Cardiovascular Pharmacology PDF

In the name of God 1 Cardiovascular Pharmacology M. Ghazi-Khansari; PhD Department of Pharmacology School of Medicine Tehran University of Medical Sciences  Review of Hemodynamics Circulatory system – heart and blood vessels Arteries – transport blood to tissues Arterio...

In the name of God 1 Cardiovascular Pharmacology M. Ghazi-Khansari; PhD Department of Pharmacology School of Medicine Tehran University of Medical Sciences  Review of Hemodynamics Circulatory system – heart and blood vessels Arteries – transport blood to tissues Arterioles – regulate local blood flow Capillaries – sites of exchange, fluid O2, CO2, nutrients etc. Venules – collect blood from capillaries Reminder Veins – transport blood back to heart Blood moves within vessels – higher pressure to lower pressure ***Resistance to flow depends on vessel diameter, length and viscosity of blood  Cardiac Output Cardiac Output: is the volume of blood pumped by each ventricle per minute CO = SV x HR Stroke Volume: volume of blood pumped by each ventricle per beat or stroke(averages 70 ml/beat) Heart Rate: heart beats/min(averages 70 beats/min)  Cardiac Output Stroke Volume: volume of blood pumped per beat or stroke(averages 70 ml/beat) Heart Rate: heart beats/min(averages 70 beats/min) CO = SV x HR= 70 ml/beat x 70 beats/min= 4,900 ml/min ≈ 5 liters/min Cardiac Output During exercise cardiac output can increase to 20 to 25 L/min Cardiac reserve: the difference between the cardiac output at rest and the maximum volume of blood the heart can pump per minute Resting cardiac output ≈ 5 L/min  Cardiac Output Cardiac output depends on heart rate and the stroke volume( cardiac output increases or decreases in response to changes in heart rate or stroke volume. i.e. when one of them increase it will increase the cardiac output) CO = SV x HR  Stroke Volume Control Two types of controls influences stroke volume: Intrinsic control The extent of venous return Extrinsic control The extent of sympathetic stimulation of the heart Both factors increase stroke volume by increasing the strength of contraction of the heart  Stroke Volume Control Intrinsic Control Intrinsic ability to regulate SV (output) in response to changes in venous return (input) Frank Starling of law of Heart Ventricular contraction is Increased venous return – proportional for muscle increase cardiac output – fiber stretch Greater Stretch= Greater Contraction Stroke Volume Control Effect of Sympathetic Stimulation on Stroke Volume Cardiac Output Regulation Regulation of cardiac output 5L /minute CO=HR X SV Heart rate Stroke volume Preload≈ Stretch Afterload≈ Pressure  Blood Pressure Blood pressure is the force exerted by the blood against a vessel wall Depends on: Volume of blood contained within the vessel Compliance or Distensability of the vessel wall Blood pressure is regulated by controlling: Cardiac output Total peripheral resistance Blood volume Blood pressure= cardiac output X peripheral resistance Cardiac output= HR X SV Total peripheral resistance depends on the radius of all arterioles as well as blood viscosity Resistance /r ( r4: radius of the vessel) Blood pressure Categories Total Peripheral Resistance Blood Pressure Regulation of Blood Pressure Cardiac output = HR x SV Baroreceptor Venous return Systemic filling pressure Auxiliary muscle pump Resistance to flow between peripheral vessels and right atrium Right atrial pressure - elevation  Regulation of Arterial Pressure Arterial pressure= peripheral resistance + cardiac output Arterial pressure: 1.The autonomic nervous system (fast) 2. The renin-angiotensin system (hours or days) 3. The kidneys (days or weeks) Drugs used in Hypertension Antihypertensive Drugs Drugs acting on the Renin-Angiotensin System Angiotensin-converting enzyme (ACE) inhibitors Angiotensin II receptor blockers (ARBs) Primary indications – hypertension, heart failure, myocardial infarction, diabetic nephropathy  Renin-angiotensin system Angiotensin I, II, III Most potent – angiotensin II Produces profound vasoconstriction and stimulates release of aldosterone and may also cause pathologic structural changes in the heart and blood vessels (especially bad after an MI) Captopril First ACE inhibitor Given po Inhibits ACE Reduction in blood volume, vasodilation, prevent remodeling Take on empty stomach Adverse effects Cough, first-dose hypotension, hyperkalemia, renal failure, fetal injury, angioedema, rash, neutropenia, impaired taste Enalapril - Enalaprilat Enalaprilat – active form (converted by liver) trade – Vasotec Can be given IV for severe hypertension Lisinopril – newer very long-acting Angiotensin II Receptor blockers Block actions of angiotensin