THE CARDIOVASCULAR SYSTEM Functions: Gas exchange( in the blood vessel) Nutrient transport and waste removal Transport

ort hormones Fight diseases Regulate body temperature Common Cardiovascular Diseases Angina pectoris A characteristic sudden, severe, pressing, chest pain radiating to the neck, jaw back and arms Caused by insufficient coronary blood flow to the myocardium leading to ischemia May last 15 sec to 15 mins Does not cause cellular death Causes: Exertion Vascular smooth muscle spasms Obstruction of blood vessels caused by atherosclerotic lesions Types: Stable angina Unstable angina Prinzmetal/Variant/Vasospastic angina Mixed forms

Stable angina Most common a.k.a typical angina pectoris Characteristics: burning, heavy or squeezing feeling in the chest Cause: reduction of coronary perfusion due to a fixed obstruction produced by coronary atherosclerosis Increased risk in: Vigorous physical activity Increase cardiac workload Relief: Rest Nitroglycerin (vasodilator) - Deponit, Transderm-Nitro Unstable Angina Between a stable angina and a myocardial infarction Chest pain occurs with increased frequency Precipitated by less effort Not relieved by rest and/ or Nitroglycerin Requires hospitalization and a more aggressive therapy to prevent death and progression to MI Prinzmetal Angina An uncommon pattern or episodic angina that occurs at rest and is due to coronary artery spasm Cause: decreased blood flow to the heart muscles due to spasm Occurs in significant coronary atherosclerosis Unrelated to physical activity, heart rate or blood pressure Responds promptly to: coronary vasodilators (i.e. Nitroglycerin and Ca channel blockers) Mixed Forms of Angina May present during effort as well as during rest May indicate the presence of a fixed obstruction associated with endothelial dysfunction Treatment: Organic nitrates: o Isosoride mononitrate (Imdur) o Isosorbide dinitrate (Isoket, Isordil) o Nitroglycerin (Deponit, TransdermNitro)

Beta blockers: o Acebutol

Atenolol (Therabloc, Tenormin, Cardioten) o Metoprolol (Neobloc, Betaloc) o Propranolol (Inderal) Ca channel blockers: o Amlodipine (Amvasc camsylate, Norvasc besylate ) o Diltiazem (Dilzem) o Felodipine (Plendil) o Nicardipine (Cardepine, Perdipine) o Nifedipine (Calcibloc, Adalat GITS) o Verapamil (Isoptin)

Treatment: Diuretics Beta-blockers ACE inhibitors Angiotensin 2 receptor antagonist Renin inhibitors Ca channel blockers Clonidine (Catapress) Methyldopa (Dopamet, Aldomet) *methyldopa and clonidine cannot be used together Diuretics Action: lowers BP initially by sodium and water excretion Cause decrease in extracellular volume, resulting in decrease in cardiac output and renal blood flow With long-term treatment, plasma volume approaches normal values but peripheral resistance decrease Therapeutic use: counteract sodium and water retention observed with other agents used in HTN management Thiazides are therefore useful in combination therapy Thiazide diuretics are not effective in patient with inadequate renal function (Clcr <50ml/min) Pharmacokinetics Orally active Absorption and elimination rates vary considerably All thiazides are ligands for the organic acid secretory system of the nephron ( may compete with uric acid for elimination) Adverse Effects May induce hypokalemia and hyperuricemia in 70% of patients May induce hyperglycemia in 10% of patient Hypomagnesemia Serum potassium levels should be closely monitored in patients predisposed to cardiac arrhythmias (i.e. left ventricular hypertrophy, ischemic heart disease or chronic heart failure) and in patient taking both thiazide diuretics and digoxin

Hypertension Sustained systolic blood pressure (SBP) of greater than 140 mmHg or a sustained diastolic blood pressure (DBP) of greater than 90 mmHg Results from increased peripheral vascular smooth muscle tone, leading to increased arteriolar resistance and reduced capacitance of the venous system Categories for Blood Pressure Levels in Adults Systolic Diastolic Normal < 120 and < 80 Prehypertension 120-139 or 80-89 High Blood Pressure: Stage 1 140-159 or 90-99 Stage 2 160 - > or 100 - > * prehypertension lifestyle change(no meds) * stage 1 diuretics/ beta-blockers Patients may be asymptomatic Chronic hypertension can lead to: o Cerebrovascular accidents(strokes) o Congestive heart disease o Myocardial infarction o Renal damage

Etiology Essential/Primary hypertension Unknown origin Increases with family history 4x more frequent among blacks than among whites More often among middle-aged males Prevalence increases with age, obesity and environmental factors (i.e. stressful lifestyle, high dietary intake of sodium and smoking) Secondary hypertension With an identifiable cause

