CHAPTER 43 CALCIUM CHANNEL BLOCKERS

Calcium channel blockers (CCBs) are drugs that prevent calcium ions from entering
cells.
- greatest effects on the heart and blood vessels
- used widely to treat hypertension, angina pectoris, and cardiac dysrhythmias
- alternative names: calcium antagonists and slow channel blockers

I. CALCIUM CHANNELS: PHYSIOLOGIC FUNCTIONS AND CONSEQUENCES OF BLOCKADE

- calcium channels are gated pores in the cytoplasmic membrane that
regulates entry of calcium ions
into cells
- calcium entry plays a critical role in the function of vascular smooth
muscle (VSM) and the heart

A. VASCULAR SMOOTH MUSCLE (VSM)

- calcium channels regulate contraction
- action potential travels down the surface of a smooth muscle cell
- calcium channels open and calcium ions flow inward
- contractile process is initiated
- blocked calcium channels prevent contraction and vasodilation occurs
- at therapeutic doses, CCBs are selectively on peripheral arterioles and
arteries and arterioles of the
heart
- CCBs have no significant effect on veins

B. HEART
- calcium channels are coupled to beta1-adrenergic receptors
- calcium channels help regulate function of:

1. Myocardium – increases force of contraction

- if channels in atrial and ventricular muscle are blocked, contractile
force will diminish

2. SA Node – pacemaker activity of SA node is regulated

- open channels allows increased spontaneous discharge of SA node
- closed channels decrease pacemaker activity
- effect of calcium channel blockade is to reduce heart rate

3. AV Node – impulses that originate in the SA node must pass through the
AV node on their way to the
ventricles - - regulation of AV conduction plays a critical role in
coordinating contraction
of the ventricles with contraction of the atria
- open channels allows increased calcium entry and more readily
discharge from the cells of the
AV node
- effect of calcium channel blockade is to decrease velocity of
conduction through the AV node
 4. Coupling of Cardiac Calcium Channels to Beta1-Adrenergic
Receptors
- in the heart, when cardiac beta1-receptors are activated, calcium
influx is enhanced
- when beta1-receptors are blocked, calcium influx is
suppressed
- both reduce force of contraction, slow heart rate, and suppress
conduction through the AV
node

II. CALCIUM CHANNEL BLOCKERS: CLASSIFICATION AND SITES OF ACTION

- differences in selectivity are based on structural differences among the
drugs themselves and
structural differences among calcium channels

A. CLASSIFICATION
1. Dihydropyridines
- largest family of calcium channel blockers and encountered
frequently
- nifedipine is the prototype
- act primarily on arterioles
- don’t affect the heart at therapeutic doses, but toxic doses can
produce dangerous cardiac
suppression

2. Phenylalkylamine (Verapamil)
- act on arterioles and the heart
- toxic doses can produce dangerous cardiac suppression

3. Benzothiazepine (Diltiazem)
- act on arterioles and the heart
- toxic doses can produce dangerous cardiac suppression

III. VERAPAMIL AND DILTIAZEM: AGENTS THAT ACT ON VASCULAR SMOOTH MUSCLE &
THE HEART

A. VERAPAMIL
- trade names: Calan, Covera-HS, Isoptin, Verelan
- blocks calcium channels in blood vessels and in the heart
- major indications are angina pectoris, essential hypertension, and cardiac
dysrhythmias

1. Hemodynamic Effects – response is the net result of:

a. Direct Effects:
 • blockade at peripheral arterioles causes dilation,
reducing arterial pressure
• blockade at arteries and arterioles of the heart increases
coronary perfusion
• blockade at the SA node reduces heart rate
• blockade at the AV node decreases AV nodal conduction
• blockade in myocardium decreases force of contraction
- reduced AV conduction is most important

b. Indirect (Reflex) Effects:

- lowering of blood pressure activates the baroreceptor
reflex causing
increased firing of sympathetic nerves to the heart
- norepinephrine released from these nerves acts to
increase heart rate, AV
conduction, and force of contraction

Direct and indirect effects tend to negate each other.

c. Net Effect:
- since direct effects are counterbalanced by indirect
effects, the drug has little
or no net effect on cardiac performance

- for most patients, heart rate, AV conduction, and

contractility are not
noticeably altered
- overall cardiovascular effect is simply vasodilation
accompanied by reduced
arterial pressure and increased coronary perfusion

2. Pharmacokinetics – administered orally and intravenously

- well absorbed following oral administration but undergoes
extensive metabolism on its first
pass through the liver (only about 20% reaches systemic
circulation)
- effects begin in 30 minutes and peak within 5 hours
- elimination is primarily by hepatic metabolism
- doses must be reduced substantially in patients with liver
dysfunction

