antilipemic agents

Drugs used in the treatment of hyperlipidemias

ByS.Bohlooli, PhD

Introduction

IntroductionUsed to prevent or slow progression of atherosclerosis

to reduce the risk of coronary artery disease and prolong life

CholesterolAdvantages

Serves as a component of cell membranes and intracellular organelle membranes

Is involved in the synthesis of certain hormones including estrogen, progesterone, testosterone, adrenal corticosteroids

Needed for the synthesis of bile salts which are needed for digestion and absorption of fats.

Introduction

CholesterolAdvantages

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.

Introduction

CholesterolOrigin

Endogenous synthesis of cholesterol increases at night

An increase in dietary cholesterol produces only a small ↑ in blood levels of cholesterol because ingestion inhibits endogenous synthesis

Dietary saturated fats ↑ blood cholesterol levels because they are converted to cholesterol in the body.

Introduction

LipoproteinsServe as carriers for transporting lipids

(cholesterol and triglycerides) in the blood.Apolipoproteins

Embedded in the lipoprotein shellThree functions

• 1. Serve as recognition sites for cell-surface receptors; allowing cells to bind and ingest the lipoprotein.

• 2. Activate enzymes that will metabolize the lipoprotein• 3. ↑ structural stability of the lipoprotein

Introduction

LipoproteinsApolipoproteins

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)

Introduction

LipoproteinsLipoproteins of importance

VLDL (very low density lipoprotein)• Contain triglycerides (TGs) and some cholesterol• Account for nearly all TGs in the blood• Contain B-100• Deliver triglycerides from the liver to adipose tissues and

muscles.

Introduction


VLDL (very low density lipoprotein)• Remnants of hydrolysis are IDL (intermediate density

lipoproteins), which can be transported to liver or converted to LDL

Introduction


LDL (low density lipoprotein)• “Bad cholesterol”• Contain cholesterol• Account for 60-70% of cholesterol in the blood• Contains B-100• Delivers cholesterol to peripheral tissues

Introduction


LDL (low density lipoprotein)• Formed from IDL, the remnants of VLDL• Makes the greatest contribution to coronary

atherosclerosis Oxidized LDL contributes to atherosclerotic plaque

• Removed from plasma via endocytosis by liver converting it to bile acids excreted in GI

Introduction


HDL (high density lipoprotein)• “Good cholesterol”• Contain cholesterol• Account for 20-30% of cholesterol in the blood• Some contain Apo A-I and Apo A-II• Apo A-I is cardioprotective• Transports cholesterol from the peripheral tissues back

to the liver – promotes cholesterol removal• Antiatherogenic

LIPOPROTEIN CLASS

DENSITY OF FLOTATION, g/ml

SIGNIFICANT APOPROTEINS

SITE OF SYNTHESIS

MECHANISM(S) OF CATABOLISM

Chylomicrons and remnants

<<1.006 B-48, E, A-I, A-IV, C-I, C-II, C-III

Intestine Triglyceride hydrolysis by LPL

ApoE-mediated remnant uptake by liver

VLDL <1.006 B-100, E, C-I, C-II, C-III

Liver Triglyceride hydrolysis by LPL

IDL 1.006-1.019 B-100, E, C-II, C-III

Product of VLDL catabolism

50% converted to LDL mediated by HL, 50% apoE-mediated uptake by liver

50% apoE-mediated uptake by liver

LDL 1.019-1.063 B-100 Product of VLDL catabolism

ApoB-100-mediated uptake by LDL receptor (~75% in liver)

HDL 1.063-1.21 A-I, A-II, E, C-I, C-II, C-III

Intestine, liver, plasma

Complex:

Transfer of cholesteryl ester to VLDL and LDL

Uptake of HDL cholesterol by hepatocytes

Characteristics of Plasma Lipoproteins

The major pathways involved in the metabolism of chylomicrons synthesized by the intestine and VLDL synthesized by the liver

Classification of Plasma Lipid Levels Total cholesterol

<200 mg/dl Desirable

200-239 mg/dl Borderline high

≥240 mg/dl High

HDL-C

<40 mg/dl Low (consider <50 mg/dl as low for women)

>60 mg/dl High

LDL-C

<70 mg/dl Optimal for very high risk (minimal goal for CHD equivalent patients)

<100 mg/dl Optimal

100-129 mg/dl Near optimal


160-189 mg/dl High

≥190 mg/dl Very high

Triglycerides

<150 mg/dl Normal


200-499 mg/dl High

≥500 mg/dl Very high

Secondary Causes of Dyslipidemia

DISORDER MAJOR LIPID EFFECTDiabetes mellitus Triglycerides > cholesterol; low HDL-C

Nephrotic syndrome Triglycerides usually > cholesterol

Alcohol use Triglycerides > cholesterol

Contraceptive use Triglycerides > cholesterol

Estrogen use Triglycerides > cholesterol

Glucocorticoid excess Triglycerides > cholesterol

Hypothyroidism Cholesterol > triglycerides

Obstructive liver disease Cholesterol > triglycerides

Treatment of hyperlipidemia

Treatment (tx)Non-Pharmacological Therapy – 1st line tx

1. Diet modification• Decrease intake of total fat and especially saturated fat• Increase fiber intake• Increase Omega-3-fatty acids (found in fish)• ↑ fruits and vegetables (antioxidants)• ↓ simple sugars (sucrose)

