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ANTIHYPERLIPIDAEMIC ANTIHYPERLIPIDAEMIC DRUGS DRUGS BY BY DR/AZZA BARAKA DR/AZZA BARAKA

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Page 1: Antihyperlipidaemic Drugs

ANTIHYPERLIPIDAEMIC ANTIHYPERLIPIDAEMIC DRUGSDRUGS

BYBY

DR/AZZA BARAKADR/AZZA BARAKA

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Learning objectivesLearning objectives

Classify the antihyperlipidemic drugs.Classify the antihyperlipidemic drugs.Explain the mechanism of action of drugs used Explain the mechanism of action of drugs used

in treatment of hypercholesterolemia & in treatment of hypercholesterolemia & hypertriglyceridemia.hypertriglyceridemia.

Deduce the different antihyperlipidemic drugs in Deduce the different antihyperlipidemic drugs in treatment of combined hyperlipidemia.treatment of combined hyperlipidemia.

Tabulate the difference between the different Tabulate the difference between the different antihyperlipidemic drugs as regards; antihyperlipidemic drugs as regards; mechanism of action, side effects & therapeutic mechanism of action, side effects & therapeutic uses.uses.

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Lipids originate from two sources: endogenous lipids, synthesized in the liver, Lipids originate from two sources: endogenous lipids, synthesized in the liver, and exogenous lipids, ingested and processed in the intestine.and exogenous lipids, ingested and processed in the intestine.

Dietary cholesterol and triglycerides are packaged into chylomicrons in the Dietary cholesterol and triglycerides are packaged into chylomicrons in the intestine, before passing into the bloodstream via lymphatics. intestine, before passing into the bloodstream via lymphatics.

Chylomicrons are broken down by lipoprotein lipase (LPL) in the capillaries of Chylomicrons are broken down by lipoprotein lipase (LPL) in the capillaries of muscle and adipose tissue to fatty acids, which then enter the cells. The muscle and adipose tissue to fatty acids, which then enter the cells. The chylomicron remnants, which have lost much of their triglyceride content, chylomicron remnants, which have lost much of their triglyceride content, are taken up by the liver for disposal.are taken up by the liver for disposal.

The liver synthesizes triglycerides and cholesterol, and packages them as The liver synthesizes triglycerides and cholesterol, and packages them as VLDLs before releasing them into the blood. When VLDLs (which consist VLDLs before releasing them into the blood. When VLDLs (which consist mainly of triglyceride) reach muscle and adipose blood vessels, their mainly of triglyceride) reach muscle and adipose blood vessels, their triglycerides are hydrolyzed by LPL to fatty acids. The fatty acids that are triglycerides are hydrolyzed by LPL to fatty acids. The fatty acids that are released are taken up by the surrounding muscle and adipose cells. During released are taken up by the surrounding muscle and adipose cells. During this process, the VLDLs become progressively more dense and turn into this process, the VLDLs become progressively more dense and turn into LDLs. While most of the resulting LDLs are taken up by the liver for LDLs. While most of the resulting LDLs are taken up by the liver for disposal, some circulate and distribute cholesterol to the rest of the body disposal, some circulate and distribute cholesterol to the rest of the body tissues.tissues.

HDLs, which are also secreted from the liver and intestine, have the task of HDLs, which are also secreted from the liver and intestine, have the task of preventing lipid accumulation. They remove surplus cholesterol from tissues preventing lipid accumulation. They remove surplus cholesterol from tissues and transfer it to LDLs that return it to the liverand transfer it to LDLs that return it to the liver

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HYPERLIPIDEMIAHYPERLIPIDEMIA

Elevated concentrations of lipid Elevated concentrations of lipid (hyperlipidemia) can lead to the development (hyperlipidemia) can lead to the development of atherosclerosis and CAD. of atherosclerosis and CAD.

