Presentation on theme: "Drugs used in the treatment of hyperlipidemias"— Presentation transcript:
1Drugs used in the treatment of hyperlipidemias ByS.Bohlooli, PhD
2Introduction Introduction Cholesterol Used to prevent or slow progression of atherosclerosis to reduce the risk of coronary artery disease and prolong lifeCholesterolAdvantagesServes as a component of cell membranes and intracellular organelle membranesIs involved in the synthesis of certain hormones including estrogen, progesterone, testosterone, adrenal corticosteroidsNeeded for the synthesis of bile salts which are needed for digestion and absorption of fats.
3Introduction Cholesterol Advantages Origin Is deposited in the stratum corneum of the skin to help ↓ evaporation of water and create impermeability to water soluble compounds (helps keep moisture in skin)OriginIs synthesized in the liver. Acetyl CoA is converted to mevalonic acid and ultimately to cholesterol by hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase.
4Introduction Cholesterol Origin Endogenous synthesis of cholesterol increases at nightAn increase in dietary cholesterol produces only a small ↑ in blood levels of cholesterol because ingestion inhibits endogenous synthesisDietary saturated fats ↑ blood cholesterol levels because they are converted to cholesterol in the body.
5Introduction Lipoproteins Serve as carriers for transporting lipids (cholesterol and triglycerides) in the blood.ApolipoproteinsEmbedded in the lipoprotein shellThree functions1. Serve as recognition sites for cell-surface receptors; allowing cells to bind and ingest the lipoprotein.2. Activate enzymes that will metabolize the lipoprotein3. ↑ structural stability of the lipoprotein
6Introduction Lipoproteins Apolipoproteins All lipoproteins that deliver lipids to peripheral tissues (nonhepatic tissues) contain apolipoprotein B-100 (Ex: VLDL, LDL)All lipoproteins that transport lipids from peripheral tissues back to the liver contain apolipoprotein A-I (Ex: HDL)
7Introduction Lipoproteins Lipoproteins of importance VLDL (very low density lipoprotein)Contain triglycerides (TGs) and some cholesterolAccount for nearly all TGs in the bloodContain B-100Deliver triglycerides from the liver to adipose tissues and muscles.
8Introduction Lipoproteins Lipoproteins of importance VLDL (very low density lipoprotein)Remnants of hydrolysis are IDL (intermediate density lipoproteins), which can be transported to liver or converted to LDL
9Introduction Lipoproteins Lipoproteins of importance LDL (low density lipoprotein)“Bad cholesterol”Contain cholesterolAccount for 60-70% of cholesterol in the bloodContains B-100Delivers cholesterol to peripheral tissues
10Introduction Lipoproteins Lipoproteins of importance LDL (low density lipoprotein)Formed from IDL, the remnants of VLDLMakes the greatest contribution to coronary atherosclerosisOxidized LDL contributes to atherosclerotic plaqueRemoved from plasma via endocytosis by liver converting it to bile acids excreted in GI
11Introduction Lipoproteins Lipoproteins of importance HDL (high density lipoprotein)“Good cholesterol”Contain cholesterolAccount for 20-30% of cholesterol in the bloodSome contain Apo A-I and Apo A-IIApo A-I is cardioprotectiveTransports cholesterol from the peripheral tissues back to the liver – promotes cholesterol removalAntiatherogenic
12Characteristics of Plasma Lipoproteins LIPOPROTEIN CLASSDENSITY OF FLOTATION, g/mlSIGNIFICANT APOPROTEINSSITE OF SYNTHESISMECHANISM(S) OF CATABOLISMChylomicrons and remnants<<1.006B-48, E, A-I, A-IV, C-I, C-II, C-IIIIntestineTriglyceride hydrolysis by LPLApoE-mediated remnant uptake by liverVLDL<1.006B-100, E, C-I, C-II, C-IIILiverIDLB-100, E, C-II, C-IIIProduct of VLDL catabolism50% converted to LDL mediated by HL, 50% apoE-mediated uptake by liver50% apoE-mediated uptake by liverLDLB-100ApoB-100-mediated uptake by LDL receptor (~75% in liver)HDLA-I, A-II, E, C-I, C-II, C-IIIIntestine, liver, plasmaComplex:Transfer of cholesteryl ester to VLDL and LDLUptake of HDL cholesterol by hepatocytesAbbreviations: apo, apolipoprotein; CHOL, cholesterol; HDL, high-density lipoproteins; IDL, intermediate-density lipoproteins; Lp(a), lipoprotein(a); LDL, low-density lipoproteins; NS, not significant (triglyceride is less than 5% of LDL and HDL); TG, triglyceride; VLDL, very-low-density lipoproteins; HL, hepatic lipase; LPL, lipoprotein lipase.
