Calcium Channel Blockers: Nicardipine
Indication
Nicardipine is used in adults for the treatment of angina pectoris and hypertension. In pediatric patients, it is used predominantly to treat hypertension. Both oral and I.V. preparations of the drug are available. The I.V. preparation is typically used in monitored inpatient settings (e.g., an intensive care unit) when oral dosing is either not possible or tighter blood pressure control is desired (e.g., early after cardiovascular surgery).
Mechanism of Action
Nicardipine prevents calcium ions from entering both vascular smooth muscle cells and myocardial cells via specific slow calcium channels. Thus, it decreases the intracellular concentration of calcium such that less calcium is available to contractile proteins in these cells. This results in vasodilation. Relaxation of coronary vascular smooth muscle specifically treats anginal pain by increasing myocardial oxygen delivery.
Dosing
Neonates (premature and full term):
Oral: no information
I.V. continuous infusion: dosing data from two studies (n = 28 patients) suggested an initial dose of 0.5βg/kg/min I.V. Doses were titrated by blood pressure over the first day to a mean maximal dose of 0.74 ± 0.41 µg/kg/min (range, 0.5-2 µg/kg/min)
Infants/children: data for infants and children are also limited, and dosing is not well established.
Oral: case reports only. Doses of 20 to 30mg/dose P.O. every 8 hours in two 14-year-old children have been reported
I.V. continuous infusion: initial, 0.5 to 1 µg/kg/min I.V., then titrate dose to achieve the desired blood pressure. Dosing changes can be made every 15 to 30 minutes. Maximum dose 4 to 5 µg/kg/min
Adults:
Oral:
Immediate release: initial, 20 mg P.O., three times per day. Titrate to response allowing at least 3 days between dose increases. Usual dose, 20 to 40 mg, three times per day
Sustained release: initial, 30 mg P.O. twice daily. Usual dosage range, 30 to 60 mg, twice daily
I.V. continuous infusion: hypertension (patients not receiving oral nicardipine): initial, 5mg/h I.V. Titrate dose by increasing infusion by 2.5mg/h every 5 to 15 minutes until target achieved or maximum dose of 15mg/h reached. Once target blood pressure is achieved, decrease infusion rate to 3 mg/h or lowest rate to achieve desired blood pressure
Pharmacokinetics
Onset of action:
Oral: 0.5 to 2 hours
I.V: within minutes
Absorption: oral dose, 100%; but large first-pass effect. Bioavailability, oral dose, 35%
Distribution: volume of distribution in adults, 8.3 L/kg
Maximum effect:
Immediate-release capsules: 1 to 2 hours
Sustained-release capsules: sustained 2 to 7 hours after dose
I.V. continuous infusion: 50% of maximum effect within 45 minutes, and final effect by 50 hours
Half-life: Dose-dependent (nonlinear) pharmacokinetics, therefore, apparent half-life depends on serum concentration
Oral dose: 2 to 4 hours over first 8 hours; terminal half-life, 8.6 hours
I.V. infusion: serum concentration decreases exponentially in 3 phases— α (2.7 minutes), β (44.8 minutes), and terminal (14.4h)
Duration:
Immediate-release capsules: less than 8 hours
Sustained-release capsules: 12 hours
I.V. single dose: 3 hours
I.V. continuous infusion: 50% decrease in 30 minutes with gradual loss of antihypertensive effect over 50 hours
Protein binding: 95%
Metabolism: saturable first-pass effect with dose-dependent pharmacokinetics. Extensive hepatic metabolism by cytochrome P450 isoenzyme, CYP3A4 Clearance: decreased in patients with hepatic dysfunction, and may be decreased with renal dysfunction
Elimination: 60% of an oral dose is excreted in the urine, with less than 1% as unchanged drug; 35% excreted in the feces. Not removed by dialysis
Monitoring Parameters
Blood pressure, heart rate, liver function, and renal function. Monitor blood pressure carefully, especially with I.V. infusion and dosing changes.
Contraindications
Hypersensitivity to nicardipine or any component, and significant aortic stenosis.
Adverse Effects
Cardiovascular: vasodilation/flushing, tachycardia, palpitations, hypotension (6% with I.V. form), orthostasis, syncope, peripheral and facial edema, increased angina, electrocardiographic changes, myocardial infarction
Respiratory: dyspnea
Central nervous system: headache, dizziness, somnolence, paresthesias, anxiety, insomnia, intracranial hemorrhage (0.7% with I.V. form)
Gastrointestinal: nausea, vomiting, dyspepsia, xerostomia, diarrhea, constipation, abdominal pain
Genitourinary: polyuria,nocturia,hematuria (0.7% with I.V. form).
Neuromuscular and skeletal: asthenia, myalgia, malaise, tremor, hypoesthesia
Endocrine/metabolic: hypokalemia (0.7% with I.V. form)
Ophthalmological: blurred vision
Cutaneous/peripheral: rash
Other: diaphoresis, injection site reaction or pain (I.V. form)
Precautions
In adult patients with severe coronary artery disease, both initiation of nica-rdipine therapy and increased dosing have been associated with increased severity and frequency of angina. Abrupt withdrawal may cause rebound angina in patients with coronary artery disease.
Negative inotropic effects may occur in those patients with congestive heart failure and left ventricular dysfunction, resulting in low cardiac output. Symptomatic hypotension may occur, especially with the I.V. form. Because vessel irritation is common, infusion sites for the I.V. form should be changed every 12 hours on therapy.
Drug-Drug Interactions
Nicardipine affects several cytochrome P450 isoenzymes and, thus, has numerous drug interactions. Serum concentrations of the following drugs may be increased by nicardipine: cyclosporine, metoprolol, vecuronium (I.V. nicardipine), and digoxin. Either serum concentrations or the effects of multiple other drugs that are substrates for various cytochrome P450 enzymes maybe affected, in eluding CYP2C8/9 substrates (e.g., amiodarone, warfarin),CYP2C19 substrates (e.g., phenytoin, propranolal), CYP2D6 substrates (e.g., selected β-blockers, lidocaine, risperidone), and CYP3A4 substrates (e.g., benzodiazepines, other calcium channel blockers, and tacrolimus).
Drugs that are strong inhibitors of the cytochrome P450 isoenzyme, CYP3A4, such as azole antifungals, clarithromycin, propofol, and protease inhibitors, may all increase serum concentrations or effects of nicardipine, whereas drugs that induce isoenzyme CYP3A4, such as carbamazepine, phenytoin, phenobarbital, and rifampin, may decrease the concentration or effects of nicardipine. Lastly, nicardipine may decrease the serum concentration or effects of common narcotic agents (e.g., codeine, hydrocodone, and oxycodone) that are prodrug substrates for isoenzyme CYP2D6.
Compatible Diluents/Administration
For oral forms of nicardipine, administration of the drug with high-fat meals may decrease peak concentrations. Concurrent use of grapefruit juice may increase serum concentration. The I.V. form should be protected from light. It can be diluted in either dextrose- (e.g., 5% dextrose in water [D5W]) or saline-based I.V. fluid,but not in lactated Ringer’s solution. Nicardipine is not compatible with 5% sodium bicarbonate, furosemide,heparin, or thiopental.
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