Inotropic Drugs and Vasopressors

Digitalis Glycosides:
digitalis, digoxin, digitoxin

Sympathomimetic Amines

Phosphodiesterase Inhibito
amrinone and milrinone

Vasopressin

and Vasopressors
Mechanism of action
Improve Contractility of Heart
Prolong Refractory period of AV node

Mechanism of action
Beta-1 agonists
--> increase cAMP--> increase Ca++ -->
--> increase force of contraction

Dopamine
Dobutamine
Norepinephri
Epinephrine
Isoproternol

Mechanism of action
Inhibit phosphodiesterase in cardiac myocytes -->
enhanced Ca++ entry in cell -->
inceased force of contraction

potent vasoconstrictor when administered IV at higher-than-natural doses

Mechanical effect Electrical effect

Inhibition of NA+/K+ pump
intracellular Na+ up
less Ca+ out of cell
--> increased contractility

Enhances vagal tone

Reduces sympathetic activity
Decreases freq of impulse through AV node
Prolonged AV refractory period

alpha

Beta-1

Beta-2

(vasoconstriction)
xxxx
x
xxxx
xxxx

(increased contractilicty)
xxxx
xxxx
xxxx
XXXX
XXXX

(vasodilation)
xx
x

tural doses

XX
XXXX

Clinical Uses
CHF due to low V contractility
does not prolong life expectancy
Anti-Arrhythmic for A-Fib, A-Flutter and PVS
S.V.Tachyarrhythmia in presence of CHF

Clincal Uses
Hypotensive states (shock)
CHF without hypotension
"Warm shock"
Cadiac arrest
Slow heart rates with high
systemic vascular resistance

Clincal Uses
Acute heart failure if conventional
vasodilators, dig, diurectics don't wor

Clincal Uses
maintaing BP in patients with vasodilatory (septic) shock

Adverse Effects
Toxic concentrations --> ectopic/reentrant rhythms
Hypokelemia w/ diuretics can further inhibit Na+/K+ pump
AV Slowing --> AV block

Adverse Effects

Notes

tachycardia and tachyarrhythmias

tachyA's
MI (increased afterload) and tachyA's
tachyA's
Myocardial ischemia

* Dopamine also interacts with dopamin

Dobutamine increaases cardiac contracti
potent vasoconstrictor at peripheral alph
At low doses, B-2 vasodilation may redu
Pure beta (1 and 2) agonist

Adverse Effects
High incidence of adverse effects
including servious ventricular arrhythmias

dilatory (septic) shock

racts with dopaminergic receptors in renal vascular beds to increase renal perfusion and
es cardiac contractility (Beta-1) but does not increase peripheral resistance because of t
r at peripheral alpha receptors
odilation may reduced total peripheral resistance and BP. At higher doses is a vasopres

enal perfusion and diuresis

tance because of the balance between alpha vasoconstriction and beta-2 vasodilation

oses is a vasopressor because alpha constriction dominates over B-2 vasodilation. Also

a-2 vasodilation

vasodilation. Also AVOID with B-blockers --> unopposed alpha constriction can cause s

riction can cause severe hypertension

Vasodilator Drugs

General: The fall of cardiac ouput in heart failure triggers vasoconstriction. Initailly is bene

ACE inhibitors:
Benazepril
catopril
enalapril
fosinopril
lisinopril
moexipril
perindopril
quinapril
ramipril
trandolapril

Angiotensin II Type I
Receptor Antagonists:
(ARB's)
candesartan
eprosartan
irbesartan
losartan
olmesartan
telmisartan
valsartan

Direct Acting Vasodilators

hydralazine

minoxidil

sodium nitroprusside

fenoldopam

diazoxide

Calcium Channel Blockers

Verapamil and diltiazem

nifedipine (and the dihydropyridin

Organic Nitrates
nitroglycerin
(sublingual tablets or sprays -> acute)
(isosorbide di/mono nitrate -> long-acting)
(IV -> hospitalized patients)

Also in the vasodilator category:

natriuretic peptides --> clinical role is still being defined because one study as

put in heart failure triggers vasoconstriction. Initailly is benefical: maximizes preload and maintains

Mechanism of action
Prevents the conversion of
Angiotensin I to Angiotensin II.