VLDLs and LDLsVLDLs and LDLs are atherogenic are atherogenic lipoproteins, whereas HDL concentrations lipoproteins, whereas HDL concentrations are inversely related to the incidence of CAD. are inversely related to the incidence of CAD.

Hence, treatments for hyperlipidemia aim to Hence, treatments for hyperlipidemia aim to reduce LDL levels and raise HDL levels.reduce LDL levels and raise HDL levels.

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High density lipoprotiensHigh density lipoprotiens Act as a reservoir for apoproteins which can be donated or received from other Act as a reservoir for apoproteins which can be donated or received from other

lipoproteins.lipoproteins. Also play a vital role in scavenging “used” cholesterol (reverse cholesterol transport): Also play a vital role in scavenging “used” cholesterol (reverse cholesterol transport):

HDL

Peripheral tissues

HDL

apoproteins

“used” cholesterol transferred to HDL and converted to cholesterol

ester

Liver

HDL receptor mediatedendocytosis by liver

Cholesterol can be converted to bile salts

for excretion orrepackaged in VLDL

for redistribution

VLDL

HDL

LDLLDL

LDLreceptor mediated

endocytosis

some cholesterol ester transferred to

circulating VLDL

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Pharmacotherapeutic options in Pharmacotherapeutic options in hyperlipidemiahyperlipidemia

I-Agents targeting endogenous cholesterol:I-Agents targeting endogenous cholesterol:a-Statins.a-Statins.b-Fibrates.b-Fibrates.C-Nicotinic acid.C-Nicotinic acid.II-Agents Targeting Exogenous CholesterolII-Agents Targeting Exogenous Cholesterola-Cholesterol Uptake Inhibitors, e.g. a-Cholesterol Uptake Inhibitors, e.g.

ezetemibe.ezetemibe.b- b- Bile acid binding resins, e.g. colestipol &

cholestyramine

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H M G – COA REDUCTASE H M G – COA REDUCTASE INHIBITORSINHIBITORS((STATINS)STATINS)

Lovastatin , fluvastatin , pravastatin , Lovastatin , fluvastatin , pravastatin , simvastatin ,atorvastatin and rosuvastatin.simvastatin ,atorvastatin and rosuvastatin.

Pharmacokinetics:Pharmacokinetics:They are subjected to extensive first-pass They are subjected to extensive first-pass

metabolism by the liver. Greater than 95% of metabolism by the liver. Greater than 95% of most of these drugs most of these drugs are bound to plasma are bound to plasma proteinsproteins..

All statins are taken All statins are taken orally at bedtimeorally at bedtime because of because of diurnal rhythm of cholesterol synthesis, diurnal rhythm of cholesterol synthesis, exceptexcept atorvastatin taken at any time atorvastatin taken at any time because of its long half-life (14 hours).because of its long half-life (14 hours).

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Mechanism of actionMechanism of actionThese are These are potent reversible competitive potent reversible competitive

inhibitors of 3-hydroxy 3-methyl glutaryl inhibitors of 3-hydroxy 3-methyl glutaryl coenzyme A reductasecoenzyme A reductase, the rate-controlling , the rate-controlling enzyme in cholesterol biosynthesis. enzyme in cholesterol biosynthesis.

They are extremely effective in lowering plasma They are extremely effective in lowering plasma concentration of LDL-C. concentration of LDL-C.

They act by inhibiting cholesterol synthesis in They act by inhibiting cholesterol synthesis in the liver, so they deplete the intracellular supply the liver, so they deplete the intracellular supply of cholesterol, which in turn triggers a of cholesterol, which in turn triggers a compensatory up-regulation of hepatic LDL compensatory up-regulation of hepatic LDL receptorsreceptors, thus, causing increased clearance of , thus, causing increased clearance of plasma LDL .plasma LDL .

