1. Treatment of Hypertension
Nancy J. Brown, M.D.
Division of Clinical Pharmacology
Vanderbilt University Medical Center

2. Classification of Blood Pressure for Adults
Category SBP DBP
Optimal < and <80
Normal < and <85
High Normal or
Hypertension Stage or
-Stage or
-Stage > or >110
The categories of hypertension stages has also been modified from previous publications and JNC reports. The terms “mild” and “moderate” hypertension are no longer used, since this may imply to the patient that treatment is not needed or optional. An additional change in classification is the elimination what was called “Stage 4 hypertension”, which occurs rarely. Patients are classified in a higher category of hypertension if either the systolic or diastolic blood pressure exceed the range listed in the table.
When SBP and DBP fall into different categories, use the higher category.

3. Examples of Identifiable Causes of Hypertension
Renal Causes
Renovascular disease • Polycystic kidneys
Renal parenchymal disease
Endocrine Causes
Pheochromocytoma • Cushing syndrome
Primary aldosteronism • Hyperparathyroidism
Exogenous causes
OTC sympathomimetics, NSAIDs, cocaine, alcohol, etc.
Although most cases or hypertension are essential, or without a detectable cause, about 15% of hypertension may be related secondary causes which require additional diagnostic procedures. If there is a high index of suspicion of an identifiable cause of hypertension, appropriate investigations should be conducted.
Exogenous causes of hypertension include use of drugs known to increase blood pressure, such as cocaine; amphetamines; immunosuppressive agents such as cyclosporine, tacrolimus and corticosteroids; erythropoietin, mineralocorticoids, anabolic steroids, and certain toxins.

4. Treatment Strategies and Risk Stratification
Blood Pressure
Stages (mm Hg) Risk Group A Risk Group B Risk Group C
High-normal Lifestyle modification Lifestyle modification Drug therapy* ( /85-89) Lifestyle modification
Stage Lifestyle modification Lifestyle modification Drug therapy ( /90-99) (up to 12 months) (up to 6 months)** Lifestyle modification
As can be seen from this table, the treatment strategies can vary based the blood pressure measurement and the risk group of a patient. Notice that non-pharmacological lifestyle modifications is an integral part of all treatment modalities. Also notice that drugs are not initiated in high normal or stage 1 hypertension until after an adequate trial of lifestyle medication has been attempted, unless evidence of end organ damage or diabetes mellitus is present.
Stages 2 and Drug therapy Drug therapy Drug therapy
(>160/>100) Lifestyle modification Lifestyle modification Lifestyle modification
* For those with heart failure, renal insufficiency, or diabetes.
** For those with multiple risk factors, clinicians should consider drugs as initial therapy plus lifestyle modification

5. Predicting physiology in HTN patients

6. JNC recommendations
b-blockers
diuretics (thiazide-type)

7. Anti-hypertensive agents

8. Age-race subgrouping as prediction of BP response
Older Blacks Younger Whites
Materson et al NEJM, 1993

9. What physicians prescribe
Siegel and Lopez, JAMA, 1997

10. Thiazide Diuretics Advantages Disadvantages
Proven morbidity and mortality benefits
Effective for many patient groups – esp older, salt-sens
Reduces edema and heart failure symptoms
Protects against osteoporosis
Increases efficacy of other antihypertensives
Inexpensive
Thiazide diuretics are initial drugs of choice for most patients, based on clear evidence of morbidity and mortality benefits. Thiazide diuretics are inexpensive, and are effective for most patient groups. In patients with heart failure symptoms and edema, diuretics may reduce excessive fluid accumulation. Thiazides also reduce renal excretion of calcium, which protects against osteoporosis, which can be beneficial particularly in postmenopausal women.
If the initial choice of drug in a hypertensive patient was not a diuretic, addition of a thiazide diuretic is likely to potentiate the effects of the other diuretic and may lead to therapeutic success.
Disadvantages to thiazide diuretics include electrolyte imbalances, particularly reductions in serum potassium and magnesium, which may cause arrhythmias, particularly in patients who are hypokalemic or are on digoxin. Diuretics can also increase serum lithium concentrations in patients receiving lithium for psychiatric reasons, necessitating a reduction in lithium dosage to prevent toxicity.
Uric acid elevations are also possible with thiazide diuretics, which may lead to gout. Although an association between elevated serum concentrations of uric acid has been associated with hypertension, the antihypertensive effects of thiazides has been well documented.
Thiazide diuretics can reduce the glomerular filtration rate of the kidney, and are relatively ineffective in patients with less than 30% of normal kidney function, or a serum creatinine of more than 2.4 mg/dl.
Thiazides may also temporarily adversely effect serum cholesterol and lipid profiles, but the long term effect of this elevation is unknown at this time.
Disadvantages
Electrolyte imbalances (K+, Mg+,  uric acid)
Ineffective in advanced renal disease (SrCr > 2.4)
Adverse effect on lipid profile

