Color Atlas of Pharmacology (Part 12): Inhibitors of the RAA System

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Inhibitors of the RAA System lasting effect than does captopril. Indications are hypertension and cardiac failure. Lowering of an elevated blood pressure is predominantly brought about by diminished production of angiotensin II. Impaired degradation of kinins that exert vasodilating actions may contribute to the effect. In heart failure, cardiac output rises again because ventricular afterload diminishes due to a fall in peripheral resistance. Venous congestion abates as a result of (1) increased cardiac output and (2) reduction in venous return (decreased aldosterone secretion, decreased tonus of venous capacitance vessels). Undesired effects. The magnitude of the antihypertensive effect of ACE inhibitors...

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124 Inhibitors of the RAA System Inhibitors of the RAA System lasting effect than does captopril. Indi- cations are hypertension and cardiac Angiotensin-converting enzyme (ACE) failure. is a component of the antihypotensive Lowering of an elevated blood pres- renin-angiotensin-aldosterone (RAA) sure is predominantly brought about by system. Renin is produced by special- diminished production of angiotensin II. ized cells in the wall of the afferent ar- Impaired degradation of kinins that ex- teriole of the renal glomerulus. These ert vasodilating actions may contribute cells belong to the juxtaglomerular ap- to the effect. paratus of the nephron, the site of con- In heart failure, cardiac output rises tact between afferent arteriole and dis- again because ventricular afterload di- tal tubule, and play an important part in minishes due to a fall in peripheral re- controlling nephron function. Stimuli sistance. Venous congestion abates as a eliciting release of renin are: a drop in result of (1) increased cardiac output renal perfusion pressure, decreased rate and (2) reduction in venous return (de- of delivery of Na+ or Cl– to the distal tu- creased aldosterone secretion, de- bules, as well as !-adrenoceptor-medi- creased tonus of venous capacitance ated sympathoactivation. The glycopro- vessels). tein renin enzymatically cleaves the Undesired effects. The magnitude decapeptide angiotensin I from its cir- of the antihypertensive effect of ACE in- culating precursor substrate angiotensi- hibitors depends on the functional state nogen. ACE, in turn, produces biologi- of the RAA system. When the latter has cally active angiotensin II (ANG II) from been activated by loss of electrolytes angiotensin I (ANG I). and water (resulting from treatment ACE is a rather nonspecific pepti- with diuretic drugs), cardiac failure, or dase that can cleave C-terminal dipep- renal arterial stenosis, administration of tides from various peptides (dipeptidyl ACE inhibitors may initially cause an ex- carboxypeptidase). As “kininase II,” it cessive fall in blood pressure. In renal contributes to the inactivation of kinins, arterial stenosis, the RAA system may be such as bradykinin. ACE is also present in needed for maintaining renal function blood plasma; however, enzyme local- and ACE inhibitors may precipitate re- ized in the luminal side of vascular endo- nal failure. Dry cough is a fairly frequent thelium is primarily responsible for the side effect, possibly caused by reduced formation of angiotensin II. The lung is inactivation of kinins in the bronchial rich in ACE, but kidneys, heart, and other mucosa. Rarely, disturbances of taste organs also contain the enzyme. sensation, exanthema, neutropenia, Angiotensin II can raise blood pres- proteinuria, and angioneurotic edema sure in different ways, including (1) may occur. In most cases, ACE inhibitors vasoconstriction in both the arterial and are well tolerated and effective. Newer venous limbs of the circulation; (2) analogues include lisinopril, perindo- stimulation of aldosterone secretion, pril, ramipril, quinapril, fosinopril, be- leading to increased renal reabsorption nazepril, cilazapril, and trandolapril. of NaCl and water, hence an increased Antagonists at angiotensin II re- blood volume; (3) a central increase in ceptors. Two receptor subtypes can be sympathotonus and, peripherally, en- distinguished: AT1, which mediates the hancement of the release and effects of above actions of AT II; and AT2, whose norepinephrine. physiological role is still unclear. The ACE inhibitors, such as captopril sartans (candesartan, eprosartan, irbe- and enalaprilat, the active metabolite of sartan, losartan, and valsartan) are AT1 enalapril, occupy the enzyme as false antagonists that reliably lower high substrates. Affinity significantly influ- blood pressure. They do not inhibit ences efficacy and rate of elimination. degradation of kinins and cough is not a Enalaprilat has a stronger and longer- frequent side-effect. Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Inhibitors of the RAA System 125 Kidney ACE inhibitors RR O HOOC N SH Captopril CH3 O HOOC N CH3 O O CH3 Renin Enalaprilat Enalapril Angiotensinogen ACE e as ("2-globulin) Angiotensin I- tid converting- ep Ang I enzyme Kinins yp ox rb Ca yl- id Angiotensin I (Ang I) Kininase pt II pe COOH Di Ang II Degradation products AC E Vascular endothelium Losartan Cl CH2OH Angiotensin II N N H H2 N N N N N Receptors H3C AT1-receptor antagonists Venous Cardiac Arterial supply output blood pressure Peripheral venous resistance capacitance vessels Resistance vessels Vasoconstriction NaCl Aldosterone Sympatho- H 2O secretion activation K+ A. Renin-angiotensin-aldosterone system and inhibitors Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
126 Drugs Acting on Smooth Muscle Drugs Used to Influence Smooth Muscle 196; F2": dinoprost; E2: dinoprostone, Organs misoprostol, sulprostone) are capable of inducing rhythmic uterine contractions Bronchodilators. Narrowing of bron- and cervical relaxation at any time. They chioles raises airway resistance, e.g., in are mostly employed as abortifacients bronchial or bronchitic asthma. Several (oral or vaginal application of misopros- substances that are employed as bron- tol in combination with mifepristone [p. chodilators are described elsewhere in 256]). more detail: !2-sympathomimetics (p. Ergot alkaloids are obtained from 84, given by pulmonary, parenteral, or Secale cornutum (ergot), the sclerotium oral route), the methylxanthine theo- of a fungus (Claviceps purpurea) parasi- phylline (p. 326, given parenterally or tizing rye. Consumption of flour from orally), as well as the parasympatholytic contaminated grain was once the cause ipratropium (pp. 104, 107, given by in- of epidemic poisonings (ergotism) char- halation). acterized by gangrene of the extremities Spasmolytics. N-Butylscopolamine (St. Anthony’s fire) and CNS disturbanc- (p. 104) is used for the relief of painful es (hallucinations). spasms of the biliary or ureteral ducts. Ergot alkaloids contain lysergic acid Its poor absorption (N.B. quaternary N; (formula in A shows an amide). They act absorption rate
Drugs Acting on Smooth Muscle 127 Bronchial asthma Biliary / renal colic O2 Spasm of smooth muscle Bronchodilation Spasmolysis Inhibition of labor Theophylline N-Butylscopolamine !2 - Sympathomimetics Induction of labor Scopolamine Oxytocin !2-Sympathomimetics Nitrates Prostaglandins e.g., fenoterol e.g., nitroglycerin F2", E2 Ipratropium Secale cornutum (ergot) Tonic contraction of uterus e.g., ergometrine O2 Contraindication: before delivery Fungus: Claviceps purpurea Indication: postpartum uterine atonia Secale alkaloids Effect on vasomotor tone e.g., ergotamine Fixation of lumen at intemediate caliber A. Drugs used to alter smooth muscle function Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
128 Cardiac Drugs Overview of Modes of Action (A) Events Underlying Contraction and Relaxation (B) 1. The pumping capacity of the heart is regulated by sympathetic and parasym- The signal triggering contraction is a pathetic nerves (pp. 84, 105). Drugs ca- propagated action potential (AP) gener- pable of interfering with autonomic ated in the sinoatrial node. Depolariza- nervous function therefore provide a tion of the plasmalemma leads to a rap- means of influencing cardiac perfor- id rise in cytosolic Ca2+ levels, which mance. Thus, anxiolytics of the benzo- causes the contractile filaments to diazepine type (p. 226), such as diaze- shorten (electromechanical coupling). pam, can be employed in myocardial in- The level of Ca2+ concentration attained farction to suppress sympathoactiva- determines the degree of shortening, tion due to life-threatening distress. i.e., the force of contraction. Sources of Under the influence of antiadrenergic Ca2+ are: a) extracellular Ca2+ entering agents (p. 96), used to lower an elevated the cell through voltage-gated Ca2+ blood pressure, cardiac work is de- channels; b) Ca2+ stored in membranous creased. Ganglionic blockers (p. 108) sacs of the sarcoplasmic reticulum (SR); are used in managing hypertensive c) Ca2+ bound to the inside of the plas- emergencies. Parasympatholytics (p. malemma. The plasmalemma of cardio- 104) and !