Clinical Pharm of Antihypertensives Flashcards
Choice of therapy in Primary hypertension
General classes typically employed as initial monotherapy:
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
Choice of therapy in primary hypertension
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
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
Generally, the magnitude of BP reduction, not choice of drug predicts reduction of what?
Cardiovascular risk
Why is monotherapy of hypertension advantageous?
increase in patient compliance, a decrease in cost, and less adverse effects
Rationale behind polypharmacy
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
When do you add a second drug for hypertension
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
Combination of hypertension drugs
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
Loop and thiazide diuretics in combination
(1) Can be combined if patients fail or become refractory to the usual dose of loop diuretics
Systolic Heart Failure Drug indication
ACE inhibitor or ARB blocker, beta blocker, diuretic, aldosterone antagonist
Post-myocardial infarction indication
ACE inhibitor, beta blocker, ARB, aldosterone antagonist
Proteinuric chronic kidney disease indication
ACE inhibitor or ARB
Angina Pectoris indication
Beta Blocker, Calcium channel blocker
Atrial fibrillation rate control indication
Beta blocker, nondihydropyridine calcium channel blocker
Atrial flutter rate control indication
Beta blocker, nondihydropyridine calcium channel blocker
BPH with htn indication
alpha blocker
essential tremor with htn indication
beta blocker (noncardioselective)
hyperthyroidism with htn indication
beta blocker
migraine with htn indication
beta blocker or calcium channel blocker
Osteoporosis with htn indication
thiazide diuretic
Raynauds with htn indication
dihydropyridine calcium channel blocker
Andgioedema contraindication
ACE inhibitor
Bronchospastic disease contraindication
beta blocker
depression contraindication
reserpine
liver disease contraindication
methyldopa
pregnancy contraindication
ACE inhibitor, ARB, renin inhibitor
Second or third degree heart block contraindication
beta blocker, nondihydropyridne
Adverse effect on comorbid conditions depression
Beta blocker, central alpha-2-agonist
adverse effect on comorbid condition gout
diuretic
adverse effect of comorbid condition hyperkalemia
aldosterone antagonist, ACE inhibitor, ARB, renin inhibitor
Adverse effect on comorbid condistion renovascular disease
ACE inhibitor, ARB, or renin inhibitor
Loop agents and thiazides in combination will often produce diuresis when either agent acting alone is minimally effective (2 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)
Metolazone (thiazide) is a popular choice for combination with?
loop agents
Combination can cause profuse diuresis and therefore
routine outpatient use is not recommended (K+ wasting is extremely common)
Potassium-sparing diuretics and loop agents or thiazides
(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
COMBINATIONS TO AVOID
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
Hypertensive Urgency
Severe hypertension (> 180/120 mmHg) without acute end-organ damage
Hypertensive Emergency
Severe hypertension (> 180/120 mmHg) with acute end-organ damage
controlled and gradual BP reduction (10-20% in the first hour and by a further 5-15% over the next 23 hr) may prevent
excessive hypotension that could lead to MI, stroke, or loss of vision
Vasodilators (IV)
Sodium nitropursside nitroglycerin nicardipine clevidipine enalaprilat Fenoldopam hydralazine
Sodium nitroprusside
considered the most effective parenteral drug for hypertensive emergencies; potential for cyanide toxicity limits prolonged use
nitroglycerin
less antihypertensive efficacy than other agents for HTN emergencies; useful adjunct in patients with cardiac ischemia or after coronary bypass surgery
nicardipine
DHP-CCB with longer onset of action and longer elimination half-life, but good safety profile
Clevidipine
ultra short-acting DHP-CCB is approved only for hypertensive emergencies
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
Fenoldopam
maintains or increases renal perfusion by dilating renal arteries; possibly a good choice for patients with renal dysfunction; avoid in glaucoma
Hydralazine
use of parenteral form limited by prolonged and unpredictable hypotensive effect; considered safe in pregnant patients
Adrenergic agonists (IV)
Phentolamine
Esmolol
labetolol
