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High Blood Pressure Medication Side Effects

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Amlodipine, sold under the brand name Norvasc among others, is a medication used to treat high blood pressure and coronary artery disease. While calcium channel blockers are not typically recommended in heart failure, amlodipine may be used if other medications are not sufficient for high blood pressure or heart related chest pain. Amlodipine is taken by mouth and has an effect for at least a day.

Common side effects include: swelling, feeling tired, abdominal pain, and nausea. Serious side effects may include low blood pressure or a heart attack. It is unclear if use is safe during pregnancy or breastfeeding. Doses should be decreased in people with liver problems and in elderly individuals. Amlodipine is a long acting calcium channel blocker of the dihydropyridine type. It works partly by increasing the size of arteries.

Amlodipine was first patented in 1986 with commercial sale beginning in 1990. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. It is available as a generic medication. Wholesale cost in the developing world is 0.003 to 0.066 USD per day for a typical dose as of 2015. In the United States, a month's supply costs less than 25 USD.


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Medical uses

Amlodipine is used in the management of hypertension and coronary artery disease in people with either stable angina (where chest pain occurs mostly after physical or emotional stress) or vasospastic angina (where it occurs in cycles) and without heart failure. It can be used as either monotherapy or combination therapy for the management of hypertension or coronary artery disease. Amlodipine can be administered to adults and children 6-17 years of age.

Combination therapy

Amlodipine can be given as a combination therapy with a variety of medications:

  • Amlodipine/atorvastatin, where amlodipine is given for hypertension or CAD and atorvastatin prevents cardiovascular events, or if the person also has high cholesterol.
  • Amlodipine/aliskiren or amlodipine/aliskiren/hydrochlorothiazide if amlodipine alone cannot reduce blood pressure. Aliskiren is a renin inhibitor, which works to reduce primary hypertension (that with no known cause) by binding to renin and preventing it from initiating the renin-angiotensin system (RAAS) pathway to increase blood pressure. Hydrochlorothiazide is a diuretic and decreases overall blood volume.
  • Amlodipine/benazepril if either drug has failed individually, or amlodipine alone caused edema. Benazepril is an ACE inhibitor and blocks the conversion of angiotensin I to angiotensin II in the RAAS pathway.
  • Amlodipine/olmesartan or amlodipine/olmesartan/hydrochlorothiazide if amlodipine is insufficient in reducing blood pressure. Olmesartan is an angiotensin II receptor antagonist and blocks part of the RAAS pathway.
  • Amlodipine/perindopril if using amlodipine alone caused edema. Perindopril is a long-lasting ACE inhibitor.
  • Amlodipine/telmisartan, where telmisartan is an Angiotensin II receptor antagonist.
  • Amlodipine/valsartan or amlodipine/valsartan/hydrochlorothiazide, where valsartan is an angiotensin II receptor antagonist.

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Contraindications

The only absolute contraindication to amlodipine is an allergy to amlodipine or any other dihydropyridines. There are several other situations, however, where amlodipine generally should not be used. In patients with cardiogenic shock, where the heart's ventricles are not able to pump enough blood, calcium channel blockers exacerbate the situation by preventing the flow of calcium ions into cardiac cells, which is required for the heart to pump. While it is generally safe to use in patients with aortic stenosis (narrowing of the aorta where it meets the left ventricle) since it doesn't inhibit the ventricle's function, it can still cause collapse in cases of severe stenosis. In unstable angina (excluding variant angina), amlodipine can cause a reflex increase in cardiac contractility (how hard the ventricles squeeze) and heart rate, which together increase the demand for oxygen by the heart itself. Patients with severe hypotension can have their low blood pressure exacerbated, and patients in heart failure can get pulmonary edema. Those with impaired liver function are unable to metabolize amlodipine to its full extent, giving it a longer half-life.

Amlodipine's safety in pregnancy hasn't been established, although it is known that there is reproductive toxicity at high doses. It is unknown whether amlodipine enters the milk of breastfeeding mothers.


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Adverse effects

Some common dose-dependent side effects of amolodipine include vasodilatory effects peripheral edema, dizziness, palpitations, and flushing. Peripheral edema (fluid accumulation in the tissues) occurs at rate of 10.8% at a 10 mg dose (versus 0.6% for placebos), and is three times more likely in women than in men. Amlodipine causes more dilation in the arterioles and precapillary vessels than the postcapillary vessels and venules. The increased dilation allows for more blood, which is unable to push through to the relatively constricted postcapillary venules and vessels; the pressure caused much of the plasma to move into the interstitial space. Amlodipine-association edema can be avoided by adding ACE inhibitors or angiontensin II. na Of the other dose-dependent side effects, both palpitations (4.5% at 10 mg vs. 0.6% in placebos) and flushing (2.6% vs. 0%) occurred more often in women; dizziness (3.4% vs. 1.5%) had no sex-bias.