11. Thiazide diuretics and risk of cardiac arrest
100 mg thiazide
50 mg thiazide
25 mg thiazide
50 mg thiazide + K-sparing
25 mg thiazide + K-sparing
Siscovick et al, NEJM, 1994

12. Systolic Hypertension in the Elderly (SHEP)*
*chlorthalidone 12.5mg mg + atenolol 25 mg
JAMA 1991

13. MRC
Atenolol
Hctz + amiloride

14. Loop Diuretics Similar to thiazides except:
Less effective in treating hypertension
except…
Effective in advanced renal disease
More potent effects on edema
No osteoporosis benefit
Wider dosing range (high ceiling)
May cause ototoxicity
There are currently four available loop diuretics, furosemide, bumetanide, torsemide and ethacrynic acid.
Loop diuretics, are similar to thiazide diuretics in many cases, but have some very important differences.
There are relatively few controlled studies demonstrating the efficacy of loop diuretics in hypertension, however experience has demonstrated efficacy of this group of drugs.
Loop diuretics do not diminish renal function unless excessive fluid depletion results in profound hypotension. For that reason, they are more likely to retain efficacy in patients with more advanced renal impairment. No diuretic is effective in patients requiring dialysis, however.
The more potent diuretic effects make loop diuretics more effective in treatment of edema. Increasing the dose of thiazides usually does not lead to an increased response on edema fluid. Loop diuretics have a wider dosage range response, and have therefore been called “high ceiling” diuretics.
Unlike thiazides, loop diuretics increase urinary calcium excretion, which will lower serum calcium and may be detrimental to patients with osteoporosis.
In some patients, loop diuretics may cause hearing loss. Adverse effects on hearing are more likely with the use of ethacrynic acid. For that reason, clinicians usually reserve ethacrynic acid only for patients with documented sulfonamide allergy, since all thiazides and all other loop diuretics contain a sulfonamide group.

15. Other Diuretics Metolazone Triamterene and Amiloride Spironolactone
Higher ceiling than other thiazides
Additive effects with loop diuretics
Triamterene and Amiloride
Weak diuretics used in combinations
Maintains serum K+ and Mg+
Spironolactone
Weak diuretic, often combined with thiazide
May cause gynecomastia (7-10%)
Maintains serum K+
High doses used in liver disease for ascites
Low doses beneficial in heart failure
Drug of choice in primary hyperaldosteronism
Metolazone is a “thiazide-like” diuretic which does not reduce the kidney’s glomerular filtration rate. This makes metolazone more effective in patients with diminished renal function. There is also evidence that metolazone is active in several areas of the kidney, which makes it attractive for mobilizing edema in patients when used in combination with a loop diuretic. If used in conjunction with a loop diuretic, excessive diuresis and electrolyte imbalance may become a problem. Some forms of metolazone are incompletely and erratically absorbed form the GI tract. A micronized form of metolazone is available which is much more potent on a weight basis, and should not be interchanged with traditional dosage forms.
Triamterene and amiloride are very weak diuretics which have potassium sparing effects. Although there is little evidence that these agents alone are effective in treatment of hypertension, concurrent use with a thiazide diuretic may reduce unwanted potassium wasting effects. The effect of combination products is variable, however, and products which contain both a potassium sparing diuretic and a thiazide diuretic may not necessarily result in normal serum potassium concentrations.
Spironolactone is an antagonist of of the sodium and fluid retaining steroid aldosterone. It is a weak diuretic which retains potassium, and has historically been used frequently in combination with a hydrochlorothiazide to prevent potassium wasting, or in high doses to prevent ascites in hepatic failure. New information has suggested an indication in treatment of sever heart failure.

