ACE Inhibitors And ARBs DSA Flashcards Preview

Renal II Final > ACE Inhibitors And ARBs DSA > Flashcards

Flashcards in ACE Inhibitors And ARBs DSA Deck (25):

List angiotensin converting enzyme inhibitors



List angiotensin receptor blockers



List drugs that block renin secrtion



List a renin inhibitor



What does the renin angiotensin system (RAS) do in response to decreased BP?

In response to decreased BP, decreased fluid volume, and increased Beta1-sympathetics, RAS is stimulated to release renin.
In crease in renin leads to increases in angiotensin I, angiotensin II, aldosterone, vasoconstriction, and NaCl/H2 reabsorption, and decreased urine output


What does the renin angiotensin system do in response to increased blood pressure?

In response to increased BP, increased fluid volume, and decreased Beta1-sympathetics, and ANP, RAS is inhibited
Decrease in renin causes decreases in angiotensin I, angiotensin II, aldosterone, vasoconstriction, and NaCl/H2O reabsorption, and increased urine output


Describe renin

Aspartyl protease that specifically catalyzes hydrolytic release of decapeptide angiotensin I from angiotensinogen
340 amino acid protein enters circulation from kidneys, where it is synthesized and stored in juxtagomerular apparatus of nephron
Sympathetic nervous system stimulation causes activation of Beta1-adrenergic receptors on juxtaglomerular cells, which stimulates release of renin from these cells


Describe angiotensinogen

Circulating protein substrate (synthesized in liver) from which renin cleaves angiotensin I
Composed of 452 AA
Amino terminal 10 AA are cleaved by renin, resulting in formation of angiotensin I
Angiotensinogen production is increased by corticosteroids, estrogens (elevated during pregnancy and in women taking estrogen-containing oral contraceptives), thyroid hormones, and angiotensin II


Describe angiotensin I

First 10 amino terminal AA of angiotensinogen.
Has little to no biologic activity
Cleaved to angiotensin II (10 AA to 8 AA) by angiotensin converting enzyme (ACE)
When given intravenously, angiotensin I is converted to angiotensin II so rapidly that the pharmacological responses to these peptides are indistinguishable


Describe angiotensin II

Exerts actions at vascular smooth muscle (contraction), adrenal cortex (stimulation of aldosterone synthesis), kidney (renin secretion inhibition), heart (cardiac hypertrophy and remodeling), and brain (resets baroreceptor reflex control of heart rate to a higher pressure), and regulates fluid and electrolyte balance and arterial blood pressure
On a molar basis, angiotensin II is approximately 40 times more potent of a vasoconstrictor than epinephrine
Most active angiotensin peptide
Activates G-protein coupled angiotensin II receptors
Rate of synthesis is determined by amount of renin released by kidneys
Removed rapidly from circulation by peptidases referred to as angiotensinase


Describe angiotensin converting enzyme (ACE) or kininase II

Catalyzes removal of carboxy terminal AA from substrate peptides
Most important substrates are angiotensin I (which it converts to angiotensin II by cleaving carboxy-terminal 2 AA from angiotensin I) and bradykinin (vasodilator which is inactivated by converting enzyme)
Widely distributed throughout body and located on luminal surface of vascular endothelial cells in most tissues


Describe angiotensin II receptors

Angiotensin II binds to 2 subtypes of G-protein coupled receptors (AT1 and AT2, with AT1 being major receptor in adults)
AT1 receptors are Gq-coupled receptors that, when activated, result in activation of phospholipase C, production of inositol triphosphate (IP3) and diacyglycerol (DAG), and smooth muscle contraction
Consequences of AT2 receptor activation include bradykinin and NO production, which results in vasodilation


Describe aldosterone

Promotes reabsorption of sodium from distal part of distal convoluted tubule and from cortical collecting renal tubules
Increases activity of both epithelial sodium channel (ENaC) and basolateral Na/K-ATPase, leading to increase in Na reabsorption and K secretion (which causes retention of water, an increase in blood volume, increase in BP, and hypokalemia)


Describe the MOA of ACE inhibitors (ACEIs)

Cause inhibition of ACE (kininase II) and prevent formation of angiotensin II (prevent inactivation of bradykinin, a potent vasodilator)
Lower BP principally by decreasing peripheral vascular resistance
Cardiac output and HR are not significantly changed, making these agents excellent choice in athletes or physically active pts


What are ACEIs approved for, and what are some characteristics?

