Calcium channel blockers

Question 1

Calcium channel blockers (CCBs; calcium antagonists) act chiefly by vaso……….. and reduction of the ………………….

Answer 1

Calcium channel blockers (CCBs; calcium antagonists) act chiefly by vasodilation and reduction of the peripheral vascular resistance.

Question 2

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.

Answer 2

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.

Question 3

CCBs are a heterogeneous group of drugs that can chemically be classified into the …… and the ………….. (Table 3-1).

Answer 3

CCBs are a heterogeneous group of drugs that can chemically be classified into the dihydropyridines (DHPs) and the non-DHPs (Table 3-1).

Question 4

CCBs common pharmacologic property being selective inhibition of ………….. in vascular smooth muscle and in the myocardium (Fig. 3-1).

Answer 4

CCBs common pharmacologic property being selective inhibition of L-type channel opening in vascular smooth muscle and in the myocardium (Fig. 3-1).

Question 5

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).

Answer 5

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).

Question 6

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.

Answer 6

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.

Question 7

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.”

Answer 7

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.”

Question 8

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.

Answer 8

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.

Question 9

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).

Answer 9

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).

Question 10

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.

Answer 10

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.

Question 11

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.

Answer 11

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.

Question 12

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.

Answer 12

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.

Question 13

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).

Answer 13

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).

Question 14

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.

Answer 14

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.

Question 15

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.

Answer 15

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.

Question 16

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.

Answer 16

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.

Question 17

For practical purposes, effects of DHPs on the …………. can be ignored.

Answer 17

For practical purposes, effects of DHPs on the sinoatrial (SA) and AV nodes can be ignored.

Question 18

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

Answer 18

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

Question 19

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.

Answer 19

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.

Question 20

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.

Answer 20

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.

Question 21

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.

Answer 21

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.

Question 22

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…..?

Answer 22

(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.

Question 23

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.

Answer 23

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.

Question 24

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.

Answer 24

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.

Question 25

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).

Answer 25

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).

Question 26

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).

Answer 26

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).

Question 27

In people with angina: Importantly the DHPs should not be used without concurrent β-blockade (risk of reflex ..............., see Fig. 3-6).

Answer 27

Importantly the DHPs should not be used without concurrent β-blockade (risk of reflex adrenergic activation, see Fig. 3-6).

Question 28

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.

Answer 28

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.

Question 29

Supraventricular tachycardia. Verapamil and diltiazem inhibit the ......... node, which explains their effect in supraventricular tachycardias. Nifedipine and other DHPs are clinically ineffective.

Answer 29

Supraventricular tachycardia. Verapamil and diltiazem inhibit the AV node, which explains their effect in supraventricular tachycardias. Nifedipine and other DHPs are clinically ineffective.

Question 30

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.

Answer 30

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.

Question 31

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.

Answer 31

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.

Question 32

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

Answer 32

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

Question 33

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.

Answer 33

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.

Question 34

``` 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). ```

Answer 34

``` 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). ```

Question 35

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).

Answer 35

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).

Question 36

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.

Answer 36

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.

Question 37

Verapamil is ineffective and harmful in the treatment of ventricular tachycardias except in certain uncommon forms.

Answer 37

Verapamil is ineffective and harmful in the treatment of ventricular tachycardias except in certain uncommon forms.

Question 38

Hemodynamically, verapamil combines arteriolar ............ with a direct ............... inotropic effect (see Table 3-2). The cardiac output and LV ejection fraction do not increase as expected following peripheral vaso........, which may be an expression of the ..........inotropic effect. At rest, the heart only drops ........... with a greater inhibition of exercise-induced tachycardia.

Answer 38

Hemodynamically, verapamil combines arteriolar dilation with a direct negative inotropic effect (see Table 3-2). The cardiac output and LV ejection fraction do not increase as expected following peripheral vasodilation, which may be an expression of the negative inotropic effect. At rest, the heart only drops modestly with a greater inhibition of exercise-induced tachycardia.

Question 39

Pharmacokinetics and interactions. Oral verapamil takes .... hours to act and peaks at ..... hours. Therapeutic blood levels (80 to 400 ng/mL) are seldom measured.

Answer 39

Oral verapamil takes 2 hours to act and peaks at 3 hours. Therapeutic blood levels (80 to 400 ng/mL) are seldom measured.

Question 40

Oral verapamil: The elimination half-life is usually ......... hours, but increases significantly during chronic administration and in patients with ........ or advanced ..... insufficiency. Despite nearly complete absorption of oral doses, bioavailability is only .....% to .......%. There is a high first-pass liver metabolism by multiple components of the ....... system, including CYP 3A4, the latter explaining why verapamil increases blood levels of several statins such as atorvastatin, simvastatin, and lovastatin, as well as ketoconazole.

Answer 40

The elimination half-life is usually 3 to 7 hours, but increases significantly during chronic administration and in patients with liver or advanced renal insufficiency. Despite nearly complete absorption of oral doses, bioavailability is only 10% to 20%. There is a high first-pass liver metabolism by multiple components of the P-450 system, including CYP 3A4, the latter explaining why verapamil increases blood levels of several statins such as atorvastatin, simvastatin, and lovastatin, as well as ketoconazole.

Question 41

Ultimate excretion of the parent compound, as well as the active hepatic metabolite norverapamil, is 75% by the ......... and 25% by the ............ Verapamil is ......... protein bound, but no interaction with warfarin has been reported. When both verapamil and digoxin are given together, their interaction causes .......... levels to rise, probably as a result of a reduction in the ......... .......... of digoxin.

Answer 41

Ultimate excretion of the parent compound, as well as the active hepatic metabolite norverapamil, is 75% by the kidneys and 25% by the gastrointestinal (GI) tract. Verapamil is 87% to 93% protein bound, but no interaction with warfarin has been reported. When both verapamil and digoxin are given together, their interaction causes digoxin levels to rise, probably as a result of a reduction in the renal clearance of digoxin.

Question 42

Norverapamil is the long-acting ..........metabolite of verapamil, which appears rapidly in the plasma after oral administration of verapamil and in concentrations similar to those of the parent compound; like verapamil, norverapamil undergoes .................. clearance during chronic dosing.

Answer 42

Norverapamil is the long-acting hepatic metabolite of verapamil, which appears rapidly in the plasma after oral administration of verapamil and in concentrations similar to those of the parent compound; like verapamil, norverapamil undergoes delayed clearance during chronic dosing.

