![Therapeutic uses :
2nd line of TTT hypertriacylglycerolemuas after
statin .
Fenofibrate and gemfibrozil are particularly
useful in treating Type III hyperlipidemia
(dysbetalipoproteinemia)
- Patients with hypertriacylglycerolemia (Type
IV [elevated VLDL] or Type V [elevated VLDL
plus chylomicron] disease) who do not respond
to diet or other drugs](https://image.slidesharecdn.com/treatmentofdyslipidemia-150531125104-lva1-app6892/75/Treatment-of-dyslipidemia-16-2048.jpg)
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Treatment of dyslipidemia
The document outlines various treatments for dyslipidemia, including non-pharmacological measures and classifications of drugs such as statins, ezetimibe, bile acid sequestrants, fibrates, and niacin, detailing their mechanisms of action, side effects, and therapeutic uses. It emphasizes the importance of combination therapy and preventive measures, including lifestyle changes. Additionally, it highlights the need for regular monitoring of liver function and specific considerations for certain populations, such as pregnant women.
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Treatment of dyslipidemia
- 1. Treatment of dyslipidemia Asma mutniID 33121670
- 2. Objectives : 1)list non-pharmacologicalmeasures for treatment of dyslipidemia . Classify drugs used in treatment of dyslipidemia .2) 3) Mention the MOA , most common side effect and the effect on lipid profile of each class . 4) outline preventive measure of dyslipidemia .
- 3. 1. HMG-CoA ReductaseInhibitors: statins Simvastatin, Fluvastatin, lovastatin, pravastatin,, atorvastatin, rosuvastatin 2. Specific cholesterol absorption inhibitors: ezetimibe 3. BILE ACID BINDING (RESINS): Cholestyramine and Colestipol, colesevelam 4. FIBRATES: Gemfibrozil, Clofibrate,, Bezafibrate,and Fenofibrate, ciprofibrate 5. Nicotinic Acid (NIACIN), Acipimox 6. Others: Omega-3-FA, orlistat, CETP inhibitors (Torcetrapib)▲ BP & mortality, Prubucol,
- 5. HMG-CoA Reductase Inhibitors:statins MOA : Statin will inhibit HMG-CoA reductase prevent catalyses the conversion of HMG-CoA to mevalonic acid inhibit cholestrol synthisis intracellular cholestrol LDL receptor LDL.c , VLDL remnants . synthesis of VLDL TG , LDL HDL 5-20 %
- 6. Cont. atorvastatin, rosuvastatin longacting inhibitor . Simvastatin, Fluvastatin, lovastatin, pravastatin short acting inhibitor giving by mouth at night ? To reduce peak cholesterol synthesis in the early morning . absorption with food . They are well absorbed and excreted by liver ,their site of action, and are subject to extensive presystemic metabolism via cytochrome p450 and glucoronidation pathway . Excretion : 80% metabolized and excreted in bile and 20% excreted unchanged drug in urine Importance ?? Frequent checkup liver and kidney function
- 7. Clinical uses ofHMG-CoA reductase inhibitors (statins) 1) Secondary prevention of CHD (e.g. angina, following myocardial infarction or stroke). 2) Primary prevention of arterial disease in patients who are at high risk of atherosclerosis. 3) Atorvastatin lowers serum cholesterol in patients with homozygous familial hypercholesterolaemia. 4) In severe drug-resistant dyslipidaemia (e.g. heterozygous familial hypercholesterolaemia), ezetimibe is combined with statin treatment. 5) 2ry hyperlipidemia e.g DM , nephrotic syndrome 6) # in pregnancy .
