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 Cl– to 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.

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

(α 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+

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