Question 43

Verapamil: Large differences of pharmacokinetics among individuals mean that dose titration is required, so that 120 mg daily may be adequate for those with hepatic impairment or for older adults. During chronic oral dosing, the formation of norverapamil metabolites and altered rates of hepatic metabolism suggest that less frequent or smaller daily doses of short-acting verapamil may be used. For example, if verapamil has been given at a dose of 80 mg three times daily, then 120 mg twice daily should be as good. Lower doses are required in older adult patients or those with advanced renal or hepatic disease or when there is concurrent β-blockade. Intravenous verapamil is much less used for supraventricular arrhythmias since the advent of adenosine and the ultra–short acting β-blocker, esmolol.

Answer 43

Large differences of pharmacokinetics among individuals mean that dose titration is required, so that 120 mg daily may be adequate for those with hepatic impairment or for older adults. During chronic oral dosing, the formation of norverapamil metabolites and altered rates of hepatic metabolism suggest that less frequent or smaller daily doses of short-acting verapamil may be used. For example, if verapamil has been given at a dose of 80 mg three times daily, then 120 mg twice daily should be as good. Lower doses are required in older adult patients or those with advanced renal or hepatic disease or when there is concurrent β-blockade. Intravenous verapamil is much less used for supraventricular arrhythmias since the advent of adenosine and the ultra–short acting β-blocker, esmolol.

Question 44

Outcome studies. Verapamil was the antihypertensive equivalent of atenolol in hypertension, with coronary artery disease (CAD) regarding major outcomes with three extra benefits: less new diabetes, less angina, and less psychological depression.25

Answer 44

Outcome studies. Verapamil was the antihypertensive equivalent of atenolol in hypertension, with coronary artery disease (CAD) regarding major outcomes with three extra benefits: less new diabetes, less angina, and less psychological depression.25

Question 45

Side effects. Class side effects are those of vasodilation causing .......... .............. These may be lessened by the long-acting preparations, so that in practice they are often not troublesome. ............. is not a side effect. ................. is specific and causes most trouble, especially in older adult patients. Rare side effects may include pain in the gums, facial pain, epigastric pain, hepatotoxicity, and transient mental confusion. In older adults, verapamil may predispose to GI bleeding.

Answer 45

Side effects. Class side effects are those of vasodilation causing headaches, facial flushing, and dizziness. These may be lessened by the long-acting preparations, so that in practice they are often not troublesome. Tachycardia is not a side effect. Constipation is specific and causes most trouble, especially in older adult patients. Rare side effects may include pain in the gums, facial pain, epigastric pain, hepatotoxicity, and transient mental confusion. In older adults, verapamil may predispose to GI bleeding.

Question 46

Contraindications to verapamil | (Fig. 3-8, Table 3-3). Contraindications, especially in the intravenous therapy of supraventricular tachycardias are:

Answer 46

Sick sinus syndrome; preexisting AV nodal disease; excess therapy with β-blockade, digitalis, quinidine, or disopyramide; or myocardial depression. In the Wolff-Parkinson-White (WPW) syndrome complicated by atrial fibrillation, intravenous verapamil is contraindicated because of the risk of anterograde conduction through the bypass tract (see Fig. 8-14). Verapamil is also contraindicated in ventricular tachycardia (wide QRS-complex) because of excess myocardial depression, which may be lethal. An exception to this rule is exercise-induced ventricular tachycardia. Myocardial depression, if secondary to the supraventricular tachycardia, is not a contraindication, whereas preexisting LV systolic failure is.

Question 47

Verapamil: Dose reduction may be required in hepatic or renal disease (see “Pharmacokinetics and Interactions” earlier in this chapter).

Answer 47

Verapamil: Dose reduction may be required in hepatic or renal disease (see “Pharmacokinetics and Interactions” earlier in this chapter).

Question 48

Drug interactions with verapamil β-blockers. Verapamil by intravenous injection is now seldom given, so that the potentially serious interaction with preexisting β-adrenergic blockade is largely a matter of history. Depending on the dose and the state of the sinus node and the myocardium, the combination of oral verapamil with a β-blocker may be well tolerated or not. In practice, clinicians can often safely combine verapamil with β-blockade in the therapy of angina pectoris or hypertension, provided that due care is taken (monitoring for heart rate and heart block). In older adults, prior nodal disease must be excluded. For hypertension, β-blocker plus verapamil works well, although heart rate, AV conduction, and LV function may sometimes be adversely affected. To avoid any hepatic pharmacokinetic interactions, verapamil is best combined with a ............ β-blocker such as atenolol or nadolol, rather than one that is metabolized in the liver, such as metoprolol, propranolol, or carvedilol.

Answer 48

Drug interactions with verapamil β-blockers. Verapamil by intravenous injection is now seldom given, so that the potentially serious interaction with preexisting β-adrenergic blockade is largely a matter of history. Depending on the dose and the state of the sinus node and the myocardium, the combination of oral verapamil with a β-blocker may be well tolerated or not. In practice, clinicians can often safely combine verapamil with β-blockade in the therapy of angina pectoris or hypertension, provided that due care is taken (monitoring for heart rate and heart block). In older adults, prior nodal disease must be excluded. For hypertension, β-blocker plus verapamil works well, although heart rate, AV conduction, and LV function may sometimes be adversely affected. To avoid any hepatic pharmacokinetic interactions, verapamil is best combined with a hydrophilic β-blocker such as atenolol or nadolol, rather than one that is metabolized in the liver, such as metoprolol, propranolol, or carvedilol.

Question 49

Drug interactions with verapamil: Digoxin. Verapamil inhibits the digoxin transporter, P-.........., to increase blood digoxin levels, which is of special relevance when both are used chronically to inhibit AV nodal conduction. In digitalis toxicity, rapid intravenous verapamil is absolutely contraindicated because it can lethally .......... AV block. There is no reason why, in the absence of digitalis toxicity or AV block, oral verapamil and digoxin should not be combined (checking the digoxin level). Whereas digoxin can be used for heart failure with atrial fibrillation, verapamil is negatively ........... and should not be used.

Answer 49

Digoxin. Verapamil inhibits the digoxin transporter, P-glycoprotein, to increase blood digoxin levels, which is of special relevance when both are used chronically to inhibit AV nodal conduction. In digitalis toxicity, rapid intravenous verapamil is absolutely contraindicated because it can lethally exaggerate AV block. There is no reason why, in the absence of digitalis toxicity or AV block, oral verapamil and digoxin should not be combined (checking the digoxin level). Whereas digoxin can be used for heart failure with atrial fibrillation, verapamil is negatively inotropic and should not be used.

