Lesson 25 - Lipid Lowering Drugs PDF

Lesson 25 Lipid lowering drugs 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 INDEX 1. LIPOPROTREIN METABOLISM AND DYSLIPIDEMIA 2. ATHEROMATOUS DISEASE 3. LIPID LOWERING DRUGS – STATINS – FIBRATES – DRUGS THAT INHIBIT CHOLESTEROL ABSO...

Lesson 25 Lipid lowering drugs 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 INDEX 1. LIPOPROTREIN METABOLISM AND DYSLIPIDEMIA 2. ATHEROMATOUS DISEASE 3. LIPID LOWERING DRUGS – STATINS – FIBRATES – DRUGS THAT INHIBIT CHOLESTEROL ABSORPTION – NICOTINIC ACID – FISH OIL DERIVATIVES INTRODUCTION CHOLESTEROL Name of the formula: Exogen (diet) CYCLOPENTANOPERHYDROPHENANTHRENE. The sterolic structure is amphipathic, with a hydrophobic part that Endogen (hepatic synthesis interacts with the fatty acid tails in cell membranes and a hydrophilic by HMG-CoA reductase) part that orients itself towards the aqueous environment. TRIGLYCERIDES Main functions of colesterol: Key component of celular membranes Important for the synthesis of biliar acids, hormones, vitamine D INTRODUCTION CHOESTEROL TRIGLYCERIDES Triglycerides represent one of the main forms of energy storage in the human body. High levels of triglycerides in the blood can increase the risk of cardiovascular diseases, TGL are lipid molecules composed making it important to monitor and manage lipid of one glycerol molecule bound to levels through diet and exercise. three fatty acids  INTRODUCTION TRIGLYCERIDES CHOESTEROL + CHOLESTEROL are transported in the bloodstream in Lipoproteins by binding: Phospholipids: These form a part of the lipoprotein structure, creating a lipid bilayer that helps to transport lipids in the aqueous environment of the bloodstream. Apolipoproteins: These are the protein components of lipoproteins, playing a crucial role in lipid transport and metabolism by acting as structural components, enzyme cofactors, and receptor ligands. https://youtu.be/SPefCq7rzDk?feature=shared 1. LIPOPROTREIN METABOLISM AND DYSLIPIDEMIA Cholesterol and triglycerides, are transported in the plasma as lipoproteins, of which there are four classes: HDL - High Density Lipoproteins (contain apoA1 and apoA2) LDL - Low Density Lipoproteins (contain apoB-100) VLDL - Very-low-density lipoprotein particles (contain apoB-100) Chylomicrons (contain apoB-48) The higher the LDL and the lower the HDL cholesterol, the higher the risk of ischaemic heart disease.  CHOLESTEROL METABOLISM Endogenous Pathway (Internal Cholesterol Production): Hepatocytes produce cholesterol (denoted as "C") through the HMG-CoA reductase enzyme pathway. Exogenous Pathway (Dietary Cholesterol): Cholesterol from the diet is absorbed in the intestine, with NPC1L1 , the transport protein responsible for this uptake. Bile acids help digest dietary fats and cholesterol. Cholesterol Uptake & Lipoprotein Metabolism: LDL transports cholesterol to tissues. Excess LDL is taken up by the liver. HDL collects cholesterol from tissues and transports it back to the liver. Other Notable Processes: CETP (Cholesteryl Ester Transfer Protein) transfers cholesterol esters between HDL and LDL. Bile acids are produced in the liver and either reused or excreted. Frederickson/World Health Organization classification of hyperlipoproteinaemia 2. Atheromatous disease Atheroma, also known as atherosclerosis, is a condition where lipid deposits (plaques) build up inside the large and medium-sized arteries. These plaques are made up of cholesterol, proteins, and other substances that circulate in the bloodstream. Atheromas can grow and lead to serious cardiovascular issues such as coronary artery disease, peripheral artery disease, heart attacks, or stroke Atherosclerosis is one of the leading causes of death and disability in industrialized countries, primarily due to its role in myocardial infarction (heart attack) and other cardiovascular diseases. -Symptoms occur only when blood flow through the vessel is reduced. – Plaque rupture leads to platelet activation and thrombosis 2. Atheromatous disease Risk factors like diabetes, dyslipidemia, and smoking cause endothelial dysfunction, leading to atherosclerosis. A healthy endothelium produces nitric oxide (NO), which protects blood vessels by maintaining dilation and reducing inflammation. Endothelial dysfunction reduces NO, promoting the formation of atherosclerotic plaques. Clinical trials show that improving risk factors lowers the risk of cardiovascular events. Treatments like statins, PCSK9 inhibitors, and lifestyle changes improve endothelial function and slow down atherosclerosis progression. https://youtu.be/IkxxiaXdMmU?si=aN3-Z_EV9sqccwan  3. Drug treatment STATINS SIMVASTATIN, ATORVASTATIN, ROSUVASTATIN Mechanism of action Specific, reversible, competitive HMG-CoA reductase inhibitors, (rate- limiting enzyme in cholesterol synthesis) Also: Increase synthesis of LDL-receptors Increases cholesterol associated to HDL ATORVASTATIN Long-lasting inhibitor. Main biochemical effects Reduce plasma LDL. Some reduction in plasma TG and increase in HDL. 3. Drug treatment STATINS Pharmacokinetics Short-acting statins are administered orally at night to reduce peak cholesterol synthesis in the early morning. Well absorbed and extracted by the liver, their site of action. First-pass effect 3. Drug treatment STATINS Pleiotropic actions of statins Improved endothelial function Reduced vascular inflammation Reduced platelet aggregability Stabilization of atherosclerotic plaque Antithrombotic actions Enhanced fibrinolysis Immune suppression Protection against sepsis Protector role in heart, vessels and nervous system!  