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Renal II Exam 2 > 8-4 DSA ACE Inhibitors & ARBs > Flashcards

8-4 DSA ACE Inhibitors & ARBs Flashcards

1
Q

What are 2 major angiotensin converting enzyme inhibitors?

A

Captopril

Enalapril

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2
Q

What are 2 major angiotensin receptor blockers?

A

Losartan

Valsartan

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3
Q

What are 2 drugs that block renin secretion?

A

clonidine

propranolol

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4
Q

What is the name of a drug that inhibits renin?

A

Aliskiren

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5
Q

What is the ultimate outcome of RAS stimulation?

A

restore normal blood pressure by regulating vasoconstriction and NaCl/H2O reabsorption

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6
Q

What activates RAS?

A

Decreased blood pressure or fluid volume triggers stimulation of the RAS by increasing sympathetic activation

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7
Q

What inhibits RAS?

A

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

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8
Q

What are the major components of RAS?

A

Renin

angiotensin

angiotensin I

Angiotensin II

Converting enzyme

angiotensin II receptors

Aldosterone

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9
Q

What does renin do?

A

protease - cleaves angiotensin I from angiotensinogen

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10
Q

Where does renin come from, and what stimulates its release?

A

synthesized & stored in JGA of nephron

SNS stimulation to JGA beta1 receptors stimulates release

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11
Q

What does angiotensinogen do?

A

becomes angiotensin I

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12
Q

Where does angiotensinogen come from?

A

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)

synthesized in liver, continually circulating

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13
Q

What does angiotensin I do? What is interesting about it when infused?

A

Angiotensin I has little to no biologic activity

Cleaved to angiotensin II 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

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14
Q

On a relative basis, what is the activity of angiotensin II? What determines its synthesis rate?

A

Ang II is more potent than Hugh Hefner with a fresh bottle of sildenafil

(40x more potent vasoconstrictor than epi, most active angiotensin peptide)

Rate of synthesis determined by amt of renin release from kidneys

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15
Q

Where does Ang II work?

A

Exerts actions at vascular smooth muscle (contraction)

adrenal cortex (stimulation of aldosterone synthesis)

kidney (renin secretion inhibition)

heart (cardiac hypertrophy and remodeling)

brain (resets the baroreceptor reflex control of heart rate to a higher pressure)

regulates fluid and electrolyte balance and arterial blood pressure

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16
Q

Ang II is pretty potent. How is it controlled?

A

Removed rapidly from circulation by peptidases referred to as angiotensinase

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17
Q

What does converting enzyme do?

A

Converting enzyme (angiotensin converting enzyme (ACE) or kininase II):

Catalyzes the removal of carboxyl terminal amino acids from substrate peptides

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18
Q

What are some important substrates for converting enzyme?

A

angiotensin I (which it converts to angiotensin II by cleaving the carboxy-terminal two amino acids from angiotensin I)

bradykinin (a vasodilator which is inactivated by converting enzyme)

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19
Q

Where is converting enzyme located?

A

fixed and widely distributed throughout the body

located on the luminal surface of vascular endothelial cells in most tissues

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20
Q

What does ang II bind?

A

Angiotensin II binds to two subtypes of G-protein coupled receptors (AT1 and AT2, with AT1 being the major receptor in adults)

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21
Q

What kind of receptors are AT1?

A

Ang II receptor

Gq-protein coupled receptors

when activated, result in activation of phospholipase C, production of inositol triphosphate (IP3) and diacylglycerol (DAG), and smooth muscle contraction

22
Q

What kind of receptor is AT2?

A

Ang II receptor

Consequences of AT2 receptor activation include bradykinin and nitric oxide (NO) production, which results in vasodilation

23
Q

What does aldosterone do?

A

Promotes the reabsorption of sodium from the distal part of the distal convoluted tubule and from the cortical collecting renal tubules

24
Q

How does aldosterone increase Na+ reabsorption from the DCT and cortical collecting renal tubules?

A

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)

25
Q

What 4 targets can be used to inhibit the RAS system? What is the ultimate goal?

A

ultimate goal: decreased BP/stop HTN

1) ACE inhibitors
2) ARBs
3) direct renin inhibitors
4) sympatholytics

26
Q

What is the MOA of ACEIs?

A

Angiotensin converting enzyme inhibitors (ACEIs):

cause inhibition of ACE (aka kininase II) and prevent the formation of angiotensin II

(also prevent the inactivation of bradykinin, a potent vasodilator)

27
Q

How do ACEIs lower BP?

A

ACEIs lower BP principally by decreasing peripheral vascular resistance

28
Q

Why are ACEIs a good choice for physically active patients?

A

cardiac output and heart rate are not significantly changed

these agents an excellent choice in athletes or physically active patients (ACEIs are not banned by the NCAA or US Olympic Committee while diuretics are)

29
Q

What diseases are ACEIs helpful with?

A

ACEIs are approved for:

hypertension

nephropathy (+/- diabetes)

heart failure (HF)

left ventricular dysfunction (+/- after acute myocardial infarction (AMI))

AMI

prophylaxis of cardiovascular events

30
Q

There are many ACEIs on the market. How do they differ?

