Cardiac Pharmacology

Senior Medical Student Lecture Series

Dr. John R. Vyselaar, R3
Objectives
After this discussion you should be able to know and understand:
.. The different major classes of cardiac drugs
.. Their mechanisms of action (and significant pharmacologic details)
.. Their clinical uses
.. Their significant side effects

Beta Blockers
Mechanism of Action
.. Antagonize the binding of catecholamines to ß-adrenergic receptors
o ß1 receptors: cardiac myocytes and conduction cells (e.g. Purkinje fibers,
pacemaker cells)
o ß2 receptors: bronchial smooth muscle cells, and peripheral vascular
smooth muscle

.. Beta blockers differ in their selectivity for the two types. Some examples in
clude:

Non-selective ß-blockers (i.e. block both

ß1 and ß2 receptors)
ß1-selective ß-blockers
Propranolol
Atenolol
Labetolol (also a1 antagonism)
Metoprolol
Carvedilol
Bisoprolol (more selective)

.. By interfering with catecholamine action beta blockers decrease cardiac

inotropy (force of contraction), chronotropy (heart rate), and conduction
velocity. These are effects of blocking ß1 receptors.
.. Many beta blockers also affect peripheral resistance:
o Beta blockers with ß2 antagonism increase peripheral resistance (e.g.
propranolol)
o Beta blockers that also provide a1 antagonism can decrease peripheral
resistance (e.g. labetolol)
.. The effects of beta blockade are also mild when someone is at rest, because
adrenergic tone is low. When the sympathetic nervous system is activated, e.g.
exercise, the effects of beta-blockade are much more obvious and significant.

Clinical Uses
.. Ischemic heart disease: decrease myocardial oxygen demand by reducing heart
rate, blood pressure (afterload) and contractility
o Proven to improve survival and reduce reinfarction rate after MI (both by
reducing oxygen demand, and perhaps by antiarrhythmic effects)
indicated in acute ischemia

.. Hypertension: mechanism is not well understood (most beta blockers actually

increase total peripheral resistance)
o Initially reduces cardiac output (slow heart rate and decrease
contractility
o Chronically possibly reduce renin secretion, may have CNS effects

.. Tachyarrhythmias discussed later

.. Congestive heart failure proven to improve morbidity and mortality in
chronic compensated CHF (a state of high adrenergic tone); helpful in both
systolic and diastolic dysfunction

Side Effects
.. Fatigue most patients experience this to some degree when starting a beta-
blocker
o usually lessens as the patient gets used to the drug
o believed to be a CNS effect

.. Exacerbate bronchospasm in patients with asthma or COPD

o An effect of blocking ß2 receptors; can occur with non-selective beta
blockers, or with high doses of ß1-selective ß-blockers

.. Conduction blocks (antagonize ß1 receptors at AV node)

.. Worsen heart failure if used acutely (negative chronotropic effects)
.. Can precipitate vasospasm
o Raynaud s phenomenon
o Claudication and gangrene in peripheral vascular disease

.. Rebound angina if the drug is abruptly discontinued beta-receptors are

upregulated during adrenergic blockade, then when the drug is stopped there is a
n
excessive adrenergic response
o Therefore taper the drug when discontinuing!

.. Negative effects on cholesterol profile: reduce HDL, increase triglycerides

.. Impair recovery from hypoglycemia in diabetics, or mask the symptoms of
hypoglycemia (tachycardia)

Calcium Channel Blockers

Mechanism of Action
.. Block the entry of calcium through membrane channels in cardiac and smooth
muscle cells
o CCBs block the L-type channel (rather than the T-type) that maintains
phase 2 of a normal cardiac action potential (the plateau )
.. Blocking calcium channels decreases the amount of calcium available to
contractile proteins within cells, this process:
o Reduces cardiac contractility by preventing calcium entry into cardiac
myocytes, CCBs reduce the release of further calcium from the
sarcoplasmic reticulum, thereby reducing the amount of calcium available
to intracellular contractile proteins
o Reduces vascular smooth muscle tone impairs the formation of the
calcium-calmodulin complex that stimulates myosin light chain kinase,
which in turn allows myosin and actin to interact and cause contraction

