Hypolipidaemic Drugs

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Chapter: Essential pharmacology : Hypolipidaemic Drugs And Plasma Expanders

The hypolipidaemic drugs have attracted considerable attention because of their potential to prevent cardiovascular disease by retarding the accelerated atherosclerosis in hyperlipidaemic individuals.


HYPOLIPIDAEMIC DRUGS

 

These are drugs which lower the levels of lipids and lipoproteins in blood.

 

The hypolipidaemic drugs have attracted considerable attention because of their potential to prevent cardiovascular disease by retarding the accelerated atherosclerosis in hyperlipidaemic individuals.

 

Lipid Transport

 

Lipids are carried in plasma in lipoproteins after getting associated with several apoproteins; plasma lipid concentrations are dependent on the concentration of lipoproteins. The core of lipoprotein globules consists of triglycerides (TGs) or cholesteryl esters (CHEs) while the outer polar layer has phospholipids, free cholesterol (CH) and apoproteins. The lipoproteins have been divided into 6 classes on the basis of their pCh. No. size and density. They also differ in the nature of apoproteins, the ratio of TG and CHE, tissue of origin and fate. These are given in Table 45.1.

 


 

Dietary lipids are absorbed in the intestine with the help of bile acids. Chylomicrons (Chy) are formed and passed into lacteals—reach blood stream via thoracic duct. During their passage through capillaries, the endothelium bound lipoprotein lipase hydrolyses the TGs into fatty acids which pass into muscle cells to be utilized as energy source and in fat cells to be reconverted into TGs and stored. The remaining part—chylomicron remnant (Chy. rem.) containing mainly CHE and little TG is engulfed by liver cells, which have receptors for the surface apoproteins of Chy. rem., and digested. Free CH that is liberated is either stored in liver cells after re-esterification or incorporated into a different lipoprotein and released in blood or excreted in bile as CH/bile acids.

 


 

Liver secretes very low density lipoproteins (VLDL) containing mainly TG and some CHE into blood. VLDL is acted upon by endothelial lipoprotein lipase in the same way as on Chy and the fatty acids pass into adipose tissue and muscle; the remnant called intermediate density lipoprotein (IDL) now contains more CHE than TG. About half of the IDL is taken back by the liver cells by attachment to another receptor (LDL receptor), while the rest loses the remaining TGs gradually and becomes low density lipoprotein (LDL) containing only CHE. The LDL circulates in plasma for a long time; its uptake into liver and other tissues is dependent on the need for CH. NO. The rate of LDL uptake is regulated by the rate of LDL receptor synthesis in a particular tissue.

 

The CHE of LDL is deesterified and used mainly for cell membrane formation. The CH released into blood from degradation of membranes is rapidly incorporated in high density lipoproteins (HDL), esterified with the help of an enzyme lecithin: cholesterol acyltransferase (LCAT) and transferred back to VLDL or IDL, completing the cycle.

 

The excess lipoproteins in plasma are phagocytosed by macrophages for disposal. When too much of lipoproteins have to be degraded in this manner, CH is deposited in atheromas (in arterial walls) and xanthomas (in skin and tendons). Raised levels of VLDL, IDL and LDL (rarely Chy and Chy. rem. also) are atherogenic, while HDL may be protective, because HDL facilitates removal of CH from tissues.

 

Hyperlipoproteinaemias can be:

 

Secondary: associated with diabetes, myxoedema, nephrotic syndrome, chronic alcoholism, drugs (corticosteroids, oral contraceptives, β blockers) etc.

 

Primary: due to:

 

·      A single gene defect: is familial and called ‘monogenic’ or genetic.

· Multiple genetic, dietary and physical activity related causes: ‘polygenic’ or multifactorial.

 

On the whole, LDL is the primary carrier of plasma CHE, and VLDL that of TGs. The important features of major types of hyperlipoproteinaemias are given in Table 45.2.

