Managing an Inadequate Response to the First Agent
Changing Doses or Drugs, Adding Drugs
Less than 50% of patients respond to the initial choice of antihypertensive therapy. Some consideration should be given as to why the blood pressure did not achieve the intended goal to the selected medication. There are several approaches to managing an inadequate response to the first agent. These include changing the dose or the drug and adding drugs.
Preliminary considerations
Several questions should be asked when a patient has not responded adequately to initial antihypertensive drug therapy. Is the drug an appropriate drug for initial therapy? Is this an appropriate drug given the patient’s demographics? Is the timing of blood pressure measurement for the drug’s duration appropriate? Is the patient adherent to drug therapy? Is there a drug interaction that is preventing the hypotensive agent from being effective? Is the patient consuming an excess amount of sodium?
Inappropriate Initial Therapy
Some drugs are inappropriate for the initial therapy of hypertension. Direct vasodilators (e.g., hydralazine and minoxidil) are never used as initial antihypertensive therapy. Sympathetic activation and reflex tachycardia leads to rapid tolerance to these drugs by causing sodium and water retention. Peripheralacting sympathetic drugs such as reser-pine and a2-stimulants (i.e., methyldopa, clonidine, guanabenz, guanfacine) may be initially effective, but volume-related pseudotolerance will develop. Finally, loop diuretics (i.e., bumetanide, ethacrynic acid, and furosemide) are inappropriate therapy for patients who have normal renal function because of their short duration of action; thiazide diuretics are more effective. By contrast, for patients who have abnormal renal function, loop diuretics are appropriate with abnormal renal function.
Demographics
Failure to take into account demographics may also explain the inadequate response to a first agent. In general, hypertension in African Americans is more responsive to monotherapy with the diuretics and calcium antagonists than to angiotensin-converting enzyme (angiotensin-converting enzyme) inhibitors, angiotensin receptor blockers, and β-blockers. This observation only applies to group data and not individual patients. When a diuretic is added to the less effective drugs, there is no difference in the efficacy in African-Americans vs Caucasians. Gender and age do not alter drug responsiveness.
Drug Duration and Timing of blood pressure Measurement
If there is a mismatch between the pharmacologic duration of the antihypertensive agent and the timing of blood pressure measurement, there may be an apparent lack of drug effectiveness. This can be avoided by choosing drugs that are long-acting with at least 50% of peak effect remaining at the end of 24 h and being aware of the pharmacokinetics of the chosen drug.
Adherence
Poor adherence to antihypertensive therapy is an important factor for the low blood pressure control rate of 27% in the United States. However, patient adherence to a drug regimen may be difficult to assess. Clues to noncompliance are suggested by a lack of knowledge about the drugs or dosing, failure to keep appointments, evasive answers to direct questions concerning compliance, and complaints about cost or side effects. To improve patient adherence to drug therapy, national guidelines recommend the following :
1. Communicate clearly with the patient.
2. Establish the goal of antihypertensive therapy.
3. Reduce blood pressure gradually to minimize adverse effects.
4. Educate the patient about hypertension and involve him or her in the treatment.
5. Keep care inexpensive and simple, and integrate pill taking into routine activities of daily living.
6. Prescribe medications according to pharmacologic principles favoring long-acting formulations.
7. Stop unsuccessful therapy and try a different approach.
Noncompliance seems to be related to the costs of the drugs, level of education, regimen complexity, and side effects of the drug.
Drug Interactions
Many drugs interfere with the efficacy of antihypertensive agents: corticosteroids, monoamine oxidase inhibitors, nonsteroidal anti-inflammatory drugs, tricyclic antidepressants, oral contraceptives, and sympathomimetic medications (e.g., phenylephrine, phenylpropanolamine. Nonsteroidal anti-inflammatory drugs deserve special emphasis because they are so easily obtained as over-the-counter drugs. These drugs attenuate the antihypertensive effects of most antihypertensive drugs. I generally try acetaminophen, salsalate, or sulindac because these agents are less likely to cause sodium retention.
Excessive alcohol remains an important drug that is associated with higher blood pressure levels. Ethanol may be an important secondary cause of hypertension. It may make the patient refractory to single or multiple drugs. It also appears to independently cause hemorrhagic strokes even after its hypertensive effects are considered.
Sodium Excess
Although all patients do not necessarily benefit from sodium restriction, excess sodium intake may be responsible for an inadequate response to a drug. Failure to restrict sodium intake may negate the effectiveness of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers; however, calcium antagonists may be more resistant to a high sodium intake. A simple approach is to check a 24-h urine sodium sample. Excretion of > 120 meq of sodium in 24 h reflects a failure to restrict salt intake. Remember that 85% of sodium intake is added in the processing or preparation of food.
Changing the drug dose
Once the causes of an inadequate response to therapy have been excluded, one is left with the possibility of increasing the dose of the drug (titration), changing drugs (substitution), or adding additional drugs (combination). When antihypertensive therapy is initiated with a single agent, begin with low doses and titrate the dose upward after 4-6 wk if blood pressure is not controlled. Shorter intervals of titration can result in unnecessary additional medication and untoward symptoms.