- 8. cont.. side effect : mostcommon : muscle pain (myalgia )1) 2) GIT disturbance 3) raised concentration of liver enzyme in plasma 4) insomnia 5) rash rarly : 1)myositis ( common in lean body mass and uncorrected hypothyroidism pt . 2) angio-oedema
- 9. Specific Cholesterol Absorption Inhibitors(Ezetimibe=zetia) MOA : inhibit absorption of cholesterol from duodenum by blocking transport protein (NPC1L1) in the brush border of enterocyte without affecting the absorption of fat soluble vitamins , TG or bile acid . Adverse effect : 1. GIT: Diarrhea, abdominal pain, hepatitis if combined with statins, rarely myositis alone or with statins 2. CNS: Headache, fatigue, dizziness 3. Skin: Allergic reactions (rare)
- 10. Therapeutic uses of ezetimibe 1)In compination with statin to treat hypercholesterolemia. 2) Alone in mild cases or when statin is contraindication Patients with moderate to severe hepatic insufficiency should not be treated with ezetimibe.
- 11. Bile Acid Sequestrants(Resins) and colesevelamCholestyramine and colestipol MOA : These drugs bind to bile acid (cholesterol metabolite) and bile salts in small intestine form resins bile acid complex which is insoluble complex excreted in feces preventing the bile acid reabsorption and returning to liver bile acid concentration increase conversion of cholesterol to bile acid by hepatocyteintracellular cholesterol uptake of LDL LDL level in plasma .
- 12. Side effect : Minimalsystemic effect because it dose not absorbed from GIT . in high doses and elderly ::Local effect -Bulky unappetizing and inconvenient . - GIT : abdominal fullness , diarrhea , constipation , nausea , bloating in colesevelam is less . - decrease absorption of fat soluble vit. (ADEK) but not colesevelam . - Hypernatremia and Hyperchloremia
- 13. Therapeutic uses Drug ofchoice in TTT of hyperlipidemia In children & pregnant women Hypercholestrolemia; Type IIA, and IIB Alone or + Statins or Niacin .
- 14. 4. FIBRATES: Gemfibrozil, Clofibrate,,Bezafibrate,and Fenofibrate, ciprofibrate MOA : • -peroxisome proliferator activated receptor (PPAR) which is nuclear receptor that regulate lipid metabolism. • -activation of this receptor bind to peroxisome proliferator response elements fibrates-mediated gene expression increase expression of lipoprotein lipase • decrease triacylglycerol concentration. also increase HDL level by increase expression of apo AI and apo AII.
- 15. :Adverse effect offibrates 1) Muscles: rare Myalgia & Myositis (▲Kidney,Liver) ▲if +Statins (Simvastatin+Gemfibrozil) less with fenofibrate 2) GIT: (the most common) 5% Dyspepsia, abdominal pain, nausea, diarrhea, (▲Liver enzymes 3% 3) Skin 2%: Rash, urticaria, hair loss 4) Blood: ▼WBCS, anemia, ▼ K► Arrhythmias 5) Others; Headache, fatigue, impotence.
- 16. Therapeutic uses : 2ndline of TTT hypertriacylglycerolemuas after statin . Fenofibrate and gemfibrozil are particularly useful in treating Type III hyperlipidemia (dysbetalipoproteinemia) - Patients with hypertriacylglycerolemia (Type IV [elevated VLDL] or Type V [elevated VLDL plus chylomicron] disease) who do not respond to diet or other drugs
- 17. 5. Nicotinic Acid(NIACIN), Acipimox • 1-strongly inhibition of lipolysis in adipose tissue decrease circulating free fatty acids decrease triacylglycerol synthesis in liver decrease VLDL production decrease plasma LDL concentration. • 2-niacin cause highly increase in HDL level by : • increase secretion of tissue plasminogen activator. • Decrease the level of plasma fibrinogen. • So .. It’s decrease triglyceride and LDL including Lp(a), and increase HDL
- 18. Adverse Effects: 1. CVS:flushing arrhythmias. Postural hypotnsion 2. Skin: pruritis, rash, dry skin, ↑pigmentation, acanthosis nigricans 3. GI: nausea, vomiting, diarrhea, flatulence, dyspepsia, activation of peptic ulcer 4. Liver; Hepatotoxicity 5. Endocrine: Insulin resistance and hyperglycemia. Not acipimox 6. ▲Uric acid: Hyperuricemia 20% (gout) 7. CNS: headache, dizziness. Blurring vision (Macular edema).
