Adverse Drug Reactions: Cardiac, Endocrine & Hematologic

QT prolongation and torsades de pointes

Mechanism. Most drugs that lengthen the QT interval block the rapid component of the delayed-rectifier potassium current (IKr), carried by the hERG channel. Slower phase 3 repolarization prolongs the ventricular action potential; L-type Ca²⁺ channels can then reactivate and produce early afterdepolarizations, which trigger torsades de pointes, a polymorphic ventricular tachycardia whose QRS axis twists around the baseline and which can degenerate into ventricular fibrillation. Blocking the fast Na⁺ current, by contrast, widens the QRS.

Offending drugs, grouped by family:

• Antiarrhythmics: class IA (quinidine, procainamide, disopyramide) and class III (sotalol, dofetilide, ibutilide, amiodarone).
• Anti-infectives: macrolides, fluoroquinolones and azole antifungals.
• Antipsychotics: haloperidol and many others.
• Antidepressants: tricyclics.
• Antiemetics: ondansetron and other 5-HT₃ antagonists.
• Opioids: methadone, especially at high doses.

Risk amplifiers. Hypokalemia (often diuretic induced), hypomagnesemia, bradycardia or pauses, female sex, structural heart disease, congenital long QT syndrome, combining two QT-prolonging drugs, and adding a CYP3A4 inhibitor that raises the level of a QT drug all multiply the danger.

Treatment. IV magnesium sulfate is first line even when serum magnesium is normal. Correct potassium, stop the offending drugs, and use overdrive pacing or isoproterenol to raise the heart rate when recurrences are pause dependent. Pulseless or unstable torsades is treated with unsynchronized defibrillation.

Amiodarone lengthens the QT more than most drugs yet rarely causes torsades, because its multichannel block keeps repolarization uniform across the myocardium.

Cardiomyopathy, coronary vasospasm and flushing

Anthracyclines. Doxorubicin and daunorubicin cause a dilated cardiomyopathy whose risk rises with cumulative dose, steeply beyond roughly 400–550 mg/m² of doxorubicin. LVEF is measured by echocardiography or MUGA scan before and during treatment.

Trastuzumab. HER2 (ERBB2) signaling helps stressed cardiomyocytes survive; blocking it lowers LVEF, most often after prior anthracycline exposure.

Coronary vasospasm. Cocaine blocks reuptake of norepinephrine and dopamine, producing α₁-mediated coronary vasoconstriction plus platelet activation and thrombosis. Triptans (5-HT_1B/1D agonists) and ergots (ergotamine, methylergonovine) constrict coronary smooth muscle, so they are contraindicated in coronary artery disease and vasospastic (Prinzmetal) angina. The fluoropyrimidines 5-fluorouracil and capecitabine can also provoke vasospastic angina.

In cocaine-associated chest pain, give benzodiazepines, nitrates and calcium channel blockers; classic board teaching avoids a pure β-blocker acutely because unopposed α₁ stimulation can worsen vasospasm.

Flushing. Rapid vancomycin infusion directly degranulates mast cells without IgE, flushing the face, neck and upper trunk with pruritus. It is not an allergy: infuse over at least 60 minutes, pretreat with an antihistamine, and continue the drug. Niacin flushing is mediated by prostaglandins (chiefly PGD₂) and is blunted by aspirin about 30 minutes beforehand. Adenosine causes brief flushing, chest tightness and dyspnea, and dihydropyridine calcium channel blockers flush through arteriolar dilation.

Endocrine and metabolic effects

SIADH. Drugs that increase ADH release or action cause euvolemic hyponatremia with inappropriately concentrated urine (osmolality above 100 mOsm/kg, urine Na⁺ above 30 mEq/L). SSRI-associated hyponatremia is most common in older adults. Management starts with stopping the drug and restricting free water.

Nephrogenic DI. Lithium enters principal cells of the collecting duct through ENaC and downregulates aquaporin-2, so urine stays dilute despite high ADH and does not concentrate after desmopressin; serum sodium runs high-normal with polyuria and thirst. Demeclocycline blocks ADH action as well, which is why it is used deliberately for SIADH. Amiloride blocks lithium entry through ENaC and treats lithium-induced nephrogenic DI; thiazides and NSAIDs reduce polyuria but raise lithium levels.

Gynecomastia. Spironolactone and cimetidine block androgen receptors, ketoconazole inhibits androgen synthesis at CYP17, digoxin has an estrogen-like steroid structure, and GnRH agonists such as leuprolide suppress testosterone. Estrogens, 5α-reductase inhibitors, alcohol and marijuana are other causes. Eplerenone, a selective mineralocorticoid-receptor antagonist with little antiandrogen activity, replaces spironolactone when gynecomastia develops.

