Antihyperlipidemia Notes (updated Jan 2025) PDF

Module of Metabolism ANTIHYPERLIPIDAEMIA Prepared by: Assoc. Prof. Dr Kamisah Yusof Dept. of Pharmacology, Faculty of Medicine, UKMMC,...

Module of Metabolism ANTIHYPERLIPIDAEMIA Prepared by: Assoc. Prof. Dr Kamisah Yusof Dept. of Pharmacology, Faculty of Medicine, UKMMC, Universiti Kebangsaan Malaysia. Email: [email protected] 1 HYPERLIPOPROTEINEMIA CLASSIFICATIONS Clinical Designation Main Features Familial hyperchylomicronemia ↑↑ chylomicron (↑↑ TG, ↑ cholesterol) Familial hypercholesterolemia ↑ LDL Combined hyperlipoproteinemia/ ↑ VLDL, hyperlipidemia ↑ LDL Familial hyperlipidemia ↑ IDL, ↑ -lipoproteins (LDL) (↑ cholesterol, ↑ TG) Familial hypertriglyceridemia ↑ VLDL (↑ TG, ↑ or abnormal cholesterol) ↓ HDL Mixed hypertriglyceridemia ↑↑ chylomicron ↑↑ VLDL Familial hyperalphalipoproteinemia ↑ HDL Dysbetalipoproteinemia ↑ VLDL (↑ cholesterol) ↑ IDL CLASSIFICATION OF ANTIHYPERLIPIDEMIC DRUGS 1. Bile acid binding resins  Cholestyramine  Cholestipol  Colesevelam 2. HMG-CoA reductase inhibitors (statins)  Lovastatin  Mivastatin  Simvastatin  Atorvastatin 3. Nicotinic acid (niacin) 4. Fibrates First generation Second generation  Clofibrate  Fenofibrate  Gemfibrozil  Bezafibrate  Ciprofibrate 5. Probucol 6. Intestinal sterol absorption inhibitor  Ezetimibe 2  elect nancy side preg , und BILE ACID BINDING RESINS (BILE ACID SEQUESTRANTS) Drugs Cholestyramine, Cholestipol, Colesevelam Route of administration Oral Mechanism of action The resins are cationic resins (highly positive charged or anion- exchange resins) that bind negatively to charged bile acids and bile salts in the small intestine. The resin-bile acid complex is later excreted in the feces, thus preventing the bile acids from returning to the liver by enterohepatic circulation. Compensatory mechanism  ↓ Hepatic cholesterol due to increased de novo production of bile acids from cholesterol, as a result of reduced bile acid concentration.  Upregulation (↑ production) of hepatic LDL receptors  Increase in uptake of LDL and IDL from plasma  Increase in HMG-CoA reductase activity Effects on plasma lipid  ↓ plasma LDL (20%)  ↑ plasma VLDL-TG (15-20%) (due to resin-induced synthesis of bile acid which is accompanied by an ↑ in hepatic TG synthesis)  No predictable effect on plasma HDL Side effects Abdominal bloating Nausea Constipation Dyspepsia (indigestion) Malabsorptions (rare) of vitamin K (can lead to hypoprothrombinemia) and folate Impairment of other drugs absorption (other orally administered drugs should be taken one hour before or 4 hours after the resins) Steatorrhoea (in high dose) Clinical indications Hypercholesterolemia Pruritis in cholestatic patients (due to accumulation of bile acids in patients with biliary obstruction) Digitalis (antiarrhythmic) toxicity Contraindications In patients with severe hypertriglyceridemia Others Resins are hygroscopic powders and hydrophilic gel. They are insoluble in water, unaffected by digestive enzymes and not absorbed from intestinal tract. The only hypocholesterolemic drugs recommended for children after 7-8 years of age. 3  HMG-COA REDUCTASE INHIBITORS (STATINS) Drugs Prodrugs: Lovastatin, Simvastatin Active drugs: Mivastatin, Atorvastatin, Fluvastatin, Rosuvastatin Route of administration Oral Mechanism of action Inhibit HMG-CoA reductase in the liver competitively, the rate- limiting step in the biosynthesis of cholesterol. Decrease oxidative stress and vascular inflammation with increased stability of atherosclerotic lesions. Compensatory mechanism  ↑ production of HMG-CoA reductase  Upregulation (production) of LDL receptors  ↑ uptake of LDL and IDL from plasma Effects on plasma lipid ↓ plasma LDL (20 – 55%) ↓ plasma VLDL-TG (25%) ↑ plasma HDL (10 – 13%) Side effects ↑ plasma transaminases (1 – 2% of patients)  Usually not associated with other evidence of hepatic toxicity. Plasma transaminase activity should be regularly measured.  