.. Two broad classes:

o Dihydropyridines: e.g. amlodipine, felodepine, nifedipine profound
vasodilatation, little negative inotropy
o Non-dihydropyridines: e.g. verapamil, diltiazem both cause some
vasodilation, but significantly decrease contractility, and also suppress
AV node conduction (T-type calcium channels) therefore slowing heart
rate
.. Be cautious using beta-blockers and non-dihydropyridine CCBs
together this combination may precipitate conduction blocks

Clinical Uses
.. Ischemic heart disease decrease contractility (and in non-dihydropyridine
CCBs decrease heart rate) therefore reducing myocardial oxygen demand
o The dihydropyridines (esp. amlodipine) also have profound peripheral
vasodilatory effects, that reduce afterload thereby decreasing myocardial
workload
o Unlike beta-blockers, CCBs have generally NOT been shown to reduce
morbidity and mortality in CAD therefore they are usually considered
second-line agents (e.g. the patient unable to tolerate a beta-blocker
because of severe bronchospasm)
o In fact short acting CCBs may increase mortality during acute coronary
ischemia

.. CCBs also vasodilate the coronary arteries this makes them useful (and first-
line
treatment) for vasopastic (Prinzmetal s) angina
.. Hypertension especially dihydropyridines, often more effective in elderly tha
n
other agents
.. Tachyarrhythmias later

Side Effects
.. Hypotension due to excessive peripheral vasodilation
.. Peripheral edema vasodilation again
.. Dihydropyridines headache, flushing
.. Non-dihydropyridines bradycardia, AV block
.. Worsen CHF if used in acute decompensation

Cardiac Glycosides (Digoxin)

Mechanism of Action
.. Extract of foxglove plant
.. Two effects on the heart:
o Mechanical effect (positive inotropy) inhibits the sarcolemmal
Na+/K+ ATPase pump, increasing intracellular sodium, which through
an exchange protein leads to increased calcium in the sarcoplasmic
reticulum
.. This in turn results in greater amounts of calcium being released
to the myofilaments with each electrical excitation, thereby
enhancing the force of each contraction.

o Electrical effect (negative chronotropy) digoxin affects cardiac tissue

electrical properties directly, and also modifies autonomic nervous system
activity, increasing vagal tone and decreasing sympathetic activity.
.. Decreases AV nodal conduction velocity, and enhances the
refractory period, therefore reducing transmission of atrial
impulses to the ventricles.

Clinical Uses
.. Congestive heart failure useful in systolic heart failure, since it augments
contractility, thereby improving cardiac output, improving LV emptying, and
decreasing ventricular filling pressures
o Not useful in high-output failure or diastolic dysfunction
o Less popular now that other therapies available with better evidence for
morbidity and mortality benefits in CHF (often a third-line agent)
o Unlike ACE-inhibitors and beta blockers, digoxin has been shown to NOT
affect mortality in CHF, although it does improve symptoms

.. Tachydysrhythmias by reducing the number of impulses transmitted through

the AV node, digoxin provides effective rate control of atrial fibrillation and
atrial flutter
o By slowing AV nodal impulse conduction and increasing the refractory
period, digoxin can interrupt reentrant circuits and terminate PSVT
o Also less commonly used since the advent of beta-blockers and CCBs, but
still widely used for supraventricular arrhythmias, especially with
concomitant CHF

Side Effects
.. Narrow therapeutic index, renal excretion
o Toxicity more likely if hypokalemic (further inhibition of Na+/K+
ATPase), hypomagnesemic, hypercalcemic; toxicity may occur even if
serum digoxin level is normal

.. Can divide into cardiac and systemic side-effects

.. Cardiac: Enhances cellular automaticity, and formation and propagation of re-
entrant arrhythmias (SVT, acclerated junctional rhythm, VPBs, V tach)
o Also enhances vagal tone variable degrees of AV block
o In short any arrhythmia!
.. Systemic: Nausea, vomiting, anorexia (affects the medulla); fatigue, weakness
,
other non-specific symptoms, yellow-green halo
.. Digoxin toxicity treatment correct electrolyte imbalances, treat arrhythmias
as
per ACLS, Digibind (anti-digoxin antibody fragment)
o The higher the K+, the more severe the digoxin toxicity

