Nifedipine

Nifedipine is an antihypertensive agent belonging to Calcium Channel Blocker.

Nifedipine is a dihydropyridine calcium channel blocker indicated for the management of several subtypes of angina pectoris, and hypertension.

It is almost completely absorbed in the gastrointestinal tract but has a bioavailability of 45-68%. The steady-state volume of distribution of nifedipine is 0.62-0.77L/kg and the volume of distribution of the central compartment is 0.25-0.29L/kg. Nifedipine is 92-98% protein bound in serum. Nifedipine is predominantly metabolized by CYP3A4. Nifedipine is also minorly metabolized to dehydro nifedipine.

Nifedipine shows common side effects like Swelling of extremities, Dizziness, Flushing, Headache, Heartburn, Nausea, Muscle cramps, Mood change, Nervousness, Cough, Indigestion, Palpitations, Wheezing, Low blood pressure (hypotension), transient, Hives, Itching, Constipation, Chest pain, Swollen gums, Agranulocytosis, Erectile dysfunction, etc.

Nifedipine is available in the form of Oral Tablet and Oral Capsule.

Nifedipine is available in India, US, Canada, Japan, China, Russia, and Germany.

Nifedipine belonging to the Calcium Channel Blocker, acts as an antihypertensive agent.

Nifedipine blocks voltage gated L-type calcium channels in vascular smooth muscle and myocardial cells. This blockage prevents the entry of calcium ions into cells during depolarization, reducing peripheral arterial vascular resistance and dilating coronary arteries. These actions reduce blood pressure and increase the supply of oxygen to the heart, alleviating angina.

The onset of action of Nifedipine occurs within 20min (by Conventional), 30min (by Extended),

The Duration of Action for Nifedipine in the body is approximately 8 hours (by Conventional), 24 hours (by Extended).

The Tmax was found within 30-120 min (by Conventional), 6 hours (by Extended), following the administration of Nifedipine.

Nifedipine is available in the form of Oral Tablet and capsule.

Nifedipine Tablet and capsule take orally usually once or 3-4 times a day.

Nifedipine is used to treat high blood pressure and other heart complications. The medicine should be taken in conjunction with a proper diet and regular exercise. It is also used in managing chest pain.

Nifedipine an antihypertensive agent belonging to Calcium-channel Blocker. It lowers blood pressure by relaxing the blood vessels, so the heart does not have to pump as hard. It controls chest pain by increasing the supply of blood and oxygen to the heart.

Nifedipine is approved for use in the following clinical indications

• Adult Hypertension

Nifedipine is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.

• Pediatric Hypertension

Use of Nifedipine should be under the supervision of a specialist experienced in the management of pediatric hypertension in the inpatient tertiary setting and used only after other alternatives have been shown to be ineffective. Current pediatric blood pressure guidelines do not recommend nifedipine for the management of acute severe hypertension, as other safe and effective alternatives are available for use in the pediatric population.

• Vasospastic Angina

Nifedipine is indicated for the management of vasospastic angina confirmed by any of the following criteria: 1) classical pattern of angina at rest accompanied by ST segment elevation, 2) angina or coronary artery spasm provoked by ergonovine, or 3) angiographically demonstrated coronary artery spasm. In those patients who have had angiography, the presence of significant fixed obstructive disease is not incompatible with the diagnosis of vasospastic angina, provided that the above criteria are satisfied. Nifedipine may also be used where the clinical presentation suggests a possible vasospastic component, but where vasospasm has not been confirmed, e.g., where pain has a variable threshold on exertion, or in unstable angina where electrocardiographic findings are compatible with intermittent vasospasm, or when angina is refractory to nitrates and/or adequate doses of beta blockers.

• Chronic Stable Angina (Classical Effort-Associated Angina)

Nifedipine is indicated for the management of chronic stable angina (effort-associated angina) without evidence of vasospasm in patients who remain symptomatic despite adequate doses of beta blockers and/or organic nitrates or who cannot tolerate those agents. In chronic stable angina (effort-associated angina), nifedipine has been effective in controlled trials of up to eight weeks duration in reducing angina frequency and increasing exercise tolerance, but confirmation of sustained effectiveness and evaluation of long-term safety in these patients is incomplete. Controlled studies in small numbers of patients suggest concomitant use of nifedipine and beta blocking agents may be beneficial in patients with chronic stable angina, but available information is not sufficient to predict with confidence the effects of concurrent treatment, especially in patients with compromised left ventricular function or cardiac conduction abnormalities. When introducing such concomitant therapy, care must be taken to monitor blood pressure closely, since severe hypotension can occur from the combined effects of the drugs.

