Public Safety Training Facility
Monroe Community College
Rochester, New York
MCC PARAMEDIC PROGRAM CME
Calcium Channel Antagonists
Influx of Calcium Ions (Ca++) through the cell membrane and sarcoplasmic
reticular membrane is a key trigger for a number of intracellular bioactivities.
Membranes form water and ion-impermeable barriers that allow localized
compartmentalization to occur. The most basic function of these membranes
is to isolate these compartments from outside environments and allow for
specialized reactions to take place. Some means must exist for entry
(influx) and exit (efflux) of solutes for the regulation of cell volume
and as a means of allowing chemical interactions. This influx is
accomplished using specialized pores or channels through the membrane.
These ion channels are specific for ions and are opened and closed by various
means, including: ligand binding, voltage-dependency and, in the
case of vascular smooth muscle, stretch-opening.
The concept of ligand binding is simple, a chemical (ligand) binds to
a receptor site forming a ligand-receptor bond. Neurotransmitters,
such as norepinephrine, are considered ligands. [Figure
1] This bond changes the electrical structure of the protein
gate and it opens. Voltage-dependency is more akin to a light switch.
When no electrical current is flowing through a light bulb, there is no
light. Similarly, when the membrane is at rest
or is in a hyperpolarized state, the ion channels remain closed.
When depolarization occurs, the rapid movement of sodium (Na+)
into the cell causes the inner surface of the cell membrane to became
positively charged. This change in electrical charge causes the voltage-dependent
proteins of the ion channel to again change shape, opening the channel
to ion flow. Ion flow always follows the concentration gradient (most
The intracellular concentration of unbound calcium ions determines the
activity of the contractile tissues in cardiac and vascular smooth muscle
cells. Voltage-gated calcium channels are present in all muscle and
nerve cells as well as many secretory cells. These calcium ion channels
have been differentiated into four sub-types. These include:
T (transient), N (neural), P (purkinje[brain]) and L (long- lasting
[slow]). T-type channels are found in smooth muscle, skeletal
muscle and cardiac myocytic membranes. They have a low conductance
(only allow small amounts of ion passage) and a short opening time (fast
channels). T-type channels are thought to have a role in initiation
of action potentials, but none in contractility. N-type channels
are found only in neurons and are thought to play a direct role in release
of neurotransmitter quantal packages into the synapse and are insensitive
to calcium antagonists. P-type channels are found only in cerebellar
purkinje neurons in the brain and, as such, are not discussed here. The
majority of calcium antagonists affect L-type calcium slow channels. L-type
channels are found extensively in both myocardial and vascular tissues,
as well as in the smooth muscle of the gut.
The voltage-dependent L-type, ligand (receptor)-operated, calcium channel
is composed of five sub-units of transmembrane proteins. The a1
appears to be the primary site for binding all three of the primary calcium
channel blockers: the 1,4-dihydropyridines, the phenylalkylamines,
and the benzothiazepines. While all three types
of calcium antagonists are thought to attach to the same receptor,
their affinity for the receptor changes according to the state of the receptor
(rest, activated, or inactivated). This is known as state or use-dependence
and is thought by some researchers to involve the reshaping of the receptor
site when it is in various states, producing, in essence, three different
receptor sites. Other sources simply indicate that there are three separate
receptor sites on the a1 subunit
of the L-type channel. For simplicity sake, we will concentrate on
the latter or these two theories.
As previously mentioned, the L-type channels are found in a variety
of tissues. Yet this range of target tissues is not necessarily reflected
in pharmacologic or therapeutic activity. For example, skeletal muscle
tissue is relatively unaffected by calcium channel blockage, as evidenced
by the fact that there is no associated loss of postural tone during treatment.
The activity of a calcium antagonist, or agonist for that matter, may well
be affected by the location of the receptor site and the frequency of channel
activity. The verapamil and diltiazem binding sites are located internally,
deep within the channel. Access to the receptor is therefore enhanced
when the channel is open. The rapidly firing tissues of the myocardium
and the atrioventricular (AV) node provide ample opportunity for the binding
of these agents, which are pharmacologically active in myocardial and cardiac-contractile
tissues. Nifedipine, a 1,4-dihydropyridine calcium antagonist, is
preferential to the binding sites in vascular smooth muscle, which exist
more frequently in a depolarized (closed, not reactive) state.
Of the three types of calcium antagonists mentioned, the dihydropyridine
are the most active at causing peripheral vasodilatation. However,
at therapeutic doses, any calcium antagonist will have a varying degree
of vasodilatation. Phenylalkylamines, such as Verapamil and benzothiazepines,
such as Diltiazem, are very effective at slowing supraventricular tachydysrhythmias,
especially reentrant varieties. This is due to the slowing of nodal repolarization
(prolonging refractoriness). Additionally, Verapamil and Diltiazem
slow the rapid ventricular rates associated with uncontrolled atrial fibrillation
or flutter. However, use of calcium channel blockers in patients
with wide complex atrial fibrillation/flutter associated with pre-excitation
syndromes such as WPW (Wolff-Parkinson-White) is contraindicated due to
an enhance retrograde conduction of signals which may cause accelerated
reentrant tachydysrhythmias. Diltiazem has no significant effects
on heart tissues that are fast sodium channel dependent, (e.g. His-Purkinje
tissue, atrial and ventricular muscle tissue).
