ACEI's, ARBS, vasodilators and sympathoplegics!

Question 1

-epril

Answer 1

ACE inhibitors

Question 2

• sartan

Answer 2

ARBs

Question 3

list of ACE inhibitors

Answer 3

Benazepril
***Captopril
***Enalapril - IV admin
Enalaprilat
Fosinopril
Lisinopril
Moexipril
Perindopril
Quinapril 
Ramipril
Trandolapril

Question 4

list of ARBs

Answer 4

Azilsartan
Candesartan
Eprosartan
Irbesartan
***Losartan
Olmesartan
Telmisartan
***Valsartan

Question 5

drugs that block renin secretion?

Answer 5

• clonidine

- propanolol

Question 6

Renin inhibitors

Answer 6

Aliskiren

Question 7

RAAS system

Answer 7

drop in sodium/blood pressure –> renin secretion from kidneys

renin goes to liver and converts ANG –> ANG I

ANGI is converted to ANG II by ACE in the liver

ANGII results in:

• sodium retenion, H20 retenteion in kidneys
• release of corticotropin and adiuretin and thirst stimulation in brain
• increased production of aldosterone in adrenals
• increased vasoconstriction and increased blood pressure of blood vessels

Question 8

3 major effects of ANG II?

Answer 8

1. altered peripheral resistance: cause direct vasoconstriction, increased symp discharge –> rapid pressor response
2. altered renal function: direct increase of sodium reabsorption in proximal tubule, release of ALDO and renal vasoconstriction –> Slow pressor response
3. altered cardiovascular structure: vascular and cardiac hypertrophy and remodelling (increased ECM proteins, growth factors and proto-oncogenes)

Question 9

strategies to decrease RAAS?

Answer 9

Diuretics 
Aldosterone receptor (MR) antagonists

ACE inhibitors (ACEIs)
Angiotensin II receptor blockers (ARBs)
Renin inhibitors

β-blockers

Question 10

captopril/enalapril MOA

Answer 10

inhibit the conversion of angiotensin I to the more active angiotensin II; also prevent degradation of bradykinin and other vasodilator peptides

** thus it downregulates a vasoconstrictor and UPREGULATES a vasodilator

Question 11

indications of ACE inhibitors?

Answer 11

hypertension, heart failure, left ventricular dysfunction, prophylaxis of future cardiovascular events (e.g., MI, CAD, stroke) and nephropathy (+/- diabetes)

Question 12

benefits of ACE inhibitors in HTN?

Answer 12

Lowers TPR and mean, diastolic, and systolic BP

Cardiac function in patients with uncomplicated hypertension is little changed

Stroke volume and cardiac output may increase slightly with sustained treatment

Baroreceptor function and cardiovascular reflexes are not compromised

Responses to postural changes and exercise are little impaired

Evidence that ACEIs are superior in treating HTN in patients with diabetes

Improve endothelial function and reduce CV events more so than CCBs or diuretic and β-blocker combo

Question 13

Adverse effects of ACE inhibitors?

Answer 13

Hypotension
*Cough (caused by reduced metabolism of bradykinin)
*Angioedema
*Hyperkalemia – avoid K+-sparing diuretics
Acute renal failure – particularly in patients with renal artery stenosis
Fetopathic potential (teratogen) – **contraindicated in pregnancy
Proteinuria
Skin rash
Dysgeusia (altered sense of taste)

Drug interactions: antacids, capsaicin, NSAIDs, K+-sparing diuretics, digoxin, lithium, allopurinol

Question 14

type 1 diabetics with renal disease?

Answer 14

ACEIs prevent/delay the progression of renal disease in type 1 diabetics and in patients with nondiabetic nephropathies (results mixed in type 2 diabetics)

Question 15

ACEIs role on renal vasculature?

Answer 15

ACEIs vasodilate efferent arterioles > afferent arterioles
Reduces back pressure on the glomerulus and reduces protein excretion
ACEIs usually improve renal blood flow and Na+ excretion rates in CHF

In rare cases, ACEIs can cause a rapid decrease in GFR, leading to acute renal failure
Can occur anytime during therapy, even after months or years of uneventful ACEI treatment

Question 16

risk factors for ACEIs?