A

Eleven approved ACEIs differ in regard to potency, prodrug vs. active metabolite, and pharmacokinetics

Captopril - no active metabolites, renal elimination, 75% bioavail. (decreased with food), half life 2 hours

Enalapril - active metabolite is enalaprit (can do IV administration for HTN emergencies), renal elimination, 60% bioavail., half life <2 hours, or 11 hours for IV

31
Q

The effects of many ACEIs are potentially sensitive to differences in liver metabolism. Why?

A

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

32
Q

How do you dose ACEIs?

A

Dosing is based on ½ life

(e.g., lisinopril is able to be dosed once-daily while captopril must be given 3-4 times daily)

33
Q

What are some common adverse effects with ACEIs?

A

Adverse effects common to all ACEIs include:

hypotension

dry cough (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)

angioedema

hyperkalemia (more likely to occur in patients with renal insufficiency or diabetes)

34
Q

What is a disastrous side effect of ACEIs? Why?

A

Acute renal failure can occur(especially in patients with bilateral renal artery stenosis or stenosis of the renal artery of a solitary kidney)

Conditions causing renal hypoperfusion include systemic hypotension, high-grade renal artery stenosis, ECF volume contraction (simplified as “dehydration” in the Figure), administration of vasoconstrictor agents (eg, NSAIDs or cyclosporine, not shown), and CHF. These conditions typically increase renin secretion or Ang II production. Ang II constricts the efferent arteriole to a greater extent than the afferent arteriole, such that glomerular hydrostatic pressure and GFR can be maintained despite hypoperfusion. When these conditions occur in ACE inhibitor–treated patients, Ang II formation and effect are diminished, and GFR may decrease. GFR is usually maintained or improved in patients with CHF unless one of the other conditions is also present.

35
Q

What group of patients are ACEIs contraindicated for, even if they have healthy kidneys?

A

ACEIs are contraindicated during pregnancy:

Teratogenicity during the first trimester

Fetal hypotension, anuria, and renal failure during the second and third trimesters
Fetal malformations and death may occur during second and third trimesters

36
Q

What are some drug-drug interactions that should be avoided with ACEIs? Why?

A

potassium supplements or potassium sparing diuretics (can result in hyperkalemia)

nonsteroidal anti-inflammatory drugs (may impair some of the antihypertensive effects of ACEIs by blocking bradykinin-mediated vasodilation, which is partly prostaglandin mediated)

37
Q

What is the MOA of ARBs?

A

Angiotensin receptor blockers (ARBs)

MOA: ARBs cause selective blockade of angiotensin II receptors (AT1-type)

38
Q

Which is more selective: ARBs or ACEIs? Why?

A

ARBs have no effect on bradykinin metabolism and are therefore more selective antagonists of angiotensin effects than ACE inhibitors

39
Q

What conditions can ARBs treat?

A

Used to treat:

hypertension

diabetic nephropathy

HF

HF or left ventricular dysfunction after AMI

prophylaxis of cardiovascular events

40
Q

What does inhibtion of Ang II activity result in?

A

blockade of angiotensin II-induced contraction of vascular smooth muscle

pressor responses

aldosterone secretion

changes in renal function

cellular hypertrophy and hyperplasia

41
Q

What are the differences between ARBs and ACEIs? Any difference in therapeutic outcomes?

A

Therapeutic outcome differences: jury is still out

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

42
Q

What are some adverse effects associated with ARBs? Contraindications?

A

ARB adverse effects are similar to those of ACEIs, though cough and angioedema occur at significantly lower rates

ARBs are contraindicated during pregnancy or in patients with nondiabetic renal disease

Avoid concomitant use of potassium supplements or potassium sparing diuretics

43
Q

How is losartan metabolized?

A

Losartan is metabolized by CYP450 enzymes to a more potent metabolite (14% of dose)

44
Q

How does clonidine work in regards to renin?

A

MOA: an agonist of α2-receptors in the brainstem

α2-receptors cause inhibition of sympathetic vasomotor centers

centrally mediated reduction in renal sympathetic nerve activity

Ultimate effect is a reduction of renin secretion

45
Q

What does propranolol do in regards to renin secretion?

A

Propranolol (and other β-blockers):

nonspecific antagonist of adrenergic β-receptors

Act on juxtaglomerular cells

blocks β1-receptor stimulated release of renin

decreases blood pressure

(also decreases BP by decreasing cardiac output and decreasing sympathetic outflow from the CNS)

46
Q

Are there direct renin inhibitors?

A

Aliskiren

first effective, oral renin inhibitor

approved by the FDA in 2007 for the treatment of hypertension

47
Q

What is the effect of renin?

A

produces a dose-dependent reduction in plasma renin activity

resulting in decreased angiotensin I and II and aldosterone concentrations

48
Q

Why is aliskiren so different in terms of renin?

A

The decrease in baseline plasma renin activity is in contrast to the rise in plasma renin activity produced by ACE inhibitors, ARBs, and diuretics

49
Q

How effective is aliskiren at reducing BP? How quickly?

A

Decreases in blood pressure are similar to those produced by ACEIs and ARBs

Substantial proportion (85-90%) of antihypertensive effect attained within 2 weeks of initiation of therapy

50
Q

What are some contraindications with aliskiren?

A

Possible fetal and neonatal morbidity and mortality when used during pregnancy; use with caution in patients with kidney insufficiency

51
Q
A

Renal II Exam 2 (8 decks)

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