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136 Cardiac Drugs

Antiarrhythmic Drugs

The electrical impulse for contraction (propagated action potential; p.138) originates in pacemaker cells of the sinoatrial node and spreads through the atria, atrioventricular (AV) node, and adjoining parts of the His–Purkinje fiber system to the ventricles (A). Irregularities of heart rhythm can interfere dangerously with cardiac pumping function.

I. Drugs for Selective Control of Sinoatrial and AV Nodes

In some forms of arrhythmia, certain drugs can be used that are capable of selectively facilitating and inhibiting (green and red arrows, respectively) the pacemaker function of sinoatrial or atrioventricular cells.

Sinus bradycardia. An abnormally low sinoatrial impulse rate (< 60/min) can be raised by parasympatholytics. The quaternary ipratropium is preferable to atropine, because it lacks CNS penetrability (p.108). Sympathomimetics also exert a positive chronotropic action; they have the disadvantage of increasing myocardial excitability (and automaticity) and, thus, promoting ectopic impulse generation (tendency to extrasystolic beats). In cardiac arrest, epinephrine, given by intrabronchial instillation or intracardiac injection, can be used to reinitiate heart beat.

Sinus tachycardia (resting rate > 100 beats/ min). β-Blockers eliminate sympatho-excita- tion and lower cardiac rate. Sotalol is noteworthy because of its good antiarrhythmic action (caution: QT-prolongation)

Atrial flutter or fibrillation. An excessive ventricular rate can be decreased by verapamil (p.126) or cardiac glycosides (p.134). These drugs inhibit impulse propagation through the AV node, so that fewer impulses reach the ventricles.

II. Nonspecific Drug Actions on Impulse Generation and Propagation

In some types of rhythm disorders, antiarrhythmics of the local anesthetic, Na+- channel blocking type are used for both prophylaxis and therapy. These substances block the Na+ channel responsible for the fast depolarization of nerve and muscle tissues. Therefore, the elicitation of action potentials is impeded and impulse conduction is delayed. This effect may exert a favorable influence in some forms of arrhythmia, but can itself act arrhythmogenically. Unfortunately, antiarrhythmics of the local anesthetic, Na+-channel blocking type lack suf - cient specificity in two respects: (1) other ion channels of cardiomyocytes, such as K+ and Ca+ channels, are also affected (abnormal QT prolongation); and (2) their action is not restricted to cardiac muscle tissue but also impacts on neural tissues and brain cells. Adverse effects on the heart include production of arrhythmias and lowering of heart rate, AV conduction, and systolic force. CNS side effects are manifested by vertigo, giddiness, disorientation, confusion, motor disturbances, etc.

Some antiarrhythmics are rapidly degraded in the body by cleavage (see arrows in B); these substances are not suitable for oral administration but must be given intravenously (e.g., lidocaine).

Irrespective of the cause underlying atrial fibrillation, formation of a thrombus may occur in the atria, because blood stagnates in the auricles. From such a thrombus an embolus may be dislodged and carried into the arterial supply of the brain, precipitating a stroke. Itistherefore imperative toinstitute anticoagulant therapy in atrial fibrillation. For immediate effect, heparin preparations are indicated; subsequently, changeover to vitamin K antagonists (e.g., phenprocoumon) may be made. As long as episodes of arrhythmia occur, therapy must be continued.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

 

Antiarrhythmic Drugs

137

A. Cardiac impulse generation and conduction

 

 

Sinus node

 

 

 

Para-

 

Atrium

sympatholytics

 

β -Sympatho-

 

 

 

 

mimetics

 

AV-node

 

 

Bundle of His

 

 

Tawara (AV node)

β -Blocker

 

Verapamil

 

bundle branches

 

Purkinje

Cardiac

 

glycoside

 

fibers

 

Ventricle

Vagal

 

 

stimulation

 

B. Antiarrhythmics of the Na+-channel blocking type

Main effect

Antiarrhythmic effect

Adverse effects

CNS disturbances

Arrhythmia

Cardiodepression

Antiarrhythmics of the local anesthetic (Na+-channel blocking) type:

Inhibition of impulse generation and conduction

Esterases

 

 

 

 

 

 

 

 

 

Procaine

 

O

 

 

 

 

 

 

C2H5

 

 

 

 

 

 

+

H2N

C

 

 

O

 

CH2

 

CH2

 

NH

 

 

 

 

 

 

 

 

 

 

 

C2H5

 

 

 

 

 

 

Procainamide

 

O

 

 

 

 

 

C2H5

 

 

 

 

+

H2N

C

 

N

 

CH2

 

CH2

 

NH

 

 

 

H

 

 

 

 

 

C2H5

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CH3

 

O

Lidocaine

 

 

C2H5

 

 

 

+

N C

CH2 NH

H

 

 

 

C2H5

CH3

CH3

H

Mexiletine

 

