Verapamil

Verapamil is an antihypertensive agent belonging to Calcium Channel Blocker.

Verapamil is a non-dihydropyridine calcium channel blocker used in the treatment of angina, arrhythmia, and hypertension.

Verapamil well absorbed from the GI tract. Bioavailability is approximately 20-35% (oral). Time to peak plasma concentration: 1-2 hours (oral). Crosses the placenta; enters breast milk. The volume of distribution: 3.89 L/kg. Plasma protein binding: Approx 90%. Extensively metabolized hepatically to at least 12 metabolites (e.g., nor verapamil as primary metabolites). Excreted Via urine (70% as metabolites, 3-4% as unchanged drug) feces (16%). Terminal half-life: 2-8 hours; increases to 4.5-12 hours (after oral repeated dose).

Verapamil shows common side effects like Nausea, constipation; headache, dizziness; or low blood pressure, etc.

Verapamil is available in the form Oral tablet and Oral capsule and Injectable solution.

Verapamil is available in India, US, UK, Canada, France, Germany and Italy.

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

Mechanism of action for hypertension and Angina

Inhibition of calcium influx prevents the contraction of vascular smooth muscle, causing relaxation/dilation of blood vessels throughout the peripheral circulation - this lowers systemic vascular resistance (i.e., afterload) and thus blood pressure. This reduction in vascular resistance also reduces the force against which the heart must push, decreasing myocardial energy consumption and oxygen requirements and thus alleviating angina.

Mechanism of action for Arrhythmia

Electrical activity through the AV node is responsible for determining heart rate, and this activity is dependent upon calcium influx through L-type calcium channels. By inhibiting these channels and decreasing the influx of calcium, verapamil prolongs the refractory period of the AV node and slows conduction, thereby slowing and controlling the heart rate in patients with arrhythmia.

The time taken for Verapamil to show its effect is 1-2 hours (by immediate release) and 1-5 minutes (by IV).

The Duration of action of Verapamil is approximately 6-8 hours (orally) and 10-20 minutes (by IV).

The Tmax was found within 1-2 hours (by immediate release) and 5-11 hours (extended release) of following the administration.

Verapamil is available in the form of Oral tablet, Capsule, and Injectable solution.

Verapamil tablet and capsule are taken orally once a day. Verapamil injection is taken intravenously in single and several doses.

Verapamil is a non-dihydropyridine calcium channel blocker used in the treatment of angina, arrhythmia, and hypertension. It is also used for the treatment of Chest pain associated with cocaine ingestion, with or without evidence of acute coronary syndrome, Cluster headache, Prevention, Migraine Prevention and Supraventricular tachycardia.

Verapamil is an antihypertensive agent belonging to Calcium Channel Blocker.

Verapamil inhibits entry of Calcium ions into the slow channels or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization. It relaxes coronary vascular smooth muscle and coronary vasodilation, increases myocardial oxygen delivery, and slows automaticity and AV node conduction.

• Hypertension

Adult Oral Dose

Immediate release

Initial: 40 to 80 mg 3 times daily; increase dose as needed at weekly intervals; usual dose: 120 to 360 mg/day in 3 divided doses.

Maximum dose: 480 mg/day in 3 divided doses.

Extended release:

Initial: 120 or 180 mg once daily; increase dose as needed at weekly intervals; usual dose: 120 to 360 mg/day in 1 to 2 divided doses.

Maximum dose: 480 mg/day in 1 to 2 divided doses.

Extended-release (delayed-onset/PM formulation):

Initial: 100 or 200 mg once daily at bedtime; increase dose as needed at weekly intervals; usual dose: 100 to 300 mg once daily at bedtime.

Maximum dose: 400 mg once daily at bedtime.

• Angina pectoris

Chronic stable angina (alternative agent)

Adult Oral Dose

Immediate release:

Initial: 80 to 120 mg 3 times daily; increase as needed at ≥1- to 2-day intervals to effective antianginal dose

Maximum dose: 480 mg/day in 3 divided doses.