Common but non-dose related side effects are fatigue (4.5% vs. 2.8% with a placebo), nausea (2.9% vs. 1.9%), abdominal pain (1.6% vs. 0.3%), and somnolence (1.4% vs. 0.6%).Some side effects are quite rare, occurring less than 1% of the time: blood disorders, impotence, depression, insomnia, tachycardia, or gingival enlargement, hepatitis, and jaundice.


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Overdose

Although rare, amlodipine overdose toxicity can result in widening of blood vessels, severe low blood pressure, and fast heart rate. Toxicity is generally managed with fluid replacement monitoring ECG results, vital signs, respiratory system function, glucose levels, kidney function, electrolyte levels, and urine output.Vasopressors are also administered when low blood pressure is not alleviated by fluid resuscitation).


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Interactions

Several drugs interact with amplodipine to increase levels of amlodipine in the body. CYP3A inhibitors, by nature of inhibiting the enzyme that metabolizes amlodipine, CYP3A4, is one such drug. Others include the calcium-channel blocker diltiazem, the antibiotic clarithromycin, and possibly some antifungals. Amlodipine also causes several drugs to increase in levels, including cyclosporine, simvastatin, and tacrolimus (the increase in the last one being more likely in people with CYP3A5*3 genetic polymorphisms). When more than 20 mg of simvastatin, a lipid-lowering agent, is given with amlodipine, there is also an increased risk of myopathy. Giving amlodipine with Viagra increases the risk of hypotension.


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Pharmacology

Mechanism of action

Amlodipine an angioselective calcium channel blocker and inhibits the movement of calcium ions into vascular smooth muscle cells and cardiac muscle cells. The ability of cardiac muscle and vascular smooth muscle to contract is dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes, with a greater effect on vascular smooth muscle cells. This causes vasodilation and a reduction peripheral vascular resistance, thus lowering blood pressure. Its effects on cardiac muscle also prevents excessive constriction in the coronary arteries.

Negative inotropic effects can be detected in vitro, but such effects have not been seen in intact animals at therapeutic doses. Among the two stereoisomers [R(+), S(-)], the (-) isomer has been reported to be more active than the (+) isomer. Serum calcium concentration is not affected by amlodipine. And it specifically inhibits the currents of L-type Cav1.3 channels in the zona glomerulosa of the adrenal gland.

The mechanisms by which amlodipine relieves angina are:

  • Stable angina: amlodipine reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, thereby lowering myocardial oxygen demand, at any given level of exercise.
  • Variant angina: amlodipine blocks spasm of the coronary arteries and restores blood flow in coronary arteries and arterioles in response to calcium, potassium, epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro.

Amlodipine has additionally been found to act as an antagonist of the mineralocorticoid receptor, or as an antimineralocorticoid.

Pharmacokinetics

Amlodipine has been studied in healthy volunteers following oral administration of 14C-labelled drug. Amlodipine is well absorbed by the oral route with a mean oral bioavailability around 60%; the half-life of amlodipine is about 30 h to 50 h, and steady-state plasma concentrations are achieved after 7 to 8 days of daily dosing. Its long half-life and high bioavailability are largely in part of its high pKa (8.6); it is ionized at physiological pH, and thus can strongly attract proteins. It is slowly metabolized in the liver by CYP3A4, with its amine group being oxidized and its side ester chain being hydrolyzed, resulting in an inactive pyridine metabolite. Renal elimination is the major route of excretion with about 60% of an administered dose recovered in urine, largely as inactive pyridine metabolites. However, renal impairment does not significantly influence amlodipine elimination.


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History

Pfizer's patent protection on Norvasc lasted until 2007; total patent expiration occurred later in 2007. A number of generic versions are available. In the United Kingdom, tablets of amlodipine from different suppliers may contain different salts. The strength of the tablets is expressed in terms of amlodipine base, i.e., without the salts. Tablets containing different salts are therefore considered interchangeable. The efficacy and tolerability of a fixed-dose combination of amlodipine and perindopril, an angiotensin converting enzyme inhibitor, have recently been confirmed in a prospective, observational, multicentre trial of 1250 hypertensive patients.

The medical form comes as besylate, mesylate or maleate.


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Veterinary use

Amlodipine is used to treat hypertension in cats and dogs. In cats, it is considered to be the first line of treatment due to its high success rate and few side effects. Systemic hypertension in cats is often a sign of another illness, and amlodipine is most often given to cats with kidney disease, which causes high blood pressure by increase local RAAS activity Amlodipine decreases proteinuria in most cats with chronic kidney disease; and is sometimes given together with an ACE inhibitor, which prevents potential damage to the glomeruli. While amlodipine is used in dogs, it is often as add-on to ACE inhibitors, which are the first line of drugs for canine hypertension. Amlodipine is used more commonly to treat congestive heart failure in dogs, as well as mitral valve regurgitation. Side effects are quite rare, but cats on amlodipine have a possibility of developing azotemia (high concentration of nitrogen), hypokalemia, reflex tachycardia, lethargy, and weight loss. In dogs, it acts as a diuretic, and chronic use can lead to gingival hyperplasia.

Source of the article : Wikipedia



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