Approved for HTN, nephropathy (+/-diabetes), heart failure, left ventricular dysfunction (+/- after acute myocardial infarction), AMI, and prophylaxis of CV events
11 approved ACEIs differ in regard to potency, prodrug vs active, and pharmacokinetics
All ACEIs except for captopril and lisinopril are prodrugs that are 100-1000x less potent than active metabolite but have much better oral bioavailabilty
Dosing is based on half-life (lisinopril is able to be dosed once-daily, while captopril must be given 3-4x daily)


Describe toxicity and adverse effects of ACEIs

Hypotension, acute renal failure (esp. In pts with bilateral renal artery stenosis or stenosis of renal artery of solitary kidney), hyperkalemia (more likely to occur in pts with renal insufficiency or diabetes), dry cough, and angioedema

ACEI cough is common side effect and is often primary reason for terminating therapy with agent (some ACEIs cause cough more than others)

Contraindicated in pregnancy
-fetal hypotension, anuria, and renal failure during 2nd and 3rd trimesters
-fetal malformations and death may occur during 2nd and 3rd trimesters
-teratogenicity during 1st trimester

Drug-drug interactions that should be avoided include potassium supplements or potassium sparing diuretics (can result in hyperkalemia) and NSAIs (may impair some of antihypertensive effects of ACEIs by blocking bradykinin-mediated vasodilation, which is partly prostaglandin mediated)


Describe angiotensin receptor blockers (ARBs) and their MOA

MOA: cause selective blockade of angiotensin II receptors (AT1-type)
Have no effect on bradykinin metabolism and are therefore more selective antagonists of angiotensin effects than ACEIs
Used to treat HTN, diabetic nephropathy, HF, HF or left ventricular dysfunction after AMI, and prophylaxis of CV events
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


Describe differences between ARBs and ACEIs

ARBs reduce activation of AT1 receptors more effectively than do ACEIs
ARBs permit activation of AT2 receptors
ACEIs increase levels of number of ACE substrates, including bradykinin


Describe toxicity and adverse effects of ARBs

Similar to those of ACEIs, though cough and angioedema occur at significantly lower rates
Not recommended during pregnancy or in pts with nondiabetic renal disease


What metabolizes losartan to a more potent metabolite (14% of dose)?



Describe clonidine

MOA: agonist of alpha2-receptors in brainstem
When stimulated, alpha2-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


Describe propranolol

MOA: nonspecific antagonist of adrenergic beta-receptors
Act on juxtaglomerular cells by blocking beta1-receptor stimulated release of renin and thereby decreases BP (also decreases BP by decreasing cardiac output and decreasing sympathetic outflow from CNS)


Describe renin inhibitor aliskiren

First effective, oral renin inhibitor and was approved by FDA in 2007 for treatment of hypertension
Produces a dose-dependent reduction in plasma renin activity, resulting in decreased angiotensin I and II and aldosterone concentrations
Decrease in baseline plasma renin activity is in contrast to rise in plasma renin activity produced by ACEIs, ARBs, and diuretics
Decreases in BP are similar to those produced by ACEIs and ARBs
Substantial proportion (85-90%) of antihypertensive effect attained within 2 weeks of initiation of therapy
Possible fetal and neonatal morbidity and mortality when used during pregnancy
Use with caution in pts with kidney insufficiency


Describe monotherapy vs polypharmacy in HTN

Although monotherapy of HTN is advantageous due to increase in pt compliance, decrease in cost, and less adverse effects, polypharmacy is often required to treat many pts with HTN
Rationale behind polypharmacy is that each of the drugs acts on one of a set of interacting mutually compensatory regulatory mechanisms for maintaining blood pressure
In practice, when HTN does not respond adequately to a regimen of one drug, a second drug from a different class with a different MOA and different patter of toxicity is added


List examples of combos for polypharmacy treatment of HTN

ACEIs and calcium channel blockers (trandolapril/verapamil)
ACEIs and diuretics (benazepril/hydrochlorothiazide)
ARBs and diuretics (valsartan/hydrochlorothiazide)
Beta-blockers and diuretics (propranolol/hydrochlorothiazide)
Centrally acting agent and diuretic (reserpine/chlorothiazide)
Diuretic and diuretic (spironolactone/hydrochlorothiazide)