16. - Blockers Advantages Disadvantages
Proven morbidity and mortality benefits
Reduces mortality rate post-MI (non-ISA)
Benefit in chronic stable angina
Available generics are inexpensive
Disadvantages
Bronchospasm in asthmatics
Potential for excessive bradycardia
Adverse effects of lipid profile
Masks symptoms of hypoglycemia
Relatively high incidence of impotence
There is adequate evidence that treatment of hypertension with beta-blocker agents reduces the induced of hypertension related morbidity and mortality.
A number of studies have confirmed that use of a beta-blocker drug such as atenolol, metoprolol, propranolol or timolol in patients immediately following an acute myocardial infarction can reduce the incidence of death by about 30%.
Resting heart rate is lowered, and exercise induced heart rate increases are blunted by beta-blocker drugs, making them attractive agents in most cases of chronic stable angina.
In addition, many of the commonly used beta-blocker drugs are available in generic form, making agents in this class affordable to almost all patients who would benefit from their use.
There are several disadvantages with the use of beta-blocker drugs.
Bronchospasm is possible in patients with asthma, particularly in patients who have been shown to benefit from beta agonist drugs such as albuterol. Some agents, such as atenolol or metoprolol are relatively free of adverse pulmonary effects in low doses, however this benefit is lost as dosage is increased. In general, beta-blocker drugs should be used with caution, if at all, in patients with bronchospastic diseases.
The heart rate lowering effects of beta-blockers can cause excessive bradycardia in overdose, or in some patients with pre-existing bradycardia or conduction disorders.

17. ACE Inhibitors (ACE-I)
Advantages:
Minimal adversities on quality of life.
Protects against hypokalemia
Prevents LV remodeling post-MI
Protects against diabetic renal insufficiency
Effective in treating/preventing CHF (decreases LVH)
Disadvantages:
May induce cough after several weeks (3-30%)
May induce hyperkalemia (4-5%)
May cause rash, taste dysgeusia; rare angioedema
Avoid in renal artery stenosis
Contraindicated in pregnancy (2nd & 3rd trimesters)
Angiotensin Converting Enzyme Inhibitors, commonly called ACE inhibitors, interfere with the bodies ability to produce Angiotensin II. Angiotensin II is a potent vasoconstrictor which also modifies both renal function and cardiac muscle growth and remodeling. ACE inhibitors reduce blood pressure, and have been shown to reduce morbidity and mortality in many studies.
ACE inhibitors reduce serum aldosterone, a hormone which leads to renal potassium wasting. ACE inhibitors have been shown to reduce potassium wasting and hypokalemia that may be associated with thiazide or loop diuretics. In addition, the combination of an ACE Inhibitor and a diuretic is a potent antihypertensive combination. Improvement in cardiac muscle remodeling which occurs after acute myocardial infarction is likely due to both direct effects on tissues through a number of mechanisms; and indirect effects due to decreased in cardiac afterload, which reduces stress on the heart. Benefits in treating and preventing heart failure are likely due to reduced vascular tone, which improves cardiac output and reduces pulmonary circulation pressure; and prevention of abnormal heart tissue formation. The beneficial effects on the kidney have been shown to include a reduction in the rate of renal damage in patients with diabetes and other risk factors for end stage kidney disease.

18. Primary outcomes in HOPE

19. Angiotensin II Receptor Blockers (ARB)
Advantages
Similar benefits to ACE-I (CHF, HTN)
ACE-I cough not observed
Angioedema extremely rare
Disadvantages
Contraindicated in pregnancy
Hyperkalemia possible
Fewer clinical trials
Relatively expensive (no generics)
In comparison to ACE inhibitors, which prevent formation of Angiotensin II, the Angiotensin II receptor blocker drugs work by blocking effects of circulating angiotensin II.
Antihypertensive effects of the AT II blocker drugs is similar in many aspects to those of ACE inhibitors. Since this class of drugs does not block enzymes responsible for bradykinin degradation, the incidence of both drug induced cough and angioedema is exceedingly low, and possibly not greater than that seen with placebo.
Effects on fetal circulation and perfusion of the kidney are essentially similar to ACE inhibitors, making the contraindications for this drug class similar to that of the ACE inhibitor drug class.
In addition, since this drug class is relatively new, it has been studied less completely than ACE inhibitors. Furthermore, the lack of generics increases the cost of the entire drug class, to as much as $1 to $2 daily, or more.

