Public Safety Training Facility

Monroe Community College
Rochester, New York


Calcium Channel Antagonists
RP Breese, EMT-P
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 to least).

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
Systemic Hypertension
Angina Pectoris 
Vasospastic Angina 
Arrhythmias (Supraventricular tachycardia) 
Migraine Headache 
Peripheral Vascular Disease 
Raynaud's Phenomenon 
Primary pulmonary hypertension
Table 2:  Cardiovascular Uses of Calcium Channel Blockers
 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.  

Peripheral Edema
Exacerbated CHF
AV Conduction disturbances
Table 3:  Adverse effects of intravenous calcium antagonists
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.
Generic Name
Diltiazem 0.25mg/kg initial followed by 0.35mg/kg (generally 15 - 25 mg Slow IVP or as a drip over 10 minutes)
Verapamil 0.075mg/kg (generally 2.5 - 15 mg Slow IVP)
Table 4:Dosage and Administration Information
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;
7.  Singh, et al:  Cardiovascular Pharmacology and Therapeutics, 1stEd. 1994, Churchill Livingstone


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Updated: November 10, 1997