Lipid-lowering drugs

Atherosclerosis and lipoprotein metabolismAtheromatous disease is ubiquitous and underlies the commonest causes of death (e.g. myocardial infarction) and disability (e.g. stroke) in industrialcountriesHypertension and dyslipidemia are ones of the most important risk factors, amenable to drug therapy ATHEROMA is a focal disease of the intima of large and medium-sized arteries A t h e r o g e n e s i s involves several stages: endothelial dysfunction with altered PGI2 and NO synthesis monocyte attachment endothelial cells bind LDL oxidatively modified LDL is taken up by macrophages having taken up oxidised LDL, these macrophages (now foam cells) migrate subendothelially atheromatous plaque formation rupture of the plaque

Atherosclerosis and lipoprotein metabolismLIPIDS, including CHOLESTEROL (CHO) and TRIGLYCERIDES (TG), are transported in the plasma as lipoproteins, of which there are four classes: - chylomicrons transport TG and CHO from the GIT to the tissues, where they are split by lipase, releasing free fatty acids.There are taken up in muscle and adipose tissue. Chylomicron remnants are taken up in the liver - very low density lipoproteins (VLDL), which transport CHO and newly synthetised TG to the tissues, where TGs are removed as before, leaving: - low density lipoproteins (LDL) with a large component of CHO, some of which is taken up by the tissues and some by the liver, by endocytosis via specific LDL receptors - high density lipoproteins (HDL).which absorb CHO derived from cell breakdown in tissues and transfer it to VLDL and LDL

Atherosclerosis and lipoprotein metabolismThere are two different pathways for exogenous and endogenous lipids:THE EXOGENOUS PATHWAY: CHO + TG absorbed from the GIT are transported in the lymph and than in the plasma as CHYLOMICRONS to capillaries in muscle and adipose tissues. Here the core TG are hydrolysed by lipoprotein lipase, and the tissues take up the resulting FREE FATTY ACIDS CHO is liberated within the liver cells and may be stored, oxidised to bile aids or secreted in the bile unaltered . Alternatively it may enter the endogenous pathway of lipid transpor in VLDL

Atherosclerosis and lipoprotein metabolismEXOGENOUS PATHWAY

(According to Rang, Dale 1999)CHOBile ductv.portaeGITbile acidsENDOGENOUS PATHWAY for lipids

EXOGENOUS PATHWAY for lipids

chylomicrTGCHOchylomicrremnbile acids CHOFig.1aPeripheral tissuesENDOGENOUSPARTHWAY

Fat+ CHO+ fatty acids

HEPATOCYTE

CHO

TG Fatty acids

Atherosclerosis and lipoprotein metabolismTHE ENDOGENOUS PATHWAYCHO and newly synthetised TG are transported from the liver as VLDL to muscle and adipose tissue, there TG are hydrolysed and the resulting FATTY ACIDS enter the tissues The lipoprotein particles become smaller and ultimetaly become LDL , which provides the source of CHO for incorporation into cell membranes, for synthesis of steroids, and bile acids Cells take up LDL by endocytosis via LDL receptors that recognise LDL apolipoproteins CHO can return to plasma from the tissues in HDL particles and the resulting cholesteryl esters are subsequently transferred to VLDL or LDL One species of LDL lipoprotein - is associated with atherosclerosis (localised in atherosclerotic lesions). LDL can also activate platelets, constituting a further thrombogenic effect

(According to Rang, Dale 1999)CHOBile ductv.portaeGITbile acidsENDOGENOUS PATHWAY for lipids

EXOGENOUS PATHWAY for lipids

bile acids CHOFig.1bPeripheral tissues

HEPATOCYTE

ACoAMVALDLreceptors VLDLTGCHOlipaseCHOCHO CHOLDLHDLCHOUptakeof CHOFattyacidsCHOfrom cellsCHO

Dyslipidemia

Dyslipidemia can be primary or secondary. The primary forms are genetically determined Secondary forms are a consequence of other conditions such as diabetes mellitus, alcoholism, nephrotic syndrome, chronic renal failure, administration of drug

