cardio pharm .pdf

Cardiology Chapters 12-14, 35 Pathophysiologic Approach to Pharmacotherapeutics 1 (MSPA 520) Fall 2023 Learning Objectives 1. 2. 3. 4. 5. 6. 7. 8. 9. Classify antianginal drugs according to their effects on oxygen supply and/or demand. Identify the pertinent treatment risks and benefits of antia...

Cardiology Chapters 12-14, 35 Pathophysiologic Approach to Pharmacotherapeutics 1 (MSPA 520) Fall 2023 Learning Objectives 1. 2. 3. 4. 5. 6. 7. 8. 9. Classify antianginal drugs according to their effects on oxygen supply and/or demand. Identify the pertinent treatment risks and benefits of antianginal drugs. Differentiate between the role of Beta blockers, diuretics, ACE inhibitors and angiotensin II receptor blockers (ARBs) in the treatment of heart failure. Develop an appropriate pharmacotherapy regimen for a patient with heart failure. Compare and contrast the side-effect profile of individual antiarrhythmics dividing them by class. List the factors that would guide selection of a specific antiarrhythmic for an individual patient. Characterize each class of antiarrhythmic drug according to effects on ion channels, basic electrophysiologic outcomes, and proposed mechanisms. Describe the mechanism of action, effects on lipids and lipoproteins, dosing guidelines, adverse effects, drug interactions, patient monitoring for patients using statins and other antilipemics. Match the lipid-lowering drugs with specific lipid disorders such as hypercholesterolemia, combined hyperlipidemia, and hypertriglyceridemia to maximize the changes in lipids and lipoproteins. Antianginal Drugs Chapter 12 3 Definitions • Ischemic Heart Disease (IHD) • Imbalance between myocardial O2 supply and demand • Decreased blood flow to tissue resulting in a lack of oxygen supply • Coronary Heart Disease (CHD) – Atherosclerotic narrowing of one or more coronary arteries • Acute Coronary Syndrome • Unstable Angina • Acute MI • Sudden Cardiac Death • Chronic Stable Angina • Angina Pectoris • Clinical manifestation of myocardial ischemia à chest pain 4 Pathophysiology of IHD 5 Myocardial Oxygen Demand • Heart rate • Contractility • Systolic (intramyocardial) wall tension • Tension in heart wall • Affected by ventricular volume and pressure • Function of preload and afterload • Preload • Initial stretching of cardiac myocytes prior to contraction • Ventricular and diastolic volume • Afterload • Pressure that the heart must eject blood against • Systemic vascular resistance 6 7 Angina • Latent manifestation of ischemia • May occur with any degree of stenosis • 50% of left main or 75% of other major coronary arteries considered clinically significant • Stenosis >90% = virtually no flow 8 Vasospastic or Variant (Prinzmetal) Angina • Can occur at site or partially occluded lesion and cause transient and abrupt reduction in vessel diameter • May be due to autonomic control • Younger patient and those with fewer risk factors • +/- ST segment elevation • Often occurs during the night or early morning hours 9 Risk Factors • Non-modifiable • Family history of premature CV event • Age > 45 years for males, 55 for females • Modifiable • Sedentary lifestyle • Diabetes • Tobacco consumption • Overweight • Hypertension • Dyslipidemia 10 Treatment Goals • Increase quantity of life • Prevent acute coronary syndromes • Increase quality of life • Relieve symptoms • Prevent symptoms 11 Treatment • Lifestyle • Change modifiable risk factors • Revascularization – stabilization of atherosclerotic plaque • Percutaneous coronary intervention (PCI) • Coronary artery bypass grafting (CABG) • Pharmacotherapy • Decrease heart rate, contractility, systolic wall tension (↓ O2 demand) • Calcium channel blockers, nitrates, beta blockers • Increase coronary blood flow (↑ O2 supply) • Calcium channel blockers, nitrates, aspirin, clopidogrel 12 Antianginals • Beta blockers • Calcium channel blockers • Dihydropyridine • Non-dihydropyridine • Nitrates • Ranolazine • Ivabradine 13 Beta Blockers • Demand • Supply • Minimal effect on oxygen supply – slowed HR may improve diastolic perfusion 14 Beta Blockers • First line therapy for prevention of angina attacks in the absence of contraindications • Population • Useful for patients with limited exercise capacity due to angina, HTN, anxiety, supraventricular arrhythmias, heart-failure, post-MI • Drug selection • Beta-1 selective: metoprolol, atenolol • Non-selective: propranolol, nadolol • Third gen. agents: carvedilol, labetalol 15 Beta Blockers • Contraindications • HR < 60 BPM • Systolic BP < 100 mmHg • AV block • Acute decompensated heart failure • Precautions • Reactive airway disease • Systolic heart failure • Diabetes • Peripheral vascular disease 16 Beta Blockers • Adverse reactions • Hypotension, bradycardia, hyperglycemia, dyslipidemia • Fatigue, sexual dysfunction, nightmares, worsened claudication • Monitoring: Heart rate, blood sugar, lipids • Avoid rapid discontinuation 17 Calcium Channel Blockers • Demand • Supply • Mild dilation in areas of fixed stenosis • Relief of vasospasm 18 