L 37 Final Antidyslipidemic Agents (1).pdf

1 37 Anti-Dyslipidemic Drugs ILOs By the end of this lecture, students will be able to 1. Classify the different anti-dyslipidemic drug groups based on their lipid specificity. 2. Interpret the difference in action of statins and ezetimibe in relevant to their selected use. 3. Distinguish between me...

1 37 Anti-Dyslipidemic Drugs ILOs By the end of this lecture, students will be able to 1. Classify the different anti-dyslipidemic drug groups based on their lipid specificity. 2. Interpret the difference in action of statins and ezetimibe in relevant to their selected use. 3. Distinguish between members of statins regarding solubility, potency, duration of action, etc. 4. Interpret how fibrates exert their action and how and when it can be used with statins. 5. Clarify the possible use of the other anti-dislipidemic agents. 6. Recommend an appropriate anti-dyslipidemic therapy in different clinical scenarios of dyslipidemia Anti-Dyslipidemic agents are a diverse group of drugs that reduce the level of lipids and lipoproteins. According to the kind of lipid reduced they are classified into: I. Anti-hypercholesterolemic agents: Statins, Ezetimibe. II. Ani-hyper-triglyceridemic agents: Fibrates (PPAR-α) and omega three fatty acids. III. Mixed anti-dyslipidemic agents: Niacin. STATINS: HMG-COA Reductase Inhibitors These are drugs that INHIBIT 1. Cholesterol Synthesis, in the liver by reversible competitive inhibition of the rate limiting step of its formation; HMG-COA Reductase Enzyme. When this occurs, the liver senses that cholesterol is inhibited, so it upregulates LDL-Receptors that will uptake the circulating cholesterol, thus reducing its blood level. 2. Intermediate Compounds involved in differentiation, proliferation, mobilization, …etc. i.e. involved in inflammatory reactions, especially those linked to cholesterol accumulation. i.e involved in expression of proteins linked to synthesis and clearance of varied lipoproteins. Figure-1: Statins mechanism of action These drugs are classified:  According to lipid solubility into hydrophilic, lipophilic, or mixed.  The hydrophilic agents are eliminated by the kidney and have minimal drug interactions. OMNIA NAYEL 2  The lipophilic agents are metabolized by the liver and have many drug interactions. They can cause dose-dependent elevation in hepatic enzymes that requires regular checkup, and are more liable to induce different degree of myopathy, which can be diagnosed by serum creatine kinase (CK) level by an increase to 3.5 fold upwards.  According to duration of action, some have long half-life, thus taken once daily any time, while others are short-acting so given twice daily, one at night at peak time of endogenous cholesterol synthesis.  According to potency, statins can variably modulate lipid profile manifested by a significant decrease mainly in total cholesterol and LDL-C. They can induce some reduction in TG (decreasing VLDL secretion and increasing lipoprotein clearance) and an elevation in HDL-C (increasing ApoA-1 synthesis) Thus, they are: - The major anti-hypercholesterolemic agents used in treatment of dyslipidemia specially hypercholestrolemia. They can also help alone or with other anti-dyslipidemic drugs to control mixed dyslipidemias. - The drug of choice in hypertriglyceridemia in diabetics; as these patients have small dense LDL-C as a result of lipoprotein remodeling that are extremely atherogenic. - During (by its action on metabolic intermediates) or following (by its cholesterol-lowering action) ischemic insults as acute myocardial infarction and stroke. STATINS are never given during pregnancy and are used cautiously under 18 years of age. EZETIMIBE: Selective Cholesterol Absorption Inhibitor The drug inhibits the selective-cholesterol transporter: Neiman-Peck Transporter (NPC1L1), i.e., thus inhibits exogenous cholesterol intake, which stimulates the liver to up-regulate its LDL-R. Figure-2: Ezetimibe mechanism of action It is given as monotherapy in mild cases of hypercholesterolemia, but it is more given as adjuvant to statins in resistant cases of hypercholesterolemia specially that it has a rather safe profile. OMNIA NAYEL 3 FIBRATES: PPAR- Agonists PPAR- is a transcription factor, which when binds to its agonist fibrates; it modulates gene: - Expression of lipoprotein lipase – free fatty acids (FFA) transporters - enzymes of beta oxidation and ketogenesis - Apo AI and AII. - Repression of enzymes of FFA and TG synthesis - cytokines, adhesion molecules, and some mediators of inflammation. The net effect is a decrease in TG and VLDL, a modest decrease in LDL-C (increasing LDLR clearance) , and an increase in HDL-C (increase expresion of ApoA-I and AII. They are used as monotherapy in hypertriglyceridemia. They are combined to statins in mixed dyslipidemia; better with hydrophilic agents as with lipophilic members myopathy development can increase. They can improve glucose tolerance and suppress serum uric acid if elevated. Figure-3: Fibrates mechanism of action FIBRATES are never given during pregnancy and used cautiously in renal and hepatic impairment. Omega 3 Fatty Acids They are polyunsaturated fatty acids (PUFA)derived from fatty fish oil. It possess a weak PPAR-α agonistic effect They are protective to the cell membrane specially against oxidative stress. Inhibits TXA2 (platelets), Vit-K dependent clotting factors and alter PAI-1 synthesis. They are: Adjuvant therapy in Hypertriglyceridemia Can also inhibit platelet aggregation. Therefore, they are cardio-protective. Figure-4: Omega-3-Fatty acids NIACIN: Nicotinic Acid It is a vitamin B3,that:  Acts on a specific receptor in adipose tissue to inhibit hormone sensitive lipase; decreasing lipolysis and availability of FFA for TG synthesis in liver.  Activates lipoprotein lipase to increase VLDL circulatory clearance  Decrease clearance of Apo A from plasma thus increases its blood levels. OMNIA NAYEL 4 It thus can decrease efficiently hypertriglyceridemia and hypertcholestrolemia and is the best drug to elevate HDL. It is used as mono therapy specially when there is contraindications for fibrates or statins and as combined therapy with them or other anti-dyslipidemic agents in mixed dyslipidemias. It has a problem in producing pruritus, sensation of warmth, and flushing (prostaglandin mediated), but this can be avoided by using aspirin a hour before its intake or the use of slowrelease formulations. It can induce myalgia specially when combined to statin or fibrates and can elevate blood glucose and uric acid, thus it is better avoided in diabetics and gout. Figure 5: Niacin mechanism of action FFA: free fatty acids, VLDL: very low-density lipoprotein. Cholestyramine : Bile Acid Sequestrants Is an ion exchange polymer [resins] that adsorbs bile a. Used to lower hypertriglyceridemia, hypercholesterolemia or in mixed dyslipidemia by adsorbing bile acids and eliminating it in stools thus reducing exogenous lipid absorption. This will enhance uptake of circulating LDL to eliminate the endogenous cholesterol by secretion in bile, to intestine, to be lost in stools. So, it can be given as monotherapy or in combination with other anti-dyslipidemic agents. Other indications: 1. Hepatitis &/or diarrhea by making bile osmotically inactive, thus decreasing its irritation 2. In toxicity of some drugs of lipid nature permitting their loss in stools A major draw back in use is that it adsorbes to it, steroids & fat soluble vitamins. So these have to be replaced as supplements. If there is need to avoid such loss in stools, the drug should be taken 4 hours spaced away from meals. ___________________ OMNIA NAYEL