1. LIPID-LOWERING DRUGS Dr. Arwa Mahmood Fuzi Alsarraf

2. Objectives  Describe the groups of lipid lowering drugs  Describe the mode of action  Their indication  The clinical use

3. Indications To prevent cardiovascular disease in all those at high risk of atherosclerosis,include  Those who already have atherosclerotic disease  Diabetics aged over 40 years.  Abnormal lipid concentration  Other risk factors (smoking, blood pressure, impaired glucose tolerance, male sex, age, premature menopause, ethnicity, obesity, triglyceride concentration, and a family history of premature cardiovascular disease). Those with a 10-year risk of cardiovascular disease of 20% or more stand to benefit from drug treatment.

4. Lowering the concentration of low-density lipoprotein (LDL) cholesterol and raising high-density lipoprotein (HDL) cholesterol slows the progression of atherosclerosis. Lipid-regulating drug treatment must be combined with  Advice on diet and lifestyle measures,  Lowering of raised blood pressure.  Management of diabetes.

5. For preventing cardiovascular disease events in those at high risk  A target total cholesterol concentration of less than 4 mmol/litre (or a reduction of 25% if that produces a lower concentration) and  A target LDL-cholesterol concentration of less than 2 mmol/litre (or a reduction of 30% if that produces a lower concentration).

6. Classification Statins Fibrates Ezetimibe Anion-exchange resins Nicotinic acid group Omega -3 fatty acid compounds

7. STATINS (HMG CoA) reductase inhibitors (Atorvastatin, Fluvastatin, Pravastatin, Rosuvastatin, And Simvastatin) Competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme a (HMG COA) reductase, an enzyme involved in cholesterol synthesis in the liver. More effective than other lipid-regulating drugs at lowering LDL- Cholesterol concentration but they are less effective than the fibrates in reducing triglyceride concentration. However, statins reduce cardiovascular disease events and total mortality irrespective of the initial cholesterol concentration.

8. Indications  All patients with coronary heart disease (history of angina or acute myocardial infarction ), occlusive arterial disease (peripheral vascular disease, non-haemorrhagic stroke, or transient ischaemic attacks).  For all patients over 40 years with diabetes mellitus  Prevention of cardiovascular disease in asymptomatic individuals at increased risk (10-year cardiovascular disease risk of 20% or more)

9. Caution  History of liver disease or with a high alcohol intake (should be avoided in active liver disease). Liver-function tests should be carried out before and within 1 – 3 months of starting treatment and thereafter at intervals of 6 months for 1 year  Hypothyroidism should be managed adequately before starting treatment with a statin.  Caution if there is risk for myopathy or rhabdomyolysis  Avoided in porphyria

10. Contraindication  Active liver disease (or persistently abnormal liver function tests),  In pregnancy (adequate contraception required during treatment and for 1 month afterwards)  Breast-feeding

11. Side effects  Reversible myositis is a rare but significant side-effect.  Headache  Altered liver-function tests ( rarely, hepatitis)  Paraesthesia  Gastro-intestinal effects (abdominal pain, flatulence, constipation, diarrhoea, nausea and vomiting).  Rash and hypersensitivity reactions (including angioedema and anaphylaxis) rarely

12. ATORVASTATIN (LIPITOR)  Primary hypercholesterolaemia and combined hyperlipidaemia, 10 mg once daily; increased at intervals of at least 4 weeks to max. 80 mg once daily  Familial hypercholesterolaemia, initially 10 mg daily, increased at intervals of at least 4 weeks to 40 mg once daily; if necessary, further increased to max 80 mg once daily (or 40 mg once daily combined with anion-exchange resin in heterozygous familial hypercholesterolaemia)  Prevention of cardiovascular events in type 2 diabetes, 10 mg once daily

13. FLUVASTATINE (LESCOL(  Hypercholesterolaemia or combined hyperlipidaemia, initially 20 – 40 mg daily in the evening, adjusted at intervals of at least 4 weeks; up to 80 mg daily  Prevention of progression of coronary atherosclerosis, 40 mg daily in the evening  Following percutaneous coronary intervention, 80 mg daily

14. ROSUVASTATINE (CRESTOR(  Initially 5 – 10 mg once daily increased if necessary at intervals of at least 4 weeks to 20 mg once daily, increased after further 4 weeks to 40 mg daily ( only in severe hypercholesterolaemia with high cardiovascular risk and under specialist supervision)  Elderly initially 5 mg once daily  Patient of asian origin, initially 5 mg once daily increased if necessary to max. 20 mg daily

15. SIMVASTATINE (ZOCOR(  Primary hypercholesterolaemia, combined hyperlipidaemia, 10 – 20 mg daily at night, adjusted at intervals of at least 4 weeks; usual range 10 – 80 mg once daily at night  Homozygous familial hypercholesterolaemia, 40 mg daily at night or 80 mg daily in 3 divided doses (with largest dose at night)  Prevention of cardiovascular events, initially 20 – 40 mg once daily at night, adjusted at intervals of at least 4 weeks; max. 80 mg once daily at night

16. FIBRATES Bezafibrate, Ciprofibrate, Fenofibrate, and Gemfibrozil  Act mainly by decreasing serum triglycerides; they have variable effects on LDL-cholesterol.  Although a fibrate may reduce the risk of coronary heart disease events in those with low HDL-cholesterol or with raised triglycerides, a statin should be used first.  Fibrates may be considered first-line therapy in those whose serum-triglyceride concentration is greater than 10 mmol/litre.

