ANTIHYPERTENSIVE DRUGS. DiureticAgents. Antilipidemic Agents
Goal
The goal of this session is to make students familiar with the pharmacology of antihypertensive drugs and with basic principles of rational pharmacotherapy of essential hypertension, hypertensive urgency and hypertensive emergency.
Learning Objectives
After attending this session and reading provided information, student should be able to able to:
1. Discuss the pharmacological properties of various oral antihypertensive drugs
2. List the properties of an “ideal” antihypertensive drug
3. List the first-line drugs for treatment of essential hypertension
4. Discuss the main adverse effects of first-line antihypertensive drugs
5.List target blood pressure and at least two drugs of choice for hypertensive patients with co-existing diseases
6. Discuss the rationale for combining antihypertensive drugs
7. List the drugs for treatment of hypertensive crisis (emergency and urgency)
8. Discuss the treatment algorithm for the hypertensive patient
I. Pharmacology of Oral Antihypertensive Drugs
1.1 Diuretics
A. Thiazides: Bendroflumethiazide [NATURETIN]; Benzthiazide [EXNA]; Chlorothiazide [DIURIL]; Hydrochlorothiazide [HYDRODIURIL]; Hydroflumethiazide [SALURON]; Methyclothiazide
[ENDURON]; Polythiazide [RENESE]
B. Thiazide-like: Chlorthalidone [HYGROTON]; Indapamide [LOXOL]; Metolazone [MYKROX, ZAROXOLYN]
Mechanism of action: Inhibition of the sodium/chloride symport in distal convoluted tubule and subsequent reduction in sodium and chloride re-absorption. The initial drop in BP is due to increased sodium excretion and water loss and reduced extracellular fluid and plasma volume, whereas the chronic action of TZD diuretics is due to reduction of peripheral vascular resistance. There is evidence that TZDs have some direct vasodilating properties and decreases vasocontrictor response of vascular smooth muscle cells to other vasoconstricting agents.
At low doses TZDs (12.5-25 mg of hydrochlorothiazide [HCTZ] or its equivalent) are relatively well tolerated. Very rarely they cause severe rash, thrombocytopenia and leucopenia. The most common side effect is hypokalemia. Reduction in serum potassium varies with the dose and is between 0.3-1 mmol. Thiazides may increase plasma lipid elevation, and induce glucose intolerance and hyperuricemia. These adverse effects are less frequent with low doses. Importantly, the metabolic side effects of diuretics do not compromise their expected beneficial effects on cardiovascular morbidity and mortality.
As antihypertensive agents TZDs may be particularly useful in elderly patients, African Americans, patients with mild or incipient heart failure, when cost is crucial, and in patients with poor control of salt intake. Low dose TZDs are combined with other first line antihypertensive drugs. The use of TZDs should be avoided in patients with NIDDM, hyperlipidemia or gout. C. Na Channel Inhibitors (K-Sparing): Amiloride [MIDAMOR]; Triamterene [DYRENIUM, MAXZIDE]
Potassium-sparing diuretics produce little reduction in blood pressure themselves. They may be useful in combination with other diuretics to prevent hypokalemia.
D. Aldosterone Antagonists (K-Sparing): Sironolactone [ALDACTONE]; Eplerenone [ INSPRA™]
Spironolactone is a specific aldosterone antagonist, with mild antihypertensive effect. The hypotensive mechanism of spironolactone is unknown. It is possibly due to the ability of the drug to inhibit aldosterone’s effect on arteriole smooth muscle. Spironolactone also can alter the extracellular-intracellular sodium gradient across the membrane. Spironolactone inhibits the effects of aldosterone on the distal renal tubules. Unlike amiloride and triamterene, spironolactone exhibits its diuretic effect only in the presence of aldosterone, and these effects are enhanced in patients with hyperaldosteronism. Aldosterone antagonism enhances sodium, chloride, and water excretion, and reduces the excretion of potassium, ammonium, and phosphate. Spironolactone improves survival and reduces hospitalizations in patients with severe heart failure (NYHA Class IV) when added to conventional therapy (ACE inhibitor and a loop diuretic, with or without digoxin).
Eplerenone is approved for treatment of hypertension and for the treatment of post-myocardial infarction patients with heart failure. It is a more selective aldosterone receptor antagonist, similar in action to spironolactone, with lower incidence of side effects (gynecomastia) due to its reduced affinity for glucocorticoid, androgen, and progesterone receptors. It is more expensive than spironolactone.
1.2. Beta Blockers ( …. OLOL )
Beta blockers, also known as beta-adrenergic blocking agents, are drugs that block norepinephrine and epinephrine
(adrenaline) from binding to beta receptors oerves. There are three types of beta receptors and they control several functions based on their location in the body.
· Beta-1 (β1) receptors are located in the heart, eye, and kidneys;
· beta (β3) receptors are located in fat cells.
What are some examples of beta blockers?
· betaxolol (Betoptic, Betoptic S)
· bisoprolol fumarate (Zebeta)
· labetalol (Trandate, Normodyne)
· metoprolol (Lopressor, Toprol XL)
· propranolol (Inderal, InnoPran)
· timolol ophthalmic solution (Timoptic)
What are the side effects of beta blockers?
· Rash, blurred vision, muscle cramps, and fatigue may also occur.
· Central nervous system effects of beta blockers include:
· Beta blockers that block β2 receptors may cause shortness of breath inasthmatics.
· As with other drugs used for treating high blood pressure, sexual dysfunction may occur.
For what conditions are beta blockers used?
Beta blockers are used for treating:
· tremor,
Are there any differences between beta blockers?
Beta blockers differ in the type of beta receptors they block and, therefore, their effects.
With which drugs do beta blockers interact?
Beta-blockers may be classified based on their ancillary pharmacological properties. Cardioselective agents have high affinity for cardiac β and less affinity for bronchial and vascular β2 receptors compared with non-selective agents and this reduces (but does not abolish) β 2 receptor-mediated side effects. However, with increasing doses cardiac selectivity disappears. Lipid-soluble agents cross the blood-brain barrier more readily and are associated with a higher incidence of central side effects. Some beta-blockers have intrinsic sympathomimetic activity – ISA (i.e., they stimulate β receptors when background sympathetic nervous activity is low and block them when background sympathetic nervous activity is high). Therefore, theoretically BBs with ISA are less likely to cause bradycardia, bronchospasm, peripheral vasoconstriction, to reduce cardiac output, and to increase lipids. BBs with ISA are less frequently used in the treatment of hypertension.
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1.3. Alpha-1 adrenergic receptor blockers ( …. OSIN )
Alpha1-Adrenergic Blockers
Definition
Alpha1-adrenergic blockers are drugs that work by blocking the alpha1-receptors of vascular smooth muscle, thus preventing the uptake of catecholamines by the smooth muscle cells. This causes vasodilation and allows blood to flow more easily.
Purpose
These drugs, called alpha blockers for short, are used for two main purposes: to treat high blood pressure (hypertension) and to treat benign prostatic hyperplasia (BPH), a condition that affects men and is characterized by an enlarged prostate gland.
High blood pressure
High blood pressure puts a strain on the heart and the arteries. Over time, hypertension can damage the blood vessels to the point of causing stroke, heart failure or kidney failure. People with high blood pressure may also be at higher risk for heart attacks. Controlling high blood pressure makes these problems less likely. Alpha blockers help lower blood pressure by causing vasodilation, meaning an increase in the diameter of the blood vessels, which allows blood to flow more easily.
Benign prostatic hyperplasia (bph)
This condition particularly affects older men. Over time, the prostate, a donut-shaped gland below the bladder, enlarges. When this happens, it may interfere with the passage of urine from the bladder out of the body. Men who are diagnosed with BPH may have to urinate more often. Or they may feel that they caot completely empty their bladders. Alpha blockers inhibit the contraction of prostatic smooth muscle and thus relax muscles in the prostate and the bladder, allowing urine to flow more freely.
Description
Commonly prescribed alpha blockers for hypertension and BPH include doxazosin (Cardura, prazosin (Minipress) and terazosin (Hytrin). Prazosin is also used in the treatment of heart failure. All are available only with a physician’s prescription and are sold in tablet form.
Recommended dosage
The recommended dose depends on the patient and the type of alpha blocker and may change over the course of treatment. The prescribing physician will gradually increase the dosage, if necessary. Some patients may need as much as 15-20 mg per day of terazosin, 16 mg per day of doxazosin, or as much as 40 mg per day of prazosin, but most people benefit from lower doses. As the dosage increases, so does the possibility of unwanted side effects.
Alpha blockers should be taken exactly as directed, even if the medication does not seem to be working at first. It should not be stopped even if symptoms improve because it needs to be taken regularly to be effective. Patients should avoid missing any doses, and should not take larger or more frequent doses to make up for missed doses.
Precautions
Alpha blockers may lower blood pressure to a greater extent than desired. This can cause dizziness, lightheadedness, heart palpitations, and fainting. Activities such as driving, using machines, or doing anything else that might be dangerous for 24 hours after taking the first dose should be avoided. Patients should be reminded to be especially careful not to fall when getting up in the middle of the night. The same precautions are recommended if the dosage is increased or if the drug has been stopped and then started again. Anyone whose safety on the job could be affected by taking alpha blockers should inform his or her physician, so that the physician can take this factor into account when increasing dosage.
Some people may feel drowsy or less alert when using these drugs. They should accordingly avoid driving or performing activities that require full attention.
People diagnosed with kidney disease or liver disease may also be more sensitive to alpha blockers. They should inform their physicians about these conditions if alpha blockers are prescribed. Older people may also be more sensitive and may be more likely to have unwanted side effects, such as fainting, dizziness, and lightheadedness.
Key terms
Adrenergic — Refers to neurons (nerve cells) that use catecholamines as neurotransmitters at a synapse.
