Farmacologa Cardiovascular SISTEMA CIRCULATORIO FUNCIONES PRINCIPALES Transportar y

Farmacología Cardiovascular

SISTEMA CIRCULATORIO: FUNCIONES PRINCIPALES • Transportar y distribuir sustancias esenciales a los tejidos • Remover desechos metabólicos • Ajustar la provisión de oxígeno y nutrientes en diferentes estados metabólicos • Regulación de la temperatura corporal • Comunicación humoral

Un sistema complicado

Que se puede simplificar SERIES AND PARALLEL CIRCUITS

CICLO CARDIACO

Potencial de acción cardíaco ATRIUM VENTRICLE 0 mv mv 0 -80 mv SA NODE mv 0 -80 mv time

Conductacias del PA cardíaco

Corrientes y PA cardíaco Fast K closes Fast K reopens Slow K opens ("Delayed rectifier")

Del PA al ECG

AV NODE AND AV BLOCKS FOCUS ON N REGION NORMAL 1 ST DEGREE PROLONGUED AV CONDUCTION TIME 2 ND DEGREE 1/2 ATRIAL IMPULSES CONDUCTED TO VENTRICLES 3 RD DEGREE VAGAL MEDIATION IN N REGION/COMPLETE BLOCK ECG

ENFERMEDAD CARDÍACA • Cardiovascular disease is the major cause of death • Cardiovascular function based on – Cardiac pumping ability • Pace-making electrical signals • Force of contraction • Height of ventricle discharge pressure – Integrity of vasculature • Presence of blockage • Muscular tone/structural integrity • Pressure drop needed to move blood to and through capillary beds – Blood volume/composition • Water, electrolyte, iron balances • Lipid and protein composition

Patologías cardiovasculares que requieren farmacoterapia • • Hipertensión Arritmia Falla cardíaca Trastornos de flujo vascular

I. Background to Hypertension Regulation of Blood Pressure • Arterial blood pressure due to combination of cardiac output (CO) and total peripheral resistance (TPR) • CO – regulated by heart rate and stroke volume (CO = HR x SV) • TPR function of – Viscosity of blood (hematocrit) – Length of blood vessels – Blood vessel luminal diameter (especially precapillary arterioles)

Cardiac Output • Heart rate – Function of • sympathetic, vagal nervous activity • Neuro-hormonal substances – 1° angiotensin II – 2º vasopression (anti-diuretic hormone = ADH) • Stroke volume – Function of • Venous return (function of venous tone [contractile state] and circulating blood (vascular) volume) – Venous tone function of sympathetic activity (α 1, α 2 receptors) – Vascular volume depends on » Intake of fluids (thirst) » Output of fluids (urine, sweat, etc) » Distribution of fluids (Starling’s law) • Myocardial contractility (MC proportional to sympathetic tone [β 1 receptors])

Characteristics of some adrenoceptors Tissues (sympatheticreceptors nerves) and effects α 1 α 2 constrict/ dilate β 1 β 2 Smooth muscle Arteries/ veins dilate Skeletal muscle dilate Heart Rate (increase) Force of contraction increase

Autonomic Regulation of the Heart • Heart Rate – Parasympathetic input via vagus nerve causes decrease in HR (dominates) – Sympathetic input to sino-atrial node causes increase in HR (usually minor) • Heart contractility – Increased by sympathetic activity causing release of epinephrine, norepinephrine from adrenal gland

Hipertensión

Antihypertensive Classes • diuretics • beta blockers • angiotensin-converting enzyme (ACE) inhibitors • calcium channel blockers • vasodilators

Alpha 1 Blockers Stimulate alpha 1 receptors -> hypertension Block alpha 1 receptors -> hypotension • doxazosin (Cardura®) • prazosin (Minipress®) • terazosin (Hytrin®)

Central Acting Adrenergics • Stimulate alpha 2 receptors – inhibit alpha 1 stimulation • hypotension • clonidine (Catapress®) • methyldopa (Aldomet®)

Peripheral Acting Adrenergics • • • reserpine (Serpalan®) inhibits the release of NE diminishes NE stores leads to hypotension Prominent side effect of depression – also diminishes seratonin

Adrenergic Side Effects • Common – dry mouth, drowsiness, sedation & constipation – orthostatic hypotension • Less common – headache, sleep disturbances, nausea, rash & palpitations

