8-4 DSA ACE Inhibitors & ARBs Flashcards
What are 2 major angiotensin converting enzyme inhibitors?
Captopril
Enalapril
What are 2 major angiotensin receptor blockers?
Losartan
Valsartan
What are 2 drugs that block renin secretion?
clonidine
propranolol
What is the name of a drug that inhibits renin?
Aliskiren
What is the ultimate outcome of RAS stimulation?
restore normal blood pressure by regulating vasoconstriction and NaCl/H2O reabsorption
What activates RAS?
Decreased blood pressure or fluid volume triggers stimulation of the RAS by increasing sympathetic activation
What inhibits RAS?
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
What are the major components of RAS?
Renin
angiotensin
angiotensin I
Angiotensin II
Converting enzyme
angiotensin II receptors
Aldosterone
What does renin do?
protease - cleaves angiotensin I from angiotensinogen
Where does renin come from, and what stimulates its release?
synthesized & stored in JGA of nephron
SNS stimulation to JGA beta1 receptors stimulates release
What does angiotensinogen do?
becomes angiotensin I
Where does angiotensinogen come from?
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
What does angiotensin I do? What is interesting about it when infused?
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
On a relative basis, what is the activity of angiotensin II? What determines its synthesis rate?
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
Where does Ang II work?
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
Ang II is pretty potent. How is it controlled?
Removed rapidly from circulation by peptidases referred to as angiotensinase
What does converting enzyme do?
Converting enzyme (angiotensin converting enzyme (ACE) or kininase II):
Catalyzes the removal of carboxyl terminal amino acids from substrate peptides
What are some important substrates for converting enzyme?
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)
Where is converting enzyme located?
fixed and widely distributed throughout the body
located on the luminal surface of vascular endothelial cells in most tissues
What does ang II bind?
Angiotensin II binds to two subtypes of G-protein coupled receptors (AT1 and AT2, with AT1 being the major receptor in adults)
What kind of receptors are AT1?
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
What kind of receptor is AT2?
Ang II receptor
Consequences of AT2 receptor activation include bradykinin and nitric oxide (NO) production, which results in vasodilation
What does aldosterone do?
Promotes the reabsorption of sodium from the distal part of the distal convoluted tubule and from the cortical collecting renal tubules
How does aldosterone increase Na+ reabsorption from the DCT and cortical collecting renal tubules?
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)
What 4 targets can be used to inhibit the RAS system? What is the ultimate goal?
ultimate goal: decreased BP/stop HTN
1) ACE inhibitors
2) ARBs
3) direct renin inhibitors
4) sympatholytics
What is the MOA of ACEIs?
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)
How do ACEIs lower BP?
ACEIs lower BP principally by decreasing peripheral vascular resistance
Why are ACEIs a good choice for physically active patients?
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)
What diseases are ACEIs helpful with?
ACEIs are approved for:
hypertension
nephropathy (+/- diabetes)
heart failure (HF)
left ventricular dysfunction (+/- after acute myocardial infarction (AMI))
AMI
prophylaxis of cardiovascular events
There are many ACEIs on the market. How do they differ?
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
The effects of many ACEIs are potentially sensitive to differences in liver metabolism. Why?
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
How do you dose ACEIs?
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)
What are some common adverse effects with ACEIs?
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)
What is a disastrous side effect of ACEIs? Why?
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.
What group of patients are ACEIs contraindicated for, even if they have healthy kidneys?
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
What are some drug-drug interactions that should be avoided with ACEIs? Why?
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)
What is the MOA of ARBs?
Angiotensin receptor blockers (ARBs)
MOA: ARBs cause selective blockade of angiotensin II receptors (AT1-type)
Which is more selective: ARBs or ACEIs? Why?
ARBs have no effect on bradykinin metabolism and are therefore more selective antagonists of angiotensin effects than ACE inhibitors
What conditions can ARBs treat?
Used to treat:
hypertension
diabetic nephropathy
HF
HF or left ventricular dysfunction after AMI
prophylaxis of cardiovascular events
What does inhibtion of Ang II activity result in?
blockade of angiotensin II-induced contraction of vascular smooth muscle
pressor responses
aldosterone secretion
changes in renal function
cellular hypertrophy and hyperplasia
What are the differences between ARBs and ACEIs? Any difference in therapeutic outcomes?
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
What are some adverse effects associated with ARBs? Contraindications?
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
How is losartan metabolized?
Losartan is metabolized by CYP450 enzymes to a more potent metabolite (14% of dose)
How does clonidine work in regards to renin?
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
What does propranolol do in regards to renin secretion?
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)
Are there direct renin inhibitors?
Aliskiren
first effective, oral renin inhibitor
approved by the FDA in 2007 for the treatment of hypertension
What is the effect of renin?
produces a dose-dependent reduction in plasma renin activity
resulting in decreased angiotensin I and II and aldosterone concentrations
Why is aliskiren so different in terms of renin?
The decrease in baseline plasma renin activity is in contrast to the rise in plasma renin activity produced by ACE inhibitors, ARBs, and diuretics
How effective is aliskiren at reducing BP? How quickly?
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
What are some contraindications with aliskiren?
Possible fetal and neonatal morbidity and mortality when used during pregnancy; use with caution in patients with kidney insufficiency