3. Therapeutic Uses
a. Angina Pectoris – verapamil is approved for vasospastic angina
and effort-induced
angina
- benefits in both derive from vasodilation
 b. Essential Hypertension – verapamil is a first line agent for
chronic hypertension
- drug lowers blood pressure by promoting dilation of
arterioles

c. Cardiac Dysrhythmias – verapamil is used to slow ventricular

rate in patients with atrial flutter, atrial fibrillation, and
paroxysmal supraventricular tachycardia
- benefits derive from suppressing impulse conduction
through the AV node
which prevents the atria from driving the ventricles
at an excessive rate

4. Adverse Effects
a. Common Effects – generally well tolerated
- constipation occurs frequently and is the most common
complaint
- can be especially severe in the elderly
- can be minimized by increasing dietary fluids and
fiber
- results from blockade of calcium channels in
smooth muscle of the
intestine
- other common effects – dizziness, facial flushing,
headache, and edema of
the ankles and feet – occur secondary to
vasodilation
- gingival hyperplasia (overgrowth of gum tissue) may
also develop

b. Cardiac Effects – blockade of calcium channels in the heart can

compromise cardiac
function
- in the SA node = bradycardia
- in the AV node = partial or complete AV block
- in the myocardium = decreased contractility
- when the heart is healthy, effects are minimal
- when the heart has certain diseases, effects seriously
exacerbate dysfunction
- special caution must be used in patients with
cardiac failure
- must not be used at all in patients with sick sinus
syndrome or 2 - ornd

3rd-degree AV block

5. Drug Interactions
a. Digoxin – depresses impulse conduction through the AV node
- used concurrently with verapamil, the risk of AV block
is increased
 - patients using the combination should be monitored
closely
- verapamil increases plasma levels of digoxin by about
60%, increasing the
risk of digoxin toxicity
- if toxicity appears, digoxin dosage should be
reduced

b. Beta-Adrenergic Blocking Agents – decreases heart rate, AV

conduction, and
contractility
- used concurrently with verapamil, there is a risk of
excessive
cardiosuppresion
- to minimize this risk, administration of beta
blockers and IV verapamil
should be separated by several hours

6. Toxicity
a. Clinical Manifestations – overdose can produce severe
hypotension and cardiotoxicity
(bradycardia, AV block, ventricular tachydysrhythmias)

b. Treatment – verapamil can be removed from the GI tract with

an emetic or with gastric
lavage followed by a cathartic
- IV calcium gluconate can counteract both vasodilation
and negative inotropic
effects but will not reverse AV block

c. Hypotension – can be treated with IV norepinephrine, which

promotes vasoconstriction
by activating alpha1 receptors on blood vessels and
increases cardiac output
by activating beta1 receptors in the heart
- placing the patient in Trendelenburg’s position (inclined
with the head down)
and administered IV fluids may also help

d. Bradycardia and AV Block – can be treated with isoproterenol

(beta-adrenergic agonist) and with atropine
(anticholinergic drug that can block parasympathetic
influences on the heart)
- electronic pacing may be required

e. Ventricular Tachydysrhythmias – preferred treatment is direct

current (DC)
cardioversion
- antidysrhythmia drugs can be tried
 7. Preparations, Dosage, and Administration
Oral – available in regular tablets, sustained release tablets,
sustained release capsules, and
time released formulation that, when administered at
bedtime, produces
maximum levels in the morning
- sustained, timed, and extended release formulations are
approved only for
hypertension
- patients should be instructed to swallow formulations intact,
without crushing or
chewing
- dosages should be reduced for elderly patients and for
patients with advanced renal
or liver disease

Intravenous – used for dysrhythmias

- blood pressure and electrocardiogram (EKG) should be
monitored and equipment for
resuscitation should be immediately available
B. DILTIAZEM
- trade names: Cardizem, Cartia XT, Dilacor, Diltia XT, Tiazac
- blocks calcium channels in the heart and blood vessels
- lowers blood pressure through arteriolar dilation, and because its direct
suppressant actions are
balanced by reflex cardiac stimulation, has little net effect on the
heart
- used for angina pectoris, essential hypertension, and cardiac
dysrhythmias (atrial flutter, atrial
fibrillation, paroxysmal supraventricular tachycardia)

1. Pharmacokinetics
- oral formulation is well absorbed and extensively metabolized on
its first pass through the liver
- effects begin rapidly (within a few minutes) and peak within half an
hour
- undergoes nearly complete metabolism prior to elimination in the
urine and feces

