Clinical Pharm of Antihypertensives

Question 1

Choice of therapy in Primary hypertension

General classes typically employed as initial monotherapy:

Answer 1

i) ACE Inhibitors/ARBs
ii) Calcium channel blockers (long-acting)
iii) Thiazide diuretics
iv) Beta-blockers are NOT typically used in the absence of a specific indication

Question 2

Choice of therapy in primary hypertension

Exhibit roughly equal efficacy, but some patients will respond to one drug and not to another

Answer 2

i) Some predictable differences, e.g., black patients respond better to thiazide diuretics and CCBs, and respond poorly to ACE inhibitors and beta-blockers
ii) ACE inhibitors and ARBs are recommended in mild-to-moderate chronic kidney disease with or without diabetes because these agents are renoprotective
iii) See also table below from UpToDate, will make cards for those

Question 3

Generally, the magnitude of BP reduction, not choice of drug predicts reduction of what?

Answer 3

Cardiovascular risk

Question 4

Why is monotherapy of hypertension advantageous?

Answer 4

increase in patient compliance, a decrease in cost, and less adverse effects

Question 5

Rationale behind polypharmacy

Answer 5

1) each of the drugs acts on one of a set of interacting, mutually compensatory regulatory mechanisms for maintaining blood pressure
2) minimal toxicity: Two or three drugs at half standard doses might have greater efficacy and less toxicity than one drug at standard or twice standard dose

Question 6

When do you add a second drug for hypertension

Answer 6

when hypertension does not respond adequately to a regimen of one drug, a second drug from a different class with a different MOA and different pattern of toxicity is added

Question 7

Combination of hypertension drugs

Answer 7

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)
vii) Triple drug regimens are also common and typically include a thiazide diuretic, a dihydropyridine CCB, and either an ACE inhibitor, an angiotensin receptor blocker, or a renin inhibitor

Question 8

Loop and thiazide diuretics in combination

Answer 8

(1) Can be combined if patients fail or become refractory to the usual dose of loop diuretics

Question 9

Systolic Heart Failure Drug indication

Answer 9

ACE inhibitor or ARB blocker, beta blocker, diuretic, aldosterone antagonist

Question 10

Post-myocardial infarction indication

Answer 10

ACE inhibitor, beta blocker, ARB, aldosterone antagonist

Question 11

Proteinuric chronic kidney disease indication

Answer 11

ACE inhibitor or ARB

Question 12

Angina Pectoris indication

Answer 12

Beta Blocker, Calcium channel blocker

Question 13

Atrial fibrillation rate control indication

Answer 13

Beta blocker, nondihydropyridine calcium channel blocker

Question 14

Atrial flutter rate control indication

Answer 14

Beta blocker, nondihydropyridine calcium channel blocker

Question 15

BPH with htn indication

Answer 15

alpha blocker

Question 16

essential tremor with htn indication

Answer 16

beta blocker (noncardioselective)

Question 17

hyperthyroidism with htn indication

Answer 17

beta blocker

Question 18

migraine with htn indication

Answer 18

beta blocker or calcium channel blocker

Question 19

Osteoporosis with htn indication

Answer 19

thiazide diuretic

Question 20

Raynauds with htn indication

Answer 20

dihydropyridine calcium channel blocker

Question 21

Andgioedema contraindication

Answer 21

ACE inhibitor

Question 22

Bronchospastic disease contraindication

Answer 22

beta blocker

Question 23

depression contraindication

Answer 23

reserpine

Question 24

liver disease contraindication

Answer 24

methyldopa

Question 25

pregnancy contraindication

Answer 25

ACE inhibitor, ARB, renin inhibitor

Question 26

Second or third degree heart block contraindication

Answer 26

beta blocker, nondihydropyridne

Question 27

Adverse effect on comorbid conditions depression

Answer 27

Beta blocker, central alpha-2-agonist

Question 28

adverse effect on comorbid condition gout

Answer 28

diuretic

Question 29

adverse effect of comorbid condition hyperkalemia

Answer 29

aldosterone antagonist, ACE inhibitor, ARB, renin inhibitor

Question 30

Adverse effect on comorbid condistion renovascular disease

Answer 30

ACE inhibitor, ARB, or renin inhibitor

Question 31

Loop agents and thiazides in combination will often produce diuresis when either agent acting alone is minimally effective (2 reasons)

