Hypertension (BB, ARB, ACEi)

Question 1

What are the 4 general classes of drugs used to treat HTN?

Answer 1

Diuretics, Sympathoplegic agents, Direct Vasodilators, Agents which act to block production or actions of Angiotensin.

Question 2

General idea of how Diuretics work to decrease HTN?

Answer 2

They deplete the body of sodium and thereby of fluids. There might be other mechanisms that isn’t understood yet.

Question 3

General idea of how Sympathoplegic agents work?

Answer 3

They act to decrease vascular resistance, inhibit the heart rate, or increase the venous pooling.

Question 4

General idea of how Direct vasodilators and Angiotensin blockers work?

Answer 4

Vasodilators will relax the vascular smooth muscles and thereby increase dilation. Angiotensin blocks inhibit vasoconstriction and can also potentially lead to fluid loss.

Question 5

What is the problem of administering a drug that alters the sympathetic function on its own?

Answer 5

The body will compensate using mechanisms that are not reliant on the adrenergic nerves, i.e. they will have increased retention of sodium by the kidneys and thus expand the blood volume:
For this reason, one ought to administer a diuretic in addition to a drug that messes with the sympathetic function to have the best effect.

Question 6

General uses of Beta Adrenergic Receptor Blockers (Beta Blockers?)

Answer 6

They have Tx for HTN, certain arrythmias, Ischemic Heart disease, and CHF.

Question 7

What are some compelling indications of using Thiazide Diuretics? Contraindications?

Answer 7

Heart failure, advanced age, volume dependent HTN, low renin HTN, systolic HTN.
Contraindication: Gout

Question 8

Side effects of Thiazide Diuretics?

Answer 8

Hypokalemia, hyperuricemia, glucose intolerance, hypercalcemia, impotence

Question 9

Compelling indications of using ACE inhibitors?

Answer 9

HF, LVH, Proteinuria, Diabetic nepropathy, Chronic Kidney Disease (CKD), post MI

Question 10

Contraindication of ACE inhibitors?

Answer 10

Pregnancy, hyperkalemia

Question 11

AE’s of ACE inhibitors?

Answer 11

Cough, angioedema, hyperK, Acute Renal Failure in b/l Renal Artery Stenosis, rash

Question 12

Angiotensin Receptor blockers should be used when…

Answer 12

For whatever you would’ve used ACEi for, use this when pt cannot tolerate ACEi.

Question 13

Contraindication of ARBs

Answer 13

Same as ACE, preg and hyperK

Question 14

AE’s of ARB’s?

Answer 14

Angiedema (rare), hyperK, potential increase in creatinine lvls in pt’s with b/l renal artery stenosis.

Question 15

When would you use Beta Blockers?

Answer 15

Angina, HF, post MI, migraine, tachyarrythmia

Question 16

CI’s of ß blockers?

Answer 16

Asthma, COPD, heart block

Question 17

AE’s of ß blockers?

Answer 17

Bronchospasm, bradycardia, HF, fatigue, decreased exercise tolerance

Question 18

What releases renin and what stimulates the release of Renin?

Answer 18

Released from kidney cortex, in response to reduced arterial pressure, sympathetic neural stimulation, and reduced Na delivery/increased sodium conc at the distal renal tubule.

Question 19

What is the activity of renin?

Answer 19

Renin acts as a protease, it cleaves the inactive angiotensin I (dicapeptide angiotensinogen) into active angiotensin I.

Question 20

What converts angiotensin I to II and where is this primarily occurring?

Answer 20

Primarily by Angiotensin Converting Enzyme (ACE, also called kinninogen II), which is found in endothelial cells (particularly in the epithelial cells of the lungs).

Question 21

What can angiotensin II turn into and where does this occur?

Answer 21

It can turn into angiotensin III which occurs in the adrenal gland.

Question 22

What is the function of angiotensin II?

Answer 22

It acts as a vasoconstrictor and a sodium retainer (both II and III stimulates the release of aldosterone).

Question 23

What is the function of ACE (aka peptidyl dipeptidase and kininase II)?

Answer 23

To convert angiotensin I to II, (when it does this it is ACE or peptidyl dipeptidase) and to also inactivate Bradykinin – under the name plasma kininase (kininase II) into inactive metabolites and thereby inhibit vasodilation.

Question 24

Describe the Bradykinin pathway.

Answer 24

Kinninogen → (Kallikrein) → Bradykinin, which has 2 functions:

1. Bradykinin can increase prostoglandin synthesis → vasodilation → decreased BP.
2. Bradykinin on its own can stimulate vasodilation, possibly by releasing NO → decreased peripheral resistance → decreased BP.

Question 25

How does the drug Captopril work?

