8-14 DSA - Pharmacology of Antihypertensives Flashcards
In primary HTN, what are the general classes employed as initial monotherapy?
ACE Inhibitors/ARBs
Calcium channel blockers (long-acting)
Thiazide diuretics
Beta-blockers are NOT typically used in the absence of a specific indication
Why do the recommendations for black people differ for treating essential HTN?
Exhibit roughly equal efficacy, but some patients will respond to one drug and not to another
- black patients respond better to thiazide diuretics and CCBs, and respond poorly to ACE inhibitors and beta-blockers
What classes of medications are recommended in kidney disease and HTN?
ACE inhibitors and ARBs are recommended in mild-to-moderate chronic kidney disease with or without diabetes because these agents are renoprotective
What is predictive of reduction in CV risk in patients with primary HTN?
Generally, the magnitude of BP reduction, not choice of drug, predicts reduction of cardiovascular risk
What are the advantages of monotherapy in treating HTN?
Although monotherapy of hypertension is advantageous due to an increase in patient compliance, a decrease in cost, and less adverse effects
What are the advantages in polypharmacy in treating HTN?
, polypharmacy is often required to treat many patients with hypertension
What is the rationale behind polypharmacy?
The rationale behind polypharmacy 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
What are some examples of polypharmacy combinations to treat HTN?
ACEIs and calcium channel blockers (trandolapril/verapamil)
ACEIs and diuretics (benazepril/hydrochlorothiazide)
ARBs and diuretics (valsartan/hydrochlorothiazide)
β-blockers and diuretics (propranolol/hydrochlorothiazide)
Centrally acting agent and diuretic (reserpine/chlorothiazide)
Diuretic and diuretic (spironolactone/hydrochlorothiazide, see below)
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
What is a common choice if a patient no longer responds to the usual dose of loop diuretic?
loop and thiazide diuretic
Loop agents and thiazides in combination will often produce diuresis when either agent acting alone is minimally effective. What are the reasons for this?
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
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)
For systolic heart failure, what combinations of drugs produce major improvement independent of BP?
ACE inhibitor or ARB
beta blocker
diuretic
aldosterone antagonist
For post-MI infarction, which drugs produce major improvement in outcome independent of BP?
ACE inhibitor
beta blocker
ARB
aldosterone antagonist
For proteinuric kidney disease, which drugs produce major improvement in outcome independent of BP?
ACE inhibitor or ARB
For angina pectoris, which drugs produce major improvement in outcome independent of BP?
Beta blocker
Ca++ channel blocker
For atrial fib rate control, which drugs produce major improvement in outcome independent of BP?
Beta blocker
non-dihydropyridine Ca++ channel blocker
For atrial flutter rate control, which drugs produce major improvement in outcome independent of BP?
beta blocker
non-dihydropyridine Ca++ channel blocker
For BPH, which drugs are likely to have a favorable effect on symptoms in comorbid conditions?
alpha blocker
For essential tremor, which drugs are likely to have a favorable effect on symptoms in comorbid conditions?
Beta blocker (noncardioselective)
For hyperthyroidism, which drugs are likely to have a favorable effect on symptoms in comorbid conditions?
beta blocker
For migraines, which drugs are likely to have a favorable effect on symptoms in comorbid conditions?
beta blocker
Ca++ channel blocker
For osteoporosis, which drugs are likely to have a favorable effect on symptoms in comorbid conditions?
thiazide diuretic
For Raynaud’s Syndrome, which drugs are likely to have a favorable effect on symptoms in comorbid conditions?
Dihydropyridine Ca++ channel blocker
What is an important contraindication for an ACE inhibitor?
Angioedema
What is an important contraindication for beta blockers?
bronchospastic disease
What is an important contraindication for reserpine?
depression
What is an important contraindication for methyldopa?
liver disease
What is an important contraindication for pregnancy?
ACE inhibitor
ARB
renin inhibitor
What is an important contraindication for second or third degree heart block?
beta blocker
non-dihydropyridine Ca++ channel blocker
Which drugs may have an adverse effect on the comorbid condition of gout?
diuretic
Which drugs may have an adverse effect on the comorbid condition of depression?
beta blocker
central alpha-2 agonist
Which drugs may have an adverse effect on the comorbid condition of hyperkalemia?
aldosterone antagonist
ACE inhibitor
ARB
renin inhbitor
Which drugs may have an adverse effect on the comorbid condition of hyponatremia?
thiazide diuretic
Which drugs may have an adverse effect on the comorbid condition of renovascular disease?
ACE inhbitor
ARB
renin inhbitor
Is loop diuretic combination recommended for routine outpatient use? Why?
Combination can cause profuse diuresis and therefore, routine outpatient use is not recommended (K+ wasting is extremely common)
What is a popular choice for combination with loop agents?
thiazide
What is a common side effect of loop agents and thiazide diurectic combination therapy? How is it managed?