Answer 16

induced acute renal failure

MAP insufficient for adequate renal perfusion

• Poor cardiac output
• Low systemic vascular resistance

Volume depletion (diuretic use)

Renal vascular disease
- Bilateral renal artery stenosis
- Stenosis of dominant or single kidney
- Afferent arteriolar narrowing (HTN, cyclosporin A)
- Diffuse atherosclerosis in smaller renal vessels
Vasoconstrictor agents (NSAIDs, cyclosporine)

***All cause renal hypoperfusion

don’t combine ACE, ARB or renin inhibitor –> ARF

Question 17

ANG II Receptor blockers

Answer 17

• LOSARTAN, VALSARTAN

MOA: selectively block AT1 receptors, which leads to
↓ contraction of vascular smooth muscle
↓ aldosterone secretion
↓ pressor responses
↓ cardiac cellular hypertrophy and hyperplasia

No effect on bradykinin metabolism

Therapeutic uses: hypertension, diabetic nephropathy, HF, HF or left ventricular dysfunction after AMI, and prophylaxis of cardiovascular events

Adverse effects similar to ACEIs but less cough and edema; contraindicated during pregnancy

Question 18

ACEI’s vs ARBs?

Answer 18

ARBs reduce activation of AT1 receptors more effectively than do ACE inhibitors

ARBs permit activation of AT2 receptors (vasodilation)

ACE inhibitors increase the levels of a number of ACE substrates, including bradykinin (vasodilation)

Unknown whether or not these pharmacological differences result in significant differences in therapeutic outcomes

Question 19

aliskiren

Answer 19

MOA: inhibits renin and blocks the conversion of angiotensinogen to angiotensin I

Does not increase bradykinin

Rise in plasma renin levels but decreased plasma renin activity (ACEIs, ARBs, and diuretics raise plasma renin levels and activity via feedback loop)

Studies show effectiveness comparable to ACEIs and ARBs

AEs similar to ACEIs and ARBS; contraindicated in pregnancy

Question 20

clonidine

Answer 20

(1) MOA: an agonist of α2-receptors in the brainstem
(2) When stimulated, α2-receptors cause inhibition of sympathetic vasomotor centers, resulting in a centrally mediated reduction in renal sympathetic nerve activity
(3) Ultimate effect is a reduction of renin secretion.

Pharmacodynamics: lowers blood pressure by reducing cardiac output (decreased heart rate and relaxation of capacitance vessels) and reducing peripheral vascular resistance

Adverse Effects: sedation, dry mouth, depression, sexual dysfunction

(1) transdermal preparation is associated with less sedation than oral, but may cause skin reaction
(2) Abrupt withdrawal can lead to life-threatening hypertensive crisis

Clinical Use:
Essential hypertension (rarely used)
Adjunct for narcotic, alcohol, & tobacco withdrawal (unlabeled)

Question 21

Propanolol

Answer 21

(and other β-blockers)

(1) MOA: nonspecific antagonist of adrenergic β-receptors
(2) Act on juxtaglomerular cells by blocking β1-receptor stimulated release of renin and thereby decreases blood pressure (also decreases BP by decreasing cardiac output and decreasing sympathetic outflow from the CNS)

Question 22

-dipine

Answer 22

dihydropyridine CCB: ex. amlodipine, nifedipine

Question 23

amlodipine

Answer 23

DHP CCB

Question 24

Nifedipine

Answer 24

DHP CCB

Question 25

non-dihydropyridines?

Answer 25

Diltiazem, verapamil

Question 26

Diazoxide (Hyperstat IV)

Answer 26

potassium channel openers

Question 27

Fenoldopam

Answer 27

dopamine agonist - thus ensures adequate renal blood flow MOA: peripheral arteriolar dilator; natriuretic Use: administered IV for HTN emergencies and post-op HTN Adverse effects: Tachycardia, h/a flushing CI: patients with glaucoma due to increases in intraocular pressure

Question 28

Minoxidil

Answer 28

potassium channel opener

Question 29

hydralazine

Answer 29

NO modulator =Oral drug, dilates arterioles but not veins MOA: Releases nitric oxide from endothelium Clinical Uses: - controls longer term outpatient HTN - First-line therapy for hypertension in pregnancy, with methyldopa - Combination with nitrates is effective in heart failure and should be considered in patients, especially African-Americans, with both hypertension and heart failure Adverse effects: - Can induce fluid and sodium retention - Headache, nausea, anorexia, sweating, flushing, palpitations - Reflex tachycardia can provoke angina in patients with ischemic heart disease - Lupus-like syndrome (reversible on drug withdrawl)

