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128

Inhibitors of the RAA System

 

 

ACE Inhibitors

elimination. Enalaprilat has a stronger and

 

longer-lasting effect than captopril.

 

 

 

 

 

 

Angiotensin-converting enzyme (ACE) is a

Indications are hypertension and cardiac

 

 

component of the antihypotensive renin–

failure.

 

 

angiotensin–aldosterone (RAA) system. Re-

Lowering of elevated blood pressure is

 

 

nin is produced by specialized smooth

predominantly brought about bydiminished

 

 

muscle cells in the wall of the afferent arte-

production of angiotensin II. Impaired deg-

 

 

riole of the renal glomerulus. These cells

radation of kinins that exert vasodilating ac-

 

 

belong to the juxtaglomerular apparatus,

tions may contribute to the effect.

 

 

the site of contact between afferent arteriole

In heart failure, cardiac output rises again

 

 

and distal tubule, which plays an important

after administration of an ACE inhibitor be-

 

 

part in controlling nephron function. Stimuli

cause ventricular afterload diminishes ow-

 

 

 

eliciting release of renin are: drop in renal

ing to a fall in peripheral resistance. Venous

 

 

perfusion pressure, decreased rate of deliv-

congestion abates as a result of (1) increased

 

 

ery of Na+ or Clto the distal tubules, as well

cardiac output and (2) reduction in venous

 

 

as β-adrenoceptor-mediated sympathoacti-

return (decreased aldosterone secretion, de-

 

 

vation. The glycoprotein renin enzymatically

creased tonus of venous capacitance ves-

 

 

cleaves the decapeptide angiotensin I from

sels).

 

 

its circulating precursor substrate angioten-

 

 

 

sinogen. The enzyme ACE, in turn, produces

Undesired effects. The magnitude of the

 

 

biologically active angiotensin II from angio-

antihypertensive effect of ACE inhibitors de-

 

 

tensin I.

 

pends on the functional state of the RAA

 

 

ACE is a rather nonspecific peptidase that

system. When the latter has been activated

 

 

can cleave C-terminal dipeptides from vari-

by loss of electrolytes and water (resulting

 

 

ous peptides (dipeptidyl carboxypeptidase).

from treatment with diuretic drugs), by car-

 

 

As “kininase II,” it contributes to the inacti-

diac failure, or by renal arterial stenosis, ad-

 

 

vation of kinins, such as bradykinin. ACE is

ministration of ACE inhibitors may initially

 

 

also present in blood plasma; however, en-

cause an excessive fall in blood pressure. Dry

 

 

zyme localized in the luminal side of vascu-

cough is a fairly frequent side effect, possibly

 

 

lar endothelium is primarily responsible for

caused by reduced inactivation of kinins in

 

 

the formation of angiotensin II.

the bronchial mucosa. In most cases, ACE

 

 

Angiotensin II can raise blood pressure in

inhibitors are well tolerated and effective.

 

 

different ways, including (1) vasoconstric-

Newer analogues include lisinopril, perindo-

 

 

tion in both the arterial and venous limb of

pril, ramipril, quinapril, fosinopril, benaze-

 

 

the circulation; (2) stimulation of aldoste-

pril, cilazapril, and trandolapril.

 

 

rone secretion, leading to increased renal

 

 

 

reabsorption of NaCl and water, hence an

Antagonists at angiotensin II receptors.

 

 

increased blood volume; (3) a central in-

Two receptor subtypes can be distinguished:

 

 

crease in sympathotonus and, peripherally,

AT1, which mediates the above actions of

 

 

enhanced release and effects of norepi-

angiotensin II; and AT2, whose physiological

 

 

nephrine. Chronically elevated levels of an-

role is still unclear. Losartan is an AT1 recep-

 

 

giotensin II can increase muscle mass in

tor antagonist whose main (antihyperten-

 

 

heart and arteries (trophic effect).

sive) and side effects resemble those of ACE

 

 

 

 

inhibitors. However, because it does not in-

 

