ACE Inhibitors/Angiotensin Agonists & Diuretics

Question 1

Renin release and HTN

Answer 1

Renin is released by juxtaglomerular cells in the kidney (Think juxtaposition)
1. Due to drop in blood pressure in pre-glomerular arteries (<90 mmHg systolic BP)
2. Due to low NaCl in the distal tubule of the kidney (via sensors in Macula Densa)
3. Increased Sympathetic Nervous Activity (b1), or other signaling mechanisms

Question 1

Degradation of angiotensinogen

Answer 1

Renin: an aspartic acid protease that converts angiotensinogen (a glycoprotein) to angiotensin I (an essentially inactive decapeptide precursor to angiotensin II). –> Angiotensin Converting Enzyme (ACE): a dipeptidase that converts angiotensin I to angiotensin II (active peptide; the octapeptide responsible for pressor and Na+ and fluid retention responses). –> angiotensinases (aminopeptidase A) converts angiotensin II to angiotensin III (deactivated) –> inactive products

Question 2

Renin inhibitor: aliskiren

Answer 2

Action: direct inhibitor of renin and thus decreases formation of angiotensin I from angiotensinogen
Clinical Use: not first-line for hypertension – effective in reducing renin leading to a drop in blood pressure
Problems: minor; Not in Pregnant and nursing mothers
Note: drugs that block beta1 receptors inhibit release of renin due to interaction with beta1 receptors on juxtaglomerular cells in kidney

Question 3

ACE inhibitors: drugs ending with “-pril”

Answer 3

benazepril, captopril, enalapril, enalaprilat, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril

Question 4

Many ACE inhibitors are ester-containing ____

Answer 4

pro-drugs that are 100 to 1000 times less potent than the active drug, but have a much better oral bioavailability than the active molecules. Such esters must undergo esterase-catalyzed hydrolysis to be active. The resulting acids are named with the suffix ‘at’

Question 5

ACE inhibitor classes

Answer 5

sulfhydryl
dicarboxyl
phosphorous

Question 6

Sulfhydryl-containing ACE inhibitors

Answer 6

structurally related to Captopril
(e.g., fentiapril, pivalopril, zofenopril, and alacepril)

Question 7

Dicarboxyl-containing ACE inhibitors

Answer 7

structurally related to Enalapril (most potent) (e.g., lisinopril, benazepril, quinapril, moexipril, ramipril, trandolapril, perindopril, spirapril,, pentopril, and cilazapril)

Question 8

Phosphorous-containing ACE inhibitors

Answer 8

structurally related to fosinopril

Question 9

ACE inhibitors - lisinopril

Answer 9

most commonly used; Well tolerated; t1/2 = 12 h; Not a prodrug; available mixed with HCTZ (zestoretic)

Question 10

ACE inhibitors - enalapril

Answer 10

Prodrug (contains an ester), hydrolyzed to active diacid enalaprilat; Oral (Enalapril maleate salt); IV (Enalaprilat, oral availability much worse due to the acid); Similar to lisonopril

Question 11

ACE inhibitors - captopril

Answer 11

Thiol-containing, not a prodrug; Useful for Supine Hypertension-Orthostatic Hypotension; Short acting t1/2 < 3 hrs; Side effect: rash; Neutropenia / agranulocytosis in some patients (rare)

Question 12

Fosinopril sodium

Answer 12

phosphate-containing
prodrug (requires hydrolysis to become active)

Question 13

ACE inhibitors: captopril, lisinopril

Answer 13

Action: inhibit angiotensin converting enzyme (ACE)
* Reduce vasoconstriction due to angiotensin II
* Reduce myocardial mitogenic activity and thus decrease myocardial hypertrophy and remodeling
* Reduce sodium and water retention caused by aldosterone release
* Reduce total peripheral resistance
Clinical Use:
First-line monotherapy for hypertension; heart failure
* Particularly useful in whites but not people of African descent
* Particularly beneficial in patients with heart failure, or with chronic kidney disease
(diminish proteinuria and stabilize renal function)
* Better for patients with diabetes than thiazides, better for patients with ischemic heart disease than direct vasodilators
Problems:
* Cough, angioedema, hyperkalemia
* Should not be used in pregnancy due to fetal hypotension/renal failure/mortality
* ACE-i/ARBs are used in renal artery stenosis, but not if GFR drops by more than 30%
* NSAIDs may reduce effectiveness

Question 14

ACE inhibitors: AEs

Answer 14

Bradykinin produces vasodilation, in part mediated by prostaglandins
* NSAIDs (block production of prostaglandins) may decrease ACE inhibitor hypotensive effects due to decreased the bradykinin component of vasodilation
* Cough (up to 40%) and angioedema of lips and tongue due to accumulation of bradykinin
Hyperkalemia due to decreased production of aldosterone. (potassium inhibits aldosterone receptors) - Risk is increased with use of
potassium supplements
or potassium-sparing diuretics

Question 15

Angioedema SE

Answer 15

Black patients are at a 4-5-fold higher risk of angioedema than White patients. This appears related to certain genetic polymorphisms.