Although not approved, there have been certain off-label indications. These include

• Anal fissure

Nifedipine administered topically as a local vasodilator in conjunction with supportive measures.

• High-altitude pulmonary edema (adjunctive therapy)

Nifedipine also indicated for management of high-altitude pulmonary edema.

• Pulmonary arterial hypertension (group 1)

Nifedipine only used for rigorously selected group 1 pulmonary arterial hypertension patients with a positive vasoreactivity test and under the care of a pulmonary hypertension specialist.

• Hypertensive emergency in pregnancy or postpartum

For acute-onset, severe, persistent hypertension, Nifedipine is used.

• Raynaud phenomenon and Tocolysis

Nifedipine also used for management of Raynaud phenomenon and Tocolysis.

• Adult Hypertension

Extended-release tablets:

Initial dose: 30 to 60 mg orally once a day

Maintenance dose: 30 to 90 mg orally once a day

Maximum dose: Up to 120 mg/day.

• Pediatric Hypertension

Children and Adolescents

Immediate release: Oral: 0.04 to 0.25 mg/kg/dose; maximum single dose: 10 mg/dose; may repeat if needed every 4 to 6 hours; monitor carefully; maximum daily dose: 1 to 2 mg/kg/day.

• Angina Pectoris

Immediate-release capsules:

Initial dose: 10 mg orally 3 times a day

Maintenance dose: 10 to 30 mg orally 3 to 4 times a day

Maximum doe: 180 mg/day

Extended-release tablets:

Initial dose: 30 to 60 mg orally once a day

Maintenance dose: 30 to 90 mg orally once a day

Maximum dose: Up to 120 mg/day

• Angina Pectoris Prophylaxis

Immediate-release capsules:

Initial dose: 10 mg orally 3 times a day

Maintenance dose: 10 to 30 mg orally 3 to 4 times a day

Maximum doe: 180 mg/day

Extended-release tablets:

Initial dose: 30 to 60 mg orally once a day

Maintenance dose: 30 to 90 mg orally once a day

Maximum dose: Up to 120 mg/day

• Anal fissure (off-label use)

Peri-anal: 0.2% to 0.3% ointment or gel: After cleansing, apply around fissure(s) 2 to 4 times daily for 4 weeks.

• High-altitude pulmonary edema (off-label use)

Oral: Extended release: 30 mg every 12 hours starting 24 hours prior to ascent; continue for 5 days after reaching maximal altitude; can extend beyond 5 days in high-risk circumstances.

• Pulmonary arterial hypertension (group 1) (off-label use)

Oral: Extended release:

Initial: 30 to 60 mg once daily; titrate gradually and with close hemodynamic monitoring; reported dose range: 120 to 240 mg/day.

• Hypertensive emergency in pregnancy or postpartum (off-label use)

Oral: Extended release:

Initial: 30 mg; repeat 30 mg after 1 to 2 hours if target BP is not achieved; if systolic or diastolic BP remains above threshold after the second dose, another class of agents should be considered.

• Raynaud phenomenon (off-label use)

Oral: Immediate release: Initial: 10 mg 3 times daily; may titrate by 10 mg increments as needed based on response and tolerability, up to 30 mg 3 times daily; transition to an Extended-Release formulation for maintenance therapy.

Note: Only for short-term use in hospitalized patients with severe digital ischemia.

• Tocolysis (off-label use)

Oral: Immediate release: Initial: 20 to 30 mg as a loading dose, followed by 10 to 20 mg every 3 to 8 hours for up to 48 hours; maximum dose: 180 mg/day.

Nifedipine is available in various strengths as 10mg, 20mg, 30mg, 60mg and 90mg.

Nifedipine is available in the form of Oral Tablet and capsule.

Avoid grapefruit juice while taking Nifedipine.

 Nifedipine is contraindicated in patients with

● Known hypersensitivity reaction to Nifedipine.

• Excessive Hypotension

Although in most patients the hypotensive effect of nifedipine is modest and well tolerated, occasional patients have had excessive and poorly tolerated hypotension. These responses have usually occurred during initial titration or at the time of subsequent upward dosage adjustment and may be more likely in patients using concomitant beta-blockers. Severe hypotension and/or increased fluid volume requirements have been reported in patients who received immediate release capsules together with a beta-blocking agent and who underwent coronary artery bypass surgery using high dose fentanyl anesthesia. The interaction with high dose fentanyl appears to be due to the combination of nifedipine and a beta-blocker, but the possibility that it may occur with nifedipine alone, with low doses of fentanyl, in other surgical procedures, or with other narcotic analgesics cannot be ruled out. In nifedipine-treated patients where surgery using high dose fentanyl anesthesia is contemplated, the physician should be aware of these potential problems and, if the patient's condition permits, sufficient time (at least 36 hours) should be allowed for nifedipine to be washed out of the body prior to surgery.

