Page 202 - Basic _ Clinical Pharmacology ( PDFDrive )

188 SECTION III Cardiovascular-Renal Drugs

Angiotensinogen Kininogen

Renin Kallikrein
–
Aliskiren Increased
prostaglandin
Angiotensin I Bradykinin synthesis

Angiotensin-converting enzyme
(kininase II)

–
Angiotensin II Inactive
ACE metabolites
inhibitors
ARBs
– –
Vasoconstriction Aldosterone Vasodilation
secretion
Spironolactone,
eplerenone
–
Increased peripheral Increased sodium Decreased peripheral
vascular resistance and water retention vascular resistance

Increased Decreased
blood pressure blood pressure

FIGURE 11–5 Sites of action of drugs that interfere with the renin-angiotensin-aldosterone system. ACE, angiotensin-converting enzyme;
ARBs, angiotensin receptor blockers.

ACE inhibitors have a particularly useful role in treating patients effective in most patients. All of the ACE inhibitors except fos-
with chronic kidney disease because they diminish proteinuria and inopril and moexipril are eliminated primarily by the kidneys;
stabilize renal function (even in the absence of lowering of blood doses of these drugs should be reduced in patients with renal
pressure). This effect is particularly valuable in diabetes, and these insufficiency.
drugs are now recommended in diabetes even in the absence of
hypertension. These benefits probably result from improved intra- Toxicity
renal hemodynamics, with decreased glomerular efferent arteriolar
resistance and a resulting reduction of intraglomerular capillary Severe hypotension can occur after initial doses of any ACE inhibi-
pressure. ACE inhibitors have also proved to be extremely useful tor in patients who are hypovolemic as a result of diuretics, salt
in the treatment of heart failure and as treatment after myocardial restriction, or gastrointestinal fluid loss. Other adverse effects com-
infarction, and there is evidence that ACE inhibitors reduce the mon to all ACE inhibitors include acute renal failure (particularly
incidence of diabetes in patients with high cardiovascular risk (see in patients with bilateral renal artery stenosis or stenosis of the renal
Chapter 13). artery of a solitary kidney), hyperkalemia, dry cough sometimes
accompanied by wheezing, and angioedema. Hyperkalemia is more
Pharmacokinetics & Dosage likely to occur in patients with renal insufficiency or diabetes. Bra-
dykinin and substance P seem to be responsible for the cough and
Captopril’s pharmacokinetic parameters and dosing recommenda- angioedema seen with ACE inhibition.
tions are listed in Table 11–2. Peak concentrations of enalaprilat, ACE inhibitors are contraindicated during the second and
the active metabolite of enalapril, occur 3–4 hours after dosing third trimesters of pregnancy because of the risk of fetal hypoten-
with enalapril. The half-life of enalaprilat is about 11 hours. Typi- sion, anuria, and renal failure, sometimes associated with fetal
cal doses of enalapril are 10–20 mg once or twice daily. Lisinopril malformations or death. Recent evidence also implicates first-
has a half-life of 12 hours. Doses of 10–80 mg once daily are trimester exposure to ACE inhibitors in increased teratogenic risk.