In patients with evidence of hepatic toxicity, the therapy should be discontinued. ↑ plasma creatine phosphokinase with generalized pain/weakness in skeletal muscles (10% of patients)  Indicates rhabdomyolysis, then myoglobinuria.  Therapy should be discontinued. Clinical indications  Hypercholesterolemia with/without hypertriglyceridemia  Combined hyperlipoproteinemia.  Restricted use in children with familial hypercholesterolemia (extremely high LDL level) > 8 years of age. Contraindication In pregnancies and nursing mothers  HMG-CoA reductase is important in developing fetus/babies Drug Interactions Concomitant use with amiodarone or verapamil ↑ risk of myopathy. Others The most effective cholesterol lowering drugs (the most effective in reducing LDL). Single daily dose Statins (except atorvastatin and rosuvastatin) should be administered in the evening because cholesterol biosynthesis occurs predominantly at night. Lovastatin and simvastatin are inactive prodrugs which are hydrolyzed to their active drugs in the liver, while others (pravastatin, fluvastatin and atorvastatin) are active drugs. A standard practice to initiate reductase inhibitor therapy after myocardial infarction. 4  NICOTINIC ACID (NIACIN) Drugs Niacin (Vitamin B3) Route of administration Oral Mechanism of action Inhibits lipolysis in peripheral tissues - Inhibits VLDL secretion - ↓ LDL production - ↓ esterification of fatty acids to triglyceride in the liver ↑ lipoprotein lipase activity Effects on plasma lipid ↓ plasma VLDL-TG (20 – 80%) ↓ plasma LDL (10 – 15%) ↑ plasma HDL ↓ plasma Lp(a) Side effects Cutaneous flush and pruritus (face and upper trunk)  Prostaglandin mediated  Relieved by aspirin Vomiting, diarrhea, dyspepsia Hyperglycemia in diabetic patients Hyperuricemia - may reactivate gout Hepatotoxicity Clinical indications  Hypercholesterolemia  Hypertriglyceridemia  Hyperlipidemia Contraindication In pregnancy  Shown to cause birth defects in experimental animals In children  Its safety and efficacy not established. inhibitor pasta a Others A water-soluble B complex vitamin. ~ The > only drug that lowers lipoprotein (a). The most versatile that favourably affects all lipid parameters. 5  FIBRATES Drugs 1st generation: Clofibrate, Gemfibrozil 2nd generation: Fenofibrate, Bezafibrate, Ciprofibrate Route of administration Oral Mechanism of action  Lipid lowering property through peroxisome proliferators- activated receptors (PPAR) -mediated stimulation of fatty acid oxidation  ↓ Hepatic synthesis and secretion of VLDL into plasma  ↑ Lipoprotein lipase activity, therefore ↑ hydrolysis of TG in the chylomicrons and VLDL.  ↑ Synthesis of apo A1  ↓ expression of apoC-III  ↑ Hepatic uptake of IDL Effects on plasma lipid ↓ Plasma VLDL-TG (22 – 55%) ↑ Plasma HDL (10 -25%) 1st generation – No consistent effect on plasma LDL 2nd generation - ↓ Plasma LDL (15 – 20%) Side effects  GIT side effects  Rash, urticaria  Cholelithiasis (gallstone)  Rhabdomyolysis Clinical indications  Hypercholesterolemia with/without hypertriglyceridemia  Drug of choice to treat severe hypertriglyceridemia  Chylomicronemia syndrome Contraindication In patients with renal failure  - Fibrates are excreted in theCurine as fenofibric acidC (active metabolite) and glucuronide conjugates In pregnancies -  Shown embryocidal and teratogenic effects in experimental animals In lactating mothers  A potential for tumorigenicity in animal studies In children  Its safety and efficacy not established. Drug interactions - Fibrates are highly bound to albumin - displace warfarin (oral