1. VERAPAMIL HISTORY
(How was Verapamil discovered?)

Verapamil is a product of Genpharm Inc.

From its modest beginnings in 1983 as an R&D facility, Genpharm has grown to be one of Canada 's top 20 pharmaceutical companies. Today, Genpharm Inc. is a leading manufacturer of generic pharmaceuticals, with prescription products encompassing all major therapeutic classes. Genpharm's Hospital Division supplies an expanding range of equipment and pharmaceuticals for renal dialysis and is quickly becoming recognized as a leader in this field.

Genpharm Inc. is one of many affiliated companies, which comprise the worldwide group of Merck Generics, a subsidiary of Merck KGaA, the oldest pharmaceutical company in the world.

Note: World-drugs.net sells generic version of Verapamil

2. VERAPAMIL FACTS

Verapamil is a medical drug that acts as an L-type calcium channel blocker. Verapamil is used in the treatment of hypertension, angina pectoris, and some types of arrhythmia.

3. ABOUT VERAPAMIL MEDICATION

What is High Blood Pressure (Hypertension)?

High blood pressure, also known as hypertension, is a serious disease affecting your heart and blood vessels. It occurs when the blood exerts too much pressure against the walls of the blood vessels. In fact, that is what the term hypertension means: "too much" (hyper) "pressure" (tension). It affects upwards of 58 million people nationwide.

High blood pressure is serious because it places you at risk for certain life threatening and disabling conditions. If left untreated, High blood pressure could lead to heart attack, kidney disease, and/or stroke.

This happens because as your blood continuously exerts too much pressure against the walls of the blood vessels, it places extra stress on the heart and blood vessels.

Blood pressure is measured in two numbers, systolic (top or higher number) and diastolic (lower number). The higher number is the maximum pressure, which occurs when the heart beats (systole), and the lower number is the lowest pressure measured when the heart relaxes between beats (diastole), just before the next contraction. A systolic reading of 140 or greater and a diastolic reading of 90 or greater is considered high.

The normal blood pressure is less than 120/80. In fact, for every 20/10 increase in blood pressure, your risk of cardiovascular events, such as heart attack or stroke, is DOUBLED.

 

Symptoms of High Blood Pressure

High blood pressure is sometimes called the "silent killer" because the symptoms are rarely seen or felt. So, even though it might be upsetting to be told that you have High blood pressure, it's good that your doctor has discovered it. Treatment can help avoid the serious, long-term effects of High blood pressure.

What are antihypertensives?

Antihypertensives are medications used to treat High blood pressure (hypertension). Although some patients do not need to take medication to control their High blood pressure, anyone who is prescribed medication needs to take it exactly as prescribed to avoid the serious medical problems associated with the condition. People taking Antihypertensives are also encouraged to make healthy lifestyle changes, such as quitting smoking, losing weight and getting regular exercise. Furthermore, they are encouraged to speak with their physician before taking any prescription medications, such as narcotics, or over-the-counter medications, such as diet pills.

Finally, people with High blood pressure are urged to be patient as the type and level of their medication are adjusted for optimal results. This is especially important because the vast majority of patients have no symptoms, making hypertension the silent killer.

There are a wide variety of Antihypertensives and combinations of different medications that are available, and it may take some time before the ideal treatment has been found and finely tuned to the patients needs.

Antihypertensives include:

Diuretics ("water pills")
Diuretics are sometimes called "water pills" because they work in the kidney and flush excess water and sodium from the body.

Beta Blockers
Beta-blockers reduce nerve impulses to the heart and blood vessels. This makes the heart beat slower and with less force. Blood pressure drops and the heart works less hard.

Alpha Blockers
Alpha-blockers reduce nerve impulses to blood vessels, which allows blood to pass more easily, causing the blood pressure to go down.

Alpha-Beta Blockers
Alpha-beta-blockers work the same way as alpha-blockers but also slow the heartbeat, as beta-blockers do. As a result, less blood is pumped through the vessels and the blood pressure goes down.

Nervous System Inhibitors
Nervous system inhibitors relax blood vessels by controlling nerve impulses. This causes the blood vessels to become wider and the blood pressure to go down.

Angiotensin Converting Enzyme (ACE) Inhibitors
Angiotensin converting enzyme (ACE) inhibitors prevent the formation of a hormone called angiotensin II, which normally causes blood vessels to narrow. The ACE inhibitors cause the vessels to relax and blood pressure goes down.