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Pharmacological actionsPharmacological actionsEffect onEffect on LDL-C:LDL-C: Statins decrease LDL-C by two Statins decrease LDL-C by two

mechanisms:mechanisms:Up-regulation of LDL-R with increase of clearance of LDL-C Up-regulation of LDL-R with increase of clearance of LDL-C

and decrease LDL-C.and decrease LDL-C.Decrease of very low density lipoprotein (VLDL) production Decrease of very low density lipoprotein (VLDL) production

because cholesterol is a required component of VLDL which because cholesterol is a required component of VLDL which is a precursor of LDL-Cis a precursor of LDL-C

Effect on VLDL:Effect on VLDL: Decreased VLDL production mediated Decreased VLDL production mediated by decreased C, a required component of VLDL.by decreased C, a required component of VLDL.

Effect on HDL-C:Effect on HDL-C: Statins induce modest increase in Statins induce modest increase in HDL-C, this might be due to the ability of statins to HDL-C, this might be due to the ability of statins to reduce plasma CETP activity (mediates the transfer of reduce plasma CETP activity (mediates the transfer of cholesteryl esters from HDL to apoB-containing cholesteryl esters from HDL to apoB-containing lipoproteins in exchange for triglycerides).lipoproteins in exchange for triglycerides).

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Adverse effectsAdverse effects1.1. Hepatotoxicity (increased serum transaminase).Hepatotoxicity (increased serum transaminase).

2.2. Myopathy (increased creatine kinase) especially Myopathy (increased creatine kinase) especially when combined with: when combined with:

other lipid lowering drugs: i)Fibrates. ii) Niacin.other lipid lowering drugs: i)Fibrates. ii) Niacin. other drugs that are metabolized by 3A4 isoform of other drugs that are metabolized by 3A4 isoform of

cytochrome P450 e.g.: erythromycin, cyclosporine, cytochrome P450 e.g.: erythromycin, cyclosporine, verapamil, ketoconazole.verapamil, ketoconazole.

3.3. G.I.T upset.G.I.T upset.

4.4. Headache.Headache.

N.BN.B:: liver transaminases and CK must be regularly liver transaminases and CK must be regularly measured during therapy with statins measured during therapy with statins

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ContraindicationsContraindications1.1. Pregnancy & lactation (Cholesterol is important for normal Pregnancy & lactation (Cholesterol is important for normal

development, and it is possible that statins could cause serious development, and it is possible that statins could cause serious problems). The effects of high cholesterol do not cause problems). The effects of high cholesterol do not cause problems for many years or even decades. Therefore, if a problems for many years or even decades. Therefore, if a woman does not take her statin or other cholesterol woman does not take her statin or other cholesterol medications during breastfeeding, it will likely have only a medications during breastfeeding, it will likely have only a minimal impact on her long-term risks. Therefore, it is best to minimal impact on her long-term risks. Therefore, it is best to wait until you have weaned your child before starting or wait until you have weaned your child before starting or resuming a statin medication resuming a statin medication

2.2. Active liver diseases.Active liver diseases.N.B. The American Academy of Pediatrics is recommending that N.B. The American Academy of Pediatrics is recommending that

kids as young as 8 years old be given cholesterol drugs in hope kids as young as 8 years old be given cholesterol drugs in hope of preventing future heart diseaseof preventing future heart disease. .

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Drug interactionsDrug interactions

Potentiate the action of oral anticoagulant and Potentiate the action of oral anticoagulant and antidiabetic drugs (displacement from plasma antidiabetic drugs (displacement from plasma protein binding sites).protein binding sites).

N.B. N.B. : Pravastatin: Pravastatin and fluvastatin are the statins and fluvastatin are the statins of choice to be given to a patient taking other of choice to be given to a patient taking other drugs metabolized by cytochrome 3A4 system. drugs metabolized by cytochrome 3A4 system.