-blockers (p. 92) prevent the myocytes extends into the cell interior transmission of autonomic nerve im- in the form of tubular invaginations pulses to heart muscle cells by blocking (transverse tubuli). the respective receptors. The trigger signal for relaxation is 2. An isolated mammalian heart the return of the membrane potential to whose extrinsic nervous connections its resting level. During repolarization, have been severed will beat spontane- Ca2+ levels fall below the threshold for ously for hours if it is supplied with a activation of the myofilaments (3 10–7 nutrient medium via the aortic trunk M), as the plasmalemmal binding sites and coronary arteries (Langendorff regain their binding capacity; the SR preparation). In such a preparation, only pumps Ca2+ into its interior; and Ca2+ those drugs that act directly on cardio- that entered the cytosol during systole myocytes will alter contractile force and is again extruded by plasmalemmal beating rate. Ca2+-ATPases with expenditure of ener- Parasympathomimetics and sym- gy. In addition, a carrier (antiporter), pathomimetics act at membrane re- utilizing the transmembrane Na+ gradi- ceptors for visceromotor neurotrans- ent as energy source, transports Ca2+ out mitters. The plasmalemma also harbors of the cell in exchange for Na+ moving the sites of action of cardiac glycosides down its transmembrane gradient (the Na/K-ATPases, p. 130), of Ca2+ an- (Na+/Ca2+ exchange). tagonists (Ca2+ channels, p. 122), and of agents that block Na+ channels (local anesthetics; p. 134, p. 204). An intracel- lular site is the target for phosphodies- terase inhibitors (e.g., amrinone, p. 132). 3. Mention should also be made of the possibility of affecting cardiac func- tion in angina pectoris (p. 306) or con- gestive heart failure (p. 132) by reduc- ing venous return, peripheral resis- tance, or both, with the aid of vasodila- tors; and by reducing sympathetic drive applying !-blockers. Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Cardiac Drugs 129 Drugs with Drugs with direct action indirect action Nutrient solution Psychotropic drugs Force Sympatholytics Rate Ganglionic blockers !-Sympathomimetics Para- Cardiac Phosphodiesterase inhibitors glycosides sympathetic Force Rate Sympathetic Parasympathomimetics Catamphiphilic Epinephrine Ca-antagonists Local anesthetics A. Possible mechanisms for influencing heart function + - Ca2 10 3M Membrane potential Contraction [mV] electrical excitation 0 Ca-channel Sarcoplasmic reticulum Action potential Heart muscle cell Ca2+ 10-5M -80 Transverse tubule t + - Ca2 10 3M Force Relaxation Na+ Ca2+ Ca-ATPase Na/Ca- Contraction exchange Ca2+ Ca2+ Na+ Na+ Ca2+ Plasma- 10-7M lemmal binding sites 300 ms t B. Processes in myocardial contraction and relaxation Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
130 Cardiac Drugs Cardiac Glycosides area postrema leads to nausea and vom- iting. Disturbances in color vision are Diverse plants (A) are sources of sugar- evident. containing compounds (glycosides) that Indications for CG are: (1) chronic also contain a steroid ring (structural congestive heart failure; and (2) atrial formulas, p. 133) and augment the con- fibrillation or flutter, where inhibition of tractile force of heart muscle (B): cardio- AV conduction protects the ventricles tonic glycosides. cardiosteroids, or “digi- from excessive atrial impulse activity talis.” and thereby improves cardiac perfor- If the inotropic, “therapeutic” dose mance (D). Occasionally, sinus rhythm is exceeded by a small increment, signs is restored. of poisoning appear: arrhythmia and Signs of intoxication are: (1) car- contracture (B). The narrow therapeutic diac arrhythmias, which under certain margin can be explained by the mecha- circumstances are life-threatening, e.g., nism of action. sinus bradycardia, AV-block, ventricular Cardiac glycosides (CG) bind to the extrasystoles, ventricular fibrillation extracellular side of Na+/K+-ATPases of (ECG); (2) CNS disturbances — altered cardiomyocytes and inhibit enzyme ac- color vision (xanthopsia), agitation, tivity. The Na+/K+-ATPases operate to confusion, nightmares, hallucinations; pump out Na+ leaked into the cell and to (3) gastrointestinal — anorexia, nausea, retrieve K+ leaked from the cell. In this vomiting, diarrhea; (4) renal — loss of manner, they maintain the transmem- electrolytes and water, which must be brane gradients for K+ and Na+, the neg- differentiated from mobilization of ac- ative resting membrane potential, and cumulated edema fluid that occurs with the normal electrical excitability of the therapeutic dosage. cell membrane. When part of the en- Therapy of intoxication: adminis- zyme is occupied and inhibited by CG, tration of K+, which inter alia reduces the unoccupied remainder can increase binding of CG, but may impair AV-con- its level of activity and maintain Na+ and duction; administration of antiarrhyth- K+ transport. The effective stimulus is a mics, such as phenytoin or lidocaine (p. small elevation of intracellular Na+ con- 136); oral administration of colestyra- centration (normally approx. 