Medications to Control Hyperlipidemia

Coronary Heart Disease Risk Factors † Positive risk factors „ Age: Male > 45 years Female >55 years or women with premature menopause not on estrogen replacement therapy

„ Family Hx of premature CHD(MI, CA) prior to55 years of age in father or brother, 65 for females „ Smoker „ HTN >140/90 or on HTN meds „ Low HDL level: 60mg/dL (subtract one risk factor)

When do we start Medication Therapy † Dietary therapy „ LDL 100-160dL and CHD risk factors

† Drug therapy „ LDL 130-190mg/dL CHD risk factors

Three Basic Classes of Lipids † Triglycerides † Steroids † Phospholipids

† Total cholesterol 60) † Triglycerides>150

Triglycerides (Neutral Fats) † † † †

Most common Three fatty acids attached to glycerol Energy source 90% of total lipids in the body

Steroids † Steroid nucleus or ring † Natural vital component of cellular membranes † Necessary for production of: „ Vitamin D „ Bile salts „ Cortisol, estrogen, testosterone

† Body makes enough cholesterol † Not necessary in diet

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Phospholipids

Cholesterol Metabolism

† Phosphorous group replaces one of the fatty acids † Essential to building cellular membranes † Lecithins

† Increased blood cholesterol equals increased risk of cardiovascular disease † Plaque buildup occurs in the vessel walls

Lipoproteins † Cholesterol not soluble in the blood † Inner core of lipid, outer core of protein † Water soluble and travels freely in the blood

Low-density Lipoproteins (LDL) † Highest amount of cholesterol † Created in liver † Build plasma membranes and produce steroids † Stored in tissues † Contribute to plaque deposits and CHD † Aka bad cholesterol

Three Most Common Lipoproteins, Based on Weight or Density:

† Low-density lipoproteins (LDL) † High-density lipoproteins (HDL) † Very low-density lipoproteins (VLDL)

High-Density Lipoproteins (HDL) † Picks up cholesterol † Returns it to the liver † Becomes part of bile and excreted in feces † Aka good cholesterol

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Very Low-Density Lipoproteins (VLDL) † Triglyceride carrier † Converted to LDL in blood † High levels are associated with pancreatitis

National Cholesterol Education Program (NCEP) Recommendations for Therapeutic Lifestyle Changes

† Increase physical activity † Maintain optimum weight † Maintain a healthy diet „ Reduce dietary saturated fats and cholesterol „ Increase soluble fiber in diet

Other Lifestyle Changes Include

HMG CoA Reductase Inhibitors (Statins)

† † † † †

Tobacco cessation Control of hypertension Stress reduction Limiting high sugar foods Increasing Omega-3 fatty acids in the diet † Avoiding transfatty acids in the diet

† Drugs of first choice in reducing blood lipid levels † Reduce LDL, triglyceride, and VLDL levels † Raise HDL levels (good cholesterol)

Inhibit HMG CoA Reductase

Effect Not Permanent

† Critical enzyme in cholesterol synthesis † Liver produces less cholesterol † More LDL receptors † More LDL removed from blood † Blood levels of LDL and cholesterol reduced

† Take statins for the rest of life † Or until controlled by lifestyle changes

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Contra-I for Statins (HMG-CoA reductase inhibitors) † † † †

Drug allergy Pregnancy (X) Liver disease Elevated liver enzymes

Statin Adverse Effects † Central Nervous „ HA, dizziness, blurred vision, fatigue,nightmare, insomnia

† Gastrointestinal „ Constipation, cramps, diarrhea, nausea, change in bowel function

† Skin rashes

The OMG side effect

Interactions with Statins

† Rhabdomylosis

† Oral anticoagulants † Other antilipemic † Oral antidiabetic drugs † Erythromycin, † Gemfibrozil † Insulin † Niacin † Grapefruit juice

„ Breakdown of muscle tissue (myoglobin) „ Myoglobin is the oxygen carrying pigment of muscle tissue „ Protein in urine may lead to renal damage.

† Report any unexplained muscle pain!

