Pharm DSA

Question 1

General Classes Typically Employed as Initial Monotherapy for primary (essential) hypertension

Answer 1

i) Angiotensin Converting Enzyme (ACE) Inhibitors/Angiotensin II Receptor Blockers (ARBs)
ii) Calcium Channel Blockers, CCBs (long-acting, most often dihydropyridine)
iii) Thiazide Diuretics
iv) Beta (β)-Blockers are NOT typically used in the absence of a specific indication

Question 2

Specific patient populations with hypertension

Answer 2

i) Black patients – thiazides more effective than ACE inhibitors; no differences in outcomes between diuretics and CCBs (except CCBs less effective in preventing heart failure); increased risk of adverse outcomes with ACE inhibitors compared to CCBs; thus, thiazides and CCBs recommended first-line.
ii) Chronic kidney disease (CKD) – ACE inhibitors and ARBs are recommended in chronic kidney disease with or without diabetes because these agents are renoprotective. NOTE: this recommendation applies regardless of race or diabetes status.

Question 3

What predicts reduction of cardiovascular risk?

Answer 3

c) Generally, the magnitude of blood pressure reduction, not choice of drug, predicts reduction of cardiovascular risk.

Question 4

WHat are some drawbacks to polypharmacy?

Answer 4

a) Although monotherapy of hypertension is advantageous due to an increase in patient compliance, a decrease in cost, and less adverse drug reactions, polypharmacy is often required to treat many patients with hypertension.

Question 5

The rationale behind polypharmacy

Answer 5

is that each of the drugs acts on one of a set of interacting, mutually compensatory regulatory mechanisms for maintaining blood pressure.

Additional rationale is 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

In practice, when hypertension does not respond adequately to a regimen of one drug,

Answer 6

a second drug from a different class with a different MOA and different pattern of toxicity is added.

Question 7

Polypharmacy for hypertension examples (not a comprehensive list)

Answer 7

i) ACE inhibitors and calcium channel blockers (amlodipine/benazepril)
ii) ACE inhibitors and diuretics (enalapril/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, see below)
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

Answer 8

(1) Can be combined if patients fail or become refractory to the usual dose of loop diuretics.
(2) Loop agents and thiazides in combination will often produce diuresis when either agent acting alone is minimally effective; for two reasons:
(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 9

a popular thiazide choice for combination with loop agents

Answer 9

Metolazone

Question 10

why is routine outpatient use of loop and thiazide combinations not recommended?

Answer 10

Loop and thiazide combinations can cause profuse diuresis. Combination requires close hemodynamic, fluid, and electrolyte monitoring.

Question 11

ii) Potassium-Sparing Diuretics and Loops or Thiazides

Answer 11

(1) Hypokalemia is a common adverse effect of carbonic anhydrase inhibitors, loop diuretics, and thiazides. This 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 hypertension) 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 12

Antihypertensive Drug Combinations to Avoid

Answer 12

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

Question 13

Systolic heart failure (compelling indications)

Answer 13

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

Question 14

Post-myocardial infarction (compelling indications)

Answer 14

ACE inhibitor, beta blocker, ARB, aldosterone antagonist

Question 15

Proteinuric chronic kidney disease (compelling indications)

Answer 15

ACE inhibitor or ARB

Question 16

Angina pectoris (compelling indications)

Answer 16

Beta blocker, calcium channel blocker

Question 17

Atrial fibrillation rate control (compelling indications)

Answer 17

Beta blocker, nondihydropyridine calcium channel blocker

Question 18

Atrial flutter rate control (compelling indications)

Answer 18

Beta blocker, nondihydropyridine calcium channel blocker

Question 19

Benign prostatic hyperplasia (favorable effect)

Answer 19

alpha blocker

Question 20

Essential tremor (favorable effect)

Answer 20

Beta blocker (noncardioselective)

Question 21

Hyperthyroidism (favorable effect)

Answer 21

beta blocker

Question 22

Migraine (favorable effect)

Answer 22

beta blockerr, calcium channel blocker

Question 23

osteoporosis (favorable effect)

Answer 23

thiazide diuretic

Question 24

Raynaud’s syndrome

Answer 24

dihydropyridine calcium channel blocker

Question 25

Angioedema Contraindications

Answer 25

ACE inhibitor

Question 26

Bronchospastic disease Contraindications

Answer 26

Beta blocker

Question 27

Depression Contraindications

Answer 27

Reserpine

Question 28

Liver disease Contraindications

Answer 28

Methyldopa

Question 29

Pregnancy (or at risk for) contraindications

Answer 29

ACE inhibitor, ARB, renin inhibitor

Question 30

Second or third degree heart block contraindications

Answer 30

Beta blocker, nondihydropyridine calcium channel blocker

Question 31

Depression (adverse effect on comorbid conditions)

Answer 31

Beta blocker, central alpha-2 agaonist

Question 32

Gout (adverse effect on comorbid conditions)

Answer 32

Diuretic

Question 33

Hyperkalemia (adverse effect on comorbid conditions)

Answer 33

Aldosterone antagonist, ACE inhibitor, ARB, renin inhibitor

Question 34

Hyponatremia (adverse effect on comorbid conditions)

Answer 34

Thiazide diuretic

Question 35

Renovascular disease (adverse effect on comorbid conditions)

Answer 35

ACE inhibitor, ARB, or renin inhibitor

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

What may prevent excessive hypotension that could lead to myocardial infarction, stroke, or loss of vision? (hypertensive emergency)

Answer 38

d) In general, controlled and gradual blood pressure reduction (by ~10-20% in the first hour and further 5-15% over the next 23 hours) may prevent excessive hypotension that could lead to myocardial infarction, stroke, or loss of vision.
e) There are some exceptions to the rule regarding gradual blood pressure reduction (e.g., acute aortic dissection, systolic blood pressure rapidly lowered to 100-120 mmHg in 20 minutes).