II Losartan (Cozaar) – does not cause angioedema or cough Approved for hypertension only Doesn’t appear to cause hyperkalemia Contraindicated in pregnancy Calcium Channel Blockers Prevent calcium from entering cells Used for hypertension, angina, cardiac dysrhythmias Calcium channels in vascular smooth muscle – when blocked – prevents contraction and therefore, vasodilation Calcium in the heart Positive inotropic effect Slows heart rate if blocked If blocked – slows conduction thru AV node Calcium channels are coupled with beta1 adrenergic receptors – have identical effects Verapamil Blocks calcium channels in the blood vessels and heart Given for angina, hypertension and dysrhythmias Vasodilation most noticeable effect Given orally or IV Verapamil Adverse effects – constipation, dizziness, h/a, bradycardia, hypotension, edema of ankles and feet Diltiazem Vasodilation – lowers blood pressure Given for hypertension, angina, dysrhythmias Nifedipine Dihydropyridines – act mainly on vascular smooth muscle Blocks calcium channels in vascular smooth muscle – vasodilation Given for angina, hypertension Adverse effects – dizziness, h/a, reflex tachycardia Other Dihydropyridines Nicardipine – Cardene Amlodipine – Norvasc Felodipind – Plendil Nimodipine – Nimotop – selective blockade of calcium channels in cerebral blood vessels Vasodilators Indications – hypertension, angina, heart failure Some only arterioles, some only veins Some have effects on both Adverse effects related to vasodilation Postural hypotension Reflex tachycardia Expansion of blood volume Vasodilators Hydralazine Apresoline – dilation of arterioles Treats hypertension Less postural hypotension Others Minoxidil – severe with resistant hypertension Diazoxide (hyperstat): for severe hypertension. Diazoxide causes smooth muscle relaxation leading to systemic and pulmonary vasodilation Nitroprusside – hypertensive emergencies – causes venous and arteriolar dilation – given IV Drugs for hypertension Should include lifestyle modification and drug therapy Primary (essential) Secondary Treatment is usually life-long and non- compliance is a problem Consequences of hypertension Heart disease, kidney disease, blindness, stroke Virtually no symptoms Goal of treatment – systolic < 140 and diastolic < 90 Management - lifestyle Weight loss Sodium restriction Alcohol restriction Exercise Smoking cessation Maintenance of potassium and calcium intake Pharmacologic Therapy Sites of action and effects produced 1. Brainstem: SBP >200mmHg 2. Sympathetic Ganglia – used for emergencies 3. Terminal of adrenergic nerves 4. Beta 1 receptors on the heart 5. Alpha 1 – adrenergic receptors on blood vessels Pharmacology Therapy Continue 6. Vascular smooth muscle 7. Renal tubules 8. Beta 1 receptors on juxtaglomerular cells 9. Angiotensin-converting enzyme 10. Angiotensin II receptors Initial Drug Selection With no other conditions – may be diuretics and beta blockers Comorbid conditions Benefits of multi-drug therapy Dosing Step-down therapy Co-morbid conditions Renal disease – ACE inhibitors, diuretics Diabetes – ACE inhibitors, alpha blockers, low-dose diuretics Populations at risk African americans Children and adolescents Elderly Promoting compliance Little to no symptoms No effects from medications unless side effects Expensive Promoting compliance Educate patient Teach self-monitoring Work to minimize side effects Make the patient a partner Simple as possible! Make appointment easy Management of hypertensive emergencies (Cardiogenic Shock)  Inotrope An inotrope is an agent that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions. Positively inotropic agents increase the strength of muscular contraction.  Positive inotropic agents increase myocardial contractility, and are used to support cardiac function in conditions such as decompensated congestive heart failure, cardiogenic shock, septic shock, myocardial infarction, cardiomyopathy Calcium sensitisers – Levosimendan Catecholamines – Dopamine, Dobutamine, Epinephrine, Isoproterenol, Norepinephrine Digoxin Phosphodiesterase inhibitors – Milrinone, Amrinone  Negative inotropic agents decrease myocardial contractility, and are used to decrease cardiac workload in conditions such as angina. Beta blockers - carvedilol, bisoprolol and metoprolol Calcium channel blockers - Diltiazem,Verapamil Intracellular concentrations of cAMP Cyclic-AMP  Cardiovascular Actions of cAMP- dependent PDE (type3) Inhibitors Systemic Circulation Vasodilation Increased organ perfusion Decreased systemic vascular resistance Decreased arterial pressure Cardiopulmonary Increased contractility and heart rate Increased stroke volume and ejection fraction Decreased