumption, with platelets falling below 150 109/L or a 50% or greater reduction in platelet counts The incidence of HIT ranges from 0.1% to 5.0%; thrombosis develops in 25% to 50% of those affected.118 Risk factors for HIT include the type of heparin (unfractionated heparin low-molecular-weight heparin) and the duration of exposure (.5 days) Untreated HIT can progress to life-threatening thrombosis A scoring system such as the Ts can help predict the likelihood of HIT.119,120 It evaluates four criteria: (1) degree of thrombocytopenia; (2) timing of platelet count fall, (3) presence of thrombosis or other HIT complications, (4) and other causes of thrombocytopenia An immunologic assay, such as enzymelinked immunosorbent assay, and platelet activation assay are useful in ruling out HIT.118 Owing to the potential severe sequelae of HIT, all forms of heparin should be discontinued promptly upon any suspicion of HIT; anticoagulation with a nonheparin product, such as argatroban or bivalirudin, should be initiated to prevent thrombosis.119 Once platelet count has recovered, warfarin therapy can begin, with a minimum 5-day overlap with the nonheparin agent Treatment of HIT requires anticoagulation for a minimum of weeks and should be prolonged to a minimum of months if thrombosis is involved Heparin should be avoided in the future for most patients diagnosed with HIT.119 Endocrine and Metabolic Owing to the complexity of the biochemical processes that influence the endocrine and metabolic balance of the body, several medications have the potential to alter neuroendocrine hormonal production, binding, transport, and signaling In addition, exogenous drug administration may change hormonal counter-regulatory efforts The most common types of medication-induced endocrine disorders include alterations in carbohydrate metabolism (i.e., changes in blood glucose), electrolyte abnormalities, thyroid changes, and variations in acid-base status.121 Hypoglycemia most commonly occurs due to overtreatment with insulin or diabetic medications, while drug-induced hyperglycemia commonly occurs due to decreased insulin secretion, alterations in liver glucose metabolism and production, or increased insulin resistance.121 Table 124.3 lists common medications associated with hypoglycemia and hyperglycemia subdivided by neuroendocrine effect.121–125 Glucocorticoids are perhaps the most well-known medications to cause hyperglycemia, which occurs by impairing insulin sensitivity and promoting hepatic gluconeogenesis.126 This ADR appears to be dose dependent and is usually reversible upon discontinuing therapy However, long-term glucocorticoid therapy inhibits the function of the hypothalamic-pituitary-adrenal (HPA) axis, which can cause adrenal insufficiency if corticosteroids are stopped abruptly.127 Adrenal insufficiency is a serious and potentially lifethreatening side effect of corticosteroid use As a result, glucocorticoid replacement therapy in the setting of stress—such as acute illness, trauma, or surgery—should be considered when patients with a history of chronic corticosteroid use present to the ICU.127 Such patients may also require physiologic glucocorticoid replacement dosing.127 Electrolyte abnormalities are frequently seen in critically ill patients and can lead to significant morbidity and mortality Although this can occur for many different reasons, several medications are known to cause electrolyte derangements The most common ADRs include alterations in serum sodium, potassium, magnesium, and calcium (see Table 124.3).121,128–130 Hyponatremia is often secondary to a dilutional effect (excess water retention) or a depletional effect (excessive loss of sodium with or without water) Diuretics are a common class of medications that cause depletional hyponatremia by promoting urinary loss of sodium Dilutional hyponatremia is often secondary to effects on antidiuretic hormone (ADH), such as the syndrome of inappropriate ADH secretion (SIADH), or drugs that stimulate ADH release or enhance its effects.121 Critically ill patients are also at significant risk for developing hypernatremia The etiology is often multifactorial, but drugs can increase serum sodium concentration via free water loss or administration of hypertonic sodium solutions (e.g., sodium bicarbonate and sodium chloride infusions).129 Free water loss can occur by drug-induced renal losses, such as medications that induce nephrogenic or central diabetes insipidus Hypernatremia can also occur in response to GI losses (e.g., vomiting, diarrhea, fistulas) if the losses are not adequately replaced.129 Additionally, some medications, such as TMP-SMX, can cause renal salt wasting.128 Hypokalemia is directly affected by medications that increase potassium excretion or increase sodium-potassium adenosine triphosphatase (Na-K-ATPase) activity causing potassium influx into the cells In contrast, drug-induced hyperkalemia can develop when medications lead to decreased Na-K-ATPase activity or block sodium channels in principal