Adrenergic receptor — There are three families of adrenergic receptors, alpha1, alpha2 and beta, and each family contains three distinct subtypes. Each of the nine subtypes are coded by separate genes, and display specific drug specificities and regulatory properties.
Alpha blockers — Medications that bind alpha adrenergic receptors and decrease the workload of the heart and lower blood pressure. They are commonly used to treat hypertension, peripheral vascular disease, and hyperplasia.
Arteries — Blood vessels that carry oxygenated blood away from the heart to the cells, tissues, and organs of the body.
Catecholamines — Family of neurotransmitters containing dopamine, norepinephrine and epinephrine, produced and secreted by cells of the adrenal medulla in the brain. Catecholamines have excitatory effects on smooth muscle cells of the vessels that supply blood to the skin and mucous membranes and have inhibitory effects on smooth muscle cells located in the wall of the gut, the bronchial tree of the lungs, and the vessels that supply blood to skeletal muscle. There are two different main types of receptors for these neurotransmitters, called alpha and beta adrenergic receptors. The catecholamines are therefore are also known as adrenergic neurotransmitters.
Hyperplasia — The abnormal increase in the number of normal cells in a given tissue.
Hypertension — Persistently high arterial blood pressure.
Neurotransmitter — Substance released from neurons of the peripheral nervous system that travels across the synaptic clefts (gaps) of other neurons to excite or inhibit the target cell.
Palpitation — Rapid, forceful, throbbing, or fluttering heartbeat.
Receptor — A molecular structure in a cell or on the surface of a cell that allows binding of a specific substance that causes a specific physiologic response.
Synapse — A connection betweeerve cells, by which nervous excitation is transferred from one cell to the other.
Vasodilation — The increase in the internal diameter of a blood vessel that results from relaxation of smooth muscle within the wall of the vessel thus causing an increase in blood flow.
It should be noted that alpha blockers do not cure high blood pressure. They simply help to keep the condition under control. Similarly, these drugs will not shrink an enlarged prostate gland. Although they will help relieve the symptoms of prostate enlargement, the prostate may continue to grow, and it eventually may be necessary to have prostate surgery.
Alpha blockers may lower blood counts. Patients may need to have their blood checked regularly while taking this medicine.
Anyone who has had unusual reactions to alpha blockers in the past should let his or her physician know before taking the drugs again. The physician should also be told about any allergies to foods, dyes, preservatives, or other substances.
The effects of taking alpha blockers during pregnancy are not fully understood. Women who are pregnant or planning to become pregnant should inform their physicians. Breastfeeding mothers who need to take alpha blockers should also talk to their physicians. These drugs can pass into breast milk and may affect nursing babies. It may be necessary to stop breastfeeding while being treated with alpha blockers.
Side effects
The most common side effects are dizziness, drowsiness, tiredness, headache, nervousness, irritability, stuffy or runny nose, nausea, pain in the arms and legs, and weakness. These problems usually go away as the body adjusts to the drug and do not require medical treatment. If they do not subside or if they interfere with normal activities, the physician should be informed.
If any of the following side effects occur, the prescribing physician should be notified as soon as possible:
- fainting
- shortness of breath or difficulty breathing
- fast, pounding, or irregular heartbeat
- swollen feet, ankles, wrists
Other side effects may occur. Anyone who has unusual symptoms after taking alpha blockers should contact his or her physician.
Interactions
Doxazosin (Cardura) is not known to interact with any other drugs. Terazosin (Hytrin) may interact with nonsteroidal anti-inflammatory drugs, such as ibuprofen (Motrin), and with other blood pressure drugs, such as enalapril (Vasotec), and verapamil (Calan,Verelan). Prazosin (Minipress) may interact with beta adrenergic blocking agents such as propranolol (Inderal) and others, and with verapamil (Calan, Isoptin.) When drugs interact, the effects of one or both of the drugs may change or the risk of side effects may be greater.
Prazosin [MINIPRESS] Terazosin [HYTRIN] Doxazosin [CARDURA]
Alfuzosin [UROXATRAL] Tamsulosin [FLOMAX]
1.4. Angiotensin Converting Enzyme Inhibitors (ACEIs; … PRIL)
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ACE inhibitor ( Angiotensin-converting enzyme inhibitor; any of a class of drugs that reduce peripheral arterial resistance by inactivating an enzyme that converts angiotensin I to the vasoconstrictor angiotensin II, used in the treatment of hypertension, congestive heart failure, and other cardiovascular disorders. |
Angiotensin-converting enzyme (ACE) inhibitor
A drug that relaxes blood vessel walls and lowers blood pressure.
ACE inhibitor
Angiotensin-converting enzyme inhibitor Pharmacology Any of a family of drugs that are used to manage essential HTN, ↓ CHF-related M&M Pros ACEIs are cardioprotective and vasculoprotective; cardioprotective effects include improved hemodynamics and electric stability, ↓ SNS activity and ↓ left ventricular mass; vasculoprotective benefits include improved endothelial function, vascular compliance and tone, and direct antiproliferative and antiplatelet effects; ACEIs also stimulate PG synthesis, ↓ the size of MIs, ↓ reperfusion injury and complex ventricular arrhythmias; ACEIs are the treatment of choice in CHF with systolic dysfunction; they are vasodilators which ↓ preload and afterload; ACEI-induced ↓ in angiotensin II inhibits the release of aldosterone, which in turn ↓ sodium and water retention which, by extension, ↓ preload; ACEIs improve hemodynamics of CHF by ↓ right atrial pressure, pulmonary capillary wedge pressure, arterial BP, as well as pulmonary and systemic vascular resistances; ACEIs ↑ cardiac and stroke indices by the left ventricle and ↓ the right ventricular end-diastolic volumes, thereby resulting in ↑ cardiac output, while simultaneously ↓ cardiac load and myocardial O2 consumption; ACEIs also downregulate the SNS, which is linked to the pathogenesis of CHF Adverse effects Idiopathic–eg, rashes, dysgeusia, BM suppression; class-specific–eg, hypotension, renal impairment, hyperkalemia, cough, angioneurotic edema, the latter 2 of which are mediated by small vasoactive substances, eg, bradykinin, substance P, and PG-related factors
ACE inhibitor Effects in Heart Disease
Cardioprotective effects
· Restores balance between myocardial O2 supply & demand
· Reduces left ventricular preload and afterload
· Reduces left ventricular mass
· Reduces sympathetic stimulation
Vasculoprotective effects
· Antiproliferative & antimigratory effects on smooth muscle & inflammatory cells
· Antiplatelet effects
· Improved arterial compliance and tone
· Improved and or restored endothelial function
· Antihypertensive
· Possibly, antiatherosclerotic effect
ACE inhibitor
A class of drugs (angiotensin-converting enzyme inhibitors) that block the conversion of angiotensin I to angiotensin II, used in the treatment of hypertension and congestive heart failure and in the prevention of microvascular complications of diabetes mellitus (DM).
The renin-angiotensin system is involved in the regulation of blood pressure and electrolyte balance. Angiotensinogen, a globulin formed in the liver, is converted to angiotensin I by renin, an enzyme produced by the juxtaglomerular cells of renal afferent arterioles. Renin release can be triggered by a drop in systemic blood pressure (either directly through baroreceptors or indirectly through reduction in renal tubular fluid, as in hypotension or dehydration) or in serum sodium chloride concentration. Angiotensin I is converted by the ACE, a glycoprotein produced chiefly in the lung, to angiotensin II. (ACE also degrades bradykinin, a vasodilator.) Angiotensin II is a potent vasoconstrictor and neurotransmitter, which raises peripheral vascular resistance and induces sodium retention by stimulating the adrenal cortex to secrete aldosterone. In addition, angiotensin II stimulates cell migration and the growth and proliferation of vascular smooth muscle. Because it plays a pivotal role in the pathogenesis of essential hypertension, congestive heart failure, and diabetic nephropathy, drugs that block production of angiotensin II are useful in those disorders. ACE inhibitors have an established place in the treatment of essential hypertension, congestive heart failure, and left ventricular dysfunction after myocardial infarction. Their effectiveness in hypertension is less marked in black patients than in nonblacks. ACE inhibitors may lessen cardiovascular risk by improving endothelial dysfunction, reducing inflammation, and promoting fibrinolysis by inhibiting plasminogen activator inhibitor-1. The protection afforded by these agents against vascular complications of DM is independent of their effect on blood pressure. They can slow the progression of diabetic nephropathy in patients with Type 1 DM, and of microalbuminuria in those with Type 2 DM, even in the absence of hypertension. Studies have shown a 50% reduction in the risk of the combined end-points of death, dialysis, and renal transplantation in patients with Type 1 DM who were treated with the ACE inhibitor captopril. In addition, ACE inhibitors may prevent development of DM iondiabetic hypertensive patients. Their potentiation of the effects of bradykinin may account for their ability to enhance insulin sensitivity and may explain their apparent benefit in preventing new-onset Type 2 DM. The usefulness of these agents is limited by their tendency to elevate levels of blood urea nitrogen and creatinine, particularly in conjunction with diuretic therapy and in patients with renal disease or congestive heart failure, and to cause nonproductive cough.
