CH 45 pg 497-504 Calcium Channel Blockers

Question 1

What are calcium channels?

Answer 1

gated pores in the cytoplasmic membrane that regulate the entry of calcium ions into cells

Question 2

What does calcium play a critical role in?

Answer 2

calcium entry plays a critical role in the function of vascular smooth muscle and the heart

Question 3

How do calcium channels regulate contraction in vascular smooth muscle?

Answer 3

When an action potential travels down the surface of a smooth muscle cell, calcium channels open and calcium ions flow inward, thereby initiating the contractile process
-if calcium channels are blocked, contraction will be prevented and vasodilation will result

Question 4

at therapeutic doses, where do CCBs selectively act?

Answer 4

on peripheral arterioles and arteries and arterioles of the heart

Question 5

Calcium channels in the heart

Answer 5

-help regulate the myocardium, the sinoatrial (SA) node
-Calcium channels at all three sites are coupled to beta 1- adrenergic receptors

Question 6

Calcium Channels- myocardium

Answer 6

in cardiac muscle, calcium entry has positive inotropic effects
-increases the force of contraction

If calcium channels in atrial and ventricular muscle are blocked, contractile force will diminish

Question 7

Calcium channels- SA node

Answer 7

-Pacemaker activity of the SA node is regulated by calcium influx
-when calcium channels are open, spontaneous discharge of the SA node increases
-conversely, when calcium channels close, pacemaker activity declines
the effect of calcium channel blockade is to reduce heart rate

Question 8

Calcium Channels- AV node

Answer 8

-regulation of AV conduction plays a critical role in coordinating the contraction of the ventricles with the contraction of the atria (because impulses that originate in the SA node must pass through the AV node on their way to the ventricles
-the excitability of AV nodal cells is regulated by calcium entry. When calcium channels are open, calcium entry increases, and cells of the AV node discharge more readily

-the effect of calcium channel blockade is to decrease velocity of conduction through the AV node

Question 9

coupling of cardiac calcium channels to Beta1-adrenergic receptors

Answer 9

-in the heart, calcium channels are coupled to beta 1-adrenergic receptors
-when cardiac beta1 receptors are activated, calcium influx is enhanced
-conversely, when beta1 receptors are blocked, calcium influx is suppressed
-CCBs and beta blockers have identical effects on the heart; they both reduce force of control, slow heart rate, and suppress conduction through the AV node

Question 10

Classification of CCBs

Answer 10

CCBs belong to three chemical families:
1. Dihydropyridines (nifedipine is prototype)
2. Phenylalkylamine (Verapamil is the only one)
3. Benzothiazepine (Diltiazem is the only one)

Drugs names are important, family names are not

Question 11

Sites of Action

Answer 11

-At therapeutic doses, the dihydropyridines act primarily on arterioles (can produce dangerous cardiac suppression at toxic doses)
-Verapamil and diltiazem act on arterioles and the heart

Question 12

What drugs act on the vascular smooth muscle and heart

Answer 12

Verapamil and Diltiazem

Question 13

What drugs act on the vascular smooth muscle and heart

Answer 13

Verapamil and Diltiazem

Question 14

Verapamil indications

Answer 14

-blocks calcium channels in blood vessels and in the heart
-major indications: angina pectoris, essential hypertension, cardiac dysrhythmias
-prototype

Question 15

Hemodynamic effects of Verapamil

Answer 15

the overall hemodynamic response to verapamil is the net result of
1. direct effects on the heart and blood vessels
2. reflex responses

Question 16

direct hemodynamic effects of verapamil

Answer 16

by blocking calcium channels in the heart and blood vessels, verapamil has five direct effects:
1. blockade at peripheral arterioles causes dilation, and thereby reduces arterial pressure
2. blockade at arteries and arterioles of the heart increases coronary perfusion
3. blockade at the SA node reduces HR
4. blockade at the AV node decreases AV nodal conduction
5. blockade in the myocardium decreases the force of contraction

Question 17

Indirect hemodynaic effects of verapamil

Answer 17

-verapamil-induced lowering of blood pressure activates the baroreceptor reflex, causing increased firing of sympatheic nerbes to the heart
-norepinephrine released from these nerves acts to increase HR, AV conduction, and force of contraction
-however, since these same three parameters are suppresed by the direct actions of verapamil, the direct and indirect effectrs tend to neutralize each other