Answer 31

(a) Salt and water reabsorption in either the thick ascending loop (blocked by loop diuretics) or DCT (blocked by thiazides) can increase when the other is blocked; inhibition of both can produce more than an additive diuretic response (b) Thiazides often produce mild natriuresis (sodium excretion) in the PCT that is usually masked by increased absorption in the thick ascending loop; this combination can therefore block Na+ reabsorption from all three segments (PCT, ascending loop, and DCT)

Question 32

Metolazone (thiazide) is a popular choice for combination with?

Answer 32

loop agents

Question 33

Combination can cause profuse diuresis and therefore

Answer 33

routine outpatient use is not recommended (K+ wasting is extremely common)

Question 34

Potassium-sparing diuretics and loop agents or thiazides

Answer 34

(1) Hypokalemia is a common side effect of loop agents and thiazide diuretics, which can initially be managed with dietary NaCl restriction (decreases Na+ delivery to the K+-secreting CCT, thus reducing K+ secretion; has also been shown to potentiate the effects of diuretics in essential HTN) or KCl supplementation (2) Alternatively, the addition of K+-sparing diuretics can lower K+ secretion (3) This combination is generally safe but should be avoided in patients with renal insufficiency and in those receiving angiotensin antagonists

Question 35

COMBINATIONS TO AVOID

Answer 35

i) ACE inhibitors, ARBs, and renin inhibitors (only one at a time) ii) Beta-blockers and non-dihydropyridine CCBs iii) Potassium-sparing diuretics and ACE inhibitors/ARBs/renin inhibitors

Question 36

Hypertensive Urgency

Answer 36

Severe hypertension (> 180/120 mmHg) without acute end-organ damage

Question 37

Hypertensive Emergency

Answer 37

Severe hypertension (> 180/120 mmHg) with acute end-organ damage

Question 38

controlled and gradual BP reduction (10-20% in the first hour and by a further 5-15% over the next 23 hr) may prevent

Answer 38

excessive hypotension that could lead to MI, stroke, or loss of vision

Question 39

Vasodilators (IV)

Answer 39

``` Sodium nitropursside nitroglycerin nicardipine clevidipine enalaprilat Fenoldopam hydralazine ```

Question 40

Sodium nitroprusside

Answer 40

considered the most effective parenteral drug for hypertensive emergencies; potential for cyanide toxicity limits prolonged use

Question 41

nitroglycerin

Answer 41

less antihypertensive efficacy than other agents for HTN emergencies; useful adjunct in patients with cardiac ischemia or after coronary bypass surgery

Question 42

nicardipine

Answer 42

DHP-CCB with longer onset of action and longer elimination half-life, but good safety profile

Question 43

Clevidipine

Answer 43

ultra short-acting DHP-CCB is approved only for hypertensive emergencies

Question 44

Enalaprilat

Answer 44

rarely used due to slow onset and long duration of action; hypotensive response is unpredictable and dependent on plasma volume and plasma renin activity

Question 45

Fenoldopam

Answer 45

maintains or increases renal perfusion by dilating renal arteries; possibly a good choice for patients with renal dysfunction; avoid in glaucoma

Question 46

Hydralazine

Answer 46

use of parenteral form limited by prolonged and unpredictable hypotensive effect; considered safe in pregnant patients

Question 47

Adrenergic agonists (IV)

Answer 47

Phentolamine Esmolol labetolol

Question 48

Phentolamine

Answer 48

nonselective α-blocker used to treat patients with hypertension due to elevated catecholamines (cocaine intoxication, pheochromocytoma)

Question 49

Esmolol

Answer 49

rapid but short-acting β1-blocker used to treat aortic dissection or postoperative hypertension

Question 50

Labetolol

Answer 50

combined α- and β-blocker that may be safe in patients with active coronary disease

Question 51

Considerations for pharmacotherapy with htn in pregnancy

Answer 51

i) Consider risks and benefits for both mother and fetus ii) Maternal benefit is well-established for treatment of severe hypertension (systolic pressure ≥ 160 mmHg and/or diastolic pressure ≥ 110) in reduction of stroke risk (1) Timing of delivery: if cesarean delivery is imminent, pharmacotherapy may not be necessary iii) Maternal or fetal benefits have not been shown for treatment of mild to moderate hypertension iv) All anti-hypertensives cross the placenta; some may inhibit fetal growth

Question 52

Acute management for severe hypertension in pregnancy drug choices

Answer 52

labetalol (IV) Hydralazine (IV) Calcium channel blockers Nitroglycerin (IV)

Question 53

Acute management for severe hypertension in pregnancy labetalol

Answer 53

effective, rapid onset of action, good safety profile

Question 54

Acute management for severe hypertension in pregnancy hydralazine

Answer 54

has been used extensively in the setting of preeclampsia

Question 55

Acute management for severe hypertension in pregnancy calcium channel blockers

Answer 55

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

Question 56

Acute management for severe hypertension in pregnancy nitroglycerin

Answer 56

is a good option for HTN associated with pulmonary edema

Question 57

Long-term oral therapy for htn in pregnancy drug options

Answer 57

