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

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

Cardioten®) o Metoprolol (Neobloc®. Perdipine®) o Nifedipine (Calcibloc®. 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. Aldomet®) *methyldopa and clonidine cannot be used together Diuretics  Action: lowers BP initially by sodium and water excretion  Cause decrease in extracellular volume. obesity and environmental factors (i. Atenolol (Therabloc®.e. Adalat GITS®) o Verapamil (Isoptin®) o Treatment:  Diuretics  Beta-blockers  ACE inhibitors  Angiotensin 2 receptor antagonist  Renin inhibitors  Ca channel blockers  Clonidine (Catapress®)  Methyldopa (Dopamet®. resulting in decrease in cardiac output and renal blood flow  With long-term treatment. stressful lifestyle. high dietary intake of sodium and smoking)  Secondary hypertension  With an identifiable cause . left ventricular hypertrophy. Tenormin®.> * 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. Betaloc®) o Propranolol (Inderal®) Ca channel blockers: o Amlodipine (Amvasc® camsylate. Norvasc® besylate ) o Diltiazem (Dilzem®) o Felodipine (Plendil®) o Nicardipine (Cardepine®. 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 .e.> or 100 . 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.

angina pectoris.e. 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. rate or contractility  Decrease the secretion of aldosterone. 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. 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. thus lowering the BP and decreasing salt and water retention  ARBs do not increase bradykinin levels .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 ß1 and ß2 receptors)  Selective ß1 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. 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. supraventricular tachyarrythmia. 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. resulting in decreased sodium water retention  Blocks ACE  Cleaves angiotensin I to form angiotensin II. ACE inhibitors slow down the progression of diabetic nephropathy and decrease albuminuria  Used in CHF management  Standard care for post-MI patients. previous myocardial infarction.

doxazosin. 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. 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. prazosin. 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.   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.g. 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. 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 . angina.

progressive disorder in which the heart is unable to pump sufficient blood to meet the needs of the body  Cardiac symptoms: dyspnea. 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. 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 . hypertrophy and fibrosis  The geometry of the heart becomes less elliptical and more spherical. 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.

tocainide  Class IC  MOA: sodium channel blockade  Markedly slows Phase 0 depolarization in the ventricles  E. spontaneous depolarization during diastole (Phase 4).e. lidocaine.g. diminishes conduction velocity in the Purkinje fibers  Has a very narrow therapeutic index . 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.g.Pacemaker Cells  Produce a slow. sotalol  Class IV  MOA: calcium channel blockade  Inhibits the action potential in SA and AV node  E. esmolol. flecainide.g. decreases automaticity in the AV node  Extremely short half-life (6-15 sec)  Digoxin (Lanoxin)  Shortens the refractory period in the AV myocardial cells. mexiletine. quinidine  Class IB  MOA: sodium channel blockade  Shortens Phase 3 repolarization in the ventricles  E. disopyramide. amiodarone. hypoxia. diltiazem.g.and potassium. thereby converting a unidirectional block into a bidirectional block Drugs  Class IA  MOA: sodium channel blockade  Slows Phase 0 depolarization in the ventricles  E. dofetilide. caused by an inward positive current carried by sodium.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. propranolol  Class III  MOA: potassium channel blockade  Prolongs Phase 3 repolarization in the ventricles  E.g. metoprolol.g. propaferone  Class II  MOA: beta adrenergic blockade  Inhibits Phase 4 depolarization in SA and AV nodes  E. verapamil Other Agents  Adenosine (Cardiovert)  Naturally occurring nucleoside  Decreases conduction velocity. procainamide. prolongs the refractory period. they may generate competing stimuli  May occur in myocardial cell damage (i.

The Heart Action Potential .

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