Question 18

Net Hemodynamic Effect of Verapamil

Answer 18

-drug has little or no effect on cardiac performance (because the direct effects on the heart are counterbalanced by indirect effects)
-for most patients, HR, AV conduction, and contractility are not noticeable altered
-the overall cardiovascular effect of verapamil is simplt vasodilation accompanied by reduced arterial pressure and increased coronary perfusion

Question 19

Verapamil Pharmacokinetics

Answer 19

administer orally or IV
-undergoes extensive metabolism on its first pass through the liver (only about 20% of an oral dose reaches the systemic circulation) effects begin 30 mins after administrtion and peak within 5 hours

Question 20

Verapamil therapeutic uses

Answer 20

1. Angina Pectoris (benefits derive from vasodilation)
2. Essential hypertension (2nd line agent; thiazide diuretics are 1st)
3. **Cardiac dysrhythmias **(when administered IV, it is used to slow ventricular rate in pts with atrial flutter, atrial fibrillation, and paroxysmal aupraventricular tachycardia (benefits derive from suppressing impulse conduction through the AV node, thereby preventing the atria from driving the ventricles at an excessive rate)

Question 21

Verapamil Adverse Effects

Answer 21

Common Effects: constipation (caused by blockade of calcium channls in smooth musle of intestine), dizziness, facial flushing, headaches, edema of ankles and feet
Cardiac Effects: In the SA node, calcium channel blockade can cause bradycardia; In the AV node, blockade can cause partial or complete AV block. In the myocardium–> blockade can decrease contractility
usually affect healthy hearts, use with caution in certain cardiac diseases

Question 22

Verapamil Drug and Food Interactions

Answer 22

-Digoxin (suppresses impulse conduction through the AV node–> risk of AV block is increased)
-Beta-adrenergic blocking agents (same effects on the heart–> decrease HR, AV conduction and contractility. Concurrent use puts pt at risk of excessive cardiosuppression)
-Grapefruit juice (can inhibit the intestinal and hepatic metabolism of many drugs thus raise their levels)

Question 23

Diltiazem Actions and Uses

Answer 23

-blocks calcium channels in the heart and blood vessels
-the actions and applications are similar to verapamil
-both drugs lower blood pressure through arteriolar dilaion, and because their direct suppressant actions are balanced by reflec cardiac stimulation, both hace little net effect on the heart
1. angina pectoris
2. essential hypertension
3. cardiac dysrhythmias

Question 24

Diltiazem Actions and Uses

Answer 24

-blocks calcium channels in the heart and blood vessels
-the actions and applications are similar to verapamil
-both drugs lower blood pressure through arteriolar dilaion, and because their direct suppressant actions are balanced by reflec cardiac stimulation, both hace little net effect on the heart
1. angina pectoris
2. essential hypertension
3. cardiac dysrhythmias

Question 25

Diltiazem Pharmacokinetics

Answer 25

-oral= well absorbed and then extensively metabolized on its first pass through the liver -bioavailability is about 50% -effects begin rapidly and peak within half an hour -drug undergoes nearly complete metabolism before elimination in the urine and feces

Question 26

Diltiazem adverse effects

Answer 26

similar to thos of verapamil, except diltiazem causes less constipation common: dizziness, flushing, headache, edema of ankles and feet -can exacerbate cardiac dysfunction in pts with bradycardia, sick sinus syndrome, HF, or second-degree or third-degree AV block -like other CCBs, diltiazem can cause chronic eczematous rash in older adults

Question 27

Dihydropyridines -Nifedipine

Answer 27

Act mainly on vascular smooth muscle -blocks calcium channels in vsm and thereby promotes vasodilation -in contrast to verapamil, nifedipine produces very little blockade of calcium channels in the heart -cannot be used to treat dysrhythmias, doesnt cause cardiac suppression, and is less likely than verapamil to exacerbat pre-existing cardiac disorders -more likely to cause tachycardia -does not cause constipation