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FIBRIC ACID DERIVATIVE (Fibrates)FIBRIC ACID DERIVATIVE (Fibrates)Preparations: Preparations: Gemfibrozil , fenofibrate , clofibrate .Gemfibrozil , fenofibrate , clofibrate .Mechanism of action:Mechanism of action:Ligand for the nuclear transcription regulator, peroxisome proliferator-Ligand for the nuclear transcription regulator, peroxisome proliferator-

activated receptor-activated receptor-αα (PPAR- (PPAR- αα) in the liver, heart, kidney, & ) in the liver, heart, kidney, & skeletal muscle. skeletal muscle. N.B The PPAR-a are a class of intracellular receptors that modulate fat metabolism. It is through PPAR-a that fibrates lead to:

Increased LPL activity, which Increased LPL activity, which increases clearance of VLDL & increases clearance of VLDL & chylomicron in plasma.chylomicron in plasma.

Increased FFA uptake by the liver. Increased FFA uptake by the liver. Decreased VLDL due to increased fatty acid metabolism( beta Decreased VLDL due to increased fatty acid metabolism( beta

oxidation), by inducing oxidation), by inducing Acyl-coenzymeA synthetases , which is Acyl-coenzymeA synthetases , which is a a crucial crucial enzyme that facilitate the uptake and permit the metabolism of fatty acids. enzyme that facilitate the uptake and permit the metabolism of fatty acids.

Increased LDL-C uptake by the liver.Increased LDL-C uptake by the liver. Raises HDL cholesterol levels (by increasing Apo A-I and II Raises HDL cholesterol levels (by increasing Apo A-I and II

expression in hepatocytes).expression in hepatocytes). Increase excretion of hepatic cholesterol in bile , thus endogenous Increase excretion of hepatic cholesterol in bile , thus endogenous

hepatic cholesterol synthesis may be decreased. hepatic cholesterol synthesis may be decreased.

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PPARsPPARs PPARs functions as a ligand-activated transcription factor. PPARs functions as a ligand-activated transcription factor. Upon binding to hypolipidemic drugs, PPARs are activated. Upon binding to hypolipidemic drugs, PPARs are activated. They then bind to peroxisome proliferator response elements, They then bind to peroxisome proliferator response elements,

which are localized in numerous gene promoters. In particular, which are localized in numerous gene promoters. In particular, PPARs regulates the expression of genes encoding for proteins PPARs regulates the expression of genes encoding for proteins involved in lipoprotein structure and function. involved in lipoprotein structure and function.

Several such genes have been identified, including those of Several such genes have been identified, including those of apoC-III, apoA-I, apoA-II, apoA-IV, acyl coenzyme A oxidase, apoC-III, apoA-I, apoA-II, apoA-IV, acyl coenzyme A oxidase, and possibly that of lipoprotein lipase. and possibly that of lipoprotein lipase.

The transcriptional downregulation of apoC-III and the The transcriptional downregulation of apoC-III and the upregulation of lipoprotein lipase by fibrates enhance both the upregulation of lipoprotein lipase by fibrates enhance both the intravascular lipolysis of TG-rich lipoproteins as well as their intravascular lipolysis of TG-rich lipoproteins as well as their tissue catabolism via apoE-mediated binding to specific cellular tissue catabolism via apoE-mediated binding to specific cellular receptors. receptors.

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Adverse effectsAdverse effects

G.I.T upset,rash, urticariaG.I.T upset,rash, urticariaMyopathyMyopathySince fibrates increase the cholesterol content Since fibrates increase the cholesterol content

of bile, they increase the risk for gallstones. of bile, they increase the risk for gallstones.

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Drug interactionsDrug interactions1.1. Increased risk of myopathy when combined with Increased risk of myopathy when combined with

statins.statins.

2.2. Displace drugs from plasma proteins( e.g. oral Displace drugs from plasma proteins( e.g. oral anticoagulants and oral hypoglycemic drugs).anticoagulants and oral hypoglycemic drugs).

Contraindications:Contraindications:

1- Patients with impaired renal functions.1- Patients with impaired renal functions.

2- Pregnant or nursing women.2- Pregnant or nursing women.

3-Preexisting gall bladder disease.3-Preexisting gall bladder disease.