Calcium Channel Blockers 19 Calcium Channel Blockers • Place in therapy • Initial therapy for reduction of symptoms when beta blockers are contraindicated or are not tolerated (NDHP) • In combination with beta blockers when initial treatment with beta blockers is not successful (DHP) • In combination with long-acting nitrates • Population • Contraindications/intolerance to beta blockers, vasospastic angina, severe peripheral vascular disease, asthma, uncontrolled diabetes, LV dysfunction (DHP only) • Drug selection • NDHP for initial therapy • DHP when combined with beta blocker • Avoid short acting agents! (nifedipine) 20 Calcium Channel Blockers • Contraindications • Systolic BP < 100 mmHg • HR < 60 BPM (NDHP) • Acute heart failure (NDHP) • Ejection fraction < 40% (NDHP) • AV block • Precautions • Concurrent beta blocker use (NDHP) • CYP3A4 interactions 21 Calcium Channel Blockers • Adverse reactions • Hypotension • DHP: headache, flushing, peripheral edema • Monitoring • Relief of symptoms • Heart rate (NDHP) • Education • Dizziness, constipation 22 Nitrates • Demand • Supply • Dilating coronary arteries • Relief of vasospasm • Antithrombotic/antiplatelet effects 23 Nitrates Short acting • Agents • Nitroglycerin (SL tabs and spray) • Relieves acute symptoms of myocardial ischemia and effort-induced angina • Dosed every 5 minutes until relief or EMS arrives Long Acting • Agents • Nitroglycerin (TD patch and ointment) – 12 hrs on, 12 hrs off • Isosorbide Dinitrate (Imdur) TID • Isosorbide Mononitrate (Isordil) – once daily • Alternative or add-on therapy for symptom reduction after failure with BB and CCB Patient Education • Short-Acting Nitrates • • • • Sitting or standing may enhance effects Store in original packaging, cool dry place Replace tablet 3-6 months after opening Apply or spray under the tongue • Long-Acting Nitrates • Ointment • • • • • • ½-2 inches/dose (15 mg/inch) 12 hours on, 12 hours off Squeeze onto calibrated paper Spread ointment on chest in a thin 2”x2” layer Keep covered with applicator paper Wipe off previous dose before adding new dose • Transdermal patch • 12 hours on, 12 hours off 25 Nitrates: Treatment Considerations • AE: Headache, hypotension, reflex tachycardia • Tachyphylaxis – pharmacodynamic tolerance; unclear mechanism • • • • Depletion of cofactors Stimulation of counter-regulatory responses (RAS, SNS) Plasma volume expansion Decreased enzyme activity • Nitrate free interval when patient has lowest symptom frequency • Contraindications • Aortic valve stenosis, obstructive cardiomyopathy • Concurrent use of phosphodiesterase inhibitors • Sildenafil (Viagra®), Tadalafil (Cialis®), Vardenafil (Levitra®) • Concurrent use may lead to hypotension, MI/stroke 26 Nitrates and PDE5 inhibitor Interaction 27 Ranolazine (Ranexa) • Blocks excessive prolongation of late inward sodium current in myocardial cells • Decreases diastolic wall tension • Reduces oxygen consumption • Does not affect HR or BP • May be used as a first-line agent for chronic stable angina • Reduces anginal frequency and increases exercise capacity • AE: Dizziness, HA, nausea, constipation; may increase QTc interval on EKG Ivabradine (Corlanor) • Heart rate lowering drug approved for chronic HF; used offlabel for chronic stable angina • Blocks mixed Na+-K+ current in SA node responsible for cardiac impulse initiation • May reduce frequency of angina attacks and improve exercise tolerance • AE: Headache, bradycardia, AV block, atrial fibrillation • May cause fetal toxicity • CYP3A4 substrate: increased toxicity with concurrent CYP3A4 inhibitors Approach to Angina Treatment Occasional angina episode Sublingual nitroglycerin Mild angina with exertion (predictable) Prophylactic therapy Unstable angina Prophylactic SL nitroglycerin or isosorbide dinitrate Beta blocker, long-acting nitrate, CCB, ranolazine Antithrombotic drugs (aspirin); coronary revascularization. Avoid CCB’s Calcium channel blockers Calcium channel blockers Long-acting nitrate (low dose beta blocker may not help angina sx) Variant angina Asthma comorbidity Heart failure Chronic Heart Failure Chapter 13 31 Etiology of CHF • Heart failure – impairment of the ventricle to fill with blood or eject blood into the circulation • Causes • Ischemic heart disease, MI – 50-60% of cases • Hypertension • Idiopathic dilated cardiomyopathy • Other cardiomyopathies – alcoholic, viral, hypertrophic • Drug induced (e.g. doxorubicin, mitoxantrone) 32 Systolic vs Diastolic Dysfunction • Systolic Dysfunction • Decreased contractility – ventricles do not empty properly • Causes • Loss of myocardial muscle mass • Left ventricular hypertrophy • Dilated cardiomyopathies • Assessed as reduced ejection fraction (< 45%) • Diastolic Dysfunction • Impaired relaxation • Decreased ventricular filling, thus decreased cardiac output • Causes • Left ventricular hypertrophy • Thicker, stiffer ventricles relax less efficiently • Ischemia • Impair removal of Ca from cytosol back into sarcoplasmic reticulum • HF symptoms with preserved ejection fraction • HF with