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CH. 47 RAAS Pharm 2

Types of angiotensin

Angiotensin I

Angiotensin II

Actions of angiotensin II

  • Vasoconstriction

  • Release of aldosterone

  • Alteration of cardiac and vascular structure

Angiotensin lll

Actions of aldosterone

  • Regulation of blood volume and blood pressure

  • Pathologic cardiovascular effects

Formation of angiotensin II by renin and angiotensin-converting enzyme (ACE)

Renin

  • Catalyzes the formation of angiotensin I from angiotensinogen

Regulation of renin release

  1. When BP falls the kidneys sense this and Release renin into blood stream 

  2. Renin goes to liver and splits angiotensin from it

  3. Angiotensin I is inactive (doesn’t cause any effects), flows through your bloodstream and is split into pieces by angiotensin-converting enzyme (ACE) in your lungs and kidneys. One of those pieces is angiotensin II, an active hormone.

  • Angiotensin-converting enzyme (kinase II) Catalyzes the conversion of angiotensin I (inactive) to angiotensin II (highly active)

  1. Angiotensin II causes the muscular walls of small arteries (arterioles) to constrict (narrow), which increases blood pressure. Angiotensin II also triggers your adrenal glands to release aldosterone and your pituitary gland to release antidiuretic hormone (ADH, or vasopressin).

  2. Together, aldosterone and ADH cause your kidneys to retain sodium. Aldosterone also causes your kidneys to release (excrete) potassium through your urine.

  3. The increase in sodium in your bloodstream causes water retention. This increases blood volume and blood pressure

ACE (angiotensin-converting enzyme) inhibitors 

Overall effects and MOA

  • Reduces levels of angiotensin ll

  • increases levels of Bradykin

     ☆effects of reduced angiotensin 2

inhibiting ACE stops the conversion of angiotensin 1 to angiotensin 2 

  • low angiotensin 2 results in decreased: vasodilation, blood volume, cardiac/vascular remodeling, potassium retention, and fetal injury 

     ☆effects of increased bradykinin

inhibiting ACE stops the conversion of bradykinin into an inactive form

  • bradykinin is released in response to tissue damage, injury or infection. It triggers the Release of inflammatory peptides and prostaglandin

  • moves blood towards the injury which leads to swelling and pain

  • Increased vasodilation and cough

  • rarely leads to angioedema 

Therapeutic uses for ACE inhibitors

  • Hypertension

  • Heart failure

  • Myocardial infarction (MI)

  • Diabetic and nondiabetic nephropathy

  • Prevention of MI, stroke, and death in patients at high cardiovascular risk

Adverse effects

  • First-dose hypotension 

  • Fetal injury

  • Cough

  • Angioedema: a potentially life-threatening reaction. patients report edema of the tongue, lips, or eyes. emergency care should be sought immediately. The patient must never take ACE inhibitors again. 

  • hyperkalemia 

  • renal failure 

  • neutropenia

Drug Interactions

  • Diuretics

  • Antihypertensive agents

  • Drugs that raise potassium levels

  • Lithium

  • Nonsteroidal anti-inflammatory drugs

Preparation, Dosage, & Administration 

  • Except for enalaprilat, all ACE inhibitors are administered orally

  • All are available in single-drug formulations

  • Except for captopril and moexipril, all oral formulations may be administered without regard to meals

Angiotensin 2 receptor Blockers 

Overall effects and MOA

  • Block access of angiotensin II

  • Cause dilation of arterioles and veins

  • Prevent angiotensin II from inducing pathologic changes in cardiac structure

  • Potassium Retention 

  • Decrease release of aldosterone

  • Increase renal excretion of sodium and water

  • Do not inhibit kinase II

  • Do not increase levels of bradykinin

What are the main differences between ACE inhibitors and Angiotensin ll receptor Blockers?

  1. ACE inhibitors inhibit kinase 2 activity and increase levels of Bradykinin while Angiotensin ll receptor Blockers do not

  2. no cough because bradykinin does not build up with angiotensin II receptor blockers 

  3. no first dose hypotension with angiotensin II receptor blockers 

Therapeutic uses for Angiotensin II receptor blockers 

  • Hypertension, heart failure, myocardial infarction

  • Diabetic nephropathy

  • Patient unable to tolerate ACE inhibitors: Protection against MI, stroke, and death from cardiovascular (CV) causes in high-risk patients

  • May prevent development of diabetic retinopathy

  • New data show that ACE inhibitors and angiotensin II receptor blockers (ARBs) are not effective for primary prevention of nephropathy in normotensive diabetic patients 

Adverse effects of Angiotensin II receptor blockers 

  • Fetal injury

  • Angioedema

  • renal failure 

Direct Renin inhibitors

  • Aliskiren {tekturna}

Overall effects and MOA

  • Binds tightly with renin and inhibits the cleavage of angiotensin l to angiotensin ll

Side effects of Direct Renin inhibitors

  • Cough

  • Fetal injury

  • GI effects

  • Hyperkalemia 

  • Angioedema

  • And death 

Aldosterone Antagonists 

  • Eplerenone {Inspra}

Overall effects and MOA

  • Selective blockade of aldosterone receptors

Therapeutic Uses of Aldosterone Antagonists

  • Hypertension

  • Heart failure

Side effects of Aldosterone Antagonists

  • Hyperkalemia 

Drug interactions of Aldosterone Antagonists

  • Inhibitors of CYP3A4

  • Drugs that raise potassium levels

  • Use with caution when combined with lithium

  • Spironolactone {Aldactone}

Overall effects and MOA

  • Blocks aldosterone receptors

  • Binds with receptors for other steroid hormones 

Therapeutic Uses of Aldosterone Antagonists

  • Hypertension

  • Heart failure

Side effects of Aldosterone Antagonists

  • Hyperkalemia 

  • Gynecomastia (man boob)

  • Menstrual irregularities 

  • Impotence 

  • Hirsutism (lady beard)

  • Deepening of the voice