 

Classification

 

1.     HMGCoA reductase inhibitors (Statins):

 

Lovastatin, Simvastatin, Pravastatin, Atorvastatin, Rosuvastatin

 

2.     Bile acid sequestrants (Resins):

 

Cholestyramine, Colestipol

 

3.     Activate lipoprotein lipase (Fibric acid derivatives):

 

Clofibrate, Gemfibrozil, Bezafibrate, Fenofibrate.

 

4.     Inhibit lipolysis and triglyceride synthesis:

 

       Nicotinic acid

 

5.     Others:

 

 Ezetimibe, Gugulipid.

 

The mechanism of action and profile of lipid lowering effect of important hypolipidaemic drugs is summarized in Table 45.3.



 

HMG-CoA REDUCTASE INHIBITORS (STATINS)

 

Introduced in the 1980s, this class of compounds are the most efficacious and best tolerated hypolipidaemic drugs. They competitively inhibit conversion of 3Hydroxy3methyl glutaryl coenzyme A (HMG-CoA) to mevalonate (rate limiting step in CH synthesis) by the enzyme HMG-CoA reductase. Therapeutic doses reduce CH synthesis by 20–50%. This results in compensatory increase in LDL receptor expression on liver cells increased receptor mediated uptake and catabolism of IDL and LDL. Over long-term, feedback induction of HMG-CoA reductase tends to increase CH synthesis, but a steady state is finally attained with a dose-dependent lowering of LDL-CH levels.

 

Different statins differ in their potency and maximal efficacy in reducing LDL-CH. NO. The daily dose for lowering LDL-CH by 30–35% is lovastatin 40 mg, pravastatin 40 mg, simvastatin 20 mg, atorvastatin 10 mg, rosuvastatin 5 mg. Moreover, at their maximum recommended doses simvastatin, atorvastatin and rosuvastatin can reduce LDL-CH by upto 45–55%, while the ceiling effect of lovastatin and pravastatin is 35–40% LDL-CH reduction. All statins produce peak LDL-CH lowering after 1–2 weeks therapy. Hepatic synthesis of VLDL is concurrently reduced and its removal from plasma is enhanced.

 

A dose-dependent effect is seen with all statins. With lovastatin a mean reduction of LDL-CH by 25% at 20 mg/day, 32% at 40 mg/day and 40% at 80 mg/day has been measured. A concurrent fall by 10–30% in plasma TG level, probably due to reduction of VLDL occurs. A rise in HDLCH by 5–15% is also noted. Simultaneous use of bile salt sequestrant augments the LDL lowering effect upto 60% and addition of nicotinic acid to this combination may boost the effect to 70% reduction in LDL-CH. NO. Statins are effective in secondary hyper-cholesterolaemias also. The more efficacious statins (simvastatin, atorvastatin, rosuvastatin) given at their higher doses effectively reduce TGs (by 25% to 35%) when they are moderately raised, but not when they are markedly raised.

 

Because HMG-CoA reductase activity is maximum at midnight, all statins are administered at bed time to obtain maximum effectiveness. However, this is not necessary for atorvastatin and rosuvastatin, which have long plasma t½.

 

All statins, except rosuvastatin are metabolized primarily by CYP3A4. Inhibitors and inducers of this isoenzyme respectively increase and decrease statin blood levels.

 

Lovastatin It is the first clinically used statin; is lipophilic and given orally in the precursor lactone form. Absorption is incomplete and first pass metabolism is extensive. Metabolites are excreted mainly in bile. The t½ is short (1–4 hours).

 

Dose: 10–40 mg/day (max. 80 mg).

 

ROVACOR, AZTATIN, LOVAMEG 10, 20 mg tabs.

 

Simvastatin It is twice as potent as lovastatin; also more efficacious. A greater rise in HDLCH (when low) has been noted with simvastatin than others. Like lovastatin, it is lipophilic and given in the lactone precursor form. Oral absorption is better and first pass metabolism extensive; t½ is 2–3 hr.