preserved LV function 33 Left-Sided vs Right-Sided Heart Failure • Left-Sided • Left ventricle does not adequately pump blood forward • Pressure increases in pulmonary circulation • Leads to pulmonary congestion and edema • Orthopnea, tachypnea • Cough • Right-sided • Congestion in veins lead to ankle edema • Increased workload for left side of heart • Ascites • Hepatomegaly • Constipation • Jugular vein distension Treatment Goals • Stable/Chronic HF (Oral therapy) • Symptomatic improvement • Slow or reverse deterioration in myocardial function • Prolong survival • Treat underlying conditions • Control arrythmias • Prevent thrombosis • Treat anemia • Acute/Decompensated HF (IV therapy) • Symptomatic improvement • Restore perfusion • Minimize cardiac damage • Prevent mortality 36 Treatment • Lifestyle • Dietary sodium and fluid restriction • Physical activity may improve functional status • Pharmacotherapy • Increase cardiac output • Positive inotropes, vasodilators • Reduce pulmonary and systemic congestion • Vasodilators, diuretics • Slow or reverse cardiac remodeling (best mortality benefits) • ACEI, Beta-blockers 37 Diuretics • For removal of sodium/water -> reduced afterload • Thiazide diuretics • Not potent enough for most HF patients • Loop diuretics • Mainstay of HF therapy • Decreases sodium and water retention thus decreasing preload to provide symptomatic benefits • No evidence to show they decrease progression or mortality • Monitoring patient’s weight is a good way to detect worsening fluid overload (> 1 lb/day over several days) 38 ACE Inhibitors • Decrease preload • Decrease afterload • Decrease sympathetic activation • Decrease left ventricular hypertrophy, dilation, and remodeling • Slows heart failure progression • Decreased mortality 39 ACEI Problems • Impairment of renal function • Hypotension • Elevation of serum potassium • Cough • Angioedema 40 Beta Blockers in HF • Classically considered contraindicated in heart failure • Beta blockers with mortality benefit • • • • Carvedilol (Coreg®) Metoprolol succinate (Toprol XL®) Bisoprolol (Zebeta®) Nevibolol (Bystolic) • Keys to therapy • Patient should be stable prior to initiation • In hospital preferred • Start with very low doses • Titrate up slowly over 6-8 weeks total • Monitor for worsening HF signs and symptoms Benefits of Beta Blockers • Improved exercise tolerance • Hemodynamic improvements (inc. in EF) • Slowed disease progression • Decreased hospitalizations • Decreased need for transplant • Decreased mortality • Place in therapy • First line therapy in Class II-IV heart failure • Patients should be on ACEI and BB irrespective of symptoms 42 Aldosterone Antagonists • Spironolactone • Mortality reduction in grade III or IV HF • Patients not eligible if K > 5 or SCr > 2.5 • Gynecomastia in men ~10% (may respond to dec. dose) • Eplerenone • No gynecomastia • Mechanism • Neurohormonal inhibition, slowed remodeling of LV • Slowed progression of HF • Increases salt and water excetion 43 Hydralazine/Isosorbide Dinitrate • BiDil – oral fixed dose combination • Hydralazine 37.5 mg – arteriolar dilator; increases ventricular output • Isosorbide dinitrate 20 mg – has venous dilating properties; reduces filling pressure and venous congestion • Found to have a particular benefit in African-Americans in subgroup analyses of heart failure trials • Improved survival • Prolonged time to rehospitalization • AE: • Common: headache, dizziness, weakness • Hypotension, especially with PDE-5 inhibitors • Associated with drug-induced lupus Neprilysin Inhibitor • Neprilysin – endopeptidase enzyme that degrades bradykinin and natriuretic peptides • Inhibition of this enzyme can decrease cardiac remodeling • Sacubitril – prodrug of neprilysin inhibitor available as combination with ARB valsartan (Entresto) • Decreases mortality in patients with systolic HF • Avoid use with ACEI: due to increased angioedema risk Digoxin • Lactone ring and steroid nucleus essential for activity • Sugar molecules influence absorption, half-life and metabolism Inotropic Action of Digoxin Digitalis inhibits Na+K+ ATPase 2 K+ Ex ATPase 3 Na+ 3 Na+ Na+ Intracellular Na Concentration increases Ca++ Na+ Na+ Ca concentration increases Fiber shortening increases Digoxin • Mechanism of Action • Inotropic agent - older mechanism • Increase force of cardiac muscle contraction • Neurohormonal – newer mechanism • • • • Decrease sympathetic and increase parasympathetic nervous system activity Resensitize baro-reflex Decrease Renin-Angiotensin-Aldosterone system Decreased remodeling and structural changes • Therapeutic Drug Monitoring • Target levels: 0.5-1 ng/mL • Higher concentrations may be associated with worse outcomes in HF patients Digoxin • Clinical benefits • • • • • Improvement in symptoms Improved exercise tolerance Improve quality of life Decreased number of hospitalizations NO SURVIVAL BENEFIT • Place in therapy • No evidence of slowed disease progression • Primary use in symptomatic patients on optimal doses of ACE inhibitors/beta blockers and diuretics • First line for patients with atrial fibrillation and HF for rate control properties • Considered in patients with symptomatic HF and systolic dysfunction 49 Digoxin Toxicity • GI – anorexia, nausea • Visual disturbances • Blurred vision • Photophobia • Shining lights around objects, Yellow-green halos • Central Symptoms • Delirium, confusion • Fatigue • Dizziness • Abnormal dreams • Cardiac • Nodal slowing ↑ PR interval ↓ QT interval, depress ST segment • Bradycardia • Digoxin induced after depolarization Digoxin Contraindications • Advanced AV block • Severe bradycardia or sick sinus syndrome • PVC’s and ventricular tachycardia • Hyperkalemia • Hypomagnesaemia • Hypercalcemia • Wolf-Parkinson-White Digoxin Immune Fab (Digibind®) • Antibody which binds to the antigen-binding site of Ig • Produced by immunization of healthy sheep with digoxin coupled to human serum albumin • Affinity higher for digoxin than affinity of digoxin and Na+K+ ATPase • Rapidly reverse toxicity Milrinone (Primacor) • Cyclic AMP phosphodiesterase-3 inhibitor • Exerts inotropic and vasodilator actions • Direct stimulation of myocardial contraction • Balanced arterial and venous dilation • Decreased afterload • Increased cardiac output • Administered parenterally in patients with decompensated heart failure • Long term use is associated with higher mortality and morbidity than placebo • AE: arrythmias, rare thrombocytopenia and hepatic injury Other Inotropic Agents • Useful for acute decompensated HF with severe hypotension • Dobutamine – synthetic selective beta-1 agonist • IV infusions stimulates force of contraction more than rate of contraction. • Short term use to stabilize patients. • Dopamine – IV infusions maintain renal function. Actions through dopamine and beta receptors Heart Failure Management Strategy Most patients ACEI or ARB + Beta-blocker. Diuretics as needed CrCl>30, K+<5.0 Adequate BP on ACEI Black patients HR>70 on max tolerated dose of beta blocker Persistent symptoms; exercise intolerance Acute Heart Failure Aldosterone antagonist Use sacubitril/valsartan instead of ACEI/ARB Hydralazine, nitrates Ivabradine Digoxin Hospitalization, IV vasodilators, diuretics, inotropes, oxygen Antiarrythmics Chapter 14 Conduction system • Specialized cardiac cells • SA Node • AV Node • Bundle of HIS • Purkinje Fibers Ventricular Action Potential 1 + 10mv 2 3 0 4 - 90 mv Na+ K+ K+, CLNa/K ATPase Ca++ SA Node Action Potential 2 0 mv Phase 4, Na+ K+ 0 3 4 - 60 mv Ca++ K+ Na/K ATPase Mechanisms of Arrhythmias • Abnormal impulse formation • Altered automaticity • After-depolarization • Abnormal impulse conduction • Reentry • Unidirectional block Antiarrhythmic drugs • Principles of therapy • Identify and remove precipitating factors (hypoxia, ischemia, electrolytes) • Establish goals of therapy – termination of ongoing arrhythmia or prevention of arrhythmia (symptoms, frequency & reproducibility, structural damage) • Minimize risks – all antiarrhythmics may induce arrhythmias • Electrophysiology of heart as a “moving target” • Ischemia may alter resting membrane potential, conduction velocity, intracellular Ca++, repolarization rate Singh-Vaughan Williams Classification • Class I: Na+ channel blockers – decrease excitability • Class 1A (open>inactivated) • Class 1B (inactivated>open) • Class 1C (open>inactivated) • Class II: Beta-blockers – prolong AV refractoriness, prolong conduction, increase energy required for fibrillation • Class III: Potassium channel blockers – action potential prolongation • Class IV: Calcium channel blockers – decrease slow-response cells excitability • Others – adenosine, digoxin Indications • Class IA – Supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation prevention and PVC prevention • Class IB – Ventricular tachycardia, ventricular fibrillation prevention, symptomatic ventricular beats • Class IC – Life threatening ventricular tachycardia, or fibrillation, refractory supraventricular tachycardia • Class II – Supraventricular tachycardia, fibrillation • Class III – Refractory ventricular tachycardia, atrial fibrillation, flutter, supraventricular tachycardia • Class IV – Supraventricular tachycardia • Misc agents - Supraventricular tachycardia Sodium Channel Sodium Channel Blockers • Class IA • Slows rapid (Phase 0) depolarization • Slow conduction • Prolong action potential • Channel Affinity • open > inactivated • Dissociation • Intermediate Quinidine (Quinalan, Cardioquin, Quinidex®) • D-Isomer of Quinine Direct actions: • Slows conduction • Prolongs refractory period • Slows rate of rise of Phase 0 • Increases threshold for excitability • Decreases automaticity • Indirect actions: • Anticholinergic • alpha-blocker at higher doses Quinidine • Clinical Indications: • Maintain rhythm with atrial flutter or fibrillation • Control Ventricular Tachycardia • Conversion of Atrial Flutter and Fibrillation (very limited use) • Anticoagulants and Digitalis • Clinical interactions - CYP 2D6 inhibitor (codeine, morphine) • Toxicity: • • • • • • • • Nausea, vomiting, diarrhea (30-50%) Arrhythmias (ventricular and atrial) Hypotension Thrombocytopenia (may be fatal) Cinchonism - tinnitus, dizziness, blurred vision Quinidine Sudden Death Torsades de Pointes (2-8%) Immunological reactions Procainamide (Procan, Pronestyl ®) • Amide derivative of procaine • Actions • Short duration of action (3 - 4 hours) Slow release preparation • Less anticholinergic activity • No a - blocking activity • Active acetylated metabolite (NAPA) • Class Three activity • Fast acetylators may increase active metabolite Procainamide • Adverse effects: • Hypotension • Slowing of conduction • Nausea • Lupus like syndrome (25-50%, more often in slow acetylators) • Torsades de pointes • Bone marrow suppression (0.2%) • IV - Better tolerated than quinidine • Oral – poorly tolerated long term Disopyramide (Norpace®) • Actions: • Effects similar to Quinidine • More anticholinergic actions • Negative inotropic effects • Clinical Indications: • Ventricular tachycardia • Supraventricular arrhythmias (Flutter, fibrillation) Disopyramide • Toxicity: • Hypotension • Antimuscarinic effects • Conduction disturbances • Congestive heart failure (↓ contractility) • Torsades de Pointes • Contraindicated: heart block, hypersensitivity, glaucoma Sodium Channel Blockers • Class IB • Shorten Phase 3 • Decrease ectopic foci automaticity • Channel affinity • Inactivated >open • Higher affinity in ischemic tissue, little effect in normal tissue • Dissociation • Rapid (<1 sec) Lidocaine (Xylocaine®) • Local anesthetic • Actions: • • • • • Given IV – loading dose + continuous infusion Binds open or inactivated channel, recovery very rapid Most effective on Na channels in ischemic tissue Less effect on normal tissue Not effective against atrial arrhythmias • Clinical Indications: • • • • Wolff-Parkinson-White Ventricular tachycardia, premature beats Ventricular fibrillation Acute MI Lidocaine • Toxicity: • CNS toxicity: drowsiness, confusion, restlessness, muscle twitches, seizures, nystagmus (early sign of toxicity) • Hypersensitivity • Increases AV conduction • Contraindications: seizures, age Mexiletine (Mexitil®) • Analog of lidocaine with oral bioavailability • Decreases automaticity, conduction in ventricles • Effective in congenital long QT syndrome • Toxicity • Nausea, vomiting, tremor • Blood dyscrasias (rare) • CNS effects, Hepatotoxicity Sodium Channel Blockers • Class IC • Slow Phase 0 • Slow conduction • Prolongs refractory period • Affect normal heart • Channel affinity • open > inactivated • Dissociation • very slow Flecainide (Tambocor®) • Actions: • Blocks Na+ channels and K+ channels in ventricles, slows recovery of Na channel • Prolongs PR, QRS and QT intervals • Long half- life (14 hours), Oral, IV • Prevent premature ventricular contractions Flecainide (Tambocor®) • Clinical Indications: • Life-threatening sustained ventricular arrhythmias • Supraventricular arrhythmias • Use only in patients without significant structural damage to heart • Adverse Effects • Blurred vision, tremor • Ventricular tachycardia resistant to treatment • Bronchospasm • Seizures • Thrombocytopenia • ↑ mortality in MI Propafenone (Rythmol®) • Same mechanism as Flecainide • Beta-blocking activity • Toxicity • Pro-arrhythmic • Dizziness, blurred vision, bradycardia, • Bronchospasm, beta-adrenergic blockade • Agranulocytosis, anemia, thrombocytopenia • May worsen CHF Class ll - Beta Blockers • Slow conduction • Decrease automaticity • Prolong AV conduction • Decrease Phase 4 depolarization Class II – Beta-blockers • Esmolol (Brevibloc) • IV beta-blocker with short half-life (6-8 mins) • Ideal for acute treatment of supraventricular tachycardia • Metoprolol, Propranolol • Oral or IV administration • Treatment of supraventricular and ventricular arrythmias Class III - K+ Blockers • Reduces potassium efflux • Prolongs phase 3 repolarization • Prolong refractory period • Prolong duration of action potential Amiodarone (Pacerone) • Organic iodine compound analogous to thyroid hormone) • t½ =40 days (26-107) – • Delayed onset of action (~2 wks), slow elimination • May require loading doses • Indications (all-purpose antiarrhythmic): • Recurrent ventricular tachycardia or fibrillation resistant to other drugs • Maintain normal rate in atrial fibrillation • IV – terminate acute ventricular tachycardia or fibrillation replacing lidocaine in MI Amiodarone (Cordarone®) • Actions: • Blocks potassium channels • Blocks inactivated sodium channels • Blocks calcium channels • Blocks a and b-receptors • Decreases automaticity • Decreases conduction • Prolongs refractory periods Amiodarone Toxicities • Hypotension • Pneumonitis, pulmonary fibrosis (potentially fatal) • Neurotoxicity, neuropathy, muscle weakness, ataxia • Blue-grey skin color, photosensitivity • Corneal deposits • Thyroid abnormalities (hyper, hypo) • Hepatic dysfunction • Interactions - increases digoxin, warfarin, flecainide, phenytoin, procainamide Dronaderone (Multaq) • Structural analog of amiodarone without iodine atoms • Reduces action on thyroid metabolism • Multichannel actions similar to amiodarone • 24-hour half-life; bioavailability increased with food • CYP 3A4 substrate – caution with protease inhibitors and azole antifungals • Used in persistent atrial fibrillation • Avoid use in acute decompensated heart failure Ibutilide (Corvert®) • Prolongs opening of inward Na channel which counteracts opening of K channels • Prolongs repolarization • Prolongs action potential • Indication: IV (1 mg over 10 min) to convert atrial flutter (5070%) or fibrillation (30-50%) • Toxicity: • Torsades de Pointes (6%) • Heart block Dofetilide (Tikosyn®) • Potent pure K channel blocker • Indications: • Normal rhythm in atrial fibrillation • Limited availability to those with special training • Adverse effects: • Torsades de pointes (1-3%) • Marked QT prolongation • Mainly eliminated unchanged in kidneys Sotalol (Betapace®) • Beta-blocking activity • Inhibits K+ channels • Decreases Phase 4 depolarization • Inhibits K+ currents, increases action potential duration, ↓ AV node conduction, • Indications: atrial flutter and fibrillation, ventricular tachyarrhythmia • Toxicity: • Torsades de Pointes • Beta-blocking activity, e.g. bronchospasm Class IV - Ca Channel Blockers • Decrease automaticity • Blocks L-type channel • Slow AV node conduction • Negative inotropic Verapamil (Calan), Diltiazem(Cardizem) • Blocks both activated and inactivated channels • Most effective in most active tissue • Decreases AV conduction • Suppresses SA node • Clinical Indications: • Supraventricular Tachycardia (PSVT) • Atrial fibrillation • Toxicity: • Hypotension, edema • Hepatic metabolism, caution in liver damage • Avoid in ventricular arrhythmias, sick sinus syndrome, depressed cardiac function Adenosine • Activates potassium channels in atria and blocks Ca++ channels • Hyperpolarizes cells • Decreases conduction velocity, may stop heart for 2-3 seconds • Decreases automaticity, prolongs refractory period • t½= 10 seconds • Clinical Indications: • Paroxysmal supraventricular tachycardia • Wolff-Parkinson-White • Toxicity: • Flushing 20% • Shortness of breath • Burning in chest Digoxin • Na/K ATPase inhibition • Slows AV conduction • Inhibits Ca channels in AV node • Indirectly increases Parasympathetic tone decreases sympathetic • Can induce heart block • Clinical Indications: • Slow ventricular rate • Induce Heart Block (Atrial flutter, fibrillation) • Toxicity: • nausea, vomiting, diarrhea, anorexia • CNS- confusion, delirium, headache seizures, visual disturbances • Avoid calcium blockers, β-blockers Magnesium Sulfate • Indication: Torsades de Pointes IV (1-2 grams) • Toxicity: • Bradycardia • Flushing • Headache • Respiratory paralysis Lipid Lowering Agents Chapter 35 97 Lipoproteins and Lipid Transport • Lipids (insoluble in water) are transported in blood as lipoproteins with a hydrophilic shell • Chylomicrons – transport dietary lipids from intestine to adipose tissue and liver • VLDL – assembled in liver; deliver triglycerides (TG) to adipose tissue • LDL – transports cholesterol to peripheral tissue for incorporation into cell membranes and steroids • HDL – contain high protein levels; deliver cholesterol esters to the liver; enables delivery of VLDL triglycerides to adipose tissue • Lipoprotein (a) – unknown function; found in atherosclerotic plaques Lipoprotein Metabolism and Atherosclerosis Lipoprotein Characteristics Lipoprotein Class TG: Chol Ratio Site of Synthesis Mechanism of Catabolism CM 10:1 Intestine TG hydrolysis by LPL; uptake by liver VLDL 5:1 Liver TG hydrolysis by LPL IDL 1:1 Product of VLDL catabolism 50% converted to LDL: 50% uptake by liver LDL Not significant Product of VLDL breakdown ApoB-100 mediated uptake by LDLR HDL Not significant Intestine, liver Transfer of CE to VLDL and LDL; uptake by liver LDL Receptor Action Lysosome Genetic mutations of LDL receptor pathway • Heterozygous familial hypercholesterolemia (FH) • single mutant gene for LDL receptor • 1/2 normal number LDL receptors • cholesterol twice normal • Homozygous FH • 2 mutant genes for LDL receptor • no functional LDL receptors • cholesterol level as high as 1000 mg/dL Drugs used to treat Dyslipidemia Francis, G. A. et al. CMAJ 2005;172:495-497 Copyright ©2005 Canadian Medical Association or its licensors Antihyperlipidemics • HMG-CoA reductase inhibitors (Statins) • • • • • • • Atorvastatin Fluvastatin Lovastatin Pitavastatin Pravastatin Rosuvastatin Simvastatin • Cholesterol absorption inhibitor • Ezetimibe • Fibrates • Fenofibrate • Gemfibrozil • Bile acid sequestrants • Cholestyramine • Colesevelam • Colestipol • Nicotinic acid • Fish oil (EPA/DHA) • PCSK9 Inhibitors • Evolucumab • Alirocumab HMG-CoA Reductase Inhibitors • Agents • Lovastatin (Mevacorâ) • Simvastatin (Zocorâ) • Pravastatin (Pravacholâ) • Fluvastatin (Lescolâ) • Atorvastatin (Lipitorâ) • Rosuvastatin (Crestorâ) • Pitavastatin (Livalo®) • MOA: Competitive inhibition of the rate-limiting enzyme in cholesterol biosynthesis -> leads to increased hepatic uptake of LDL Pleiotropic Effects of Statins • Improves endothelial