Statins † † † † †

Atrovastatin (Lipitor)dose anytime Fluvastatin (Lescol) Lovastatin (Mevacor) Pravastatin (Pravachol) Simvastatin (Zocor)

† Can lead to rhabdomyolysis

Administration † Give all statins orally † Give in the evening † Monitor for muscle injury

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Bile Acid Sequestrants

Bile Acid sequestrants Contra-I

† Bile acid resins bind cholesterol in the intestines so it can’t be reabsorbed † Cholesterol eliminated in feces † Reduces LDL levels † 2nd line drugs to statins † Lower LDL 15-30% † Increase HDL 3-8%

† Drug allergy † Biliary or bowel obstruction

Bile Acid Sequestrants Adverse Effects

Bile Acid sequestrants Interactions (messy powders)

† GI/Usymptoms

† Interaction due to absorption of other drugs † (Take 1 hour before and 4-6 hrs after these drugs) † These drugs affect the absorption of fat soluble vitamin (DEAK of Cards) †

„ Heartburn, nausea, belching, and bloating. (take with meals to reduce effects) „ Constipation (instruct to increase dietary fiber) „ May cause mild increases in the triglyceride levels. „ Other: bleeding, tinnitus, burnt odor of urine.

Bile Acid Sequestrants

Administration

† Choestyramine(Questran) † Colesevelam(Welchol) † Colestipol (Colestid)

† More frequent side effects than statins † Sometimes given in combination with statins † Can prevent absorption of other medications

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Nicotinic Acid † Aka niacin - water-soluble B-complex vitamin † High dosages needed to produce antilipidemic effects † Primary use is to decrease VLDL levels † Secondary effect is to decrease LDL levels 10-20% and triglycerides 30-70% † Increases HDL levels 20-35% † Side effects limit use † Often used in combination with a statin or bile acid sequestrant

Niacin Contra-I † † † †

Liver disease Hypertension Peptic ulcer Active hemorrhagic process

Niacin † In large doses, it may produce vasodilation that is limited to the cutaneous vessels. Re: prostalandins † Niacin also causes the release of Histamine: increase GI mobility and acid secretion. † Niacin may also stimulate the break down of fibrin clost.

Niacin Adverse Effects † † † †

Flushing, hyperpigmentation Pruritus GI distress Blurred vision, glucose intolerance, dry eyes, hepatotoxicity

† Taking aspirin 30 min before niacin can minimize flushing † Titrate up doses of Niacin for pt to tolerate

Fibric Acid Agents/Fibrates † Activate lipoprotein lipase(breakdown of cholesterol) † Most effective agent in reducing VLDL and triglyceride levels † Increases HDL 25% but very little effect on LDL levels † Replaced by the statins

Fibric Acid agents Contra-I † Severe Liver or Kidney disease † Gallbladder disease

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Fibric Acid Agents Adverse Effects

Fibric Acid Sequestrants Drug interactions

† GI: nausea,vomiting, diarrhea, gallstones, acute appendicitis † GU: impotence, decreased urine output, hematuria, UTI † Other: drowsiness, rash, pruritus, alopecia, eczema, vertigo, HA

† Gemfibrozil: enhance the action of oral anticoagulants † Risk of Rhabdomyolysis if taken with statins † Decrease Hb level, Hct, WBC † Increase AST, ACT, bilirubin levels

Fibric Acid Agent † Gemfibrozil (Lopid) † Clofibrate (Atromid-S) † Fenofibrate(Tricor)

Ezetimibe † Blocks absorption of dietary cholesterol † LDL and triglycerides are reduced † Slight increase in HDL † Well tolerated by patients

Newer Approaches to Treating Hyperlipidemia † Ezetimibe (Zetia) † Fixed-dose combination therapy

Fixed-Dose Combination Therapy † † † †

Allows for lower doses of each agent Potentially fewer side effects Better patient compliance Synergistic effect

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New Trend in Treatment of CHD † Combine an antihypertensive with an antihyperlipidemic † Targeted at the many patients with both hypertension and elevated cholesterol

Hemostasis - Process of Stopping the Flow of Blood † Internally and externally † Prevent bleeding from wounds which could lead to shock or even death

Three Basic Steps to Hemostasis † Injured vessel constricts to slow blood flow † Platelets adhere to injured area and aggregate, plugging damaged vessel † Coagulation cascade occurs thus forming insoluble fibrin strands which slows blood flow more

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Major steps in the coagulation cascade

Coagulation Cascade - Series of Complex Steps † Injured cells release prothrombin activator † Prothrombin activator changes prothrombin to thrombin † Thrombin changes fibrinogen to fibrin † Fibrin forms an insoluble web over injured area which stops blood flow

Mechanism of action of anticoagulants

Coagulation-Modifier Drugs † Anticoagulants † Thrombolytics † Hemostatics

Disorders Commonly Treated with Coagulation-modifying Drugs

Anticoagulants

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Anticoagulants

Anticoagulants - Prevent the Formation of Clots † Inhibiting specific clotting factors in the coagulation cascade † Diminishing the clotting action of platelets † Both ways increase the time to form clots