ACE in·hi·bi·tor (ās in-hibi-tŏr)
Class of drugs (angiotensin-converting enzyme inhibitors) that blocks conversion of angiotensin I to angiotensin II; used to treat hypertension and other disorders.
angiotensin-converting enzyme inhibitor; ACE inhibitor pharmacological agent preventing conversion of angiotensin I to angiotensin II (thereby controlling vasoconstriction and reducing blood pressure), used in the treatment of heart failure, hypertension (especially diabetic patients with associated nephropathy) and in the long-term management of patients with myocardial infarction; used with care in patients on diuretics and those with renal dysfunction
ACEIs block the renin-angiotensin system activity by inhibiting the conversion of the biologically inactive angiotensin I to angiotensin II, a powerful vasoconstrictor and stimulator of release of sodium-retaining hormone aldosterone. These effects result in decreased peripheral vascular resistance and reduction in aldosterone plasma levels. ACE inhibitors also reduce the breakdown of the vasodilator bradykinin, which may enhance their action but is also responsible for their most common side effect, cough. ACE inhibitors reduce central adrenergic tone and influence renal hemodynamics (i.e., reduce intraglomerular hypertension) that may have beneficial effects in proteinuric renal disease. The ACEIs tend to be less effective as antihypertensives in patients who tend to have lower renin levels (African Americans and elderly). This relative ineffectiveness can be overcome by using high doses of ACEI or by adding a diuretic. Captopril is short acting, sulfhydryl-group containing agent; Beenazepril, enalapril, fosinopril, moexipril, quinapril, ramipril, spirapril are pro-drugs that in the body have to be converted to active metabolites; and lisinopril is active non metabolized ACEI. In addition to treatment of hypertension, various ACEIs are approved for treatment of heart failure, left ventricular dysfunction, diabetic nephropathy, and acute MI.
1.5. Angiotensin II Receptor Antagonists (ARBs; …SARTAN )
Pharmacology Any of a family of agents-eg losartan and valsartan, which block the binding of angiotensin II–A-II to its cognate cell membrane receptors–AT1, AT2, and others; 1st generation ARAs included the sartan family of agents, which only block AT1, interacting with the amino acids in the transmembrane domains, blocking the binding of A-II to AT1; an alternative to ACEI therapy for Pts with CHF; unlike ACEIs, ARAs do not interfere with bradykinin and prostaglandin metabolism, interference which has been linked to some of the adverse effects of ACEI therapy, particularly to cough and angioedema.
Losartan [COZAAR] Valsartan [DIOVAN] Irbesartan [AVAPRO] Candesartan [ATACAND]
Eprosartan [TEVETEN] Tasosartan [VERDIA] Telmisartan [MICARDIS}
1.6. Calcium Channel Blockers (CCBs)
Definition
Calcium channel blockers are medicines that slow the movement of calcium into the cells of the heart and blood vessels. This, in turn, relaxes blood vessels, increases the supply of oxygen-rich blood to the heart, and reduces the heart’s workload.
Purpose
Calcium channel blockers are used to treat high blood pressure, to correct abnormal heart rhythms, and to relieve the type of chest pain called angina pectoris. Physicians also prescribe calcium channel blockers to treat panic attacks and bipolar disorder (manic depressive illness) and to prevent migraine headache.
Precautions
Seeing a physician regularly while taking calcium channel blockers is important. The physician will check to make certain the medicine is working as it should and will watch for unwanted side effects. People who have high blood pressure often feel perfectly fine. However, they should continue to see their prescribing physician even when they feel well so that he can keep a close watch on their condition. They should also continue to take their medicine even when they feel fine.
Calcium channel blockers will not cure high blood pressure, but will help to control the condition. To avoid the serious health problems associated with high blood pressure, patients may have to take this type of medication for the rest of their lives. Furthermore, the blockers alone may not be enough. People with high blood pressure may also need to avoid certain foods and keep their weight under control. The health care professional who is treating the condition can offer advice as to what measures may be necessary. Patients being treated for high blood pressure should not change their diets without consulting their physicians.
Anyone taking calcium channel blockers for high blood pressure should not take any other prescription or over-the-counter medication without first checking with the prescribing physician, as some of these drugs may increase blood pressure.
Some people feel drowsy or less alert than usual when taking calcium channel blockers. Anyone who takes these drugs should not drive, use machines, or do anything else that might be dangerous until they have found out how the drugs affect them.
People who normally have chest pain when they exercise or exert themselves may not have the pain when they are taking calcium channel blockers. This could lead them to be more active than they should be. Anyone taking calcium channel blockers should therefore consult with the prescribing physician concerning how much exercise and activity may be considered safe.
Some people get headaches that last for a short time after taking a dose of this medication. This problem usually goes away during the course of treatment. If it does not, or if the headaches are severe, the prescribing physician should be informed.
Patients taking certain calcium channel blockers may need to check their pulse regularly, as the drugs may slow the pulse too much. If the pulse is too slow, circulation problems may result. The prescribing physician can show patients the correct way to check their pulse.
This type of medication may cause the gums to swell, bleed, or become tender. If this problem occurs, a medical physician or dentist should be consulted. To help prevent the problem, care should be taken when brushing and flossing the teeth. Regular dental checkups and cleanings are also recommended.
Older people may be unusually sensitive to the effects of calcium channel blockers. This may increase the chance of side effects.
Special conditions
People with certain medical conditions or who are taking certain other medicines may develop problems if they also take calcium channel blockers. Before taking these drugs, the prescribing physician should be informed about any of these conditions:
ALLERGIES. Anyone who has had a previous unusual reaction to any calcium channel blocker should let his or her physician know before taking the drugs again. The physician should also be notified about any allergies to foods, dyes, preservatives, or other substances.
PREGNANCY. The effects of taking calcium channel blockers during pregnancy have not been studied in humans. However, in studies of laboratory animals, large doses of these drugs have been reported to cause birth defects, stillbirth, poor bone growth, and other problems when taken during pregnancy. Women who are pregnant or who may become pregnant should check with their physicians before using these drugs.
BREASTFEEDING. Some calcium channel blockers pass into breast milk, but there have beeo reports of problems iursing babies whose mothers were taking this type of medication. However, women who need to take this medicine and want to breastfeed their babies should check with their physicians.
OTHER MEDICAL CONDITIONS. Calcium channel blockers may worsen heart or blood vessel disorders.
The effects of calcium channel blockers may be greater in people with kidney or liver disease, as their bodies are slower to clear the drug from their systems.
Certain calcium channel blockers may also cause problems in people with a history of heart rhythm problems or with depression, Parkinson’s disease, or other types of parkinsonism.
USE OF CERTAIN MEDICINES. Taking calcium channel blockers with certain other drugs may affect the way the drugs work or may increase the chance of side effects.
As with most medications, certain side effects are possible and some interactions with other substances may occur.
Side effects
Side effects are not common with this medicine, but some may occur. Minor discomforts, such asdizziness, lightheadedness, flushing, headache, and nausea, usually go away as the body adjusts to the drug and do not require medical treatment unless they persist or they are bothersome.
If any of the following side effects occur, the prescribing physician should be notified as soon as possible:
· breathing problems, coughing or wheezing
· irregular, fast, or pounding heartbeat
· slow heartbeat (less than 50 beats per minute)
· skin rash
· swollen ankles, feet, or lower legs
Other side effects may occur. Anyone who has unusual symptoms after taking calcium blockers should contact the prescribing physician.
Interactions
Calcium channel blockers may interact with a number of other medications. When this happens, the effects of one or both of the drugs may change or the risk of side effects may increase. Anyone who takes calcium channel blockers should not take any other prescription or nonprescription (over-the-counter) medicines without first checking with the prescribing physician. Substances that may interact with calcium channel blockers include:
· Diuretics (water pills). This type of medicine may cause low levels of potassium in the body, which may increase the chance of unwanted effects from some calcium channel blockers.
· Beta-blockers, such as atenolol (Tenormin), propranolol (Inderal), and metoprolol (Lopressor), used to treat high blood pressure, angina, and other conditions. Also, eye drop forms of beta blockers, such as timolol (Timoptic), used to treat glaucoma. Taking any of these drugs with calcium channel blockers may increase the effects of both types of medicine and may cause problems if either drug is stopped suddenly.
· Digitalis heart medicines. Taking these medicines with calcium channel blockers may increase the action of the heart medication.
· Medicines used to correct irregular heart rhythms, such as quinidine (Quinidex), disopyramide (Norpace), and procainamide (Procan, Pronestyl). The effects of these drugs may increase if used with calcium channel blockers.
· Anti-seizure medications such as carbamazepine (Tegretol). Calcium channel drugs may increase the effects of these medicines.
· Cyclosporine (Sandimmune), a medicine that suppresses the immune system. Effects may increase if this drug is taken with calcium channel blockers.
· Grapefruit juice may increase the effects of some calcium channel blockers.
The above list does not include every drug that may interact with calcium channel blockers. The prescribing physician or pharmacist will advise as to whether combining calcium channel blockers with any other prescription or nonprescription (over-the-counter) medication is appropriate or not.
Description
Calcium channel blockers are available only with a physician’s prescription and are sold in tablet, capsule, and injectable forms. Some commonly used calcium channel blockers include amlopidine (Norvasc), diltiazem (Cardizem), isradipine (DynaCirc), nifedipine (Adalat, Procardia), nicardipine (Cardene), and verapamil (Calan, Isoptin, Verelan).
The recommended dosage depends on the type, strength, and form of calcium channel blocker and the condition for which it is prescribed. Correct dosage is determined by the prescribing physician and further information can be obtained from the pharmacist.
Calcium channel blockers should be taken as directed. Larger or more frequent doses should not be taken, nor should doses be missed. This medicine may take several weeks to noticeably lower blood pressure. The patient taking calcium channel blockers should keep taking the medicine, to give it time to work. Once it begins to work and symptoms improve, it should continue to be taken as prescribed.
This medicine should not be discontinued without checking with the prescribing physician. Some conditions may worsen when patients stop taking calcium channel blockers abruptly. The prescribing physician will advise as to how to gradually taper down before stopping the medication completely.
Risks
A report from the European Cardiology Society in 2000 found that patients taking certain calcium channel blockers had a 27% greater risk of heart attack, and a 26% greater risk of heart failurethan patients taking other high blood pressure medicines. However, there are many patients affected by conditions that still make calcium channel blockers the best choice for them. The patient should discuss this issue with the prescribing physician.
Normal results
The expected result of taking a calcium channel blocker is to either correct abnormal heart rhythms, return blood pressure to normal, or relieve chest pain.