Question 39

Drug options for hypertensive emergencies: Vasodilators (7)

Answer 39

(1) Sodium nitroprusside: considered the most effective parenteral drug for hypertensive emergencies; potential for cyanide toxicity limits prolonged use.
(2) Nitroglycerin: less antihypertensive efficacy than other agents for hypertensive emergencies; useful adjunct in patients with cardiac ischemia or after coronary bypass surgery.
(3) Nicardipine: dihydropyridine (DHP)-CCB with longer onset of action and longer elimination t1/2, but good safety profile.
(4) Clevidipine: ultra short-acting DHP-CCB, approved only for hypertensive emergencies.
(5) Enalaprilat: rarely used due to slow onset and long duration of action; hypotensive response is unpredictable and dependent on plasma volume and plasma renin activity.
(6) Fenoldopam: maintains or increases renal perfusion by dilating renal arteries; possibly a good choice for patients with renal dysfunction; avoid in glaucoma.
(7) Hydralazine: use of parenteral form limited by prolonged and unpredictable hypotensive effect; considered safe in pregnant patients

Question 40

Drug options for hypertensive emergencies: Adrenergic antagonists

Answer 40

(1) Phentolamine: nonselective α-blocker, used to treat patients with hypertension due to elevated catecholamines (cocaine intoxication, pheochromocytoma).
(2) Esmolol: rapid, short-acting β1-blocker used in aortic dissection or postoperative hypertension.
(3) Labetolol: combined α- and β-blocker that may be safe in patients with active coronary disease (since it does not increase heart rate).

Question 41

Oral agents for hypertensive emergencies– when?

Answer 41

: usually given after a suitable period (often 8-24 hours) of blood pressure control at target. Once oral medications are given, intravenous therapy is tapered and discontinued.

Question 42

Hypertension in Pregnancy: Considerations for Pharmacotherapy

Answer 42

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 antihypertensives cross the placenta; some may inhibit fetal growth.

Question 43

Acute management of severe hypertension in pregnancy: drug options

Answer 43

(1) Labetalol (IV): effective, rapid onset of action, good safety profile.
(2) Hydralazine (IV): has been used extensively in the setting of preeclampsia.
(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) is a good option for hypertension associated with pulmonary edema.

Question 44

Drug options for hypertension in pregnancy: long-term oral therapy

Answer 44

(1) Methyldopa: 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 (although not preferred due to side effects and possibility of rebound hypertension if stopped suddenly).
(2) Labetalol: more rapid onset of action than methyldopa; alternatives in this category include pindolol and long-acting metoprolol; safety is controversial.
(3) Nifedipine (extended release); other CCBs, including non-DHPs, have been used in pregnant patients, but only small numbers of patients are reported in the literature.
(4) Hydralazine: due to reflex tachycardia, monotherapy is not recommended; hydralazine may be combined with methyldopa or labetalol if needed as add-on therapy.
(5) Thiazide diuretics: 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 45

Agents Contraindicated During Pregnancy

Answer 45

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; last resort for urgent control of severe refractory hypertension.

Question 46

Clinical Pharmacology of Diuretic Agents

Answer 46

a) A common use for diuretics is 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 47

Edematous states treated with diuretics: Heart Failure

Answer 47

Heart failure reduces cardiac output, which results in a decrease in blood pressure and blood flow to the kidney; decreases in blood pressure and blood flow is sensed as hypovolemia and leads to renal retention of salt and water; pulmonary or interstitial edema occurs when the plasma volume increases and the kidney continues to retain salt and water, which then leaks from the vasculature.

Question 48

Edematous states treated with diuretics: Kidney disease

Answer 48

(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; however, patients with mild cases of renal disease can be effectively treated with diuretics when they retain sodium; diuretics are beneficial in glomerular diseases, such as systemic lupus erythematosus or diabetes mellitus, that exhibit renal retention of salt and water.
(3) Loop and thiazide diuretics are beneficial in individuals that develop hyperkalemia associated with early stage renal failure.

Question 49

Edematous states treated with diuretics: Hepatic Cirrhosis

Answer 49

Diuretics are useful when edema and ascites (accumulation of fluid in the abdominal cavity) become severe due to liver disease; however, overly aggressive use of diuretics can be disastrous in patients with liver disease (more so than heart failure).

Question 50

Nonedematous States Treated with Diuretics: Hypertension

Answer 50

(1) Thiazides are often used because of their diuretic and mild vasodilator activities. Although hydrochlorothiazide is used most widely, chlorthalidone may be more effective (longer t1/2).
(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 51

Nonedematous States Treated with Diuretics: Nephrolithiasis

Answer 51

(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 52

Nonedematous States Treated with Diuretics: Hypercalcemia

Answer 52

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

Question 53

Nonedematous States Treated with Diuretics: Diabetes Insipidus

Answer 53

(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.