Lecture 3: ACEis, ARBs, and Direct Renin Inhibitors

Angiotensinogen

• Hepatic glycoprotein

• Circulating concentration determines the rate of angiotensin formation

• High concentrations = increased blood pressure.

Renin

-Renal glycoprotein enzyme

-primary regulator of RAAS activity

Antiotensin I

Precursor to angiotensin II with no biological activity

Angiotensin Converting Enzyme (ACE)

• Enzyme of the vascular endothelium

• Converts angiotensin I to angiotensin II

-inactivates bradykinin

Aldosterone

• Mineralocorticoid synthesized in the adrenal cortex

• Regulates fluid status in the body

- Increases renal excretion of potassium

• Increases reabsorption of sodium, bicarbonate, and water in the kidneys

Angiotensin II (AngII)

-potent pressor via vasoconstriction, nervous system interactions, and stimulation of E and NE release

Angiotensin II (AngII)

-Mitogenic Activity in vascular and cardiac muscle cells

-stimulates production and release of aldosterone

-inactivated in the plasma by peptidases

Angiotensin Receptors (AngRs)

-Primary activity: vasoconstriction via a nitric oxide dependent pathway

-activation via contraction of the vascular smooth muscle

-binds with equal affinity by angiotensin II

AT1

what subtype of AngR:

-most abundant in vascular smooth muscle

-upregulated in heart failure and myocardial infarction

Counteracts action of AT1

what is the role of the Angiotensin Receptors, AT2?

Angiotensin II

inhibitor of renin release

Angiotensin-Converting Enzyme Inhibitors (ACEis)

inhibitors of angiotensin II formation and degrades bradykinin

Angiotensin Receptor Blockers (ARBs)

-competitive antagonists of AT1 receptors

Aliskiren

inhibitor of renin activity

Eplerenone and Spironolactone

antagonists of aldosterone receptors

Beta-blockers

inhibitors of renin release

Angiotensin-converting enzyme inhibitors (ACEIs)

-Lisinopril

-Captopril

-Enalapril

-Ramipril

Angiotensin-converting enzyme inhibitors (ACEIs)

-decreases angiotensin II and aldosterone

-increases renin

-decreases peripheral vascular resistance, arterial/venous pressure, cardiac afterload/preload

Angiotensin-converting enzyme inhibitors (ACEIs)

-decreases aldosterone secretion

-renal Na+ retention decreases

-increase in renal K+ retention

Angiotensin-converting enzyme inhibitors (ACEIs)

indications:

• Hypertension

• Heart failure

• Post-myocardial infarction

• Diabetes with early signs of renal impairment

• Hypertensive crisis

Fetal Toxicity

black box warning for ACEIs

Angiotensin-converting enzyme inhibitors (ACEIs)

CIs:

-history of angiodema

-coadministration with Aliskiren

ADRs:

-hyperkalemia

-dry cough

-angioedema

-hepatic failure

-jaundice

-hypotension

• SCr

• K+

• BP

three things you should monitor in a pt taking an ACEI

Angioedema

ACE inhibitors are the leading cause of drug-induced ____________________

Icatibant

treatment for angioedema

Angiotensin Receptor Blockers (ARBs)

• Losartan

• Candesartan

• Irbesartan

• Valsartan

• Telmisartan

Angiotensin Receptor Blockers (ARBs)

-increase angiotensin II and renin

-no effect on bradykinin (no cough)

-indications: hypertension, heart failure, post-MI, T2D, and nephropathy

Angiotensin Receptor Blockers (ARBs)

CIs:

-non-diabetic renal disease

-coadministration with aliskiren in diabetes

ADRs:

-hyperkalemia

-hypotension

-angioedema

-acute renal failure

Fetal Toxicity

black box warning for Angiotensin Receptor Blockers (ARBs)

Xsartan

when pregnancy is confirmed, you should discontinue which ARB as soon as possible

Direct Renin Inhibitors (DRi)

• Prevents cleavage of angiotensinogen and formation of

angiotensin I

• Lowers plasma renin activity, levels of angiotensin I and II

Aliskiren

-for hypertension (not initial therapy)

-ADRs: diarrhea, hyperkalemia, hypotension, rash, SJS, acute renal failure

-DIs: NSAIDs, K+ sparing drugs, ACEIs, ARBs, Triamterene, and amiloride

Use in pregnancy

black box warning for Aliskiren

Aldosterone Antagonists

-Eplerenone

-Spironolactone

Aldosterone Antagonists

-competitive antagonist of aldosterone receptors

Eplerenone

-for hypertension, congestive heart failure after MI

-ADR: hyperkalemia

-CI: baseline K > 5.5 or CrCl <30 mL/min

Spironolactone

-for hypertension, hypokalemia, primary hyperaldosteronism, severe heart failure, ascities assoc with cirrhosis of the liver

Sprionolactone

CIs:

-anuria

-acute renal insufficiency

-significant renal impairment

-hyperkalemia

-Addison's Disease

-use with eplerone

Spironolacton

ADRs:

-hyperkalemia

-headache

-ataxia

-lethargy

-gynecomastia

-erectile dysfunction

-irregular menses

-diarrhea

-acute renal failure

Tumorigenic Activity (in rats) (avoid unnecessary use)

black box warning for Spironolactone

Hypertensive disorder in Pregnancy

Risks for ________________________________:

• Eclampsia

• Maternal stroke

• Organ damage

• Placental abruption

• Premature birth

• Low birth weight

• Mortality

Preeclampsia

• Onset >20 weeks with signs of organ damage

• Proteinuria, thrombocytopenia, impaired hepatic function, renal insufficiency, pulmonary edema, cerebral disturbance, and/or visual disturbance

-Methyldopa

-Nifediphine

-Labetalol

women w/ hypertension who become pregnant, or are planning to become pregnant, should be transitioned to which medications

Bradykinin

Accumulation of _____________________ is thought to contribute to the development of ACEI-induced cough

African-American race and smoking

risk factors for angioedema

Pregnancy

ACEIs, ARBs and DRIs are all contraindicated in _____________________