Continuing Education Activity

Nifedipine is a calcium channel blocker in the dihydropyridine subclass. It is primarily used as an antihypertensive and as an anti-anginal medication. FDA-approved indications include chronic stable angina, hypertension. It also has other off-label indications. This activity outlines the indications, mechanism of action, methods of administration, important adverse effects, contraindications, monitoring, and toxicity of nifedipine, so providers can direct patient therapy successfully in instances where nifedipine provides a benefit to patient care.

Objectives:

• Identify the mechanism of action of nifedipine.
• Discuss the therapeutic mechanism of action of nifedipine.
• Summarize the adverse event profile associated with nifedipine therapy.
• Review the importance of improving care coordination among the interprofessional team to enhance care delivery for patients who can benefit from therapy with nifedipine.

Indications

Nifedipine is a calcium channel blocker that belongs to the dihydropyridine subclass. It is primarily used as an antihypertensive and antianginal medication.

FDA Approved Indications[[1][2][2][3][4][5][6]

1. Chronic stable angina - Nifedipine reduced the frequency of angina and increased the mean exercise time in the IMAGE trial. Reflex tachycardia may limit its effectiveness; the addition of a beta-blocker can overcome this limitation. A long-acting formulation is preferred (extended-release). 
2. Vasospastic angina - It can be used as a second line of treatment. 
3. Hypertension - May be used as monotherapy or in combination with several different medications to manage hypertension (such as ACE inhibitor, ARB, thiazide diuretic).

Off-label Uses[7][8][9][10][11]

1. Raynaud phenomenon
2. Severe hypertension during pregnancy and post-partum hypertension
3. High altitude pulmonary edema
4. Pulmonary arterial hypertension (group 1)
5. Achalasia
6. Distal ureteric calculi
7. Tocolysis

Mechanism of Action

During the depolarization phase of smooth muscle cells, there is an influx of calcium ions through voltage-gated channels. Nifedipine inhibits the entry of calcium ions by blocking these voltage-dependent L-type calcium channels in vascular smooth muscle and myocardial cells. Reduced intracellular calcium reduces peripheral arterial vascular resistance and dilatation of coronary arteries, leading to a reduction in systemic blood pressure and increased myocardial oxygen delivery. Nifedipine thus has hypotensive and antianginal properties.

Administration

Nifedipine is available in both immediate and extended-release preparations. Its initial marketing was in a short-acting, immediate-release formulation that required multiple daily dosing. These preparations caused rapid vasodilation followed by reflex sympathetic activation, resulting in side effects such as headaches, palpitations, and flushing. These side effects led to the launch of extended-release preparations, which have shown to have a sustained 24-hour anti-hypertensive effect and fewer side effects.

Extended-release preparations are available in 30, 60, and 90 mg tablets. Dosage adjustments should ideally occur at 7- to 14-day intervals. The same total daily dosage should apply when switching from immediate to extended-release preparations. Patients may take immediate-release formulations without regard to meals. A few specific extended-release preparations require ingestion on an empty stomach. 

Immediate-release preparations have an onset of action within 20 minutes with a plasma half-life of about 4 to 7 hours. Extended-release preparations have an approximate duration of action of about 24 hours.  It undergoes hepatic metabolism via the CYP3A4 pathway. Extended-release preparations have a bioavailability of up to 89% relative to the immediate-release formulation. Bioavailability significantly increases in patients with liver failure necessitating dosage adjustment (due to reduced clearance of the medication). 

Recommended Dosages

Chronic Stable Angina

• Immediate-release: 10 to 20 mg three times daily; maximum dose of 180 mg per day
• Extended-release: 30 or 60 mg daily; maximum dose of 120 mg per day

Vasospastic Angina

• Extended-release: 30 or 60 mg daily; maximum dose of 120 mg per day

Hypertension

• Extended-release: 30 or 60 mg daily; maximum dose of 120 mg per day  

Hypertensive Emergency During Pregnancy or Postpartum Period

• Immediate-release: 10 mg; may repeat with a 20 mg dose in 20 minutes  

Adverse Effects

Adverse effects present in about 20 to 30% of patients prescribed nifedipine. These are primarily the result of the vasodilatory properties of nifedipine.

