Continuing Education Activity

Nisoldipine is a medication used in the management of hypertension. It falls under the class of dihydropyridine calcium channel blockers. This activity reviews the indications, mechanism of action, and contraindications for nisoldipine as a valuable agent in treating and managing hypertension. This activity will highlight the mechanism of action, adverse effects, and other key factors such as dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions pertinent for members of the interprofessional team in the treatment and care of patients with hypertension and related conditions.

Objectives:

• Identify the mechanism of action of nisoldipine.
• Describe the potential adverse effects of nisoldipine.
• Review the appropriate monitoring for patients taking nisoldipine.
• Summarize interprofessional team strategies for improving care coordination and communication to advance nisoldipine and improve outcomes.

Indications

Nisoldipine is an FDA-approved 1,4-dihydropyridine calcium-channel blocker for the management of hypertension. The drug may be used alone or in combination with other antihypertensive agents (i.e., Angiotensin-Converting Enzyme Inhibitors, diuretics, or beta-blockers).[1] The medication is also safe and effective for use in the geriatric population. Off-label, nisoldipine may be used for the treatment of certain ischemic heart conditions such as stable angina or prinzmetal angina.[2]

Mechanism of Action

Nisoldipine falls under the class of dihydropyridine calcium channel blockers. The drug acts on the systemic smooth muscle cells by inhibiting the influx of calcium and by blocking the voltage-gated calcium channels located on the cells — the reduction in the calcium results in the dilation of coronary and systemic arteries. Nisoldipine exhibits both antihypertensive and anti-anginal activity due to its ability to reduce systemic blood pressure and the myocardial oxygen demand (thereby increasing myocardial oxygen delivery to cells).[3] This action ultimately results in vasodilation and decreases peripheral vascular resistance. 

Nisoldipine is metabolized in the liver via the CYP3A4 pathway and excreted through the renal pathway. It has a half-life of between 9 to 18 hours and a bioavailability of about 5%.[4] The drug does not manifest any changes in the serum calcium concentrations and is insoluble in water.[5]

Administration

Nisoldipine is available as an oral formulation as an extended-release tablet ( 20 mg, 30 mg, and 40 mg ) or as an extended-release hydrogel ( 8.5 mg, 17 mg, and 34 mg ). The patient should take the medication on an empty stomach or an hour after meals. The drug is to be swallowed whole with water and not crushed or divided.[6] The dosing adjustment recommendations are on weekly intervals based on patient response. Avoid grapefruit juice and high-fat meals with the medication administration due to their effect on drug bioavailability.[7]

For Hypertension

• In adults: Extended-release hydrogel is started at 17 mg by mouth daily, and the maximum daily dose is 34 mg by mouth daily.[8] It is increased by 8.5 mg every week or at longer intervals to achieve optimum blood pressure. The maintenance dose for nisoldipine ranges between 17 to 34 mg daily. In comparison, the original extended-release formulation is started at 20 mg per day up to the maximum dose of 40 mg daily. The dose is increased every two to four weeks to achieve optimum blood pressure control. Either of these formulations can be used in combination with ACE inhibitors, ARBs, beta-blockers, or thiazide diuretics if monotherapy is insufficient to attain the blood pressure goal.
• In the geriatric population: It is started at 8.5 mg orally each day.

For Ischemic Heart Conditions

• In adults: 8.5 to 34 mg of extended-release hydrogel formulation by mouth daily.
• In the geriatric population: 8.5 mg orally each day.

Patients with Hepatic Impairment

• 8.5 to 10 mg orally daily (do not exceed 30 mg daily)

Patients with Renal Impairment

• Because the pharmacokinetics of nisoldipine is not significantly different in patients with various degrees of renal impairment, dose adjustments are not required in patients with mild to moderate renal impairment.

However, drug safety and efficacy in the pediatric population, pregnant women, and breastfeeding women remain unestablished.[9]

The equivalency of Nisoldipine dose is as follows.

Adverse Effects

Though nisoldipine is a well-tolerated medication among patients, it does have some side effects mainly associated with its vasodilating property. Common adverse effects associated with nisoldipine include flushing, vasodilation (4%), hypotension, syncope, peripheral edema (7% to 29% and it is dose-related), headache (22%), dizziness (3% to 10%), and nausea (2%). Additionally, chest pain (2%), palpitations (3%), dermatitis (2%), pharyngitis  (5%), and sinusitis (3%) may also exhibit in individuals taking nisoldipine. Conditions such as anemia, anxiety, alopecia, difficulty swallowing, gingival hyperplasia, or ischemia are associated with less than 1% of the population taking the drug.[10] 

In less than 1 % population taking nisoldipine following adverse reactions are reported in postmarketing surveillance.

Abnormal hepatic function tests increased blood urea nitrogen, increased nonprotein nitrogen, increased creatine phosphokinase, increased serum creatinine, anorexia, hepatomegaly, abnormal dreams, amnesia, anxiety, ataxia, cerebral ischemia,  cerebrovascular accident, depression, drowsiness,  insomnia, abnormal T waves on ECG, ejection murmur (systolic), first-degree atrioventricular block, atrial fibrillation,  myocardial infarction, cardiac failure (decompensated),  supraventricular tachycardia amblyopia, blepharitis, diaphoresis,  glaucoma, keratoconjunctivitis, exfoliative dermatitis, facial edema, alopecia, dermal ulcer, hypersensitivity reaction (e.g.,  chest tightness, hypotension, angioedema, shortness of breath, skin rash, and /or tachycardia), maculopapular rash, increased appetite, oral mucosa ulcer, anemia, hematuria, colitis,  diarrhea, dysgeusia, dyspepsia,  dysphagia,   dysuria,  epistaxis,  gastritis, gastrointestinal hemorrhage, gingival hyperplasia,  glossitis, leukopenia, malaise, melena, fever,  flu-like symptoms, arthralgia, arthritis, gout, bruise,  herpes simplex infection, herpes zoster, cellulitis, dyspnea, asthma, diabetes mellitus, hypertension, hypokalemia, hypotension, decreased libido, and gynecomastia are reported by manufacturer's product label.

