1 / 24

Hyperlipidemia hyperlipoproteinemia or dyslipidemia

Hyperlipidemia hyperlipoproteinemia or dyslipidemia. Dr Laith M Abbas Al- Huseini M.B.Ch.B , M.Sc., M.Res ., Ph.D. Department of Pharmacology and Therapeutics. Types of lipoproteins. Chylomicrons (TGs) : → fat globule formed in GIT from dietary TG.

Télécharger la présentation

Hyperlipidemia hyperlipoproteinemia or dyslipidemia

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Hyperlipidemiahyperlipoproteinemia or dyslipidemia Dr Laith M Abbas Al-Huseini M.B.Ch.B, M.Sc., M.Res., Ph.D. • Department of Pharmacology and Therapeutics

  2. Types of lipoproteins • Chylomicrons (TGs): → fat globule formed in GIT from dietary TG. • VLDL (TGs and cholesterol) → endogenously synthesized in liver. Degraded by LPL into free fatty acids (FFA) for storage in adipose tissue and for oxidation in tissues such as cardiac and skeletal muscle.

  3. Types of lipoproteins • 3. IDL (TGs, cholesterol); and LDL (cholesterol) → derived from VLDL hydrolysis by lipoprotein lipase. Normally, about 70% of LDL is removed from plasma by hepatocytes. • 4. HDL (protective) →exert several antiatherogenic effects. They participate in retrieval of cholesterol from the artery wall and inhibit the oxidation of atherogenic lipoproteins & removes cholesterol from tissues to be degraded in liver.

  4. The pathology of lipids • When oxidized LDL cholesterol gets high, atheroma formation in the walls of arteries occurs, which causes atherosclerosis. • HDL cholesterol is able to go and remove cholesterol from the atheroma. • Atherogenic cholesterol (apolipoprotein (apo) B-100) → LDL, VLDL, IDL

  5. Causes of Hyperlipidemia • Diet • Hypothyroidism • Nephrotic syndrome • Anorexia nervosa • Obstructive liver disease • Obesity • Diabetes mellitus • Pregnancy • Obstructive liver disease • Acute heaptitis • Systemic lupus erythematousus • AIDS (protease inhibitors)

  6. Management of Hyperlipidemia • I- Diet: • Avoid saturated fatty acids (animal fats) and give unsaturated fatty acids (plant fats). • Regular consumption of fish oilwhich contains omega 3 fatty acids and vitamins E and C (antioxidants). • II- Exercise: • ↑ HDL levels and insulin sensitivity. • III- Drug therapy: the primary goal of therapy is to decrease levels of LDL . An increase in HDL is also recommended.

  7. A- HMG –COA reductase inhibitors (statins): • Competitive Inhibitors of HMG CoAreductase, the rate-limiting step in cholesterol synthesis. • Simvastatin, lovastatin, atorvastatin, rosuvastatin , pravastatin, pitavastatinandfluvastatin. •  In 2009 the world statins market generated over $27bn inrevenues. • Therapeutic benefits include plaque stabilization, improvementof coronary endothelial function, inhibition of platelet thrombus formation, and anti-inflammatory activity.

  8. Mechanism of action:(statins) • Structural analogues of HMG COA reductase (the rate limiting enzyme in cholesterol synthesis) → reduction of cholesterol synthesis in liver → compensatory ↑ in synthesis ofLDL receptors on hepatic and extra hepatic tissues →Increase in hepatic uptake of circulating LDL which decreases plasma LDL cholesterol . • - Decrease TGs to some extent and ↑ HDL. • - Cardio protective: vasodilators and decrease atherosclerosis (stabilize plaque). • Therapeutic uses: • - Effective in all types of hyperlipidemiaexceptthose who are homozygous for familial hypercholesterolemia (lack of LDL receptors). • Usually combined with other drugs.

