Flashcards in ACE inhibitors and ARBs DSA Deck (27):
A list of ACE inhibitors. The red ones have stars next to them.
b) * Captopril
c) * Enalapril
f) * Lisinopril
List of Angiotensin Receptor Blockers (ARBs)
e) * Losartan
h) * Valsartan
Drugs that block renin secretion
Renin Angiotensis System (RAS) general description and effects
The RAS is a key homeostatic regulator of blood pressure. RAS stimulation and inhibition, restore normal blood pressure by regulating vasoconstriction and NaCl/H2O reabsorption. Decreased blood pressure or fluid volume triggers stimulation of the RAS by increasing sympathetic activation. Conversely, increased blood pressure or fluid volume triggers inhibition of the RAS by attenuating sympathetic discharge.
ANP, atrial natriuretic peptide, is a powerful vasodilator that also inhibits the RAS.
(1) An aspartyl protease that specifically catalyzes the hydrolytic release of the decapeptide angiotensin I from angiotensinogen; major determinant of angiotensin II production.
(2) The 340 amino acid protein enters circulation from the kidneys, where it is synthesized and stored in the juxtaglomerular apparatus of the nephron.
(3) Sympathetic nervous system stimulation causes activation of β1-adrenergic receptors on juxtaglomerular cells, which stimulates the release of renin from these cells.
(1) Circulating protein substrate of renin; synthesized in the liver; composed of 452 amino acids.
(2) Cleavage of amino terminal 10 amino acids by renin results in the formation of angiotensin I.
(3) Angiotensinogen production is continuous, but can be increased by inflammation, corticosteroids, insulin, estrogens (elevated during pregnancy and in women taking estrogen-containing oral contraceptives), thyroid hormones, and angiotensin II.
(1) Angiotensin I has little to no biologic activity.
(2) Cleaved to angiotensin II by angiotensin-converting enzyme (ACE).
(3) When given intravenously, angiotensin I is converted to angiotensin II so rapidly that the pharmacological responses to these peptides are indistinguishable.
(1) On a molar basis, angiotensin II is approximately 40 times more potent of a vasoconstrictor than norepinephrine.
(2) The most active angiotensin peptide.
(3) Activates G-protein coupled angiotensin II receptors (see below).
(4) Rate of synthesis is determined by the amount of renin released by the kidneys.
(5) Exerts actions at vascular smooth muscle (contraction), adrenal cortex (stimulation of aldosterone synthesis), kidney (inhibition of renin secretion), heart (cardiac hypertrophy and remodeling), and brain (resets the baroreceptor reflex control of heart rate to a higher pressure) and regulates fluid and electrolyte balance and arterial blood pressure.
(6) Removed rapidly from circulation by peptidases referred to as angiotensinase.
Converting Enzyme (ACE or kininase II)
(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.
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.
(1) Promotes the reabsorption of sodium from the distal part of the distal convoluted tubule and from the cortical collecting renal tubules.
(2) 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 blood pressure, and hypokalemia).
Inhibition of the Renin-Angiotensin System: 4 strategies
Four pharmacologic strategies can be used to limit the actions of angiotensin II: (1) ACE inhibitors, (2) ARBs, (3) direct renin inhibitors, and (4) sympatholytics.
Angiotensin-Converting Enzyme (ACE) Inhibitors: MOA
i) MOA: inhibit ACE (aka kininase II) and prevent the formation of angiotensin II (also prevent the inactivation of bradykinin, a potent vasodilator).
(1) ACE inhibitors lower blood pressure principally by decreasing peripheral vascular resistance; cardiac output and heart rate are not significantly changed, making these agents an excellent choice in athletes or physically active patients (ACE inhibitors are not banned by the NCAA or U.S. Olympic Committee while diuretics are).
Angiotensin-Converting Enzyme (ACE) Inhibitors: PK
ii) PK: eleven approved ACE inhibitors differ in regard to potency, prodrug with active metabolite vs. active parent, and pharmacokinetics (see table below).
(1) All ACE inhibitors (except captopril, lisinopril, and enalaprilat) are prodrugs that are 100-1000 times less potent than the active metabolite; however, parent drug has much better oral bioavailability.