Extended-release: Initial: 180 mg once daily; increase as needed at 7- to 14-day intervals to effective antianginal dose.

Maximum dose: 480 mg/day in 1 to 2 divided doses.

Vasospastic angina

Adult Oral Dose

Immediate release:

Initial: 80 to 120 mg 3 times daily; increase as needed at ≥1- to 2-day intervals to effective antianginal dose.

Maximum dose: 480 mg/day in 3 divided doses.

Extended-release: Initial: 180 mg once daily; increase as needed at 7- to 14-day intervals to effective antianginal dose.

Maximum dose: 480 mg/day in 1 to 2 divided doses.

• Atrial fibrillation or atrial flutter, rate control (alternative agent):

Acute ventricular rate control

Adult IV Dose

Bolus: Initial: 5 to 10 mg over ≥2 minutes; if there is an inadequate response, the dose may be repeated after 15 to 30 minutes; if there is an adequate response after 1 to 2 bolus doses, then may begin a continuous infusion.

Continuous infusion: Initial: 5 mg/hour; titrate to goal heart rate up to a maximum of 20 mg/hour.

Chronic ventricular rate control:

Adult Oral Dose

Immediate release

Initial: 40 mg 3 to 4 times daily; increase as needed to achieve rate control.

Maximum dose: 480 mg/day in 3 to 4 divided doses.

Extended-release (off-label use)

Initial: 120 or 180 mg once daily; increase as needed to achieve rate control.

Maximum dose: 480 mg/day in 1 to 2 divided doses.

• Chest pain associated with cocaine ingestion, with or without evidence of acute coronary syndrome (off-label use):

Adult IV Dose

Bolus: Initial: 2.5 to 5 mg over ≥2 minutes; may repeat after 15 minutes if needed.

• Cluster headache, prevention (off-label use):

Adult Oral Dose

Immediate release

Initial: 40 to 80 mg 3 times daily; increase dose every 1 to 2 weeks until headaches subside, or adverse reactions develop; usual effective dose: 240 to 480 mg/day in 3 to 4 divided doses.

Extended release

Initial: 240 mg in 2 divided doses; increase dose every 1 to 2 weeks until headaches subside, or adverse reactions develop; usual effective dose: 240 to 480 mg/day in 2 divided doses.

• Migraine, prevention (off-label use):

Adult Oral Dose

Immediate release

Initial: 40 mg 3 times daily; titrate every 1 to 2 weeks based on patient response and tolerability up to 480 mg/day in 3 to 4 divided doses.

Extended release

Initial: 120 mg once daily; titrate every 1 to 2 weeks based on patient response and tolerability up to 480 mg/day in 2 to 3 divided doses.

• Supraventricular tachycardia (alternative agent):

Acute treatment (off-label use):

Adult IV Dose

Bolus: Initial: 5 to 10 mg over ≥2 minutes; if the response is insufficient after 15 to 30 minutes, a second bolus dose of 10 mg over 2 minutes may be administered. If 2 bolus doses do not terminate the arrhythmia, consider alternative therapy.

Chronic maintenance:

Adult Oral Dose

Immediate release

Initial: 40 mg 3 to 4 times daily; increase as needed for heart rate control.

Maximum dose: 480 mg/day in 3 to 4 divided doses.

Extended-release (off-label use)

Initial: 120 mg once daily; increase as needed for heart rate control.

Maximum dose: 480 mg/day in 1 to 2 divided doses.

Pediatric IV Dose (off-label use)

Infants: 0.1 to 0.2 mg/kg/dose (usual: 0.75 to 2 mg/dose) may repeat dose after at least 30 minutes if response inadequate; optimal interval not defined; patient should be monitored closely.

Children and Adolescents 1 to 15 years: 0.1 to 0.3 mg/kg/dose (usual dose: 2 to 5 mg/dose); maximum dose: 5 mg/dose; may repeat dose in 15 to 30 minutes if response inadequate; maximum dose for second dose: 10 mg/dose.

Adolescents ≥16 years:

Initial dose: 0.1 to 0.3 mg/kg/dose.