Beta-blockers Reduce BP primarily by decreasing cardiac output May also decrease symptomatic outflow from the CNS and inhibit the release of rennin from the kidney Decrease the formation of angiotensin II and aldosterone secretion Prototype: Propranolol (acts on both 1 and 2 receptors) Selective 1 blockers: metoprolol and atenolol Beta-blockers must be administered with caution to asthmatic hypertensive patients and in patients with acute heart failure or peripheral vascular disease Therapeutic Use Subsets of population Beta blockers are more effective for hypertensive in whites than black patients and in young compared to elderly patients Concomitant disease Beta blockers are useful in treating conditions coexisting with HTN (i.e. supraventricular tachyarrythmia, previous myocardial infarction, angina pectoris, chronic heart failure and migraine headaches) Pharmacokinetics Beta-blockers are orally active Propanolol undergoes extensive and highly variable first-pass metabolism May take several weeks to develop their full effects Adverse Effects Bradycardia CNS effects (fatigue, lethargy, insomnia and hallucinations) Hypotension Decreased libido May cause impotence Alterations in serum lipid patterns Beta blockers may Disturb lipid metabolism Decrease HDL cholesterol Increase plasma TGs

Drug Withdrawal Abrupt withdrawal may induce angina, MI or even sudden death in patients with HDL (rebound hypertension) Beta-blockers must be tapered over 2 to 3 weeks in case of patients with both HDL and hypertension ACE Inhibitors Lower BP by reducing potential vascular resistance without reflexively increase cardiac output, rate or contractility Decrease the secretion of aldosterone, resulting in decreased sodium water retention Blocks ACE Cleaves angiotensin I to form angiotensin II, which is a potent vasoconstrictor Responsible for the breakdown of bradykinin Therapeutic Use ACE inhibitors are most effective in hypertensive patients who are white and young Along with ARBs, ACE inhibitors slow down the progression of diabetic nephropathy and decrease albuminuria Used in CHF management Standard care for post-MI patients, started 24 hours after end of event Adverse Effect Dry cough(10% incidence) Rash Fever Altered taste Hypotension(in hypovolemic state) Hyperkalemia Angioedema First-dose syncope Fetotoxic (CI for pregnant women) Reversible renal failure (in patients with severe bilateral renal artery stenosis) Angiotensin II Receptor Antagonists Alternative to ACEIs Prototype: Losartan MOA: produce arteriolar and venous dilation and block aldosterone secretion, thus lowering the BP and decreasing salt and water retention

ARBs do not increase bradykinin levels

ARBs decrease the nephrotoxicity of diabetes Their adverse effects are similar to those of ACEIs Also fetotoxic

Renin Inhibitors Aliskiren (Rasilez): directly and selectively inhibits renin Act earlier in the RAAS than ACEIs and ARBs Can be used in combination therapy Adverse Effects Diarrhea, especially at higher doses Cough and angioedema (less incidence than with ACEIs) Contraindicated in pregnancy Hyperkalemia (especially in combination with valsartan) Calcium Channel Blockers Action: block the entry of calcium ions into the cells by binding to L-type voltage-sensitive calcium channels in the heart and in smooth muscles of the coronary and peripheral vasculature. This causes vascular smooth muscle relaxation and dilation of arterioles Therapeutic Uses CCBs have an intrinsic natriuretic effect Useful in hypertensive patients who also have asthma, angina, diabetes and/or peripheral vascular disease Black hypertensives respond well to CCBs Pharmacokinetics Must have short half-life following an oral dose Between 3 to 8 hours Requires multiple daily doses to sustain action (usually TID) Except for amlodipine very long half-life Adverse Effects Verapamil o Constipation (10% incidence) o Negative inotropic and dromotropic effects (CI in CHF and atriventricular block) Felodipine, nifedipine, amlodipine o Dizziness o Headaches o Fatigue Alpha Blockers Actions:

Produce a competitive block alpha-1adrenoreceptors Decrease peripheral vascular resistance Lower atrial BP by causing relaxation of both arterial and venous smooth muscles Can cause only minimal changes in cardiac output, renal blood flow and GFR E.g. prazosin, doxazosin, terazosin

Prazosin Used to treat mild to moderate hypertension Used in combination with propranolol or a diuretic for additive effects Adverse Effects Postural hypertension Salt and water retention Reflex tachycardia First-dose syncope Increased risk of CHF with doxazosin Patient can develop tolerance towards alphablockers in prolonged use Clonidine Action: diminishes central adrenergic outflow Useful in hypertensive cases inadequately responsive to multiple drug therapy Does not decrease renal blood flow or GFR Used in management of hypertension complicated by renal disease Pharmacokinetics Absorbed well following oral administration Excretion: renal Adverse Effects Sodium and water retention (often used with diuretics) Sedation Drying of nasal mucosa Rebound hypertension in abrupt withdrawal Methyldopa (Aldomet) Actions: Converted to methylnorepinephrine centrally to diminish adrenergic outflow from the CNS Reduces total peripheral resistance and decreases BP Does not diminish cardiac output and flood flow to vital organs