Question 50

Drug interactions with verapamil: Antiarrhythmics. The combined negative inotropic potential of verapamil and ...... is considerable. Co-therapy with ........ may also give added negative inotropic and dromotropic effects.

Answer 50

The combined negative inotropic potential of verapamil and disopyramide is considerable. Co-therapy with flecainide may also give added negative inotropic and dromotropic effects.

Question 51

Drug interactions with verapamil: Statins. Verapamil inhibits the hepatic ........., and therefore potentially increases the blood levels of atorvastatin, simvastatin, and lovastatin, which are all metabolized by this isoenzyme.21

Answer 51

Statins. Verapamil inhibits the hepatic CYP3A isoenzyme, and therefore potentially increases the blood levels of atorvastatin, simvastatin, and lovastatin, which are all metabolized by this isoenzyme.21

Question 52

Drug interactions with verapamil: Other agents. Phenobarbital, phenytoin, and rifampin induce the cytochrome systems metabolizing verapamil so that its blood levels fall. Conversely, verapamil inhibits hepatic CYP3A to increase blood levels of cyclosporin, carbamazepine (Tegretol) and theophylline, as mentioned in the package insert. This inhibition is also expected to increase blood levels of ketoconazole and sildenafil. Cimetidine has variable effects.

Answer 52

Other agents. Phenobarbital, phenytoin, and rifampin induce the cytochrome systems metabolizing verapamil so that its blood levels fall. Conversely, verapamil inhibits hepatic CYP3A to increase blood levels of cyclosporin, carbamazepine (Tegretol) and theophylline, as mentioned in the package insert. This inhibition is also expected to increase blood levels of ketoconazole and sildenafil. Cimetidine has variable effects.

Question 53

Therapy of verapamil toxicity. There are few clinical reports on management of verapamil toxicity. Intravenous ........... (1 to 2 g) or half that dose of .........., given over 5 minutes, helps when heart failure or excess hypotension is present. If there is an inadequate response, positive inotropic or vasoconstrictory catecholamines (see Chapter 5, p. 180) are given, or else glucagon. An alternative is ............ Intravenous ........(1 mg) or ......... is used to shorten AV conduction. A pacemaker may be needed.

Answer 53

Therapy of verapamil toxicity. There are few clinical reports on management of verapamil toxicity. Intravenous calcium gluconate (1 to 2 g) or half that dose of calcium chloride, given over 5 minutes, helps when heart failure or excess hypotension is present. If there is an inadequate response, positive inotropic or vasoconstrictory catecholamines (see Chapter 5, p. 180) are given, or else glucagon. An alternative is hyperinsulinemic-euglycemic therapy. Intravenous atropine (1 mg) or isoproterenol is used to shorten AV conduction. A pacemaker may be needed.

Question 54

Clinical indications for verapami: People: In chronic stable effort angina, verapamil acts by a combination of .......reduction and a mild ........ inotropic effect, plus reduction of exercise-induced ........ and coronary ................... The heart rate usually stays the same or falls modestly.

Answer 54

In chronic stable effort angina, verapamil acts by a combination of afterload reduction and a mild negative inotropic effect, plus reduction of exercise-induced tachycardia and coronary vasoconstriction. The heart rate usually stays the same or falls modestly. Abrupt withdrawal of verapamil may precipitate rebound angina.

Question 55

Hypertension. Verapamil is approved for mild to moderate hypertension in the United States. Besides the outcome study in CAD with hypertension (preceding section), in a long-term, double-blind comparative trial, mild to moderate hypertension was adequately controlled in 45% of patients given verapamil 240 mg daily, versus 25% for hydrochlorothiazide 25 mg daily, versus 60% for the combination. Higher doses of verapamil might have done even better. Combinations can be with diuretics, β-blockers, ACE inhibitors, angiotensin receptor blockers (ARBs), or centrally acting agents. During combination with α-blockers, a hepatic interaction may lead to excess ,,,,,,,,,,,,,,,,,

Answer 55

Verapamil is approved for mild to moderate hypertension in the United States. Besides the outcome study in CAD with hypertension (preceding section), in a long-term, double-blind comparative trial, mild to moderate hypertension was adequately controlled in 45% of patients given verapamil 240 mg daily, versus 25% for hydrochlorothiazide 25 mg daily, versus 60% for the combination. Higher doses of verapamil might have done even better. Combinations can be with diuretics, β-blockers, ACE inhibitors, angiotensin receptor blockers (ARBs), or centrally acting agents. During combination with α-blockers, a hepatic interaction may lead to excess hypotension.

Question 56

Verapamil for supraventricular arrhythmias. Verapamil is licensed for the prophylaxis of repetitive supraventricular tachycardias, and for rate control in chronic atrial fibrillation when given with digoxin (note interaction). For acute attacks of supraventricular tachycardias, when there is no myocardial depression, a bolus dose of 5 to 10 mg (0.1 to 0.15 mg/kg) given over 2 minutes restores sinus rhythm within 10 minutes in 60% of cases (package insert). However, this use is now largely supplanted by intravenous adenosine (see Fig. 8-7). When used for uncontrolled atrial fibrillation but with caution if there is a compromised LV failure, verapamil may safely be given (0.005 mg/kg/min, increasing) or as an intravenous bolus of 5 mg (0.075 mg/kg) followed by double the dose if needed. In atrial flutter, AV block is increased. In all supraventricular tachycardias, including atrial flutter and fibrillation, the presence of a bypass tract (WPW syndrome) contraindicates verapamil.

Answer 56

Verapamil for supraventricular arrhythmias. Verapamil is licensed for the prophylaxis of repetitive supraventricular tachycardias, and for rate control in chronic atrial fibrillation when given with digoxin (note interaction). For acute attacks of supraventricular tachycardias, when there is no myocardial depression, a bolus dose of 5 to 10 mg (0.1 to 0.15 mg/kg) given over 2 minutes restores sinus rhythm within 10 minutes in 60% of cases (package insert). However, this use is now largely supplanted by intravenous adenosine (see Fig. 8-7). When used for uncontrolled atrial fibrillation but with caution if there is a compromised LV failure, verapamil may safely be given (0.005 mg/kg/min, increasing) or as an intravenous bolus of 5 mg (0.075 mg/kg) followed by double the dose if needed. In atrial flutter, AV block is increased. In all supraventricular tachycardias, including atrial flutter and fibrillation, the presence of a bypass tract (WPW syndrome) contraindicates verapamil.