ACE Inhibitors
Mechanism of Action
.. Block the angiotensin converting enzyme, found throughout vascular tissue,
that converts angiotensin I to angiotensin II
o Recall renin converts angiotensinogen to angiotensin I, then ACE converts
angiotensin I to angiotensin II
o Angiotensin II then binds the AT1 receptor and causes vasoconstriction
and aldosterone release (which in turn causes sodium resorption by the
kidney and increased ECFV)
o ACE also intactivates bradykinin, a potent vasodilator

.. Therefore, ACE inhibitors produce vasodilation (by blocking angiotensin II

formation and prolonging bradykinin half-life) and decrease ECFV
.. Both of these reduce blood pressure

Clinical Uses
.. Hypertension: effective in most patients
o Improve renal blood flow by dilating both afferent and efferent
arterioles proven to slow the progression to nephropathy in diabetic
hypertensive patients

.. Congestive heart failure: decrease afterload, thereby increasing cardiac

output; also reduce harmful adrenergic stimulation
o Blood pressure often does not fall in normotensives (BP = CO x TPR)
o Proven to improve survival in patients with symptomatic heart failure

.. Ischemic heart disease: Proven to reduce the incidence of heart failure and
recurrent ischemic events immediately after an MI
o Also reduce ventricular remodeling (scar) post-infarct by
antihypertensive and other mechanisms
o Of all drugs, ACE-inhibitors provide the greatest long-term benefit in
patients with ventricular dysfunction after an infarct

Side Effects
.. Hypotension rare unless volume depleted from aggressive diuresis (BP then
more dependant on vasoconstrictive effects of angiotensin)
.. Hyperkalemia by reducing aldosterone concentrations
o More likely in renal insufficiency, diabetes, and with potassium-sparing
diuretics

.. Renal insufficiency ACE inhibitors may decrease renal perfusion when given
to patients with volume depletion
.. Bilateral renal artery stenosis renal function may abruptly worsen due to
vasodilation of the efferent arteriole, which decreases glomerular perfusion
pressure
.. Dry cough 15% of patients believed to be due to increased bradykinin levels
.. Angioedema, agranulocytosis - rare
Angiotensin Receptor Blockers
Mechanism of Action
.. Block angiotensin receptors
o AT1 adult vasculature
o AT2 fetal tissue (therefore both ACE-inhibitors and ARBs are
contraindicated in pregnancy)

.. Therefore produce vasodilation, naturesis and hypotension

.. Produce more complete angiotensin blockade than ACE-inhibitors (some other
enzymes also convert angiotensin I to II)
.. Do not block bradykinin degradation

Clinical Uses
.. Limited evidence for long term mortality benefit few studies available
.. Hypertension similar efficacy to ACE-inhibitors
.. Congestive heart failure appear to be as effective as ACE-inhibitors (1 study
)
although do not confer any additional benefit when the two are combined
.. Ischemic heart disease little evidence

Side Effects
.. Hypotension as for ACE-inhibitors
.. Hyperkalemia as for ACE-inhibitors\
.. Generally well tolerated, no dry cough
.. ARBs are generally used as second-line therapy in patients unable to tolerate
an ACE-inhibitor (esp. if due to dry cough)

Nitrates
Mechanism of Action
.. Converted to nitric oxide at the plasma membrane of vascular smooth muscle
o NO then activates guanylate cyclase, which converts GTP to cGMP
o cGMP then produces vascular smooth muscle relaxation

.. At low doses, nitrates produce preferential venous dilation -> venous pooling
,
decreased venous return, and decreased preload
.. Also some mild arterial dilation occurs affecting the coronary arteries, and
the
facial and meningeal arteries
.. At higher doses, nitrates also produce arteriolar dilation -> systemic loweri
ng of
blood pressure
.. In some patients this hypotensive effect can produce a reflex tachycardia