Key terms
Angina pectoris — A feeling of tightness, heaviness, or pain in the chest, caused by a lack of oxygen in the muscular wall of the heart.
Bipolar disorder — A severe mental illness, also known as manic depression, in which a person has extreme mood swings, ranging from a highly excited state—sometimes with a false sense of well-being—to depression.
Migraine — A throbbing headache that usually affects only one side of the head. Nausea, vomiting, increased sensitivity to light, and other symptoms often accompany migraine.
Methyl-dopa [ALDOMET], Clonidine [CATAPRES]
fall in both cardiac output and peripheral vascular resistance.
Hydralazine [APRESOLINE], Minoxidil [LONITEN]
1.9. Adrenergic Neural Terminal Inhibitors
Guanethidine [ISMELIN], Guanadrel [HYCOREL], Reserpine
1.10. Ganglionic Blockers (Mecamylamine [INVERSINE])
II. Antihypertensive Drugs for Treatment of Hypertensive Crisis
1. Definition of Hypertensive Crisis
Normal blood pressure: SBP <120, DBP <80 mmHg
Prehypertension: SBP 120-139; DBP 80-89 mmHg
Hypertension Stage 1: SBP140-159; DBP 90-99 mmHg
Hypertension Stage 2: SBP >160; DBP >100 mmHg
Hypertensive crisis (Hypertensive Emergency vs. Hypertensive Urgency)
2. Therapeutic principles in hypertensive crisis
2.1. Therapeutic objectives in hypertensive crisis:
For hypertensive urgency therapeutic goal is to reduce BP during the period of 1-24 hours.
8. Drugs given by intermittent intravenous infusion:
– Labetalol: combined + adrenergic receptor blocker
– Enalaprilat: ACE inhibitor, active metabolite of pro-drug enalapril.
III. Selection of Antihypertensive Drug (s)
Properties of the “ideal” antihypertensive drug
Presence of other risk factors for cardiovascular disease & target organ damage
The most important indications for diuretics are: Mobilization of edemas (A): In edema
NaCl Reabsorption in the Kidney (A)
The smallest functional unit of the kidney is the nephron. In the glomerular capillary loops, ultrafiltration of plasma fluid into Bowman’s capsule (BC) yields primary urine. In the proximal tubules (pT), approx. 70% of the ultrafiltrate is retrieved by isoosmotic reabsorption of NaCl and water. In the thick portion of the ascending limb of Henle’s loop (HL), NaCl is absorbed unaccompanied by water. This is the prerequisite for the hairpin countercurrent mechanism that allows build-up of a very high NaCl concentration in the renal medulla. In the distal tubules (dT), NaCl and water are again jointly reabsorbed. At the end of the nephron, this process involves an aldosterone- controlled exchange of Na+ against K+ or H+. In the collecting tubule (C), vasopressin (antidiuretic hormone, ADH) increases the epithelial permeability for water, which is drawn into the hyperosmolar milieu of the renal medulla and thus retained in the body.
Energy liberated during this influx can be utilized for the coupled outward transport of another particle against a gradient. From the cell interior, Na+ is moved with expenditure of energy (ATP hydrolysis) by Na+/K+-ATPase into the extracellular space. The enzyme molecules are confined to the basolateral parts of the cell membrane, facing the interstitium; Na+ can, therefore, not escape back into tubular fluid. All diuretics inhibit Na+ reabsorption. Basically, either the inward or the outward transport of Na+ can be affected.
Osmotic Diuretics (B)
Diuretics of the Sulfonamide Type
failure; hypercalcemia. Ethacrynic acid is classed in this group although it is not a sulfonamide.
Potassium-Sparing Diuretics (A)
stimulated protein synthesis would become noticeable only if existing proteins had become nonfunctional and needed to be replaced by de novo synthesis. A particular adverse effect results from interference with gonadal hormones, as evidenced by the development of gynecomastia (enlargement of male breast). Clinical uses include conditions of increased aldosterone secretion, e.g., liver cirrhosis with ascites
Plant that have diuretic properties
High Cholesterol: Cholesterol-Lowering Medication
Sometimes cholesterol medication is recommended in addition to a low-saturated fat, low-refined carbohydrate, and high-fiber diet to lower cholesterol.
Cholesterol is an important part of your cells and also serves as the building block of some hormones. The liver makes all the cholesterol the body needs. But cholesterol also enters your body from dietary sources, such as animal-based foods like milk, eggs, and meat. Too much cholesterol in your blood can increase the risk of coronary artery disease.
The first line of treatment for abnormal cholesterol is usually to eat a diet low in saturated and trans fats, and high in fruits and vegetables, nuts, and seeds, and to increase exercise. But for some, these changes alone are not enough to lower blood cholesterol levels. These people may need medicine, in addition to making lifestyle changes, to bring their cholesterol down to a safe level.
Cholesterol-lowering drugs include:
Statins
Niacin
Bile-acid resins
Fibric acid derivatives
Cholesterol absorption inhibitors
Cholesterol-lowering medicine is most effective when combined with a healthy diet and exercise.
How Do Statins Work?
Statins block the production of cholesterol in the liver itself. They lower LDL, the “bad” cholesterol, and triglycerides, and have a mild effect in raising HDL, the “good” cholesterol. These drugs are the first line of treatment for most people with high cholesterol. Statins have been shown in multiple research studies to reduce the risk of cardiovascular events like heart attacks and death from heart disease. Side effects can include intestinal problems, liver damage, and in a few people, muscle tenderness.
Statins also carry warnings that memory loss, mental confusion, high blood sugar, and type 2 diabetes are possible side effects. It’s important to remember that statins may also interact with other medications you take.
Examples of statins include:
Atorvastatin (Lipitor)
Fluvastatin (Lescol)
Lovastatin (Mevacor)
Pravastatin (Pravachol)
Simvastatin (Zocor)
Rosuvastatin (Crestor)
How Does Nicotinic Acid Work?
Nicotinic acid is a B-complex vitamin. It’s found in food, but is also available at high doses by prescription. It lowers LDL cholesterol and raises HDL cholesterol. The main side effects are flushing, itching, tingling and headache. A recent research study suggested that adding nicotinic acid to statin therapy was not associated with a lower risk of heart disease. Examples of nicotinic acid medication include:
Nicolar and Niaspan
How Do Bile Acid Resins Work?
These drugs work inside the intestine, where they bind to bile from the liver and prevent it from being reabsorbed into the circulatory system. Bile is made largely from cholesterol, so these drugs work by depleting the body’s supply of cholesterol. The most common side effects are constipation, gas and upset stomach. Examples of bile acid resins include:
Questran and Questran Light
Colestid
WelChol
How Do Fibrates Work?
Fibrates reduce the production of triglycerides and can increase HDL cholesterol. Examples of fibrates include:
Atromid
Tricor
Lopid
Ezetimibe lowers bad LDL cholesterol by blocking cholesterol absorption in the intestine. Research studies have not found that ezetimibe is associated with a lower risk of heart disease.
What Are the Side Effects of Cholesterol-Lowering Drugs?
The side effects of cholesterol-lowering drugs may include:
Muscle aches*
Abnormal liver function
Allergic reaction (skin rashes)
Heartburn
Dizziness
Abdominal pain
Constipation
Decreased sexual desire
Flushing with nicotinic acid
Are There Foods or Other Drugs I Should Avoid While Taking Cholesterol-Lowering Medicine?
You should limit grapefruit juice and fresh grapefruit consumption while taking statins, as grapefruit can interfere with the liver’s ability to metabolize these medications. Talk with your doctor about your other medications, as it may be appropriate to adjust the dosing of your cholesterol medication depending on interactions.
Although a change in life-style is often the method of first choice for lipid lowering, lipid-lowering drugs, in general, help to control elevated levels of different forms of lipids in patients with hyperlipidemia. While one group of drugs, statins, lowers cholesterol, the other group, fibrates, is known to take care of fatty acids and triglycerides. In addition, other drugs, such as ezetimibe, colesevelam, torcetrapib, avasimibe, implitapide, and niacin are also being considered to manage hyperlipidemia. As lipids are very critical for cardiovascular diseases, these drugs reduce fatal and nonfatal cardiovascular abnormalities in the general population. However, a number of recent studies indicate that apart from their lipid-lowering activities, statins and fibrates exhibit multiple functions to modulate intracellular signaling pathways, inhibit inflammation, suppress the production of reactive oxygen species, and modulate T cell activity. Therefore, nowadays, these drugs are being considered as possible therapeutics for several forms of human disorders including cancer, autoimmunity, inflammation, and neurodegeneration. Here I discuss these applications in the light of newly discovered modes of action of these drugs.
Keywords: Fibrate, statin, pleiotropic function, signal transduction, human disorder
Introduction
Lipids are important biomolecules. Cholesterol, for example, is an essential component of the human cell membrane and a precursor for steroid hormones and bile acids. Triglycerides also play an important role in transferring energy from food into body cells. However, any biomolecule in excess is not good for human health. Similarly, elevation of different forms of lipids in the bloodstream, a condition generally termed hyperlipidemia, causes a constant health problem. Because lipids are carried in the bloodstream, hyperlipidemia is always a threat to coronary arteries and the most important risk factor for coronary heart disease.
However, to fight these problems, human wit has acquired several drugs, commonly known as lipid-lowering drugs. One group of drugs (statins) lowers cholesterol by interfering with the cholesterol biosynthetic pathway. On the other hand, fibrates decrease fatty acid and triglyceride levels by stimulating the peroxisomal β-oxidation pathway. Apart from these drugs, ezetimibe, which selectively inhibits intestinal cholesterol absorption, cholestyramine, colestipol, and colesevelam, which sequester bile acids, torcetrapib, which inhibits cholesterol ester transfer protein, avasimibe, which inhibits acyl-CoA: cholesterol acyltransferase, implitapide, which inhibits microsomal triglyceride transfer protein, and niacin, which modifies lipoproteins, are providing clinicians with several therapeutic options for lipid lowering. However, based on medical use, importance, and popularity, statins and fibrates are way ahead of the others. Recent experimental data have revealed that both statins and fibrates display a broad spectrum of activities in addition to their lipid-lowering properties. As a result, statins and fibrates are now being considered as possible medicines in a variety of human disorders.