ventricular preload (secondary to increased output( Decreased pulmonary capillary pressure Drugs for Angina Goals – prevent MI and death Prevention of pain and myocardial ischemia 3 types of angina Chronic stable angina Variant angina (Prinzmetal’s) Unstable angina Nitroglycerin Organic nitrate Acts on vascular smooth muscle to promote vasodilation Primarily works on veins Modest dilation arterioles Decreases oxygen demand by decreasing venous return – stable angina Routes of administration Oral, sublingual, IV, buccal, transdermal Crosses membranes easily Adverse effects – headache, tachycardia, hypotension Do not combine with other drugs causing vasodilation (Viagra) or hypotensive drugs Tolerance can occur – give lowest dose possible Drug – free period every day Long – acting preparations vs preparations for acute attack Indications for Nitroglycerin Acute angina Prophylaxis against angina IV therapy – blood pressure, MI, unstable angina Drugs for Heart Failure ACE inhibitors Diuretics Beta blockers Digoxin Spironolactone Heart failure Major causes – hypertension, myocardial infarction Inadequate tissue perfusion from a failing pump, volume overload  The vicious cycle in heart failure Cardiac dilation Increased sympathetic tone Water retention and increased blood volume Reduced cardiac output decreases renal perfusion, leading to reduced natriuresis and diuresis and increased activation of the renin– angiotensin–aldosterone system (RAAS). Classification of severity of heart failure I – no limitation of physical activity II – slight limitation III – marked limitation IV – symptoms occur at rest Non drug therapy Sodium limitation Avoid large amounts fluid Lose weight if indicated Avoid alcohol Mild activity Drug therapy ACE inhibitors Adequate dosing is important – often too low Maybe angiotensin II receptor blockers Hydralazine and isosorbide combo if cannot tolerate ACE Additional drug therapy Diuretics Beta blockers – Coreg Spironolactone – aldosterone receptor blocker – works with ACE inhibitors Inotropic agents Digoxin Cardiac glycoside – improves cardiac performance – positive inotrope Narrow therapeutic range Competes with potassium for binding – when potassium is low, Digoxin is high  How Digitalis Works ? Na+/K+ ATPase Na+/Ca2+ Exchanger Out Na+ Na+ ATP ADP + Pi Ca++ Ca++ K+ In ( Cytosol) Heart Cell Digoxine [ Ca2+ ]cytosol contraction Effects of Digitalis Na-K ATPase Na-Ca Exchanger 2 K+ 3 Na+ Ca2+ Myofilaments Ca2+ 3 Na+ CONTRACTILITY Effects of Digoxin Increases cardiac output Decreased sympathetic tone Increased urine output Decreased renin release Does not prolong life Also effects electrical activity – decreased conduction thru AV node, decreases automaticity of SA node Adverse effects DYSRHYTHMIAS TOXICITY – very narrow therapeutic index – hypokalemia makes it easier for toxicity to occur GI – disturbances Fatigue Visual disturbances Therapeutic blood levels Important to know -.5-2.0ng/ml But patient may be “toxic” even if within the normal range Measures to treat toxicity – pacemaker, antidysrhythmics, digibind Serum Electrolytes Affect Toxicity K+ Hypokalemia: increase toxicity Hyperkalemia: decrease toxicity Mg2+ Hypomagnesemia: increases toxicity Ca2+ Hypercalcemia: increases toxicity Antiarrhythmic agent Tachydysrhythmias vs bradydysrhythmias Alteration in electrical impulses in heart Conduction system of the heart Supraventricular vs ventricular tachydysrhythmias Antiarrhythmic agent Class I agents interfere with the sodium (Na+) channel. Class II agents are anti-sympathetic nervous system agents. Most agents in this class are beta blockers. Class III agents affect potassium (K+) efflux. Class IV agents affect calcium channels and the AV node. Antiarrhythmic agent Adverse effect Long half-life Bad side effects – pulmonary toxicity Bluish discoloration of skin GI side effects: Constipation Liver dysfunction Thyroid dysfunction Ringing in the ears (tinnitus) Headache and dizziness Adenosine Stops supraventricular tachycardia Extremely short half-life Nonpharmacologic treatment An Automatic Implantable Cardioverter Defibrillator (AICD), is a small electronic device that is implanted into your chest to monitor and correct an abnormal heart rhythm, or arrhythmia. Catheter Ablation: involves passing thin, flexible tubes, called catheters, through the blood vessels to the heart. Drugs that lower LDL cholesterol levels Why do we have cholesterol? Where does it come from? Diet Liver – enzyme helps to make it (HMG CoA) Drugs inhibit this enzyme Saturated fats cause greater increases in cholesterol than increases in dietary cholesterol Lipoproteins Help to carry lipids (triglycerides and cholesterol in blood) VLDLs Contain