  9. Adverse effects • 1- Increase in liver enzymes (serum transaminases should be monitored continuously, CI in hepatic dysfunction). • 2-Myopathy and muscle damage.Inhibits the production of CoQ10, which is essential for the creation of ATP. • Muscle fatigue and weakness is caused by • thedisruption of CoQ10 production (95% • source of ATP) and resulting lack of ATP • production -esp. in heart, liver and kidney • which have the highestCoQ10 concentrations. • 3- Cataract and GIT upset. • 4- Increase in warfarin levels. • 5- CI in pregnancy and nursing mothers (safety in pregnancy is not established), lactation, children and teenagers.

  10. B- Bile acids Sequestrants (resins): • Cholestyramine, colestipoland colesevelam. • Mechanism of action: anion exchange resins;bind bile acids in the intestine forming complex →loss of bile acidsin the stools →↑ conversion of cholesterol into bile acids in the liver. • Decreased concentration of intrahepatic cholesterol → compensatory increase in LDL receptors →↑ hepatic uptake of circulating LDL → ↓ serum LDL cholesterol levels.

  11. Therapeutic uses: • Treatment of type IIA and IIB hyperlipidemias (along with statins when response to statins is inadequate or alternative when they are contraindicated). • Useful for Pruritus in biliary obstruction (↑ bile acids). • Treatment of  diarrhea resulting from bile acid mal-absorption or secondary to Crohn's disease or the postcholecystectomy syndrome. • Pharmacokinetics: • Orally given but neither absorbed nor metabolically altered by intestine, totally excreted in feces.

  12. Adverse effects: • Constipation is the most common. • ↓ absorption of fat soluble vitamins (A, D, K, E) , ↓ Vit K → hypoprothrombinemia. • ↓ absorption of many drugs as digitoxin, warfarin, aspirin, phenobarbitone.

  13. C-Fibrates (activators of lipoprotein lipase) • Fenofibrateand gemfibrozil. • Mechanism of action: • Agonists at PPAR (peroxisomeproliferator-activated receptor)→ expression of genes responsible for increased activity of plasma lipoprotein lipase enzyme → hydrolysis of VLDL and chylomicrons→ ↓serum TGs • Increase clearance of LDL by liver & ↑ HDL. • Therapeutic uses: • Hypertriglyceridemia (the most effective in reduction TGs) - combined hyperlipidemia (type III) if statins are contraindicated.

  14. Pharmacokinetics: • Completely absorbed after oral administration. • Highly bound to plasma proteins, extensively metabolized, excreted in urine. • Adverse effects: • GIT disturbances. • Gall stones (increased biliary cholesterol excretion). • Muscle pain and myopathy (patients with renal impairment are at risk). • Increase warfarin levels (competitive plasma protein binding) • CI:in pregnancy, lactating women, renal and hepatic dysfunction, gall stones.

  15. D-Niacin (Nicotinic acid)(Inhibitor of lipolysis) • The first and cheapest anti hyperlipidemic. • Decrease both TGs (VLDL) and cholesterol (LDL) levels. • Mechanism of action: • It is a potent inhibitor of lipolysisin adipose tissues → • ↓ mobilization of FFAs (major precursor of TGs) to the liver → • ↓ VLDL(after few hours). • Since LDL is derived from VLDL so ↓ VLDL → ↓ LDL(after few hours). • ↑ HDL levels by decreasing its catabolic rate. • ↓ endothelial dysfunction →↓ thrombosis and ↓ fibrinogen levels.

  16. Pharmacokinetics: • Orally given, niacin (vitamin B3) converted in the body to the amide, which is incorporated into niacinamide adenine dinucleotide (NAD). • Therapeutic uses: • Familial hyperlipidemias (type IIB) (↑VLDL and↑ LDL). • Sever hypercholesterolemia, combined with fibrates or cholestyramine. • Adverse effects: • Cutaneous flush (PG- mediated, ↓ by aspirin) and pruritus. • GIT disturbances. • Reversible elevations in hepatic aminotransferases • Glucose intolerance due to insulin resistance. • Gouty arthritis (hyperurecemia). • Myopathy (rare).