 

Dose: 5–20 mg/day (max. 40 mg)

 

SIMVOTIN, SIMCARD, ZOSTA 5, 10, 20 mg tabs.

 

Pravastatin It is hydrophilic and given in the active form. At low doses it is equipotent to lovastatin, but at higher doses (40–80 mg/day), CH lowering effect is less. It can be employed when reduction of LDL-CH by < 25% is contemplated. An additional action of decrease in plasma fibrinogen level has been observed. The t½ is 1–3 hours.

 

PRAVATOR 10, 20 mg tabs.

 

Atorvastatin This newer statin is more potent and appears to have the highest LDL-CH lowering efficacy at maximal daily dose of 80 mg. At this dose a greater reduction in TGs is noted if the same was raised at baseline. Atorvastatin has a much longer plasma t½ of 18–24 hr than other statins, and has additional antioxidant property.

 

Dose: 1040 mg/day (max. 80 mg)

 

AZTOR, ATORVA, ATORLIP 10, 20 mg tabs.

 

Rosuvastatin This is the latest and the most potent statin (10 mg rosuvastatin ~ 20 mg atorvastatin), with a plasma t½ of 18–24 hours. Greater LDL-CH reduction can be obtained in severe hypercholesterolaemia; partly due to its longer persistence in the plasma. In patients with raised TG levels, rosuvastatin raises HDLCH by 15–20% (greater rise than other statins).

 

Dose: Start with 5 mg OD, increase if needed upto 20 mg/ day, (max 40 mg/day)

 

ROSUVAS, ROSYN 5, 10, 20 mg tabs.

 

Adverse Effects

 

All statins are remarkably well tolerated; overall incidence of side effects not differing from placebo. Notable side effects are:

 

·    Headache, nausea, bowel upset, rashes.

·    Sleep disturbances (probably more with lipophilic drugs).

·    Rise in serum transaminase can occur, but liver damage is rare.

·    Muscle tenderness and rise in CPK levels occurs infrequently. Myopathy is the only serious reaction, but is rare (< 1 per 1000). Few fatalities due to rhabdomyolysis are on record. Myopathy is more common when nicotinic acid/gemfibrozil or CYP3A4 inhibitor— ketoconazole/ erythromycin/cyclosporine/ HIV protease inhibitor is given concurrently. Gemfibrozil inhibits the hepatic uptake of statins by the organic anion transporter OATP2. Fenofibrate interferes the least with statin uptake/metabolism and should be preferred for combining with them.

 

Use

 

Statins are the first choice drugs for primary hyperlipidaemias with raised LDL and total CH levels, with or without raised TG levels (Type IIa, IIb, V), as well as for secondary (diabetes, nephrotic syndrome) hyper-cholesterolaemia.

 

Efficacy of statins in reducing raised LDL-CH associated mortality and morbidity is now well established.

 

In the ‘Scandinavian Simvastatin Survival Study’ (4S study, 1994), patients with history of MI (80%) or angina (20%) and raised serum CH level (> 212 mg/dl) were treated with simvastatin or placebo. Simvastatin reduced total CH by 25%, LDL-CH by 35%, raised HDLCH by 8%. Over a period of 6 years coronary artery disease (CAD) mortality was less by 42%, overall mortality by 30% and cerebrovascular events by 30% in the simvastatin group. Similar results have been obtained with other statins, e.g. the West of Scotland Coronary Prevention Study (WOSCOPS) in men with no history of MI has found pravastatin to lower risk of MI by 31% and all cause mortality by 22%.

 

Subsequent studies like Long-term intervention with pravastatin in ischaemic disease (LIPID1998), Airforce/ Texas coronary atherosclerosis prevention study (AFCAPS/TexCAPS1998), Cholesterol and recurrent events (CARE1998), and trials conducted by Heart Protection Study Collaborative Group (2002, 2004) in over 20,000 patients have confirmed the mortality and morbidity benefits of statins, including stroke prevention.