2. Adverse Effects – causes less constipation than verapamil

- most common effects are dizziness, flushing, headache, and edema
of the ankles and feet
- can exacerbate cardiac dysfunction in patients with bradycardia,
sick sinus syndrome, heart
failure, or 2nd- or 3rd-degree AV block

3. Drug Interactions – can exacerbate digoxin-induced suppression of AV

conduction
 - can intensify cardiosuppressant effects of beta blockers
- patients receiving concurrent doses should be monitored closely for
cardiac status

4. Preparations, Dosage, and Administration

Oral – tablets, sustained release capsules
IV – available

III. DIHYDROPYRIDINES: AGENTS THAT ACT MAINLY ON VASCULAR SMOOTH MUSCLE

- these drugs produce significant blockade of calcium channels in blood
vessels and minimal blockade in the heart

A. NIFEDIPINE
- trade names: Adalat, Nifedical, Procardial
- blocks calcium channels in VSM and thereby promotes vasodilation
- unlike verapamil, nifedipine produces very little blockade of channels in
the heart
- cannot be used to treat dysrhythmias
- does not cause adverse cardiac suppression
- is less likely to exacerbate pre-existing cardiac disorders
- more likely to cause reflex tachycardia

1. Hemodynamic Effects
a. Direct Effects – limited to blockade of calcium channels in VSM
- in peripheral arterioles causes vasodilation, lowering
arterial pressure
- in arteries and arterioles increases coronary perfusion
- does not block cardiac calcium channels at therapeutic
doses, therefore does
not significantly reduce automaticity, AV
conduction, or contractile
force

b. Indirect (Reflex) Effects – by lowering blood pressure, activates

baroreceptor reflex,
causing sympathetic stimulation of the heart
- cardiac stimulation is unopposed, increasing heart rate
and contractile force
- reflex effects occur primarily with fast acting
formulation
- baroreceptor is turned on only by a rapid fall in
blood pressure
- blood levels of nifedipine rise quickly, blood
pressure drops quickly
and reflex is activated
 - with sustained release formulation blood levels of
nifedipine rise slowly, blood
pressure falls slowly and reflex is blunted

c. Net Effect – overall hemodynamic response is simply the sum

of direct effect
(vasodilation) and indirect effect (reflex cardiac
stimulation)
- nifedipine lowers blood pressure, increases heart
rate and increases
contractile force

2. Pharmacokinetics – well absorbed following oral administration but

undergoes extensive first pass
metabolism (only about 50% reaches systemic circulation)
- with fast acting formulation, effects begin rapidly and peak in 30
minutes
- with sustained release formulation, effects begin in 20 minutes and
peak in 6 hours
- fully metabolized prior to excretion in urine

3. Therapeutic Uses
a. Angina Pectoris – indicated for vasospastic angina and for
angina of effort
- usually combined with a beta blocker to prevent reflex
stimulation of the heart
which could intensify anginal pain

b. Hypertension – used to treat essential hypertension and for

hypertensive emergencies
- only sustained release formulation is approved for
essential hypertension
- rapid acting formulation is used for hypertensive
emergencies

4. Adverse Effects
- can cause flushing, dizziness, headache, peripheral edema and
gingival hyperplasia
- does not cause much constipation
- not likely to exacerbate AV block, heart failure, bradycardia, or sick
sinus syndrome
- does cause reflex tachycardia - - increases cardiac oxygen demand
and can increase pain in
patients with angina
- to prevent this effect, nifedipine can be combined with a beta
blocker
- rapid acting formulation has been associated with increased
mortality in patients with
myocardial infarction and unstable angina
 - high dosage should be administered with caution, if at all

5. Drug Interactions
a. Beta Adrenergic Blockers – used concurrently to prevent reflex
tachycardia
- beta blockers can decrease the adverse cardiac effects
of nifedipine
- beta blockers can intensify the adverse cardiac effects
of verapamil and
diltiazem

6. Toxicity – in excessive dosage, loses selectivity

- toxic doses affect the heart in addition to blood vessels
- overdose is the same as verapamil
7. Preparations, Dosage, and Administration
- available in capsules and sustained release tablets
- patients should be instructed to swallow sustained release
tablets whole, without
crushing or chewing

8. Other Dihydropyridines
Nicardipine – trade name: Cardene, Cardene SR, Cardene IV
Amlodipine – trade name: Norvasc
Isradipine – trade name: DynaCirc, DynaCirc CR
Felodipine – trade name: Plendil
Nimodipine – trade name: Nimotop
Nisoldipine – trade name: Sular