Withdrawal Effects: Studies have shown that the abrupt withdrawal of nisoldipine may result in chest palpitations, chest pain, or increased severity of angina or hypertension. Thus the medication must be slowly tapered over time.[5]

Contraindications

Nisoldipine is contraindicated in individuals with hypersensitivity to the drug or other dihydropyridine calcium channel blockers. Caution is necessary for the elderly population due to higher drug plasma concentrations; recommendations are to start at a lower dose for safety.

Breastfeeding women should avoid this drug due to the risk of excretion into breast milk. Due to the lack of well-controlled studies, pregnant women should avoid drug use to prevent any teratogenicity. Avoid concurrent use with cytochrome P450 inducers and inhibitors.[11] Nisoldipine is also contraindicated with grapefruit products and high-fat meals (i.e., cheese, white bread, fried potatoes) due to its effect on absorption.[12] Individuals diagnosed with GERD or a hiatal hernia should exercise caution when using nisoldipine due to its action on the esophageal sphincter.[13]

Warnings/Precautions

Hypotension/syncope: Hypotension with or without syncope is rarely reported, and target blood pressure should be attained at a rate appropriate for the patient's clinical condition. Clinicians should closely monitor patients during initial dosing and at dosage titrations.

Peripheral Edema: The most common adverse reaction of nisoldipine is peripheral edema, which occurs within two to three weeks of therapy initiation.

Angina/ Myocardial Infarction: Extreme caution is necessary for patients with aortic stenosis, myocardial infarction, or hypotension due to the risk of reflex tachycardia resulting in the possible exacerbation of angina or worsening of myocardial infarction (MI), especially in the absence of concomitant beta-blockade. Though rare, patients with coronary artery disease may have increased frequency or severity of angina when starting nisoldipine. Safety measures are advised in patients with heart failure or left ventricular dysfunction and severe bradycardia due to the drug's hypotensive effect.

Heart failure (HF): According to ACC/AHA heart failure guidelines, calcium channel blockers, in general, should be avoided in patients with heart failure due to lack of benefit and/or worsening of outcomes.[14]

Hepatic impairment: Use with caution in patients with severe hepatic impairment.[15]

Monitoring

Individuals taking nisoldipine should undergo monitoring to relieve symptoms and any adverse effects pertaining to the medication. The patient's blood pressure should be carefully observed during each clinic visit and at home. It is also essential to monitor the cardiac function (i.e., heart rate) for any abnormalities at each physician visit and make dose adjustments accordingly. It is also crucial to taper the dose slowly and make adjustments at weekly intervals. Liver function (LFTs) monitoring is required in individuals with hepatic impairment. No dose adjustments are necessary for renal impairment.[16]

The medication should be stored in a cool place, away from heat and moisture.[17]

Toxicity

Toxicity due to nisoldipine has its basis in clinical status and history. As described above, hypotension, coupled with reflex tachycardia, can present when patients take an overdose on dihydropyridine calcium channel blockers such as nisoldipine. In some severe cases of nisoldipine toxicity, the clinician will note hypotension with bradycardia. Secondary findings of confusion, heart failure, and abnormal ECG changes such as PR prolongation can indicate toxicity. Additionally, hyperglycemia in patients without diabetes can suggest calcium channel blockers poisoning.[18]

If toxicity is suspected, resuscitation is a priority. IV fluids and atropine for bradycardia are necessary alongside frequent reassessments by clinical staff. If a patient presents with severe symptoms, maintaining the airway, IV isotonic crystalloid, calcium salts, glucagon, insulin, and vasopressor therapy are all viable options and usable collectively. Activated charcoal should be administered in all patients suspected of nisoldipine overdose.[13]

Enhancing Healthcare Team Outcomes

An interprofessional healthcare team is the optimal means to successfully manage patients treated with dihydropyridine calcium channel blockers such as nisoldipine. Providers must be knowledgeable regarding the symptoms of toxicity. A team consisting of nurses, laboratory technicians, pharmacists, physicians, and other healthcare professionals is necessary to optimize care to improve clinical outcomes in case of overdose. Pharmacists should offer to consult about the use of glucagon, insulin, and vasopressor therapy. A toxicologist consult should also take place when indicated. Cardiologists, intensivists, and the emergency team may have involvement in managing a patient further as many of these cases require further interventional management during the hospital course, including maintenance of an airway. By coordinating care, a patient on nisoldipine who may be experiencing toxicity or adverse symptoms can be successfully managed.

Interprofessional team dynamics will also serve to prevent nisoldipine adverse reactions. The prescriber can consult a pharmacist to verify dosing and check the medication record for potential drug interactions. Nursing will be able to perform much of the monitoring necessary at follow-up visits and help determine patient compliance and treatment effectiveness. Both the pharmacist and nursing should promptly alert the prescriber to any concerns, so adjustments to the regimen (either dosing or agent selection) can be made and lead to improved patient outcomes. [Level 5]