Sistema renina-angiotensina

ACE Inhibitors RAAS Angiotensin I . ACE Angiotensin II 1. potent vasoconstrictor - increases BP 2. stimulates Aldosterone - Na+ & H 2 O reabsorbtion

Renin-Angiotensin Aldosterone System • • Angiotensin II = vasoconstrictor Constricts blood vessels & increases BP Increases SVR or afterload ACE-I blocks these effects decreasing SVR & afterload

ACE Inhibitors • Aldosterone secreted from adrenal glands cause sodium & water reabsorption • Increase blood volume • Increase preload • ACE-I blocks this and decreases preload

Angiotensin Converting Enzyme Inhibitors • • captopril (Capoten®) enalapril (Vasotec®) lisinopril (Prinivil® & Zestril®) quinapril (Accupril®) ramipril (Altace®) benazepril (Lotensin®) fosinopril (Monopril®)

Calcium Channel Blockers • Used for: • Angina • Tachycardias • Hypertension

Antagonistas de calcio como vasodilatadores

Calcium Channel Blockers • diltiazem (Cardizem®) • verapamil (Calan®, Isoptin®) • nifedipine (Procardia®, Adalat®)

CCB Site of Action diltiazem & verapamil nifedipine (and other dihydropyridines)

CCB Action • diltiazem & verapamil • decrease automaticity & conduction in SA & AV nodes • decrease myocardial contractility • decreased smooth muscle tone • decreased PVR • nifedipine • decreased smooth muscle tone • decreased PVR

Side Effects of CCBs • Cardiovascular • hypotension, palpitations & tachycardia • Gastrointestinal • constipation & nausea • Other • rash, flushing & peripheral edema

Diuretics • Thiazides: • chlorothiazide (Diuril®) & hydrochlorothiazide (HCTZ®, Hydro. DIURIL®) • Loop Diuretics • furosemide (Lasix®), bumetanide (Bumex®) • Potassium Sparing Diuretics • spironolactone (Aldactone®)

Diuretic Site of Action. Distal tubule proximal tubule Collecting duct loop of Henle

Mechanism • Water follows Na+ • 20 -25% of all Na+ is reabsorbed into the blood stream in the loop of Henle • 5 -10% in distal tubule & 3% in collecting ducts • If it can not be absorbed it is excreted with the urine • Blood volume = preload !

Side Effects of Diuretics • • • electrolyte losses [Na+ & K+ ] fluid losses [dehydration] myalgia N/V/D dizziness hyperglycemia

Vasodilators • • diazoxide [Hyperstat®] hydralazine [Apresoline®] minoxidil [Loniten®] sodium Nitroprusside [Nipride®]

Mechanism of Vasodilators • Directly relaxes arteriole smooth muscle • Decrease SVR = decrease afterload

Nitratos como vasodilatadores

Side Effects of Vasodilators • hydralazine (Apresoline®) – Reflex tachycardia • sodium nitroprusside (Nipride®) – Cyanide toxicity in renal failure – CNS toxicity = agitation, hallucinations, etc.

II. Background to Arrhythmia Rhythm of the Heart • Human heart is fourchambered • Chambers need to contract sequentially (atria, then ventricles) and in synchronicity • Also need relaxation between contractions to allow refilling of chambers • Above controlled electrically (Purkinje fibers allow rapid, organized spread of activation)

Regulation of Heart Rate – Primarily accomplished by sinoatrial node (SA) • Located on right atrium • Receives autonomic input • When stimulated, SA signals atrial contractile fibers atria depolarization and contraction (primes ventricles with blood) – Depolarization picked up by atrioventricular node (AV node) depolarizes ventricles blood discharged to pulmonary artery and dorsal aorta eventually rest of body

Sequential Discharge of SA and AV nodes

Dysrhythmia Generation • Abnormal conduction • Analogies: – One way valve – Buggies stuck in muddy roads

Antiarrítmicos: conducción cardíaca

Antiarrítmicos: bloqueo de canales de sodio

Warning! • All antidysrhythmics have arrythmogenic properties • In other words, they all can CAUSE dysrhythmias too!