anticoagulant) from albumin -  warfarin effect Others Posssess antiatherothrombotic effects  Inhibition of coagulation  ↑ fibrinolysis 6  PROBUCOL Route of administration Oral Mechanism of action Cu Its mechanism in lowering cholesterol level remains uncertain. Inhibits the oxidation of cholesterol, resulting in the ingestion of the oxidized cholesterol-laden LDLs by macrophages. Effects on plasma lipid ↓ Plasma cholesterol ↓ LDL ↓ HDL No effect on TG. Side effects  Prolong QT interval (cardiac arrhythmia)  Mild gastrointestinal disturbance (diarrhea, flatulence, abdominal pain) Clinical indications Hypercholesterolemia (particularly type IIA) Contraindications In patients with an abnormal long QT interval. Others Carried in LDL particles and accumulated in adipose tissues. It possesses antioxidant property which may be important in blocking atherosclerosis. Its use is limited due to its effect on HDL. Care should be taken if probucol is administered together with other drugs that also prolong QT interval (such as digitalis, quinidine and terfenadine). Due to its long half life (up to 500 hours), it should be discontinued at least 6 months before attempting pregnancy. 7  INTESTINAL STEROL ABSORPTION INHIBITOR Drug Ezetimibe Route of administration Oral ! Mechanism of action Selectively inhibits intestinal absorption of dietary cholesterol and phytosterol It inhibits reabsorption of cholesterol excreted in the bile Effects on plasma lipid ↓ Plasma TC ↓ Plasma LDL (19%) ↑ Plasma HDL (minimal) Side effects  Low incidence of impaired hepatic function with a small increase in incidence when given with a statin.  Muscle weakness  Pancreatitis Contraindication Should be precautiously used in pregnancies and breastfeeding when benefits outweigh the risk.  Animal studies have revealed evidence of increased incidences of common fetal skeletal findings.  Ezetimibe crossed the placenta in animal studies. Patients with active liver disease. Unexplained, persistently abnormal tests of liver function. Clinical indications  Hypercholesterolemia  Phytosterolemia  In children (> 6 years old) with familial hypercholesterolemia. Others Usually taken in addition to other antihyperlipidaemic agents. 8  PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9) INHIBITORS D = Drugs Evolucumab Alirocumab Route of administration Subcutaneous (once or twice monthly) Mechanism of action Proprotein convertase subtilisin/kexin type 9 (PCSK9)  An enzyme that binds to LDL receptors  Prevents LDL being removed from blood PCSK9 Inhibitors – make more LDL receptors are available Effects on plasma lipid ↓ Plasma LDL (50-60%) ↑ Plasma HDL (5-10%) ↓ Plasma Lp(a) (25%) ↓ Plasma TG Side effects  Injection site reactions (swelling, redness etc)  Hypersensitivity (rare)  Flu-like symptoms  Headache Clinical indications  Familial hypercholesterolemia > 10 y10]  Clinical atherosclerotic cardiovascular disease (needs additional reduction in LDL)  Statin intolerance Contraindication Pregnancies:  Limited safety data and the potential for harm to the fetus. Others  The degree of reduction in Lp(a) can vary based on individual genetic factors.  Not all patients will experience a significant reduction in Lp(a), and the long-term impact of Lp(a) lowering on cardiovascular outcomes is still being evaluated. 