Calcium channel blockers Flashcards
Calcium channel blockers (CCBs; calcium antagonists) act chiefly by vaso……….. and reduction of the ………………….
Calcium channel blockers (CCBs; calcium antagonists) act chiefly by vasodilation and reduction of the peripheral vascular resistance.
CCBs: They remain among the most commonly used agents for hypertension and angina. Their major role in these conditions is now well understood, based on the results of a series of large trials.
CCBs: They remain among the most commonly used agents for hypertension and angina. Their major role in these conditions is now well understood, based on the results of a series of large trials.
CCBs are a heterogeneous group of drugs that can chemically be classified into the …… and the ………….. (Table 3-1).
CCBs are a heterogeneous group of drugs that can chemically be classified into the dihydropyridines (DHPs) and the non-DHPs (Table 3-1).
CCBs common pharmacologic property being selective inhibition of ………….. in vascular smooth muscle and in the myocardium (Fig. 3-1).
CCBs common pharmacologic property being selective inhibition of L-type channel opening in vascular smooth muscle and in the myocardium (Fig. 3-1).
Distinctions between the DHPs and non-DHPs are reflected in different binding sites on the ………………….., and in the greater vascular selectivity of the ……………… In addition, the non-DHPs, by virtue of …………….., reduce the heart rate (heart rate–lowering [HRL] agents).
Distinctions between the DHPs and non-DHPs are reflected in different binding sites on the calcium channel pores, and in the greater vascular selectivity of the DHP agents. In addition, the non-DHPs, by virtue of nodal inhibition, reduce the heart rate (heart rate–lowering [HRL] agents).
Thus verapamil and diltiazem more closely resemble the β-blockers in their therapeutic spectrum with, however, one major difference: CCBs are contraindicated in heart failure.
Thus verapamil and diltiazem more closely resemble the β-blockers in their therapeutic spectrum with, however, one major difference: CCBs are contraindicated in heart failure.
Pharmacologic properties
Calcium channels: L and T types:
The most important property of all CCBs is selectively to inhibit the ………. flow of charge-bearing calcium ions when the calcium channel becomes permeable or is “open.”
The most important property of all CCBs is selectively to inhibit the inward flow of charge-bearing calcium ions when the calcium channel becomes permeable or is “open.”
Previously, the term slow channel was used, but now it is realized that the calcium current travels much faster than previously believed, and that there are at least two types of calcium channels, the L and T.
Previously, the term slow channel was used, but now it is realized that the calcium current travels much faster than previously believed, and that there are at least two types of calcium channels, the L and T.
The conventional long-lasting opening calcium channel is termed the …….. channel, which is blocked by ……. and increased in activity by catecholamines. The function of the L-type is to admit the substantial amount of calcium ions required for initiation of contraction via calcium-induced calcium release from the ………. (see Fig. 3-1).
The conventional long-lasting opening calcium channel is termed the L-type channel, which is blocked by CCBs and increased in activity by catecholamines. The function of the L-type is to admit the substantial amount of calcium ions required for initiation of contraction via calcium-induced calcium release from the sarcoplasmic reticulum (see Fig. 3-1).
The …………. channel opens at more negative potentials than the L-type. It plays an important role in the initial depolarization of …………… and is relatively upregulated in the failing myocardium. Currently there are no specific T-type blockers clinically available.
The T-type (T for transient) channel opens at more negative potentials than the L-type. It plays an important role in the initial depolarization of sinus and atrioventricular (AV) nodal tissue and is relatively upregulated in the failing myocardium. Currently there are no specific T-type blockers clinically available.
Cellular mechanisms: β-blockade versus CCBS
Both these categories of agents are used for angina and hypertension, yet there are important differences in their subcellular mode of action.
Both have a ……… inotropic effect, whereas only CCBs relax ……… and (to a much lesser extent) other ……………. (Fig. 3-2). CCBs “block” the entry of calcium through the calcium channel in both ……….and………, so that less calcium is available to the contractile apparatus. The result is ……….. and a …………… inotropic effect, which in the case of the DHPs is usually modest because of the ………….. of peripheral vasodilation.
Both have a negative inotropic effect, whereas only CCBs relax vascular and (to a much lesser extent) other smooth muscle (Fig. 3-2). CCBs “block” the entry of calcium through the calcium channel in both smooth muscle and myocardium, so that less calcium is available to the contractile apparatus. The result is vasodilation and a negative inotropic effect, which in the case of the DHPs is usually modest because of the unloading effect of peripheral vasodilation.