Maximum dose: 5 mg/dose.

Pediatric Oral Dose (off-label use)

Children and Adolescents:

Immediate release: 2 to 8 mg/kg/day in 3 divided doses; maximum daily dose: 480 mg/day.

• Ventricular arrhythmias:

Idiopathic left ventricular tachycardia (off-label use):

Acute idiopathic left ventricular tachycardia

Adult IV Dose

Bolus: 5 to 10 mg over ≥2 minutes; if no response after 15 to 30 minutes, may give 1 additional 10 mg bolus dose.

Prevention of idiopathic left ventricular arrhythmias:

Adult Oral Dose

Immediate release: 120 mg 3 times daily.

Extended release: 240 to 480 mg/day in 1 to 2 divided doses.

Non sustained ventricular tachycardia or ventricular premature beats, symptomatic (alternative agent) (off-label use):

Adult Oral Dose

Immediate release

Initial: 80 mg 3 times daily; if needed, titrate for symptom control and tolerability.

Maximum dose: 480 mg/day in 3 to 4 divided doses.

Extended release

Initial: 240 mg/day in 1 to 2 divided doses; if needed, titrate for symptom control and tolerability.

Maximum dose: 480 mg/day in 1 to 2 divided doses.

Verapamil is available in various strengths as 40mg, 80mg, 100mg, 120mg, 180mg, 200mg, 240mg, 300mg, 360mg and 2.5mg/mL.

Consumption of grapefruit juice is not recommended while receiving Verapamil due to an increase in the risk of side effects such as dizziness, headache, and swelling of hands and feet.

Verapamil is contraindicated in patients with

● Severe hypotension or cardiogenic shock

● Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker)

● Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker)

● Severe congestive heart failure (unless secondary to a supraventricular tachycardia amenable to Verapamil therapy)

● Patients receiving intravenous beta-adrenergic blocking drugs (e.g., propranolol). Intravenous Verapamil and intravenous beta-adrenergic blocking drugs should not be administered in close proximity to each other (within a few hours), since both may have a depressant effect on myocardial contractility and AV conduction.

● Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff Parkinson-White, Lown-Ganong-Levine syndromes). These patients are at risk to develop ventricular tachyarrhythmia including ventricular fibrillation if Verapamil is administered.

● Ventricular tachycardia. Administration of intravenous Verapamil to patients with wide complex ventricular tachycardia (QRS≥ 0.12 sec) can result in marked hemodynamic deterioration and ventricular fibrillation. Proper pretherapy diagnosis and differentiation from wide-complex supraventricular tachycardia is imperative in the emergency room setting.

● Known hypersensitivity to Verapamil hydrochloride

• Heart Failure

Verapamil has a negative inotropic effect which, in most patients, is compensated by its afterload reduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In previous clinical experience with 4,954 patients primarily with immediate-release verapamil, 87 (1.8%) developed congestive heart failure or pulmonary edema. Avoid verapamil in patients with severe left ventricular dysfunction (e.g., ejection fraction less than 30% or moderate to severe symptoms of cardiac failure) and in patients with any degree of ventricular dysfunction if they are receiving a beta-adrenergic blocker. Control patients with milder ventricular dysfunction, if possible, with optimum doses of digitalis and/or diuretics before verapamil treatment is started.

• Hypotension

Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels which may result in dizziness or symptomatic hypotension. In hypertensive patients, decreases in blood pressure below normal are unusual. The incidence of hypotension observed in 4,954 patients enrolled in clinical trials of other verapamil formulations was 2.5%. In clinical studies of Verapamil, 1.7% of the patients developed significant hypotension. Tilt table testing (60 degrees) was not able to induce orthostatic hypotension.

• Elevated Liver Enzymes

Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Such elevations have sometimes been transient and may disappear even in the face of continued verapamil treatment. Several cases of hepatocellular injury related to verapamil have been proven by rechallenge; half of these had clinical symptoms (malaise, fever, and/or right upper quadrant pain) in addition to elevations of SGOT, SGPT and alkaline phosphatase. Periodic monitoring of liver function in patients receiving verapamil is therefore prudent.

