| Indication |
For treating mild to moderate hypertension, use as an adjunct in
treating congestive heart failure, and may be used to slow the rate of
progression of renal disease in hypertensive individuals with diabetes
mellitus and microalbuminuria or overt nephropathy. |
| Pharmacodynamics |
Following oral administration, fosinopril is rapidly and
completely hydrolyzed to its principle active metabolite, fosinoprilat.
Hydrolysis is thought to occur in the gastrointestinal mucosa and liver.
Fosinoprilat is a competitive inhibitor of ACE, a peptidyl dipeptidase
that is part of the RAAS. The RAAS is a homeostatic mechanism for
regulating hemodynamics, water and electrolyte balance. During
sympathetic stimulation or when renal blood pressure or blood flow is
reduced, renin is released from the granular cells of the
juxtaglomerular apparatus in the kidneys. In the blood stream, renin
cleaves circulating angiotensinogen to ATI, which is subsequently
cleaved to ATII by ACE. ATII increases blood pressure using a number of
mechanisms. First, it stimulates the secretion of aldosterone from the
adrenal cortex. Aldosterone travels to the distal convoluted tubule
(DCT) and collecting tubule of nephrons where it increases sodium and
water reabsorption by increasing the number of sodium channels and
sodium-potassium ATPases on cell membranes. Second, ATII stimulates the
secretion of vasopressin (also known as antidiuretic hormone or ADH)
from the posterior pituitary gland. ADH stimulates further water
reabsorption from the kidneys via insertion of aquaporin-2 channels on
the apical surface of cells of the DCT and collecting tubules. Third,
ATII increases blood pressure through direct arterial vasoconstriction.
Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells
leads to a cascade of events resulting in myocyte contraction and
vasoconstriction. In addition to these major effects, ATII induces the
thirst response via stimulation of hypothalamic neurons. ACE inhibitors
inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced
increases in blood pressure. ACE (also known as kininase II) is also
involved in the enzymatic deactivation of bradykinin, a vasodilator.
Inhibiting the deactivation of bradykinin increases bradykinin levels
and may further sustain the effects of fosinoprilat by causing increased
vasodilation and decreased blood pressure. |
| Mechanism of action |
There are two isoforms of ACE: the somatic isoform, which exists
as a glycoprotein comprised of a single polypeptide chain of 1277; and
the testicular isoform, which has a lower molecular mass and is thought
to play a role in sperm maturation and binding of sperm to the oviduct
epithelium. Somatic ACE has two functionally active domains, N and C,
which arise from tandem gene duplication. Although the two domains have
high sequence similarity, they play distinct physiological roles. The
C-domain is predominantly involved in blood pressure regulation while
the N-domain plays a role in hematopoietic stem cell differentiation and
proliferation. ACE inhibitors bind to and inhibit the activity of both
domains, but have much greater affinity for and inhibitory activity
against the C-domain. Fosinoprilat, the active metabolite of fosinopril,
competes with ATI for binding to ACE and inhibits and enzymatic
proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases
blood pressure by inhibiting the pressor effects of ATII as described
in the Pharmacology section above. Fosinoprilat also causes an increase
in plasma renin activity likely due to a loss of feedback inhibition
mediated by ATII on the release of renin and/or stimulation of reflex
mechanisms via baroreceptors. |
| Absorption |
Average absolute absorption is 36%. The primary site of absorption
is the proximal small intestine (duodenum/jejunum). Food slows the rate
of absorption with no effect on the extent of absorption. |
| Volume of distribution |
Not Available |
| Protein binding |
Fosinoprilat is ≥95% protein bound |
| Metabolism |
Since fosinoprilat is not biotransformed after intravenous
administration, fosinopril, not fosinoprilat, appears to be the
precursor for the glucuronide and p-hydroxy metabolites. |
| Route of elimination |
After oral administration of radiolabeled fosinopril,
approximately half of the absorbed dose is excreted in the urine and the
remainder is excreted in the feces. |
| Half life |
12 hours |
| Clearance |
|
| Toxicity |
Human overdoses of fosinopril have not been reported, but the most
common manifestation of human fosinopril overdosage is likely to be
hypotension. Oral doses of fosinopril at 2600 mg/kg in rats were
associated with significant lethality. The most common adverse effects
include dizzines, cough, fatigue, and headache. |