Answer 25

It’s an ACEi. It inhibits ACE and thus prevents the creation of Angiotensin II and its downstream effect, and also inhibits ACE’s secondary activity (under the name of kininogen II) to metabolize bradykinin, thus it potentiates the activity of bradykinin and its vasodilation effects.

Question 26

What is Enalapril?

Answer 26

It is a prodrug (oral) → hydrolized to enalaprilat primarily in the liver → does the same thing as captopril. Enalaprilat can be given IV for emergencies.

Question 27

What is Lisinopril?

Answer 27

A lysine derivitive of enalaprilat, thus it does the same thing as captopril.

Question 28

Name the drugs of the ACEi?

Answer 28

Captopril, Enalapril (Enalaprilat), Lisinopril, [benazepril, fosinopril, moexipril, perindopril, quinapril, ramipril and trandopril – all these are prodrugs and are long-acting members of this class].

Question 29

Primary effect of ACEi?

Answer 29

–| ACE, and as a result decrease peripheral resistance by preventing the vasoconstriction and Na retention abilities of angiotensin II, and also inducing vasodilation by –| bradykinin metabolism by ACE. NO effect in cardiac output or HR.

Question 30

Do ACEi induce reflexive sympathetic (and if it does, which patients would have CI to it?)

Answer 30

If it activated reflexive sympathetic stimulation, you couldn’t give it to patients with ischemic heart disease, but ACEi DOES NOT induce reflexive sympathetic stimulation thus no reflexive tachycardia.

Question 31

Do we want to give ACEi to patients with chronic kidney disease?

Answer 31

Yes, for it decreases proteinuria and stabilizes renal function – particularly useful in diabetics, so use this even if diabetics dont have HTN yet.

Question 32

Why do ACEi seem to help diabetics, specifically in terms of improved renal function?

Answer 32

ACEi induces decreased glomerular efferant arteriolar resistance → decreased intraglomerular arteriolar pressure → better intrarenal hemodynamics.

Question 33

What are other indications of ACEi besides HTN?

Answer 33

Diabetics (to improve renal function), HF, post MI, and recent evidence indicates that it decreases the incidence of diabetes in patients with high cardiovascular risk.

Question 34

Which drug is the “classical” ß blocker and what does it do?

Answer 34

Propranolol, used to treat both HTN and ichemic heart disease.

Question 35

When would ß blockers be especially useful to use?

Answer 35

To prevent reflexive tachycardia in response to using a direct vasodilator, it also reduces mortality rate post MI and HF, thus ß blockers are especially useful in treating pt’s with HTN that have HF or suffers from post MI.

Question 36

AE of ACEi?

Answer 36

For patients who are hypovolemic (due to GI fluid loss, diuretics, salt restriction) → severe hypotention can result. Acute renal failure esp if patient has b/l renal artery stenosis or of solitary kidney.
Hyper K
DRY COUGH sometimes accompanied by wheezing and angioedema, this might be due to increased Bradykinin and Substance P accumilation (due to inactivation of bradykinin metabolism)

Question 37

Pregnancy and ACEi?

Answer 37

Increased teratogenic risk in all 3 trimesters, can cause fetal hypotension, anurea and renal failure → fetal death.

Question 38

Specific AE of Captopril?

Answer 38

If given at high doses w/ patients that have renal insufficiency → neutropenia and proteinuria.

Question 39

Minor AE of ACEi?

Answer 39

Altered sense of taste, allergic skin rashes, and drug fever (10% of patients).

Question 40

DDI of ACEi?

Answer 40

Any K supplements or K sparing diuretics → Hyper K.

NSAIDs will prevent bradykinin mediated vasodilation, thus reduce hypotension capabilities of ACEi.

Question 41

MOA of Propranolol?

Answer 41

It is a non selective –| of beta receptors (both 1 and 2). It functions primarily by decreasing cardiac output.

1. It –| ß1 receptors → –| of stimulation of renin production by catecholamines
2. Might also act on peripheral presynaptic ß adrenoceptors → reduce sympathetic vasoconstriction.

Question 42

Administration of Propranolol?

Answer 42

It’s x2 daily dosing.

Question 43

AE’s of Propranolol?

Answer 43

Principal AE is blockade of cardiac, vascular and bronchial ß receptors, particularly a problem in patients that already suffers from bradycardia, cardiac conduction disease, asthema, peripheral vascular insufficiency and diabetes.

Question 44

Why is it not ok to spontaneously discontinue Propranolol after prolonged use?

Answer 44

Trigger withdrawal symptoms: nervousness, tachycardia, increased intensity of angina, increased HTN, MI ← all of this might be due to the up-regulation or super sensitivity of ß adrenoceptors.

Question 45

Which are the most widely used ß blockers for HTN? What does Metoprolol do specifically?