7 mM). mine (p. 154, 156) for binding and pre- Concomitantly, the amount of Ca2+ mo- venting absorption of digitoxin present bilized during systole and, thus, con- in the intestines (enterohepatic cycle); tractile force, increases. It is generally injection of antibody (Fab) fragments thought that the underlying cause is the that bind and inactivate digitoxin and decrease in the Na+ transmembrane digoxin. Compared with full antibodies, gradient, i.e., the driving force for the fragments have superior tissue penet- Na+/Ca2+ exchange (p. 128), allowing the rability, more rapid renal elimination, intracellular Ca2+ level to rise. When too and lower antigenicity. many ATPases are blocked, K+ and Na+ homeostasis is deranged; the mem- brane potential falls, arrhythmias occur. Flooding with Ca2+ prevents relaxation during diastole, resulting in contracture. The CNS effects of CG (C) are also due to binding to Na+/K+-ATPases. En- hanced vagal nerve activity causes a de- crease in sinoatrial beating rate and ve- locity of atrioventricular conduction. In patients with heart failure, improved circulation also contributes to the re- duction in heart rate. Stimulation of the Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Cardiac Drugs 131 Helleborus niger Christmas rose Convallaria Digitalis purpurea majalis Red foxglove Lily of the valley A. Plants containing cardiac glycosides Arrhythmia Contracture Contraction Time ´therapeutic´ ´toxic´ Dose of cardiac glycoside (CG) Na+ Na/K-ATPase CG CG Na+ Na+ Na+ Ca2+ Coupling Ca2+ Ca2+ CG K+ K+ K+ K+ Heart muscle cell CG CG B. Therapeutic and toxic effects of cardiac glycosides (CG) Disturbance of "Re-entrant" color vision excitation in atrial fibrillation Cardiac glycoside Excitation of N. vagus: Decrease in Heart rate ventricular rate Area postrema: nausea, vomiting C. Cardiac glycoside effects on the CNS D. Cardiac glycoside effects in atrial fibrillation Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
132 Cardiac Drugs Substance Fraction Plasma concentr. Digitalizing Elimination Maintenance absorbed free total dose dose % (ng/mL) (mg) %/d (mg) Digitoxin 100 1 20 1 10 0.1 Digoxin 50–90 1 1.5 1 30 0.3 Ouabain
Cardiac Drugs 133 Ouabain Plasma Digoxin 95% Digitoxin 35% 0% Albumin Liver- cell Digitoxin Digoxin Cleavage of sugar Conjugation Deconjugation Intestinal epithelium Renal tubular epithelium Plasma t 1 9h 2 – 3 days 5 – 7 days 2 A. Pharmacokinetics of cardiac glycosides Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
134 Cardiac Drugs Antiarrhythmic Drugs ic, Na+-channel blocking type (B) are used for both prophylaxis and therapy. The electrical impulse for contraction Local anesthetics inhibit electrical exci- (propagated action potential; p. 136) tation of nociceptive nerve fibers (p. originates in pacemaker cells of the si- 204); concomitant cardiac inhibition noatrial node and spreads through the (cardiodepression) is an unwanted ef- atria, atrioventricular (AV) node, and fect. However, in certain types of ar- adjoining parts of the His-Purkinje fiber rhythmias (see above), this effect is use- system to the ventricles (A). Irregular- ful. Local anesthetics are readily cleaved ities of heart rhythm can interfere dan- (arrows) and unsuitable for oral admin- gerously with cardiac pumping func- istration (procaine, lidocaine). Given ju- tion. diciously, intravenous lidocaine is an ef- I. Drugs for selective control of si- fective antiarrhythmic. Procainamide noatrial and AV nodes. In some forms and mexiletine, congeners endowed of arrhythmia, certain drugs can be used with greater metabolic stability, are ex- that are capable of selectively facilitat- amples of orally effective antiarrhyth- ing and inhibiting (green and red ar- mics. The desired and undesired effects rows, respectively) the pacemaker func- are inseparable. Thus, these antiar- tion of sinoatrial or atrioventricular rhythmics not only depress electrical cells. excitability of cardiomyocytes (negative Sinus bradycardia. An abnormally bathmotropism, membrane stabiliza- low sinoatrial impulse rate (100 beats/min). !-Blockers eliminate sympathoexcitation and decrease car- diac rate. Atrial flutter or fibrillation. An ex- cessive ventricular rate can be de- creased by verapamil (p. 122) or cardiac glycosides (p. 130). 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. Impulses originating at loci outside the sinus node are seen in supraventricular or ventricular extrasystoles, tachycardia, atrial or ventricular flutter, and fibrilla- tion. In these forms of rhythm disorders, antiarrhythmics of the local anesthet- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Cardiac Drugs 135 Sinus node Para- sympatholytics Atrium !