- 19. Therapeutic uses •Niacin lowersplasma levels of both cholesterol and triacylglycerol. Therefore, it is particularly useful in the treatment of familial hyperlipidemia 1. Not widely used due to ADR 2. Useful in all forms of dyslipidemia (# type1) 3. In hypertriglyceridemia (III, IV, V) with or without levated LDL. 4. Mostly used to lower VLDL & raise HDL 5. Adjunct to; statins, fibrates; (Niacin + Statins)► myopathy 6. Prevention of pancreatitis
- 20. Other drugs usedto lowering lipid 1) Omega 3 fatty acid (fish oil ) reduce plasma triglyceride concentrations but increase cholesterol . - Antiarrhythmic risk of cardiac death in MI -inhibition of platelet function & plasma fibrinogen prolonged bleeding time. - anti-inflammatory effect alteration leukotriene biosynthesis - Anti-plaques adhesion of molecule 2) CETP inhibitors: Torcetrapib ▲HDL
- 21. non-pharmacological measures fortreatment of dyslipidemia Our goal is increase HDL and decrease LDL 1 ) supplement healthy habit . 2) Moderate alcohol consumption raise HDL. 3) Regular exercise also increase circulating HDL . 4) Antioxidants (e.g vit. C and vit E ) . 5) Oestrogen (has antioxidant property) in women protect them from atherosclerosis . 6) Fish oil : supply omega 3 FA that decrease LDL .
- 22. effect of drugson lipid profile TGHDLLDLType of drugs 14-29%6-12%25-60%HMG-coA reductase inhibtor (statin) 30-50%14-35%10-20%Niacin 30-60%11-13%4-21%fibrates Nutral3%10-18%Bile acid sequestrants (Resins) 9%1%18%Ezetimibe
- 23. preventive measures of dyslipidemia Primaryprevention (Risk factors) 1- Diet control ; ↓protein intake , CHO, fat, salt . Total cholesterol should be < 200 . Antioxidants as vit.E , C , nuts,cereals, fresh fruit & vegetables . Fish oil : supply omega 3 FA that decrease LDL . 2- Regular check body weight , BP . 3- quit smoking and alcohol . 4- Physical activity . 5- Control oral contraceptive . 6) TTT of hypertension and , to lesser extent , DM 7) Reduce the incidence of symptomatic atheromatous disease . 8) Reduce atrial thrombosis by antithrombotic drugs .
- 24. Secondary prevention (Earlystage) 1- Screening : A- All adult > 20 y (Fasting lipid profile) B- High risk group (Fasting lipid profile) 2-↓complications .. Tertiary prevention (Late stage) ↓impairments . Rehabilitation ..
- 26.
- 27. Usesmetabol ism Lipid profile ADReffectMOAdrug 1ry hyperlipidemia 2ry hyperlipedemia 1ry and 2ry preventionof CHD # pregnancy , children <8 L and K disease In liver by cytochrom e p450 LDL 20-35% TG 10-35% HDL 10% Hepatotoxici ty Myopathy The most potent C agent ( Rosuvastatin the most potent one ) HMG- coA reductase inhibiter Statins In combination with statin in hypercholes terolemia or alone in mild cases or when statins is contraindica tion Metabol ized in gout and liver by conjugat ion and excreted in bile to feces 80% and C 50 % LDL 20 % Mild side effect . Has no serious ADR unless if it’s combined with statin (hepatitis Dec. C absorption in 50%( but not TG,bile acid , fat soluble vit) C absorption by dec. NPC1L1 transport protein Ezetimibe
- 28. UsesmetabolismLipid profileADRMOAdrug In children and pregnancy - Hypertriglyce ridemiaalone or + stastin or niacin Not absorbed or metabolite and totally excreted by feces LDL 15-30% TG 20 % HDL 5% GIT Dec. absorption of fat soluble vit. And folic acid but not colesevelm Inc. hypertriglycer idemia in pt with CHL Bind with bile acid to form non- soluble non- absorpable complex Resins -In sever inc. in TG -Combined with otheer drugs in Sever resistance dyslipidemia -Mixed dyslipidemia ( ^ in C and TG) - In pt with low HDL and risk of atheromatus disease (e.g type 2 DM -Albumin binding 90 % -In liver glucoronoide EHC -kideny 70% as glucoronoid e HDL 15-20% TG 50% -- GIT (most commo n) -Gallstones Anemia leukopenia rash peroxisome proliferator activated receptor Fibrates
- 29. UsesMetabolis m Lipid profile ADRMOADrug As adjunct to astatin and diet in dyslipidem ia especially when associated with low HDL and raised TG - Used when statin containdica tion. Conjugatio n with glycin to form nicotinuric acid then excreted in urine TG 33- 45% LDL 20- 30% HDL 30- 40% -CVS flushing , postural hyperte Ntion -skin:pruritis , rash Liver : hypatotoxcic ty - hyperglycim ea strongly inhibition of lipolysis in adipose tissue decrease circulating free fatty acids decrease triacylglycerol synthesis in liver decrease VLDL production decrease plasma LDL concentration niacin
- 31.