Question 30

sodium nitroprusside

Answer 30

NO modulator - Used to treat hypertensive emergencies, heart failure, & angina (nitrates) - Pharmacodynamic effects Dilates both arterial and venous vessels—decreases TPR and venous return Decreases both preload & afterload Mainly relaxation of large veins --> decreased venous return --> decreased preload --> decreased O2 demand (major effect), smaller decrease in afterload Adverse effects Nitroprusside: excessive hypotension, cyanide poisoning

Question 31

nitroglycerine

Answer 31

organic nitrate NO modulator * prototype* - cause release of NO via enzymatic action - Used to treat hypertensive emergencies, heart failure, & angina (nitrates) - Pharmacodynamic effects Dilates both arterial and venous vessels—decreases TPR and venous return Decreases both preload & afterload Mainly relaxation of large veins --> decreased venous return --> decreased preload --> decreased O2 demand (major effect), smaller decrease in afterload Nitrates: orthostatic hypotension, syncope, throbbing headache Compensatory responses contributing to the development of tolerance: tachycardia, increased cardiac contractility, retention of salt and water CI: intracrnail pressure is elevated

Question 32

-olol

Answer 32

Beta blockers

Question 33

-zosin

Answer 33

alpha 1 antagonists

Question 34

clonidine

Answer 34

alpha 2 agonist

Question 35

guanabenz

Answer 35

alpha 2 agonist

Question 36

guanfacine

Answer 36

alpha 2 agonist

Question 37

methyldopa

Answer 37

alpha 2 agonist Pharmacodynamics: lowers blood pressure by reducing peripheral vascular resistance; variable reduction in heart rate and cardiac output Pharmacokinetics: Methyldopa is an analog of L-dopa; it is converted to α-methylnorepinephrine by an enzymatic pathway that directly parallels synthesis of norepinephrine from L-dopa Adverse Effects: sedation, dry mouth, lack of concentration, sexual dysfunction

Question 38

dihydropyridines vs. nonDHPs?

Answer 38

i) Dihydropyridines (DHPs) (1) Prototypes: Nifedipine, Amlodipine (2) MOA: Blocks vascular L-type calcium channels > cardiac channels ii) Non-Dihydropyridines (1) Prototypes: Verapamil, Diltiazem (2) MOA: Nonselective block of vascular and cardiac L-type calcium channels

Question 39

PD of CCB's?

Answer 39

i) All CCBs block L-type calcium channels (voltage-gated), which are responsible for Ca++ flux into smooth muscle cells, cardiac myocytes, and SA and AV nodal cells in the heart. iv) Effects on smooth muscle: All CCBs cause vasodilation, which decreases peripheral resistance. Arterioles are more sensitive than veins; orthostatic hypotension is not usually a problem. Relaxation of arteriolar smooth muscle leads to decreased afterload and decreased O2 demand by the heart. (thus work as anti-anginal agents) v) Effects on cardiac muscle include reduced contractility throughout the heart and decreases in SA node pacemaker rate and AV node conduction velocity.

Question 40

how do CCPs affect cardiac mm?

Answer 40

CCBs can produce a negative inotropic effect In myocytes, Na+ entry through “fast” channels in the primary carrier of current in the depolarization event, but Ca++ entry through “slow” channels (L-type) is an additional component Ca++ entry may also induce Ca++ release from SR Ca++ binds to troponin, relieving troponin inhibition of the contractile apparatus, and allows actin-myosin contraction Inotropic effects of Verapamil > Diltiazem > DHPs

Question 41

why do DHPs not affect cardiac mm?

Answer 41

DHPs relax vascular smooth muscle at lower concentrations than required for direct action on the heart Greater vasodilation with DHPs elicits reflex increase in sympathetic tone that overcomes the negative inotropic effects

Question 42

what could cause heart block?

Answer 42

use of beta blockers with non-DHP CCB's

Question 43

how do non-DHP's affect the heart?

Answer 43

Verapamil & diltiazem block channel, delay recovery of channel, & are frequency dependent Therefore, verapamil & diltiazem  the rate of SA node depolarization + slow AV nodal conduction These properties makes them useful for treatment of supraventricular tachyarrhythmias but dangerous in patients with slowed nodal conduction

Question 44

PK properties of CCBs?

Answer 44

DHPs with long plasma half-lives are prefered to minimize reflex cardiac effects and extend release preparations are available ex. amlodopine

Question 45

clinical use of CCBs?