20. Calcium Channel Blockers A Diverse Class of Drugs
Dihydropyridines
Short half-life associated with increased risk of
mortality
Several sustained-release products are available
One agent (amlodipine) has a long half-life
Used following subarachnoid hemorrhage
Diltiazem and Verapamil
The calcium channel blocking agents are potent agents which reduce peripheral vascular resistance, making them valuable agents in the treatment of hypertension.
Three distinct groups from this class of drugs were recommended for use in treatment of hypertension. Calcium channel blocking agents in the dihydropyridine class are potent arteriolar smooth muscle relaxing agents which have little direct effect on the heart in recommended doses. The vasodilating effect of the dihydropyridine group of drugs may lead to an indirect increase heart rate. In contrast, the rate lowering vasodilating agents diltiazem and verapamil have a direct negative chronotropic effect on the heart, producing a reduction in heart rate.
All currently available calcium blocking agents have negative inotropic actions in the heart, making them potentially hazardous agents to use in patients with heart failure who have diminished cardiac function. Dihydropyridine drugs cause less of a negative inotropic action, and appear to be relatively safe drugs to use in heart failure.
Mibefradil, a rate lowering vasodilator, belonged to another group of calcium channel blocking agents. Mibefradil was recommended in the JNC VI report, however it inhibited enzymes in the cytochrome P450 system responsible for eliminating many commonly used drugs. Mibefradil was withdrawn from sale shortly after publication of JNC VI due to difficulties with drug interactions.
Sustained release products are acceptable

21. Dihydropyridines Short acting Sustained release products
not recommended for use in blood pressure control due to increased mortality
Sustained release products
Procardia XL®, Adalat CC®, Cardene SR®, Plendil®, DynaCirc CR®, Sular®
Dosage forms should not be split/crushed
GI transit limits value with 24 hour dosage forms
Most of the dihydropyridine type calcium channel blocker drugs have a short biological half-life ranging which would make multiple daily dosing necessary. The wide blood pressure swings caused by nifedipine and nicardipine make these drugs dangerous to use, and they are not recommended for use by JNC VI.
Sustained-release forms of nifedipine, nicardipine, felodipine, isradipine and nisoldipine are all recommended for use by JNC VI. These sustained release products produce a longer duration of effects by limiting the rate of dissolution of the drug in the gut, thereby limiting the rate of absorption. These products are unsafe to use in a patient who can not swallow intact tablets of capsules, since crushing or chewing of these sustained release dosage forms would be expected to increase the effect and decrease the duration of action of the dosage form.
Amlodipine, in contrast, is a dihydropyridine drug which has a very long biological half life. Crushing or chewing does not effect the absorption of amlodipine, making it the dihydropyridine drug of choice in patients who can not swallow intact tablets or who are fed through a feeding tube.
One agent with a long half-life is recommended
Amlodipine
Crushing/splitting does not affect bioavailability

22. Side effects of Dihydropyridines
Reflex tachycardia
May precipitate angina
Peripheral edema
Dizziness
Flushing
Headache
Gingival hyperplasia (rare)
Side effects of the dihydropyridine type calcium channel block agents include reflex tachycardia, which may increase cardiac work and precipitate angina in some patients with chronic stable angina. Peripheral edema in the lower extremities occurs commonly, and is thought to be due to increased hydrostatic pressure and reflex postcapillary constriction
Dizziness and flushing are side effects thought to be caused by the rapid onset of vasodilation. This is less common with sustained-release dosage forms of dihydropyridine drugs, or amlodipine.
Headache occurs in about 10% to 20% of patients taking dihydropyridine drugs, and is most common with non-sustained release forms of nifedipine and nicardipine.
Gingival hyperplasia, a gradual growth of the gums which can cover the teeth, is a very uncommon side effect of dihydropyridines, occurring in <1% of patients. Gum growth responds to discontinuation of drug.