 

ACE inhibitors, such as captopril and enalap-

hibit degradation of kinins, it does not cause

 

 

rilat, the active metabolite of enalapril, occu-

dry cough. Losartan is used in the therapy of

 

 

py the enzyme as false substrates. Af nity

hypertension. Other analogues are valsartan,

 

 

significantly influences ef cacy and rate of

irbesartan, eprosartan, and candesartan.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

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

 

 

 

 

ACE Inhibitors

129

A. Renin-angiotensin-aldosterone system and inhibitors

 

 

 

 

 

 

Kidney

 

 

 

ACE inhibitors

 

 

 

RR

 

 

 

 

 

 

 

 

 

 

O

O

 

 

 

 

 

 

 

HO

C

C

CH

CH2

SH

 

 

 

 

 

N

CH3

 

 

Captopril

 

 

 

 

 

 

 

 

 

 

 

 

O

O

 

 

 

 

 

 

 

HO

C

C

CH

NH

CH

CH2

CH2

 

 

 

 

N

CH3

 

C

O

 

 

 

 

 

 

 

 

 

 

Renin

 

 

 

 

O

CH2

CH3

 

 

Enalaprilat

 

 

Enalapril

 

 

 

 

 

 

Angiotensinogen

 

ACE

 

 

 

 

 

2-globulin)

 

 

 

 

 

Kinins

 

Ang I

Angiotensin

 

 

 

 

 

 

I-converting

 

 

 

 

 

 

 

enzyme

carboxypeptidase

 

 

 

Angiotensin I (Ang I)

 

Dipeptidyl

 

 

 

 

 

Kininase

 

COOH

(biologically inactive)

 

 

 

 

 

 

 

II

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Ang II

 

 

 

 

 

Degradation

 

ACE

 

 

 

 

 

 

products

Vascular

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

endothelium

 

 

 

 

 

 

 

 

 

Losartan

 

 

CH2OH

 

 

 

Angiotensin II

 

 

Cl

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

N

N

 

 

 

H

 

H2N

 

 

 

 

 

 

N

N

 

 

H3C

 

 

 

 

 

N

N

 

Receptors

 

 

 

 

 

 

 

 

 

 

AT1-receptor antagonists

 

 

 

 

 

Venous

HMV

 

 

 

 

RR

 

supply

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Peripheral

 

 

 

 

 

 

resistance

 

 

Venous

Resistance vessels

 

 

 

 

capacitance vessels

 

 

 

 

Vasoconstriction

 

 

 

 

 

 

 

 

NaCl

Aldosterone

 

 

 

 

Sympatho-

 

H2O

secretion

 

 

 

 

activation

 

 

 

 

 

 

 

 

 

 

 

K+

 

 

 

 

 

 

 

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

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

130 Drugs Acting on Smooth Muscle

Drugs Used to Influence Smooth Muscle Organs

Bronchodilators. Narrowing of bronchioles raises airway resistance, e.g., in bronchial or bronchitic asthma. Several substances that are employed as bronchodilators are described elsewhere in more detail: β2-sympa- thomimetics (p.88; given by pulmonary, parenteral, or oral route), the methylxanthine theophylline (p.338; given parenterally or orally), and the parasympatholytics ipratropium and tiotropium (p.108).

Spasmolytics. N-butylscopolamine (p.108) is used for the relief of painful spasms of the biliary or ureteral ducts. Its poor absorption (N.B. quaternary N; absorption rate < 10%) necessitates parenteral administration. Because the therapeutic effect is usually weak, a potent analgesic is given concurrently, e.g., the opioid meperidine. Note that some spasms of intestinal musculature can be effectively relieved by organic nitrates (in biliary colic) or by nifedipine (esophageal hypertension and achalasia).

