- ANTI HYPERLIPIDIMICS drugs pharmacology

Antihypertensive drugs

1. ANTI HYPERLIPIDEMIC AGENTS CODE: CV2-Ph-005 DR. MAH-E-NOOR ASSISTANT PROFESSOR PHARMACOLOGY

2. CLINICAL SCENARIO A 55-year-old male patient with a history of hypertension and family history of coronary artery disease presents with a lipid profile showing:- LDL-C: 180 mg/dL- HDL-C: 40 mg/dL- Triglycerides: 200 mg/Dl. The patient is started on statin therapy. Which of the following is the primary mechanism of action of statins in reducing LDL-C levels? Inhibition of HMG-CoA reductase Activation of lipoprotein lipase Inhibition of cholesterol absorption in the gut Increased excretion of bile acids Stimulation of LDL receptors

3. LEARNING OBJECTIVES Hyperlipidemia / Dyslipidemia Basic Concept Treatment of Dyslipidemias MOA, Uses, Adverse Effects of Drugs used in the treatment of dyslipidemia

4. INTRODUCTION Dyslipidemia also termed hyperlipidemia , refers to deranged levels of lipids in the blood such as cholesterol (TC), triglycerides (TGs) or lipoproteins which may be very low density (VLDL), intermediate density (IDL), low density (LDL), or high density (HDL). Causes: Genetic predisposition Cigarette smoking Obesity High caloric diet and an inactive lifestyle can all lead to hyperlipidemia.

5. Hyperlipidemia can lead to: Atherosclerotic plaque formations resulting in cardiovascular diseases such as angina, myocardial infarction and stroke. Many metabolic diseases e.g. diabetes mellitus are associated with hyperlipidemia. It is also a leading cause of obesity and its consequent problems.

6. Pathogenesis: Underlying the disease is an abnormality in one or more blood lipid levels i.e. TC -----(<200) mg/dl TGs -----(<150) mg/dl VLDL -----(<30) mg/dl LDL -----(<130) mg/dl HDL -----(>60) mg/dl

7. Apolipoproteins are proteins that bind to lipids (oil-soluble substances such as fat and cholesterol) to form lipoproteins. They also serve as enzyme cofactors for specific enzymes involved in the metabolism of lipoproteins.

8. Diagnosis: Fasting (12 hr ) serum lipid profile Total Cholesterol Triglycerides HDL Total Cholesterol=HDL+VLDL+LDL VLDL= Triglycerides 5 LDL=Total Cholesterol - HDL-TGs/5

9. TYPES OF HYPERLIPIDEMIA

10. Treatment of dyslipidemia includes dietary modification, exercise and medication including Statins, Niacin, Fibrates and Bile acid binding resins. Uses: Rx of hyperlipidemia / dyslipidemia and its consequent effects like CVD etc. General MOA: ↓ Synthesis of cholesterol in liver ↓ Absorption from intestines ↓ Bile reuptake into liver from intestines ↓ TC, TGs, VLDL, LDL & ↑ HDL

11. STATINS Classification: Simvastatin Lovastatin Rosuvastatin Atorvastatin Pitavastatin Pravastatin

12. MOA: Act by competitively inhibiting HMG-CoA reductase, the first and key rate-limiting enzyme of the cholesterol biosynthetic pathway. Statins mimic the natural substrate molecule, HMG-CoA, and compete for binding to the HMGCR enzyme. They decrease the synthesis of VLDL in liver consequently lowering TGs level. HDL levels are increase due to unknown mechanisms. Statins increase expression of hepatic LDL receptors to compenstate decreased cholesterol synthesis in liver. LDL receptors lead to cleaarance of LDL thus reducing their levels.

13. AEs: Myopathy – Rhabdomyolysis due to inhibition of mevalonate (essential for maintaining muscle integrity) Hepatotoxicity Renal damage CI: Pregnancy ( Teratogenecity ) Kids except Pitavastatin (for 8 years old) & Pravastatin (for 10 years old)

14. STEROL (ABSORPTION INHIBITORS) Ezetimibe - Plant sterol MOA: ↓ Intestinal cholesterol uptake by inhibiting NPC 1L1 transporter in enterocytes. This leads to decrease transport of cholesterol from intestine to the liver thus increasing expression of LDL receptors which remove LDL from the circulation therefore reducing LDL levels in blood. AEs: Hepatic dysfunction Myositis

15. (BILE ACID BINDING) RESINS Colestipol Cholestyramine Colesevelam MOA: Prevents reabsorption of bile acids from GIT. This deficiency increases the demand for bile acids (composed of cholesterol) thus increasing synthesis of LDL receptors to bring more LDL cholesterol in the liver. This leads to decrease level of LDL in liver.

16. AEs: Constipation Bloating Gritty unpleasant taste Nausea Pruritis Interaction - ↓ Absorption of vitamins & drugs.

17. FIBRATES Gemfibrozil Fenofibrates MOA: Activate nuclear PPAR- (Peroxisome proliferator-activated receptor) found in metabolically active tissues. In adipose tissue - ↑ lipoprotein lipase thus reducing TGs. In liver - ↑ oxidation of fatty acids ↓ expression of Apo - C III which usually inhibits lipoprtein lipase & ↑ expression of Apo A – I & II that are major components of HDL.

18. AEs: Skin rashes ( Gemfibrozil ) GIT disturbances like nausea ↓ WBC count ↓ Hematocrit Myopathy Hepatic dysfunction Should be given with caution in pts. with Cholelithiasis or Cholestasis as it increases the cholesterol component of bile. Interaction – potentiate anticoagulant drug actions.

19. NIACIN – Nicotinic Acid Extended release Sustained release MOA: ↓ Inhibits hormone sensitive lipase that converts TGs into free fatty acids in adipose tissue . This leads to decrease transport of free fatty acids to liver for the synthesis of TGs consequently reducing VLDL synthesis. This causes ↓ LDL production, Max ↑ HDL levels due to unknown mechanisms.

20. AEs: Flushing (due to PG release) Pruritus GIT disturbances Hepatotoxicity Hyperurecemia Gout ↓ Carbohydrate / glucose tolerance / impairment of insulin sensitivity. Tolerance

21. OMEGA 3 FATTY ACIDS MOA: They decrease TGs by decreasing TGs synthesis. AEs: GIT disturbances like nausea, vomiting and diarrhea Fishy after taste Increased risk of bleeding

22. NEWER DRUGS MISCELLANEOUS DRUGS Probucol – Has antioxidant action. It inhibits oxidation of LDL. Guguipid – Decrese LDL and increase HDL levels. CEPT Inhibitors – ( Cholesteryl Ester TG Transport Protein) increase HDL. Avasimibe – inhibits enzyme ACAT-1 (acyl coenzyme A: cholesterol acyl transferase – 1) which forms cholesterol ester from cholesterol.

23. PCSK 9 INHIBITORS Evolocumab Alirocumab MOA: PCSK 9 is an enzyme circulating in blood that binds to LDL receptors on liver cells and promot their degradation. The inhibitors are monoclonal antibodies that inactivate PCSK 9. They also remove LDL from the blood. AEs: Injection site reactions Flue like symptoms Neurocognative problems

24. DRUGS FOR PATIENTS WITH HOMOZYGOUS FAMILIAL HPERCHOLESTEROLEMIA Lomitapide : MOA: MTP (Microsomal TGs Transfer Protein) inhibitors. AE: Cause deranged LFTs Mipomersen MOA: Targets Apo-B. this decreases productions of VLDL & LDL. AE: Cause injection site reactions

25. THANK YOU ANY QUESTIONS?