23. Rate Lowering Calcium Antagonists
Verapamil and diltiazem
Advantages
Rate control in supraventricular tachyarrhythmias
May be beneficial in hypertrophic cardiomyopathy
Disadvantages
Diltiazem and verapamil are particularly desirable agents to use in patients with hypertension in conjunction with either angina or supraventricular tachyarrhythmias. These rate lowering vasodilator drugs are beneficial in treatment of angina for a number of reasons. In patients with vasospastic angina, the incidence of coronary vasospasm is reduced; and in patients with chronic stable angina, they reduce both resting heart rate and exercise induced increase of heart rate, which may precipitate ischemia.
Both diltiazem and verapamil decrease the rate of impulse transmission through the AV node, which may be useful in controlling the ventricular rate in atrial fibrillation. Which given intravenously they may be useful in terminating episodes of paroxysmal supraventricular tachycardia.
Negative inotropic effects from diltiazem and verapamil decrease contractility. This may be possibly beneficial in some patients with hypertrophic cardiomyopathy, however it is more likely to be problematic in patients with mild to moderate heart failure. Advanced heart failure is a contraindication for the use of diltiazem or verapamil.
The smooth muscle relaxing effects of diltiazem and verapamil may cause constipation, particularly in elderly patients. Verapamil tends to cause constipation more commonly than diltiazem.
Another possibly serious side effect of both diltiazem and verapamil is excessive bradycardia, which can be seen in overdose, of if used in combination with other rate lowering drugs, or in patients with underlying conduction system disease.
Negative inotropic effects (may unmask CHF)
Constipation (particularly with verapamil)
Significant bradycardia possible in some patients

24. Antihypertensive drugs to avoid in patients with a low resting heart rate
Beta Blocker drugs
Acebutolol
Atenolol
Betaxolol
Metoprolol
Nadolol
Propranolol
Timolol
Rate lowering CCB drugs
Diltiazem
Mibefradil
Verapamil
Central alpha-2 drugs
Clonidine
Methyldopa
In general, drugs which decrease heart rate should be avoided in patients with a low resting heart rate, unless a functioning artificial pacemaker is in place. A combination of two different agents which reduce heart rate may increase risk of profound bradycardia.
In addition to diltiazem and verapamil, most beta blocker drugs should be avoided in patients with a low resting heart rate.
The central alpha-2 agents clonidine and methyldopa can also cause clinically significant bradycardia, particularly in the high doses recommended for hypertensive urgencies.

25. CCBs and CAD: summary Short-acting CCBs should not be used.
Long-acting dihydopyridines are appropriate in elderly patients who don't tolerate thiazide diuretics.
ACEI are drug-of-choice in diabetes mellitus.
CCBs should be used like vasodilators in combination therapy.

26. Prazosin, doxazosin, and terazosin (tamsulosin not indicated for HTN)
1- Receptor Blockers
Prazosin, doxazosin, and terazosin (tamsulosin not indicated for HTN)
Advantages
Beneficial in BPH (prostatism)
Favorable trend in lipid profile
Disadvantages
Orthostatic hypotension
First dose syncope
Increased risk of heart failure in patients on doxazosin in ALLHAT
Three alpha 1 receptor blocker drugs are approved for treatment of hypertension in the United States. Chronic use of these agents produces vasodilation and a modest reduction in blood pressure. They tend to be relatively ineffective if used as monotherapy, but may be beneficial in patients treated concurrently with either a diuretic or beta blocking drug.
Prazosin, doxazosin and terazosin are considered to be effective in increasing symptoms of benign prostatic hypertrophy in males who have difficulty in initiating or maintaining the flow of urine. They have also been shown to have some limited ability to reduce in serum cholesterol, although the significance of this observation is not known.
The primary side effect of this class of drugs is profound orthostatic hypotension, which often occurs shortly after taking the first dose of the drug. This “first-dose effect” is usually seen within 90 minutes of an initial dose, and may occur in as many as half of patients concurrently taking either a beta blocker or diuretic. To avoid this complication, low initial doses of drug are used initially, with the first dose being given immediately before bedtime or other period of inactivity.
The relative efficacy of this drug class has recently been questioned following release of the preliminary results of the ALLHAT trial, which compared doxazosin to a diuretic (chlorthalidone), amlodipine, lisinopril. The doxazosin arm of the study was stopped prematurely due to an increased incidence in the onset of heart failure in patients randomized to doxazosin. Details on other drugs in this study are anticipated within the next two years.
JAMA 2000;283:

27. Central a2-Agonists Clonidine, guanabenz, guanfacine, and methyldopa
Advantage
Lowers heart rate
Disadvantages
Sedation
Depression
Dry mouth
Clonidine - rebound hypertension
Methyldopa - autoimmune hepatitis and drug fever
Relatively high incidence of impotence
The central alpha acting agents lower blood pressure by stimulating receptors in the brainstem, resulting in a reduction in sympathetic outflow from the CNS. These agents reduce both cardiac output and peripheral resistance.
Drugs in this class are effective in patients who require a heart rate lowering drug but cannot tolerate the negative inotropic effects of diltiazem, verapamil, or beta blockers. The rapid onset of hypotensive effects also makes clonidine tablets a good option in treatment of hypertensive urgencies in patients able to take oral drugs. Clonidine is also available in patches which release a controlled amount of drug daily for up to a week, however the onset of full effect may not be seen for several days, making interim oral doses necessary.
Drugs in this class do have a significant number of adversities. Sedation is a common adverse effect seen with all agents in this class. Depression is also common, particularly when higher doses are used. Dry mouth and nasal dryness may also be a problem. Clonidine withdrawal in patients who are receiving doses greater than 0.3mg daily makes it a relatively poor drug to use in patients with a history of noncompliance with taking medications.
A side effect seen only with methyldopa include drug fever and an autoimmune hepatitis, both of which resolve with drug discontinuation.
These agents are also highly likely to cause impotence, and should be avoided in males with a history of erectile dysfunction.

28. Direct Vasodilators Hydralazine Minoxidil Advantage
Useful in CHF (with concurrent ISSDN)
Disadvantages
Lupus syndrome
Headache (~10%) and reflex tachycardia
Minoxidil
Advantage
Most potent oral agent
Two direct vasodilator drugs are useful in treatment of hypertension, hydralazine and minoxidil.
Hydralazine is most commonly used in combination with isosorbide dinitrate (ISSDN) in treatment of heart failure. The dosage which has been shown to reduce mortality in heart failure was quite high: 75mg hydralazine in combination with 40mg ISSDN dosed either three or four times daily.
Disadvantages seen with hydralazine include an autoimmune reaction, similar to lupus. Lupus is most commonly seen after at least 6 months of dosing, and is more common in women. Incidence may be as high as 10% in patients receiving doses of 200mg daily.
Hydralazine can cause a reflex tachycardia as a response to vasodilation. Use of a rate lowering antihypertensive blunts this response and increases antihypertensive efficacy.
Minoxidil is perhaps the most potent oral antihypertensive agent. It is most commonly reserved for use in patients unresponsive to conventional agents. Minoxidil causes a profound reflex tachycardia and fluid retention. For this reason, it is best to give the drug in combination with both a rate lowering antihypertensive drug and a loop diuretic.
Hypertrichosis, or excessive growth of hair on the face, back, arms and legs occurs in all patients who receive the drug for a prolonged period of time. This is particularly offensive to some people, and may result in non-compliance.
Some patients may develop a small pericardial effusion who taking minoxidil. In the event that clinically significant effusions occur, they with resolve with drug discontinuation.
Disadvantages
Reflex tachycardia and edema
(Can precipitate MI due to increased oxygen demand)
Hirsutism
Pericardial effusion

29. JNC and other recommendations
Initial drug choice
Not at goal BP
No response/side effects Partial response
Substitute drug from
Opposite arm
Add agent from
opposite arm
Not at Goal BP
Combination Rx/ Secondary HTN