Sites of action of drugs used for treatment of dislypidemia

Treatment of hyperlipidemia

TreatmentNon-Pharmacological Therapy – 1st line tx

2. Exercise (will ↑ HDL levels)3. Reduce risk factors if possible

Drug TherapyNiacin (vitamin B3)

• Decreases VLDL and LDL and significantly ↑ HDL• MOA

1. Inhibits VLDL secretion into the blood thereby preventing production of LDL

2. Increases clearance of VLDL via lipoprotein lipase pathway

Niacin: chmeistry

Antilipemic agents

NiacinMOA

3. Inhibits FFA release from adipose tissues by inhibiting the intracellular lipase system

4. 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

Antilipemic agents

NiacinIndications

Drug of choice for ↓ levels of TG (VLDL) in pts at risk for pancreatitis

Mixed 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.

Antilipemic agents

Niacin - Adverse effectsFlushing

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

Antilipemic agents

Niacin - Adverse effectsPruritis, rashes, dry skinacanthosis nigricans (eruption of velvet warty

benign growths and hyperpigmentation)Associated with insulin resistanceWill have to d/c drug if occurs

Nausea 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

Antilipemic agents

Niacin - Adverse effectsHepatotoxicity

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

Antilipemic agents

Niacin - Adverse effectsHyperuricemia

Occurs in about 1/5 of ptsOccasionally precipitates gout

HypotensionEspecially seen in pts on antihypertensive meds

Can ↑ homocysteine levels which ↑ risk of CAD (give folic acid to ↓ homocysteine levels)

Fibrates: chemistry

Hepatic and peripheral effects of fibrates

Antilipemic agents

Fibrates (gemfibrozil, fenofibrate, clofibrate, bezafibrate)Little or no effect on LDL↓ VLDL (TG)moderate ↑ of HDLMOA

Ligand for the nuclear transcription regulator, peroxisome proliferator-activated receptor-α (PPAR- α)

MOA mostly unknown

Antilipemic agents

FibratesMOA

↑ 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

Antilipemic agents

FibratesIndication: Hypertriglyceridemia

Gemfibrozil – 600mg QD-BID (half life 1.5hrs)Fenofibrate – 1-3 67mg tablets QD (half life 20hrs)Taken with food - ↑ absorptionMax reduction of VLDL is achieved within 3-4 weeks

of treatmentAdverse Effects

RashesGI disturbances (nausea, abdominal pain, diarrhea)

Antilipemic agents

Fibrates - Adverse EffectsGallstones (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)

Antilipemic agents

Fibrates - Adverse EffectsHepatoxicityArrythmiasHypokalemiaDisplaces warfarin from plasma albumin since

drug is highly protein bound. Need to ↓ warfarin dose

Bile Acid-Binding Resins :chemistry

Antilipemic agents

Bile Acid-Binding Resins (colestipol and cholestyramine)Will ↓ LDL, may ↑ VLDL (would require niacin

combo if ↑ TG prior to tx)MOA

Bile 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.

Antilipemic agents

Bile Acid-Binding ResinsMOA

↑ 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%)

Antilipemic agents

Bile Acid-Binding Resins Indication

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/ fluid

Adverse EffectsMax reductions of LDL occur in one monthMust be taken with meals

Antilipemic agents

Bile Acid-Binding ResinsAdverse Effects

ConstipationBloating, indigestion, nauseaLarge doses may impair absorption of fats or fat soluble

vitamins (A, D, E, and K)Drug Interactions

Resins 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)

chemistry

Antilipemic agents

HMG COA Reductase Inhibitors (“statins”) (lovastatin, fluvastatin, pravastatin, simvastatin, atorvastatin, cerivastatin)Most Effective for ↓ LDLWill ↑ HDL and ↓ VLDLFewest adverse effects and tolerated best

Inhibition of HMG-CoA reductase

Antilipemic agents

(“statins”)MOA

Inhibits hepatic HMG CoA reductaseInhibition 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

Antilipemic agents

(“statins”)MOA

↓ inflammation at the plaque siteImprove 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

Antilipemic agents

(“statins”) – IndicationsUsed alone to ↓ LDLUsed 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)

Antilipemic agents

(“statins”) – IndicationsAtorvastatin 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

Antilipemic agents

(“statins”) – IndicationsNew Drug: Altocor®

Extended release lovastatinSlightly more effective than regular lovastatinTake without food

Antilipemic agents

(“statins”) – Adverse EffectsSince LDL cholesterol levels will return to

pretreatment values if drugs are withdrawn, treatment must continue lifelong

Statins are pregnancy category Xrash, GI disturbances (dyspepsia, cramps,

flatulence, constipation, abdominal pain)

Antilipemic agents

(“statins”) – Adverse EffectsHepatotoxicityMyopathy (0.5% of pts)

Risk highest with lovastatin and especially in combination with Fibrates

Cyp3A4 drug interactions with all statins excepts for pravastatin and fluvastatin

Ezetimibe:chemistry

Antilipemic 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

Inhibitors of Cholesteryl Ester Transfer Protein

a plasma glycoprotein synthesized by the liver

mediates the transfer of cholesteryl esters In animal models

inhibition of CETP result in:higher HDL levels decreased LDL levels resistance to developing atherosclerosis

JTT-705 and torcetrapib

antilipemic agents

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