Kruse ACE inhibitors

Question 1

the major components of RAS

Answer 1

1. Renin
2. angiotensinogen

Question 2

renin

Answer 2

Renin

(1) An aspartyl protease: catalyzes hydrolytic release of the decapeptide angiotensin I from angiotensinogen
(2) The 340 amino acid protein enters circulation from the kidneys
(3) it is synthesized and stored in the juxtaglomerular apparatus of the nephron
(4) Sympathetic nervous system stimulation –> activation of β1-adrenergic receptors on juxtaglomerular cells–> stimulates release of renin from these cells

Question 3

Angiotensinogen

Answer 3

1) synthesized in the liver
2) stimulated by thyroid hormone, estrogens, angiotensin II, corticosteroids
3) 452 amino acids

circulates in blood and converted into angiotensin I by renin

Question 4

angiotensin I

Answer 4

1) derived from the terminal 10 amino acids of angiotensinogen
2) has no intrinsic biological activity
3) converted to angiostensin II (10 aa–> 8 aa) by angiotensin converting enzyme so rapidly the two are indistinguishable

Question 5

converting enzyme

Answer 5

Convertingenzyme(angiotensinconvertingenzyme(ACE) or kininaseII)

(1) Catalyzes the removal of carboxyl terminal amino acids from substrate peptides
(2) Most important substrates are angiotensin I (which it converts to angiotensin II by

cleaving the carboxy-terminal two amino acids from angiotensin I) and bradykinin (a

vasodilator which is inactivated by converting enzyme)

(3) Widely distributed throughout the body and located on the luminal surface of vascular

endothelial cells in most tissues

Question 6

angiotensin II causes…

Answer 6

1. SM: vascular smooth muscle constriction
   * 40x more potent as vasoconstrictor that epinephrine
2. Kidneys

• decreases renin release from the kidneys
• stimulates aldosterone release from the adrenal cortex

3. brain: resets baroreceptor reflex in the brain regulating heart rate to a higher blood pressure
4. heart: stimulates cardiac remodeling and cardiac hypertrophy
5. small vasculature and salt exchanges: regulates fluid/electrolyte balance and artirolar BP
6. directly proportional to renin levels
7. rapidly neutralized by angiotensinase

Question 7

clom

Question 8

Angiotensin II receptors

Answer 8

Angiotensin II receptors

(1) Angiotensin II binds to two subtypes of G-protein coupled receptors (AT1 and AT2, with

AT1 being the major receptor in adults)

(2) AT1 receptors are Gq-protein coupled receptors that, when activated, result in activation

of phospholipase C, production of inositol triphosphate (IP3) and diacylglycerol (DAG),

and smooth muscle contraction

(3) Consequences of AT2 receptor activation include bradykinin and nitric oxide (NO)

production, which results in vasodilation

Question 9

aldosterone

Answer 9

Increases the activity of both the epithelial sodium channel (ENaC) and the basolateral

Na+/K+-ATPase, leading to an increase in Na+ reabsorption and K+ secretion (which causes retention of water, an increase in blood volume, an increase in BP, and hypokalemia)

Question 10

two classes of drugs that act selectively on the RAS

Answer 10

are the ACE inhibitors and the ARBs

Question 12

these agents are “an excellent choice” for athletes/physical active people

Answer 12

ACEI: reduce blood pressure by lowering peripheral vascular resistance but do not alter cardiac output or heart rate

ACEIs are not banned by the NCAA or US Olympic Committe: diuretics are

Question 13

indications for ACEI

Answer 13

1. hypertension
2. nephropathy (+/- diabetese)
3. Acute myocardial infarction (AMI)
4. Left ventricular dysfunction (+/- AMI)
5. cardiovascular disease

Question 14

All ACEIs except for ______ are prodrugs that are 100-1000 times less potent than the active metabolite but have a much better oral bioavailability

Answer 14

captopril and lisinopril

Question 15

Adverse effects common to all ACEIs

Answer 15

1. hypotension
2. Aacute kidney failure
   * especially in bilateral/unilateral renal stenosis
3. dry ough
4. angioedema

5. HYPERKALEMIA

• more likely to occur in patients with renal insufficiency ( GFR <500 ml/day) or diabetes

Question 16

ACEI AEs (the big ones)

Answer 16

1. systemic hypoperfusion
2. coadministration with vasoconstrictors like cyclosporin and NSAIDs
3. dehydration
4. CHF

Reason: since ACEI cause vasoconstriction of the efferent arteriole (increasing GFR) and the causes above cause the release of renin when GFR falls, if a severe cause for renin release occurs like hypotension is occuring, ACEI will prevent decreases renin’s necessary effects

Question 17

ACEI cough

Answer 17

is a common side effect and is often a primary reason for terminating therapy with the agent (some ACEIs cause cough more than others and choosing an appropriate agent is often by trial and error)

Question 18

ACEI and contraindications

Answer 18

• pregnancy
  
  • first trimester: teratogenic
  • seoncd and third trimester: malformations
  • second and third trimester: potters sequence (aneuria, hypotension)

Question 19

Drug-drug interactions and ACEI

Answer 19

potassium supplements and potassium sparing diuretics, both can result in hyperkalemia

NSAIDS: may impair some of the antihypertensive effects of ACEIs by blocking bradykinin-mediated vasodilation, which is partly prostaglandin mediated

Question 20

ACEI by name

Answer 20

1. Benazepril
2. Captopril
3. Enalapril, Enalaprilat
4. Fosinopril
5. Lisinopril
6. Moexipril
7. Perindopril
8. Quinapril
9. Ramipril
10. Trandolapril

Question 21

IV administration is approved for hypertensive emergencies

Answer 21

enalaprilat, active metabolite of enalapril

Question 22

the ACEI metabolized by both kidney and liver

Answer 22

fosinoprilat and trandolaprilat