30. Anti-hypertensive agents

31. Combination Therapies
Beta-blockers and diuretics
ACE inhibitors and diuretics
Angiotensin II antagonists and diuretics
Calcium antagonists and ACE inhibitors
Other combinations
JNC VI is the first consensus report which recommends use of some combinations of antihypertensive agents.
The use of a combination agent may be beneficial in improving compliance. These combinations may also offer a decreased incidence of side effects compared to equivalent antihypertensive doses of single agents. Since may drug insurance plans require that the patient pay a set fee for each prescription, the cost to a patient on such a plan will be reduced. In some cases, however, use of two separate prescriptions for inexpensive generics drugs (such as generic forms of a diuretic and beta blocker agent) may be much less expensive than a brand name equivalent combination product, particularly if the patient is without insurance coverage.
The most adventitious drug combinations include use of a low dose of diuretic in combination with either a beta blocker, ACE inhibitor, or an angiotensin II receptor blocker drug. Combinations of an ACE inhibitor and a calcium channel blocking agent are particularly useful, since the incidence of peripheral edema caused by the calcium channel blocker is blunted if an ACE inhibitor is used.
Other combinations are also listed in Table 8 of JNC VI.

32. rate-controlling drug (usually β-blocker)
diuretic (loop if minoxidil)
potent vasodilator
Variations
+ ACE I or ARB (to minimize vasodilator)
+ α-blocker (to complement β-blocker)
+ thiazide (to enhance anti-hypertensive effect of minoxidil)

33. Think secondary causes: Hyperaldosteronism in resistant hypertension
Calhoun et al. Hypertension 2000

34. Characteristic PA (n=18) 20%! Est Htn (n=70) Age, y 51.2±10.5*
57.91±1.7
Black/White
10/8
34/36
BMI, kg/M2
33.8±8.2
32.18±.2
SBP, mmHg
158±17.9
159±25.8
DBP, mmHg
92±11.7
89±16.9
# anti-htn
4.2±0.9
3.8±0.9
K<3.6mEq/L or suppl
13 (72%)†
14 (20%)
PAC, ng/dL
19.2±10.7†
10.8±7.7
PRA, mg/ml/hr
0.3±0.2†
3.2±5.4
Ratio
80.6±53.0†
22.9±32.8
Urine aldosterone mg
21.0±10.3†
7.9±4.8

35. Effect of spironolactone in resistant hypertension

36. Compelling Indications (Based on randomized controlled trials)
Initial Drug Choices
Compelling Indications
(Based on randomized controlled trials)
Heart failure
- ACE inhibitors
- Diuretics (spironolactone)
Myocardial Infarction
- Beta-blockers (non-ISA)
- ACE inhibitors (with systolic dysfunction)
Diabetes mellitus (type 1) with proteinuria
Isolated systolic hypertension (older person)
- Diuretics preferred
- Long-acting DHP calcium antagonists
Patients with underlying diseases, or risk of developing a certain diseases may be placed on alternate agents known to modify the natural history or assist in treating other illnesses. In some cases there is compelling information demonstrating benefit if specific classes of drugs are used.
In patients with heart failure, ACE inhibitors have been shown to improve mortality and reduce symptoms, and should be used unless contraindications exist. Diuretics do not reduce mortality rate in heart failure, but may improve symptoms of pulmonary congestion and edema.
As mentioned earlier, both beta blocker drugs and ACE inhibitors have been shown to reduce mortality if used following an acute myocardial infarction. Although trials demonstrating benefit were of short duration (at least 6 weeks for ACE inhibitors and up to two years for beta blockers), hypertensive patients might benefit from chronic therapy using drugs from both of these classes of compounds.
ACE inhibitors have been shown to significantly reduce in progression to renal impairment in patients with insulin dependent diabetes mellitus and proteinuria. The goal blood pressure in this group of patients should be less than 130/85 mm Hg. Renal protection has also been demonstrated with calcium antagonists, although a preponderance of evidence supports use of ACE inhibitors.
Isolated systolic hypertension, which is most common in elderly patients, is best treated with a thiazide diuretic. Multiple clinical trials support the use of either hydrochlorothiazide or chlorthalidone in low doses. One trial using nitrendipine, a dihydropyridine calcium channel blocker drug not available in the United States, supports a reduction in the risk of stroke in patients with isolated systolic hypertension. However, the drug of choice in these patients remain a thiazide diuretic.