Lipid-lowering drugsSeveral drugs are used to decrease plasma LDL-CHODrug therapy to lower plasma lipids is only one approach to treatment and is used in addition to dietary management and correction of other modifiable cardiovascular risk factors

LIPID-LOWERING DRUGS

(According to Rang, Dale 1999)CHOBile ductv.portaeGITbile acidsENDOGENOUS PATHWAY for lipids

EXOGENOUS PATHWAY for lipids

bile acids CHOFig.1cPeripheral tissuesfat+ CHO+ fatty acids

HEPATOCYTE

ACoAMVALDLreceptors VLDLTGCHOlipaseCHOCHO CHOLDLHDLCHOUptakeof CHOFattyacidsFattyacidsCHOfrom cellsChylomikr TGCHOGITChylomikr remnCHOTGSTATINSSTATINSFIBRATES FIBRATESFIBRATESRESINS

LIPID-LOWERING DRUGS StatinsHMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors. The reductase catalyses the conversion of HMG-CoA to mevalonic acidRosuvastatin>atorvastatin>simvastatin=lovastatin>pravastatin>fluvastatin decrease hepatic CHO synthesis

Several studies demonstrated positive effects on morbidity and mortality

increase in synthesis of CHO receptors + increased clearance of LDL

Statins

Promising pharmacodynamic actions: improved endothelial function reduced vascular inflammation and platelet aggregability antithrombotic action stabilisation of atherosclerotic plaques increased neovascularisation of ischaemic tissue enhanced fibrinolysis immune suppression osteoclast apoptosis and increased synthetic activity in osteoblasts

Statins

Pharmacokineticswell absorbed when given orallyextracted by the liver (target tissue), undergo extensive presystemic biotransformation

Simvastatin is an inactive pro-drug

Statins

A d v e r s e e f f e c t s: mild gastrointestinal disturbances

increased plasma activities in liver enzymes severe myositis (rhabdomyolysis) and angio-oedema (rare)

LIPID-LOWERING DRUGS Fibrates

- stimulate the beta-oxidative degradation of fatty acids - liberate free fatty acids for storage in fat or for metabolism in striated muscle

- increase the activity of lipoprotein lipase, hence increasing hydrolysis of triglyceride in chylomicrons and VLDL particles

reduce hepatic VLDL production and increase hepatic LDL uptake

Fibrates

O t h e r e f f e c t s : improve glucose tolerance inhibit vascular smooth muscle inflammation

fenofibrate clofibrate gemfibrozil ciprofibrate

Fibrates

A d v e r s e e f f e c t s: in patients with renal impairment myositis (rhabdomyolysis) myoglobulinuria, acute renal failure Fibrates should be avoided in such patients and also in alcoholics)

mild GIT symptoms

LIPID-LOWERING DRUGS Bile acid binding resins

sequester bile acids in the GIT prevent their reabsorption and enterohepatic recirculation

The r e s u l t is: decreased absorption of exogenous CHO and increased metabolism of endogenous CHO into bile acid acids

increased expression of LDL receptors on liver cells

increased removal of LDL from the blood

reduced concentration of LDL CHO in plasma (while an unwanted increase in TG)

Bile acid binding resins

A d v e r s e e f f e c t s:

GIT symptoms - nauzea, abdominal bloating, constipation or diarrhea resins are unappetising. This can be minimized by suspending them in fruit juice interfere with the absorption of fat-soluble vitamins and drugs (chlorothiazide, digoxin, warfarin)

These drugs should be given at last 1 hour before or 4-6 hours after a resin

LIPID-LOWERING DRUGS Others

Nicotinic acid inhibits hepatic TG production and VLDL secretion modest reduction in LDL and increase in HDL

A d v e r s e e f f e c t s:flushing, palpitations , GIT disturbances

LIPID-LOWERING DRUGS Others

Fish oil (rich in highly unsaturated fatty acids)the omega-3 marine TG - reduce plasma TG but increase CHO (CHO is more strongly associated wih coronary artery disease)the effects on cardiac morbidity or mortality is unproven( although there is epidemiological evidence that eating fish regularly does reduce ischemic heart disease)Reduced VLDL, reduced TG. May increased LDL in some patient.