Lipid-lowering drugs
Most of the lipid-lowering drugs are classified mainly into two groups – statins and fibrates.
Statins
The statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and, thereby, suppress cholesterol biosynthesis In the 1970s, Dr. Endo and colleagues in Japan were studying how certain fungi protected themselves against others. As ergosterol, a derivative of cholesterol, is an essential component of fungi membrane, they were prompted to investigate if inhibition of cholesterol biosynthesis was one such mechanism. In 1978, they reported the discovery of mevastatin, the first statin drug. Eventually, through the laboratory of Drs. Goldstein and Brown, these drugs emerged as the most effective means of reducing elevated levels of plasma cholesterol. There are currently seven statins available in pharmaceutical form – lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, and pitavastatin. First-generation statins, such as lovastatin and mevastatin, were isolated from fungi. However, second- and third-generation statins have been developed by either modification of first-generation statins or chemical synthesis in the laboratory. In general, statins share similar chemical characteristics, with second- and third-generation statins having several aromatic rings and an aliphatic fatty acid side chain, and first generation statins having a decalin ring and an aliphatic side chain.Schematic diagram depicting the various functions of statins. Statins suppress HMG-CoA reductase and thereby inhibit geranylation of Rac and farnesylation of Ras. Because both Rac and Ras are coupled to the transcription of proinflammatory molecules via …
Fibrates
In contrast to statins, this group of drugs does not inhibit cholesterol biosynthesis. However, these drugs stimulate β-oxidation of fatty acids mainly in peroxisomes and partly in mitochondria. Therefore, this group of drugs is known to lower plasma levels of fatty acid and triacylglycerol. Clofibrate was the first such drug, developed in Japan in the 1960s. Eventually, the discovery of several other fibrate drugs such as ciprofibrate, bezafibrate, fenofibrate, and gemfibrozil has revolutionized lipid-lowering research. However, the enthusiasm has been short-lived, because prolonged use of some of these drugs like clofibrate and ciprofibrate causes peroxisome proliferation leading to hepatomegaly and tumor formation in the liver of rodents. Therefore, there are concerns about widespread use of these drugs in humans. Only gemfibrozil and fenofibrate, due to their milder effect on peroxisome proliferation, are being used as lipid-lowering drugs in humans.
Mode of action of statins
Inhibition of cholesterol biosynthetic pathway
Statins came into the limelight due to their inhibitory effect on cholesterol biosynthesis. In humans, cholesterol is synthesized from acetyl-CoA via multiple reactions. HMG-CoA reductase is the key rate-limiting enzyme of this biosynthetic pathway. Statins are structural analogues of HMG-CoA and thereby inhibit HMG-CoA reductase competitively with an affinity about 1000–10,000 times greater than that of the natural substrate. In addition to direct inhibition of cholesterol synthesis, statins have also been shown to lower plasma cholesterol levels indirectly due to up-regulation of the low-density lipoprotein (LDL) receptor.
Inhibition of small G protein activation
The activity of several proteins involved in intracellular signaling cascades is dependent on post-translational modification by isoprenylation. As described in isoprenoids such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate are intermediates in the cholesterol biosynthetic pathway. These intermediates serve as important lipid attachment molecules for the γ subunit of heterotrimeric G proteins and small G proteins, such as Ras, Rho, and Rac. Inactive GDP-bound Ras, Rho, and Rac are localized in the cytoplasm. After isoprenylation, these small G proteins are translocated to the membrane and converted to active GTP-bound forms. Subsequently, activated Ras, Rho, and Rac modulate functions of multiple downstream signaling molecules. Because mevalonate is a precursor of isoprenoids, statins inhibit the synthesis of isoprenoids and thereby suppress the activation of small G proteins.
Suppression of proinflammatory molecules
The idea of investigating the role of the mevalonate pathway in the regulation of inducible nitric oxide (NO) synthase (iNOS) and proinflammatory cytokines came from the fact that intermediates of this biochemical pathway are isoprenoids, which are known to play an important role in activating small G proteins like Ras and Rac as described above. Interestingly, Pahan et al. have shown that lovastatin inhibits the activation of NF-κB and the expression of iNOS and proinflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6] in lipopolysaccharide (LPS)-stimulated rat primary astrocytes. In fact, this landmark finding has revolutionized statin research. Nowadays, statin drugs are being widely considered as potential therapeutic agents against various neuroinflammatory and neurodegenerative disorders. Because lovastatin inhibits HMG-CoA reductase, both mevalonate and farnesyl pyrophosphate (FPP) are capable of reversing the inhibitory effect of lovastatin on the expression of iNOS and the activation of NF-κB. However, addition of ubiquinone and cholesterol to astrocytes does not prevent the inhibitory effect of lovastatin. These results suggest that depletion of FPP, rather than end products of the mevalonate pathway, is responsible for the observed inhibitory effect of lovastatin on the expression of iNOS.
Suppression of LPS-induced activation of NF-κB and expression of iNOS in glial cells by farnesyltransferase inhibitors suggests an important role for the farnesylation reaction in the regulation of the iNOS gene. Consistent with a role of farnesylation in the activation of p21Ras, a dominant-negative mutant of p21Ras(S17N) also attenuated activation of NF-κB and expression of iNOS in rat and human primary astrocytes. Statins also block interferon (IFN)-γ-inducible and constitutive transcription of the major histocompatibility complex (MHC) class II transactivator (CIITA), which regulates nearly all MHC class II gene expression. Recently, Cordle and Landreth have also indicated that statins inhibit fibrillar Aβ-induced expression of iNOS in mouse BV-2 microglial cells by inhibiting isoprenylation of Rac. Taken together, these studies suggest that mevalonate metabolites regulate the expression of iNOS in glial cells via modulating isoprenylation of small G proteins.
Stimulation of endothelial NOS
In patients with atherosclerosis and hypercholesterolemia, endothelial function is known to be impaired due to decreased synthesis of endothelium-derived NO. In vascular walls, NO is synthesized from endothelial nitric oxide synthase (eNOS). Although statins inhibit the expression of iNOS, these drugs have been found to stimulate eNOS-derived NO production. This beneficial effect of statins is found to be independent of cholesterol lowering. Reversal of this effect by geranylgeranyl pyrophosphate but not FPP suggests that Rac/Rho but not Ras play a role in down-regulation of eNOS. In addition, Akt has been shown to phosphorylate eNOS and increase the production of NO. On the other hand, mevalonate, an intermediate of the cholesterol biosynthetic pathway, inhibits phosphatidylinositol-3 (PI-3) kinase and thereby attenuates the activation of protein kinase B (Akt). These studies suggest that statins may also favor the up-regulation of eNOS by inhibiting the synthesis of mevalonate and thereby activating the PI-3 kinase-Akt pathway. Furthermore, according to Feron et al., atorvastatin increases NO production by decreasing the expression of caveolin-1, a negative regulator of eNOS.
Inhibition of migration and proliferation of smooth muscle cells
Migration and proliferation of smooth muscle cells (SMCs) play an important role in the pathogenesis of atherosclerosis. Small G proteins, such as Ras and Rho, are known to promote SMC migration and proliferation. While Ras promotes cell cycle progression via activation of the MAP kinase pathway, Rho/Rho kinase induces cell proliferation via destabilization of the inhibitor of cyclin-dependent kinase, p27kip1 . Because statins are capable of inhibiting the activation of Ras and Rho, these drugs also suppress SMC migration and proliferation.
Inhibition of reactive oxygen species production
Reactive oxygen species (ROS) play many important roles in intracellular signal transduction. Several inflammatory and degenerative stimuli induce the production of ROS via the activation of NADPH oxidase. NADPH oxidase is a five-subunit protein that generates superoxide from molecular oxygen and is composed of two membrane-bound subunits, gp91phox and p22phox, and at least two cytosolic subunits, p47phox and p67phox. Phosphorylation of p47phox results in translocation of the p47phox-p67phox complex to the membrane, where it interacts via multiple binding sites with gp91phox and p22phox. This complex remains incomplete without the participation of Rac, a small G protein, which is known to associate with p67phox and gp91phox. As mentioned above, statins inhibit geranylgeranylation of Rac and thereby attenuate NADPH oxidase-mediated generation of superoxide.
Switching of T-helper cells
CD4 T helper (Th) cells play an important role in controlling two different arms of immunity – cell-mediated immunity and antibody-mediated immunity. While Th1 cells play an important role in cell-mediated immunity, Th2 cells induce humoral or antibody-mediated immunity. The polarization of Th0 (naive) cells into functionally distinct subsets (Th1 and Th2) are characterized by the patterns of cytokines they produce, with Th1 cells producing IFN-γ, and Th2 cells producing IL-4 and IL-10. Sometimes, Th2 cells are able to negatively regulate Th1 cell-mediated responses, thus acting in an anti-inflammatory capacity. In healthy human beings, there is a proper balance between Th1 and Th2 cells. However, once the balance is lost, it leads to immune-related disorders. It has been suggested that altering the Th1/Th2 balance in vivo toward Th2 function could protect against Th1-type autoimmune disease. Interestingly, statins have been found to favor the polarization toward Th2. In experimental allergic encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), statins induce the differentiation of neuroantigen-primed T cells from the Th1 to Th2 mode. While activated (tyrosine-phosphorylated) signal transducer and activator of transcription (STAT) 4 has a key role in IL-12-dependent Th1 lineage commitment, activation of STAT6 is required for IL-4-dependent Th2 lineage commitment. Interestingly, atorvastatin treatment suppresses the formation of activated STAT4 but stimulates the activation of STAT6 in T cells from atorvastatin-treated or phosphate-buffered saline-treated mice.