- 32. Questions ^,^ The mosteffective TG lowering drug is fibrates The drug causing hepatitis is statin Best drug to increase HDL is niacin TTT od dyslipidemia in pregnant women resine Drug can be used in primary previntion of dyslipidemia statin . Ezetimibe is contraindication in hepatic insufficiency . The least drug cause abdominal side effect from bile acid sequestrant is colesevelam The most common side effect of fibrate is GIT problem
Editor's Notes
- #5 Lipids and cholesterol are transported in the bloodstream as complexes of lipid and protein known aslipoproteins. These consist of a central core of hydrophobic lipid (including triglycerides and cholesteryl esters) encased in a hydrophilic coat of polar phospholipid, free cholesterol andapoprotein. There are four main classes of lipoprotein, differing in the relative proportion of the core lipids and in the type of apoprotein (various kinds of apoA and apoB, see below). Apoproteins bind to receptors specific for each that mediate uptake of lipoprotein particles into liver, blood or other tissues. Lipoproteins differ in size and density, and this latter property, measured originally by ultracentrifugation but now commonly estimated by simpler methods, is the basis for their classification into: HDL particles (contain apoA1 and apoA2), diameter 7–20 nm LDL particles (contain apoB-100), diameter 20–30 nm very-low-density lipoprotein (VLDL) particles (contain apoB-100), diameter 30–80 nm chylomicrons (contain apoB-48), diameter 100–1000 nm. Each class of lipoprotein has a specific role in lipid transport, and there are different pathways for exogenous and for endogenous lipids, as well as a pathway for reverse cholesterol transport (Fig. 23.1). In the exogenous pathway, cholesterol and triglycerides absorbed from the ileum are transported as chylomicrons in lymph and then blood, to capillaries in muscle and adipose tissue. Here, triglycerides are hydrolysed by lipoprotein lipase, and the tissues take up the resulting free fatty acids and glycerol. The chylomicron remnants, still containing their full complement of cholesteryl esters, pass to the liver, bind to receptors on hepatocytes and undergo endocytosis. Cholesterol liberated in hepatocytes is stored, oxidised to bile acids, secreted unaltered in bile, or can enter the endogenous pathway. In the endogenous pathway, cholesterol and newly synthesised triglycerides are transported from the liver as VLDL to muscle and adipose tissue, where triglyceride is hydrolysed to fatty acids and glycerol; these enter the tissues as described above. During this process, the lipoprotein particles become smaller but retain a full complement of cholesteryl esters and become LDL particles. LDL provides the source of cholesterol for incorporation into cell membranes and for synthesis of steroids (see Chs 32 and 34) but is also key in atherogenesis. Cells take up LDL by endocytosis via LDL receptors that recognise apoB-100. Cholesterol can return to plasma from the tissues in HDL particles (reverse cholesterol transport). Cholesterol is esterified with long-chain fatty acids in HDL particles, and the resulting cholesteryl esters are transferred to VLDL or LDL particles by a transfer protein present in the plasma and known as cholesteryl ester transfer protein (CETP). Lipoprotein(a), or Lp(a), is a species of LDL that is associated with atherosclerosis and is localised in atherosclerotic lesions. Lp(a) contains a unique apoprotein, apo(a), with structural similarities to plasminogen (Ch. 24). Lp(a) competes with and inhibits the binding of plasminogen to its receptors on the endothelial cell. Plasminogen is normally the substrate for plasminogen activator, which is secreted by and bound to endothelial cells, generating the fibrinolytic enzyme plasmin (see Fig. 24.10). The effect of the binding of Lp(a) is that less plasmin is generated, fibrinolysis is inhibited and thrombosis promoted.