CCBs inhibit vascular contraction.
In smooth muscle (see Fig. 3-2), calcium ions regulate the contractile mechanism independently of troponin ….. Interaction of calcium with …….. forms calcium-…….., which then stimulates …………… (MLCK) to phosphorylate the …………. to allow actin-myosin interaction and, hence, contraction. ……………… inhibits the MLCK.
CCBs inhibit vascular contraction.
In smooth muscle (see Fig. 3-2), calcium ions regulate the contractile mechanism independently of troponin C. Interaction of calcium with calmodulin forms calcium-calmodulin, which then stimulates myosin light chain kinase (MLCK) to phosphorylate the myosin light chains to allow actin-myosin interaction and, hence, contraction. Cyclic adenosine monophosphate (AMP) inhibits the MLCK.
In contrast to CCBs; β-blockade, by lessening the formation of ……………., removes the inhibition on MLCK activity and therefore promotes …………… in smooth muscle, which explains why asthma may be precipitated, and why the peripheral …………………… often rises at the start of β-blocker therapy (Fig. 3-3).
In contrast, β-blockade, by lessening the formation of cyclic AMP, removes the inhibition on MLCK activity and therefore promotes contraction in smooth muscle, which explains why asthma may be precipitated, and why the peripheral vascular resistance often rises at the start of β-blocker therapy (Fig. 3-3).
CCBs versus β-blockers.
CCBs and β-blockers have hemodynamic and neurohumoral differences. Hemodynamic differences are well defined (see Fig. 3-3). Whereas β-blockers inhibit the ……………….. by decreasing renin release and oppose the …………… state in heart failure, CCBs as a group have no such inhibitory effects. This difference could explain why β-blockers but not CCBs are an important component of the therapy of heart failure.
CCBs and β-blockers have hemodynamic and neurohumoral differences. Hemodynamic differences are well defined (see Fig. 3-3). Whereas β-blockers inhibit the renin-angiotensin system by decreasing renin release and oppose the hyperadrenergic state in heart failure, CCBs as a group have no such inhibitory effects. This difference could explain why β-blockers but not CCBs are an important component of the therapy of heart failure.
CCBs and carotid vascular protection.
Experimentally, both nifedipine and amlodipine give …………. protection and promote formation of ……………. Furthermore, several CCBs including amlodipine, nifedipine, and lacidipine have inhibitory effects on carotid atheromatous disease. Similar protective effects have not consistently been found with β-blockers. There is increasing evidence that such vascular protection may be associated with improved clinical outcomes.
Experimentally, both nifedipine and amlodipine give endothelial protection and promote formation of nitric oxide. Furthermore, several CCBs including amlodipine, nifedipine, and lacidipine have inhibitory effects on carotid atheromatous disease. Similar protective effects have not consistently been found with β-blockers. There is increasing evidence that such vascular protection may be associated with improved clinical outcomes.
Classification of calcium channel blockers:
Dihydropyridines
The DHPs all bind to the same sites on the ……-subunit (the N sites), thereby establishing their common property of calcium channel antagonism (Fig. 3-4). To a different degree, they exert a greater inhibitory effect on ………. muscle than on the ……………, conferring the property of ……….. selectivity (see Table 3-1, Fig. 3-5). There is nonetheless still the potential for ………………….depression, particularly in the case of agents with less selectivity and in the presence of prior …………….l disease or β-blockade.
The DHPs all bind to the same sites on the α1-subunit (the N sites), thereby establishing their common property of calcium channel antagonism (Fig. 3-4). To a different degree, they exert a greater inhibitory effect on vascular smooth muscle than on the myocardium, conferring the property of vascular selectivity (see Table 3-1, Fig. 3-5). There is nonetheless still the potential for myocardial depression, particularly in the case of agents with less selectivity and in the presence of prior myocardial disease or β-blockade.
For practical purposes, effects of DHPs on the …………. can be ignored.
For practical purposes, effects of DHPs on the sinoatrial (SA) and AV nodes can be ignored.