Clinical Uses
.. Angina (acute and chronic) venodilation reduces preload, lowering
ventricular wall stress and myocardial oxygen demand; in addition they
directly dilate the coronary arteries
 .. Short and long acting formulations are available (spray, tablets, patch,
intravenously)
.. Vasospastic angina useful because of vasodilatory effect on the coronary
arteries
.. Also useful in acute CHF venodilation relieves pulmonary edema

Side Effects
.. Hypotension
.. Reflex tachycardia
.. Headache and flushing due to facial and meningeal arterial dilation

Class I Antiarrhythmics
Mechanism of Action
.. Block Na+ channels that are responsible for the phase 0 depolarization of the
action potential
.. Divided into three subclasses of drugs depending on the magnitude of sodium
channel block, and their effect on repolarization
.. Class IA: Moderate Na-channel blockade, prolong repolarization
o Suppress ectopic foci because they increase cellular action potential
(thereby slowing depolarization and allowing the unaffected SA node to
resume control)
o Suppress re-entrant arrhythmias because they reduce cellular conduction
velocity (by slowing depolarization) and prolong the refractory
(repolarization) period

.. Class IB: Minimal Na-channel blockade, shorten repolarization

o Preferentially affect diseased/ischemic ventricular cells, little effect on
healthy ventricular tissue or atrial cells
o More effective blockade in these tissues because different biochemical
milleu allows more effective Na-channel blockade
o Inhibit some re-entrant arrhythmias by reducing conduction velocity; also
suppress ectopic foci by raising action potential

.. Class IC: Strong Na-channel blockade, little effect on repolarization

o Markedly slow conduction velocity in atrial and ventricular tissue, and in
Purkinje fibers
o Do not affect repolarization in most tissues, however do prolong the
refractory period in AV nodal tissue and bypass tract tissue

Clinical Uses
.. Class IA: effective for a wide variety of re-entrant and ectopic arrhythmias
(both
supraventricular and ventricular): atrial fibrillation, atrial flutter (a rhythm
-
conversion approach), paroxysmal SVT, V tach
o Examples: quinidine, procainamide (most popular and safest)
.. Class IB: effective only against V tach or V fib, especially due to ischemia
or
digitalis toxicity
o Examples: Lidocaine, tocanide, diphenylhydantoin; all are metabolized
hepatically and therefore must be dose-reduced in hepatic disease

.. Class IC: usually used to treat ventricular arrhythmias, occasionally used

against supraventricular arrhythmias
o Significant proarrhythmic effects studies show increased mortality
for treatment of asymptomatic ventricular arrhythmias (i.e. VPCs or non-
sustained V tach); also some evidence that they increase mortality if used
in structurally diseased heart (e.g. after MI)
o Therefore their use is usually reserved for life-threatening ventricular
arrhythmias, and as a second-line agent for supraventricular tachycardias
(esp. atrial fib in a structurally normal heart)

Side Effects
.. Class IA: prolong QT interval can precipitate torsades de points
o Some anticholinergic effects can increase AV nodal conduction, and
therefore increase ventricular rate in patients with atrial fibrillation or
flutter (therefore use in combination with an AV nodal blocking agent,
e.g. a CCB or beta-blocker)
o Mild peripheral effects -> mild hypotension
o Systemic side effects: GI, rash, fever, anticholinergic side effects
o 1/3rd of patients will develop a lupus-like syndrome after six months of
treatment resolves with drug discontinuation
o May slow digoxin elimination (hepatic cytochrome interference)
especially quinidine

.. Class IB: CNS confusion, dizziness, seizures (dose-related), nausea, diarrhea

,
rare blood cell dyscrasia
o Do NOT lengthen the QT interval, therefore unlikely to cause
arrhythmia (i.e. torsades de points)

.. Class IC: proarrhythmic dangerous drugs to use!

o Mild negative inotropy can precipitate CHF
o CNS confusion, dizziness, blurred vision
o Taste disturbance