  17. E- Ezetimibe (cholesterol absorption inhibitors) • Inhibits intestinal cholesterol absorption → ↓ concentration of intrahepatic cholesterol→ compensatory ↑ in LDL receptors→↑ uptake of circulating LDL →↓ serum LDL cholesterol levels (17%). • Usedin hypercholesterolemia together with statins & diet regulation. • Adverse effects: diarrhea and abdominal pain. • CI in patients with liver dysfunction.

  18. Omega-3 fatty acids • Omega-3 polyunsaturated fatty acids (PUFAs) are essential fatty acids • that are predominately used for triglyceride lowering. • Inhibit VLDL and triglyceride synthesis in the liver. • The omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoicacid (DHA) are found in marine sources such as tuna, halibut, and salmon. • Approximately 4 g of marine-derived omega-3 PUFAs daily decreases • serum triglyceride concentrations by 25% to 30%. • Over-the-counter or prescription fish oil capsules (EPA/DHA) can be used for supplementation. • Omega-3 PUFAs can be considered as an adjunct to other lipid-lowering therapies for individuals with significantly elevated triglycerides • (≥500 mg/dL). • The most common side effects include GI effects (abdominal pain, nausea, diarrhea), bleeding risks, and a fishy aftertaste.

  19. INHIBITION OF MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN Microsomal triglyceride transfer protein (MTP) plays an essential role in the accretion of triglycerides to nascent VLDL in liver, and to chylomicrons in the intestine. Its inhibition decreases VLDL secretion and consequently the accumulation of LDL in plasma. An MTP inhibitor, lomitapide, is available but is currently restricted to patients with homozygous familial hypercholesterolemia.

  20. ANTISENSE INHIBITION OF APO B-100 SYNTHESIS Mipomersenis an apo B 20-mer antisense oligonucleotide that targets apoB-100 gene, mainly in the liver. It is important to note that the apo B-100 gene is also transcribed in the retina and in cardiomyocytes. Subcutaneous injections of mipomersenreduce levels of LDL. Mild to moderate injection site reactions and flu-like symptoms can occur. The drug is available only for use in homozygous familial hypercholesterolemia

  21. CETP INHIBITION Cholesteryl ester transfer protein (CETP) transfers cholesterol from HDL cholesterol to VLDL and LDL. Its inhibitors are under active investigation. The first drug in this class, torcetrapib, aroused great interest because it markedly increased HDL and reduced LDL. However, it was withdrawn from clinical trials because it increased cardiovascular events and deaths in the treatment group. Anacetrapiband evacetrapibare analogs currently in phase 3 clinical trials

  22. PCSK9 INHIBITION • Proproteinconvertasesubtilisin/kexin type 9 (PCSK9) is an enzyme competes with the hepatocytes for binding to the receptor for LDL preventing its removal from the blood. • Inhibitors of PCSK9 lead to more LDL receptors be present on the surface of the liver and will remove more LDL cholesterol from the blood.  • Therapeutic agents currently include antibodies (eg, evolocumab, alirocumab) and antisense oligonucleotides. • LDL reductions of up to 70%. • No serious adverse effects have been reported in ongoing trials. • Development of small molecules with this action is also underway. Studies of this strategy should be approached with caution because of the established role of PCSK9 in normal neuronal apoptosis and cerebral development.

  23. AMP KINASE ACTIVATION AMP-activated protein kinase(AMPK) acts as a sensor of energy status in cells. When increased ATP availability is required, AMP kinaseincreases fatty acid oxidation and insulin sensitivity, and inhibits cholesterol and triglyceride biosynthesis. Although the trials to date have been directed at decreasing LDL levels, AMP kinase activation may have merit for management of the metabolic syndrome and diabetes. An agent combining AMP kinase activation and ATP citrate lyase inhibition is in clinical trials.

  24. Combination drug therapy • If no improvement within 6 weeks with a single drug therapy, the dose should be increased. If no improvement after 3 months change the drug or consider combination therapy: • Bile acid resins can be safely combined with statins or nicotinic acid (↓ LDL, VLDL cholesterol levels respectively). • Ezetimibe + statins → synergistic effects. • Fibrates and statins are CI → myopathy. • Nicotinic acid and statins (must be cautiously used) → myopathy.

More Related