ACE Inhibitors

Angiotensin-converting enzyme, or ACE, inhibitors are used to treat high blood pressure, congestive heart failure, and some other diseases or conditions. The structural basis for the many ACE inhibitors is the venom from the pit viper. The first ACE inhibitor, captopril, entered the U.S. market in 1981. ACE inhibitors inhibit both ACE and another enzyme called kininase. Inhibition of both these enzymes leads to the widening of blood vessels and improved blood flow. The most serious side effects of treatment are kidney damage and potential damage to the fetus if taken during pregnancy.

Types
Numerous ACE inhibitors have been marketed since captopril (Capoten) was introduced in1981:


 * Benazepril (Lotensin)
 * Enalapril and enalaprilat (Vasotec oral and injectable)
 * Fosinopril (Monopril)
 * Lisinopril (Zestril and Trinivil)
 * Moexipril (Univasc)
 * Terindopril (Aceon)
 * Quinapril (Accupril)
 * Ramipril (Altace)
 * Trandolapril (Mavik)

Uses
ACE inhibitors are used in adults. The drugs effects on the cardiovascular system make them useful for several conditions: * treatment of high blood pressure * treatment of heart failure * prevention of diabetic neuropathy (painful and abnormal sensations experienced by many people with diabetes) Often ACE inhibitors are used in combination with diuretics, or “water pills.” Commercial formulations of pills that contain both an ACE inhibitor and diuretic are available.

How ACE Inhibitors Work
The renin-angiotensin system regulates blood pressure. When blood pressure is low, the system releases rennin from the kidneys. Renin cleaves a protein called angiotensinogen to form angiotensin I. ACE converts angiotensin I into angiotensin II, which is an extremely potent vasoconstrictor. Angiotensin II increases blood pressure by narrowing blood vessels and initiating other physiologic responses that promote water and sodium resorption by the kidneys. ACE inhibitors prevent the conversion of angiotensin I into angiotensin II. As a result, blood vessels remain in a widened state and sodium is excreted in the urine. This last effect reduces water absorption in the kidneys, which also helps to lower blood pressure. ACE inhibitors also decrease blood pressure via a second mechanism. ACE has a very similar structure to that of the kininase enzyme. Kininase breaks down bradykinin, a protein that causes blood vessels to constrict. ACE inhibitors also reduce blood pressure by inhibiting kininase. By reducing blood pressure, ACE inhibitors reduce the workload of the heart, improve blood flow, and increase the amount of blood the heart can pump. These effects help relieve the symptoms of heart failure.

Side Effects
Some common side effects shared by many ACE inhibitors include the following:
 * dangerously low blood pressure
 * headache
 * fatigue
 * dry cough
 * sore throat
 * dizziness
 * nausea

Risks and Precautions
Some of the most serious risks associated with ACE inhibitor use are to the fetus and the kidneys.

ACE inhibitors can cause birth defects if taken at any time during pregnancy. They can cause fetal death if taken during the last six months of pregnancy (second and third trimester). A 2006 study of 29,507 infants found that the risk for birth defects was increased more than two times if the mother had taken an ACE inhibitor during the first three months of pregnancy (first trimester).[1]

The kidney impairment associated with ACE inhibitor use can manifest as a sudden weight gain and swelling of the arms, hands, legs, and feet. These are signs of fluid accumulation due to kidney failure. They are more likely to occur in people with pre-existing kidney impairment.

Allergies and hypersensitivity reactions can develop to ACE inhibitors. Signs of a serious allergic reaction include swelling of the face, mouth, or throat, and difficulties in swallowing or breathing.

Drug Interactions
A serious interaction can occur when ACE inhibitors are given in combination with non-steroidal anti-inflammatory drugs (e.g., ibuprofen) and diuretics. These three drugs used in combination can cause renal artery stenosis, which is a narrowing of the artery that feeds the kidneys. Renal artery stenosis can lead to kidney impairment and extensive kidney damage. ACE inhibitors should not be given with Potassium-sparing diuretics as this can lead to hyperkalaemia.