Hyperglycemia. Glucocorticoids increase gluconeogenesis and insulin resistance. Thiazides reduce insulin secretion through hypokalemia and belong to a metabolic cluster of hyperglycemia, hyperlipidemia, hyperuricemia and hypercalcemia with hypokalemia and hyponatremia. Tacrolimus is more toxic to β-cells than cyclosporine and is a leading cause of post-transplant diabetes. Protease inhibitors and niacin cause insulin resistance, and atypical antipsychotics such as olanzapine and clozapine add weight gain and metabolic syndrome.

Thyroid. Lithium inhibits thyroid hormone release, causing goiter and hypothyroidism. Amiodarone is about 37% iodine by weight: the iodine load can shut down hormone synthesis (Wolff-Chaikoff effect, hypothyroidism) or cause thyrotoxicosis, either by fueling synthesis in a nodular gland (Jod-Basedow) or through destructive thyroiditis. Amiodarone also inhibits 5'-deiodinase, so T4 and reverse T3 rise while T3 falls. TSH is checked at baseline and periodically with both drugs.

Prolactin. Tuberoinfundibular dopamine tonically inhibits lactotrophs through D₂ receptors. Blocking them with typical antipsychotics, risperidone (the most prolactin-raising atypical), metoclopramide or domperidone causes galactorrhea, amenorrhea, infertility, gynecomastia, low libido and bone loss. Prolactin suppresses GnRH pulsatility, which explains the hypogonadism. Aripiprazole, a partial D₂ agonist, and clozapine or quetiapine largely spare prolactin.

Marrow failure and hemolysis

Agranulocytosis. An absolute neutrophil count below 500/μL can follow clozapine (which requires regular ANC monitoring), carbamazepine, the thionamides propylthiouracil and methimazole, dapsone, colchicine and ganciclovir or valganciclovir; TMP-SMX and sulfasalazine are other causes. Fever or sore throat in a patient taking one of these drugs means stopping it and checking a CBC with differential immediately.

Aplastic anemia. Pancytopenia with a hypocellular, fat-replaced marrow. Chloramphenicol causes a common, dose-related, reversible marrow suppression and a rare idiosyncratic, often fatal aplastic anemia; in neonates it also causes gray baby syndrome. Carbamazepine and felbamate are the anticonvulsant culprits, and felbamate's boxed warnings for aplastic anemia and hepatic failure restrict it to refractory epilepsy.

G6PD deficiency. G6PD is the rate-limiting enzyme of the hexose monophosphate shunt and the red cell's only source of NADPH, which keeps glutathione reduced. Without it, oxidant drugs denature hemoglobin into Heinz bodies; splenic macrophages remove the inclusions and leave bite cells, and hemolysis is both intravascular and extravascular, typically within 1–3 days of exposure. Rasburicase converts uric acid to allantoin and releases hydrogen peroxide. The disorder is X-linked, so G6PD status should be checked before primaquine, tafenoquine, dapsone or rasburicase.

The G6PD assay can read falsely normal during an acute episode because young reticulocytes carry more enzyme; repeat it about 3 months later.

Megaloblastic anemia, thrombocytopenia and thrombosis

Megaloblastic anemia. Methotrexate inhibits dihydrofolate reductase (DHFR); trimethoprim and pyrimethamine inhibit human DHFR more weakly; phenytoin impairs folate absorption. Hydroxyurea (a ribonucleotide reductase inhibitor), zidovudine and 5-fluorouracil also impair DNA synthesis and cause macrocytosis. Leucovorin (folinic acid) is an already-reduced folate that bypasses DHFR and rescues normal cells from methotrexate; vitamin B12 cannot.

Heparin-induced thrombocytopenia. IgG antibodies recognize complexes of heparin and platelet factor 4 and activate platelets through Fc receptors, so the platelet count falls by more than 50% about 5–10 days into therapy (sooner with heparin exposure in the prior 100 days) while arterial and venous thrombosis develops.

Warfarin started during acute HIT can cause venous limb gangrene or skin necrosis because protein C falls before the procoagulant factors.

Other thrombocytopenia. Linezolid causes duration-dependent myelosuppression, mainly thrombocytopenia, in courses longer than about 2 weeks. Quinine induces drug-dependent antibodies against platelet glycoproteins that cause abrupt, severe thrombocytopenia.

Venous thromboembolism. Oral estrogens raise hepatic synthesis of fibrinogen and factors II, VII, VIII and X, lower protein S and antithrombin, and create acquired resistance to activated protein C; factor V Leiden multiplies the risk. Tamoxifen and raloxifene carry a similar DVT/PE risk. Epoetin and darbepoetin raise the risk of thrombosis, stroke and hypertension, particularly when hemoglobin is pushed above about 11 g/dL. Thalidomide and lenalidomide also require VTE prophylaxis.