Question 57

Other uses for verapamil. In hypertrophic cardiomyopathy, verapamil has been the CCB best evaluated. It is licensed for this purpose in Canada. When given acutely, it ............................ Verapamil should not be given to patients with .............. No long-term, placebo-controlled studies with verapamil are available. In retrospective comparisons with propranolol, verapamil appeared to decrease sudden death and gave better 10-year survival. The best results were obtained by a combination of septal myectomy and verapamil. A significant number of patients on long-term verapamil develop severe side effects, including SA and AV nodal dysfunction, and occasionally overt heart failure.

Answer 57

Other uses for verapamil. In hypertrophic cardiomyopathy, verapamil has been the CCB best evaluated. It is licensed for this purpose in Canada. When given acutely, it lessens symptoms, reduces the outflow tract gradient, improves diastolic function, and enhances exercise performance by 20% to 25%. Verapamil should not be given to patients with resting outflow tract obstruction. No long-term, placebo-controlled studies with verapamil are available. In retrospective comparisons with propranolol, verapamil appeared to decrease sudden death and gave better 10-year survival. The best results were obtained by a combination of septal myectomy and verapamil. A significant number of patients on long-term verapamil develop severe side effects, including SA and AV nodal dysfunction, and occasionally overt heart failure.

Question 58

Atypical ventricular tachycardia. Some patients with exercise-induced ventricular tachycardia caused by triggered automaticity may respond well to verapamil, as may young patients with idiopathic right ventricular outflow tract ventricular tachycardia (right bundle branch block and left axis deviation). However, verapamil can be lethal for standard wide complex ventricular tachycardia, especially when given intravenously. Therefore, unless the diagnosis is sure, verapamil must be avoided in ventricular tachycardia. In intermittent claudication, carefully titrated verapamil increased maximum walking ability.

Answer 58

Atypical ventricular tachycardia. Some patients with exercise-induced ventricular tachycardia caused by triggered automaticity may respond well to verapamil, as may young patients with idiopathic right ventricular outflow tract ventricular tachycardia (right bundle branch block and left axis deviation). However, verapamil can be lethal for standard wide complex ventricular tachycardia, especially when given intravenously. Therefore, unless the diagnosis is sure, verapamil must be avoided in ventricular tachycardia. In intermittent claudication, carefully titrated verapamil increased maximum walking ability.

Question 59

Summary. Among CCBs, verapamil has the widest range of approved indications, including all varieties of angina (effort, vasospastic, unstable), supraventricular tachycardias, and hypertension. Indirect evidence suggests good safety, but nonetheless with risks of heart block and heart failure. Compared with atenolol in hypertension with CAD, there was less new diabetes, fewer anginas, and less psychological depression. Verapamil combined with β-blockade runs the risk of heart block; thus a DHP with β-blockade is much better.

Answer 59

Summary. Among CCBs, verapamil has the widest range of approved indications, including all varieties of angina (effort, vasospastic, unstable), supraventricular tachycardias, and hypertension. Indirect evidence suggests good safety, but nonetheless with risks of heart block and heart failure. Compared with atenolol in hypertension with CAD, there was less new diabetes, fewer anginas, and less psychological depression. Verapamil combined with β-blockade runs the risk of heart block; thus a DHP with β-blockade is much better.

Question 60

Diltiazem: Although molecular studies show different channel binding sites for diltiazem and verapamil (see Fig. 3-4), in clinical practice they have somewhat similar therapeutic spectra and contraindications, so that they are often classified as the ................ agents (see Fig. 3-5).

Answer 60

Although molecular studies show different channel binding sites for diltiazem and verapamil (see Fig. 3-4), in clinical practice they have somewhat similar therapeutic spectra and contraindications, so that they are often classified as the non-DHPs or HRL agents (see Fig. 3-5).

Question 61

Clinically, diltiazem is used for the same spectrum of disease as is verapamil: angina pectoris, hypertension, supraventricular arrhythmias, and rate control in atrial fibrillation or flutter (see Fig. 3-7). Of these, diltiazem is approved in the United States to treat angina (effort and vasospastic) and hypertension, with only the intravenous form approved for supraventricular tachycardias and for acute rate control.

Answer 61

Clinically, diltiazem is used for the same spectrum of disease as is verapamil: angina pectoris, hypertension, supraventricular arrhythmias, and rate control in atrial fibrillation or flutter (see Fig. 3-7). Of these, diltiazem is approved in the United States to treat angina (effort and vasospastic) and hypertension, with only the intravenous form approved for supraventricular tachycardias and for acute rate control.

Question 62

Diltiazem has a low side-effect profile, similar to or possibly better than that of verapamil; specifically the incidence of constipation is much lower (Table 3-4). On the other hand, verapamil is registered for more indications. Is diltiazem less a cardiodepressant than verapamil? There are no strictly comparable clinical studies to support this clinical impression.

Answer 62

Diltiazem has a low side-effect profile, similar to or possibly better than that of verapamil; specifically the incidence of constipation is much lower (Table 3-4). On the other hand, verapamil is registered for more indications. Is diltiazem less a cardiodepressant than verapamil? There are no strictly comparable clinical studies to support this clinical impression.

Question 63

Pharmacokinetics. Following oral administration of diltiazem, more than 90% is absorbed, but bioavailability is approximately 45% (first-pass ....... metabolism). The onset of action of short-acting diltiazem is within ....... minutes (oral), with a peak at ........ hours. The elimination half-life is ........ hours; hence, dosage every 6 to 8 hours of the short-acting preparation is required for sustained therapeutic effect.

Answer 63

Pharmacokinetics. Following oral administration of diltiazem, more than 90% is absorbed, but bioavailability is approximately 45% (first-pass hepatic metabolism). The onset of action of short-acting diltiazem is within 15 to 30 minutes (oral), with a peak at 1 to 2 hours. The elimination half-life is 4 to 7 hours; hence, dosage every 6 to 8 hours of the short-acting preparation is required for sustained therapeutic effect.

Question 64

The therapeutic plasma concentration range is 50 to 300 ng/mL. Protein binding is ..... % to ......%.

Answer 64

The therapeutic plasma concentration range is 50 to 300 ng/mL. Protein binding is 80% to 86%.

Question 65

Diltiazem is acetylated in the .....to deacyldiltiazem (40% of the activity of the parent compound), which accumulates with chronic therapy. Unlike verapamil and nifedipine, only ......% of diltiazem is excreted by the kidneys (65% by the GI tract). Because of the hepatic CYP3A4 interaction, the FDA warns that the 10-mg dose of simvastatin should not be exceeded in patients taking diltiazem.