``` methyldopa labetalol nifedipine (ER) hydralazine thiazide diuretics ```

Question 58

Long-term oral therapy for htn in pregnancy methyldopa

Answer 58

long-term safety for the fetus has been demonstrated; mild antihypertensive of limited efficacy; sedative effect is bothersome to already fatigued patients; clonidine is another centrally acting sympatholytic that is considered safe in pregnant women

Question 59

Long-term oral therapy for htn in pregnancy labetolol

Answer 59

more rapid onset of action than methyldopa; alternatives in this category include pindolol and long-acting metoprolol; safety is controversial

Question 60

Long-term oral therapy for htn in pregnancy nifedipine

Answer 60

other CCBs , including non-DHPs, have been used in pregnant patients, but only small numbers of patients are reported in the literature

Question 61

Long-term oral therapy for htn in pregnancy hydralazine

Answer 61

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 62

Long-term oral therapy for htn in pregnancy thiazides

Answer 62

use is controversial due to potential fluid loss; some guidelines suggest they are safe to continue in patients who began taking them prior to pregnancy; generally only introduced during pregnancy if pulmonary edema has developed

Question 63

Agents contraindicated during pregnancy

Answer 63

ACE inhibitors, ARBs, direct renin inhibitors and nitroprusside

Question 64

contraindicated during pregnancy ACE inhibitors, ARBs, direct renin inhibitors

Answer 64

these drugs are associated with significant fetal renal and cardiac abnormalities

Question 65

contraindicated during pregnancy Nitroprusside

Answer 65

possible fetal cyanide poisoning if used for more than a few hours; last resort for urgent control of severe refractory HTN

Question 66

Clinical pharmacology of diuretic agents

Answer 66

a) A common use for diuretics is for the reduction of peripheral or pulmonary edema that has accumulated as a result of cardiac, renal, or vascular diseases that reduce blood delivery to the kidney b) Physiologically, this reduction is sensed as a lack of effective arterial blood volume and leads to salt and water retention, followed by edema formation

Question 67

edematous states treated with diuretics

Answer 67

Heart failure kidney disease hepatic cirrhosis

Question 68

Heart failure diuretics use

Answer 68

(1) Heart failure reduces cardiac output, which results in a decrease in blood pressure and blood flow to the kidney (2) Decreases in BP and blood flow is sensed as hypovolemia and leads to renal retention of salt and water (3) Pulmonary or interstitial edema occur when the plasma volume increases and the kidney continues to retain salt and water, which then leaks from the vasculature