Mechanism of action
ARB's compete with AII for AT1
receptors

Mechanism of action
unknown

increase in K+ channel permeability

selective agonist of D1 receptors

activation of K+ channels

Mechanism of action
ability to impede the influx of Ca++
through channels in cardiac and
smooth muscle cells
these two drugs aslo delay the
recovery of the Ca++ channel
to its preactivated state
ability to impede the influx of Ca++
through channels in cardiac and

smooth muscle cells

Mechanism of action
NO -> activates cGMP which accumulates

clinical role is still being defined because one study associated it with increased mortalit

itailly is benefical: maximizes preload and maintains systemic BP.

May ultimately cause excessive ve

Effect
Angiotensin II normally causes
vasoconstriction and release of aldosterone
Blocking formation of Angiotensin II -->
decreases systemic arterial pressure
facilitates natriuresis (by reducing Na+ reabsorptio
reduces adverse ventricular remodeling
Also, ACE inhibitors impede degradation of the
natural vasodilator Bradykinin, allowing for BK to
accumulate and contriubute to antihypertensive effect

Effect
Inhibit AII-mediated effects (similar to ACE inhibitor)
*Do not affect bradykinin levels

Effect
arteriolar vasodilation (no effect on veins)

arteriolar vasodilation (w/o significant venodilation)

dilator of both arteries and veins

arteriolar vasodilator
maintains/enhances renal perfusion
potent arteriolar dilator

Effect
--> vasodilation of vascular smooth muscle
negative inotropic cardiac effect
-> suppress AV node conduction

--> vasodilation of vascular smooth muscle

negative inotropic cardiac effect

Effect
smooth muscle relaxation and vasodilation (esp. of ve
reduction in ventricular filling (reduces preload)

one study associated it with increased mortality

BP.

May ultimately cause excessive venous return and pulm. congestion. Vasodilator therapy is dire

Clinical Uses
Hypertension (most cases including diabetic)
Heart failure:
reduce peripheral vascular resistance
reduce cardiac filling pressures
increase cardiac output

nsive effect

Clinical Uses
Hypertension (as effective as ACE inhibitors)
Heart failure for patients intolerant of ACE inhibitor

Clinical Uses
anti-hypertensive; long-term oral

severe or intractable hypertension; long-term oral

hypertensive emergencies, IV (potency and rapidity)

preload and afterload modulation in severe CHF

Episodes of severe HTN; continuous IV infusion

infrequently used (used to be use for HTN emergenci

Clinical Uses
All:
angina
hypertension (particularly in elderly patients)

Verapamil and Diltiazem:

Supraventriculr arrhythmias
(increased refractory period of AV node)

Clinical Uses
angina
coronary artery spasm

congestion. Vasodilator therapy is directed at modulating the excessive constriction.

Adverse Effects
Generally well tolerated
up to 15% develop cough
Rare:
hypotension
hyperkalemia

Adverse Effects
no cough
Rare:
hypotension
hyperkalemia

Adverse Effects
reflex tachycardia,
headache, palpitations, flushing, nausea, anorexia

reflex tachycardia
fluid retention
excess hair growth
thiocynate toxicity
blurred vision
tinnitus
disorientation/ nausea
headache, dizziness, tachycardia
increases intraocular prerssure
reflex tachycardia
hyperglycemia

Adverse Effects
V&D: hypotension (excession vasodilation)
bradycardia (AV block)
V: CHF, constipation
D: Peripheral Edema
Dihydropyridines:
hypotension
headache, flushing

peripheral edema

Adverse Effects
hypotension, reflex tachycardi
headache & flushing

directed at modulating the excessive constriction.

Notes
* not used in pregnancy because of fetal injury in 2nd/3rd trimesters
* primarily excreted through urine --> dosages reduced w/ renal dysfunction

* primarily exreted in bile

Notes:

* administer with B-blocker to avoid reflex tachycardia from baroreceptor reflex

s, flushing, nausea, anorexia

* co-administer with B-blocker

* B-blocker often administered concurrently to counteract reflex sympathetic in

* does not cause thiocynate toxicity that nitroprusside does

* avoid in patients with glaucoma

Notes:

xcession vasodilation)
** becase of the side effect of bradycardia, verapamil and diltaizem should be u

** the safety of short acting CCB's has been called into question --> only the

Notes:

efficacy of long-acting nitrates is attenuated by rapid development of drug toler

ents on B-blocker.

d be used in most cases.

se. Need a drug free interval of several hours each day.