Calcium Channel Blockers
CCBs keep calcium from entering the muscle cells of the heart and blood vessels. This causes the blood vessels to relax and pressure goes down.

Angiotensin Receptor Blockers (formal medical name angiotensin-2-receptor antagonists, known as "sartans" for short). These agents are sometimes prescribed together, for instance an ACE inhibitor along with a calcium channel blocker.

Angiotensin antagonists shield blood vessels from angiotensin II. As a result, the vessels become wider and blood pressure goes down.

Common calcium channel blockers include:

• Amlodipine
• Diltiazem
• Verapamil
• Felodipine
• Isradipine
• Nicardipine
• Nifedipine

In general, antihypertensives work through one or more of the following mechanisms:

Verapamil

Verapamil is an antihypertensive chemically belonging to the class of medications called calcium channel blockers.

Verapamil is used alone or in combination with other medications to treat High blood pressure and chest pain (angina).

Verapamil acts specifically on the muscle cells in the walls of arteries, causing them to relax. This allows the arteries in the body to widen, an effect that has two main uses.

The relaxing and widening of the small arteries in the body decreases the resistance that the heart has to push against in order to pump the blood around the body. This reduces the pressure within the blood vessels. Verapamil can therefore be used to treat High blood pressure.

The widening effect on the small arteries and the arteries in the heart also improves the blood and therefore oxygen supply to the heart. This feature means Verapamil can be used to treat angina. The chest pain of angina is caused by insufficient oxygen supply to the heart. As Verapamil improves this oxygen supply, and also reduces the effort the heart has to make to pump blood, it can be taken regularly to prevent angina attacks 

 

Verapamil works by slowing the movement of calcium through the muscle cells that are found in the walls of blood vessels. Verapamil does this by blocking 'calcium channels' in these muscle cells. Calcium is needed by muscle cells in order for them to contract, so by depriving them of calcium, Verapamil causes the muscle cells to relax.

WORKING OF CALCIUM CHANNEL BLOCKERS

Substances in the body can make the arteries narrower. One of these substances is calcium. Calcium enters through special channels and makes the smooth muscle tighten. The artery becomes narrower and blood pressure increases.

Verapamil is a calcium channel blocker. Verapamil blocks the channels that calcium uses to enter muscle cells lining the artery. When calcium is blocked, the muscle relaxes. The artery widens and blood pressure goes down. 

Causes of High Blood Pressure

There are 2 main types of High blood pressure:

[1] Primary, Essential or Idiopathic. These 3 words all mean the same, & are medical terms for "unknown cause". 90% of cases of hypertension are of unknown cause.

There are a number of things that make it worse, one being stress & another being clogged arteries. Just like when a pipe is partly blocked with gunk it needs higher pressure to get fluid through it, so if your arteries are clogged with fat your heart steps up the pressure to get the blood through. A third factor is overweight. If you are too big you have a larger volume of small blood vessels so the heart has to pump harder & raise the pressure to supply them. A fourth is nicotine, a chemical in tobacco, which narrows arteries & so raises the pressure needed to get the blood through them. 

[2] Secondary hypertension . This means the High blood pressure is due to some known cause. Only 10% of cases have a known cause.

Some of these are:

[a] Kidney disease. If one of the kidneys has narrowing of the artery bringing its blood supply, or has damaged tubules, which can't handle your fluid & salt, you may get hypertension.

[b] Adrenal disease. The adrenal glands are a pair of small organs on the top of your kidneys. They produce lots of chemicals or hormones, which control salt & sugar in the body. One such hormone is aldosterone. This conserves salt, & if it conserves too much the blood pressure rises. Another is corticosteroid or steroid hormone. Too much of this will cause weight gain & grow too much body hair. This too can produce hypertension.

Another part of your adrenal gland produces adrenalin & nor-adrenalin. These are stress hormones, also called 'fight or flight' hormones. They will spit out adrenalin to make the heart pump faster, so more blood will go to your muscles ready for you to fight or run.

[c] Parathyroid disease. These are tiny glands in the neck, which produce a hormone controlling the calcium in your blood & bones. If they over act & pull too much calcium out of your bones into your blood, they may damage the kidneys or constrict your arteries causing High blood pressure.