• Accessory Bypass Tract (Wolff-Parkinson-White or Lown-Ganong Levine)

Some patients with paroxysmal and/or chronic atrial flutter or atrial fibrillation and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil (or digitalis). Although a risk of this occurring with oral verapamil has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated. Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral verapamil.

• Atrioventricular Block

The effect of verapamil on AV conduction and the SA node may lead to asymptomatic first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR interval prolongation is correlated with verapamil plasma concentrations, especially during the early titration phase of therapy. Higher degrees of AV block, however, were infrequently (0.8%) observed in previous verapamil clinical trials. Marked first-degree block or progressive development to second- or third-degree AV block requires a reduction in dosage or, in rare instances, discontinuation of verapamil and institution of appropriate therapy depending upon the clinical situation.

• Patients with Hypertrophic Cardiomyopathy

In 120 patients with hypertrophic cardiomyopathy, idiopathic hypertrophic subaortic stenosis (IHSS) (most of them refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. Three patients died in pulmonary edema; all had severe left ventricular outflow obstruction and a history of left ventricular dysfunction. Eight other patients had pulmonary edema and/or severe hypotension; abnormally high (over 20 mm Hg) pulmonary capillary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Concomitant administration of quinidine preceded the severe hypotension in 3 of the 8 patients (2 of whom developed pulmonary edema). Sinus bradycardia occurred in 11% of the patients, second-degree AV block in 4%, and sinus arrest in 2%. It must be appreciated that this group of patients had a serious disease with a high mortality rate. Most adverse effects responded well to dose reduction and only rarely did verapamil have to be discontinued.

Consumption of alcohol is not recommended while receiving Verapamil due to the increase in the risk of side effects such as dizziness and confusion.

Verapamil is excreted into human milk. In case studies where verapamil concentration in human milk was calculated, the nursing infant doses ranged from less than 0.01% to 0.1% of the mother's verapamil dose. Consider possible infant exposure when verapamil is administered to a nursing woman.

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 the use of the drug in pregnant women despite potential risks.

Consumption of grapefruit juice is not recommended while receiving this Verapamil due to an increase in the risk of side effects such as dizziness, headache, and swelling of hands and feet.

Common Adverse effects

Bradycardia, worsening heart failure, transient asystole, hypotension, dizziness, flushing, fatigue, headache, dyspnoea, peripheral edema, constipation, nausea, abnormal liver function, skin reactions, gingival hyperplasia, extrapyramidal symptoms. Rarely, gynecomastia, Hepatotoxicity, emotional depression, rotary nystagmus, sleepiness, vertigo, muscle fatigue, or diaphoresis.

• CYP3A4 Inhibitors and Inducers

In vitro metabolic studies indicate that verapamil is metabolized by cytochrome P450 CYP3A4, CYP1A2, and CYP2C. Clinically significant interactions have been reported with inhibitors of CYP3A4 (e.g., erythromycin, ritonavir) causing elevation of plasma levels of verapamil. Hypotension, bradyarrhythmia, and lactic acidosis have been observed in patients receiving concurrent telithromycin, an antibiotic in the ketolide class of antibiotics. Inducers of CYP3A4 (e.g., rifampin) have caused a lowering of plasma levels of verapamil.

• HMG-CoA Reductase Inhibitors

The use of HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with verapamil has been associated with reports of myopathy/rhabdomyolysis. Co-administration of multiple doses of 10 mg of verapamil with 80 mg simvastatin resulted in exposure to simvastatin 2.5-fold that following simvastatin alone. Limit the dose of simvastatin in patients on verapamil to 10 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required as verapamil may increase the plasma concentration of these drugs.

• Grapefruit Juice

Grapefruit juice may significantly increase concentrations of verapamil. Grapefruit juice given to nine healthy volunteers increased S- and R- verapamil AUC0-12 by 36% and 28%, respectively. Steady-state Cmax and Cmin of S-verapamil increased by 57% and 16.7%, respectively with grapefruit juice compared to control. Similarly, Cmax and Cmin of R-verapamil increased by 40% and 13%, respectively. Grapefruit juice did not affect half-life, nor was there a significant change in AUC0-12 ratio R/S compared to control. Grapefruit juice did not cause a significant difference in the pharmacokinetics of norverapamil. This increase in verapamil plasma concentration is not expected to have any clinical consequences.