• Increased Angina And/or Myocardial Infarction

Rarely, patients, particularly those who have severe obstructive coronary artery disease, have developed well-documented increased frequency, duration and/or severity of angina or acute myocardial infarction upon starting nifedipine or at the time of dosage increase. The mechanism of this effect is not established.

• Beta-Blocker Withdrawal

When discontinuing a beta-blocker, it is important to taper its dose, if possible, rather than stopping abruptly before beginning nifedipine. Patients recently withdrawn from beta blockers may develop a withdrawal syndrome with increased angina, probably related to increased sensitivity to catecholamines. Initiation of nifedipine treatment will not prevent this occurrence and on occasion has been reported to increase it.

• Congestive Heart Failure

Rarely, patients (usually while receiving a beta-blocker) have developed heart failure after beginning nifedipine. Patients with tight aortic stenosis may be at greater risk for such an event, as the unloading effect of nifedipine would be expected to be of less benefit to these patients, owing to their fixed impedance to flow across the aortic valve.

• Gastrointestinal Obstruction Requiring Surgery

There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of Nifedipine. Bezoars can occur in very rare cases and may require surgical intervention. Cases of serious gastrointestinal obstruction have been identified in patients with no known gastrointestinal disease, including the need for hospitalization and surgical intervention. Risk factors for a gastrointestinal obstruction identified from post-marketing reports of Nifedipine include alteration in gastrointestinal anatomy (severe gastrointestinal narrowing, colon cancer, small bowel obstruction, bowel resection, gastric bypass, vertical banded gastroplasty, and colostomy), hypomotility disorders (constipation, gastroesophageal reflux disease, ileus, obesity, hypothyroidism, and diabetes) and concomitant medications (H2-histamine blockers, nonsteroidal anti-inflammatory drugs, laxatives, anticholinergic agents, and levothyroxine).

Alcohol can make the side effects from Nifedipine worse.

Nifedipine is excreted in human milk. Nursing mothers are advised not to breastfeed their babies when taking the drug.

Pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Avoid grapefruit juice while taking Nifedipine.

• Common Adverse effects

Peripheral edema, Dizziness, Flushing, Headache, Heartburn, Nausea, Muscle cramps, Mood change, Nervousness, Cough, Dyspnea, Palpitations, Wheezing Hypotension, transient, Urticaria, Pruritus, Constipation, Chest pain.

• Rare Adverse effects

Gingival hyperplasia, Agranulocytosis, Erectile dysfunction, Exfoliative or bullous skin adverse events (e.g., erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), Photosensitivity reactions, Acute generalized exanthematous pustulosis.

• Beta-adrenergic blocking agents:

Experience in over 1400 patients with Procardia capsules in a noncomparative clinical trial has shown that concomitant administration of nifedipine and beta-blocking agents is usually well tolerated, but there have been occasional literature reports suggesting that the combination may increase the likelihood of congestive heart failure, severe hypotension, or exacerbation of angina.

• Long-acting Nitrates:

Nifedipine may be safely co-administered with nitrates, but there have been no controlled studies to evaluate the antianginal effectiveness of this combination.

• Digitalis:

Administration of nifedipine with digoxin increased digoxin levels in nine of twelve normal volunteers. The average increase was 45%. Another investigator found no increase in digoxin levels in thirteen patients with coronary artery disease. In an uncontrolled study of over two hundred patients with congestive heart failure during which digoxin blood levels were not measured, digitalis toxicity was not observed. Since there have been isolated reports of patients with elevated digoxin levels, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing nifedipine to avoid possible over- or under-digitalization.

• Coumarin Anticoagulants:

There have been rare reports of increased prothrombin time in patients taking coumarin anticoagulants to whom nifedipine was administered. However, the relationship to nifedipine therapy is uncertain.

