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 cardíacom

v

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-80mv

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-80mv

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-80mv

ATRIUM VENTRICLE

SA NODE

time

Conductacias del PA cardíaco

Fast K closes Slow K opens

Fast K reopens

("Delayed rectifier")

Corrientes y PA cardíaco

Del PA al ECG

AV NODE AND AV BLOCKS

FOCUS ON N REGION

NORMAL

ECG

1ST DEGREE

PROLONGUED AVCONDUCTION TIME

2ND DEGREE

1/2 ATRIAL IMPULSES CONDUCTED TO VENTRICLES

3RD DEGREE

VAGAL MEDIATIONIN N REGION/COMPLETEBLOCK

• 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

ENFERMEDAD CARDÍACA

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 (α1, α2 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 [β1 receptors])

Characteristics of some adrenoceptors (sympathetic nerves)

α1 α2 β1 β2

Smooth muscle Arteries/

veins

constrict constrict/

dilate

dilate

Skeletal

muscle

dilate

Heart

Rate (increase)

Force of

contraction

increase

Tissues and effects receptors

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

Alpha1 Blockers

Stimulate alpha1 receptors -> hypertension

Block alpha1 receptors -> hypotension

• doxazosin (Cardura®)

• prazosin (Minipress®)

• terazosin (Hytrin®)

• doxazosin (Cardura®)

• prazosin (Minipress®)

• terazosin (Hytrin®)

Central Acting Adrenergics

• Stimulate alpha2 receptors – inhibit alpha1 stimulation

• hypotension

• clonidine (Catapress®)

• methyldopa (Aldomet®)

• 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

Angiotensin I

ACE

Angiotensin II

1. potent vasoconstrictor

- increases BP

2. stimulates Aldosterone

- Na+ & H2O

reabsorbtion

ACE Inhibitors

.

RAAS

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 otherdihydropyridines)

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®,

HydroDIURIL®)

• Loop Diuretics

• furosemide (Lasix®), bumetanide (Bumex®)

• Potassium Sparing Diuretics

• spironolactone (Aldactone®)

Diuretic Site of Action

.

loop of Henle

proximaltubule

Distal tubule

Collecting duct

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 four-chambered

• 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 des 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

• Beta1 receptors in heart attached to Ca++ channels– Gradual Ca++ influx responsible for

automaticity

• Beta1 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 O2, nutrients, etc– Remove CO2, 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 CARDÍACACAUSES: Impairment of electrical activity

Muscle damageValvular defectsCardiomyopathiesResult 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 2nd messenger pathway• Hyperpolarization of membrane• Decreased conduction velocity via slow potentials• No effect on fast potentials

• Profound side effects possible (but short-lived)

Misc. Agents

• Cardiac Glycocides

• digoxin (Lanoxin®)– Inhibits NaKATP 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