Table 1 : Classification
of Calcium Antagonists Based on Chemical Grouping
Table 2: Cardiovascular
Uses of Calcium Channel Blockers
Arrhythmias (Supraventricular tachycardia)
Peripheral Vascular Disease
Primary pulmonary hypertension
The chief hemodynamic effect of calcium antagonists is vasodilatation
of the coronary and peripheral arteries. 1,4-dihydropyridines, such
as nifedipine have a potent vasodilatory effect on both coronary and peripheral
arteries. Diltiazem has approximately the same effect on coronary
artery vasodilatation, but is much less potent as a peripheral vasodilator
than either nifedipine or verapamil. Verapamil, a benzothiazepine,
has less vasodilatory effects than diltiazem and has an intermediate effect
on peripheral vasculature. All calcium channel blockers reduce
the vasopressor effects of norepinephrine and have been demonstrated to
cause a transient blockade of angiotensin II.
All calcium antagonist possess negative inotropic effects on myocardium.
Verapamil is the most potent negative inotrope, followed by nifedipine,
then diltiazem. At therapeutic dose, verapamil and diltiazem- but
not nifedipine or other dihydropyridines- are active in conductive tissue.
Verapamil is more effective in slowing AV conduction, while diltiazem has
a more pronounced effect on the sinus node. Intravenous verapamil
and diltiazem are both useful in the treatment of supraventricular tachydysrhythmias.
However, nifedipine as well as all 1,4-dihydropyridines have little negative
dromotropic or chronotropic effects and may cause increases in heart rate
due to sympathetic stimulation. This presents a clear contraindication
for the use of nifedipine or other dihydropyridines in patients with tachydysrhythmias.
The majority of adverse effects of oral calcium antagonists are listed
below and also include constipation as the chief adverse reaction due to
the affinity of these medications for the smooth muscle of the gut.
Adverse effects of intravenous calcium antagonists are associated
with the vasodilatory effects of the class. These adverse effects
are outlined in Table 3.
Table 3: Adverse
effects of intravenous calcium antagonists
AV Conduction disturbances
Contraindications to calcium channel blockers include bradydysrhythmias,
SA node or AV node conduction disturbances, hypotension, congestive heart
failure, dilated cardiomyopathies with or without history of acute myocardial
infarction and pre-excitation syndromes, such as Wolff-Parkinson-White
because of increased ventricular rate and enhanced accessory pathway conduction.
Calcium antagonists worsen dysrhythmias associated with digitalis toxicity,
and are therefore contraindicated. Additionally, dihydropyridines
are contraindicated post MI because of an unopposed sympathetic reflex,
which is likely to increase heart rate and aggravate myocardial ischemia.
Drug interactions have been reported with concomitant use of calcium antagonists,
beta-adrenergic antagonists and class Ia antiarrhythmics, such as quinidine.
This is due to a synergistic prolongation of refractoriness, especially
that of the AV node.
Table 4:Dosage and
||0.25mg/kg initial followed by 0.35mg/kg (generally 15 - 25 mg Slow
IVP or as a drip over 10 minutes)
||0.075mg/kg (generally 2.5 - 15 mg Slow IVP)
Calcium ion influx is crucial in neuronal, muscular and hormonal activities
of all cells, particularly those of the cardiovascular system. Vascular
tone, conduction and heart rate may require modification in the patient
with cardiovascular disease. Understanding the actions of any of
the myriad of medications that the patient may take at home, as well as
medications carried by the prehospital provider is essential for the safe
and efficacious delivery of emergency medicine. Calcium antagonists
come in different varieties and have differing effects. Choosing
when to administer, or just as importantly, when to withhold any
medication is the mark of the true clinician.
1. Haber, E: Molecular
Cardiovascular Medicine, 1995, Scientific American
2. Norlander M,
Thalen P: Effects of felodipine on local and neurogenic control of vascular
resistance. J Cardio Pharmocol.
3. Hess P: Calcium
channels in vertebrate cells. Annu Rev Neurosci 13:337, 1990
4. Mitchell, et
al: Comparative clinical electrophysiologic effects of diltiazem
and nifedipine: a review. Am J Cardiol 18:629, 1982
5. Triggle DJ:
Calcium-channel drugs: structure-function relationships and selectivity
of action. J Cardiovasc Pharmacol 18 (suppl.10):S1, 1991
6. Peopho, RW:
Pharmacology of the CCB; www.cc.emory.edu/WHSC/MED/CME/CCB/pharm.htm
7. Singh, et al:
Cardiovascular Pharmacology and Therapeutics, 1stEd. 1994, Churchill Livingstone
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Updated: November 10, 1997