Answer 65

Diltiazem is acetylated in the liver to deacyldiltiazem (40% of the activity of the parent compound), which accumulates with chronic therapy. Unlike verapamil and nifedipine, only 35% of diltiazem is excreted by the kidneys (65% by the GI tract). Because of the hepatic CYP3A4 interaction, the FDA warns that the 10-mg dose of simvastatin should not be exceeded in patients taking diltiazem.

Question 66

Diltiazem doses. The dose of diltiazem is 120 to 360 mg, given in four daily doses of the short-acting formulation or once or twice a day with slow-release preparations. Cardizem SR permits twice-daily doses. For once-daily use, Dilacor XR is licensed in the United States for hypertension and Cardizem CD and Tiazac for hypertension and angina.

Answer 66

The dose of diltiazem is 120 to 360 mg, given in four daily doses of the short-acting formulation or once or twice a day with slow-release preparations. Cardizem SR permits twice-daily doses. For once-daily use, Dilacor XR is licensed in the United States for hypertension and Cardizem CD and Tiazac for hypertension and angina.

Question 67

Intravenous diltiazem (Cardizem injectable) is approved for arrhythmias but not for acute hypertension. For acute conversion of paroxysmal supraventricular tachycardia, after exclusion of WPW syndrome (see Fig. 8-14) or for slowing the ventricular response rate in atrial fibrillation or flutter, it is given as 0.25 mg/kg over 2 minutes with electrocardiogram and BP monitoring. If the response is inadequate, the dose is repeated as 0.35 mg/kg over 2 minutes. Acute therapy is usually followed by an infusion of 5 to 15 mg/hr for up to 24 hrs. Diltiazem overdose is treated as for verapamil (see p. 77).

Answer 67

Intravenous diltiazem (Cardizem injectable) is approved for arrhythmias but not for acute hypertension. For acute conversion of paroxysmal supraventricular tachycardia, after exclusion of WPW syndrome (see Fig. 8-14) or for slowing the ventricular response rate in atrial fibrillation or flutter, it is given as 0.25 mg/kg over 2 minutes with electrocardiogram and BP monitoring. If the response is inadequate, the dose is repeated as 0.35 mg/kg over 2 minutes. Acute therapy is usually followed by an infusion of 5 to 15 mg/hr for up to 24 hrs. Diltiazem overdose is treated as for verapamil (see p. 77).

Question 68

Side effects. Normally side effects of the standard preparation are few and limited to headaches, dizziness, and ankle edema in approximately 6% to 10% of patients (see Table 3-4). With high-dose diltiazem (360 mg daily), constipation may also occur. When the extended-release preparation is used for hypertension, the side-effect profile resembles placebo.

Answer 68

Normally side effects of the standard preparation are few and limited to headaches, dizziness, and ankle edema in approximately 6% to 10% of patients (see Table 3-4). With high-dose diltiazem (360 mg daily), constipation may also occur. When the extended-release preparation is used for hypertension, the side-effect profile resembles placebo.

Question 69

Side effects. Nonetheless, bradycardia and first-degree AV block may occur with all diltiazem preparations. In the case of intravenous diltiazem, side effects resemble those of intravenous verapamil, including hypotension and the possible risk of asystole and high-degree AV block when there is preexisting nodal disease. In postinfarct patients with preexisting poor LV function, mortality is increased by diltiazem, not decreased. Occasionally, severe skin rashes such as exfoliative dermatitis are found.

Answer 69

Nonetheless, bradycardia and first-degree AV block may occur with all diltiazem preparations. In the case of intravenous diltiazem, side effects resemble those of intravenous verapamil, including hypotension and the possible risk of asystole and high-degree AV block when there is preexisting nodal disease. In postinfarct patients with preexisting poor LV function, mortality is increased by diltiazem, not decreased. Occasionally, severe skin rashes such as exfoliative dermatitis are found.

Question 70

Contraindications. Contraindications resemble those of verapamil (see Fig. 3-8, Table 3-3): preexisting marked depression of the sinus or AV node, hypotension, myocardial failure, and WPW syndrome. Postinfarct LV failure with an ejection fraction of less than 40% is a clear contraindication.

Answer 70

Contraindications. Contraindications resemble those of verapamil (see Fig. 3-8, Table 3-3): preexisting marked depression of the sinus or AV node, hypotension, myocardial failure, and WPW syndrome. Postinfarct LV failure with an ejection fraction of less than 40% is a clear contraindication.

Question 71

Drug interactions and combinations. Unlike verapamil, the effect of diltiazem on the blood digoxin level is ................As in the case of verapamil, there are the expected ............... with β-blockers. Nonetheless, diltiazem plus β-blocker may be used with care for angina watching for excess bradycardia or AV block or hypotension. Diltiazem may increase the bioavailability of oral propranolol perhaps by displacing it from its binding sites (package insert).

Answer 71

Drug interactions and combinations. Unlike verapamil, the effect of diltiazem on the blood digoxin level is often slight or negligible. As in the case of verapamil, there are the expected hemodynamic interactions with β-blockers. Nonetheless, diltiazem plus β-blocker may be used with care for angina watching for excess bradycardia or AV block or hypotension. Diltiazem may increase the bioavailability of oral propranolol perhaps by displacing it from its binding sites (package insert).

Question 72

Occasionally diltiazem plus a DHP is used for refractory coronary artery spasm, the rationale being that two different binding sites on the calcium channel are involved (see Fig. 3-4). Diltiazem plus long-acting nitrates may lead to excess ........... As in the case of verapamil, but probably less so, diltiazem may inhibit .............., which is expected to increase blood levels of cyclosporin, ketoconazole, carbamazepine (Tegretol), and sildenafil.21 Conversely, cimetidine inhibits the hepatic cytochrome system breaking down diltiazem to increase circulating levels.

Answer 72

Occasionally diltiazem plus a DHP is used for refractory coronary artery spasm, the rationale being that two different binding sites on the calcium channel are involved (see Fig. 3-4). Diltiazem plus long-acting nitrates may lead to excess hypotension. As in the case of verapamil, but probably less so, diltiazem may inhibit CYP3A cytochrome, which is expected to increase blood levels of cyclosporin, ketoconazole, carbamazepine (Tegretol), and sildenafil.21 Conversely, cimetidine inhibits the hepatic cytochrome system breaking down diltiazem to increase circulating levels.

