perindopril (Rx)

>10%

Headache (23%)

Cough (12%)

1-10%

Dizziness (8%)

Back pain (6%)

Lower extremity pain (5%)

Abnormal ECG (2%)

Palpitation (1%)

Depression (2%)

Somnolence (1%)

Menstrual disorder (1%)

Edema (4%)

ALT increased (2%)

Sexual dysfunction (male 1%)

Sleep disorder (3%)

Chest pain (2%)

Nausea/vomiting (2%)

Flatulence (1%)

Rash (2%)

Hyperkalemia (1%)

Tinnitus (2%)

Frequency Not Defined

Intestinal angioedema

Liver failure (rare)

Leukopenia

Pruritus

Stroke

Syncope

Urinary retention

Vertigo

Amnesia

Angioedema, More frequent in black patients (0.1%), Angioedema of lips, More frequent in black patients (0.1%), Angioedema of throat, More frequent in black patients (0.1%)

Contraindications

Hypersensitivity to perindopril/other ACE inhibitors

History of hereditary or angioedema associated with previous ACE inhibitor treatment

Coadministration of neprilysin inhibitors (eg, sacubitril) with ACE inhibitors may increase angioedema risk; do not administer ACE inhibitors within 36 hr of switching to or from sacubitril/valsartan

Bilateral renal artery stenosis

Do not coadminister with aliskiren in patients with diabetes mellitus or with renal impairment (ie, GFR <60 mL/min/1.73 m²)

Cautions

Apheresis (LDL) with dextran sulfate, hypertrophic cardiomyopathy, collagen vascular disease, excessive hypotension - volume depletion, hemodialysis with high flux membrane, aortic stenosis

ACE inhibition also causes increased bradykinin levels which putatively mediates angioedema

Coadministration with mTOR inhibitors (eg, temsirolimus) may increased risk for angioedema

Dual blockade of the renin angiotensin system with ARBs, ACE inhibitors, or aliskiren associated with increased risk for hypotension, hyperkalemia, and renal function changes (including acute renal failure) compared to monotherapy

Symptomatic hypotension is most likely to occur in patients who have been volume or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea or vomiting; in patients with ischemic heart disease or cerebrovascular disease, an excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular accident; If excessive hypotension occurs, place patient in a supine position and, if necessary, treat with intravenous infusion of physiological saline; perinopril treatment can usually be continued following restoration of volume and blood pressure

Discontinue immediately if pregnant (see Contraindications and Black Box Warnings)

Less effective in blacks

Renal impairment may occur

Neutropenia/agranulocytosis reported

Cough may occur within the first few months

Cholestatic jaundice may occur

Renal impairment

Pregnancy Category: D

Discontinue as soon as pregnancy detected; during the second and third trimesters of pregnancy, drugs that act directly on the renin-angiotensin have been associated with fetal injury that includes hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death

Lactation: not known if distributed into breast milk; use caution

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Angiotensin converting enzyme (ACE) inhibitors dilate arteries and veins by competitively inhibiting the conversion of angiotensin I to angiotensin II (a potent endogenous vasoconstrictor) and by inhibiting bradykinin metabolism; these actions result in preload and afterload reductions on the heart

ACE inhibitors also promote sodium and water excretion by inhibiting angiotensin-II induced aldosterone secretion; elevation in potassium may also be observed

ACE inhibitors also elicit renoprotective effects through vasodilation of renal arterioles

ACE inhibitors reduce cardiac and vascular remodeling associated with chronic hypertension, heart failure, and myocardial infarction

Pharmacokinetics

Half-life: 1.5-3 hr (perindopril);3-10 hr (perindoprilat):

Onset: 1-2 hr (peak response PO for HTN)

Peak plasma time: 1 hr (PO; perindopril); 3-7 hr (perindoprilat)

Therapeutic concentration range: 80-150 ng/mL

Renal clearance: 1.5 L/h (perindopril), 6-10 L/hr (perindoprilat total body: 21-31 L/h perindopril): 46 L/hr) (perindoprilat)

Excretion: Urine (75%)

Duration: 24 hr

Bioavailability: 75% (perindopril); 20-30% (perindoprilat)

Protein bound: 60% (perindopril); 10-20% (perindoprilat)

Vd: 0.22 L/kg (perindopril); 0.16 L/kg (perindoprilat)

Metabolism: Liver (88 -96%)

Metabolites: Perindoprilat (active), glucuronide derivatives (inactive)

Dialyzable: HD: yes