Question 28

Nifedipine Direct Hemodynamic effects

Answer 28

-effects are limited to blockade of calcium channels in VSM -bockade of calcium channels in peripheral arterioles cause vasodilation and thus lowers arterial pressure -at usual therapeutic doses, the drug has no direct suppresant effects on automaticity, AV conduction, or contractile force

Question 29

Nifedipine indirect hemodynamic effects

Answer 29

by lowering BP, nifedipine activates the baroreceptor reflex, thereby causing sympathetic stimulation of the heart -because Nifedipin lacks direct cardiosuppresant actions, cardiac stimulation is unoppsed, and hence heart rate and contractile force increases -reflex effects occur primarily with the immediate-release formulation of nifedipine, not with the SR formulation (this is because the baroreceptor reflex is turned on only by a rapid fall in blood pressure)

Question 30

Nifedipine net effects

Answer 30

sum of direct effect (vasodilation) and indirect effect (reflex cardiac stimulation) 1. lowers BP 2. increases HR (transient & occur primarily with the IR formulation) 3. increases contractile force (transient & occur primarily with the IR formulation)

Question 31

Nifedipine Therapeutic uses

Answer 31

1. Angina pectoris (indicated for vasospastic angina and angina of effort); usually combined with a beta blocker to prevent reflex stimulation of hte heart) 2. Hypertension (only ER formulation used)

Question 32

Nifedipine Adverse Effects

Answer 32

similar to those of verapamil- flushing, dizziness, headache, peripheral edema, gingival hyperplasia and may pose a risk of chronic exzematous rash in older adults. -contrast to verapamil- causes little constipation, causes minimal blockade of calcium channels in the heart

Question 33

Nifedipine Immediate release safety alert

Answer 33

-associated with increased mortality in patients with myocardial infarction and unstable angina

Question 34

Nifedipine Drug Interactions

Answer 34

-Beta Adrenergic Blockers; whereas beta blockers can decrease the adverse cardiac effects of nifedipine, they can intensify the adverse cardiac effects of verapamil and diltizem

Question 35

Nicardipine

Answer 35

-Dihydropyridine -at therapeutic doses, nicardipine produces selective blockade of calcium channels in blood vessels and has minimal direct effects on the heart -indications: essential hypertension and effort-induced angina pectoris -adverse effects: flushing, headaches, asthenia (weakness), dizziness, palpitations, and edema of the ankles and feet. rash may develop in older adults -can be combined with a beta blockers to promote therapeutic effects and suppress reflex tachycardia

Question 36

Amlodipine

Answer 36

-Dihydropyridine -at therapeutic doses, produces selective blockade of calcium channels in blood vessels, having minimal direct effects on the heart -indications: essential hypertension & angina pectoris (effort induced and vasospastic) -administered orally & absorbed slowly (peak levels=6-12 hours). long half life (30-50 hrs). -principal adverse effects= peripheral and facial edema -causes little reflex tachycardia

Question 37

Isradipine

Answer 37

-Dihydropyridine -produces relatively selective blockade of calcium channels in blood vessels -approced only for hypertension -rapidly absorbed following oral administration but undergoes exrtensive first-pass metabolism -common side effects= facial flushing, headaches, dizziness, and ankle edema, eczematous rash may develop in older patients -causes minimal reflex tachycardia

Question 38

Felodipine

Answer 38

-dihydropyridine -produces selective blockae of calcium channels in blood vessels -approved only for hypertension -well absorbed following oral administration and undergoes extensive first pass metabolism (low bioavailability) -characteristic adverse effects: reflex tachycardia, peripheral edema, headache, facial flushing, dizziness. Gingival hyperplasia has been reported

Question 39

Nimodipine

Answer 39

-dihydropyridine -produces selective blockade of calcium channels in CEREBRAL BLOOD VESSELS -only approved application is prophylaxis of neurologic injury following rupture of an intracranial aneurysm -never given IV

Question 40

Nisoldipine

Answer 40

-produced selective blockade of calcium channels in blood vessels -minimal direct effects on the heart -approved for hypertension -common side effects= dizziness, headache, peripheral edema -reflex tachycardia may also occur -eczematous rash may develop in older patients