Lipid lowering drugsSelective cholesterola absorbtion inhibitorEzetimibe is prodrug activated form to glucoronide, inhibit cholesterol from dietary and biliary sources, doesnt effect on fat soluable Vit and TG

How to asses patient with dislipidemia/suspect dislipidemia?

STEP ONE: SCREENING

ATP III Classification of LDL, Total, and HDL Cholesterol (mg/dL)LDL Cholesterol Primary Target of Therapy

STEP TWO: ASSESSMENT FOR PRESENCE OF HIGH RISK CORONARY HEART DISEASE EQUIVALENTS

Identify presence of clinical atherosclerotic disease that confers high risk for coronary heart disease (CHD) events (CHD risk equivalent):Clinical CHDSymptomatic carotid artery diseasePeripheral arterial diseaseAbdominal aortic aneurysmDiabetes is considered a CHD risk equivalent in ATP III

STEP THREE: ASSESSMENT OF MAJOR RISK FACTORS

Determine presence of major risk factors (other than LDL) That Modify LDL Goals:Cigarette smokingHypertension (BP >140/90 mmHg or on antihypertensive medication)Low HDL cholesterol (

STEP FOUR: IF 2 OR MORE MAJOR RISK FACTORS OTHER THAN LDL ARE PRESENT THEN ASSESS 10-YEAR CHD RISK

If 2+ risk factors (other than LDL) are present without CHD or CHD risk equivalent, assess 10-year (short-term) CHD risk (see Framingham tables).Three levels of 10-year risk are:>20% this is considered a CHD risk equivalent10-20%20% means that 20 out of 100 individuals will develop coronary heart disease or a coronary event within 10 years.

STEP FIVE: DETERMINE THE RISK CATEGORY

Determine risk category by:Establishing LDL goal of therapyDetermining need for therapeutic lifestyle changes (TLC)Determining level for drug consideration

STEP FIVE: DETERMINE THE RISK CATEGORY

LDL Cholesterol Goals and Cutoff Points for Therapeutic Lifestyle Changes (TLC) and Drug Therapy in Different Risk CategoriesRisk CategoryLDL GoalLDL level at which to initiate TLCLDL level at which to consider drug therapyCHD or CHD Risk Equivalents (10 year risk factor >20%)

STEP SIX: THERAPEUTIC LIFESTYLE CHANGES

TLC Diet:Saturated fat

STEP SEVEN: CONSIDER DRUG THERAPY

Consider drug simultaneously with TLC for CHD and CHD equivalentsConsider adding drug to TLC after 3 months for other risk categories.

STEP SEVEN: CONSIDER DRUG THERAPY

CARDINAL POINT OF TREATMENTDecreased LDL is primary targetStatin are the preferred initial treatment choice, shuld be used at sufficient to lower LDL by 30%-40%.If maximal dose of statin is unable to achieve goal of LDL, then statin + ezetimibe or statin + bile acid sequester are useful combinationIf TG are 200 to 499 mg/dl after LDL goal has been reached, consider adding niacin or fibrate.If TG > 500 mg/dl, use fibrate or niacin to lower TG and prevent pancreatitisIf HDL ow after LDL goal reached, consider adding niacin or fibrate

Case One:Mark Guttman is a 39 year old white male living in Stamford, Connecticut. Mr. Guttman is here to see you for a follow up to an initial routine health care maintenance exam.

Past Medical HistoryNoneNot on any medicationsNo known allergiesSocial HistorySmokes tobacco pack a dayOccasional EtOH at social functions onlyNo drug useWorks as a teacher in a middle schoolWas born in Westchester County, NY and lived in Connecticut is entire lifeSingle, Not sexually active currentlyFamily HistoryFather is alive and healthy, Age 60Mother has diabetes, Age 59No siblings or children

Pertinent Physical ExamBP 135/80BMI 28.1Waist Circumference 38 inchesFasting Cholesterol PanelTotal Cholesterol (220 mg/dl/5.6 mmol/L)LDL 162 mg/dl/4.2mmol/LHDL 38 mg/dl/0.98 mmol/LTriglycerides 165 mg/dl/1.8 mmol/L

Case One:What treatment strategies for hyperlipidemia should be offered to Mr. Guttman?1.?2.?3.?4.?5.?6.?