 

Beneficial effects in subjects who have raised CH levels but no evidence of CAD may relate to improved coronary artery compliance and atheromatous plaque stabilization due to suppression of macrophage mediated inflammation, reducing chances of plaque rupture and thrombus formation. Improvement in endothelial function due to increased NO production and reduction in LDL oxidation are proposed as additional mechanisms by which statins may exert anti-atherosclerotic action. On the basis of these results as well as the excellent patient acceptability, the statins are being increasingly used for primary and secondary hyper-cholesterolaemia with or without raised TG levels. They are the first choice drugs for dyslipidaemia in diabetics.

 
BILE ACID SEQUESTRANTS (RESINS)

 

Cholestyramine and Colestipol

 

These are basic ion exchange resins supplied in the chloride form. They are neither digested nor absorbed in the gut: bind bile acids in the intestine interrupting their enterohepatic circulation. Faecal excretion of bile salts and CH (which is absorbed with the help of bile salts) is increased. This indirectly leads to enhanced hepatic metabolism of CH to bile acids. More LDL receptors are expressed on liver cells: clearance of plasma IDL, LDL and indirectly that of VLDL is increased.

 

 

Resins have been shown to retard atherosclerosis, but are not popular clinically because they are unpalatable, inconvenient, have to be taken in large doses, cause flatulence and other g.i. symptoms, interfere with absorption of many drugs and have poor patient acceptability.

 

 

FIBRIC ACID DERIVATIVES

 

The fibrates (isobutyric acid derivatives) primarily activate lipoprotein lipase which is a key enzyme in the degradation of VLDL resulting in lowering of circulating TGs. This effect is exerted through paroxisome proliferator-activated receptor α (PPARα) that is a gene transcription regulating receptor expressed in liver, fat and muscles. Activation of PPARα enhances lipoprotein lipase synthesis and fatty acid oxidation. PPARα may also mediate enhanced LDL receptor expression in liver seen particularly with second generation fibrates. Fibrates decrease hepatic TG synthesis as well. A peripheral effect reducing circulating free fatty acids has also been shown.

 

 

Drugs in this class primarily lower TG levels by 20–50%, generally accompanied by 10–15% decrease in LDL-CH and a 10–15% increase in HDLCH. NO. In some patients with hyper-triglyceridaemia LDL-CH may rise, partly because of inability of LDL receptor to clear the excess number of LDL pCh. No.s generated by enhanced VLDL catabolism. The increase in HDLCH is at least in part due to transfer of surface lipid components from catabolized VLDL to HDL, and partly due to increased production of HDL apoproteins (apo AI, apo AII) by liver. Gemfibrozil also appears to reduce VLDL secretion by liver.

 

LDL composition may be altered. Gemfibrozil and bezafibrate have been shown to shift small dense LDL pCh. No.s (believed to be more atherogenic) to larger less dense pCh. No.s.

 

Clofibrate

 

It was a widely used hypolipidaemic drug, but later evidence showed that it does not prevent atherosclerosis, therefore has gone out of use.

 

Gemfibrozil

 

This fibric acid derivative effectively lowers plasma TG level by enhancing breakdown and suppressing hepatic synthesis of TGs. Besides high efficacy in type III hyperlipoproteinemia, gemfibrozil has shown action in subjects with raised blood CH in addition. In the ‘Helsinki Heart Study’ men without known CAD treated with gemfibrozil had a 34% reduction in fatal and nonfatal MI, though overall mortality was not affected. Additional actions to decrease the level of clotting factor VII-phospholipid complex and promotion of fibrinolysis have been observed, which may contribute to the anti-atherosclerotic effect.

 

Pharmacokinetics

 

Gemfibrozil is completely absorbed orally, metabolized by glucuronidation and undergoes some enterohepatic circulation. It is excreted in urine; elimination t½ 1–2 hr.

 

Adverse Effects

 

Common side effects are epigastric distress, loose motions.