Question 16

Angiotensin II receptor blockers (ARBs)

Answer 16

don’t affect bradykinin pathway, therefore have different SEs (no dry cough)

Question 17

ARBs drugs

Answer 17

“-sartans”
candesartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, eprosartan

Question 18

Angiotensin II receptor blockers

Answer 18

• block angiotensin II receptors with a much higher affinity for
  the AT1 receptor versus the AT2 receptor.
• Losartan is the prototypical drug in this class
• The rank order of potency for these agents are: candesartan = omesartan > irbesartan = eprosartan > telmisartan = valsartan = EXP 3174 (the active metabolite of losartan) > losartan (metabolite has high activity, why it is still potent)
• Design based on the carboxy terminus of angiotensin II (try to mimic angiotensin II)
• Essential Hypertension. All administered P.O.. Largely excreted in the feces.

Question 19

ARBs structure activity relationships

Answer 19

Acidic group: o-Phenylcarboxylic acid (or the tetrazole isostere - has much better PK properties compared to carboxylate), or carboxylic acid
* Substituted Imidazole or isosteric equivalent
* A second carboxylic acid group (in some cases).

Question 20

Angiotensin II receptor blocker: losartan, valsartan - Action

Answer 20

Action:
* Competitive antagonist at angiotensin II receptor (AT1)– blocks effects of angiotensin II produced by ACE and by local tissue enzymes other than ACE
* Reduction in angiotensin II mediated vasoconstriction
* Decreased peripheral resistance: decreased afterload
* Decreased aldosterone secretion, decrease salt and water retention, decreased preload
* Decreased sympathetic activity from angiotensin II stimulation (thus reduce renin release)
* Decreased myocardial and vascular remodeling
* Decreased cardiomyoctye apoptosis
* Reduce total peripheral resistance

Question 21

Angiotensin II receptor blocker: losartan, valsartan - Clinical use and adverse effects

Answer 21

Clinical Use:
* Often used in patients who do not tolerate ACE inhibitors
* Valsartan – combined with Sacubitril
* First-line monotherapy for hypertension (often replacement for patients who do not tolerate ACE
inhibitors)
Adverse Effects:
Hypotension, hyperkalemia, lower rate of angioedema but may still occur, fetal pathologies, reduction in GFR Note:
* ARBs do not inhibit the breakdown of bradykinin as do ACE inhibitors and thus are not associated with the ACE inhibitor persistent cough
* ACE-I and ARBs are less effective in African-Americans than other races as monotherapy for hypertensio but appropriate for heart failure

Question 22

Angiotensin II receptor blocker: losartan, valsartan - particularly useful in pts

Answer 22

With diabetes (compared to thiazides)
* With ischemic heart disease (compared to direct vasodilators)
* Patients with chronic kidney disease (diminish proteinuria and stabilize renal function)

Question 23

Aldosterone (mineralocorticoid) receptor antagonist: spironolactone, eplerenone - MOA

Answer 23

Mechanism of Action (potassium-sparing diuretic):
* Aldosterone receptor antagonist (collecting tubules of nephron), thus blocks reabsorption of sodium and decreases blood pressure (mildly)
* “Potassium-sparing” diuretic
* Effectiveness in heart failure likely not primarily due to diuretic effect and
may be related to:
* Increased production of aldosterone in the diseased heart promoting
development of cardiac hypertrophy, remodeling, and fibrosis
* Maintenance of normal potassium levels thus decreasing the risk of
arrhythmias

Question 24

Aldosterone (mineralocorticoid) receptor antagonist: spironolactone, eplerenone - Clinical use and adverse effects

Answer 24

Clinical Use:
* Chronic heart failure – reduces mortality
* Others – aldosteronism, hypertension. Not monotherapy for hypertension
but used to reduce hypokalemia
Adverse Effects:
* Hyperkalemia;
* Spironolactone: lack of receptor specificity and interaction with other steroid receptors; e.g. antiandrogen effects gynecomastia and impotence

Question 25

Thiazides: chlorthalidone, hydrochlorothiazides - MOA

Answer 25

Action: diuretic blocking the sodium-chloride symporter (NCC) on the
distal convoluted tubule. (target: sodium-chloride symptorter, action site: distal convoluted tubule)
* Initially: related to diuretic effect (reduce blood volume and cardiac output)
* Long-term thiazides lower peripheral vascular resistance (mechanism not clear but may influence contractility of vascular smooth muscle)

Question 26

Thiazides: chlorthalidone, hydrochlorothiazides - Clinical use and adverse effects

Answer 26

Clinical use: first-line monotherapy for mild-moderate hypertension; often combine with sympatholytic agent or vasodilator to reduce fluid
* Particularly effective in people of African ancestry
* Not drug of choice for patients with diabetes, hyperlipidemia, gout
problems: hypokalemia, metabolic alkalosis, hyperuricemia, hypercalcemia, hyperglycemia, hyperlipidemia

Question 27

Thiazide diuretics short and long term effects

Answer 27

increase sodium and water excretion
short-term effects: decrease blood volume, decrease cardiac output
long-term effects: decrease sodium content of smooth muscle cells, decrease muscle sensitivity to vasopressors, decrease peripheral vascular resistance
both lead to a decrease in BP

Question 28

Other diuretics: current recommendations

Answer 28

Loop diuretics are NOT recommended as first line monotherapy for the management of hypertension. Single doses are potent but short acting. Increasing doses to twice a day greatly increases the risk of side effects.
K+- sparing diuretics are NOT recommended as first line monotherapy for the management of hypertension because they are weak and associated with hyperkalemia is some conditions and patients.

Question 29

HTN in pregnancy

Answer 29

Management:
* Methyldopa
* Labetalol, metoprolol (and other beta blockers)
Drugs to avoid in pregnancy:
* ACE inhibitors, ARBs, direct renin inhibitors
* Aldosterone (mineralocorticoid) receptor antagonists