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NICOTINIC ACID(NIACIN)NICOTINIC ACID(NIACIN)Mechanism of action:Mechanism of action:

1.1. In adipose tissueIn adipose tissue: it binds to adipose : it binds to adipose nicotinic acid nicotinic acid receptors, this will lead to receptors, this will lead to decrease in free fatty acids decrease in free fatty acids mobilization from adipocytes to the liver resulting in mobilization from adipocytes to the liver resulting in TG TG and thus VLDL synthesis.and thus VLDL synthesis.

2.2. In liver:In liver: niacin inhibits hepatocyte diacylglycerol niacin inhibits hepatocyte diacylglycerol acyltransferase-2, a key enzyme for TG synthesis. Thus, it acyltransferase-2, a key enzyme for TG synthesis. Thus, it decreases VLDL production (decreased TG synthesis and decreases VLDL production (decreased TG synthesis and estrification).estrification).

3.3. In plasmaIn plasma: it increases LPL activity that increases : it increases LPL activity that increases clearance of VLDL & chylomicron.clearance of VLDL & chylomicron.

4.4. Niacin also promotes hepatic apoA-I production and slows Niacin also promotes hepatic apoA-I production and slows hepatic clearance of apoA-I and HDL through as-yet hepatic clearance of apoA-I and HDL through as-yet unknown mechanisms. unknown mechanisms.

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Pharmacological actionsPharmacological actions Effect on VLDL:Effect on VLDL: Decreased VLDL by: Decreased VLDL by: 1) decreased synthesis in liver; 1) decreased synthesis in liver;

2) increased clearance in plasma.2) increased clearance in plasma. Effect on LDL: Effect on LDL: Decreased LDL due to reduction Decreased LDL due to reduction

in its precursor (VLDL).in its precursor (VLDL). Effect on HDL:Effect on HDL: Induces modest increase in HDL- Induces modest increase in HDL-

C (The catabolism of HDL can be inhibited by C (The catabolism of HDL can be inhibited by nicotinic acid through a mechanism that is largely nicotinic acid through a mechanism that is largely unknown). Niacin also promotes hepatic apoA-I unknown). Niacin also promotes hepatic apoA-I production and slows hepatic clearance of apoA-I production and slows hepatic clearance of apoA-I and HDL through as-yet unknown mechanisms. and HDL through as-yet unknown mechanisms.

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Therapeutic UsesTherapeutic Uses

Niacin is the most effective medication for Niacin is the most effective medication for increasing HDL cholesterol levels and it increasing HDL cholesterol levels and it has positive effects on the complete lipid has positive effects on the complete lipid profile.profile. It is useful for patients with mixed It is useful for patients with mixed dyslipidemias. dyslipidemias.

Niacin appears to exert the greatest Niacin appears to exert the greatest beneficial effects on the widest range of beneficial effects on the widest range of lipoprotein abnormalities lipoprotein abnormalities

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Adverse effectsAdverse effects

1.1. Pruritus, flushing The niacin flush results from the Pruritus, flushing The niacin flush results from the stimulation of prostaglandins D(2) and E(2) by stimulation of prostaglandins D(2) and E(2) by subcutaneous Langerhans cells via the niacin subcutaneous Langerhans cells via the niacin receptor. This flush is avoided by low dose aspirin receptor. This flush is avoided by low dose aspirin 325 mg ½ h before niacin. 325 mg ½ h before niacin.

2.2. Reactivation of peptic ulcer (Reactivation of peptic ulcer (because it stimulates stimulates histamine release resulting in increased gastric histamine release resulting in increased gastric motility and acid production .motility and acid production .

3.3. Hepatotoxicity.Hepatotoxicity.4.4. Hyperglycemia which is believed to be caused by an Hyperglycemia which is believed to be caused by an

increase in insulin resistance. increase in insulin resistance. 5.5. Increased uric acid level( due to decreased uric acid Increased uric acid level( due to decreased uric acid

excretion).excretion).