9 Drugs C ATP‐CITRATE LYASE INHIBITORS Bempedoic acid  A prodrug (activated by very‐long‐chain acyl‐CoA synthetase‐1 – not present in skeletal muscle) Route of administration Oral Mechanism of action ATP‐citrate lyase or ATP citrate synthase  Important step in fatty acid biosynthesis (upstream of HMG-CoA reductase) ATP‐citrate lyase inhibitors   cholesterol synthesis  LDL Effects on plasma lipid ↓ Plasma LDL (20-30%) Side effects Muscle pain Allergic reaction ↑ blood uric acid ↑ liver enzymes Contraindication Severe liver impairment In pregnancy:  Animal studies revealed evidence of adverse effects on fetal development. Breastfeeding mothers (not recommended):  Unknown whether the drug is excreted in human milk. Clinical indications Adults with heterozygous familial hypercholesterolemia An adjunctive or alternative therapy to statins Atherosclerotic Cardiovascular Disease (ASCVD) Others Less impact on muscle function compared to statins Not for use in children (lack of clinical safety data in the pediatric population) 10  DRUGS UNDER DEVELOPMENT CHOLESTERYL ESTER TRANSFER PROTEIN (CETP) INHIBITORS Drugs Torcetrapib  Increased cardiovascular events and death  Withdrawn from clinical trials Anacetrapib Dalcetrapib Route of administration Oral Mechanism of action Inhibits cholesteryl ester transfer protein (CETP), leading to accumulation of mature HDL particles and reduction in the transport of cholesteryl esters to liver. Effects on plasma lipid ↓ Plasma LDL ↑ Plasma HDL Side effects Mild gastrointestinal symptoms (nausea or abdominal discomfort) Clinical indications Atherosclerotic cardiovascular disease (ASCVD) Dyslipidemia Others Currently not in market, still in Phase 3 clinical trials. Commonly prescribed with statins. Not recommended for use in children (lack safety data). 11 & COMBINATION THERAPY Therapy Outcomes Statins and resins Synergistic effect on plasma lipid. Further reduces LDL to almost 80%.  Resin-induced VLDL  is reduced by statins. Nicotinic acid and resins Synergistic effect on plasma lipid. Statins and nicotinic acid Nicotinic acid enhances the effects of statins but the risk of myopathy increases when statin doses greater than 25% of maximum.  Maintain the dose pf statin < 25% maximal dose The most efficacious and practical combination for the treatment of familial combined hyperlipoproteinemia. Statins and ezetimibe Synergistic effect on plasma lipid (all statins).  Simvastatin + ezetimibe - 52% in  LDL  Other statins + ezetimibe - 25% in  LDL Increases risk of C 2 Statins and fibrates rhabdomyolysis (myopathy) especially combination of statins and gemfibrozil. Fibrates and resins Useful in patients with familial hyperlipidemia who are intolerant of niacin  But may  risk of cholelithiasis. Resins + nicotinic acid + statins For patients with severe elevated LDL  Little toxicity observed  Effective dose of individual drugs may be lower than each is used alone. Statin -  hepatic cholesterol production PCSK9i + Statins PCSK9i -  hepatic clearance of LDL  Net effect:  LDL PCSK9i + Ezetimibe  LDL Bempedoic acid + statin When statins alone are insufficient 12 SELF ASSESSMENT 1. Mr WW was started on a drug for his hyperlipidemia. After each dose, he complained of flushing and itchiness, which were relieved with aspirin. Select the most likely drug that gives rise to these effects. A. Cholestyramine. B. Ezetimibe. C. Gemfibrozil. D. Lovastatin. D E. Niacin. Theme: Antihyperlipidemic drugs Options: A. Atovarstatin B. Cholestyramine C. Clofibrate D. Ezetimibe E. Fluvastatin F. Lovastatin G. Niacin H. Simvastatin Lead-in: For each of the following scenario, select the most likely drug used. Stems: 2. En. Om, a 54-year-old man with a history of coronary artery disease was prescribed a drug which reduces plasma LDL, triglyceride and lipoprotein (a), and increases plasma HDL. G 3. A 50-year-old lady who was given a drug to treat her hyperlipidemia, complained of constipation and bloating. She was advised to increase her dietary fiber to relieve the symptoms. B 4. Mr JFK, a hyperlipidemic patient was prescribed a drug which acts by increasing the activity of lipoprotein lipase, resulting a decrease in plasma triglyceride level. G Answer: 1E; 2G; 3B; 4G 13