Skin rashes, body ache, eosinophilia, impotence, headache and blurred vision have been reported. Myopathy is uncommon. Gemfibrozil + statin increases risk of myopathy.

Incidence of gallstone is not increased as seen with clofibrate.

It is contraindicated during pregnancy.

 

GEMPAR, NORMOLIP 300 mg cap. LOPID 300 mg cap, 600 mg and 900 mg tabs.

 

Use

 

In a dose of 600 mg BD taken before meals, gemfibrozil is the drug of choice for patients with markedly raised TG levels, whether or not CH levels are also raised. Episodes of acute pancreatitis are prevented in patients with chylomicronaemia and severe hyper-triglyceridaemia. It is most effective in type III hyper-lipoproteinaemia; also a first line drug in type IV and type V disease. It may be used as an adjuvant drug in type IIb patients.

 

Bezafibrate

 

This second generation fibric acid derivative is an alternative for gemfibrozil in mixed hyper-lipidaemias (type III, IV and V). Though it has also been indicated in hyper-cholesterolaemia (type II), it is inferior to statins and resins. It has not shown propensity to increase LDL-CH in hyper-triglyceridaemic patients and appears to have greater LDL-CH lowering action than gemfibrozil. Decreased level of circulating fibrinogen and glucose has been demonstrated. The 5 year ‘Bezafibrate Coronary Atherosclerosis Intervention Trial’ (BECAIT) in young male post-MI subjects has shown it to slow atherosclerotic process and reduce coronary events.

 

Adverse effects and contraindications of bezafibrate are similar to other fibrates. Main side effects are g.i. upset, myalgia, rashes. Dose reduction is needed in elderly and in renal insufficiency. Action of oral anticoagulants may be enhanced.

 

In contrast to other fibrates, combination of bezafibrate with a statin has not so far been found to increase the incidence of rhabdomyolysis.

 

Dose: 200 mg TDS with meals.

 

BEZALIP 200, 400 mg tab.

 

Fenofibrate

 

Another 2nd generation prodrug fibric acid derivative which has greater HDL–CH raising and greater LDL-CH lowering action than other fibrates: may be more appropriate as an adjunctive drug in subjects with raised LDL-CH levels in addition to raised TG levels. No rise in LDL-CH has been observed in patients with high TG levels. Its t½ is 20 hr. Adverse effects are myalgia, hepatitis, rashes. Cholelithiasis and rhabdomyolysis are rare. Fenofibrate appears to be the most suitable fibrate for combining with statins, because statin metabolism is minimally affected and enhancement of statin myopathy risk is lower. Indications of fenofibrate are similar to that of gemfibrozil.

 

Dose: 200 mg OD with meals.

 

FENOLIP, LIPICARD 200 mg cap.

 

NICOTINIC ACID (NIACIN)

 

It is a B group vitamin (see Ch. No. 67) which in much higher doses reduces plasma lipids. This action is unrelated to its vitamin activity and not present in nicotinamide. When nicotinic acid is given, TGs and VLDL decrease rapidly, followed by a modest fall in LDL-CH and total CH. A 20–50% reduction in plasma TGs and 15–25% reduction in CH levels has been recorded. Nicotinic acid is the most effective drug to raise HDL-CH; a 20–35% increase is generally obtained. Relatively lower dose suffices to raise HDL–CH.

 

Nicotinic acid reduces production of VLDL in liver by inhibiting TG synthesis. Indirectly the VLDL degradation products IDL and LDL are also reduced. No direct effect on CH and bile acid metabolism has been found. It inhibits intracellular lipolysis in adipose tissue and increases the activity of lipoprotein lipase that clears TGs.

 

 

A cell surface G-protein coupled receptor which negatively regulates adipocyte adenylyl cyclase has been found to selectively bind nicotinic acid, and has been called ‘niacin receptor’. Nicotinic acid appears to inhibit lipolysis in adipose tissue by decreasing hormone stimulated intracellular cAMP formation through this receptor. Hepatic VLDL production is believed to be decreased due to reduced flow of fatty acids from adipose tissue to liver.