Destabilization of fibrillar amyloid-β peptides
Fibrillar forms of amyloid-β (Aβ) peptide play an important role in the pathogenesis of Alzheimer’s disease (AD). These are 39- to 43-residue peptides released due to proteolytic processing of the transmembrane precursor glycoprotein, amyloid precursor protein (APP). The amyloidogenic pathway requires that APP be sequentially cleaved by β– and γ-secretases. β-Secretase cleaves APP close to the membrane to produce βAPPs (secreted), and a 12-kDa, C100 transmembrane stub, subsequently cleaved by γ-secretase to produce the Aβ peptide and a cytoplasmic fragment with a very short half life. On the other hand, α-secretase cleaves APP within the Aβ sequence thus preventing its formation. Statin treatment has recently been suggested to decrease amyloidogenic APP processing by reducing cellular cholesterol levels. Recent studies have suggested that treatment with statins or depletion of cholesterol appears to increase α-secretase cleavage of APP in cells, whereas β-secretase cleavage and secreted Aβ levels are decreased. In contrast, cholesterol enrichment leads to elevated amyloidogenic processing of APP. In agreement with this, Sidera et al. have demonstrated that high cellular cholesterol levels decrease the glycosylation of mature oligosaccharides in β-secretase leading to its inhibition. On the other hand, in the presence of lovastatin, the glycosylation process is stimulated, thereby attenuating the function of β-secretase. However, lovastatin does not inhibit β-secretase in vitro.
Mode of action of fibrates
Activation of nuclear hormone receptors
One of the hallmarks of functions of fibrate drugs is the activation of peroxisome proliferator-activated receptor (PPAR). PPARs are a group of three nuclear hormone receptor isoforms, PPAR-γ, PPAR-α, and PPAR-δ, encoded by different genes. However, fibrate drugs like clofibrate and fenofibrate have been shown to activate PPAR-α with tenfold selectivity over PPAR-γ . Bezafibrate acts as a pan-agonist that shows similar potency on all three PPAR isoforms. WY-14643, the 2-aryl-thioacetic acid analogue of clofibrate, is a potent murine PPAR-α agonist as well as a weak PPAR-γ agonist. Although these drugs activate PPARs, direct binding of these drugs with PPARs has not been demonstrated. However, in response to fibrate drugs, PPAR-α heterodimerizes with retinoid X receptor-α (RXR-α), and the resulting heterodimer modulates the transcription of genes containing peroxisome proliferator-responsive elements (PPREs) in their promoter sequenc. In addition to fibrates, a number of natural ligands, such as polyunsaturated fatty acids (PUFAs), leukotriene B4 (LTB4), 8-S-hydroxy eicosatetraenoic acid (8-S-HETE), and prostaglandin J2 (PGJ2), are also known to activate PPARs. In the absence of ligands, all three isoforms of PPAR bind to various transcription co-repressors, such as nuclear receptor co-repressor (NCoR) and silencing mediator for retinoid and thyroid hormone receptor (SMRT), and histone deacetylases (HDACs) in a DNA-independent manner. On the other hand, ligand-mediated activation of PPARs leads to dissociation of co-repressors and concomitant association with various co-activators, such as steroid receptor co-activator 1 (SRC1) and histone acetylases (CBP/p300). Recent studies have also identified a PPAR-α-interacting cofactor (PRIC) complex containing many co-activators, such as PPAR-binding protein (PBP), PPAR-interacting protein (PRIP), PRIP-interacting protein with methyltransferase domain (PIMT), and others].
Stimulation of fatty acid oxidation
Fatty acids are β-oxidized mainly in mitochondria. Only very long chain and long-chain fatty acids are β-oxidized in peroxisomes. After chain shortening in peroxisomes, fatty acids are believed to be transported into mitochondria for complete β-oxidation. However, fibrate drugs are known to stimulate mainly peroxisomal β-oxidation ccordingly, after clofibrate treatment, peroxisomal fatty acid β-oxidation increases up to 20-fold in the liver of rodents. Hepatocytes isolated from clofibrate-fed rats also oxidize more and esterify less of incoming fatty acids than do normal hepatocytes. This increase in fatty acid oxidation is particularly striking for very long chain fatty acids (>C22:0), as these are particularly β-oxidized in peroxisomes. This stimulatory effect is mediated by PPAR-α, and a PPRE, consisting of an almost perfect direct repeat of the sequence TGACCT spaced by a single base pair, has also been identified in the upstream regulatory sequences of each of the genes involved in peroxisomal β-oxidation]. In addition to stimulating β-oxidation, fibrate drugs are also known to stimulate fatty acid ω-oxidation in the liver, and they prevent or reduce the effects of some inhibitors of fatty acid oxidation, such as 4-pen-tenoate, and decanoyl-carnitine. Fibrates also increase the activity of acyl-CoA synthetase and the CoA content of liver while the level of malonyl-CoA, the precursor of de novo fatty acid synthesis, goes down. Apart from stimulating fatty acid oxidation-associated molecules, fibrates also increase lipolysis via PPAR-α-dependent up-regulation of lipoprotein lipase.
Peroxisome proliferation and hepatocarcinogenesis
Fibrates are also termed peroxisome proliferators, because prolonged administration of fibrates to rodents typically leads to proliferation of peroxisomes and hepatomegaly. Continuous administration of fibrate drugs to rodents for 40–50 weeks also leads to the formation of hepatic tumor. However, the mode of action underlying fibrate-induced hepatocarcinogenesis has not yet been fully delineated. In response to fibrate drugs, PPAR-α is believed to mediate alterations in gene expression that eventually lead to increased cell proliferation, decreased apoptosis and increased signaling for replicative DNA synthesis in the liver. These alterations ultimately enable mutant cell populations to proliferate and become neoplastic. It is also known that a number of proteins required for transition into the S phase of the cell cycle are increased by fibrates, probably via the involvement of PPAR-α . However, functional PPREs have not been characterized in gene promoters of these regulatory molecules. Fibrate drugs have been suggested to induce oxidative stress, which ultimately contributes to an increase in hepatocyte proliferation and oxidative DNA damage. This hypothesis gains momentum as fibrates induce marked up-regulation of peroxisomal acyl-CoA oxidase, the fatty acid β-oxidizing enzyme that produces H2O2, without concomitant increase in the peroxisomal marker catalase, the H2O2-degrading enzyme].
Suppression of proinflammatory molecules
Similar to statins, fibrate drugs also inhibit the production of different proinflammatory molecules. Fibrates repress cytokine-induced IL-6 production in SMCs, iNOS activity in murine macrophages, and VCAM-1 expression in endothelial cells. The physiological relevance of these observations is further corroborated by the demonstration that fibrates lower plasma levels of inflammatory cytokines such as IL-6, TNF-α, and IFN-γ in patients with atherosclerosis. Interestingly, not only fibrate, but also PPAR-γ ligands have been reported to inhibit production of inflammatory cytokinesby monocytes/macrophages in vitro.
Fibrate drugs also exhibit an anti-inflammatory effect in brain cells. For example, according to Xu et al., all the fibrate drugs tested (ciprofibrate, fenofibrate, gemfibrozil, and WY-14643) inhibit cytokine-induced production of NO in microglia in a dose-dependent manner. Xu et al. also demonstrated that fibrates inhibit the secretion of the proinflammatory cytokines IL-1β, TNF-α, IL-6, and IL-12 p40 and the chemokine MCP-1 by LPS-stimulated microglia. Although mechanisms behind the anti-inflammatory effect of fibrates are currently unknown, these drugs may limit inflammation in part by inducing the expression of IκBα, which blocks the activation of NF-κB, a transcription factor critical in the activation of a variety of proinflammatory molecules.
We have also demonstrated that gemfibrozil and clofibrate inhibit the expression of iNOS and the production of NO in human astrocytes. Although gemfibrozil induces PPRE-dependent reporter activity in human astrocytes, this drug inhibits the expression of iNOS independent of PPAR-α . Gemfibrozil has been found to markedly inhibit the activation of different proinflammatory transcription factors, such as NF-κB, AP-1, and C/EBPβ, which are required for the transactivation of the human iNOS promoter.
Switching of T helper cells
Being important immunomodulators, fibrates also modify functions of T cells. Fibrates are ligands of PPAR-α and resting T cells express PPAR-α. Marx et al. have demonstrated that fibrates alone are sufficient to inhibit IL-2, TNF-α, and IFN-γ production by activated CD4+ T cells. Fibrates also induce splenocyte production of IL-4, a cytokine important in the differentiation of Th2 cells that are generally believed to protect against the development of EAE. In addition, WY-14643, the synthetic agonist of PPAR-α, has been shown to induce apoptosis of lymphocytes, which may protect against autoimmune diseases by ablating autoreactive lymphocytes. Lovett-Racke et al. have demonstrated that fibrates suppress the differentiation of Th1 cells while promoting the differentiation of neuroantigen-primed T cells toward the Th2 mode. Although underlying mechanisms are poorly understood, a recent study suggests that PPAR-α also plays a physiologic role in regulating T-bet, an inducible transcription factor important in the initiation of cytokine gene transcription, particularly Th1 cytokines. This study demonstrates that PPAR-α present in the cytoplasm of T cells is able to negatively regulate the transcription of T-bet that favors the production of IFN-γ by T cells. This regulation occurred independently of DNA binding, suggesting that there may be several mechanisms by which PPAR-α can influence T cell activation and cytokine production.