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ContraindicationsContraindications

1.1. Gout.Gout.

2.2. Peptic ulcer.Peptic ulcer.

3.3. Hepatotoxicity.Hepatotoxicity.

4.4. Diabetes mellitus.Diabetes mellitus.

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EzetimibeEzetimibe

Mechanism of action:Mechanism of action:

- Impairs dietary and biliary cholesterol absorption at the - Impairs dietary and biliary cholesterol absorption at the brush border of the intestines without affecting brush border of the intestines without affecting fat-soluble fat-soluble vitamins.vitamins.

- Reducing the pool of cholesterol absorbed from the diet - Reducing the pool of cholesterol absorbed from the diet results in a reduced pool of cholesterol available to the liver.results in a reduced pool of cholesterol available to the liver.

-The liver in turn will upregulate the LDL receptor, -The liver in turn will upregulate the LDL receptor, trapping more LDL particles from the blood and result in a trapping more LDL particles from the blood and result in a fall in measured LDL cholesterol .fall in measured LDL cholesterol .

Adapted from van Heek M et al Br J Pharmacol 2000;129:1748-1754.

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PharmacokineticsPharmacokinetics

Elimination half-life of ezetimibe approximately 22 Elimination half-life of ezetimibe approximately 22 hourshours

Long half-life:Long half-life:

1.1. Permits once-daily dosingPermits once-daily dosing

2.2. May improve complianceMay improve compliance

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BILE ACID BINDING RESINS(BAS)BILE ACID BINDING RESINS(BAS)E.g. E.g. colestipol ,cholestyramine and colestipol ,cholestyramine and Colesevelam Colesevelam Mechanism of action:Mechanism of action:1- When resins are given orally, they are not absorbed, they bind 1- When resins are given orally, they are not absorbed, they bind

to bile acids in the intestinal lumen, prevent their reabsorption to bile acids in the intestinal lumen, prevent their reabsorption and increase their excretion, thus interrupt the enterohepatic and increase their excretion, thus interrupt the enterohepatic circulation of bile acids.circulation of bile acids.

2-Since bile acids inhibit the enzyme that catalysis the rate 2-Since bile acids inhibit the enzyme that catalysis the rate limiting step in the conversion of cholesterol to bile acids, their limiting step in the conversion of cholesterol to bile acids, their removal results in increased breakdown of hepatic cholesterol. removal results in increased breakdown of hepatic cholesterol.

3-However, a compensatory increase occurs in the rate of 3-However, a compensatory increase occurs in the rate of biosynthesis of cholesterol which is insufficient to compensate biosynthesis of cholesterol which is insufficient to compensate for the increased catabolism and up-regulation of LDL-R on for the increased catabolism and up-regulation of LDL-R on hepatocytes thus the plasma and tissue cholesterol levels hepatocytes thus the plasma and tissue cholesterol levels decrease. decrease.

4-In addition, since bile acids are required for intestinal 4-In addition, since bile acids are required for intestinal absorption of cholesterol, these resins decrease cholesterol absorption of cholesterol, these resins decrease cholesterol absorption from the G.I.T. absorption from the G.I.T.

NB:NB: They may produce, however, a rise in VLDL. They may produce, however, a rise in VLDL.

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Pharmacological actionsPharmacological actions

Effect on LDL-C:Effect on LDL-C: It decreases cholesterol It decreases cholesterol content of hepatocytes leading to up-regulation content of hepatocytes leading to up-regulation of LDL-receptors with increased LDL-of LDL-receptors with increased LDL-cholesterol clearance from blood and cholesterol clearance from blood and decreased LDL-cholesterol level.decreased LDL-cholesterol level.

Effect on VLDL:Effect on VLDL: It produces transient increase in It produces transient increase in TG level in normal subjects which return to TG level in normal subjects which return to base line. In borderline patient (e.g. TG >250 base line. In borderline patient (e.g. TG >250 mg/dl), it produces marked increase in TG, mg/dl), it produces marked increase in TG, which is dangerous. which is dangerous.