Phentolamine
nonselective α-blocker used to treat patients with hypertension due to elevated catecholamines (cocaine intoxication, pheochromocytoma)
Esmolol
rapid but short-acting β1-blocker used to treat aortic dissection or postoperative hypertension
Labetolol
combined α- and β-blocker that may be safe in patients with active coronary disease
Considerations for pharmacotherapy with htn in pregnancy
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
Acute management for severe hypertension in pregnancy drug choices
labetalol (IV)
Hydralazine (IV)
Calcium channel blockers
Nitroglycerin (IV)
Acute management for severe hypertension in pregnancy labetalol
effective, rapid onset of action, good safety profile
Acute management for severe hypertension in pregnancy hydralazine
has been used extensively in the setting of preeclampsia
Acute management for severe hypertension in pregnancy 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
Acute management for severe hypertension in pregnancy nitroglycerin
is a good option for HTN associated with pulmonary edema
Long-term oral therapy for htn in pregnancy drug options
methyldopa labetalol nifedipine (ER) hydralazine thiazide diuretics
Long-term oral therapy for htn in pregnancy 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
Long-term oral therapy for htn in pregnancy labetolol
more rapid onset of action than methyldopa; alternatives in this category include pindolol and long-acting metoprolol; safety is controversial
Long-term oral therapy for htn in pregnancy nifedipine
other CCBs , including non-DHPs, have been used in pregnant patients, but only small numbers of patients are reported in the literature
Long-term oral therapy for htn in pregnancy 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
Long-term oral therapy for htn in pregnancy thiazides
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
Agents contraindicated during pregnancy
ACE inhibitors, ARBs, direct renin inhibitors and nitroprusside
contraindicated during pregnancy ACE inhibitors, ARBs, direct renin inhibitors
these drugs are associated with significant fetal renal and cardiac abnormalities
contraindicated during pregnancy Nitroprusside
possible fetal cyanide poisoning if used for more than a few hours; last resort for urgent control of severe refractory HTN
Clinical pharmacology of diuretic agents
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
edematous states treated with diuretics
Heart failure
kidney disease
hepatic cirrhosis
Heart failure diuretics use
(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
Kidney disease diuretic use
(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
Hepatic cirrhosis diuretic use
(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)
Nonedematous states treated with diuretics
Htn
Nephrolithiasis
Hypercalcemia
Diabetes insipidus
Htn diuretic use
(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
nephrolithiasis diuretic use
(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
hypercalcemia diuretic use
(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
Dibetes insipidus diuretic use
(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
Centrally acting sympatholytic agents hemodynamic effects
decrease - heart rate, co, tpr, and plasma renin activity
increase - plasma volume
alpha receptor antagonists hemodynamic effects
decrease - tpr
increase - heart rate, co, plasma volume
same - plasma renin activity
Diuretics effect on hemodynamics
same - heart rate, co
decrease - tpr and plasma volume
increase plasma renin activity
no ISA beta receptor antagonists hemodynamic effect
decrease - heart rate, cardiac output, tpr and plasma renin activity
increase - plasma volume
ISA beta receptor antagonist hemodynamic effects
same - heart rate, co
increase - plasma volume
decrease - tpr and plasma renin activity
Arteriolar vasodilators hemodynamic effect
increase - heart rate, co, plasma volume and palamsa renin activity
decrease - tpr
Calcium channel blockers hemodynamic effect
increase or decrease - heart rate and co
increase - plasma volume and plasma renin activity
decrease - tpr
ACE inhibitors hemodynamic effect
same - heart rate, co and plasma volume
increase - plasma renin activity
decrease - tpr
renin inhibitor hemodynamic effect
same - heart rat, co and plasma volume
decrease - tpr, plasma renin activity (but renin levels increase)
AT1 receptor antagonists hemodynamic effect
same - heart rat, co and plasma volume
decrease - tpr, plasma renin activity