• Cimetidine:

A study in six healthy volunteers has shown a significant increase in peak nifedipine plasma levels (80%) and area-under-the-curve (74%), after a one-week course of cimetidine at 1000 mg per day and nifedipine at 40 mg per day. Ranitidine produced smaller, non-significant increases. The effect may be mediated by the known inhibition of cimetidine on hepatic cytochrome P-450, the enzyme system probably responsible for the first-pass metabolism of nifedipine. If nifedipine therapy is initiated in a patient currently receiving cimetidine, cautious titration is advised.

The common side effect of Nifedipine include the following

• Common

Swelling of extremities, Dizziness, Flushing, Headache, Heartburn, Nausea, Muscle cramps, Mood change, Nervousness, Cough, Indigestion, Palpitations, Wheezing, Low blood pressure, Hives, Itching, Constipation, Chest pain, Swollen gums, Agranulocytosis, Erectile dysfunction.

• Rare

Exfoliative or bullous skin adverse events (e.g., erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), Photosensitivity reactions, Acute generalized exanthematous pustulosis.

• Pregnancy

Pregnancy Category C

Nifedipine has been shown to produce teratogenic findings in rats and rabbits, including digital anomalies similar to those reported for phenytoin. Digital anomalies have been reported to occur with other members of the dihydropyridine class and are possibly a result of compromised uterine blood flow. Nifedipine administration was associated with a variety of embryotoxic, placenta toxic, and fetotoxic effects, including stunted fetuses (rats, mice, rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice, rabbits), and prolonged pregnancy/decreased neonatal survival (rats; not evaluated in other species). On a mg/kg basis, all of the doses associated with the teratogenic embryotoxic or fetotoxic effects in animals were higher (3.5 to 42 times) than the maximum recommended human dose of 120 mg/day. On a mg/m2 basis, some doses were higher, and some were lower than the maximum recommended human dose, but all are within an order of magnitude of it. The doses associated with placenta toxic effects in monkeys were equivalent to or lower than the maximum recommended human dose on an mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Nifedipine Extended-Release Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Nursing Mothers

Nifedipine is excreted in human milk. Nursing mothers are advised not to breastfeed their babies when taking the drug

• Geriatric Use

Although small pharmacokinetic studies have identified an increased half-life and increased Cmax and AUC, clinical studies of nifedipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

• The primary cardiac symptoms of calcium channel blocker include hypotension and bradycardia. The hypotension is caused by peripheral vasodilation, myocardial depression, and bradycardia. Bradycardia results from sinus bradycardia, second-or third degree atrioventricular block, or sinus arrest with junctional rhythm. Intraventricular conduction is usually not affected so QRS duration is normal.
• In a few reported cases, overdose with calcium channel blocker has been associated with hypotension and bradycardia, initially refractory to atropine but becoming more responsive to this agent when larger doses (approaching 1g/hour for more than 24 hours) of calcium chloride was administered.

Pharmacodynamic

Nifedipine is an inhibitor of L-type voltage gated calcium channels that reduces blood pressure and increases oxygen supply to the heart.¹ Immediate release nifedipine's duration of action requires dosing 3 times daily. Nifedipine dosing is generally 10-120mg daily. Patients should be counselled regarding the risk of excessive hypotension, angina, and myocardial infarction.

Pharmacokinetics

• Absorption

It is almost completely absorbed in the gastrointestinal tract but has a bioavailability of 45-68%.

• Distribution

The steady-state volume of distribution of nifedipine is 0.62-0.77L/kg and the volume of distribution of the central compartment is 0.25-0.29L/kg. Nifedipine is 92-98% protein bound in serum. Nifedipine is 97±12% bound in a 40g/L solution of pure albumin.² Nifedipine is 51.4±5.9% protein bound in a 50mg/100mL solution of alpha-1-acid glycoprotein, and 75.5±3.5% protein bound in a 150mg/mL solution.

• Metabolism and Excretion

Nifedipine is predominantly metabolized by CYP3A4. Nifedipine is predominantly metabolized to 2,6-dimethyl-4-(2-nitrophenyl)-5-methoxycarbonyl-pyridine-3-carboxylic acid, and then further metabolized to 2-hydroxymethyl-pyridine carboxylic acid. Nifedipine is also minorly metabolized to dehydro nifedipine.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019684s023lbl.pdf
• https://www.uptodate.com/contents/nifedipine-drug-information?search=nifedipine-drug-&source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F201404
• https://medlineplus.gov/druginfo/meds/a684028.html#precautions
• https://www.syrianclinic.com/med/en/ProfDrugs/Nifedipinepd.html#pregnancy-implications
• https://reference.medscape.com/drug/procardia-xl-nifedipine-342378#10
• https://www.practo.com/medicine-info/nifedipine-200-api