• Beta Blockers

Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular conduction, and/or cardiac contractility. The combination of extended-release verapamil and beta-adrenergic blocking agents has not been studied. However, there have been reports of excess bradycardia and AV block, including complete heart block, when the combination has been used for the treatment of hypertension. For hypertensive patients, the risk of combined therapy may outweigh the potential benefits. The combination should be used only with caution and close monitoring. Asymptomatic bradycardia (36 beats/ min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eyedrops and oral verapamil. A decrease in metoprolol and propranolol clearance has been observed when either drug is administered concomitantly with verapamil. A variable effect has been seen when verapamil and atenolol were given together.

• Digitalis

Consider reducing digoxin dose when verapamil and digoxin are to be given together. Monitor digoxin level periodically during therapy. Chronic verapamil treatment can increase serum digoxin levels by 50% to 75% during the first week of therapy, and this can result in digitalis toxicity. In patients with hepatic cirrhosis the influence of verapamil on digoxin pharmacokinetics is magnified. Verapamil may reduce total body clearance and extra-renal clearance of digitoxin by 27% and 29%, respectively. If digoxin toxicity is suspected, suspend or discontinue digoxin therapy. In previous clinical trials with other verapamil formulations related to the control of ventricular response in patients taking digoxin who had atrial fibrillation or atrial flutter, ventricular rates below 50/min at rest occurred in 15% of patients, and asymptomatic hypotension occurred in 5% of patients.

• Alcohol

Verapamil has been found to significantly inhibit ethanol elimination resulting in elevated blood ethanol concentrations that may prolong the intoxicating effects of alcohol.

• Clonidine

Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with verapamil. Monitor heart rate in patients receiving concomitant verapamil and clonidine.

• Telithromycin

Hypotension and bradyarrhythmia have been observed in patients receiving concurrent telithromycin, an antibiotic in the ketolide class of antibiotics.

• Antineoplastic Agents

Verapamil can increase doxorubicin levels. The absorption of verapamil can be reduced by the cyclophosphamide, oncovin, procarbazine, prednisone (COPP), and the vindesine, adriamycin, cisplatin (VAC) cytotoxic drug regimens. Concomitant administration of R verapamil can decrease the clearance of paclitaxel.

• Quinidine

In a small number of patients with hypertrophic cardiomyopathy, concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, avoid combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy. The electrophysiological effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil significantly counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during verapamil therapy.

• Aspirin

In a few reported cases, coadministration of verapamil with aspirin has led to increased bleeding times greater than observed with aspirin alone.

• Antihypertensive agents

Verapamil administered concomitantly with oral antihypertensive agents (e.g., vasodilators, angiotensin-converting enzyme inhibitors, diuretics, beta-blockers) will usually have an additive effect on lowering blood pressure. Monitor patients receiving these combinations appropriately. Concomitant use of agents that attenuate alpha-adrenergic function with verapamil may result in a reduction in blood pressure that is excessive in some patients. Such an effect was observed in one study following the concomitant administration of verapamil and prazosin.

• Disopyramide

Until data on possible interactions between verapamil and disopyramide are obtained, do not administer disopyramide within 48 hours before or 24 hours after verapamil administration.

• Flecainide

A study in healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction.

• Carbamazepine

Verapamil therapy may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness.

• Cyclosporine

Verapamil therapy may increase serum levels of cyclosporine.

• Lithium

Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy with either no change or an increase in serum lithium levels. However, the addition of verapamil has also resulted in the lowering of serum lithium levels in patients receiving chronic stable oral lithium. Patients receiving both drugs must be monitored carefully.

• Inhalation Anesthetics

Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, titrate slowly to avoid excessive cardiovascular depression.