Answer 45

long-term outpatient therapy for hypertension, hypertensive emergencies and angina (due to reduction of O2 demand)

Question 46

adverse effects of CCBs?

Answer 46

ii) Dihydropyridines: excessive hypotension, dizziness, headache, peripheral edema, flushing, tachycardia, rash, gingival hyperplasia iii) Non-Dihydropyridines: Dizziness, headache, peripheral edema, constipation (especially verapamil), AV block, bradycardia, heart failure, lupus-like rash with diltiazem. Pulmonary edema, coughing, and wheezing are possible.

Question 47

nifedipine?

Answer 47

iv) Some studies reported increased risk of MI, stroke, or death in patients receiving short-acting nifedipine for HTN; therefore short-acting DHPs should not be used for management of chronic HTN; Slow-release and long-acting DHPs are preferred to minimize reflex cardiac effects. Nifedipine does not decrease AV conduction and therefore can be used more safely than the non-DHPs in the presence of AV conduction abnormalities.

Question 48

MOA of Diazoxide?

Answer 48

Opens potassium channels in smooth muscle (1) Increased potassium permeability hyperpolarizes the smooth muscle membrane, reducing the probability of contraction (2) Arteriolar dilator resulting in reduced systemic vascular resistance and mean arterial pressure relatively long acting - 4-12 hours after injection typically administered as 3-4 injections

Question 49

diazoxide?

Answer 49

Arteriolar vasodilation Diminishing use in hypertensive emergencies due to adverse effects: Excessive hypotension can cause stroke and MI Hyperglycemia

Question 50

Minoxidil?

Answer 50

= potassium channel opener = Arteriolar vasodilation, more effacacious than hydralazine Clinical uses include severe hypertension thats not responding to other tx and baldness (topical) Adverse effects: Headache, sweating Hypertrichosis Reflex tachycardia & edema – must be used with β-blocker & diuretic to avoid these effects

Question 51

Propanolol

Answer 51

non-selective Beta blocker

Question 52

Carvedilol

Answer 52

non selective Beta blocker and alpha 1 blocker used to reduce mortality of heart failure- administration may worsen acute CHF

Question 53

Labetalol

Answer 53

nonselective beta blocker and alpha 1 blocker

Question 54

nadolol

Answer 54

non selective beta blocker

Question 55

timolol

Answer 55

non selective beta blocker

Question 56

carteolol

Answer 56

non selective beta blocker

Question 57

penbutolol

Answer 57

non selective beta blocker

Question 58

pindolol

Answer 58

non selective beta blocker

Question 59

Metoprolol

Answer 59

B1 selective blocker most common used for HTN used to reduce mortality of heart failure- administration may worsen acute CHF

Question 60

atenolol

Answer 60

B1 selective blocker most common used for HTN

Question 61

Esmolol

Answer 61

B1 selective blocker Very rapid onset & short duration of action Used as IV infusion for peri-operative tachycardia and hypertension, hypertensive emergencies, arrhythmias Used in electroconvulsive therapy

Question 62

Bisoprolol

Answer 62

B1 selective blocker used to reduce mortality of heart failure- administration may worsen acute CHF

Question 63

betaxolol

Answer 63

B1 selective blocker

Question 64

Acebutolol

Answer 64

B1 selective blocker

Question 65

nebivolol

Answer 65

B1 selective blocker

Question 66

Doxazosin

Answer 66

alpha1 blocker

Question 67

prazosin

Answer 67

** alpha1 blocker - prevents vasoconstriction of aa. and vv; blood pressure is reduced by lowering peripheral vascular resistance - relaxes smooth mm. in prostate - results in retention of salt and water when used w/out diuretic Adverse Effects: - generally well tolerated but may cause orthostatic hypotension, dizziness, palpitations, h/a - less incidence of reflex tachycardia than non selective adrenergic blockers clinical use: - used in men w/ concurrent HTN and BPH

Question 68

Terazosin

Answer 68

alpha1 blocker

Question 69

why use propanolol?

Answer 69

* * propanolol - treat HTN by decreasing the CO --> decreased mortality after MI - especially useful in preventing the reflex tachycardia that often results from tx w/ direct vasodilators - blockade of B1 receptors inhibits renin release contraindication: asthma

Question 70

Adverse effects of propanolol?