-Sympatho- mimetics AV-node Bundle of His !-Blocker Tawara´s node Verapamil Purkinje Cardiac fibers glycoside Ventricle (Vagal stimulation) A. Cardiac impulse generation and conduction Antiarrhythmics of the local anesthetic Main effect (Na+-channel blocking) type: Inhibition of impulse generation and conduction Antiarrhythmic effect Esterases Procaine Procainamide Adverse effects Lidocaine CNS-disturbances Mexiletine Arrhythmia Cardiodepression B. Antiarrhythmics of the Na+-channel blocking type Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
136 Cardiac Drugs Electrophysiological Actions of amphiphilic molecules (p. 208, excep- Antiarrhythmics of the Na+-Channel tion: phenytoin, p. 190). Possible molec- Blocking Type ular mechanisms of their inhibitory ef- fects are outlined on p. 204 in more de- Action potential and ionic currents. tail. Their low structural specificity is The transmembrane electrical potential reflected by a low selectivity towards of cardiomyocytes can be recorded different cation channels. Besides the through an intracellular microelectrode. Na+ channel, Ca2+ and K+ channels are al- Upon electrical excitation, a characteris- so likely to be blocked. Accordingly, cat- tic change occurs in membrane poten- ionic amphiphilic antiarrhythmics af- tial—the action potential (AP). Its under- fect both the depolarization and repola- lying cause is a sequence of transient rization phases. Depending on the sub- ionic currents. During rapid depolariza- stance, AP duration can be increased tion (Phase 0), there is a short-lived in- (Class IA), decreased (Class IB), or re- flux of Na+ through the membrane. A main the same (Class IC). subsequent transient influx of Ca2+ (as Antiarrhythmics representative well as of Na+) maintains the depola- of these categories include: Class IA— rization (Phase 2, plateau of AP). A de- quinidine, procainamide, ajmaline, dis- layed efflux of K+ returns the membrane opyramide, propafenone; Class IB—lido- potential (Phase 3, repolarization) to its caine, mexiletine, tocainide, as well as resting value (Phase 4). The velocity of phenytoin; Class IC—flecainide. depolarization determines the speed at Note: With respect to classification, which the AP propagates through the !-blockers have been assigned to Class myocardial syncytium. II, and the Ca2+-channel blockers vera- Transmembrane ionic currents in- pamil and diltiazem to Class IV. volve proteinaceous membrane pores: Commonly listed under a separate Na+, Ca2+, and K+ channels. In A, the rubric (Class III) are amiodarone and the phasic change in the functional state of !-blocking agent sotalol, which both in- Na+ channels during an action potential hibit K+-channels and which both cause is illustrated. marked prolongation of the AP with a Effects of antiarrhythmics. Antiar- lesser effect on Phase 0 rate of rise. rhythmics of the Na+-channel blocking Therapeutic uses. Because of their type reduce the probability that Na+ narrow therapeutic margin, these antiar- channels will open upon membrane de- rhythmics are only employed when polarization (“membrane stabiliza- rhythm disturbances are of such sever- tion”). The potential consequences are ity as to impair the pumping action of (A, bottom): 1) a reduction in the veloc- the heart, or when there is a threat of ity of depolarization and a decrease in other complications. The choice of drug the speed of impulse propagation; aber- is empirical. If the desired effect is not rant impulse propagation is impeded. 2) achieved, another drug is tried. Combi- Depolarization is entirely absent; patho- nations of antiarrhythmics are not cus- logical impulse generation, e.g., in the tomary. Amiodarone is reserved for spe- marginal zone of an infarction, is sup- cial cases. pressed. 3) The time required until a new depolarization can be elicited, i.e., the refractory period, is increased; pro- longation of the AP (see below) contrib- utes 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 Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Cardiac Drugs 137 [mV] Membrane potential 1 2 0 Rate of Action 0 depolarization potential (AP) Speed of AP 3 propagation 4 -80 Refractory period 0 250 Time [ms] Heart muscle cell Na+ 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 activated) States of Na+-channels during an action potential 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 A. Effects of antiarrhythmics of the Na+-channel blocking type Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.