Therapeutic efficacy of statins
The current state of knowledge indicates that statins are not only lipid-lowering drugs. Due to multiple functions, these wonder drugs have emerged as possible medicines for many other chronic disorders including neurodegeneration, inflammation, demyelination, cancer, and diabetes. Below, I have tried to analyze a large body of information regarding possible treatment of several human disorders by statins.
Coronary artery disease
Data from several epidemiological studies have established statins as the most potent class of medicines for cardiovascular diseases. Being a cholesterol-lowering drug, statins are expected to ameliorate cardiovascular problems. However, in addition to lowering cholesterol, statins seem to ameliorate multiple problems in patients with atherosclerosis. For example, statins lower the levels of acute-phase proteins independent of their effects on cholesterol and thereby retard the deleterious effects of advanced atherosclerotic disease. There is increasing evidence that inflammation and the underlying cellular and molecular mechanisms contribute to the progression of atherosclerosis. The vascular inflammatory process seems to promote plaque rupture and atherothrombosis, resulting in clinical complications of atherosclerosis. Schillinger et al. have shown that the association between statin use and survival is markedly influenced by the inflammatory status of the patient, suggesting that a reduction of vascular inflammation or attenuation of the effects of inflammatory activity may be an important mechanism by which statins exhibit improved event-free survival. However, in addition to cholesterol-lowering and anti-inflammatory activities, improved endothelial function and plaque stabilization by statins in patients with atherosclerosis may also involve their anti-thrombotic, anti-proliferative, and anti-oxidative effects.
Cancer
The interest in studying the effects of statins on various forms of cancer stems from the facts that Ras is involved in at least 30% of all forms of cancer and that statins are capable of inhibiting the activation of Ras in various cell types. Statins also inhibit the growth of various cell lines either by induction of cell cycle arrest or apoptosis. In addition, lovastatin has been reported to reduce invasiveness of lymphoma cells, human glioma cells, melanoma cells, and NIH-3T3 cells in matrigel. Consistently, statins exhibit anti-tumor effects against melanoma, mammary carcinoma, pancreatic adenocarcinoma, fibrosarcoma, glioma, neuroblastoma, and lymphoma in various animal models, leading to either suppression of tumor progression, and/or inhibition of the metastatic process. Consistently, in an epidemiological analysis, fewer cases of melanoma are observed in the lovastatin-treated group compared with the control group. In pre-clinical studies, statins also potentiate the anti-tumor effects of some cytokines and chemotherapeutics. However, clinical trial results do not display particularly encouraging prospect for statin therapy in cancer. In a phase II study by Kim et al., lovastatin (35 mg/kg body weight) was administered to patients with advanced gastric adenocarcinoma. Although this drug regimen leads to transient side effects, such as myalgia and elevated serum creatine phosphokinase, the anti-tumor effect was not very obvious. In another phase I-II trial of lovastatin by Larner et al. in patients with anaplastic astrocytoma and glioblastoma multiforme, high doses of lovastatin were well-tolerated with little anti-tumor activity. In the PROSPER trial, increased incidences for breast and colon cancer were also observed in the pravastatin-treated group. However, before writing off statins from cancer trials, it should be remembered that statins specifically target Ras and, therefore, these drugs may have a better success rate against Ras-dependent cancers.
Diabetes
Patients with type 2 diabetes have an atherogenic lipid profile, which greatly increases their risk of coronary heart disease (CHD) compared with people without diabetes. An estimated 92% of individuals with type 2 diabetes, without CHD, have a dyslipidemic profile. Consistently, the Heart Protection Study demonstrated an approximately 25% relative risk reduction of a first coronary event in patients with type 2 diabetes. In the Lescol Intervention Prevention Study (LIPS), routine use of fluvastatin in patients with type 2 diabetes led to a 47% reduction in the relative risk of cardiac death. An increased oxidative stress has been suggested to contribute to the accelerated atherosclerosis and other problems in diabetic patients. Accordingly, exposure of cultured aortic endothelial cells and SMCs to a high glucose level significantly increased the oxidative stress compared with a normal glucose level. This increase was completely blocked by treatment with pitavastatin. Subsequently, administration of pitavastatin in streptozotocin-induced diabetic rats attenuated the increased oxidative stress in diabetic rats to control levels. In addition to CHD, peripheral neuropathy is a frequent and major complication of diabetes. Interestingly, rosuvastatin restores nerve vascularity, including vessel size, in type II diabetic mice to the levels of nondiabetic mice by stimulating the expression of neuronal nitric oxide synthase (nNOS) in sciatic nerves. Although the mechanisms are poorly understood, these drugs also reduce the risk of leg ulcers and kidney disease that are common in diabetic patients.
Osteoporosis
Osteoporosis is the most common form of bone-degenerating malady in humans. Statins are also emerging as wonder drugs for bone disorders, such as osteoporosis. Bone morphogenetic proteins (BMPs) are cytokines that promote differentiation of mesenchymal stem cells into differentiated osteoblasts, and bone formation. Interestingly, statins have been found to stimulate the expression of BMP-2 and this phenomenon might be linked directly to the anabolic effect of statins on bone. In addition, IL-6 plays an important role in the pathogenesis of osteoporosis. Because isoprenoid-mediated activation of Ras is involved in the induction of IL-6, statins block IL-6 induction in various cell types by depleting isoprenoids.
The role of statins in bone formation was shown in 1999 and, after that, observations of large groups of patients have pointed to a reduction in the risk of osteoporotic fractures with the use of statins compared to those using other lipid-lowering drugs or to the control group. Epidemiological analyses also indicate a reduction in the risk of osteoporotic fractures with the use of statins, but whether using these drugs may have a beneficial effect on bone turnover is not yet known. We must therefore wait for larger prospective randomized clinical trials before prescribing these drugs in osteoporotic patients.
Alzheimer’s disease
AD is a neurodegenerative disorder resulting in progressive neuronal death and memory loss. Neuropathologically, the disease is characterized by neurofibrillary tangles and neuritic plaques composed of aggregates of β-amyloid (Aβ) protein, a 40- to 43-amino acid proteolytic fragment derived from the amyloid precursor protein. In the early 1990s, the first hint about possible involvement of cholesterol in AD came from observations of enhanced prevalence of Aβ-containing senile plaques among subjects without dementia with coronary artery disease compared with individuals without dementia and heart disease. Although the underlying mechanism has not been identified, elevated levels of circulating cholesterol have been proposed to increase the risk of AD several fold. Subsequently, the cholesterol-AD nexus comes to the forefront with the direct evidence of increased levels of Aβ in cholesterol-fed New Zealand White rabbits, the small-animal model of human coronary artery disease. Interestingly, removing cholesterol from the diet of animals previously fed a cholesterol-enriched diet leads to significant reduction in brain Aβ levels, attesting an important role for cholesterol in stimulating the production of Aβ in vivo in the brain. Epidemiological studies also suggest that prior statin use in treating risk of coronary artery disease may reduce the risk of AD later in life. Recently, in a double-blind randomized trial with a 1-year exposure to atorvastatin (80 mg/day), Sparks et al. found that atorvastatin reduces circulating cholesterol levels and produces a positive signal on each of the clinical outcome measures (such as the Geriatric Depression Scale, the Alzheimer’s Disease Assessment Scale, Clinical Global Impression of Change Scale, and Neuropsychiatric Inventory Scale) compared with placebo. However, results should be substantiated by a large multi-center clinical trial in order to establish statin therapy in AD.
Multiple sclerosis
MS is the most common human demyelinating disease of the central nervous system (CNS) of unknown etiology. A broad-spectrum inflammatory process in the CNS is believed to play an important role in the loss of myelin and myelin-producing cells. Evidence has emerged that statins have immunomodulatory effects in MS. Recent reports showed that statins prevent and reverse chronic and relapsing EAE, an animal model of MS. Several immunomodulatory properties of statins may account for their beneficial clinical effect. Statins decrease the migration of leukocytes into the CNS, inhibit MHC class II and co-stimulatory signals required for activation of proinflammatory T cells, induce a Th2 phenotype in T cells, and decrease the expression of inflammatory mediators in the CNS, including NO and TNF-α . Greenwood et al. have demonstrated that treatment of brain endothelial cells in vitro with lovastatin inhibits Rho-mediated transendothelial T cell migration. Consistently, they and others also demonstrate that in acute and relapsing-remitting mouse models of MS, lovastatin treatment inhibits leukocyte migration into the CNS and attenuates the development of both acute and relapsing clinical disease. Furthermore, in vitro experiments with human immune cells have shown an immunomodulatory profile of statins comparable to that of IFN-β. Consistent with this, an open-label clinical trial of simvastatin for MS reveals a significant decrease in the number and volume of new magnetic resonance imaging (MRI) lesions and a favorable safety profile. As the evidence of the benefit of statins in MS is currently insufficient, large controlled clinical trials are needed.
Because statin treatment is being considered as a possible therapy for MS patients, it is worth mentioning that the rationale for statin treatment is MS patients should be justified. First, MS is a disease of the younger generation and, therefore, many MS patients do not experience any cholesterol-related problems before, during or after the time of MS attack. Second, the serum concentration of 24S-hydroxycholesterol reflecting brain cholesterol turnover may be a possible marker for neurodegeneration and demyelination in MS. Consistently, Teunissen et al. have demonstrated serum levels of 24S-hydroxycholesterol and lathosterol are lower in patients with primary progressive and in older relapsing remitting MS. Therefore, long-term use of statins in MS patients may eventually prove to be fatal.
Depression
A couple of studies demonstrate that long-term use of statin leads to reduced risk of depression in patients with coronary artery disease. They have demonstrated that risk of depression was 60% less in individuals using statins than in hyperlipidemic individuals not using lipid-lowering drugs. Interestingly, the use of non-statin lipid-lowering drugs yields a similar, but weaker effect. Although statins attenuate depression in susceptible patients, the molecular mechanisms associated with this beneficial effect of statin are not known. One could be the up-regulation of constitutive NOS (cNOS)-mediated NO production in brain cells by statins. As NO possesses the anti-depressant activity, statins may therefore suppress depression. Alternatively, another possible explanation could be the ‘feel-good’ effect of statins through improved quality of life due to decreased incidence of cardiovascular events.