Anti-Arrhythmic Drugs

* Among the most dangerour pharmacologic agents because of their frequent serious adve

Quick overview:
Class
Class
Class
Class

I:
Na+ channel blockade responsible for phase 0 depolarization of the
II: Beta-blockers
III: Prolongation of action potential duration
IV: Ca++ channel antagonists

* adenosine and digitalis don't fit into these classes

Class IA:

Mechanism of action

Quinidine
Procainamide
Disopyramide

moderate blockade of fast sodium channels

raises threshold potential
slows upstroke of the action potential

reduces cellular and tissue conduction velocities

Class IB:

Mechanism of action

Lidocaine
Mexiletine

inhibits fast sodium channel

shortens the actiion potential duration and
refractory period
preferentially act on diseased or ischemic cells

Class IC:

Mechanism of action

Flecainide
Propafenone

most potent sodium channel blockers

(atrial, ventricular and Purkinje fibers)

Class II:

Mechanism of action
Beta-blockers-- inhibition of cardiac sympathetic
activity
increase the effective refractory period of the AV no

Class III:
Amiodarone

Mechanism of action
significantly prolongs action potential of all
cardiac fibers
also can demonstrate class I, II and IV effects as wel

Soltalol

nonselective B-blocker with class III anii-a propertie

Also in class III

Use:
Ibutilide
acute converstion of a-fib or flutter of recent onset
Dofetilide
to convert a-fib and flutter to sinus rhythm after conversion
Bretylium tosylate used when all other attempts of resuscitation have failed for

Class IV:
Verapamil and
diltiazem

Mechanism of action
selective blockade of slow L-type Ca++ channels
potent in tissues in which action potential depends on

calcium -> SA and AV node

Adenosine

Mechanism of action
activates K+ channels which suppresses spontaneous
depolarization of SA node and slows conduction
through the AV node
decrease in inward pacemaker current

quent serious adverse affects

larization of the action potential (IA, IB, IC reflect mild, moderate and marked block, re

Effect
takes longer to reach threshold & fire action potential
most pronounced at Purkinje
little effect on SA (Ca++ channels there)

if impaired sufficiently impulse in in reentrant circuit will die out

Effect
conduction block in ischemic cells inhibiting reentrant arrhythmi

Effect
significantly prolong the refractory period within AV node and
accessory bypass tracts

Effect
may prevent triggered arrhythmias inducced by afterdepolozat
caused by excessive catecholamines
> interrupt renntrant rhythms that pass through AV node

Effect
decrease sinus node firing rate, suppress automaticity,
interrupt reentrant circuits, and prolong PR, QRS and QT interva
vasodilator and negative inotrope

prolongs duration of action potential

increases refractory period of atrial and ventricular tissue
inhibits conduction in accessory tracts

after conversion
n have failed for VT or Fibriliation

Effect

Heart rate slows

rapid atrial impulses through AV to ventricles decrease
pends on

duction

reentrant rhythms through AV node may terminate

Effect
slow the SA node firing rate and decrease AV node conduction

te and marked block, respectively)

Clinical Uses
A-fib and flutter
Paroxysmal SVT's
Ventricular tachycardia
use has declined because of
more effective strategies

Clinical Uses
Ventricular tachycardia
Digitalis induced arrhythmias
have little affect on atrial tissue

Clinical Uses
preventing A-fib and paroxysmal SVT in
patients with otherwise structurally normal hea

Clinical Uses
suppressing tachyA's induced by excessive
catecholamines
slow ventricular rate in A-fib and flutter
terminate reentrant SV arrhythmias in which AV
node is one limb of reentrant pathway
treating long QT ventricular arrhythmias (do not prolong it)

Clinical Uses
more effective than most other anti-a's for a
wide spectrum of VT's and SVT's

excreted exclusively by kidneys ->

dosage adjusted with renal disease

Clinical Uses
reentrant PSVT
slowing ventricular rate in a-fib and flutter

Clinical Uses
very short half life
most effective drug for rapid termination of
reentrant PSVT

Adverse Effects
quinidine:
GI (diarrhea)
prolongation of QT interval -> torsades de pointes
procainamide:
does not prolong the QT as much, but TdP can still be provoked
mild ganglionic blocking effects
fever and rash

Adverse Effects
lidocaine:
CNS effects: dizziness, confusion and seizures
dosage related
Mexiletine:
CNS (dizziness, tremor) and GI (nausea, vomiting)

Adverse Effects
flecainaide:
aggrevation of ventricular arrhythmias

CHF in patients with left ventricular dysfunction

CNS (confusion, dizziness, blurred vision)
propafenone:

Adverse Effects

(do not prolong it)

Adverse Effects
numerous.
pulmonary toxicity, bradycardia, aggravation of ventricular arrhythmia,
early afterdepolarizations and TdP (prolonged QT)
thyroid dysfunction, GI effects, neurologic effects,
drug interactions (warfarin, digoxin)
B-blocker effects
prolonged QT effects (TdP)

Adverse Effects
hypotension
avoided with B-blockers (combined negative inotropic effects)

Adverse Effects
very transient side affects (10 second half life)

Notes
disopyramide:
less GI effects
much greater anti-cholinergic effects (constipation, urinary retention)
pronounced negative inotropic effects
QT prolongatoin (TdP) can occur

Notes
** QT interval is not prolonged and early afterdepolariztions (and TdP) do not

Notes

** drugs in this subclass should be avoided in patients who have underlying he

** use for Ventricular arrhythmias has dimished because studies have shown in

Notes

Notes

arrhythmia,

Notes

Notes

y retention)

s (and TdP) do not occur

have underlying heart abnormalities

udies have shown increased mortality following MI

Anti-Adrenergic Drugs

Normally when a sympathetic nerve is stimulated, norepinephrine is released and stimulate

Central Adrenergic Inhibitors:

Alpha-2 agonists
(clonidine, alphamethyldopa,
guanabenz, guanfacine)

Peripheral Alpha- Adrenergic

Receptor Agonists:
a. Selective peripheral alpha-1 blockad
Prazosin
Terazosin
Doxazosin
b.

Nonslective alpha blockade

Phentolamine
Phenoxybenzamine

Beta- Adrenergic Receptor Antagonis

a. Selective beta-1 blockers
Atenolol
Betaxolol
Bisoprolol
Esmolol

Metoprolol
With B-agonist activity
Acebutolol

b. Nonselective beta blockers

Carvedilol
Labetalol
Propanolol
Nadolol
Timolol
With B-agonist activity
Carteolol
Penbutolol
Pindolol

mulated, norepinephrine is released and stimulates alpha and beta receptors.

Mechanism of action
Alpha-2 receptors are located in pre-synaptic neurons in the
When stimulated they inhibit NE release (sympathetic outflow)
to the periphery

Mechanism of action
Blocks alpha-1 only

Blocks alpha-1 and alpha-2

Mechanism of action
Blocks cardiac B-1 receptor
(myocardial recpetor blockade with less effect on bronchial a
vascular smooth muscles)

B-2 block can lead to bronchospasm and vasoconstriction

in susceptible patients

Effect

fall in BP and HR
outflow)

Effect
vasodilation

Effect
decrease myocarcial oxygen dema
slow the heart rate
reduce BP and contractility
B-1 selective: less bronchospasm

** use these for people w/ asthm

Partial B-agonist:
tend to slow the HR less than
other B-blockers

ospasm

Clinical Uses
not commonly used

Clinical Uses
rarely prescribed for HTN
used for symptoms of benign
prostatic hyperplasia

pheochromocytoma

Clinical Uses
ischemic heart disease
** improve survival and reduce
rate of reinfacrtion following
MI

HTN
Heart Failure:
Despite negative inotropic effect
** patients with all classes of
clinically stable heart failure
have survival benefit with
carvedilol, metoprolol or bisoprolol
-> low dose, augmented slowly
tachyarrhythmias
hypertrophic cardiopyopathy

Adverse Effects

Notes

sedation, bradycardia,
* have largely given way to better toler
paradoxical rise in BP if stopped suddenly

Adverse Effects

Notes

postural hypotension
headache, diziness

* have fallen out of favor in the manag

postural hypertension
reflex tachycardia (blocks A-2's normal inhibition of norepi release)
arrhythmias

Adverse Effects

Notes

fatigue

** used with caution in combo with Ca

B-2 block:
bronchospasm
vasospasm (Raynaud's)

B-1 block -> AV conduction blocks

Aprupt withdrawl -> could precipitate ischemia in CAD

elevation of triglycerides
reduction of HDL
isoprolol
insomnia, depression, impotence

way to better tolerated agents

avor in the management of HTN. Also, do not reduce mortality in chronic CHF as ACE in

in combo with Ca++ channel blockers --> both types can impair contractility and AV

onic CHF as ACE inhibitors or hydralizine + nitrates do

ontractility and AV conduction