Development
In the late 1960s, The Nobel laureate John Vane and Mick Bakhle began investigating the effects of pit viper venom on ACE. Years before, a Brazilian postdoctoral student of Vane’s had brought some venom back with him from Brazil. The investigators knew that the venom caused extensive bleeding, and the discovery of ACE a decade earlier had suggested a potential mechanism.

The pit viper venom did indeed inhibit ACE activity in laboratory tests. However, the venom would be too toxic for use in humans. Vane realized he needed to find the component of the venom that mediated ACE inhibition. Vane had trouble convincing the pharmaceutical company he was working for, Squibb, because the venom consists of peptides, which would require injection to be effective. Regardless, research on the venom continued and eventually a long-acting peptide, teprotide, was isolated. Tests in clinical trials had shown that teprotide reduced blood pressure, and did so by inhibiting ACE. However, teprotide needed to be injected. In an effort to develop an oral form, scientists had chopped up teprotide into smaller fragments and began to alter the structure of each fragment. One of these altered fragments had 200-times the potency of teprotide and could be taken orally. Squibb called the compound captopril and marketed it under the name Capoten. All the ACE inhibitors available today were made by slightly modifying the structure of captopril.

Alternatives
Alternatives

High blood pressure can frequently be managed with a healthy diet, weight, and physical activity. When medication is necessary to control blood pressure several classes of drugs are available. Depending on the on response of the patient these can be used alone or in combination.

In the UK, the A, C or D regime is used where BP is initially controlled by either A = ACE inhibitors (in those age bellow 55 or of Afro-Caribbean origin), or either C = Calcium channel blockers, or D = Diuretics (in those over 55). If a single treatment does not work, then combination therapy with either A + C, or A + B is tried. Failing that A + C + D are used.

Diuretics
Examples include: chlorthalidone (Hygroton), hydrochlorothiazide (Hydrodiuril, Microzide, Esidrix), indapamide (Lozol), metolazone (Mykrox, Zaroxolyn), bumetanide (Bumex), ethacrynic acid (Edecrin), furosemide (Lasix), torsemide (Demadex), amiloride hydrochloride (Midamor), spironolactone (Aldactone), triamterene (Dyrenium)

Beta-blockers
Examples include: acebutolol (Sectral), atenolol (Tenormin), betaxolol (Kerlone), bisoprolol fumarate (Zebeta), carteolol hydrochloride (Cartrol), metoprolol tartrate (Lopressor), metoprolol succinate (Toprol-XL), nadolol (Corgard), penbutolol sulfate (Levatol), pindolol (Visken), propranolol hydrochloride (Inderal, Inderal LA), timolol maleate (Blocadren)

Calcium channel blockers
These include diltiazem hydrochloride (Cardizem SR, Cardizem CD, Dilacor XR, Tiazac), verapamil hydrochloride (Isoptin SR, Calan SR Verelan, Covera HS), amlodipine besylate(Norvasc), felodipine (Plendil), isradipine (DynaCirc, DynaCirc CR), nicardipine (Cardene SR), nifedipine (Procardia XL, Adalat CC), nisoldipine (Sular)

Angiotensin Type II receptor blockers
Examples include: candesartan (Atacand), eprosartan (Teveten), irbesartan (Avapro), losartan (Cozaar), telmisartan (Micardis), valsartan (Diovan) Angiotensin II receptor antagonists can often be used in place of ACE inhibitors in a treatment regimen, when side effects (such as the dry cough) occur.

Research

 * A review published in 2005 summarized the effectiveness of various classes of drugs used to control blood pressure.[2] Data from over 150 clinical trials showed that ACE inhibitors lowered systolic blood pressure and diastolic blood pressure by an average of 12.5/9.5 mm Hg (systolic blood pressure/diastolic blood pressure). A review of other classes revealed that alpha1-blockers lowered the systolic/diastolic blood pressure by an average of 15.5/11.7 mm Hg, beta-blockers by an average of 14.8/12.2 mm Hg, and calcium channel blockers by an average of 15.3/10.5 mm Hg.
 * A recent meta-analysis of ACE inhibitors' role in prevention of type 2 diabetes mellitus[3] suggests that they may preserve pancreatic function and prevent new-onset diabetes, especially in patients who are hypertensive with impaired glucose tolerance.