13The major pathways involved in the metabolism of chylomicrons synthesized by the intestine and VLDL synthesized by the liverMetabolism of lipoproteins of hepatic origin. The heavy arrows show the primary pathways. Nascent VLDL are secreted via the Golgi apparatus. They acquire additional apoC lipoproteins and apolipoprotein E (apoE) from HDL. Very-low-density lipoproteins (VLDL) are converted to VLDL remnants (IDL) by lipolysis via lipoprotein lipase in the vessels of peripheral tissues. In the process, C apolipoproteins and a portion of the apoE are given back to high-density lipoproteins (HDL). Some of the VLDL remnants are converted to LDL by further loss of triglycerides and loss of apoE. A major pathway for LDL degradation involves the endocytosis of LDL by LDL receptors in the liver and the peripheral tissues, for which apo B-100 is the ligand. Dark color denotes cholesteryl esters; light color denotes triglycerides; the asterisk denotes a functional ligand for LDL receptors; triangles indicate apoE; circles and squares represent C apolipoproteins. FFA, free fatty acid; RER, rough endoplasmic reticulum.(Modified and redrawn, with permission, from Kane J, Malloy M: Disorders of lipoproteins. In: Rosenberg RN et al [editors]: The Molecular and Genetic Basis of Neurological Disease. Butterworth-Heinemann, 1993.)
14Classification of Plasma Lipid Levels Total cholesterol<200 mg/dlDesirablemg/dlBorderline high≥240 mg/dlHighHDL-C<40 mg/dlLow (consider <50 mg/dl as low for women)>60 mg/dlLDL-C<70 mg/dlOptimal for very high risk (minimal goal for CHD equivalent patients)<100 mg/dlOptimalmg/dlNear optimalmg/dlmg/dl≥190 mg/dlVery highTriglycerides<150 mg/dlNormalmg/dlmg/dl≥500 mg/dl
16Treatment of hyperlipidemia Treatment (tx)Non-Pharmacological Therapy – 1st line tx1. Diet modificationDecrease intake of total fat and especially saturated fatIncrease fiber intakeIncrease Omega-3-fatty acids (found in fish)↑ fruits and vegetables (antioxidants)↓ simple sugars (sucrose)
17Sites of action of drugs used for treatment of dislypidemia Sites of action of HMG-CoA reductase inhibitors, niacin, ezetimibe, and resins used in treating hyperlipidemias. Low-density lipoprotein (LDL) receptors are increased by treatment with resins and HMG-CoA reductase inhibitors. VLDL, very-low-density lipoproteins; R, LDL receptor.
18Treatment of hyperlipidemia Non-Pharmacological Therapy – 1st line tx2. Exercise (will ↑ HDL levels)3. Reduce risk factors if possibleDrug TherapyNiacin (vitamin B3)Decreases VLDL and LDL and significantly ↑ HDLMOA1. Inhibits VLDL secretion into the blood thereby preventing production of LDL2. Increases clearance of VLDL via lipoprotein lipase pathway
20Antilipemic agents Niacin MOA 3. Inhibits FFA release from adipose tissues by inhibiting the intracellular lipase system4. Reduces circulating fibrinogen (contributes to clot formation) and ↑ tissue plasminogen activator (clot dissolver)5. HDL catabolic rate is decreased6. Reduces the plasma level of Lp(a) lipoprotein, which can increase risk of CAD
21Antilipemic agents Niacin Indications Drug of choice for ↓ levels of TG (VLDL) in pts at risk for pancreatitisMixed elevation of LDL and VLDL (alone or in combination with reductase inh.)Elevation of TG (VLDL) and low levels of HDL (Niaspan® - approved for elevating HDL levels)Start with low dose and gradually increaseGiven 1-3g/day in divided doses or once daily with extended release. Give at night with food.