The most common adverse effects include flushing, peripheral edema, dizziness, headache. Tolerance is better with the extended-release preparations than the immediate-release preparations of nifedipine. Hypersensitivity reactions, such as pruritus, urticaria, and bronchospasms, are relatively rare. Abrupt discontinuance of the drug after prolonged use may lead to rebound hypertension or angina. 

Contraindications

Absolute Contraindication

• Hypersensitivity to nifedipine or its components
• ST-elevation myocardial infarction [12]

Relative Contraindication

• Severe aortic stenosis
• Unstable angina
• Hypotension
• Heart failure
• Moderate to severe hepatic impairment

In patients with unstable angina/non-STEMI, the use of immediate-release nifedipine is not a recommendation except with concomitant beta-blockade.[13] Immediate-release preparations of nifedipine (sublingually or orally) should be avoided in patients within hypertensive emergencies and urgencies as it is neither safe nor effective.[14] In cardiogenic shock, the heart cannot pump effectively, and this situation is exacerbated by inhibiting the influx of calcium ions into cardiac cells.[13] In severe aortic stenosis, nifedipine can cause ventricular collapse and dysfunction. In unstable angina, nifedipine causes a reflexive increase in cardiac contractility, which increases myocardial oxygen demand and worsens the ischemia. Nifedipine can exacerbate hypoperfusion to vital organs in patients with severe hypotension.[13] Furthermore, patients with hepatic impairment may not be able to metabolize nifedipine, leading to a longer half-life, putting them at an increased risk of toxicity and side effects. 

Monitoring

In general, there is no required laboratory monitoring for patients taking nifedipine. Since nifedipine is an antihypertensive medication, clinicians and patients should regularly measure blood pressure to achieve target levels. Patients should undergo monitoring for adverse side effects such as peripheral edema, dizziness, flushing. 

Toxicity

Treatment of overdose varies with the amount taken, duration since ingestion, age and, co-morbidities of the patient. Initial assessment involves securing airway, breathing, circulation, appropriate blood work, including testing for coingestants. Early consultation with poison control/ toxicology should be a priority.

An overdose of nifedipine can lead to systemic vasodilation, severe hypotension, and reflex tachycardia. Prolonged systemic hypotension can progress to shock and even death. Activated charcoal at a dose of 1 g/kg is useful if the patient presents within 1 to 2 hours of ingestion. Whole bowel irrigation should be a consideration with extended-release preparations or large quantity ingestion. Nasogastric lavage is usually ineffective. Intravenous fluid resuscitation, calcium salts, and vasopressor therapy with dopamine or norepinephrine usually alleviate the hypotension. Administration of high-dose insulin is an option as it has been shown to lower mortality and improve hemodynamics. Electrocardiographic results, vital signs, kidney function, urine output, and electrolytes require continuous monitoring. For intentional ingestion, psychiatric consultation is also necessary. Patients presenting with an overdose of immediate-release preparations need observation for 4 to 7 hours. For extended-release preparations, 24 hours of telemetry observation is ideal.

No specific antidote is available. 

Enhancing Healthcare Team Outcomes

All interprofessional healthcare team members should be familiar with the indications and contraindications of nifedipine. This includes all clinicians (including specialists, NPs, and PAs), nurses, and pharmacists. The drug can cause severe hypotension, and thus it is recommended that the dosing undergo titration from an initial low dose. Long-term patient monitoring is necessary to determine its effectiveness. Sublingual preparations are no longer recommended agents for hypertensive emergencies or urgencies due to lack of efficacy data and numerous severe adverse events such as an uncontrollable decrease in blood pressure, reflex tachycardia, and cerebral ischemia/infarction.

Given the risks, prescribing/ordering clinicians should strive to work with the interprofessional team when using nifedipine. Pharmacists should have involvement to verify dosing, particularly with the dosing differences between release formulations. They also need to conduct medication reconciliation to alert the team to any potential drug-drug interactions. Nurses will be administering the drug inpatient and are on the front lines for observing both treatment effectiveness as well as adverse events, which they should report to the clinician immediately. This collaborative interprofessional approach between clinicians, nursing, and pharmacy will better advance patient outcomes with nifedipine therapy. [Level 5]