(2) Dosing is based on t1/2 (e.g., lisinopril is dosed once-daily while captopril must be given 3-4 times daily).
Angiotensin-Converting Enzyme (ACE) Inhibitors: Therapeutic use
iii) Therapeutic Use: approved for hypertension, nephropathy (+/- diabetes), heart failure (HF), left ventricular dysfunction (+/- after acute myocardial infarction (AMI)), AMI, and prophylaxis of cardiovascular events.
ACE inhibitors: ADRs
common to all ACE inhibitors – hypotension, dry cough, angioedema, and hyperkalemia (more likely to occur in patients with renal insufficiency or diabetes).
(1) Acute renal failure can occur (especially in patients with bilateral renal artery stenosis or stenosis of the renal artery of a solitary kidney).
(2) The ACE inhibitor cough is a common side effect and is often a primary reason for terminating therapy with the agent (some cause cough more than others and choosing an appropriate agent is often by trial and error).
ACE inhibitors: CIs
second and third trimester of pregnancy – fetal hypotension, anuria, and renal failure, sometimes associated with fetal malformations and death; increased teratogenicity during the first trimester.
ACE inhibitors: DDIs:
potassium supplements or potassium sparing diuretics (can result in hyperkalemia) and nonsteroidal anti-inflammatory drugs (may impair some of the antihypertensive effects of ACE inhibitors by blocking bradykinin-mediated vasodilation, which is partly prostaglandin mediated).
ARBs (Angiotensin Receptor Blockers) MOA
i) MOA: selective blockade of angiotensin II receptors (AT1-type). No effect on bradykinin metabolism; therefore, more selective antagonists of angiotensin effects than ACE inhibitors.
(1) Inhibition of angiotensin II activity includes blockade of angiotensin II-induced contraction of vascular smooth muscle, pressor responses, aldosterone secretion, changes in renal function, and cellular hypertrophy and hyperplasia.
Differences between ARBs and ACE inhibitors
(there is debate over whether or not these pharmacological differences result in significant differences in therapeutic outcomes):
(a) ARBs reduce activation of AT1 receptors more effectively than do ACE inhibitors
(b) ARBs permit activation of AT2 receptors
(c) ACE inhibitors increase the levels of a number of ACE substrates, including bradykinin
: losartan is metabolized by CYP450 enzymes to a more potent metabolite (14% of dose).
ARB Therapeutic use
hypertension, diabetic nephropathy, HF, HF or left ventricular dysfunction after AMI, and prophylaxis of cardiovascular events.
similar to ACE inhibitors, though cough and angioedema occur at significantly lower rates.
(1) ARBs are contraindicated during pregnancy or in patients with nondiabetic renal disease.
(2) Avoid concomitant use of potassium supplements or potassium sparing diuretics.
Drugs that Block Renin Secretion
i) Several drugs that interfere with the sympathetic nervous system inhibit the secretion of renin (e.g., clonidine and propranolol).
(1) MOA: an agonist of α2-receptors in the brainstem. When stimulated, α2-receptors cause inhibition of sympathetic vasomotor centers, resulting in a centrally mediated reduction in renal sympathetic nerve activity. Ultimate effect is a reduction of renin secretion.
iii) Propranolol (and other β-blockers)
(1) MOA: nonspecific antagonist of adrenergic β-receptors. Acts on juxtaglomerular cells by blocking β1-receptor stimulated release of renin and thereby decreases blood pressure (also decreases blood pressure by decreasing cardiac output and decreasing sympathetic outflow from the CNS).
Renin Inhibitors and MOA
i) Aliskiren, first effective, oral renin inhibitor. FDA approved in 2007 for treatment of hypertension.
ii) MOA: produces a dose-dependent reduction in plasma renin activity, resulting in decreased angiotensin I and II and aldosterone concentrations.
(1) The decrease in baseline plasma renin activity is in contrast to the rise in plasma renin activity produced by ACE inhibitors, ARBs, and diuretics (see table below regarding the effects of anti-hypertensive agents on components of the RAS).
(2) Decreases in blood pressure are similar to those produced by ACE inhibitors and ARBs.
(3) Substantial proportion (85-90%) of antihypertensive effect attained within 2 weeks of initiation of therapy.