Nifedipine was the first of the DHPs. In the short-acting capsule form, originally available, it rapidly vasodilates to relieve severe hypertension and to terminate attacks of coronary spasm. The peripheral vasodilation and a rapid drop in blood pressure (BP) led to rapid reflex adrenergic activation with tachycardia (Fig. 3-6). Such proischemic effects probably explain why the short-acting DHPs in high doses have precipitated serious adverse events in unstable angina. The inappropriate use of short-acting nifedipine can explain much of the adverse publicity that once surrounded the CCBs as a group, so that the focus has now changed to the …………DHPs, which are free of such dangers.2
Nifedipine was the first of the DHPs. In the short-acting capsule form, originally available, it rapidly vasodilates to relieve severe hypertension and to terminate attacks of coronary spasm. The peripheral vasodilation and a rapid drop in blood pressure (BP) led to rapid reflex adrenergic activation with tachycardia (Fig. 3-6). Such proischemic effects probably explain why the short-acting DHPs in high doses have precipitated serious adverse events in unstable angina. The inappropriate use of short-acting nifedipine can explain much of the adverse publicity that once surrounded the CCBs as a group, so that the focus has now changed to the long-acting DHPs, which are free of such dangers.2
Hence, the introduction of truly long-acting compounds, such as amlodipine or the extended-release formulations of nifedipine (GITS, XL, CC) and of others such as felodipine and isradipine, has led to substantially fewer symptomatic side effects. Two residual side effects of note are ……, as for all arteriolar dilators, and ankle edema, caused by pre capillary ……… There is now much greater attention to the appropriate use of the DHPs, with established safety and new trials in hypertension such as ACCOMPLISH suggesting a preeminent place for initial dual therapy by DHP and CCBs with an angiotensin-converting enzyme (ACE) inhibitor.
Hence, the introduction of truly long-acting compounds, such as amlodipine or the extended-release formulations of nifedipine (GITS, XL, CC) and of others such as felodipine and isradipine, has led to substantially fewer symptomatic side effects. Two residual side effects of note are headache, as for all arteriolar dilators, and ankle edema, caused by precapillary dilation. There is now much greater attention to the appropriate use of the DHPs, with established safety and new trials in hypertension such as ACCOMPLISH suggesting a preeminent place for initial dual therapy by DHP and CCBs with an angiotensin-converting enzyme (ACE) inhibitor.
Nondihydropyridines: Heart rate–lowering agents:
Verapamil and diltiazem bind to two different sites on the …..subunit of the calcium channel (see Fig. 3-4), yet have many properties in common with each other.
Verapamil and diltiazem bind to two different sites on the α1-subunit of the calcium channel (see Fig. 3-4), yet have many properties in common with each other.
Nondihydropyridines: Heart rate–lowering agents:
The first and most obvious distinction from the DHPs is that verapamil and diltiazem both act on ……. tissue, being therapeutically effective in supraventricular tachycardias. Both tend to decrease ………….. Both inhibit …………… more than the DHPs or, put differently, are less vascular selective (see Fig. 3-5). These properties, added to peripheral ………….., lead to substantial reduction in the myocardial ……………. Such “oxygen conservation” makes the HRL agents much closer than the DHPs to the β-blockers, with which they share some similarities of therapeutic activity.
The first and most obvious distinction from the DHPs is that verapamil and diltiazem both act on nodal tissue, being therapeutically effective in supraventricular tachycardias. Both tend to decrease the sinus rate. Both inhibit myocardial contraction more than the DHPs or, put differently, are less vascular selective (see Fig. 3-5). These properties, added to peripheral vasodilation, lead to substantial reduction in the myocardial oxygen demand. Such “oxygen conservation” makes the HRL agents much closer than the DHPs to the β-blockers, with which they share some similarities of therapeutic activity.
Such “oxygen conservation” makes the HRL agents much closer than the DHPs to the β-blockers, with which they share some similarities of therapeutic activity.
Two important exceptions are…..?
(1) The almost total lack of effect of verapamil and diltiazem on standard types of ventricular tachycardia, which rather is a contraindication to their use
2) The benefits of β-blockade in heart failure, against which the HRL agents are also clearly contraindicated.
The salient features for the clinical use of these agents is shown in Table 3-2.
For supraventricular tachycardias, a …………-dependent effect is important, so that there is better access to the binding sites of the ……. when the calcium channel pore is “open.”
During …… ……………. tachycardia, the channel of the ……….node opens more frequently and the drug binds better, and hence specifically inhibits the ………. to stop the ……… path.