• Neuromuscular Blocking Agents

Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly.

• Phenobarbital

Phenobarbital therapy may increase verapamil clearance.

• Rifampin

Therapy with rifampin may markedly reduce oral verapamil bioavailability.

• Theophylline

Verapamil may inhibit the clearance and increase the plasma levels of theophylline.

• Cimetidine

The interaction between cimetidine and chronically administered verapamil has not been studied. Variable results on clearance have been obtained in acute studies of healthy volunteers; clearance of verapamil was either reduced or unchanged

• Nitrates

Verapamil has been given concomitantly with short- and long-acting nitrates without any undesirable drug interactions. The pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions.

The common side effects of Verapamil include the following

• Common
  

Nausea, constipation; headache, dizziness; or low blood pressure

• Rare

Chest pain, fast or slow heart rate, a light-headed feeling, shortness of breath (even with mild exertion), swelling, rapid weight gain, fever, upper stomach pain, not feeling well; or lung problems-anxiety, sweating, pale skin, wheezing, gasping for breath, cough with foamy mucus.

• Pregnancy

Pregnancy Category C.

Reproduction studies have been performed in rabbits and rats at oral doses up to 1.9 (15 mg/kg/day) and 7.5 (60 mg/kg/day) times the human oral daily dose, respectively, and have revealed no evidence of teratogenicity. In the rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects reflected in reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats. There are no adequate and well-controlled studies in pregnant women. Verapamil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery.

• Nursing Mothers

Verapamil is excreted into human milk. In case studies where verapamil concentration in human milk was calculated, the nursing infant doses ranged from less than 0.01% to 0.1% of the mother's verapamil dose. Consider possible infant exposure when verapamil is administered to a nursing woman.

• Geriatric Use

Clinical studies of Verapamil were not adequate to determine if subjects aged 65 or over respond differently from younger patients. Other reported clinical experience has not identified differences in response between the elderly and younger patients; however, greater sensitivity to Verapamil by some older individuals cannot be ruled out.

Symptoms: Bradycardia, hypotension, conduction abnormalities, hyperglycemia, hyperkalemia, metabolic acidosis, renal dysfunction, seizures, impaired conduction, ECG changes, arrhythmias, shock, altered mental status, and cardiac arrest.

Management: Symptomatic and supportive treatment. Place patient Trendelenburg's position and admin IV fluids. Hypotension may be treated w/ IV Ca salts or a vasopressor agent. Bradycardia or fixed 2nd- or 3rd-degree AV block may be treated w/ norepinephrine, IV atropine, isoproterenol, Calcium salt, or a temporary cardiac pacemaker. Consider endoscopy in cases of large overdoses.

• Pharmacodynamic

Verapamil is an L-type calcium channel blocker with antiarrhythmic, antianginal, and antihypertensive activity. Immediate-release verapamil has a relatively short duration of action, requiring dosing 3 to 4 times daily, but extended-release formulations are available that allow for once-daily dosing. As verapamil is a negative inotropic medication (i.e., it decreases the strength of myocardial contraction), it should not be used in patients with severe left ventricular dysfunction or hypertrophic cardiomyopathy as the decrease in contractility caused by verapamil may increase the risk of exacerbating these pre-existing conditions.

• Pharmacokinetics

Absorption

Verapamil well absorbed from the GI tract. Bioavailability is approximately 20-35% (oral). Time to peak plasma concentration: 1-2 hours (oral).

Distribution

Crosses the placenta; enters breast milk. The volume of distribution: 3.89 L/kg. Plasma protein binding: Approx 90%.

Metabolism and Excretion

Extensively metabolized hepatically to at least 12 metabolites (e.g., nor verapamil as primary metabolites). Excreted Via urine (70% as metabolites, 3-4% as unchanged drug) feces (16%). Terminal half-life: 2-8 hr; increases to 4.5-12 hr (after oral repeated dose).

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/018925s010lbl.pdf
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020943s028lbl.pdf
• https://www.uptodate.com/contents/verapamil-drug-information?search=verapamil&source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1
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