Case 2Maria De Los Santos is a 67 year old Dominican female living in Washington Heights. She has been your patient for 8 years and is here to discuss the results of her fasting lipid panel.

Past Medical HistoryDiabetes, HypertensionMeds Metformin, Ramipril onlyNo known allergiesSocial HistoryHas never smoked tobaccoNo alcohol useNo drug useWorked as an office administrator and retired 2 years agoWas born in Santiago, Dominican Republic and moved to New York City 37 years agoMarried, and sexually active currently in monogamous relationshipFamily HistoryFather is alive and has diabetes, hypertension, and peripheral vascular disease, age 87Mother has diabetes, age 88Brother has diabetes, age 65She has 3 adult children that are all healthy

Pertinent Physical ExamBP 145/81Weight 210 lbsHeight 5 8 inchBMI 31.9Waist Circumference 42 inchFasting Cholesterol PanelTotal Cholesterol 189LDL 115HDL 56Triglycerides 179

Aside from theraupetic lifestyle change, should LDL lowering drug therapy offers to Mrs.De Los santos?

Case 3Nelson Nguyen is a 43 year old Vietnamese male living in Castro Valley, CA. He has been your patient for 5 years and is here to discuss the results of his fasting lipid panel. He had been lost to follow up to your practice for 2 years. He was taking only hydrochlorathizide (was buying it on own over past 2 years you added a second hypertension med at the last visit)

Past Medical HistoryHypertensionMeds Now taking hydrochlorathizide and a beta blockerAllergies - PenicillinSocial HistorySmokes tobacco 1 pack a dayNo alcohol useNo drug useWorks as a coffee shop managerWas born in Quy Nhon, Vietnam and immigrated to the United States at age 23Married, and sexually active currently in monogamous relationshipFamily HistoryFather died at age 47 of unknown causesMother is alive and healthy in Vietnam, age 65Older brother died of a myocardial infarction at age 45Has 2 sons that are healthy and in college

Pertinent Physical ExamBP 160/90Weight 200Height 5 6BMI 32.3Waist Circumference 39 inchesFasting Cholesterol PanelTotal Cholesterol 272LDL 188HDL 42Triglycerides 202

Case 3What treatment strategies for hyperlipidemia should be offered to Mr. Nguyen?

Step 8Identify metabolic syndrome and treat, if present, after 3 months of TLC.Clinical Identification of the Metabolic Syndrome Any 3 of the following must be present:

Treat underlying causes (overweight/obesity and physical inactivity):Intensify weight managementIncrease physical activity.Treat lipid and non-lipid risk factors if they persist despite these lifestyle therapies:Treat hypertensionUse aspirin for CHD patients to reduce pro-thrombotic stateTreat elevated triglycerides and/or low HDL

STEP NINE: TREAT ELEVATED TRIGLYCERIDES

Treatment of elevated triglycerides (150 mg/dL)Primary aim of therapy is to reach LDL goalIntensify weight managementIncrease physical activityIf triglycerides are >200 mg/dL after LDL goal is reached, set secondary goal for non-HDL cholesterol (total HDL) 30 mg/dL higher than LDL goal.

Comparison of LDL Cholesterol and Non-HDL Cholesterol Goals for Three Risk CategoriesRisk CategoryLDL Goal (mg/dL)Non-HDL Goal (mg/dL)CHD and CHD Risk Equivalent (10-year risk for CHD >20%)

Treat hiperTGIf triglycerides 200-499 mg/dL after LDL goal is reached, consider adding drug if needed to reach non-HDL goal:intensify therapy with LDL-lowering drug, oradd nicotinic acid or fibrate to further lower VLDL.If triglycerides 500 mg/dL, first lower triglycerides to prevent pancreatitis:very low-fat diet (15% of calories from fat)weight management and physical activityfibrate or nicotinic acidwhen triglycerides

Treat lower HDLTreatment of low HDL cholesterol (