For supraventricular tachycardias, a frequency-dependent effect is important, so that there is better access to the binding sites of the AV node when the calcium channel pore is “open.”
During nodal reentry tachycardia, the channel of the AV node opens more frequently and the drug binds better, and hence specifically inhibits the AV node to stop the reentry path.
Regarding side effects, the non-DHPs, being less active on ……….. muscle, also have less vaso……….. side effects than the DHPs, with less flushing or headaches or pedal edema (see later, Table 3-4).
Reflex tachycardia is uncommon because of the inhibitory effects on the …… node.
Left ventricular ……… remains the major potential side effect, especially in patients with preexisting congestive heart failure (CHF). Why ………. occurs only with verapamil of all the CCBs is not known.
Regarding side effects, the non-DHPs, being less active on vascular smooth muscle, also have less vasodilatory side effects than the DHPs, with less flushing or headaches or pedal edema (see later, Table 3-4).
Reflex tachycardia is uncommon because of the inhibitory effects on the SA node.
Left ventricular (LV) depression remains the major potential side effect, especially in patients with preexisting congestive heart failure (CHF). Why constipation occurs only with verapamil of all the CCBs is not known.
Common to the effects of all types of CCBs is the inhibition of the ………… current in arterial smooth muscle, occurring at relatively…… concentrations (see Table 3-2). Hence ………… vasodilation is a major common property (see Fig. 3-3).
Common to the effects of all types of CCBs is the inhibition of the L-calcium current in arterial smooth muscle, occurring at relatively low concentrations (see Table 3-2). Hence coronary vasodilation is a major common property (see Fig. 3-3).
The shared effects are
(1) coronary vaso……. and relief of exercise-induced vaso………, and
(2) ……………… reduction resulting from BP reduction (see Fig. 3-6).
In addition, in the case of verapamil and diltiazem, slowing of the ………. with a decrease in exercise……… and a negative ………… effect probably contribute (Fig. 3-7).
The shared effects are
(1) coronary vasodilation and relief of exercise-induced vasoconstriction, and
(2) afterload reduction resulting from BP reduction (see Fig. 3-6).
In addition, in the case of verapamil and diltiazem, slowing of the sinus node with a decrease in exercise heart rate and a negative inotropic effect probably contribute (Fig. 3-7).
In people with angina: Importantly the DHPs should not be used without concurrent β-blockade (risk of reflex ……………, see Fig. 3-6).
Importantly the DHPs should not be used without concurrent β-blockade (risk of reflex adrenergic activation, see Fig. 3-6).
Hypertension.
CCBs are excellent antihypertensive agents, among the best for older adult and black patients (see Chapter 7). Overall, they are at least as effective as other antihypertensive classes in treating CHD and more effective than others in preventing stroke. Furthermore, they are almost as good as other classes in preventing heart failure. Their effect is largely independent both of sodium intake, possibly because of their mild diuretic effect, and of the concurrent use of antiinflammatory agents such as nonsteroidal antiinflammatory drugs.
In hypertension with nephropathy, both DHPs and non-DHPs reduce the …….., which is the primary aim, but ………….. reduce proteinuria better.
CCBs are excellent antihypertensive agents, among the best for older adult and black patients (see Chapter 7). Overall, they are at least as effective as other antihypertensive classes in treating CHD and more effective than others in preventing stroke. Furthermore, they are almost as good as other classes in preventing heart failure. Their effect is largely independent both of sodium intake, possibly because of their mild diuretic effect, and of the concurrent use of antiinflammatory agents such as nonsteroidal antiinflammatory drugs.
In hypertension with nephropathy, both DHPs and non-DHPs reduce the BP, which is the primary aim, but non-DHPs reduce proteinuria better.
Supraventricular tachycardia.
Verapamil and diltiazem inhibit the ……… node, which explains their effect in supraventricular tachycardias. Nifedipine and other DHPs are clinically ineffective.
Supraventricular tachycardia.
Verapamil and diltiazem inhibit the AV node, which explains their effect in supraventricular tachycardias. Nifedipine and other DHPs are clinically ineffective.
Postinfarct protection.
Although …………. are drugs of choice, both verapamil and diltiazem give some protection in the absence of prior LV failure. Verapamil is better documented.
Although β-blockers are drugs of choice, both verapamil and diltiazem give some protection in the absence of prior LV failure. Verapamil is better documented.
Vascular protection.
