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).
Arrhythmias (Supraventricular tachycardia)
Peripheral Vascular Disease
Primary pulmonary hypertension
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.
|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)|
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Updated: November 10, 1997