A drug can be titrated to its highest recommended dose; however, dose-dependent side effects have the potential for limiting titration to the maximum dose. For example, when going from a low dose to a medium dose of a dihydropyridine calcium antagonist, peripheral edema may develop. Lethargy sometimes occurs as the dose of β-blockers or a2-stimulants is increased. Constipation and atrioventricular conduction time increase with higher doses of verapamil. The metabolic side effects of diuretics become more prominent with higher doses. Thus, with upward titration, one has to strike a balance between achieving blood pressure control and increasing side effects.
Changing the drug
There are two reasons for considering changing initial drug therapy. First, if a patient experiences side effects on a low or medium dose of a drug, it is reasonable to substitute another drug from a different class. Second, an incomplete antihypertensive response on a single drug at medium or higher dose may be a reason to try another drug. Attempting to find a single drug to normalize blood pressure by testing each drug class is referred to as sequential monotherapy. Although it is appealing to find a single drug that will attain goal blood pressure, one could go through each class of first-line antihypertensive drugs and still not achieve blood pressure control. The disadvantage of sequential monotherapy is a prolonged duration of multiple medication attempts. This has the potential for creating a loss of confidence in the physician and may result in the patient seeking another physician to manage his or her care.
Remember that only 27% of hypertension patients currently have their blood pressure under control. Unless the patient has only marginally elevated blood pressure, it is unlikely that blood pressure control cannot be achieved by fully titrating a drug or substituting another drug.
Adding drugs
Adding drugs or combination drug therapy should be considered for those patients who have an incomplete therapeutic response to an initial agent. Fixed-dose combination with low-dose diuretics is also considered appropriate initial drug therapy. However, not all drugs may be used in combination. Adding an angiotensin-converting enzyme inhibitor to a β-blocker, an a2-stimulant to an arblocker, or a β-blocker to an a2-stimulant is not additive. Also, it is not wise to combine a loop diuretic and a thiazide diuretic for patients who have normal renal function to avoid volume depletion and major electrolyte disturbances. Diuretics are additive to all agents including the second-line drugs, such as a2-stimulants and reserpine. There continues to be controversy about whether diuretics and calcium antagonists are additive; however, several studies support their effectiveness in combination.
The main advantage of combining different drugs is potentiation of hypotensive effects. Fixed-dose combination products have the additional advantage of simplifying the dosing regimen, improving compliance, and lowering the dispensing cost. The disadvantages of fixed-dose combination are the use of undesirable agents, the abandonment of monotherapy, the potential loss of dosing flexibility, and the inability to determine the cause of adverse reactions.
The combination of a diuretic with a β-blocker, an angiotensin-converting enzyme inhibitor, or an angiotensin II receptor blocker overcomes the disadvantage of these agents for lower efficacy in African-Americans. If low-dose diuretics (6.25 or 12.5 mg hydrochlorothiazide) are used in combination with a second agent, then there is a lower probability of metabolic side effects. The combination of a β-blocker and a low-dose diuretic has been shown to be as effective or more effective than other agents without increased side effects.
Recently, a new group of combination agents has become available in which an angiotensin-converting enzyme inhibitor is combined with a calcium antagonist. This combination avoids a negative metabolic profile of full-dose diuretics and attenuates the dihydropyridine peripheral edema. Also the combination of verapamil and an angiotensin-converting enzyme inhibitor may be associated with less proteinuria than an angiotensin-converting enzyme inhibitor alone and may be proven to be renoprotective.
Under special circumstances, adding certain drugs may be useful not only in lowering blood pressure but controlling other problems. Using a dihydropyridine calcium antagonist with a β-blocker is effective for angina. An angiotensin-converting enzyme inhibitor and a diuretic are considered first-line therapy for hypertension with systolic heart failure; however, a combination of angiotensin receptor blocker and diuretic is a reasonable alternative. For the hypertensive patient with either hyperkinetic cardiomyopathy or hyperkinetic heart syndrome, cautiously using a β-blocker and a nondihydropyridine calcium antagonist (verapamil or diltiazem) is reasonable.
Failure to achieve blood pressure control with the combination of three rational drugs, which includes a diuretic, requires applying the preliminary considerations discussed previously as well as the suspicion of a secondary cause of hypertension. If nonadherence is a concern, I ask the patient to bring his or her medications to the clinic in the morning, observe the patient swallowing the pills, and measure his or her blood pressure throughout the day and the following morning. Referral to a hypertension specialist may be needed.
Conclusion
When managing an inadequate blood pressure response to an appropriate antihy-pertensive drug, the physician should consider the possible known causes for the lack of a response. If no cause is found, the physician is left with the possibility of changing the drug dose (titration), changing the drug (substitution), or adding drugs (combination) to the initial therapy. There is a high probability that adding drugs will be necessary. If combination therapy is chosen, there is the option of using rational multiple agents to achieve controlled blood pressure or fixed-dose combination agents. Patients appreciate fixed combinations because it saves them money and simplifies their life. Achieving target blood pressure control with the fewest side effects while reducing morbidity and mortality is the goal of therapy.
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