Increased ……….. formation in cultured endothelial cells and improved …………..function in patients may explain why CCBs slow down carotid atherosclerosis, which in turn may be explain decreased stroke. In CAMELOT, amlodipine slowed coronary atheroma and reduced cardiovascular events more than enalapril.
Increased nitric oxide formation in cultured endothelial cells and improved endothelial function in patients may explain why CCBs slow down carotid atherosclerosis, which in turn may be explain decreased stroke. In CAMELOT, amlodipine slowed coronary atheroma and reduced cardiovascular events more than enalapril.
Safety and efficacy
The ideal cardiovascular drug is both efficacious in reducing hard end points, such as mortality, stroke, and myocardial infarction (MI), and safe. Safety, which is not generally well defined, may be regarded as the absence of significant adverse effects when the drug is used with due regard for its known contraindications. In the case of CCBs, previous controversy regarding both efficacy and safety has been laid to rest by new studies that strongly and beyond doubt support the safety of long-acting CCBs
Safety and efficacy
The ideal cardiovascular drug is both efficacious in reducing hard end points, such as mortality, stroke, and myocardial infarction (MI), and safe. Safety, which is not generally well defined, may be regarded as the absence of significant adverse effects when the drug is used with due regard for its known contraindications. In the case of CCBs, previous controversy regarding both efficacy and safety has been laid to rest by new studies that strongly and beyond doubt support the safety of long-acting CCBs
In hypertension, seven large outcome trials in which more than 50,000 patients received long-acting DHPs, often amlodipine, provide overwhelming proof of the safety and efficacy of these CCBs.
Verapamil-based therapy had similar effects on coronary disease with hypertension to therapy based on atenolol in the INVEST trial, the primary end-points being all-cause deaths, nonfatal MI, or nonfatal stroke. In diabetic hypertensives long-acting DHPs are also able to improve outcome. In ALLHAT, amlodipine gave similar results in the diabetic and nondiabetic subgroups. These findings make it difficult to agree with the view that CCBs have adverse effects in diabetics, in whom the major issue is adequate BP reduction. In fact, diabetes may rather be a positive indication for preferential use of a CCB. Cancer, bleeding, and increased all-cause mortality, once incorrectly proposed as serious and unexpected side effects of the CCBs, are now all discounted.
In hypertension, seven large outcome trials in which more than 50,000 patients received long-acting DHPs, often amlodipine, provide overwhelming proof of the safety and efficacy of these CCBs.
Verapamil-based therapy had similar effects on coronary disease with hypertension to therapy based on atenolol in the INVEST trial, the primary end-points being all-cause deaths, nonfatal MI, or nonfatal stroke. In diabetic hypertensives long-acting DHPs are also able to improve outcome. In ALLHAT, amlodipine gave similar results in the diabetic and nondiabetic subgroups. These findings make it difficult to agree with the view that CCBs have adverse effects in diabetics, in whom the major issue is adequate BP reduction. In fact, diabetes may rather be a positive indication for preferential use of a CCB. Cancer, bleeding, and increased all-cause mortality, once incorrectly proposed as serious and unexpected side effects of the CCBs, are now all discounted.
Verapamil Verapamil (Isoptin, Calan, Verelan), the prototype .........agent, remains the CCB with the most licensed indications. Both verapamil and diltiazem have multiple cardiovascular effects (see Fig. 3-7).
Verapamil Verapamil (Isoptin, Calan, Verelan), the prototype non-DHP agent, remains the CCB with the most licensed indications. Both verapamil and diltiazem have multiple cardiovascular effects (see Fig. 3-7).
Electrophysiology.
Verapamil inhibits the action potential of the upper and middle regions of the ….. …….. where depolarization is …….. mediated. Verapamil thus inhibits one limb of the ……….., believed to underlie most paroxysmal ……….. tachycardias (see Fig. 8-4).
Verapamil inhibits the action potential of the upper and middle regions of the AV node where depolarization is calcium mediated. Verapamil thus inhibits one limb of the reentry circuit, believed to underlie most paroxysmal supraventricular tachycardias (see Fig. 8-4).
Verapamil Electrophysiology:
Increased ……. block and the increase in effective ………….period of the AV node explain the reduction of the ventricular rate in atrial flutter and fibrillation.
Increased AV block and the increase in effective refractory period of the AV node explain the reduction of the ventricular rate in atrial flutter and fibrillation.