Effect on HDL-C:Effect on HDL-C: Increased HDL-C Increased HDL-C

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Side effectsSide effects1.1. Constipation ,G.I.T complaints: heart burn, flatulence, Constipation ,G.I.T complaints: heart burn, flatulence,

dyspepsia.dyspepsia.2.2. Large doses may impair absorption of fats or fat soluble Large doses may impair absorption of fats or fat soluble

vitamins (A, D, E, and K) and other medications, vitamins (A, D, E, and K) and other medications, particularly warfarin and statins, that are given concurrently. particularly warfarin and statins, that are given concurrently.

N.B. Patients on multiple drug regimens should be counseled to N.B. Patients on multiple drug regimens should be counseled to administer other medications one hour before or four hours administer other medications one hour before or four hours after the BAS. after the BAS. Colesevelam Colesevelam has not been shown to interfere has not been shown to interfere with the absorption of coadministered medications and is a with the absorption of coadministered medications and is a better choice for patients on multiple drug regimensbetter choice for patients on multiple drug regimens

1.1. May May ↑↑ level of VLDL in border line patients. level of VLDL in border line patients.2.2. Chronic use of cholestyramine resin may be associated with Chronic use of cholestyramine resin may be associated with

increased bleeding tendency due to hypoprothrombinemia increased bleeding tendency due to hypoprothrombinemia associated with Vitamin K deficiency. associated with Vitamin K deficiency.

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ContraindicationsContraindications

1- Complete biliary obstruction( BECAUSE BILE 1- Complete biliary obstruction( BECAUSE BILE IS NOT secreted into the intestine).IS NOT secreted into the intestine).

2- Chronic constipation.2- Chronic constipation.

3-Severe hypertriglyceridemia(TG >400 mg/dL)3-Severe hypertriglyceridemia(TG >400 mg/dL)

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Antihyperlipedemic combinationsAntihyperlipedemic combinations Indications:Indications:

1.1. Increased VLDL during treatment of Increased VLDL during treatment of hypercholesterolemia with resins.hypercholesterolemia with resins.

2.2. Combined increase in LDL & VLDL.Combined increase in LDL & VLDL.

3.3. High LDL or VLDL not normalized with a High LDL or VLDL not normalized with a single drug.single drug.

4.4. Severe hypertriglycerdemia or Severe hypertriglycerdemia or hypercholesterolemia.hypercholesterolemia.

5.5. To take lower doses of each drug.To take lower doses of each drug.

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Resin & Niacin:Resin & Niacin:

In combined hyperlipidemia.In combined hyperlipidemia.

Advantages: Advantages:

No additional side effects.No additional side effects.

Resin decrease gastric irritation of niacin.Resin decrease gastric irritation of niacin.

May be given concomitantly.May be given concomitantly. Resin & statinResin & statin: (synergistic combination): (synergistic combination) why? why?

Because adding statins block the compensatory Because adding statins block the compensatory increase that occurs in the rate of biosynthesis of increase that occurs in the rate of biosynthesis of cholesterol induced by resins. cholesterol induced by resins.

Statin & ezetimibeStatin & ezetimibe:: (synergistic combination) (synergistic combination) why? why?

Because statin blocks synthesis of endogenous Because statin blocks synthesis of endogenous cholesterol while ezetimibe blocks exogenous cholesterol while ezetimibe blocks exogenous cholesterol.cholesterol.

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Niacin & Statins: Niacin & Statins: -In severe LDL elevation.-In severe LDL elevation. -In combined hyperlipidemia -In combined hyperlipidemia

Statins & Fibrates:Statins & Fibrates: Contraindicated (in full dose) because the Contraindicated (in full dose) because the

incidence of myopathy may increase so, incidence of myopathy may increase so, use not more than ¼ maximum dose of use not more than ¼ maximum dose of statin and use pravastatin .statin and use pravastatin .

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