Question 73

Clinical uses of diltiazem: Diltiazem for hypertension. In the major long-term outcome study on more than 10,000 patients, the Nordic Diltiazem (NORDIL) trial, diltiazem followed by an ACE inhibitor if needed to reach BP goals was as effective in preventing the primary combined cardiovascular endpoint as treatment based on a diuretic, a β-blocker, or both.39 In the smaller multicenter VA study, diltiazem was the best among five agents (atenolol, thiazide, doxazosin, and captopril) in reducing BP, and was especially effective in older adult white patients and in black patients.40 Nonetheless, reduction of LV hypertrophy was poor at 1 year of follow-up, possibly because a short-acting diltiazem formulation was used.41

Answer 73

Diltiazem for hypertension. In the major long-term outcome study on more than 10,000 patients, the Nordic Diltiazem (NORDIL) trial, diltiazem followed by an ACE inhibitor if needed to reach BP goals was as effective in preventing the primary combined cardiovascular endpoint as treatment based on a diuretic, a β-blocker, or both.39 In the smaller multicenter VA study, diltiazem was the best among five agents (atenolol, thiazide, doxazosin, and captopril) in reducing BP, and was especially effective in older adult white patients and in black patients.40 Nonetheless, reduction of LV hypertrophy was poor at 1 year of follow-up, possibly because a short-acting diltiazem formulation was used.41

Question 74

Antiarrhythmic properties of diltiazem. The main electrophysiologic effect is a depressant one on the .....node; the functional and effective ............ are prolonged by diltiazem, so that diltiazem is licensed for termination of an attack of supraventricular tachyarrhythmia and for rapid decrease of the ventricular response rate in atrial flutter or fibrillation. Only intravenous diltiazem is approved for this purpose in the United States (see “Diltiazem Doses” earlier in this chapter). Oral diltiazem can be used for the elective as well as prophylactic control (90 mg three times daily) of most supraventricular tachyarrhythmias (oral diltiazem is not approved for this use in the United States or United Kingdom). WPW syndrome is a contraindication to diltiazem.

Answer 74

Antiarrhythmic properties of diltiazem. The main electrophysiologic effect is a depressant one on the AV node; the functional and effective refractory periods are prolonged by diltiazem, so that diltiazem is licensed for termination of an attack of supraventricular tachyarrhythmia and for rapid decrease of the ventricular response rate in atrial flutter or fibrillation. Only intravenous diltiazem is approved for this purpose in the United States (see “Diltiazem Doses” earlier in this chapter). Oral diltiazem can be used for the elective as well as prophylactic control (90 mg three times daily) of most supraventricular tachyarrhythmias (oral diltiazem is not approved for this use in the United States or United Kingdom). WPW syndrome is a contraindication to diltiazem.

Question 75

Summary. Diltiazem, with its low side-effect profile, has advantages in the therapy of angina pectoris, acting by peripheral vasodilation, relief of exercise-induced coronary constriction, a modest negative inotropic effect, and sinus node inhibition. There are no outcome studies comparing diltiazem and verapamil. As in the case of verapamil, combination with β-blockade is generally not advised.

Answer 75

Summary. Diltiazem, with its low side-effect profile, has advantages in the therapy of angina pectoris, acting by peripheral vasodilation, relief of exercise-induced coronary constriction, a modest negative inotropic effect, and sinus node inhibition. There are no outcome studies comparing diltiazem and verapamil. As in the case of verapamil, combination with β-blockade is generally not advised.

Question 76

The major actions of the DHPs can be simplified to one: arteriolar dilation (see Fig. 3-5). The direct negative .......effect is usually outweighed by arteriolar ......... effects and by reflex ............. stimulation (see Fig. 3-6), except in patients with ...................

Answer 76

The major actions of the DHPs can be simplified to one: arteriolar dilation (see Fig. 3-5). The direct negative inotropic effect is usually outweighed by arteriolar unloading effects and by reflex adrenergic stimulation (see Fig. 3-6), except in patients with heart failure.

Question 77

DHP: Contraindications and cautions (Fig. 3-9, Table 3-5). These are tight ........... or ..........(danger of exaggerated pressure gradient), clinically evident ........... or LV .............. (added negative inotropic effect), and preexisting .................. Relative contraindications are subjective intolerance to the DHP and previous adverse reactions. In pregnancy, DHP should only be used if the benefits are thought to outweigh the risk of embryopathy

Answer 77

(Fig. 3-9, Table 3-5). These are tight aortic stenosis or obstructive hypertrophic cardiomyopathy (danger of exaggerated pressure gradient), clinically evident heart failure or LV dysfunction (added negative inotropic effect), and preexisting hypotension. Relative contraindications are subjective intolerance to the DHP and previous adverse reactions. In pregnancy, DHP should only be used if the benefits are thought to outweigh the risk of embryopathy

Question 78

DHP: Severe or rare side effects. In patients with LV dysfunction, the direct negative inotropic effect can be a serious problem. Rarely, side effects are compatible with the effects of excess hypotension and organ underperfusion, namely myocardial ischemia or even infarction, retinal and cerebral ischemia, and renal failure. Other unusual side effects include muscle cramps, myalgia, hypokalemia (via diuretic effect), and gingival swelling.

Answer 78

Severe or rare side effects. In patients with LV dysfunction, the direct negative inotropic effect can be a serious problem. Rarely, side effects are compatible with the effects of excess hypotension and organ underperfusion, namely myocardial ischemia or even infarction, retinal and cerebral ischemia, and renal failure. Other unusual side effects include muscle cramps, myalgia, hypokalemia (via diuretic effect), and gingival swelling.

Question 79

Amlodipine: The first of the second-generation DHPS: The major specific advantages of amlodipine (Norvasc; Istin in the United Kingdom) are (1) the slow onset of action and the long duration of activity (see Table 3-5) and (2) the vast experience with this drug in hypertension. It was the first of the longer-acting “second-generation” CCBs.

Answer 79

The major specific advantages of amlodipine (Norvasc; Istin in the United Kingdom) are (1) the slow onset of action and the long duration of activity (see Table 3-5) and (2) the vast experience with this drug in hypertension. It was the first of the longer-acting “second-generation” CCBs.