17. Caution  Fibrates can cause a myositis-like syndrome, especially if renal function is impaired.  Combination of a fibrate with a statin increases the risk of muscle effects (especially rhabdomyolysis) -gemfibrozil and statins should not be used concomitantly.  Monitoring of liver function and creatinine kinase should be considered

18. Contraindication  Severe hepatic impairment  Renal impairment  Hypoalbuminaemia  Primary biliary cirrhosis  Gall bladder disease  Nephrotic syndrome  Pregnancy  Breast-feeding

19. Side effects  Gastro-intestinal disturbances  Rash, pruritus less commonly  headache, fatigue, dizziness, insomnia rarely  Gallstones, hepatomegaly, cholestasis, hypoglycaemia, impotence, anaemia, leucopenia, thrombocytopenia, increased risk of bleeding, alopecia, photosensitivity reactions, raised serum creatinine (unrelated to renal impairment), and myotoxicity

20. Bezafibrate (bezalip) 200 mg 3 times daily fenofibrate 200 mg 1 capsule daily

21. Gemfibrazole (lopid( 300 mg cap 600mg tab (0.9 – 1.2 gm/day) Indications  Hyperlipidaemias of types IIa, II b, III, IV and V in patients who have not responded adequately to diet and other appropriate measures Side effects  Gastro-intestinal disturbances  Headache, fatigue, vertigo  Eczema, rash less commonly  Atrial fibrillation Rarely  pancreatitis, appendicitis, disturbances in liver functin, dizziness, paraesthesia, sexual dysfunction, thrombocytopenia, anaemia, leucopenia, eosinophilia, bone- marrow suppression, myalgia, myopathy, myasthenia, myositis, blurred vision, exfoliative dermatitis, alopecia, and photosensitivity

22. Anion-exchange resins Cholestyramine, Colestipol  Act by binding bile acids, preventing their reabsorption; this promotes hepatic conversion of cholesterol into bile acids; the resultant increased LDL-receptor activity of liver cells increases the clearance of LDL-cholesterol from the plasma  Thus effectively reduce LDL-cholesterol but can aggravate hypertriglyceridaemia.

23. Caution  Interfere with the absorption of fat-soluble vitamins; supplements of vitamins A, D and K may be required when treatment is prolonged. Side effects  Gastro-intestinal side-effects predominate. Constipation is common, diarrhoea, nausea, vomiting, and gastro-intestinal discomfort.  Hypertriglyceridaemia may be aggravated.  Increased bleeding tendency has been reported due to hypoprothrombinaemia associated with vitamin K deficiency.

24. Cholestyramine (4 g/sachet )  Hyperlipidaemias, particularly type IIa, in patients who have not responded adequately to diet and other appropriate measures  Pruritus associated with partial biliary obstruction and primary biliary cirrhosis  Diarrhoeal disorders Dose  Lipid reduction 12 – 24 g daily in water, in single or up to 4 divided doses; up to 36 g daily

25. Ezetimibe Inhibits the intestinal absorption of cholesterol. Ezetrol (10 mg once daily) Indications  Adjunct to dietary manipulation in patients with primary hypercholesterolaemia in combination with a statin or alone  In homozygous familial hypercholesterolaemia in combination with a statin

26. Caution  Hepatic impairment (avoid if moderate or severe(  Pregnancy  If ezetimibe is used in combination with a statin, there is an increased risk of rhabdomyolysis

27. Side effect  Gastro-intestinal disturbances  Headache, fatigue, myalgia Rarely  Arthralgia, hypersensitivity reactions including rash and angioedema, hepatitis Very rarely  Pancreatitis, cholelithiasis, cholecystitis, thrombocytopenia, raised creatine kinase, myopathy, and rhabdomyolysis

28. NICOTINIC ACID (VIT B3) Reduce perepherral fatty acid release lowers both cholesterol and triglyceride increases HDL-cholesterol.  Indicated as adjunct to statin in dyslipidaemia or used alone if statin not tolerated  Dose Initially 100 – 200 mg 3 times daily, gradually increased over 2 – 4 weeks to 1 – 2 g 3 times daily

29. Cautions Unstable angina, acute myocardial infarction, diabetes mellitus, gout, peptic ulceration\, hepatic impairment, renal impairment, pregnancy Contra-indications Arterial bleeding; active peptic ulcer disease; breast-feeding Side-effects Vasodilatation, flushing, itching, rashes, urticaria, erythema; heartburn, epigastric pain, nausea, diarrhoea, headache, malaise, dry eyes; rarely angioedema, bronchospasm, anaphylaxis

30. Omega-3 fatty acid compounds  Omega-3 fatty acid compounds may be used to reduce triglycerides, as an alternative to a fibrate and in addition to a statin, in patients with combined (mixed) hyperlipidaemia not adequately controlled with a statin alone.  A triglyceride concentration exceeding 10 mmol/litre is associated with acute pancreatitis and lowering the concentration reduces this risk.

31. caution haemorrhagic disorders, anticoagulant treatment (bleeding time increased) hepatic impairment. pregnancy Side effects  Gastro-intestinal disturbances  Less commonly taste disturbances, dizziness, and hypersensitivity reactions  Rarely hepatic disorders, headache, hyperglycaemia, acne, and rash