Therapeutic efficacy of fibrates
Discovery of multiple functions of fibrates has allowed clinicians to consider fibrates as potential therapeutic agents for various pathological states including atherosclerosis, obesity, diabetes, inflammation, and demyelination. Here, I present the current state of knowledge regarding the treatment of several chronic diseases by fibrates.
Coronary heart disease
Fibrates were introduced for treatment of hyperlipidemia. Trials with fibrates have shown a reduction in CHD risk through modification of atherogenic dyslipidemia. The benefit is believed to be due to an increased clearance of very low density lipoprotein-cholesterol, a decrease in triglycerides, an increase in plasma high-density lipoprotein (HDL)-cholesterol via decreased exchange of triglyceride and HDL-cholesterol by the cholesterol ester transfer protein (CETP), and a reduction of hepatic cholesterol biosynthesis. Consistently, in several clinical trials, fibrate drugs alone have been found to cause a significant decrease in triglycerides (20–50%) and an increase in plasma HDL-cholesterol (14–20%). Although the reduction in low-density lipoprotein (LDL)-cholesterol by fibrates always remains marginal (5–15%), in a study by Winkler et al., fenofibrate lowers atherogenic small dense LDL more effectively than atorvastatin. However, in general, fibrates seem to be particularly effective in patients for whom a disturbance of the triglyceride-HDL axis is the primary lipid disorder.
In addition to lipid-lowering activity, fibrates are also anti-inflammatory. IL-6 has been shown to play an important role in the pathogenesis of atherosclerosis. Biswas et al. reported that IL-6 induces monocyte chemotactic protein-1 expression in peripheral blood mononuclear cells and U937 macrophages. Thus, suppressing the secretion of IL-6, fibrates may indirectly inhibit the production of potent chemokines involved in monocyte recruitment into the subendothelial space, resulting in less foam cell formation.
In some instances, for better overall outcome, fibrates are also administered in combination with statin. According to Chapman, a large percentage of CHD patients on statins alone still succumb to the disease. In a randomized, double-blind, placebo-controlled crossover trial with atorvastatin and fenofibrate in patients with combined hyperlipidemia, the combination therapy was found to be safe and had beneficial additive effects on endothelial function. However, combination therapy may sometimes lead to an impairment in drug clearance, as the clearance of statin drugs from the body requires cytochrome P450-mediated chemical modification. In addition, gemfibrozil is known to inhibit cytochrome p450 and thereby may cause faulty clearance of statins. Therefore, caution must be exercised when prescribing combination therapy for CHD patients.
Obesity
Obesity itself is a disease and is a serious risk factor for many other chronic complications, such as diabetes, hypertension, dyslipidemia, and cardiovascular diseases. People become obese when the body takes in more calories than it burns off and those extra calories are stored as fat. Due to its direct stimulatory effect on the catabolism of fat, fibrates have been used as primary or adjunct therapy for several years to control obesity. In obese prone (OP) rats, fenofibrate treatment significantly (p < 0.05) reduces food intake, weight gain, feed efficiency, and adiposity to the levels seen in control obesity-resistant rats. Fenofibrate treatment also increases whole-body fatty acid oxidation, and stimulates the expression of carnitine palmitoyl transferase I, the enzyme involved in the entry of fatty acyl-CoA into mitochondria, in the liver of OP rats.
Obesity is often associated with leptin resistance, as evidenced by hyperleptinemia. Leptin is a 16-kDa protein secreted by fat cells that regulates feeding and energy expenditures by acting at sites primarily within the CNS. Obesity in humans and rodents is almost always associated with a resistance to, rather than a deficiency of, leptin. In fact, leptin itself is elevated in obesity. Leptin resistance arises from impaired leptin transport across the blood-brain barrier (BBB) and defects in leptin receptor signaling. Interestingly, gemfibrozil restores leptin transport across the BBB and in diet-induced obese rats, gemfibrozil significantly reduces the leptin level.
Diabetes
As mentioned above, patients with type 2 diabetes are at particularly high risk of atherosclerotic events. The Diabetes Atherosclerosis Intervention Study and the St. Mary’s, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention study clearly show that fibrates improve cardiovascular outcomes in patients with type 2 diabetes. In addition to lowering cardiovascular risk, fibrates may also improve insulin sensitivity in diabetic patients. Fat metabolism and sugar homeostasis are inherently related. Insulin is recognized for its role in promoting glucose uptake. However, insulin is also capable of regulating the catabolism of triglycerides through its inhibition of hormone-sensitive lipase. On the other hand, lipid abnormalities also have profound effects on glucose homeostasis. For example, according to Schulman, abnormal accumulation of triglycerides and fatty acyl-CoA in muscle and liver may result in insulin resistance. In a number of animal models, fibrates have been shown to lower plasma triglycerides, reduce adiposity and improve hepatic and muscle steatosis, thereby improving insulin sensitivity. Although fibrate drugs are widely used to treat hypertriglyceridemia in patients, surprisingly, their effects on insulin sensitivity in humans have not been thoroughly examined. Another putative beneficial effect of fibrates in diabetes that has not been much appreciated is reduction in inflammation. Subclinical inflammation always plays an important part in the pathogenesis of type 2 diabetes, primarily as a mediator of obesity-induced insulin resistance. In this connection it is worth mentioning that fibrates are also capable of reducing inflammation.
Multiple sclerosis
A recent study also suggests that fibrate drugs, such as gemfibrozil and fenofibrate, may be considered as possible therapeutics for MS. The EAE animal model is particularly useful in testing new therapeutic intervention in MS. Lovett-Racke and colleagues have demonstrated that these drugs are able to prevent and treat the disease process of EAE in mice. Although underlying mechanisms are poorly understood, anti-inflammatory property, suppression of Th1 activity, and promotion of the Th2 response might be involved in fibrate-mediated attenuation of the EAE disease process.
Are fibrate drugs safe in humans?
Fibrate drugs like ciprofibrate, clofibrate, fenofibrate, and gemfibrozil induce the proliferation of peroxisomes in rats and mice. Continuous administration of these drugs to the rodents for 40–50 weeks also leads to the formation of hepatic tumor. However, induction of hepatic tumor promotion by fibrate drugs has not been demonstrated in humans, other primates or guinea pig, species which have lost their ability to synthesize ascorbate due to inherent loss of the gulonolactone oxidase gene. Braun et al. have reported that the evolutionary loss of the gulonolactone oxidase gene may contribute to the missing carcinogenic effect of peroxisome proliferators in humans since ascorbate synthesis is accompanied by H2O2 production, and consequently its induction can be potentially harmful. Furthermore, recent studies have also revealed that humans have considerably lower levels of PPAR-α in liver than rodents, and this difference may, in part, explain the species differences in the carcinogenic response to peroxisome proliferators Therefore, hepatic tumor formation may not be a concern in humans. However, combination therapy of cerivastatin and gemfibrozil may cause myopathy and rhabdomyolysis , suggesting that such a combination therapy should be prescribed cautiously.
Conclusion
Over the past several years, scientists have achieved significant progress in unraveling newer aspects of lipid-lowering drugs. However, the contribution and importance of any biomedical field should be judged by two parameters: academic and therapeutic. From the academic point of view, it is important to create a bibliography of the regulation of various biological pathways by lipid-lowering drugs that should help in intellectual expansion of this and other fields. For example, one might predict a possible similarity with and/or merger with another subfield that might provide a more coherent approach for better understanding of a biological process. On the other hand, from the therapeutic point of view, one might expect direct application of lipid-lowering drugs in several incurable human disorders. For both aspects, there has already been outstanding success. The reason behind this lies partially in the significant increase in the aging population in recent years. As people expect to live longer, they are more likely to acquire lipid-related disorders, and that itself should boost the market for lipid-lowering drugs.
In addition to lipid-related disorders, these drugs are also stretching their arms in the direction of various human disorders including neuroinflammatory and neurodegenerative diseases. However, a number of unresolved issues raise doubts about the widespread use of lipid-lowering drugs ieurological disorders. For example, in AD, it is doubtful that cholesterol is to blame for neurodegenerative pathology. Higher neuronal cholesterol has not been shown to increase Aβproduction. It is also not known whether neurons in AD have more cholesterol than control neurons. On the contrary, the brains of AD patients show a specific down-regulation of seladin-1, a protein involved in cholesterol synthesis, and low membrane cholesterol was observed in hippocampal membranes of AD patients with the e4/e4 genotype of ApoE . Similarly, many young MS patients do not experience any lipid-related problems.
Therefore, the challenge is to maintain cholesterol or lipid homeostasis in lipid-independent disorders after the use of lipid-lowering drugs, in order to minimize side effects, and that may not be an easy task. Alternatively, specific targeting of the biological molecule/process but not an unrelated one such as lipid/cholesterol may be another option to achieve a better therapeutic outcome under these conditions. For example, inhibitors of farnesyltransferase or geranyl geranyltransferase may be considered for the treatment of cholesterol-independent disorders, as these drugs do not lower the level of cholesterol while performing one of the most important functions of cholesterol-lowering drugs, i.e., inhibition of small G protein activation. At present, these drugs are on clinical trial to stop the progression of different forms of cancer.
1. http://www.youtube.com/watch?v=VKxQgjj2yVU&feature=related
2. http://www.youtube.com/watch?v=oHTGtYsEJBo&feature=channel
3. http://www.youtube.com/watch?v=fQAx25i4_0I&feature=related
4. http://www.youtube.com/watch?v=wJKkYGe7a3k&feature=related
5. http://www.youtube.com/watch?v=OT9HhHtQruA&feature=related