Antiplatelet Agents

Thrombolytics † Dissolve life-threatening clots

Thrombolytics

Hemostatics † Promote formation of clots † Inhibit removal of fibrin

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Anticoagulants Prevent the Formation and Enlargement of Clots † Examples - heparin (Heplock), warfarin (Coumadin) † Mechanism of action - inhibit specific clotting factors which interfere with coagulation cascade in order to prevent formation or enlargement of clot † Primary use - thromboembolic disease; prevent formation of clots in veins † Adverse effects - abnormal bleeding

Coumadin † Monitoring: „ Prothombin time (PT) report INR † Goal INR for AF 2-3 † Goal INR for Mech Valves 3-4.5

† Adverse effects „ Hemorrhage-antidote is vitamin K † Fetal harm.

Coumadin † Suppresses by antagonizing vitamin K and blocks synthesis of factors VII,IX,X and prothrombin † Effects take a few days † Long term prophylaxis of venous thrombosis, mechanical heart valves, atrial fibrillation

Antiplatelet Agents Prolong Bleeding Time by Interfering with Platelet Aggregation † Example - ticlopidine (Ticlid) † Mechanism of actions „ Aspirin: inhibits thromboxane2, which prevents aggregation of platelets „ ADP receptor blockers: interfere with platelet plasma membrane, which prevents platelet aggregation „ Glycoprotein IIb/IIIa inhibitors: glycoprotein IIb/IIIa enzyme inhibited which prevents platelet aggregation

Heparin

Heparin

† Suppresses the formation of fibrin in veins, Inactivates clotting factors thrombin and Xa † Anticoagulant effect develops quickly † Uses: prevent venous thrombosis, PE, Evolving stroke, DVT, CABG, MI , renal dialysis

† Monitoring: Activated partial thromboplastin time (aPTT) † Normal aPTT 40 seconds † Therapeutic levels 60-80seconds † Adverse Effects Bleeding!!! „ Antidote is protamine sulfate „ May cause thrombocytopenia „ May be used during pregnancy

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Antiplatelet Agents Prolong Bleeding Time by Interfering with Platelet Aggregation (cont’d) † Primary uses - prevent clot formation in arteries † Adverse effects - abnormal bleeding; reduce number of neutrophils

Aspirin Antiplatelet drug COX inhibitor First generation NSAID

† Suppresses platelet aggregation by inhibition of COX-1 and COX 2 † Decreases prostaglandin synthesis † Reduces inflammation, fever, and pain

ASA

Plavix(clopidogrel)

† USEs: Pain ,fever, inflammation, prevention of thrombus in arteries (coronary arteries), PREVENTS MI and STROKE † Adverse effects: bleeding, gastric ulcers, renal impairment, † Reyes syndrome in children † Hypersensitivities in patients with allegies.

† Adenosine Diphosphate receptor antagonist, ADP receptor blocker † ANTI PLATELET DRUG † How does it work: blocks enzyme so that platelets are unable to aggregate. † Uses: prevention of stroke and MI.

Integrilin(eptifibatide) † “SUPER ASPIRIN” † How does it work: interferes with final step in platelet aggregation † Uses: acute coronary syndrome, used during angioplasty † Adverse effects: ICB, GI bleed, Hematuria, gum bleeding, thrombocytopenia, anaphylaxis.

Thrombolytics Are Used to Dissolve Existing Clots † Example - alteplase (Activase) † Mechanism of action - convert plasminogen to plasmin which causes fibrin to degrade, then preexisting clot dissolves † Primary uses - acute MI, pulmonary embolism, acute ischemic CVA, DVT, arterial thrombosis, coronary thrombosis, clear thrombi in arteriovenous cannulas and blocked IV catheters † Adverse effects - abnormal bleeding; contraindicated in patients with active bleeding or recent trauma

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Thrombolytics

Alteplase(tPA) † Converts plasminogen to plasmin † Plasmin is an enzyme that digests the fibrin matrix of clots † USES: Acute MI, PE, ischemic stroke † Adverse Effects: bleeding, intracranial hemorrhage.

Hemostatics Are Used to Promote the Formation of Clot † Example - aminocaproic (Amicar) † Mechanism of action - prevent fibrin from dissolving, which enhances stability of the clot † Primary use - prevent and treat excessive bleeding from surgical sites † Adverse effects - none listed

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