| Indication |
For the treatment of mild to moderate hypertension, as an adjunct
in the treatment of congestive heart failure (CHF), to improve survival
following myocardial infarction (MI) in individuals who are
hemodynamically stable and demonstrate symptoms of left ventricular
systolic dysfunction or signs of CHF within a few days following acute
MI, and to slow progression of renal disease in hypertensive patients
with diabetes mellitus and microalbuminuria or overt nephropathy. |
| Pharmacodynamics |
Trandolapril is the ethyl ester prodrug of a nonsulfhydryl ACE
inhibitor, trandolaprilat. Trandolapril is deesterified in the liver to
the diacid metabolite, trandolaprilat, which is approximately eight
times more active as an inhibitor of ACE than its parent compound. ACE
is 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 via 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 trandolaprilat by causing
increased vasodilation and decreased blood pressure. The blood pressure
lowering effect of trandolaprilat is due to a decrease in peripheral
vascular resistance, which is not accompanied by significant changes in
urinary excretion of chloride or potassium or water or sodium retention.
|
| 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. Trandolaprilat, the active metabolite of
trandolapril, 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. Trandolaprilat 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 |
~ 40-60% absorbed; extensive first pass metabolism results in a low bioavailability of 4-14% |
| Volume of distribution |
|
| Protein binding |
Serum protein binding of trandolapril is ~ 80% (independent of
concentration and not saturable) while that of trandolaprilat is 65 to
94% (concentration-dependent and saturable). |
| Metabolism |
Cleavage of the ester group of trandolapril, primarily in the
liver, is responsible for conversion to trandolaprilat, the active
metabolite. Seven other metabolites, including diketopiperazine and
glucuronide conjugated derivatives of trandolapril and trandolaprilat,
have been identified. |
| Route of elimination |
After oral administration of trandolapril, about 33% of parent
drug and metabolites are recovered in urine, mostly as trandolaprilat,
with about 66% in feces. |
| Half life |
The elimination half lives of trandolapril and trandolaprilat are
about 6 and 10 hours, respectively, but, similar to all ACE inhibitors,
trandolaprilat also has a prolonged terminal elimination phase that
involves a small fraction of administered drug. This likely represents
drug binding to plasma and tissue ACE. The effective half life of
elimination for trandolaprilat is 16-24 hours. |
| Clearance |
- 52 L/h [After approximately 2 mg IV doses]
|
| Toxicity |
Most likely clinical manifestations of overdose are symptoms of
severe hypotension. Most common adverse effects include cough, headache
and dizziness. The oral LD50 of trandolapril in mice was 4875
mg/kg in males and 3990 mg/kg in females. In rats, an oral dose of 5000
mg/kg caused low mortality (1 male out of 5; 0 females). In dogs, an
oral dose of 1000 mg/kg did not cause mortality and abnormal clinical
signs were not observed. |