Question 69

Kidney disease diuretic use

Answer 69

(1) Most kidney diseases cause retention of salt and water (2) When loss of renal function is severe, there is insufficient glomerular filtration to sustain a natriuretic response and diuretic agents are of little benefit (3) Patients with mild cases of renal disease can be effectively treated with diuretics when they retain sodium (4) Diuretics are beneficial in glomerular diseases, such as systemic lupus erythematosus or diabetes mellitus, that exhibit renal retention of salt and water (5) Loop and thiazide diuretics are beneficial in individuals that develop hyperkalemia associated with early stage renal failure

Question 70

Hepatic cirrhosis diuretic use

Answer 70

(1) Diuretics are useful when edema and ascites (accumulation of fluid in the abdominal cavity) become severe due to liver disease (2) Aggressive use of diuretics can be disastrous in patients with liver disease (more so than heart failure)

Question 71

Nonedematous states treated with diuretics

Answer 71

Htn Nephrolithiasis Hypercalcemia Diabetes insipidus

Question 72

Htn diuretic use

Answer 72

(1) Thiazides are often used because of their diuretic and mild vasodilator activities (2) Loop diuretics are often reserved for patients with mild renal insufficiency or heart failure (3) Diuretics are often used in combination with vasodilators (hydralazine, minoxidil) because vasodilators cause significant salt and water retention

Question 73

nephrolithiasis diuretic use

Answer 73

(1) 2/3 of kidney stones contain calcium phosphate or calcium oxalate (2) Thiazide diuretics enhance Ca2+ reabsorption in the DCT and reduce urinary Ca2+ concentration, making them appropriate agents in the treatment of kidney stones

Question 74

hypercalcemia diuretic use

Answer 74

(1) Loop diuretics reduce Ca2+ reabsorption and promote Ca2+ diuresis, but can also cause marked volume contraction when used alone (counterproductive) (2) Saline can be administered simultaneously with loop diuretics to maintain effective Ca2+ diuresis

Question 75

Dibetes insipidus diuretic use

Answer 75

(1) Can be due to either deficient production of ADH (neurogenic or central diabetes insipidus) or inadequate responsiveness to ADH (nephrogenic diabetes insipidus) (2) Supplementary ADH or one of its analogs is only effective in central diabetes insipidus (3) Thiazide diuretics can reduce polyuria and polydipsia in both types of diabetes insipidus

Question 76

Centrally acting sympatholytic agents hemodynamic effects

Answer 76

decrease - heart rate, co, tpr, and plasma renin activity increase - plasma volume

Question 77

alpha receptor antagonists hemodynamic effects

Answer 77

decrease - tpr increase - heart rate, co, plasma volume same - plasma renin activity

Question 78

Diuretics effect on hemodynamics

Answer 78

same - heart rate, co decrease - tpr and plasma volume increase plasma renin activity

Question 79

no ISA beta receptor antagonists hemodynamic effect

Answer 79

decrease - heart rate, cardiac output, tpr and plasma renin activity increase - plasma volume

Question 80

ISA beta receptor antagonist hemodynamic effects

Answer 80

same - heart rate, co increase - plasma volume decrease - tpr and plasma renin activity

Question 81

Arteriolar vasodilators hemodynamic effect

Answer 81

increase - heart rate, co, plasma volume and palamsa renin activity decrease - tpr

Question 82

Calcium channel blockers hemodynamic effect

Answer 82

increase or decrease - heart rate and co increase - plasma volume and plasma renin activity decrease - tpr

Question 83

ACE inhibitors hemodynamic effect

Answer 83

same - heart rate, co and plasma volume increase - plasma renin activity decrease - tpr

Question 84

renin inhibitor hemodynamic effect

Answer 84

same - heart rat, co and plasma volume decrease - tpr, plasma renin activity (but renin levels increase)

Question 85

AT1 receptor antagonists hemodynamic effect

Answer 85

same - heart rat, co and plasma volume decrease - tpr, plasma renin activity