 

Adverse Effects

 

The large doses needed for hypolipidaemic action are poorly tolerated. Only about half of the patients are able to take the full doses.

 

Nicotinic acid is a cutaneous vasodilator: marked flushing, heat and itching (especially in the blush area) occur after every dose. This can be minimized by starting with a low dose taken with meals and gradually increasing as tolerance develops. Aspirin taken daily largely prevents the reaction (PGs may be involved).

 

Dyspepsia is very common; vomiting and diarrhoea occur when full doses are given. Peptic ulcer may be activated.

 

Dryness and hyperpigmentation of skin can be troublesome. Other long-term effects are:

 

Liver dysfunction and jaundice. Serious liver damage is the most important risk.

Hyperglycaemia, precipitation of diabetes (should not be used in diabetics) . Hyperuricaemia and gout, atrial arrhythmias. It is contraindicated during pregnancy and in children.

 

Interaction

 

Postural hypotension may occur in patients on antihypertensives when they take nicotinic acid.

Risk of myopathy due to statins is increased.

 

Dose: Start with 100 mg TDS, gradually increase to 2–6 g per day in divided doses. It should be taken just after food to minimize flushing and itching.

NIALIP 250, 375, 500 mg tabs.

 

Use

 

Nicotinic acid is a wide spectrum hypolipidaemic drug. It is highly efficacious in hyper-triglyceridaemia (type III, IV, V) whether associated with raised CH level or not. It is mostly used to lower VLDL and raise HDL levels, and as an adjunctive drug to statins/fibrates.

 

Nicotinic acid is the most effective drug in reducing plasma TG levels and controlling pancreatitis in genetic type IV and type V disorders. Long-term use prevents further attacks of pancreatitis. Given over long-term in postMI patients, it has been found to reduce recurrences of MI and overall mortality. However, because of marked side effects, use of nicotinic acid is restricted to high risk cases only.

 

OTHER HYPOLIPIDAEMICS

 

Ezetimibe

 

It is a new drug of its own kind that acts by inhibiting intestinal absorption of cholesterol and phytosterols. It interferes with a specific CH transport protein NPC1C1 in the intestinal mucosa and reduces absorption of both dietary and biliary CH. NO. There is compensatory increase in hepatic CH synthesis, but LDL-CH level is lowered by 15–20%. The enhanced CH synthesis can be blocked by statins, and the two drugs have synergistic LDL-CH lowering effect.

 

Due to very poor aqueous solubility, ezetimibe is not absorbed as suCh. No. It is absorbed partly after getting conjugated with glucuronic acid in the intestinal mucosa secreted in bile undergoes enterohepatic circulation and is mainly excreted in faeces. A plasma t½ of 22 hours has been calculated.

 

Used alone, ezetimibe is a weak hypo-cholesterolaemic drug; LDL CH lowering beyond 15–20% is not obtained by increasing the dose. Though it may be used alone in mild hyper-cholesterolaemia when a statin is contraindicated/ not tolerated, its main value is to supplement statins without increasing their dose. The combination of ezetimibe + low dose of a statin is as effective in lowering LDL-CH as high dose of statin alone. Upto 60% decrease in LDL-CH level has been obtained with a combination of simvastatin + ezetimibe. No specific adverse effect, except reversible hepatic dysfunction and rarely myositis has been noted with ezetimibe.

 

Dose: 10 mg OD; ZETICA, EZEDOC 10 mg tab.

 

Gugulipid

 

It is a mixture of sterones obtained from ‘gum guggul’ which has been used in Ayurveda. Modest lowering of plasma CH and TGs occurs after continued use of gugulipid. It is well tolerated: loose stools are the only significant side effect.

 

Dose: 25 mg TDS; GUGLIP 25 mg tab.

  

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