Myometrial relaxants (tocolytics). β2-Sym- pathomimetics such as fenoterol, given orally or parenterally, can prevent premature labor or interrupt labor in progress when dangerous complications necessitate caesarean section. Tachycardia is a side effect produced reflexly because of β2-mediated vasodilation or a direct stimulation of cardiac β1-recep- tors. Recently, atosiban, a structurally altered oxytocin derivative, has become available. It acts as an antagonist at oxytocin receptors, is given parenterally, and lacks the cardiovascular side effects of β2-sympathomimetics, but often causes nausea and vomiting.

Myometrial stimulants. The neurohypophyseal hormone oxytocin (p.238) is given parenterally (or by the nasal or buccal route) before, during, or after labor in order to prompt uterine contractions or to enhance them. Certain prostaglandins or analogues of

them (p.196; F2α, dinoprost; E2, dinoprostone, sulprostone) are capable of inducing rhythmic uterine contractions and cervical relaxation at any time. They are mostly employed as abortifacients (local or parenteral application).

Ergot alkaloids are obtained from Secale cornutum (ergot), the sclerotium of a fungus (Claviceps purpurea) parasitizing rye. Consumption of flour from contaminated grain was once the cause of epidemic poisonings (ergotism) characterized by gangrene of the extremities (St. Anthony’s fire) and CNS disturbances (hallucinations).

Ergot alkaloids contain lysergic acid (see ergotamine formula in A). They act on uterine and vascular muscle. Ergometrine particularly stimulates the uterus. It readily induces a tonic contraction of the myometrium (tetanus uteri). This jeopardizes placental blood flow and fetal oxygen supply. Ergometrine is not used therapeutically. The semisynthetic derivative methylergometrine is used only after delivery for uterine contractions that are too weak.

Ergotamine, as well as the ergotoxine alkaloids (ergocristine, ergocryptine, ergocornine), have a predominantly vascular action. Depending on the initial caliber, constriction or dilation may be elicited. The mechanism of action is unclear; a partial agonism at α-adrenoceptors may be important. Ergotamine is used in the treatment of migraine (p.334). Its derivative, dihydroergotamine, is furthermore employed in orthostatic complaints (p.324).

Other lysergic acid derivatives are the 5-HT antagonist methysergide, the dopamine agonist bromocriptine (p.116), and the hallucinogen lysergic acid diethylamide (LSD, p.236).

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

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

Drugs Acting on Smooth Muscle

131

A. Drugs used to alter smooth-muscle function

 

Bronchial asthma

 

Biliary/renal colic

O2

 

 

 

Spasm

 

 

 

 

 

smooth muscle

 

Bronchodilation

 

Spasmolysis

Inhibition of labor

β 2-Sympathomimetics

N-Butylscopolamine

β 2-Sympathomimetics

e.g., fenoterol

e.g., salbutamol

 

 

 

CH3

Oxytocin antagonist

 

 

 

 

 

 

 

 

H3C CH2 CH2 CH2 N+

 

O

 

 

Atosiban

H3C

H

 

 

 

 

 

 

N

N

 

Scopolamine

 

 

 

Induction of labor

 

 

 

 

 

 

 

O

N

N

 

 

 

 

 

 

CH3

 

 

Nitrates

Oxytocin

Theophylline

 

 

e.g., nitroglycerin

Prostaglandins

 

 

 

 

 

Ipratropium

 

 

 

F2α , E2

Secale cornutum

 

Tonic contraction of uterus

(ergot)

 

 

 

 

 

 

 

e.g., ergometrine

 

 

 

 

 

Oxygen supply

 

 

 

 

 

diminished

 

 

 

 

 

Contraindication

Fungus:

 

 

before delivery

Claviceps purpurea

 

Indication:

 

 

 

 

 

 

 

 

 

 

postpartum

 

Secale alkaloids

 

uterine atonia

 

 

 

 

Effect on

 

 

 

 

vasomotor tone

 

 

e.g., ergotamine

 

 

 

O

 

 

 

 

H

C

NH

R

 

 

 

N

CH3

 

 

 

 

 

 

 

 

HN

 

 

 

 

 

 

 

 

 

Fixation of lumen at intermediate caliber

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

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

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