[d] Other rare causes: The pituitary, a small gland at the base of the brain, produces growth hormone. Too much of this can make you grow to 7 feet or more [2.3 metres], or if it doesn't overact till late in life it can make your bones grow thicker instead of taller. It can also cause hypertension. There are other causes, like lead poisoning or aortic coarctation. 

4.VERAPAMIL EFFECTIVENESS
(When is Verapamil best taken?)

With the immediate-release formulation, more than 90% of the orally administered dose of Verapamil is absorbed. Because of rapid biotransformation of Verapamil dose during its first pass through the portal circulation, bioavailability ranges from 20% to 35%. Peak plasma concentrations are reached between 1 and 2 hours after oral administration. Chronic oral administration of 120 mg dose of Verapamil every 6 hours resulted in plasma levels of Verapamil ranging from 125 to 400 ng/ml, with higher values reported occasionally. A nonlinear correlation between the Verapamil dose administered and Verapamil plasma levels does exist. In early dose titration with Verapamil a relationship exists between Verapamil plasma concentration and prolongation of the PR interval. However, during chronic administration this relationship may disappear. The mean elimination half-life in single-doses studies ranged from 2.8 to 7.4 hours. In these same studies, after repetitive dosing, the half-life increased to a range from 4.5 to 12.0 hours (after less than 10 consecutive doses given 6 hours apart). Half-life of Verapamil may increase during titration. No relationship has been established between the plasma concentration of Verapamil and a reduction in blood pressure.

In a randomized, single-dose, crossover study using healthy volunteers, administration of 240 mg Verapamil sustained-release with food produced peak plasma Verapamil concentrations of 79 ng/ml; time to peak plasma Verapamil concentration of 7.71 hours; and AUC (0-24 hr) of 841 ng·hr/ml. When Verapamil, sustained-release caplets were administered to fasting subjects, peak plasma Verapamil concentration was 164 ng/ml; time to peak plasma Verapamil concentration was 5.21 hours; and AUC (0-24 hr) was 1478 ng·hr/ml. Similar results were demonstrated for plasma norverapamil. Food thus produces decreased bioavailability (AUC) but a narrower peak-to-trough ration. Good correlation of dose and response is not available, but controlled studies of Verapamil sustained-release caplets have shown effectiveness of doses similar to the effective doses of Verapamil (immediate release).

In healthy men, orally administered Verapamil undergoes extensive metabolism in the liver. Twelve metabolites have been identified in plasma; all except norverapamil are present in trace amounts only. Norverapamil can reach steady-state plasma concentrations approximately equal to those of Verapamil itself. The cardiovascular activity of norverapamil appears to be approximately 20% that of Verapamil. Approximately 70% of an administered dose is excreted as metabolites in the urine and 16% or more in the feces within 5 days. About 3% to 4% is excreted in the urine as unchanged drug. Approximately 90% is bound to plasma proteins. In patients with hepatic insufficiency, metabolism of immediate-release Verapamil is delayed and elimination half¾ life prolonged up to 14 to 16 hours: the volume of distribution is increased and plasma clearance reduced to about 30% of normal. Verapamil clearance values suggest that patients with liver dysfunction may attain therapeutic Verapamil plasma concentrations with one third of the oral daily dose of Verapamil required for patients with normal liver function.

In randomized, single dose, crossover studies using healthy volunteers, administration of Verapamil extended-release tablets with food produced lower peak concentrations, delayed time to peak, and lesser total absorption (AUC), than when the product was administered to fasting subjects. Similar results were demonstrated for plasma norverapamil. Food thus produces decreased bioavailability (AUC) but a narrower peak to trough ratio. Good correlation of dose and response is not available, but controlled studies of extended-release Verapamil have shown effectiveness of doses similar to the effective doses of immediate-release Verapamil. 

5.VERAPAMIL EFFECTS ON SPECIAL POPULATION
(How do different people react to Verapamil?)

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Verapamil should be used during pregnancy only if clearly needed. Verapamil crosses the placental barrier and can be detected in umbilical blood at delivery.

Labor and Delivery

It is not known whether the use of Verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite a long history of use of Verapamil in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor.

Nursing Mothers

Verapamil is excreted in human milk. Because of the potential for adverse reactions in nursing infants from Verapamil, nursing should be discontinued while Verapamil is administered.

Pediatric Use

Safety and efficacy of Verapamil in pediatric patients below the age of 18 years have not been established.