 

O CH2

+

 

CH NH

 

 

H

 

CH3

CH3

 

 

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

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138 Cardiac Drugs

Electrophysiological Actions of Antiarrhythmics of the Na+-Channel Blocking Type

Action potential and ionic currents. The transmembrane electrical potential of cardiomyocytes can be recorded through an intracellular microelectrode. Upon electrical excitation, the resting potential shows a characteristic change—the action potential (AP). Its underlying cause is a sequence of transient ionic currents. During rapid depolarization (phase 0), there is a short-lived influx of Na+ through the membrane. A subsequent transient influx of Ca2+ (as well as of Na+) maintains the depolarization (phase 2, plateau of AP). A delayed ef ux of K+ returns the membrane potential (phase 3, repolarization) to its resting value (phase 4). The velocity of depolarization determines the speed at which the AP propagates through the myocardial syncytium.

The transmembrane ionic currents involve proteinaceous membrane pores: Na+, Ca2+, and K+ channels. In (A), the phasic change in the functional state of Na+ channels during an action potential is illustrated.

Na+-channel blocking antiarrhythmics reduce the probability of Na+ channels to open upon membrane depolarization (“membrane stabilization”). The potential consequences are (A, bottom): (1) A reduction in the velocity of depolarization and a decrease in the speed of impulse propagation; aberrant impulse propagation is impeded. (2)

Depolarization is entirely absent; pathological impulse generation, e.g., in the marginal zone of an infarction, is suppressed. (3) The time required until a new depolarization can be elicited, i.e., the refractory period, is increased; prolongation of the AP (see below) contributes to the increase in refractory period. Consequently, premature excitation with risk of fibrillation is prevented.

Mechanism of action. Na+-channel blocking antiarrhythmics resemble most local anesthetics in being cationic amphiphilic molecules (p.206; exception: phenytoin, p.191). Possible molecular mechanisms of their inhibitory effects are outlined on p.202 in more detail. Their low structural specificity is reflected by a low selectivity toward different cation channels. Besides the Na+ channel, Ca2+and K+ channels are also likely to be blocked. Accordingly, cationic amphiphilic antiarrhythmics affect both the depolarization and repolarization phases. Depending on the substance, AP duration can be increased (Class IA), decreased (Class IB), or remain the same (Class IC). Antiarrhythmics representative of these categories include: Class IA—quinidine, procainamide, ajmaline, disopyramide; Class IB—lidocaine, mexiletine, tocainide; Class IC—flecainide, propafenone.

K2+–channel blocking antiarrhythmics. The drug amiodarone and the β-blocker sotalol have been assigned to Class III, comprising agents that cause marked prolongation of AP with less effect on the velocity of depolarization. Note that Class II is represented by β-blockers and Class IV by the Ca2+-chan- nel blockers verapamil and diltiazem (see p.126).

Therapeutic uses. Because of their narrow therapeutic margin, antiarrhythmics are only employed when rhythm disturbances are of such severity as to impair the pumping action of the heart, or when there is a threat of other complications. Combinations of different antiarrhythmics are not recommended (e.g., quinidine plus verapamil). Some agents, such as amiodarone, are reserved for special cases. This iodine-containing substance has unusual properties: its elimination half-life is 50–70 days; depending on its electrical charge, it is bound to apolar and polar lipids, stored in tissues (corneal opacification, pulmonary fibrosis); and it interferes with thyroid function.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Antiarrhythmics of Na+-Channel Blocking Type

139

A. Effects of antiarrhythmics of the Na+-channel blocking type

 

 

[mV]

 

 

 

potentialMembrane

0

 

 

 

 

 

 

 

 

 

 

 

 

 

 

-80

 

 

 

 

 

 

 

 

 

 

 

 

Na+

 

 

 

Action potential

 

 

 

 

 

 

 

1

2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

0

 

 

Rate of

 

3

 

 

 

 

 

 

depolarization

 

4

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Refractory period

 

 

 

 

 

 

 

 

 

 

250 Time [ms]

 

 

0

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Heart muscle cell

Ca2+(+Na+)

 

 

K+

 

Phase 0

Phases 1,2

Phase 3

Phase 4

Fast

Slow Ca2+-entry

 

 

Na+-entry

 

 

 

Ionic currents during action potential

 

 

Na+

Na+-channels

 

Open (active)

Closed

 

Closed

Opening impossible

 

Opening possible

 

 

 

(inactivated)

 

(resting, can be

States of Na+-channels during an action potential

 

activated)

 

 

Inhibition of

Antiarrhythmics of the

 

Na+-channel opening

Na+-channel blocking type

 

 

 

Inexcitability

 

Stimulus

 

 

 

