Hyperlipidemia

pharmacotherpeutics I - 2nd Pharm D

1. HYPERLIPIDEMIA

2. Disorders of lipoprotein metabolism that result in elevated serum concentrations of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) increase the risk of an individual developing cardiovascular disease (CVD). In contrast, high-density lipoprotein cholesterol (HDL-C) confers protection against CVD, with the risk reducing as HDL-C increases . It is, therefore, clear that the term hyperlipidaemia , which was formerly used to describe disorders of lipoprotein metabolism, is inappropriate. It is more appropriate to use the term dyslipidaemia .

3. NORMAL VALUES OF LIPOPROTEINS

4. ETIOLOGY Primary dyslipidaemia Up to 60% of the variability in cholesterol fasting lipids may be genetically determined, although expression is often influenced by interaction with environmental factors.

5. Secondary dyslipidaemia Dyslipidaemias that occur secondary to a number of disorders, dietary indiscretion or as a side effect of drug therapy account for up to 40% of all dyslipidaemias .

6. RISK FACTORS

7. LIPID TRANSPORT AND LIPOPROTEIN METABOLISM When dietary cholesterol and triglycerides are absorbed from the intestine they are transported in the intestinal lymphatics as chylomicrons . The chylomicrons pass through blood capillaries in adipose tissue and skeletal muscle where the enzyme lipoprotein lipase is located, bound to the endothelium. Lipoprotein lipase is activated by apoprotein C-II on the surface of the chylomicron . The lipase catalyses the breakdown of the triglyceride in the chylomicron to free fatty acid and glycerol, which then enter adipose tissue and muscle. The cholesterol-rich chylomicron remnant is taken up by receptors on hepatocyte membranes, and in this way dietary cholesterol is delivered to the liver and cleared from the circulation.

8. LIPID PROFILE TEST Treatment should not be initiated on the basis of a single random sample. Patients must fast for 12–15 h before they can be measured. Patients must also be seated for at least 5 min prior to drawing a blood sample. Once the TC, HDL-C and triglyceride values are known it is usual to calculate the value for LDL-C using the Friedewald equation: The Friedewald equation should not be used in non-fasting individuals,

9. LIPID-LOWERING THERAPY There are five main classes of lipid-lowering agents available: • Statins • Fibrates • Bile acid binding agents • Cholesterol absorption inhibitors • Nicotinic acid and derivatives.

10. Statins The statins , which selectively inhibit 3-hydroxy-3-methylglutaryl-CoA reductase (HMG- CoA reductase ) was a significant advance in the treatment of dyslipidaemia . Their primary site of action is the inhibition of HMG- CoA reductase in the liver and the subsequent inhibition of the formation of mevalonic acid, the rate-limiting step in the biosynthesis of cholesterol. Adverse effects The commonest include gastro-intestinal symptoms, altered liver function tests and muscle aches. Myopathy (unexplained muscle soreness or weakness) leading to myoglobulinuria secondary to rhabdomyolysis is also a rare but serious potential adverse effect of all the statins that can occur at any dose.

11. In patients receiving a statin , a once-daily regimen involving an evening dose is often preferred . Several of the statins ( fluvastatin , pravastatin , simvastatin ) are claimed to be more effective when given as a single dose in the evening compared to a similar dose administered in the morning. This has been attributed to the fact that cholesterol biosynthesis reaches peak activity at night. However, atorvastatin and rosuvastatin may be taken in the morning or evening with similar efficacy. A reduction in TC and LDL-C is usually seen with all statins within 2 weeks, with a maximum response occurring by week 4 and maintained thereafter during continued therapy.

12. Fibrates Members of this group include bezafibrate , ciprofibrate , fenofibrate and gemfibrozil . They are thought to act by binding to peroxisome proliferator -activated receptor α ( PPAR- α) on hepatocytes. This then leads to changes in the expression of genes involved in lipoprotein metabolism. Fibrates take 2–5 days to have a measurable effect on VLDL-C, with their optimum effect present after 4 weeks. Fibrates should not be used first line to reduce lipid levels in either primary or secondary prevention. Fibrates can be used first line in patients with isolated severe hypertriglyceridaemia . In individuals with mixed hyperlipidaemia , fibrates may be considered when a statin or other agent is contraindicated or not tolerated.

13. Gastro-intestinal symptoms such as nausea, diarrhoea and abdominal pain are common but transient, and often resolve after a few days of treatment. Bile acid binding agents The three members of this group in current use are colestyramine , colestipol and colesevelam . Both colestyramine and colestipol were formerly considered first-line agents in the management of patients with FH but now have limited use. Following oral administration, neither colestyramine , colestipol nor colesevelam are absorbed from the gut. They bind bile acids in the intestine, prevent re-absorption and produce an insoluble complex that is excreted in the faeces. The depletion of bile acids results in an increase in hepatic synthesis of bile acids from cholesterol.

14. Bloating, flatulence, heartburn and constipation are common complaint. Each sachet of colestyramine or colestipol should be added to at least 150 or 100 mL of liquid, respectively, and stirred vigorously to avoid the powder clumping. Medication that has to be taken should be administered 1 h before (at least 4 h for colesevelam ) or at least 4 h after the bile acid binding agent. Cholesterol absorption inhibitors Ezetimibe is a 2-azetidinone derivative that interacts with a putative cholesterol transporter in the intestinal brush border membrane and thereby blocks cholesterol re-absorption from the gastro-intestinal tract. When added to a statin , ezetimibe lowers LDL-C more than with a statin alone.

15. Nicotinic acid and derivatives Nicotinic acid in pharmacological doses (1.5–6 g) lowers serum LDL-C, TC, VLDL-C, apolipoprotein B, triglycerides and Lp (a) and increases levels of HDL-C. The commonest side effect of nicotinic acid is flushing which is most prominent in the head, neck and upper torso and occurs in over 90% of patients. It clearly has a range of beneficial effects on the lipid profile and is licensed for use in combination with a statin , or by itself if the patient is statin intolerant or a statin is inappropriate.

16. Fish oils Fish oil preparations rich in omega-3 fatty acids have been shown to markedly reduce serum cholesterol. Data from several studies suggest that omega-3 fatty acids protect against CHD mortality, particularly sudden death. Commercial products available contain omega -3- acid ethyl esters ( Omacor ®) and omega-3-marine triglycerides ( Maxepa ®). Either can be used as an alternative to a fibrate or in combination with a statin . Soluble fibre Preparations containing soluble fibre , such as ispaghula husk, have been shown to reduce lipid levels. The fibre is thought to bind bile acids in the gut and increase the conversion of cholesterol to bile acids in the liver.

17. Cholesterol ester transfer protein (CETP) inhibitors CETP transfers cholesterol from HDL-C to LDL-C and VLDL-C, thereby altering the HDL-C:LDL-C ratio in a potentially unfavourable manner. As a consequence, inhibitors of CETP are expected to have a beneficial cardiovascular effect. Torcetrapib was a potent inhibitor of CETP. Newer inhibitors of CETP include dalcetrapib and anacetrapib and these look more promising.