cells of the distal nephron, leading to potassium efflux from cells.121,130,131 Hyperkalemia can also result from excessive potassium intake or impaired renal excretion of potassium via decreased aldosterone synthesis or resistance.30,131 Succinylcholine, a depolarizing neuromuscular blocker, may cause hyperkalemia as well by directly affecting ionchannel depolarization.128 Typically, this is clinically insignificant, but the change in serum potassium level is more pronounced in patients with burns, muscle trauma, neuromuscular disease, severe infection, and/or renal insufficiency.30,131,132 Overall, druginduced hyperkalemia is most common in patients with renal insufficiency or other disturbances in potassium homeostasis (e.g., hypoaldosteronism, nephropathy, renal transplantation) See Table 124.3 for drug-induced causes of hypokalemia and hyperkalemia divided by mechanism of action.30,121,128,131,132 Lastly, medications can also alter serum magnesium and calcium concentrations Primary mechanisms of drug-induced hypomagnesemia include agents that affect kidney resorption or influence transcellular shifts Nephrotoxic drugs—such as amphotericin B, cisplatin, and cyclosporine—are thought to cause magnesium loss by drug-induced injury.128 Diuretics cause hypomagnesemia through urinary excretion of magnesium, with loop diuretics causing a more pronounced effect than thiazides This is due to their site of action on the loop of Henle, where most CHAPTER 124 Adverse Drug Reactions and Drug-Drug Interactions 1473 TABLE 124.3 Drugs That Cause Endocrine/Metabolic Changes Hyperglycemia Hypoglycemia Hyponatremia Hypernatremia g Insulin Secretion h Insulin Resistance h Insulin Secretion h Loss of Sodium g ADH Asparaginase b-Blockers Cyclosporine Everolimus Glucocorticoids Octreotide Phenytoin Statins Terbutaline Thiazide diuretics b-Blockers Glucocorticoids Phenytoin Protease inhibitors SGAs Sirolimus Tacrolimus Thiazide diuretics TKIs Aspirin Insulin Pentamidine TMP-SMX Loop diuretics Thiazide diuretics Aminoglycosides Amphotericin B Foscarnet Lithium Phenytoin Alterations in Liver Glucose Metabolism Acetazolamide Amphotericin B (liposomal) Basiliximab Clonidine Isoniazid Loop diuretics Mycophenolate Rituximab Somatropin b-Blockers Glucocorticoids Oral contraceptives Hypokalemia h ADH Miscellaneous Vasopressin Desmopressin b-Blockers Octreotide SIADH Effect Miscellaneous Amiodarone Antidepressants (SSRIs, TCAs) Antiepileptics (carbamazepine, oxcarbazepine) Antipsychotics Cisplatin Cyclophosphamide Ecstasy Vinca alkaloids (vinblastine, vincristine) Miscellaneous NSAIDs (fluid retention) Spironolactone Hyperkalemia Calcium or Magnesium Thyroid h Excretion Exogenous Administration Hypomagnesemia Hypothyroidism Acetazolamide Diuretics Laxatives Penicillin G potassium Potassium supplements Stored packed red blood cells h Influx (Intracellular) h Efflux (Extracellular) b-Agonists (albuterol, terbutaline) Catecholamines Insulin Theophylline b-Blockers (nonselective selective) Digoxin toxicity Intravenous amino acids (arginine, lysine, aminocaproic acid) Mannitol (via hyperosmolality) Propofol (via PRIS) Succinylcholine Aminoglycosides Amphotericin B Calcineurin inhibitors (cyclosporine, tacrolimus) Carboplatin Cisplatin Foscarnet Loop diuretics Amiodarone Carbamazepine Lithium Methimazole Phenytoin TCAs TKIs Miscellaneous Aminoglycosides Amphotericin B Azole antifungals Corticosteroids Echinocandins (caspofungin, micafungin) Penicillins Aldosterone Deficiency/Resistance ACE inhibitors ARBs Calcineurin inhibitors (cyclosporine, tacrolimus) Heparin NSAIDs Pentamidine Spironolactone Trimethoprim (TMP-SMX) Hypocalcemia Hyperthyroidism Amiodarone Alcohol Aminoglycosides Amphotericin B Bisphosphonates Calcitonin Carbamazepine Chelation therapy Chemotherapy (cisplatin, carboplatin, 5-FU, cyclophosphamide, ifosfamide) Citrate Ethylene glycol poisoning Foscarnet Loop diuretics Phenobarbital Phenytoin Phosphate Hypercalcemia Lithium Thiazide diuretics Vitamin D toxicity ACE, Angiotensin converting enzyme; ADH, antidiuretic hormone; ARB, angiotensin II receptor blockers; NSAIDs, nonsteroidal antiinflammatory drugs; PRIS, propofol-related infusion syndrome; SGA, second-generation antipsychotics; SIADH, syndrome of inappropriate antidiuretic hormone secretion; TMP-SMX, sulfamethoxazole-trimethoprim; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants; TKIs, tyrosine kinase inhibitors; 5-FU, 5-fluorouracil ... Terbutaline Thiazide diuretics b-Blockers Glucocorticoids Phenytoin Protease inhibitors SGAs Sirolimus Tacrolimus Thiazide diuretics TKIs Aspirin Insulin Pentamidine TMP-SMX Loop diuretics Thiazide... urinary excretion of magnesium, with loop diuretics causing a more pronounced effect than thiazides This is due to their site of action on the loop of Henle, where most CHAPTER 124 Adverse Drug... incidences of 2.1% and 0.4%, respectively.114,115 Antithyroid medications, such as methimazole and propylthiouracil, are also commonly cited as causes for agranulocytosis.109,116 Heparin-induced