Class I: Sodium Channel Blockers • Decrease Na+ movement in phases 0 and 4 • Decreases rate of propagation (conduction) via tissue with fast potential (Purkinje) – Ignores those with slow potential (SA/AV) • Indications: ventricular dysrhythmias

Class Ia Agents • Slow conduction through ventricles • Decrease repolarization rate – Widen QRS and QT intervals • May promote Torsades Pointes! • PDQ: – procainamide (Pronestyl®) – disopyramide (Norpace®) – qunidine – (Quinidex®)

Class Ib Agents • Slow conduction through ventricles • Increase rate of repolarization • Reduce automaticity – Effective for ectopic foci • May have other uses • LTMD: – – lidocaine (Xylocaine®) tocainide (Tonocard®) mexiletine (Mexitil®) phenytoin (Dilantin®)

Class Ic Agents • Slow conduction through ventricles, atria & conduction system • Decrease repolarization rate • Decrease contractility • Rare last chance drug • flecainide (Tambocor®) • propafenone (Rythmol®)

Class II: Beta Blockers • Beta 1 receptors in heart attached to Ca++ channels – Gradual Ca++ influx responsible for automaticity • Beta 1 blockade decreases Ca++ influx – Effects similar to Class IV (Ca++ channel blockers) • Limited # approved for tachycardias

Class II: Beta Blockers • propranolol (Inderal®) • acebutolol (Sectral®) • esmolol (Brevibloc®)

Class III: Potassium Channel Blockers • • Decreases K+ efflux during repolarization Prolongs repolarization Extends effective refractory period Prototype: bretyllium tosylate (Bretylol®) – Initial norepi discharge may cause temporary hypertension/tachycardia – Subsequent norepi depletion may cause hypotension

Class IV: Calcium Channel Blockers • Similar effect as ß blockers • Decrease SA/AV automaticity • Decrease AV conductivity • Useful in breaking reentrant circuit • Prime side effect: hypotension & bradycardia • verapamil (Calan®) • diltiazem (Cardizem®) • Note: nifedipine doesn’t work on heart

III. Background to Congestive Heart Failure Maintenance of Normal Heart Function • Normal cardiac output needed to adequately perfuse peripheral organs – Provide O 2, nutrients, etc – Remove CO 2, metabolic wastes, etc – Maintain fluid flow from capillaries into interstitium and back into venous system if flow reduced or pressure increased in venous system build up of interstitial fluid = edema • Because CO is a function of – Heart Rate – determined by pacemaker cells in the sinoatrial node – Stroke volume – determined by fill rate and contractile force – Atrial/ventricular/valvular coordination Any negative change on above can lead to inadequate perfusion and development of the syndrome of heart failure

FALLA CARDÍACA CAUSES: Impairment of electrical activity Muscle damage Valvular defects Cardiomyopathies Result of drugs or toxins PROBLEM: Maintaining circulation with a weak pump ( Cardiac output & cardiac reserve; RAP) SOLUTIONS: Sympathetic tone via baroreceptor reflex - Heart rate and contractility -Venoconstriction ( MCP) -Vasoconstriction ( Arterial BP) Fluid retention ( MCP) -Capillary fluid shift -ADH -Renin-angiotensin-aldosterone

Glicósidos: Efectos cardíacos

IV. Background to Reduced Vascular Blood Flow: Blood Vessel Anatomy and Function • Arterial blood vessels – Smooth muscle (slow, steady contraction) – elastic tissue (stretch on systole, recoil on diastole) – Contain about 10% of blood volume – Arterioles have sphincters which regulate 70% of blood pressure • Venous blood vessels – Highly distensible, some contractility – Contain over 50% of blood volume • Capillaries – Tiny but contain greatest cross-sectional area to allow high exchange rate – Contain precapillary sphincters to regulate blood flow – 5% of blood volume All vasculature under ANS and humeral control

Misc. Agents • adenosine (Adenocard®) – Decreases Ca++ influx & increases K+ efflux via 2 nd messenger pathway • Hyperpolarization of membrane • Decreased conduction velocity via slow potentials • No effect on fast potentials • Profound side effects possible (but shortlived)

Misc. Agents • Cardiac Glycocides • digoxin (Lanoxin®) – Inhibits Na. KATP pump – Increases intracellular Ca++ • via Na+-Ca++ exchange pump – Increases contractility – Decreases AV conduction velocity

Fármacos con acción cardíaca

Tratamiento de la angina de pecho (angor)

Tratamiento del infarto agudo de miocardio

Tratamiento del infarto agudo de miocardio