Answer 45

Metoprolol and Atenolol, both cardioselective. Metoprolol is as effective at –| ß1 as Propranolol, but 50-100x less potent –| of ß2, thus although not completely cardioselective, Metoprolol causes less bronchoconstriction than Propranolol while equally effective at –| ß1.

Question 46

How does Atenolol differ from Metoprolol?

Answer 46

It isnt extensively metabolized like Metoprolol, so t(1/2) is 6 hrs and thus can be x1 daily dosing. It is less effective than Metoprolol at preventing complications of HTN, probably due to inadequate blood levels for the x1 dosing.

Question 47

Why do we care about ß adrenoceptor relative cardioselectivity?

Answer 47

Allows us to treat HTN without exacerbating the symptoms of asthma, diabetes or peripheral vascular disease.

Question 48

Metoprolol is metabolized where? When would we consider the sustained release Metoprolol?

Answer 48

By CYP2D6 with a very high first pass metabolism, this relatively short t(1/2) of 4-6 hrs, so x2 dosing daily. Sustained release formula should be considered in patients who suffers from both HTN and HF.

Question 49

What are Nadolol and Carteolol?

Answer 49

Non selective BB’s, not really metabolized and excreted in considerable amounts in the urine.

Question 50

What are Betaxolol and Bisoprolol?

Answer 50

They are ß1 selective blockers of the BB class, primarily metabolized in the liver, long half lives however, x1 daily dosing.

Question 51

What are Pindolol, Acebutolol and Penbutolol? Why would you use it?

Answer 51

BB’s that are partial agonists, (has some intrinsic sympathomimetic activity). They appear to depress cardiac output and HR less than other BB (maybe due to more agonist than antagonist effect at ß2 receptors), primarily they decrease vascular resistance:
Particularly useful in Pt’s with bradyarrythmias or Peripheral Vascular Disease (PVD).

Question 52

What is Labetalol chemically?

Answer 52

Its a BB that has both ß blocking and vasodilation effects. It comes in 4 racemic mixtures, the (S,R) is a potent alpha blocker whereas the (R,R) is a potent beta blocker (the other 2 are inactive). Comes in a 3:1 beta:alpha ratio for oral dosing
What does Labetalol do to decrease BP?
The alpha blocker reduces systemic resistance w/o messing with cardiac output or HR, whereas the beta blocker does its usual thing.

Question 53

Uses for Labetalol?

Answer 53

Useful in treating HTN of pheochromocytoma and HTN emergencies (via IV).

Question 54

What is Carvedilol? It’s t(1/2)? Its Tx uses?

Answer 54

It’s a BB similar to Labetalol, the S(-) is a non-selective beta blocker, but the S(-) and the R(+) have equal alpha blocking potency. Stereoselective metabolism in liver so varying half life (7-10 hrs on avg), and especially useful in pt’s with HTN and HF.

Question 55

What is Nebivolol? What’s special about its peripheral resistance? Does it have more or less AE’s than other HTN meds?

Answer 55

A BB that is B1 selective (D-isomer), and induces vasodilation but NOT via Alpha blocking (L-isomer). Vasodilation may be due to induction of endothelial NO synthase → increase release of NO. It ACUTELY decreases peripheral resistance as opposed to increasing it like the older agents, it is reported to have fewer side effects in comparison to other HTN meds.

Question 56

PK of Nebivolol?

Answer 56

Extensively hepatically metabolized, t(1/2) 10-12 hrs, x1 daily dosing.

Question 57

What is Esmolol? When will you use it?

Answer 57

It is a BB that is ß1 selective, and is rapidly hydrolized by RBC esterases so it needs constant IV infusion. Used only in intraoperative and postoperative management of HTN, and HTN emergencies when it is accompanied by tachycardia.

Question 58

How do ARBs differ from ACEi and why?

Answer 58

1. ARB’s just prevent Angiotensin II to bind to its target receptor, however this still has functional ACE, which still metabolize Bradykinin and thus ARBs will NOT have a vasodilation effect via Bradykinin. As a result they are more selective blockers of Angiotensin II effects than ACEi.
2. Furthermore, other things besides ACE can make angiotensin II, however ARBs prevent these from working as well, whereas ACEi will only prevent Angiotensin II produced from ACE → More complete –| of angiotensin II.

Question 59

What are common ARB drugs? Which Angiotensin II does ARBs specifically block?

Answer 59

Losartan and Valsartin, and other drugs that end with -sartan. They specifically block ATII type 1.

Question 60

Tx of ARBs? AE’s? Use in Pregnancy?

Answer 60

Similar to ACEi, it can be used for HF and chronic kidney disease. Similar AE’s and contraindicated in preg. However, cough and angioderma is less common with ARBs.

Question 61

You know this drug is an ACEi because…

Answer 61

It ends with a -pril.

Question 62

You know this drug is a BB because

Answer 62

It’s funny, for it ends with a -lol.