Rate of

Suppression

Prolongation of refractory period =

depolarization

of AP generation

duration of inexcitability

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

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140 Antianemics
Drugs for the Treatment of Anemias
Anemia denotes a reduction in red blood cell count or hemoglobin content, or both.
Erythropoiesis (A)
Blood corpuscles develop from stem cells through several cell divisions (n = 17!). Hemoglobin is then synthesized and the cell nucleus is extruded. Erythropoiesis is stimulated by the hormone erythropoietin (a glycoprotein), which is released from the kidneys when renal oxygen tension declines. A nephrogenic anemia can be ameliorated by parenteral administration of recombinant erythropoietin (epoetin alfa) or hyperglycosylated erythropoietin (darbepoetin; longer half-life than epoetin).
Even in healthy humans, formation of red blood cells and, hence, the oxygen transport capacity of blood, is augmented by erythropoietin,. This effect is equivalent to high-al- titude training and is employed as a doping method by high-performance athletes. Erythropoietin is inactivated by cleavage of sugar residues, with a biological half-life of ~ 5 hours after intravenous injection and a t½ > 20 hours after subcutaneous injection.
Given adequate production of erythropoietin, a disturbance of erythropoiesis is due to two principal causes. (1) Cell multiplication is inhibited because DNA synthesis is insuf cient. This occurs in deficiencies of vitamin B12 or folic acid(macrocytichyperchromic anemia). (2) Hemoglobin synthesis is impaired. This situation arises in iron deficiency, since Fe2+ is a constituent of hemoglobin (microcytic hypochromic anemia).
Vitamin B12 (B)
Vitamin B12 (cyanocobalamin) is produced by bacteria; vitamin B12 generated in the colon, however, is unavailable for absorption. Liver, meat, fish, and milk products are rich sources of the vitamin. The minimal requirement is about 1 µg/day. Enteral absorption ofvitamin B12 requirestheso-calledintrinsic factor” from parietal cells of the

coprotein undergoes endocytosis in the ileum. Bound to its transport protein, transcobalamin, vitamin B12 is destined for storage in the liver or uptake into tissues.

A frequent cause of vitamin B12 deficiency is atrophic gastritis leading to a lack of intrinsic factor. Besides megaloblastic anemia, damage to mucosal linings and degeneration of myelin sheaths with neurological sequelae will occur (pernicious anemia). The optimal therapy consists in parenteral administration of cyanocobalamin or hydroxycobalamin (vitamin B12a; exchange of –CN for –OH group). Adverse effects, in the form of hypersensitivity reactions, are very rare.

Folic Acid (B)

Leafy vegetables and liver are rich in folic acid (FA). The minimal requirement is

~ 50 µg/day. Polyglutamine-FA in food is hydrolyzed to monoglutamine-FA prior to being absorbed. Causes of deficiency include insuf cient intake, malabsorption, and increased requirements during pregnancy (hence the prophylactic administration during pregnancy). Antiepileptic drugs and oral contraceptives may decrease FA absorption, presumably by inhibiting the formation of monoglutamine-FA. Inhibition of dihydro-FAreductase (e.g., by methotrexate, p.300) depresses the formation of the active species, tetrahydro-FA. Symptoms of deficiency are megaloblastic anemia and mucosal damage. Therapy consists in oral administration of FA.

Administration of FA can mask a vitamin B12 deficiency. Vitamin B12 isrequired for the conversion of methyltetrahydro-FA to tetra- hydro-FA, which is important for DNA-syn- thesis (B). Inhibition of this reaction due to vitamin B12 deficiency can be compensated by increased FA intake. The anemia is readily corrected; however, nerve degeneration progresses unchecked and its cause is made more dif cult to diagnose by the absence of hematologicalchanges. Indiscriminate use of FA-containing multivitamin preparations

stomachLuellmann,. TheColorcomplexAtlasformedof Pharmacologywith this gly-© 2005can,Thiemet erefore, be harmful.

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Drugs for the Treatment of Anemias

141

A. Erythropoiesis in bone marrow

 

 

Inhibition of DNA

Erythropoetin

Inhibition of

synthesis

hemoglobin synthesis

(cell multiplication)

 

Vit. B12 deficiency

Iron deficiency

 

 

 

Folate deficiency

 

 

Very few large

 

Few small

hemoglobin-rich

 

hemoglobin-poor

erythrocytes

 

erythrocytes

B. Vitamin B12 and folate metabolism

 

 

Folic acid H4

 

 

DNA

 

 

 

synthesis

 

Vit. B12

Folic acid

H3C-

Folic acid H4

 

 

H3C- Vit. B12

 

 

 

 

Vit. B12

 

 

H3C-

 

 

 

 

Trans-

 

HCl

 

 

 

 

cobalamin II

 

 

Storage supply for

 

 

 

3 years

Vit. B12

 

Intrinsic

 

 

 

 

 

factor

 

 

 

Parietal cell

i.m.

 

 

 

Streptomyces

 

 

 

griseus

 

 

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

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