Lisinopril

Absorption

Oral

Rapid and Complete

Bioavailability

~25% reaches systemic circulation due to high first-pass metabolism

oral bioavailability may be increased in Down syndrome children

protein-rich foods increase bioavailability by ~50%

Distribution

Vd: 4 L/kg in adults

crosses the blood-brain barrier

Metabolism

Extensive first-pass effect, hepatically metabolized to active and inactive compounds

the 3 main metabolic pathways include: Aromatic hydroxylation (primarily 4-hydroxylation), N-dealkylation followed by further side-chain oxidation and direct glucuronidation

the 4 primary metabolites include: Propranolol glucuronide, naphthyloxylactic acid, and sulfate and glucuronic acid conjugates of 4-hydroxy propranolol

Note: Aromatic hydroxylation is catalyzed primarily by isoenzyme CYP2D6

side chain oxidation is mainly via CYP1A2, but also CYP2D6

4-hydroxypropranolol possesses beta-adrenergic receptor blocking activity and is a weak inhibitor of CYP2D6.

Excretion

Metabolites are excreted primarily in urine (96% to 99%)

<1% excreted in urine as unchanged drug

Additional

Onset of Action

Beta-blockade: Oral: 1 to 2 hours; IV: ≤5 minutes

Peak effect: Hypertension: A few days to several weeks.

Duration of Action

Immediate release: 6 to 12 hours

Extended-release formulations: ~24 to 27 hours

Half-Life Elimination

Neonates: Possible increased half-life

Infants (35 to 150 days of age): Median 3.5 hours; Children: 3.9 to 6.4 hours

Adults: Immediate release formulation: 3 to 6 hours; Extended-release formulations: 8 to 10 hours

Time to Peak

Immediate release: Adults: 1 to 4 hours

Infants: ≤2 hours (Hemangeol)

Extended release capsule (Inderal XL, InnoPran XL): 12 to 14 hours

Long acting capsule (Inderal LA): 6 hours

Competitive inhibitor of angiotensin-converting enzyme (ACE)

prevents conversion of angiotensin I to angiotensin II,

potent vasoconstrictor

results in lower levels of angiotensin II which causes

results in lower levels of angiotensin II which causes

a reduction in aldosterone secretion

a CNS mechanism may also be involved in hypotensive effect as angiotensin II increases adrenergic outflow from CNS

vasoactive kallikreins may be decreased in conversion to active hormones by ACE inhibitors

reducing blood pressure

General dosages

Acute coronary syndromes:

Non-ST-elevation acute coronary syndrome

Oral: Initial: 2.5 to 10 mg once daily (depending on initial blood pressure)

ST-elevation myocardial infarction:

Oral: Initial: 2.5 to 5 mg once daily initiated within 24 hours of presentation

Heart failure with reduced ejection fraction:

Oral: Initial: 2.5 to 5 mg once daily

Hypertension

Oral: Initial: 5 to 10 mg once daily

Posttransplant erythrocytosis (renal transplant recipients)

Oral: Initial: 2.5 or 5 mg once daily

Proteinuric chronic kidney disease (diabetic or nondiabetic)

Oral: Initial: 2.5 to 10 mg once daily depending on blood pressure

Indications

Heart failure with reduced ejection fraction:

Adjunctive therapy to reduce signs and symptoms of systolic heart failure.

Hypertension:

Management of hypertension in adult and pediatric patients ≥6 years of age.

ST-elevation myocardial infarction:

Treatment of acute MI within 24 hours in hemodynamically stable patients to improve survival.

Contraindications

Hypersensitivity

angioedema related to previous treatment with an ACE inhibitor

idiopathic or hereditary angioedema

concomitant use with aliskiren in patients with diabetes mellitus

coadministration with or within 36 hours of switching to or from a neprilysin inhibitor

Ex: sacubitril

concomitant use with aliskiren, angiotensin receptor blockers (ARBs), or other ACE inhibitors in patients with :

moderate to severe renal impairment (GFR <60 mL/minute/1.73 m2)

hyperkalemia (>5 mmol/L)

with heart failure who are hypotensive

concomitant use with ARBs or other ACE inhibitors in diabetic patients with end organ damage

pediatric patients <6 years

pediatric patients 6 to 16 years of age with severe renal impairment

Toxicities

gasping syndrome

large amounts of benzyl alcohol

In neonates

consists of:

metabolic acidosis

respiratory distress

gasping respirations

CNS dysfunction (including convulsions, intracranial hemorrhage)

hypotension

cardiovascular collapse

Drug interactions

Avoid

bromperidol

grass pollen allergen extract

sacubitril

Monitor

sodium phosphates

dose dependent

amphetamine

aspirin

bupivacaine

heparin

ibuprofen

Pregnancy Categories and Implications

Lisinopril crosses the placenta

Exposure to an angiotensin-converting enzyme (ACE) inhibitor during the first trimester of pregnancy may be associated with an increased risk of fetal malformations

Box warning

[US Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected.

use in pregnant women should only be considered for cases of hypertension refractory to other medications