3. Drug treatment STATINS ADRs: Statin-induced myalgia(Muscle pain) Raised concentrations of liver enzymes in plasma Insomnia Rash More serious (rare) and dose related: Skeletal muscle damage (myositis) Angio-oedema Hepatoxicity Statin therapy leads to a modest increase in the long-term incidence of type 2 diabetes mellitus. Contraindicated during pregnancy Do you remember what statins interact with? 3. Drug treatment STATINS CLINICAL USES Primary prevention of arterial disease in high risk patients, especially if there are other risk factors for atherosclerosis (diabetes or renal failure). Secondary prevention of myocardial infarction and stroke in patients with symptomatic atherosclerotic disease (e.g. angina, transient ischaemic attacks, or following myocardial infarction or stroke). Atorvastatin lowers serum cholesterol in patients with homozygous familial hypercholesterolemia. In severe drug-resistant dyslipidaemia (e.g. heterozygous FH), ezetimibe, which inhibits cholesterol absorption, is combined with statin treatment.  3. Drug treatment FIBRATES GEMFIBROZIL, FENOFIBRATE Mechanism of action Agonists at PPARα nuclear receptors that regulates the expression of genes for lipoproteinlipases (hydrolyzes triglycerides in chylomicrons and VLDL facilitating the uptake of fatty acids by tissues). Main biochemical effects Markedly reduce circulating VLDL, TG. Increase activity of lipoprotein lipase. Increase the uptake of LDL  3. Drug treatment FIBRATES ADRs: RHABDOMYOLYSIS Rhabdomyolysis is a significant medical disorder that happens when muscle fibres break down and leak their contents into the bloodstream. Particularly in patients with renal impairment Rhabdomyolysis can also be caused by statins, and the combined use of fibrates with this class of drugs is therefore generally inadvisable. Fibrates SHOULD BE AVOIDED IN ALCOHOLICS (impaired metabolism of fibrates) 3. Drug treatment FIBRATES CLINICAL USES Mixed dyslipidaemia (i.e. raised serum triglyceride as well as cholesterol) Fenofibrate is uricosuric, which may be useful where hyperuricaemia coexists with mixed dyslipidaemia. Severe hypertriglyceridaemia when dietary and other measures have failed. Combined with other lipid-lowering drugs in patients with severe treatment- resistant dyslipidaemia (increased the risk of rhabdomyolysis).  3. Drug treatment DRUGS THAT INHIBIT CHOLESTEROL ABSORPTION 1. BILE ACID-BINDING RESINS: COLESTYRAMINE, COLESTIPOL,COLESEVELAM Mechanism of action Resins wich sequester bile acids (rich in cholesterol) in the intestine and prevent their reabsorption and enterohepatic recirculation Main biochemical effects Markedly reduce circulating LDL and cholesterol ADRs: Diarrhoea Interfere with the absorption of fat-soluble vitamins, and of thiazide diuretics, digoxin and warfarin 3. Drug treatment DRUGS THAT INHIBIT CHOLESTEROL ABSORPTION 2.EZETIMIBE Mechanism of action Acts blocking a transport protein (NPC1L1) Adjunctive treatment of choice to statins in patients with severe dyslipidaemia. 27 3. Drug treatment DRUGS THAT INHIBIT CHOLESTEROL ABSORPTION CLINICAL USES As an addition to a statin when response has been inadequate (ezetimibe). For hypercholesterolaemia when a statin is contraindicated. Uses unrelated to atherosclerosis, include: Pruritus in patients with partial biliary obstruction (bile acid-binding resin) Bile acid diarrhoea, for example, caused by diabetic neuropathy (bile acid- binding resin).  4. Novel Therapies BEMPEDOIC ACID Mechanism of action Inhbitor of ATP-citrate lyase, an enzyme upstream of HMG-CoA-reductase exerts its effects on the same cholesterol synthesis pathway as the statin drugs. Cause further cholesterol reduction in patients who may already be on maximal statin doses. ADRs: Hyperuricaemia and gout Gout is a metabolic disease characterised by recurring attacks of acute inflammatory arthritis with pain, redness and swelling of the joints, caused by the deposition of uric acid crystals in the joints.  4. Novel Therapies PCSK9 INHIBITORS EVOLOCUMAB, ALIROCUMAB Mechanism of action Inhibition of PCSK9, a protein that binds to LDL receptors and stimulates LDL-C hepatic internalization. Treatment of primary hypercholesterolaemia in patients whose circulating LDL is not adequately controlled by a statin or statin/ezetimibe combination (as additional agents)  4. Novel Therapies LOMITAPIDE Mechanism of action Inhibition of the microsomal triglyceride transfer protein (MTP) MTP is involved in the loading of triglyceride onto apolipoprotein B100, which is a part of the assembly process of very low density lipoprotein (VLDL). Recently been approved as an adjunct to other treatment for homozygous FH. – Orally once a day – Reduce hepatic lipoprotein secretion. Summary: https://youtu.be/-VwH33qYjPw?si=kiT7agBI8ZpVhT4-