| Indication |
For the treatment of mild to moderate essential hypertension, mild
to moderate congestive heart failure, and to reduce the cardiovascular
risk of individuals with hypertension or post-myocardial infarction and
stable coronary disease. |
| Pharmacodynamics |
Perindopril is a nonsulfhydryl prodrug that is metabolized via
first pass effect (62%) and systemic hydrolysis (38%) to perindoprilat,
its active metabolite, following oral administration. Perindoprilat
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 perindoprilat
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. Perindoprilat, the active metabolite of
perindopril, 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. Perindopril 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 |
Rapidly absorbed with peak plasma concentrations occurring
approximately 1 hour after oral administration. Bioavailability is
65-75%. Following absorption, perindopril is hydrolyzed to
perindoprilat, which has an average bioavailability of 20%. The rate and
extent of absorption is unaffected by food. However, food decreases the
extent of biotransformation to peridoprilat and reduces its
bioavailability by 35%. |
| Volume of distribution |
Not Available |
| Protein binding |
Perindoprilat, 10-20% bound to plasma proteins |
| Metabolism |
Extensively metabolized, with only 4-12% of the dose recovered
in urine following oral administration. Six metabolites have been
identified: perindoprilat, perindopril glucuronide, perindoprilat
glucuronide, a perindopril lactam, and two perindoprilat lactams. Only
perindoprilat is pharmacologically active. Peridoprilat and
perindoprilat glucuronide are the two main circulating metabolites. |
| Route of elimination |
Perindopril is extensively metabolized following oral
administration, with only 4 to 12% of the dose recovered unchanged in
the urine. |
| Half life |
Perindopril, 1.2 hours; Peridoprilat, 30-120 hours. The long half
life of peridoprilat is due to its slow dissociation from ACE binding
sites. |
| Clearance |
- 219 – 362 mL/min [oral administration]
|
| Toxicity |
The most likely symptom of overdose is severe hypotension. The
most common adverse effects observed in controlled clinical trials
include cough, digestive symptoms, fatigue, headache, and dizziness. |