22Antilipemic agents Niacin - Adverse effects Flushing Harmless cutaneous vasodilationUncomfortable sensation of warmthOccurs after drug is started or ↑ doseLasts for the first several weeksCan give 325mg aspirin 30 minutes before each dose (prevents prostaglandin synthesis). Can also take ibuprofen QD in place of ASA
23Antilipemic agents Niacin - Adverse effects Pruritis, rashes, dry skin acanthosis nigricans (eruption of velvet warty benign growths and hyperpigmentation)Associated with insulin resistanceWill have to d/c drug if occursNausea and abdominal discomfortReduce dosage and may need to use inhibitors of gastric acid secretion or antacids (not containing aluminum)Avoid in pts with severe peptic disease
24Antilipemic agents Niacin - Adverse effects Hepatotoxicity Severe is rare, and reversibleOccurs mostly with older sustained release formsMonitor liver fx regularlyLiver injury is less likely with Niaspan® (given once daily) the new extended release formulationCarbohydrate tolerance may be moderately impaired (hyperglycemia)ReversibleCan still be given to diabetics receiving insulin
25Antilipemic agents Niacin - Adverse effects Hyperuricemia Hypotension Occurs in about 1/5 of ptsOccasionally precipitates goutHypotensionEspecially seen in pts on antihypertensive medsCan ↑ homocysteine levels which ↑ risk of CAD (give folic acid to ↓ homocysteine levels)
27Hepatic and peripheral effects of fibrates Hepatic and peripheral effects of fibrates. These effects are mediated by activation of peroxisome proliferator-activated receptor-, which modulates the expression of several proteins. LPL, lipoprotein lipase; VLDL, very-low-density lipoproteins
28Antilipemic agentsFibrates (gemfibrozil, fenofibrate, clofibrate, bezafibrate)Little or no effect on LDL↓ VLDL (TG)moderate ↑ of HDLMOALigand for the nuclear transcription regulator, peroxisome proliferator-activated receptor-α (PPAR- α)MOA mostly unknown
29Antilipemic agents Fibrates MOA ↑ activity of lipoprotein lipase for lipolysis of triglyceride (↑ clearance)↓ lipolysis in adipose tissue, ↓ FFA release↓ secretion of VLDL by liver↓ uptake of FFA by liver↑ HDL levels moderately
30Antilipemic agents Fibrates Indication: Hypertriglyceridemia Gemfibrozil – 600mg QD-BID (half life 1.5hrs)Fenofibrate – mg tablets QD (half life 20hrs)Taken with food - ↑ absorptionMax reduction of VLDL is achieved within 3-4 weeks of treatmentAdverse EffectsRashesGI disturbances (nausea, abdominal pain, diarrhea)
31Antilipemic agents Fibrates - Adverse Effects Gallstones (upper abdominal discomfort, intolerance of fried food, bloating)Gemfibrozil ↑ biliary cholesterol saturationUse with caution in pts with biliary tract ds, women, obese pts, and Native AmericansMyopathy (muscle injury)Tenderness, weakness, or unusual muscle painWill increase risk of statin-induced myopathy when used together (rhabdomyolysis has occurred rarely)
32Antilipemic agents Fibrates - Adverse Effects Hepatoxicity Arrythmias HypokalemiaDisplaces warfarin from plasma albumin since drug is highly protein bound. Need to ↓ warfarin dose
34Antilipemic agentsBile Acid-Binding Resins (colestipol and cholestyramine)Will ↓ LDL, may ↑ VLDL (would require niacin combo if ↑ TG prior to tx)MOABile acids, the metabolites of cholesterol, are normally reabsorbed in the jejunum and ileum. When resins are given, they bind to bile acids in the intestinal lumen, prevent their reabsorption and increase their excretion.