Class II Antiarrhythmics
.. Beta-blockers
.. Inhibit ectopic foci and inhibits AV nodal conduction (therefore may prolong
PR interval)
.. Very useful in suppressing arrhythmias caused by excessive catecholamine
stimulation (e.g. arrhythmias induced by exercise or emotion)
.. Atrial fibrillation and flutter inhibit AV node so slow ventricular response
(a rate-control strategy)
.. Terminate PSVT that rely upon AV nodal conduction (i.e. AVNRT)
.. Suppress ventricular arrhythmias as well; do NOT prolong QT interval
Class III Antiarrhythmics
Mechanism of Action
.. Prolong action potential and refractory period of Purkinje cells and
ventricular myocytes
o Examples: amiodarone, sotalol, bretylium, ibutilide (all different
mechanisms of action)

.. Amiodarone: powerful antiarrhythmic

o In addition to class III effects, also produces weaker sodium channel,
beta, and calcium channel blockade
o Therefore decreases SA node, automaticity, and re-entrant circuits;
prolonging PR, QRS and QT intervals
o Also has a mild vasodilator effect -> hypotension

.. Sotalol: a non-selective beta-blocker with additional class III effects

Clinical Uses
.. Amiodarone: Very effective for suppression of virtually ALL ventricular and
supraventricular tachyarrhythmias: atrial fibrillation, atrial flutter, ventricu
lar
tachycardia, ventricular fibrillation, and PSVT
o Particularly popular for patients with impaired LV function, who are at
higher risks of proarrhythmic side effects on other antiarrhythmic drugs
o Low doses are also used for long-term suppression of atrial fibrillation
and atrial flutter (rhythm-control approach)

.. Sotalol: Effective against both supraventricular and ventricular arrhythmias

o Effective at preventing atrial fibrillation after cardioversion

Side Effects
..
Amiodarone: pneumonitis -> pulmonary fibrosis (reversible if drug stopped
early)
o Bradycardia (nodal blockade) and ventricular arrhythmia (prolongs QT
interval -> torsades de pointes)
o Rarely precipitates CHF
o GI anorexia, nausea, elevation of LFTs (reversible)
o Hypo- and hyperthyroidism (inhibits peripheral conversion of T4 -> T3)
o
Neurologic proximal muscle weakness, peripheral neuropathy,
ataxia, tremors, headache, sleep disturbances
o Ocular corneal microdeposits (rarely affect vision)

.. Sotalol: Most serious risk is QT prolongation -> torsades de pointes

o Also has the usual side-effects of beta-blockers
o Often potential hypotension limits use
Class IV Antiarrhythmics
.. Non-dihydropyridine calcium-channel blockers (i.e. verapamil and diltiazem)
.. Greatest effect is on tissues where the action potential is heavily dependent
on calcium i.e. SA and AV nodal tissue
o In these tissues verapamil and diltiazem slow depolarization, decrease
conduction velocity, and increase the refractory period

.. Thus their clinical uses include:

o Slowing ventricular response (rate control) in atrial fibrillation and
flutter (AV nodal blockade)
o Termination of AV nodal re-entrant tachycardia

.. Side effects already discussed, the most important one acutely is hypotension
with intravenous infusion

Adenosine
Mechanism of Action
.. An endogenous nucleoside, very short half-life (10 seconds)
o Binds to surface receptors on cells in the conduction system, opening
potassium channels that hyperpolarize the cell membrane
o Also affects cAMP concentrations (inhibits adenylate cyclase) decreasing
conduction velocity

.. Therefore it transiently slows SA nodal firing rate, and decreases AV nodal

conduction

Clinical Uses
.. Termination of AV nodal re-entrant tachycardia (agent of choice)
.. Diagnosis of unidentified narrow complex tachycardia

Side Effects
.. Transient headache, chest pain, flushing, bronchoconstriction
o Antagonized by methylxanthines (caffeine, theophylline) so higher doses
can be required

Other Cardiac Drugs

.. Include diuretics, aspirin, plavix, heparin and more.
.. You should review these on your own time.