- #18 Nicotinic acid is a vitamin, and as such is essential for many important metabolic processes. Quite separately from this, it has been used in gram quantities as a lipid-lowering agent. It is converted to nicotinamide, which inhibits hepatic VLDL secretion , with consequent reductions in circulating triglyceride and LDL including Lp(a), and an increase in HDL. The mechanism is poorly understood but is believed to be initiated by an effect on lipolysis via a G-protein-coupled orphan receptor called HM74A and present in adipocyte membranes (see review by Karpe & Frayn, 2004). It also influences hepatic diacylglycerol transferase. Long-term administration to survivors of myocardial infarction reduced mortality in the Coronary Drug Project trial, but unwanted effects limit its clinical use. A modified-release preparation is better tolerated, and is a real, if modest, advance .
- #19 Niacin is a cheap drug with many ADR (50% do not complete the treatment) The most side effect of nicotinic acid is flushing and can be controlled by aspirin (PGD2 antagonist )
- #20 Therapeutic uses: Niacin lowers plasma levels of both cholesterol and triacylglycerol. Therefore, it is particularly useful in the treatment of familial hyperlipidemias. Niacin is also used to treat other severe hypercholesterolemias, often in combination with other antihyperlipidemic agents. In addition, it is the most potent antihyperlipidemic agent for raising plasma HDL levels, which is the most common indication for its clinical use.
- #21 Plasma triglyceride concentrations are less strongly associated with coronary artery disease than is cholesterol, but there is epidemiological evidence that eating fish regularly does reduce ischaemic heart disease, and dietary supplementation with ω-3 polyunsaturated fatty acids (PUFAs) improves survival in patients who have recently had a myocardial infarction (GISSI-Prevenzione Investigators, 1999). The mechanism may be the potent antiarrhythmic effects of PUFA (reviewed by Leaf et al., 2003). The mechanism of action of fish oil on plasma triglyceride concentrations is unknown. Fish oil is rich in PUFA, including eicosapentaenoic and docosahexaenoic acid, and it has other potentially important effects including inhibition of platelet function, prolongation of bleeding time, anti-inflammatory effects and reduction of plasma fibrinogen. Eicosapentaenoic acid substitutes for arachidonic acid in cell membranes and gives rise to 3-series prostaglandins and thromboxanes (that is, prostanoids with three double bonds in their side chains rather than the usual two), and 5-series leukotrienes. This probably accounts for their effects on haemostasis, because thromboxane A3 is much less active as a platelet-aggregating agent than is thromboxane A2, whereas PGI3 is similar in potency to PGI2 as an inhibitor of platelet function. The alteration in leukotriene biosynthesis probably underlies the anti-inflammatory effects of fish oil. Fish oil is contraindicated in patients with type IIa hyperlipoproteinaemia because of the increase in LDL that it causes. A preparation of omega 3-acid ethyl esters is licensed in the UK for prevention of recurrent events after myocardial infarction in addition to treatment of hypertriglyceridaemia; it causes less increase in LDL and fewer problems with fishy odour, weight gain and dyspepsia than the older fish oil preparations.
- #22 Antioxidant improve endotheilum function for pt. with increase oxidant stress Replacement therapy of estrogen ( in postmenopausal to treat osteoporosis) could induce thrombosis.