Transcript Diapositiva 1 - Universidad Nacional de Quilmes

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
CIRCUITOS EN SERIE
Y EN PARALELO
CICLO CARDIACO
Potencial de acción cardíaco
ATRIUM
VENTRICLE
0
mv
mv
0
-80mv
-80mv
SA NODE
mv
0
-80mv
time
Conductancias
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
NORMA
L
1ST DEGREE
PROLONGUED AV
CONDUCTION TIME
2ND DEGREE
1/2 ATRIAL IMPULSES
CONDUCTED TO VENTRICLES
3RD DEGREE
VAGAL MEDIATION
IN N REGION/COMPLETE
BLOCK
ECG
Patologías cardiovasculares que
requieren farmacoterapia
•
•
•
•
Hipertensión
Arritmia
Falla cardíaca
Trastornos de flujo vascular
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
Tissues
(sympatheticreceptors
nerves)
and effects
α1
α2
constrict
constrict/
dilate
β1
β2
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
Alpha1 Blockers
Stimulate alpha1 receptors -> hypertension
Block alpha1 receptors -> hypotension
• doxazosin (Cardura®)
• prazosin (Minipress®)
• terazosin (Hytrin®)
Central Acting Adrenergics
• Stimulate alpha2 receptors
– inhibit alpha1 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+ & H2O
reabsorbtion
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®)
Diuretics
• Thiazides:
• chlorothiazide (Diuril®) & hydrochlorothiazide (HCTZ®,
HydroDIURIL®)
• 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
Antiarrítmicos: conducción cardíaca
Antiarrítmicos: bloqueo de canales de sodio
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 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 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 2nd 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 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
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
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)
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
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
Dysrhythmia Generation
• Abnormal
conduction
• Analogies:
– One way valve
– Buggies stuck in
muddy roads
Warning!
• All antidysrhythmics have arrythmogenic
properties
• In other words, they all can CAUSE
dysrhythmias too!
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®)