Indication |
For the treatment of essential or renovascular hypertension and
symptomatic congestive heart failure. It may be used alone or in
combination with thiazide diuretics. |
Pharmacodynamics |
Enalapril is a prodrug that is rapidly metabolized by liver
esterases to enalaprilat following oral administration. Enalapril itself
has little pharmacologic activity. Enalaprilat lowers blood pressure by
antagonizing the effect 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 sustain the effects of enalaprilat 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. Enalaprilat, the principle active metabolite of
enalapril, 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. Enalapril 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. Enalaprilat's affinity for ACE
is approximately 200,000 times greater than that of ATI and 300-1000
times greater than that enalapril. |
Absorption |
55-75%, absorption is unaffected by food; enalaprilat (clinically
administered IV) is poorly absorbed, 3-12%, due to its high polarity. |
Volume of distribution |
Not Available |
Protein binding |
50-60% of enalaprilat is bound to plasma proteins |
Metabolism |
~ 60% of absorbed dose is extensively hydrolyzed to enalaprilat, primarily by liver esterases |
Route of elimination |
Excretion of enalapril is primarily renal. |
Half life |
< 2 hours for unchanged enalapril in health individuals, may be
increased in those with congestive heart failure (3.4 and 5.8 hours for
single 5- and 10-mg doses, respectively). The average terminal half
life of enalaprilat is 35-38 hours. The effective half life following
multiple doses is 11-14 hours. |
Clearance |
Not Available |
Toxicity |
Overdosage may result in marked hypotension and stupor. Most
common adverse effects include hypotension, headache, dizziness and
fatigue. |