Question 80

Amlodipine: The first of the second-generation DHPS: It binds to .................... The charged nature of the molecule means that its binding is not entirely typical, with very slow association and dissociation, so that the channel block is slow in onset and offset. Additionally, it also binds to the same sites as .................., albeit to a lesser degree, so that with justification its binding properties are regarded as unique.48

Answer 80

It binds to the same site as other DHPs (labeled N in Fig. 3-4). The charged nature of the molecule means that its binding is not entirely typical, with very slow association and dissociation, so that the channel block is slow in onset and offset. Additionally, it also binds to the same sites as verapamil and diltiazem, albeit to a lesser degree, so that with justification its binding properties are regarded as unique.48

Question 81

Pharmacokinetics. Peak blood levels are reached after ........... hours, followed by extensive hepatic metabolism to inactive metabolites. The plasma levels ............... during chronic dosage probably because of the very long half-life. The elimination half-life is .......... hours, increasing slightly with chronic dosage. In older adults, the clearance is reduced and the dose may need reduction.

Answer 81

Pharmacokinetics. Peak blood levels are reached after 6 to 12 hours, followed by extensive hepatic metabolism to inactive metabolites. The plasma levels increase during chronic dosage probably because of the very long half-life. The elimination half-life is 35 to 48 hours, increasing slightly with chronic dosage. In older adults, the clearance is reduced and the dose may need reduction.

Question 82

Regarding drug interactions, ...........digoxin levels has been found, nor is there any interaction with ............. (in contrast to verapamil and nifedipine). Because of the hepatic CYP3A4 interaction, the FDA warns that the 20-mg dose of simvastatin should not be exceeded in patients taking amlodipine.

Answer 82

Regarding drug interactions, no effect on digoxin levels has been found, nor is there any interaction with cimetidine (in contrast to verapamil and nifedipine). Because of the hepatic CYP3A4 interaction, the FDA warns that the 20-mg dose of simvastatin should not be exceeded in patients taking amlodipine.

Question 83

Hypertension. Amlodipine has an outstanding record in major BP trials (Table 3-6).49 As initial monotherapy, a common starting dose is 5 mg daily going up to 10 mg. In a large trial on mild hypertension in a middle-aged group over 4 years, amlodipine 5 mg daily was the best tolerated of the agents compared with an α-blocker, a β-blocker, a diuretic, and an ACE inhibitor.50 In the largest outcome study, ALLHAT, amlodipine had the same primary outcome (fatal and nonfatal coronary heart disease) as the diuretic and ACE-inhibitor groups, but with modestly increased heart failure while decreasing new diabetes.30 In another mega-trial, ASCOT-BP Lowering Arm, amlodipine usually in combination with the ACE inhibitor perindopril gave much better outcomes than a β-blocker usually combined with a diuretic.23 Specifically, all cardiovascular events were decreased including heart failure, new diabetes was less, and decreased mortality led to premature termination of the trial.

Answer 83

Amlodipine has an outstanding record in major BP trials (Table 3-6).49 As initial monotherapy, a common starting dose is 5 mg daily going up to 10 mg. In a large trial on mild hypertension in a middle-aged group over 4 years, amlodipine 5 mg daily was the best tolerated of the agents compared with an α-blocker, a β-blocker, a diuretic, and an ACE inhibitor.50 In the largest outcome study, ALLHAT, amlodipine had the same primary outcome (fatal and nonfatal coronary heart disease) as the diuretic and ACE-inhibitor groups, but with modestly increased heart failure while decreasing new diabetes.30 In another mega-trial, ASCOT-BP Lowering Arm, amlodipine usually in combination with the ACE inhibitor perindopril gave much better outcomes than a β-blocker usually combined with a diuretic.23 Specifically, all cardiovascular events were decreased including heart failure, new diabetes was less, and decreased mortality led to premature termination of the trial.

Question 84

Contraindications, cautions, and side effects. Amlodipine has the same contraindications as other DHPs (see Fig. 3-9). First principles strongly suggest that it should not be used in the absence of concurrent β-blockade. In heart failure CCBs as a group are best avoided but amlodipine may be added, for example, for better control of angina. In liver disease the dose should be reduced. Of the side effects, peripheral edema is most troublesome, occurring in approximately 10% of patients at 10 mg daily (see Table 3-4). In women there is more edema (15%) than in men (6%). Next in significance are dizziness (3% to 4%) and flushing (2% to 3%). Compared with verapamil, edema is more common but headache and constipation are less common. Compared with placebo, headache is not increased (package insert).

Answer 84

Amlodipine has the same contraindications as other DHPs (see Fig. 3-9). First principles strongly suggest that it should not be used in the absence of concurrent β-blockade. In heart failure CCBs as a group are best avoided but amlodipine may be added, for example, for better control of angina. In liver disease the dose should be reduced. Of the side effects, peripheral edema is most troublesome, occurring in approximately 10% of patients at 10 mg daily (see Table 3-4). In women there is more edema (15%) than in men (6%). Next in significance are dizziness (3% to 4%) and flushing (2% to 3%). Compared with verapamil, edema is more common but headache and constipation are less common. Compared with placebo, headache is not increased (package insert).

Question 85

Summary. The very long half-life of amlodipine, good tolerability, and virtual absence of drug interactions (exception: high-dose simvastatin) makes it an effective once-a-day antianginal and antihypertensive agent, setting it apart from agents that are either twice or thrice daily. Side effects are few; ankle edema is the chief side effect. Exercise-induced ischemia is more effectively reduced by amlodipine than by the β-blocker atenolol, and the combination is even better. However, the CCB–β-blocker combination is often underused, even in some studies reporting “optimally treated” stable effort angina. Amlodipine-based therapy in the notable ASCOT study in hypertension gave widespread cardiovascular protection, thereby dispelling the once-held belief that CCBs had some adverse outcome effects.

Answer 85

Summary. The very long half-life of amlodipine, good tolerability, and virtual absence of drug interactions (exception: high-dose simvastatin) makes it an effective once-a-day antianginal and antihypertensive agent, setting it apart from agents that are either twice or thrice daily. Side effects are few; ankle edema is the chief side effect. Exercise-induced ischemia is more effectively reduced by amlodipine than by the β-blocker atenolol, and the combination is even better. However, the CCB–β-blocker combination is often underused, even in some studies reporting “optimally treated” stable effort angina. Amlodipine-based therapy in the notable ASCOT study in hypertension gave widespread cardiovascular protection, thereby dispelling the once-held belief that CCBs had some adverse outcome effects.