Especially useful in hypertensive patients with renal insufficiency Adverse effects: Sedation Drowsiness

Renin-Angiotensin-Aldosterone System (RAAS)

Pharmacology Beneficial effects: Reduction of myocardial load Decreased extracellular fluid volume Improved cardiac contractility Slowing of the rate of cardiac remodeling Goals of treatment: Alleviate symptoms Slow disease progression Improve survival Classes of Drugs Inhibitors of the renin-angiotensin system ACE inhibitors ARBs Beta blockers Diuretics Inotropic agents Direct vasodilators Aldosterone antagonists Arrhythmia The heart contains specialized cells that exhibit automaticity Cardiac muscle cells can intrinsically generate rhythmic action potentials in the absence of external stimuli Dysfunction of impulse generation or conduction at any of a number of sites in the heart Arise from either: o Aberrations in impulse generation (abnormal automaticity) o Defect in impulse conduction Normal Sinus Rhythm

Heart Failure A complex, progressive disorder in which the heart is unable to pump sufficient blood to meet the needs of the body Cardiac symptoms: dyspnea, fatigue and fluid retention Cause: impaired ability of the heart to adequately fill with and/or eject blood Underlying Causes Atherosclerotic heart disease Myocardial infarction Hypertensive heart disease Valvular heart disease Dilated cardiomyopathy Congenital heart disease Most common cause: left systolic dysfunction secondary to coronary artery disease (70% of all cases) Cardiac Remodeling Characterized by loss of myocytes, hypertrophy and fibrosis The geometry of the heart becomes less elliptical and more spherical, interfering with its ability to efficiently function as a pump May be caused by chronic activation of the sympathetic nervous system and the RAA axis

Pacemaker Cells Produce a slow, spontaneous depolarization during diastole (Phase 4), caused by an inward positive current carried by sodium- and potassium- ion flows This depolarization is fastest in the sinoatrial (SA) node (the normal initiation site of the action potential) and decreases throughout the normal conduction pathway through the atrioventricular (AV) node to the Bundle of His and the Purkinje system Causes Abnormal automaticity The SA node normally sets the pace of contraction for the myocardium and latent pacemakers are depolarized by impulses coming from the SA node If other cardiac sites show enhanced automaticity, they may generate competing stimuli May occur in myocardial cell damage (i.e. hypoxia, potassium imbalance) Cells may remain partially depolarized during diastole and can reach the firing threshold earlier than normal Effects of drugs on automaticity Most anti-arrhythmic agents suppress automaticity by blocking either Na or Ca channels to reduce the ratio of these ions to K They primarily decrease the slope of Phase 4 (diastolic) depolarization and/or raises the threshold of discharge to a less negative voltage Abnormalities in impulse conduction Impulse from higher pacemaker centers are normally conducted down pathways that split to activate the entire ventricular surface Reentry: can occur if a unidirectional block caused by myocardial injury or a prolonged refractory period results in an abnormal conduction pathway The most common cause of arrhythmias Can result in premature contraction or sustained ventricular arrhythmia

Effects of drugs on conduction abnormalities Anti-arrhythmic agents prevents reentry by slowing conduction and/or increasing the refractory period, thereby converting a unidirectional block into a bidirectional block

Drugs Class IA MOA: sodium channel blockade Slows Phase 0 depolarization in the ventricles E.g. disopyramide, procainamide, quinidine Class IB MOA: sodium channel blockade Shortens Phase 3 repolarization in the ventricles E.g. lidocaine, mexiletine, tocainide Class IC MOA: sodium channel blockade Markedly slows Phase 0 depolarization in the ventricles E.g. flecainide, propaferone Class II MOA: beta adrenergic blockade Inhibits Phase 4 depolarization in SA and AV nodes E.g. esmolol, metoprolol, propranolol Class III MOA: potassium channel blockade Prolongs Phase 3 repolarization in the ventricles E.g. amiodarone, dofetilide, sotalol Class IV MOA: calcium channel blockade Inhibits the action potential in SA and AV node E.g. diltiazem, verapamil Other Agents Adenosine (Cardiovert) Naturally occurring nucleoside Decreases conduction velocity, prolongs the refractory period, decreases automaticity in the AV node Extremely short half-life (6-15 sec) Digoxin (Lanoxin) Shortens the refractory period in the AV myocardial cells, diminishes conduction velocity in the Purkinje fibers Has a very narrow therapeutic index

The Heart

Action Potential