mostly triglycerides in blood Carries from liver to adipose tissue May have link with atherosclerosis? Low-density lipoproteins Contain cholesterol as primary core lipid Delivers cholesterol to tissues (nonhepatic) Greatest contribution to coronary atherosclerosis High-density lipoproteins HDL’s carry cholesterol from tissues back to the liver – help remove cholesterol from peripheral tissue Elevation of HDL’s decreased risk of CAD LDLs help promote formation of fatty streak – surface of arterial wall lumpy Injury – inflammatory process Management of high LDL cholesterol Diet modification Reduce risk factors – smoking, exercise (lack of), hypertension, diabetes mellitus, obesity Drug therapy “Statins” – HMG CoA inhibitors – most widely used – also increase number of LDL receptors on liver cells Lovastatin, Fluvastatin, Pravastatin, Simvastatin, Atorvastatin, Cerivastatin Effects Lower LDL cholesterol Give in the evening Elevation of HDL cholesterol Additional beneficial effects Clinical trials Support primary and secondary prevention Adverse effects Hepatotoxicity, GI disturbances, myopathy Bile Acid-Binding resins Questran, Prevalite Increase LDL receptors on hepatocytes May be combined with statin Nicotinic acid Reduces LDL Raises HDL Side effects – nicotinic flushing, GI Hepatotoxic Lopid “fibrates” – lower VLDL, raise HDL Decreases synthesis of triglycerides hepatotoxic Review coagulation Vessel injury Formation of platelet plug – platelets adhere to site of injury, activation and aggregation (end result is fibrinogen bridges between glycoprotein IIb/IIIA receptors Coagulation – production of fibrin to reinforce platelet plug Review coagulation continued Intrinsic and extrinsic Factors VII, IX, X, and prothrombin require vitamin K for synthesis Antithrombin III inhibits clotting factors activity (some) so there is not widespread clotting Removal of clots Plasminogen to plasmin – enzyme that digests the fibrin meshwork of the clot Thrombosis Arterial – damage to wall or rupture of plaque – platelet aggregation Venous thrombosis – stagnation of blood initiates coagulation cascade – thrombus breaks off - embolus Parenteral anticoagulants Heparin – administered by injection Helps inactivate thrombin, factor Xa and others *Prophylaxis of venous thrombosis Half-life is short – given as bolus initially (acute) Therapeutic uses Pregnancy – if needed PE CVA DVT – acute and prevention Open heart surgery DIC Acute MI Adverse reactions Bleeding Thrombocytopenia – heparin induced Hypersensitivity Protamine sulfate for OD Monitoring of – APTT Given in units Low Molecular Weight Heparin Can be given on fix-dosed schedule and do not require APTT monitoring Less likely to cause thrombocytopenia Can be taken at home Inactivate factor Xa and cannot bind with thrombin to inactivate it Low Molecular Weight Heparin Primary use is prevention of DVT after surgery and trauma and spinal injury Increased bioavailability related to Heparin Given SC – dosage based on body weight Adverse effects Bleeding Thrombocytopenia Neurological injury with spinal anesthesia – spinal, epidural bleed Enoxaparin - Lovenox Dalteparin Ardeparin Oral anticoagulants Warfarin – Coumadin Rat poison Antagonist of vitamin K – blocks synthesis of vitamin K dependent factors in coagulation cascade Peak effects take several days Therapeutic uses Long-term prophylaxis of thrombosis Prosthetic heart valves Atrial fibrillation Must monitor PT (prothrombin time) – INR (contains a correction factor for PT) PT/INR needs to be monitored frequently Adverse reactions Warfarin has many drug interactions Hemorrhage Vitamin K can be given in case of overdose Differences between heparin and warfarin Heparin works faster than Warfarin (Coumadin), so it is often used for immediate treatment of existing blood clots or during surgery to prevent clots from forming right away. Warfarin can be supplied as an oral tablet, which makes it much more desirable for long-term use. Antiplatelet drugs Prevention of thrombosis in arteries ASA – suppresses platelet aggregation Indications – prophylaxis of MI, prevent reinfarction in patients with acute MI, prevent stroke in patients with TIA Aspirin Low dose - no greater than 325mg/day Adverse effects Adenosine diphosphate receptor antagonists Block ADP receptors preventing ADP- stimulated aggregation Ticlopidin – prevent stroke Clopidogrel – prevent stroke and MI Glycoprotein IIb/IIIa receptor antagonis Reversible blockade of IIb/IIIa receptors – inhibits final step in aggregation Used in acute coronary syndrome and Percutaneous coronary intervention  Thrombolytics Remove the clot once it is there thrombolytics or fibrinolytics“clot busters” Streptokinase tPA