35Antilipemic agents Bile Acid-Binding Resins MOA Indication ↑ excretion creates a demand for ↑ synthesis of bile acid. Liver cells must have an ↑ cholesterol supply (provided by LDL) to synthesize bile acid. Liver cells will ↑ their LDL receptors, ↑ing uptake of LDL from plasma.IndicationUsed alone to ↓ LDL (by 15-20%)Normally used as adjuncts to the statins to ↓ LDL (by 50%)
36Antilipemic agents Bile Acid-Binding Resins Indication Adverse Effects Can be used to relieve pruitis in pts who have cholestasisCan be used for severe digitalis toxicityDispensed in powder form (must be mixed with fluid). Cholestyramine 4-12g BID. Colestipol 5-30g/day in divided doses and also in 1g tablets (2-16g/day) taken w/ fluidAdverse EffectsMax reductions of LDL occur in one monthMust be taken with meals
37Antilipemic agents Bile Acid-Binding Resins Adverse Effects ConstipationBloating, indigestion, nauseaLarge doses may impair absorption of fats or fat soluble vitamins (A, D, E, and K)Drug InteractionsResins bind digoxin, warfarin, thiazide diuretics, tetracycline, thyroxine, iron salts, pravastatin, fluvastatin, folic acid, phenylbutazone, aspirin, ascorbic acid (these agents should be given 1 hour before the resin or 4 hours after)
39Antilipemic agentsHMG COA Reductase Inhibitors (“statins”) (lovastatin, fluvastatin, pravastatin, simvastatin, atorvastatin, cerivastatin)Most Effective for ↓ LDLWill ↑ HDL and ↓ VLDLFewest adverse effects and tolerated best
40Inhibition of HMG-CoA reductase Inhibition of HMG-CoA reductase. Top: The HMG-CoA intermediate that is the immediate precursor of mevalonate, a critical compound in the synthesis of cholesterol. Bottom: The structure of lovastatin and its active form, showing the similarity to the normal HMG-CoA intermediate (shaded areas).
41Antilipemic agents (“statins”) MOA Inhibits hepatic HMG CoA reductase Inhibition of cholesterol synthesis causes hepatocytes to synthesize more LDL receptorsHepatocytes are able to remove more LDLs from the bloodDecrease production of apolipoprotein B-100, thereby ↓ production of VLDL↓ plaque cholesterol content
42Antilipemic agents (“statins”) MOA ↓ inflammation at the plaque site Improve abnormal endothelial functionEnhance the ability of blood vessels to dilate↓ risk of thrombosis (inhibits platelet aggregation and blocks thrombin synthesis)Statins have high first pass extraction by liver (only a small fraction of each dose reaches the general circulation)Prodrugs – lovastatin and simvastatin
43Antilipemic agents (“statins”) – Indications Used alone to ↓ LDL Used with bile acid – binding resins to ↓ LDLUsed with niacin to ↓ LDL, ↓ VLDL, and ↑ HDLEnhanced if taken with food (except for pravastatin – taken without food)Give in the eveningHalf life is 1-3 hours (except atorvastatin – 14 hours)
44Antilipemic agents (“statins”) – Indications Atorvastatin is most efficacious agent for use in severe hypercholesterolemiaHigh potency (>40-50% LDL lowering) – atorvastatin, simvastatin, cerivastatinLow potency (20-40% LDL lowering) – lovastatin, fluvastatin, pravastatin↓ LDL within 2 weeks; max reduction in 4-6 weeks
45Antilipemic agents (“statins”) – Indications New Drug: Altocor® Extended release lovastatinSlightly more effective than regular lovastatinTake without food
46Antilipemic agents (“statins”) – Adverse Effects Since LDL cholesterol levels will return to pretreatment values if drugs are withdrawn, treatment must continue lifelongStatins are pregnancy category Xrash, GI disturbances (dyspepsia, cramps, flatulence, constipation, abdominal pain)
47Antilipemic agents (“statins”) – Adverse Effects Hepatotoxicity Myopathy (0.5% of pts)Risk highest with lovastatin and especially in combination with FibratesCyp3A4 drug interactions with all statins excepts for pravastatin and fluvastatin
49Antilipemic agents Ezetimibe ezetimibe reduced cholesterol absorption by 54%Cholesterol lowering agentWill challenge the statinsApproved for monotherapy or in combo with statinsreduction of 60% with simvastatin for LDL-C
50Inhibitors of Cholesteryl Ester Transfer Protein a plasma glycoprotein synthesized by the livermediates the transfer of cholesteryl estersIn animal modelsinhibition of CETP result in:higher HDL levelsdecreased LDL levelsresistance to developing atherosclerosisJTT-705 and torcetrapib