Question 86

Third-generation DHP CCBs inhibit ...- type calcium channels on vascular muscular cells such as those localized on postglomerular arterioles. Sadly, they had a somewhat rocky start when the prototype agent, mibefradil, had to be withdrawn after a series of successful studies because of hepatic side effects. Now there is interest in a newer agent, manidipineMuch larger trials are required to place the third-generation CCBs firmly on the therapeutic map.

Answer 86

Third-generation DHP CCBs inhibit T-type calcium channels on vascular muscular cells such as those localized on postglomerular arterioles. Sadly, they had a somewhat rocky start when the prototype agent, mibefradil, had to be withdrawn after a series of successful studies because of hepatic side effects. Now there is interest in a newer agent, manidipineMuch larger trials are required to place the third-generation CCBs firmly on the therapeutic map.

Question 87

Summary 1. Spectrum of use. CCBs (calcium antagonists) are widely used in the therapy of hypertension and underused in effort angina. The major mechanism of action is by calcium channel blockade in the arterioles, with peripheral or coronary vasodilation thereby explaining the major effects in hypertension and in effort angina. The HRL CCBs have a prominent negative inotropic effect, and inhibit the sinus and the AV nodes. These inhibitory cardiac effects are absent or muted in the DHPs, of which nifedipine is the prototype, now joined by amlodipine, felodipine, and others. Of these, amlodipine is very widely used in hypertension with proven outcome benefit. As a group, the DHPs are more vascular selective and more often used in hypertension than the HRL agents, also called the non-DHPs. Only the non-DHPs, verapamil and diltiazem, have antiarrhythmic properties by inhibiting the AV node. Both DHPs and non-DHPs are used against effort angina, albeit acting through different mechanisms and often underused especially in the United States.

Answer 87

Summary 1. Spectrum of use. CCBs (calcium antagonists) are widely used in the therapy of hypertension and underused in effort angina. The major mechanism of action is by calcium channel blockade in the arterioles, with peripheral or coronary vasodilation thereby explaining the major effects in hypertension and in effort angina. The HRL CCBs have a prominent negative inotropic effect, and inhibit the sinus and the AV nodes. These inhibitory cardiac effects are absent or muted in the DHPs, of which nifedipine is the prototype, now joined by amlodipine, felodipine, and others. Of these, amlodipine is very widely used in hypertension with proven outcome benefit. As a group, the DHPs are more vascular selective and more often used in hypertension than the HRL agents, also called the non-DHPs. Only the non-DHPs, verapamil and diltiazem, have antiarrhythmic properties by inhibiting the AV node. Both DHPs and non-DHPs are used against effort angina, albeit acting through different mechanisms and often underused especially in the United States.

Question 88

Summary: 2. Safety and efficacy. Previous serious concerns about the long-term safety of the CCBs as a group have been annulled by seven large outcome studies in hypertension, with one in angina pectoris. Nonetheless, as with all drugs, cautions and contraindications need to be honored.

Answer 88

2. Safety and efficacy. Previous serious concerns about the long-term safety of the CCBs as a group have been annulled by seven large outcome studies in hypertension, with one in angina pectoris. Nonetheless, as with all drugs, cautions and contraindications need to be honored.

Question 89

Summary: 3. Ischemic heart disease. All the CCBs work against effort angina, with efficacy and safety rather similar to β-blockers. The largest angina outcome study, ACTION, showed the benefits of adding a long acting DHP to prior β-blockade. In unstable angina the DHPs are specifically contraindicated in the absence of β-blockade because of their tendency to vasodilation-induced reflex adrenergic activation. Although the use of the HRL non-DHPs in unstable angina is relatively well supported by data, they have in practice been supplanted by β-blockers. In postinfarct patients, verapamil may be used if β-blockade is not tolerated or contraindicated, provided that there is no heart failure, although it is not licensed for this purpose in the United States. DHPs do not have good postinfarct data.

Answer 89

3. Ischemic heart disease. All the CCBs work against effort angina, with efficacy and safety rather similar to β-blockers. The largest angina outcome study, ACTION, showed the benefits of adding a long acting DHP to prior β-blockade. In unstable angina the DHPs are specifically contraindicated in the absence of β-blockade because of their tendency to vasodilation-induced reflex adrenergic activation. Although the use of the HRL non-DHPs in unstable angina is relatively well supported by data, they have in practice been supplanted by β-blockers. In postinfarct patients, verapamil may be used if β-blockade is not tolerated or contraindicated, provided that there is no heart failure, although it is not licensed for this purpose in the United States. DHPs do not have good postinfarct data.

Question 90

Summary 4. Hypertension. Strong overall evidence from a series of large outcome studies favors the safety and efficacy on hard end points, including coronary heart disease, of longer-acting DHPs. One large outcome study on coronary heart disease shows that the non-DHP verapamil gives results overall as good as atenolol with less new diabetes.

Answer 90

4.Hypertension. Strong overall evidence from a series of large outcome studies favors the safety and efficacy on hard end points, including coronary heart disease, of longer-acting DHPs. One large outcome study on coronary heart disease shows that the non-DHP verapamil gives results overall as good as atenolol with less new diabetes.

Question 91

Summary: 5. Diabetic hypertension. ALLHAT showed that amlodipine was as effective as the diuretic or the ACE inhibitor in the relative risk of cardiovascular disease. Other data suggest that initial antihypertensive therapy in diabetics should be based on an ACE inhibitor or ARB, especially in those with nephropathy. To achieve current BP goals in diabetics, it is almost always necessary to use combination therapy, which would usually include an ACE inhibitor or ARB, and a CCB besides a diuretic or β-blocker.

Answer 91

5. Diabetic hypertension. ALLHAT showed that amlodipine was as effective as the diuretic or the ACE inhibitor in the relative risk of cardiovascular disease. Other data suggest that initial antihypertensive therapy in diabetics should be based on an ACE inhibitor or ARB, especially in those with nephropathy. To achieve current BP goals in diabetics, it is almost always necessary to use combination therapy, which would usually include an ACE inhibitor or ARB, and a CCB besides a diuretic or β-blocker.

Question 92

Summary: 6. Heart failure. Heart failure remains a class contraindication to the use of all CCBs, with two exceptions: diastolic dysfunction based on LV hypertrophy, and otherwise well-treated systolic heart failure when amlodipine may be cautiously added if essential, for example, for control of angina

Answer 92

``` 6. Heart failure. Heart failure remains a class contraindication to the use of all CCBs, with two exceptions: diastolic dysfunction based on LV hypertrophy, and otherwise well-treated systolic heart failure when amlodipine may be cautiously added if essential, for example, for control of angina ```