Nifedipin

Clinical Effects:

NIFEDIPINE
  • USES: NIFEdipine is indicated for the treatment of hypertension, chronic stable angina, and variant or vasospastic angina. PHARMACOLOGY: NIFEdipine, a slow-calcium channel antagonist, selectively inhibits the transmembrane influx of calcium ions into cardiac muscle and vascular smooth muscle which are dependent upon calcium for the contractile process. The mechanism by which it relieves angina remains undetermined but it is thought to be related to the relaxation and prevention of coronary artery spasm and reduction of myocardial oxygen demand. TOXICOLOGY: Excessive doses cause vasodilation and decreased cardiac contractility. SA node suppression and suppression of conduction through the AV node are less significant with NIFEdipine than with other calcium channel blockers. EPIDEMIOLOGY: Common overdose, which may result in significant morbidity and mortality. MILD TO MODERATE TOXICITY: Patients may have asymptomatic bradycardia or mild hypotension which may manifest as dizziness, fatigue, and/or lightheadedness. A reflex tachycardia may occur with NIFEdipine overdose. SEVERE TOXICITY: Patients with severe toxicity can have profound bradycardia, dysrhythmias (including complete heart block) and hypotension resulting in cardiogenic shock and end-organ dysfunction including lethargy, syncope, altered mental status, cerebral ischemia, bowel ischemia, renal failure, metabolic acidosis, coma, and death. Hyperglycemia generally develops in patients with severe poisoning. RISK FACTORS: Seizure activity may result from acidosis, anoxia, or an existing predisposition. ADVERSE EFFECTS: COMMON (greater than 10%): Dizziness, lightheadedness, giddiness, flushing, heat sensation, headache, weakness, peripheral edema, nausea, and heartburn. OTHER EFFECTS: Muscle cramps, tremor, nervousness, mood changes, palpitation, dyspnea, cough, wheezing, transient hypotension, minor skin rashes, and photosensitivity. RARE: Gastrointestinal obstruction or ulcer (extended release formulation), and psychosis.

Range of Toxicity:

NIFEDIPINE
  • TOXICITY: The following doses are considered to be potentially toxic: ADULTS: Greater than 30 mg immediate-release or chewed extended-release, or greater than 120 mg extended-release; CHILDREN: Any amount. CASES: A woman developed persistent hypotension and acute lung injury after ingesting 4200 mg of NIFEdipine in a suicide attempt. She recovered following supportive care, including prolonged high-dose IV calcium chloride infusion. A woman developed severe hypotension after ingesting 6 grams of sustained-release NIFEdipine. She was successfully treated with supportive care, including a continuous IV calcium gluconate infusion. THERAPEUTIC DOSE: ADULT: IMMEDIATE-RELEASE CAPSULES: 10 to 30 mg 3 to 4 times daily; MAX daily dose 180 mg. EXTENDED-RELEASE TABLETS: 30 to 60 mg once daily; MAX daily dose 120 mg. PEDIATRIC: HYPERTENSIVE EMERGENCY: IMMEDIATE-RELEASE FORMULATION: Initial dose, 0.1 to 0.25 mg/kg orally or sublingually; Maximum 10 mg/dose. CHRONIC HYPERTENSION: EXTENDED-RELEASE FORMULATION: Initial dose, 0.25 to 0.5 mg/kg/day orally in 1 or 2 doses. May titrate based on response, up to 3 mg/kg/day; Maximum 120 mg/day.

Treatment:

NIFEDIPINE
  • Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Patients who have asymptomatic bradycardia can be admitted and observed with telemetry. Obtain peripheral intravenous access and monitor ECG. Mild hypotension may only require treatment with intravenous fluid administration. MANAGEMENT OF SEVERE TOXICITY: Patients with bradycardia and hypotension require standard ACLS treatment. Place a central line and consider placement of an arterial line. Standard first line treatment includes atropine for bradycardia although in a serious poisoning it is rarely effective. High dose insulin and dextrose have been effective in animal studies and multiple case reports in patients with hypotension refractory to other modalities, and should be considered early in patients with significant hypotension. Use intravenous calcium in severe poisonings although in these cases, beneficial effects of calcium infusion may be very minimal or short-lived. Repeat bolus doses or a continuous intravenous infusion are often needed. Standard vasopressors should be administered to maintain blood pressure. Lipid emulsion has been successful in animal studies and a few case reports of patients with hypotension refractory to other therapies. Intravenous glucagon has been used with variable success. In a patient whose hemodynamic status continues to be refractory despite the treatment described above, extracorporeal membrane oxygenation or cardiopulmonary bypass should be considered. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
  • Decontamination: PREHOSPITAL: Not recommended because of the potential for abrupt deterioration. HOSPITAL: Because a NIFEdipine overdose can be life-threatening, all significant ingestions should receive activated charcoal. Patients with altered mental status should be intubated prior to administration. Gastric lavage should be considered in patients with recent large ingestions if the airway is protected. Late gastric lavage may be effective following sustained-release products. Whole bowel irrigation should be considered early for patients who can protect their airway or who are intubated who have ingested sustained-release formulations; it can limit absorption from possible concretions. Whole bowel irrigation should NOT be performed in patients who are hemodynamically unstable.
  • Airway management: Intubate patients with coma, mental status depression or significant hemodynamic instability.
  • Hypotensive episode: Treat initially with fluids (insert a central venous or pulmonary artery catheter to guide fluid therapy if hypotension persists). Consider inserting an arterial line in patients with refractory hypotension. Intravenous calcium, vasopressors, high dose insulin/dextrose, and glucagon may all be useful for refractory hypotension. Pacemakers (external or internal), intraaortic balloon pump, and cardiopulmonary bypass have been used in patients refractory to other modalities.
  • Calcium: Intravenous calcium infusions have been shown to be helpful, although response is often short lived. Optimal dosing is not established; start with an initial IV infusion of about 13 to 25 mEq of calcium (10 to 20 mL of 10% calcium chloride or 30 to 60 mL of 10% calcium gluconate) followed by either repeat boluses every 15 to 20 minutes up to 3 to 4 doses or a continuous infusion starting with 0.5 mEq/kg/hr of calcium (0.2 to 0.4 mL/kg/hr of 10% calcium chloride or 0.6 to 1.2 mL of 10% calcium gluconate) and titrate as needed. Calcium dosing should be titrated to hemodynamic response rather than serum calcium concentration alone; central venous or pulmonary artery catheters may be useful to guide therapy. Monitor ECG and ionized calcium concentration. Patients with severe overdose have tolerated significant hypercalcemia (up to twice the upper limit of normal) without developing clinical or ECG evidence of hypercalcemia.
  • Insulin: Administer a bolus of 1 unit/kg of insulin followed by an infusion of 0.1 to 1 unit/kg/hr, titrated to a systolic blood pressure of greater than 90 to 100 mmHg (bradycardia may or may not respond). Reassess every 30 minutes to titrate insulin infusion. Administer dextrose bolus to patients with an initial blood glucose of less than 250 mg/dL (adults 25 to 50 mL dextrose 50%, children 0.25 g/kg dextrose 25%). Begin a dextrose infusion of 0.5 g/kg/hr in all patients. Monitor blood glucose every 15 to 30 minutes until consistently 100 to 200 mg/dL for 4 hours, then monitor every hour. Titrate dextrose infusion to maintain blood glucose in the range of 100 to 200 mg/dL. As the patient improves, insulin resistance abates and dextrose requirements will increase. Supplemental dextrose will be needed for at least several hours after the insulin infusion is discontinued. Administer supplemental potassium initially if patient is hypokalemic (serum potassium less than 2.5 mEq/L). Monitor serum potassium every 4 hours and supplement as needed to maintain potassium of 2.5 to 2.8 mEq/L.
  • Vasopressor: Anecdotal reports suggest that epinephrine, vasopressin, metaraminol, or phenylephrine may occasionally be effective in patients who do not respond to dopamine or norepinephrine.
  • Fat Emulsion: Lipid emulsion has been successful in animal studies and several case reports of patients with hypotension refractory to other therapies. Administer 1.5 mL/kg of 20% lipid emulsion over 2 to 3 minutes as an IV bolus, followed by an infusion of 0.25 mL/kg/min. If possible, discontinue after 30 to 60 minutes. Longer periods of lipid therapy should be considered if the patient’s hemodynamic stability is dependent on continued lipid infusion.
  • Glucagon: DOSE: ADULT: Optimal dosing in calcium antagonist poisoning is not established. Initially, 3 to 5 mg IV, slowly over 1 to 2 minutes; may repeat treatment with a dose of 4 to 10 mg if there is no hemodynamic improvement within 5 minutes. CHILD: 50 mcg/kg; repeat doses may be used due to the short half-life of glucagon.
  • L-Carnitine: L-carnitine may be useful to treat hypotension in the setting of calcium channel blocker overdose. It is not well studied but an animal study and one human case report suggest efficacy. The dose used in the human case report was 6 g IV followed by 1 g IV every 4 hours.
  • Phosphodiesterase inhibitor: There are case reports where a phosphodiesterase inhibitor (inamrinone, enoximone) appeared to improve blood pressure in patients unresponsive to other modalities.
  • Monitoring of patient: Serum NIFEdipine concentrations are not readily available and not helpful to guide therapy. Monitor vital signs frequently. Institute continuous cardiac monitoring and obtain serial ECGs. In patients with significant hypotension or bradycardia, monitor serum electrolytes, renal function, arterial or venous blood gas, and urine output. Obtain digoxin concentration in patients who also have access to digoxin. Monitor cardiac enzymes in patients with chest pain.
  • Enhanced elimination procedure: Hemodialysis is not of value because of the high degree of protein binding and large volume of distribution.
  • Patient disposition: HOME CRITERIA: According to the AAPCC guidelines, a healthy, asymptomatic adults with a single inadvertent ingestion of NIFEdipine 30 mg or less immediate-release or a chewed sustained-release, or 120 mg or less of a sustained-release formulation can be monitored at home. For children, there are no safe doses. OBSERVATION CRITERIA: Symptomatic patients, those with underlying cardiovascular disease, those taking beta blockers or another cardiodepressant drug, those with deliberate ingestions, and all children should be referred to a healthcare facility for treatment, evaluation and monitoring. . According to the AAPCC guidelines, a patient with an inadvertent single ingestion of NIFEdipine greater than 30 mg immediate-release or a chewed sustained-release, or greater than 120 mg sustained-release formulation should be referred to a healthcare facility. For children, ingestions of any amounts should be referred to a healthcare facility. Patients should be observed for at lease 6 hours after ingestion of immediate release and 18 to 24 hours after ingestion of sustained release formulations. Patients who develop signs or symptoms of toxicity should be admitted to an intensive care setting. ADMISSION CRITERIA: Patients who develop signs or symptoms of toxicity should be admitted to an intensive care setting. CONSULT CRITERIA: Consult a poison center or medical toxicologist in cases of severe poisonings or in cases where there is a history of a large exposure.