1. AMLODIPINE HISTORY

How was Amlodipine discovered?
Amlodipine was discovered by a research team lead by Simon Campbell.

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

2. AMLODIPINE FACTS

Amlodipine Besylate is a white crystalline powder with a molecular weight of 567.1. It is slightly soluble in water and sparingly soluble in ethanol. Amlodipine tablets are generally formulated as white tablets equivalent to 2.5, 5 and 10 mg of amlodipine for oral administration. In addition to the active ingredient, Amlodipine, each tablet contains the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and magnesium stearate

3. ABOUT AMLODIPINE 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 allow 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
• Felodipine
• Isradipine
• Nicardipine
• Nifedipine
• Verapamil

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

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

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

Amlodipine 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. Amlodipine 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 Amlodipine can be used to treat angina. The chest pain of angina is caused by insufficient oxygen supply to the heart. As Amlodipine 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.

 

Amlodipine works by slowing the movement of calcium through the muscle cells that are found in the walls of blood vessels. Amlodipine 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, Amlodipine 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.

Amlodipine is a calcium channel blocker. Amlodipine 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, but these are rare and would in all probability be easy to pin down as the reason for high blood pressure.

4. AMLODIPINE EFFECTIVENESS

When is Amlodipine best taken?
After oral administration of therapeutic doses of Amlodipine, absorption produces peak plasma concentrations between 6 and 12 hours.

Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of Amlodipine is not altered by the presence of food.

Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Elimination from the plasma is biphasic with a terminal elimination half-life of about 30-50 hours. Steady-state plasma levels of Amlodipine are reached after 7 to 8 days of consecutive daily dosing.

The pharmacokinetics of Amlodipine is not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.

5. AMLODIPINE EFFECTS ON SPECIAL POPULATION

How do different people react to Amlodipine?
Pregnancy Category C : No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats or rabbits were treated orally with up to 10-mg/kg amlodipine during their respective periods of major organogenesis. However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats administered 10-mg/kg amlodipine for 14 days before mating and throughout mating and gestation. Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose. There are no adequate and well-controlled studies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers : It is not known whether amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while Amlodipine is administered.

Pediatric Use : Safety and effectiveness of Amlodipine in children have not been established.

Geriatric Use : Clinical studies of amlodipine did not include sufficient numbers of subject's 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. Elderly patients have decreased clearance of Amlodipine with a resulting increase of AUC of approximately 40-60%, and a lower initial dose may be required.

6. AMLODIPINE EFFECTS ON MEDICAL CONDITIONS

How does Amlodipine affect your existing condition/ailment?
Use in Patients with Congestive Heart Failure : In general, calcium channel blockers should be used with caution in patients with heart failure. Amlodipine (5-10 mg per day) has been studied in a placebo-controlled trial of 1153 patients. Follow-up was at least 6 months, with a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure).

Beta-Blocker Withdrawal : Amlodipine is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be by gradual reduction of the dose of beta-blocker.

Patients with Hepatic Failure : Since the liver extensively metabolizes Amlodipine and the plasma elimination half-life (t 1/2) is 56 hours in patients with impaired hepatic function, caution should be exercised when administering Amlodipine to patients with severe hepatic impairment.

7. OTHER/ALTERNATE USES OF AMLODIPINE

What else does Amlodipine treat?
Amlodipine may be used for other purposes if prescribed by your physician.

8. ADVERSE/SIDE EFFECTS of AMLODIPINE
What are the side effects of Amlodipine?

Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. In general, treatment with Amlodipine was well tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with Amlodipine were of mild or moderate severity.

In controlled clinical trials directly comparing Amlodipine (N=1730) in doses up to 10 mg to placebo (N=1250), discontinuation of Amlodipine due to adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%).

The most common side effects of Amlodipine are headache and edema. The incidence (%) of side effects of Amlodipine, which occurred in a dose, related manner are as follows:

Adverse Event	2.5 mg N=275	5.0 mg N=296	10.0 mg N=268	Placebo N=520
Edema	1.8	3.0	10.8	0.6
Dizziness	1.1	3.4	3.4	1.5
Flushing	0.7	1.4	2.6	0.0
Palpitation	0.7	1.4	4.5	0.6

Other adverse experiences, which were not clearly dose related, but which were reported with an incidence greater than 1.0% in placebo-controlled clinical trials include the following:

Placebo-Controlled Studies
	AMLODIPINE (%) (N=1730)	PLACEBO (%) (N=1250)
Headache	7.3	7.8
Fatigue	4.5	2.8
Nausea	2.9	1.9
Abdominal Pain	1.6	0.3
Somnolence	1.4	0.6

For several adverse experiences that appear to be drug and dose related, there was a greater incidence in women than men associated with Amlodipine treatment as shown in the following table

AMLODIPINE PLACEBO ADR M=% (N=1218) F=% (N=512) M=% (N=914) F=% (N=336) Edema 5.6 14.6 1.4 5.1 Flushing 1.5   4.5 0.3 0.9 Palpitations 1.4   3.3 0.9 0.9 Somnolence 1.3   1.6 0.8 0.3

The following events occurred in patients in controlled clinical trials or under conditions of open trials or marketing experience where a casual relationship is uncertain; they are listed to alert the physician to a possible relationship:

Cardiovascular : Arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis.

Central and Peripheral Nervous System : Hypoesthesia, neuropathy peripheral, paresthesia, tremor, and vertigo.

Gastrointestinal: anorexia, constipation, dyspepsia, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.

General : allergic reaction, asthenia, back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease.

Musculoskeletal System : arthralgia, arthrosis, muscle cramps, myalgia.

Psychiatric : sexual dysfunction (male and female), insomnia, nervousness, depression, abnormal dreams, anxiety, and depersonalization.

Respiratory System : dyspnea, epistaxis.

Skin and Appendages : angioedema, erythema multiforme, pruritus, rash, rash erythematous, rash maculopapular.

These events occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies.

Special Senses : abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus.

Urinary System : micturition frequency, micturition disorder, nocturia.

Autonomic Nervous System : dry mouth, sweating increased.

Metabolic and Nutritional : Hyperglycemia, thirst.

Hemopoietic : leukopenia, purpura, thrombocytopenia.

The following events occurred in few patients: cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, and abnormal visual accommodation.

Other reactions occurred sporadically and cannot be distinguished from medications or concurrent disease states such as myocardial infarction and angina.

Amlodipine therapy has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine.

The following postmarketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In postmarketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis) in some cases severe enough to require hospitalization have been reported in association with use of Amlodipine.

Amlodipine has been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart failure, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.