Pharmacology
Drugs that Affect the Cardiovascular System
Topics
Electrophysiology
Vaughn-Williams classification
Antihypertensives
Hemostatic agents
Cardiac Function
Dependent upon
Adequate amounts of ATP
Adequate amounts of Ca++
Coordinated electrical stimulus
Adequate Amounts of ATP
Needed to:
Maintain electrochemical gradients
Propagate action potentials
Power muscle contraction
Adequate Amounts of Calcium
Calcium is ‘glue’ that links electrical and mechanical events.
Coordinated Electrical Stimulation
Heart capable of automaticity
Two types of myocardial tissue
Contractile
Conductive
Impulses travel through ‘action potential superhighway’.
A.P. SuperHighway
Sinoatrial node
Atrioventricular node
Bundle of His
Bundle Branches
Fascicles
Purkinje Network
Electrophysiology
Two types of action potentials
Fast potentials
Found in contractile tissue
Slow potentials
Found in SA, AV node tissues
Fast Potential
-80
-60
-40
-20
0
+20
RMP
-80 to 90 mV
Phase 1
Phase 2
Phase 3
Phase 4
controlled by Na+
channels = “fast channels”
Fast Potential
Phase 0: Na+ influx “fast sodium channels”
Phase 1: K + efflux
Phase 2: (Plateau) K + efflux
AND Ca + + influx
Phase 3: K+ efflux
Phase 4: Resting Membrane Potential
Cardiac Conduction Cycle
Slow Potential
-80
-60
-40
-20
0
Phase 4
Phase 3
dependent upon Ca++ channels = “slow channels”
Slow Potential
Self-depolarizing
Responsible for automaticity
Phase 4 depolarization
‘slow sodium-calcium channels’
‘leaky’ to sodium
Phase 3 repolarization
K+ efflux
Cardiac Pacemaker Dominance
Intrinsic firing rates:
SA = 60 – 100
AV = 45 – 60
Purkinje = 15 - 45
Cardiac Pacemakers
SA is primary
Faster depolarization rate
Faster Ca++ ‘leak’
Others are ‘backups’
Graduated depolarization rate
Graduated Ca++ leak rate
Potential Terms
APD
ERP
RRP
relative
refractory
period
effective refractory period
action potential duration
Dysrhythmia Generation
Abnormal genesis
Imbalance of ANS stimuli
Pathologic phase 4 depolarization
Ectopic foci
Dysrhythmia Generation
Abnormal conduction
Analogies:
One way valve
Buggies stuck in muddy roads
Reentrant Circuits
Warning!
All antidysrhythmics have arrythmogenic properties
In other words, they all can CAUSE dysrhythmias too!
AHA Recommendation Classifications
Describes weight of supporting evidence NOT mechanism
Class I
Class IIa
Class IIb
Indeterminant
Class III
View AHA definitions
Vaughn-Williams Classification
Class 1
Ia
Ib
Ic
Class II
Class III
Class IV
Misc
Description of mechanism NOT evidence
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 ? 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
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
Pharmacology
Antihypertensives
Antihypertensive Classes
diuretics
beta blockers
angiotensin-converting enzyme (ACE) inhibitors
calcium channel blockers
vasodilators
Blood Pressure = CO X PVR
Cardiac Output = SV x HR
PVR = Afterload
BP = CO x PVR
Key:
CCB = calcium channel blockers
CA Adrenergics = central-acting adrenergics
ACEi’s = angiotensin-converting enzyme inhibitors
BP = CO x PVR
Peripheral Sympathetic
Receptors
alpha beta
1. alpha blockers 2. beta blockers
Local Acting
1. Peripheral-Acting Adrenergics
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
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
C