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
What is another way to avoid hypokalemia with combination diuretic therapy?
adding K+ sparing diuretics - lowers K+ secretion
What patients should not receive K+ sparing diuretics and loop agents or thiazides?
people with renal insufficiency
those recieveing ang II antagonists
What are some combinations to avoid in treatment of HTN?
ACE inhibitors, ARBs, and renin inhibitors (only one at a time)
Beta-blockers and non-dihydropyridine CCBs
Potassium-sparing diuretics and ACE inhibitors/ARBs/renin inhibitors
What is HTN urgency?
Severe hypertension (> 180/120 mmHg) without acute end-organ damage
What is HTN emergency?
Severe hypertension (> 180/120 mmHg) with acute end-organ damage
What is the general strategy for handling HTN urgency/emergency?
Choice of agent and blood pressure goal will vary on a case-by-case basis
In general, 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
There are some exceptions to the rule regarding gradual BP reduction
What 2 drugs work well for HTN emer/urgencies
Vasodilators
Adrenergic antagonists
What vasodilators are helpful for HTN emer/rgencies?
- *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 (see below)
What are some good adrenergic antagonists for an HTN emergency?
- *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
- *Labetolo**l: combined α- and β-blocker that may be safe in patients with active coronary disease
What are some considerations for pharmacotherapy for treating HTN in pregnancy?
Consider risks and benefits for both mother and fetus
Maternal benefit is well-established for treatment of severe hypertension (systolic pressure ≥ 160 mmHg and/or diastolic pressure ≥ 110) in reduction of stroke risk
Timing of delivery: if cesarean delivery is imminent, pharmacotherapy may not be necessary
Maternal or fetal benefits have not been shown for treatment of mild to moderate hypertension
All anti-hypertensives cross the placenta; some may inhibit fetal growth
What are some drug options for treatment of acute HTN in pregnancy?
- *Labetalol (IV)**: effective, rapid onset of action, good safety profile
- *Hydralazine (IV)**: has been used extensively in the setting of preeclampsia
- *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
- *Nitroglycerin (IV)** is a good option for HTN associated with pulmonary edema
What are some choices for long-term management of HTN in pregangnt women?
- *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
- *Labetalol**: more rapid onset of action than methyldopa; alternatives in this category include pindolol and long-acting metoprolol; safety is controversial
- *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
- *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
- *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
What are some agents contraindicated during pregnancy?
ACE inhibitors, ARBs, direct renin inhibitors: these drugs are associated with significant fetal renal and cardiac abnormalities
Nitroprusside: possible fetal cyanide poisoning if used for more than a few hours; last resort for urgent control of severe refractory HTN
What is a common pathological process that diuretics are used for? What is this process ‘sensed’ by the body as?
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
Physiologically, this reduction is sensed as a lack of effective arterial blood volume and leads to salt and water retention, followed by edema formation
What edematous states are treated with diuretics?
heart failure
kidney disease
hepatic cirrhosis
How does edema occur as a result of heart failure?
Heart failure reduces cardiac output, which results in a decrease in blood pressure and blood flow to the kidney
Decreases in BP and blood flow is sensed as hypovolemia and leads to renal retention of salt and water
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
How does edema occur as a result of kidney disease?
Most kidney diseases cause retention of salt and water
When loss of renal function is severe, there is insufficient glomerular filtration to sustain a natriuretic response and diuretic agents are of little benefit
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
Loop and thiazide diuretics are beneficial in individuals that develop hyperkalemia associated with early stage renal failure
How does hepatic cirrhosis cause edema? Do you give these patients diuretics?
Diuretics are useful when edema and ascites (accumulation of fluid in the abdominal cavity) become severe due to liver disease
Aggressive use of diuretics can be disastrous in patients with liver disease (more so than heart failure)
What are some nonedematous states that are treated with diuretics?
HTN
Nephrolithiasis
Hypercalcemia
Diabetes insipidus
How is HTN treated with diuretics?
Hypertension
Thiazides are often used because of their diuretic and mild vasodilator activities
Loop diuretics are often reserved for patients with mild renal insufficiency or heart failure
Diuretics are often used in combination with vasodilators (hydralazine, minoxidil) because vasodilators cause significant salt and water retention
How is nephrolithiasis treated with diuretics?
2/3 of kidney stones contain calcium phosphate or calcium oxalate
Thiazide diuretics enhance Ca2+ reabsorption in the DCT and reduce urinary Ca2+ concentration, making them appropriate agents in the treatment of kidney stones
How is hypercalcemia treated with diuretics?
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
How is diabetes insipidus treated with diuretics?
Can be due to either deficient production of ADH (neurogenic or central diabetes insipidus) or inadequate responsiveness to ADH (nephrogenic diabetes insipidus)
Supplementary ADH or one of its analogs is only effective in central diabetes insipidus
Thiazide diuretics can reduce polyuria and polydipsia in both types of diabetes insipidus