Answer 70

Asthma/COPD: blocks the B2 receptors causing to bronchospasm Diabetes: glycogenolysis is inhibited after B2 blockade Cardiac arrythmias: see fatigue and bradychardia drug interactions with CCBs can cause heart block

Question 71

why use beta blockers?

Answer 71

``` HTN Heart failure Ischemic heart disease cardiac arrythmias glaucoma ``` B1 selectivity advantageous in treating patients w/ comorbid asthma, diabetes or peripheral vascular disease

Question 72

alpha 2 agonists

Answer 72

clonidine, methyldopa General MOA: reduce sympathetic outflow from vasomotor centers in the brainstem but allow these centers to retain or even increase their sensitivity to baroreceptor control i) Agonists at central α2 receptors ii) Slight variations in hemodynamic effects of clonidine and methyldopa suggest that these two drugs may act at different populations of central neurons Clinical Uses i) With the exception of clonidine, these agents are rarely used today; methyldopa is used for hypertension during pregnancy (see below)

Question 73

acute management of severe HTN in pregnant women?

Answer 73

(1) Labetalol (IV): effective, rapid onset of action, good safety profile (2) Hydralazine (IV) (3) Calcium Channel Blockers: sustained release nifedipine or immediate release nicardipine; nicardipine can also be given IV; data is more limited for use in pregnancy compared to labetalol and hydralazine (4) Nitroglycerin (IV)

Question 74

long term oral therapy management of HTN in pregnant women?

Answer 74

(1) Methyldopa: long-term safety for the fetus has been demonstrated; mild antihypertensive of limited efficacy; sedative effect is bothersome to already fatigued patients (2) Labetalol: more rapid onset of action than methyldopa; alternatives in this category include pindolol and long-acting metoprolol (3) Nifedipine (extended release) (4) Hydralazine: Due to reflex tachycardia, monotherapy with oral hydralazine is not recommended; hydralazine may be combined with methyldopa or labetalol if needed as add-on therapy

Question 75

contraindications of antihypertensives and pregnancy?

Answer 75

i) ACE inhibitors, ARBs, direct renin inhibitors: these drugs are associated with significant fetal renal and cardiac abnormalities ii) Nitroprusside: possible fetal cyanide poisoning if used for more than a few hours

Question 76

vasodilators used for tx of HTN emergencies?

Answer 76

(1) Sodium nitroprusside: considered the most effective parenteral drug for hypertensive emergencies; potential for cyanide toxicity limits prolonged use (2) Nitroglycerin: frequently used in patients with cardiac ischemia or after coronary bypass surgery (3) Nicardipine: parenteral formulation of this DHP-CCB is available for rapid effect (4) Clevidipine: parenteral formulation of this DHP-CCB is approved only for hypertensive emergencies (5) Fenoldopam: maintains or increases renal perfusion by dilating renal arteries; possibly a good choice for patients with renal dysfunction (6) Hydralazine: often used for hypertensive emergencies in pregnancy related to eclampsia (see above)

Question 77

adrenergic antagonists used for HTN emergencies?

Answer 77

(1) Phentolamine: α-blocker used to treat patients with hypertension due to elevated catecholamines (cocaine intoxication, pheochromocytoma) (2) Esmolol: rapid but short-acting β1-blocker used to treat aortic dissection or postoperative hypertension (3) Labetolol: combined α- and β-blocker that may be safe in patients with active coronary disease

Question 78

choice of therapy in essential HTN?

Answer 78

General classes typically employed as initial monotherapy: i) Thiazide diuretics ii) ACE Inhibitors/ARBs iii) Calcium channel blockers (long-acting) iv) Beta-blockers are NOT typically used in the absence of a specific indication Exhibit roughly equal efficacy, but some patients will respond to one drug and not to another i) Some predictable differences, e.g., black patients respond better to thiazide diuretics and CCBs, and respond poorly to ACE inhibitors and beta-blockers

Question 79

common HTN drug combinations?

Answer 79

i) ACEIs and calcium channel blockers (trandolapril/verapamil) ii) ACEIs and diuretics (benazepril/hydrochlorothiazide) iii) ARBs and diuretics (valsartan/hydrochlorothiazide) iv) β-blockers and diuretics (propranolol/hydrochlorothiazide) v) Centrally acting agent and diuretic (reserpine/chlorothiazide) vi) Diuretic and diuretic (spironolactone/hydrochlorothiazide)