function • Atherosclerotic plaque stabilization • Inhibitory effects on vascular smooth muscle cell growth • Platelet inhibition & antithrombosis • Reduced leukocyte adhesiveness • Inhibitory effects on circulatory clotting factors • Blood pressure effects • Reduced ischemia-reperfusion injury • Enhanced angiogenesis • Reduce inflammatory markers Statins - Place in therapy • Most efficacious and best tolerated of all agents • First line therapy when LDL-C lowering drugs are indicated to achieve LDL goals Statin: Pharmacokinetics Factor Atorvastatin Fluvastatin Lovastatin Pravastatin Rosuvastatin Simvastatin Pitavastatin Prodrug No No Yes No No Yes No Absorption (%) 30 98 30-31 34 40-60 60-80 tmax 2-3 0.5-1 2-4 0.9-1.6 3.0-5.0 1.3-2.4 ~1 Bioavailability 12-14 19-29 5 18 20 5 51% Effect of Food -13% -15% to +25% +50% -30% 0 0 0 80-90 >98 >95 43-54 88 95 >99% CYP3A4 CYP2C9 CYP3A4 Enzymatic and Nonenzymatic Minimal CYP CYP3A4 UGT1A3, UGT2B7 15-30 0.5-2.3 2.9 1.3-2.8 20 2-3 ~12 ≤2 <6 >10 20 10 13 15 ABSORPTION DISTRIBUTION Protein B (%) METABOLISM Major Metabolic Enzyme EXCRETION t1/2 Renal (%) Intensity of Statin Therapy Statins: Adverse Drug Reactions • Common • • • • • Headache, sleep disturbance Fatigue GI Intolerance Flu-Like Symptoms Increase in Liver Enzymes • Occurs in 0.5 to 2.5% of cases in dose-dependent manner • Serious liver problems are exceedingly rare • Manage by reducing statin dose or discontinue until levels return to normal • Myopathies – 0.2-0.4% of pts • Myalgia – mild reversible aches, no CK elevation • Myositis • Rare cases of rhabdomyolysis • Reduce by • Cautiously using statins in patients with impaired renal function • Using the lowest effective dose • Cautiously combining statins with fibrates; avoiding other drug interactions • Careful monitoring of symptoms and laboratory values • Presence of muscle toxicity requires the discontinuation of the statin Statins • Contraindications • Hepatic disease • Pregnancy • Drug Interactions – caution for increased risk of myopathy • CYP3A4 substrates (simva-, lova- >> atorva) – when combined with 3A4 inhibitors • Verapamil • Amiodarone • Grapefruit juice • Agents that independently cause muscle toxicity • Fibrates (fenofibrate is safer than gemfibrozil) • Niacin • Colchicine Ezetimibe: Mechanism of Action Ezetimibe: Mechanism of Action • Selectively inhibits intestinal cholesterol absorption • ¯ intestinal delivery of cholesterol to the liver • ­ expression of hepatic LDL receptors • ¯ cholesterol content of atherogenic particles • Ezetimibe and its active glucuronide metabolite circulate enterohepatically • Delivers agent back to the site of action • Limits systemic exposure • Availability • Ezetimibe (Zetia) • Ezetimible/Simvastatin (Vytorin) Ezetimibe • Dosing - 10 mg po daily without regard to meals • Provides additional 15%-20% LDL lowering when added to statin • Adverse Effects • GI-related effects • Elevations in hepatic transaminases w/ statins Ezetimibe • Contraindications • • • • • • Breast-feeding Pregnancy Children Elderly Hepatic disease Myopathy • Drug Interactions • Fibric acid derivatives- increase hepatobiliary side effects leading to cholelithiasis and myopathies • Bile acid sequestrants may decrease concentrations • Antacids decrease concentrations • Cyclosporine increase concentrations Fibric Acid Derivatives • Gemfibrozil (Lopid®) • Fenofibrate (Tricor®, Lofibra®, others) Fibrates: Mechanism of Action • Activates PPAR-alpha (nuclear transcription factor) • Increase in fatty acid oxidation leads to decrease in secretion of TG-rich lipoproteins (VLDL) Þ decrease in triglycerides • Increases expression of ApoA-1 Þ increase in HDL Fibrates: Pharmacokinetics Pharmacokinetic Parameter Gemfibrozil Fenofibrate (Micronized) No Yes 100% Nearly 100% (micronized) NA Extent of absorption is increased by 35% under fed vs fasted conditions 98% 99% Glucuronidation Glucuronidation Renal Elimination 70% 60% Half-life (hr) 1.3 19–27 ABSORPTION Prodrug? tmax Bioavailability Effect of food on absorption DISTRIBUTION Protein binding METABOLISM Major metabolic pathway ELIMINATION Fibrates - Dosing • Gemfibrozil: 600 mg bid • 30 min prior to breakfast and dinner • Fenofibrate: 54-160 mg daily • With meals Fibrates: Clinical Efficacy • Lipid Lowering Potential • TC ↓ 15% • LDL-C ↓ 5-20% • HDL-C ↑ 10-35% • TG ↓ 20-50% • Primary indication TG > 1000 mg/dL or low HDL Fibrates - Adverse Effects • Adverse Effects • Gastrointestinal – N/V/D, abdominal pain • Cholelithiasis • Myopathy • Contraindications • Pregnancy • Severe hepatic or renal dysfunction • Existing gall bladder disease • Drug Interactions • • • • Increased anticoagulant effects of warfarin HMG CoA reductase inhibitors Ezetimibe Bile acid sequestrants Bile Acid Resins: Mechanism of Action Gall Bladder ­ Cholesterol 7-a hydroxylase ­ Conversion of cholesterol to BA ­ BA Secretion Bile Acid Enterohepatic Recirculation Liver Terminal Ileum Reabsorption of bile acids ­ LDL Receptors ­ VLDL and LDL removal ­ BA Excretion Net Effect: ¯ LDL-C Bile acid sequestrants • Agents • Cholestyramine (Questranâ) • Colestipol HCl (Colestidâ) • Colesevelam (Welcholâ) • Mechanism of Action • Bind to bile acids in the GI → prevent enterohepatic recirculation of cholesterol → excreted in feces • Liver produces more bile acids and LDL receptors ® reduction in LDL • Not absorbed in the GI tract • Limited systemic side effects • Approved for children, adolescence and pregnancy Bile Acid Sequestrants - Dosing • Colestipol powder • starting: 5g bid • max: 30 g/day • Colestipol tabs • starting: 2 g qd-bid • max: 16 g/day • Cholestyramine • starting: 4g bid • max: 24 g/day • Colesevelam • 3.75 g/d (6 tabs) Note: Increase in dose may result only in increase in side effects without gaining more beneficial effects Bile Acid Sequestrants - Administration • Powders must be mixed with water or fruit juice • Mix in pulpy drink to mask taste • Take within 1 hr of meal • Separate other medications Bile Acid Sequestrants - Place in Therapy • Lipid-lowering potential • LDL-C: ↓15-30% • HDL-C: ↑3-5% • May increase TG • Safest drug b/c no systemic side effects • Poorly tolerated • Primary use in conjunction with a statin or for those needing only modest reductions in LDL Bile Acid Sequestrants • Adverse effects • Not absorbed from GI tract • GI effects: bloating, flatulence, fullness, constipation • Mal-absorption of vitamin ADEK and folic acid • May increase VLDL production® ­ TG • Resin (Cl-): ↑Ca++ excretion by direct binding and decreasing absorption • Contraindications • Absolute: familial dysbetalipoproteinemia (increased TG), triglycerides > 400 mg/dL • Relative: Triglycerides > 200 mg/dL Bile Acid Sequestrants - Drug Interactions • Anionic exchange resins; interfere with absorption of some drugs: • digoxin • warfarin • Thyroxine • b-blockers • thiazide diuretics • Avoid interaction by administering drug 1 hour before or 4 hours after bile acid sequestrant Niacin • Niacin is a B-complex vitamin • Nicotinic acid • Used as an antilipemic • Amide form called Niacinamide • Niacinamide (Nicotinamide) is not effective as an antilipemic Niacin - Products • Immediate Release • Niacin (supplement) • Niacor (Rx) • Long acting • Niacin (supplement) • Extended release • Niaspan (Rx) • Inositol hexaniacinate Nicotinic Acid: Mechanism of Action Mobilization of FFA Apo B VLDL TG synthesis VLDL VLDL secretion Serum LDL LDL Liver Hepatocyte Serum VLDL results in reduced lipolysis to LDL HDL Circulation Systemic Circulation Decreases hepatic production of VLDL and of apo B Niacin - Dosing • Immediate release • starting: 100-250 mg qd • max: 1.5-3 g/day (given bid or tid) • Extended release (Niaspanâ) • starting: 500 mg qd • max: 2 g/day Niacin - Place in Therapy • Lipid Lowering Potential • LDL-C: ↓10-25% • HDL-C: ↑15-35% • Triglycerides: ↓25-30% • Useful for patients with atherogenic dyslipidemia • Useful as combination therapy for patients with atherogenic dyslipidemia and elevated LDL Niacin - Adverse Effects • Cutaneous flushing • Prostaglandin mediated effect • minimized by premedication with ASA • Gastrointestinal • nausea • abdominal discomfort • With larger doses: • ­ LFTs, glucose, uric acid • Decreased glucose tolerance • Immediate release vs. Extended release Niacin - Contraindications • Contraindicated in chronic liver disease • Relative CI: • peptic ulcer disease • h/o symptomatic gout • significant hyperuricemia • diabetes (glucose intolerance) • Adverse effects • Statins • Bile acid sequestrants • EtOH • Caution with use of herbals Fish Oil • Omega-3-acid ethyl esters • DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid) • Rx product – Lovaza 1 gm capsules • Various OTC supplements • EPA only (Vascepa) • Reduce VLDL production and lower serum triglycerides by up to 50% or more • Also anti-inflammatory, blood pressure lowering effects • Lovaza may raise LDL by 31% • AE: altered taste perception, belching, GI upset, bleeding risk • Contraindicated in fish or shellfish allergy PCSK9 Inhibitors • PCSK9 (serine protease) is predominantly produced in the liver • Binds to the LDL receptor (LDLR) on the surface of hepatocytes, leading to the degradation of the LDL-R and subsequently to higher plasma LDL-C levels • Antibodies to PCSK9 allow for greater LDL-R expression and improved LDL clearance from the plasma PCSK9 Inhibitors • Commercially available agents • Evolocumab (Repatha) • Alirocumab (Praluent) • Administered via subcutaneous injection every 2 weeks • LDL-C reduction is enhanced with high-intensity statin use • Well tolerated – may cause injection-site reactions, allergic reactions • Role in therapy – added to statins to improve LDL lowering Lipid Management • Goals (ATP III) • LDL < 100 mg/dL – optimal • Precise target depend on risk factors (e.g. smoking, family hx, age, low HDL) • HDL > – 60 mg/dL(high); <40 mg/dL – low • TC <200 mg/dL – desired • TG < 150 mg/dL – normal • AHA/ACC Guideline • Do not titrate to a specific LDL cholesterol target • Measure lipids during follow-ups to assess adherence to treatment, not to achieve a specific LDL target 139 Questions? 140