Geriatric Use

Clinical studies of Verapamil, extended-release, controlled-onset capsules 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, extended-release, controlled-onset capsules by some older individuals cannot be ruled out.

Aging may affect the pharmacokinetics of Verapamil. Elimination half-life may be prolonged in the elderly.

Verapamil is highly metabolized by the liver, and about 70% of the administered dose is excreted as metabolites in the urine. Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered. In general, lower initial doses of Verapamil, extended-release, and controlled-onset capsules may be warranted in the elderly.

6.VERAPAMIL EFFECTS ON MEDICAL CONDITIONS
(How does Verapamil affect your existing condition/ailment?)

Verapamil should not be used if you suffer from irregular heartbeats (arrhythmias), low blood pressure (hypotension), life long inherited blood diseases which can cause a variety of symptoms, bradycardia (slow heart rate of less than 50 beats per minute, heart failure or cardiogenic shock. 

7.OTHER/ALTERNATE USES OF VERAPAMIL
(What else does Verapamil treat?)

Verapamil is generally effective for migraine but it takes about 2 weeks to work. Verapamil is effective in migraine variants such as hemiplegic migraine. Verapamil also may be helpful in Menieres disease, although this has not yet been documented by a controlled study.

8.ADVERSE/SIDE EFFECTS of VERAPAMIL
(What are the side effects of Verapamil?)

Serious adverse reactions are uncommon when Verapamil therapy is initiated with upward dose titration within the recommended single and total daily dose. Reversible (upon discontinuation of Verapamil) non-obstructive, paralytic ileus has been infrequently reported in association with the use of Verapamil. Reactions to orally administered Verapamil occurred at rates greater than 1.0% or occurred at lower rates but appeared clearly drug-related in clinical trials in 4954 patients are shown below.

Constipation	7.3%
Dizziness	3.3%
Nausea	2.7%
Hypotension	2.5%
Headache	2.2%
Edema	1.9%
CHF, Pulmonary edema	1.8%
Fatigue	1.7%
Dyspnea	1.4%
Bradycardia (HR <50/min)	1.4%
AV block total	1.2%
Rash	1.2%
Flushing	0.6%

In clinical trials related to the control of ventricular response in digitalized patients who had atrial fibrillation or flutter, ventricular rates below 50/min at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5% of patients.

Additional Information for Verapamil, Sustained-Release, Controlled-Release: The following reactions, reported in 2.0% or less of patients, occurred under conditions (open trials, marketing experience) where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship.

Cardiovascular: Angina pectoris, atrioventricular dissociation, chest pain, claudication, myocardial infarction, palpitations, purpura (vasculitis), syncope.

Digestive System: Diarrhea, dry mouth, gastrointestinal distress, gingival hyperplasia.

Hemic and Lymphatic: Ecchymosis or bruising.

Nervous System: Cerebrovascular accident, confusion, equilibrium disorders, insomnia, muscle cramps, paresthesia, psychotic symptoms, shakiness, somnolence.

Respiratory: Dypnea.

Skin: Arthralgia and rash, exanthema, hair loss, hyperkeratosis, macules, sweating urticaria, Stevens-Johnson syndrome, erythema multiforme.

Special Senses: Blurred vision, tinnitus.

Urogenital: Gynecomastia, galactorrhea/hyperprolactinemia, increased urination, spotty menstruation, impotence.

The following reactions to orally administered Verapamil, extended-release, controlled-onset capsules shown in table below occurred at rates of 2.0% or greater or occurred at lower rates but appeared to be drug-related in clinical trials in hypertension.

	Placebo N=116 %	All Doses Studied N=297 %
Headache	11.2	12.1
Infection	6.9	12.1
Constipation	0.9	8.8
Flu Syndrome	2.6	3.7
Peripheral edema	0.9	3.7
Dizziness	0.9	3.0
Pharyngitis	2.6	3.0
Sinusitis	2.6	3.0
Dyspepsia	1.7	2.7
Rhinitis	2.6	2.7
Diarrhea	1.7	2.4
Pain	1.7	2.4
Rash	2.6	2.4
Asthenia	3.4	2.0
ECG Abnormal	3.4	2.0
Hypertension	2.0	1.7
Edema	0.0	1.7
Nausea	0.0	1.7
Accidental Injury	0.0	1.5