Drug therapy
The decision to intervene with drug therapy is influenced mainly by the extent of blood pressure elevation, evidence of target-organ damage or other cardiovascular disease, and the presence of other cardiovascular risk factors. A classification with specific guidelines for initiating drug therapy based on these factors has been proposed.
Some general recommendations for initial selection of a drug for untreated hypertensives can be made based on available clinical evidence. An ideal antihypertensive drug formulation should have a number of important properties (Joint National Committee 1997) such as requiring only once daily dosing, preferably with a duration of action of at least 24 hours with at least 50% peak effect at the end of 24 hours (trough-to-peak ratio) with protection against the rapid rise in blood pressure that may occur on arising from sleep in the morning.
Initial drug therapy in uncomplicated patients with hypertension
The choice of the initial drug to use in a patient with hypertension remains highly variable in the practice of medicine because of a number of factors, including attitudes of the physician about the desirability of a drug (especially the concern about adverse drug effects) and heavy marketing pressure aimed at influencing the physician’s choice of drugs and tending to stress favoring newer drugs. However, based on the extensive experience from randomized clinical trials that demonstrate efficacy in preventing major clinical endpoints, use of diuretics or β-adrenergic receptor antagonists remain the preferred choice for initial therapy in uncomplicated, otherwise healthy hypertensives who are not at high immediate risk (Joint National Committee 1997). A general approach to treatment, with a goal blood pressure less than 140/90 mm Hg in these patients, is to start a diuretic or β-adrenergic antagonist at the lowest recommended starting dose.
If the therapeutic response is inadequate, the dose should be titrated upward to the full dose. If the therapeutic effect on blood pressure proves to be insufficient, there are a variety of options. If the patient has had significant adverse effects or has not had any therapeutic effect from the drug (and the physician believes the patient is taking the medication), the initial drug should be discontinued and a substitute chosen from another drug class. On the other hand, if the patient has had a partial therapeutic effect, then the second drug (either a β-adrenergic receptor antagonist or a diuretic) should be added and its dose titrated upward. Issues relating to patients who do not reach the goal blood pressure using this approach are discussed below.
Initial drug therapy in patients with hypertension who have coexisting diseases
Although β-adrenergic antagonists and diuretics remain the first line of therapy in uncomplicated patients, a wide range of other factors may suggest that another class of drugs would be appropriate for first-line therapy in selected patients. In general, antihypertensive drugs may have either favorable or unfavorable effects on these conditions. For some diseases, the indication may be very compelling for selecting specific drug classes, for example, Angiotensin-converting enzyme inhibitors in type I diabetics with proteinuria, Angiotensin-converting enzyme inhibitors in patients with congestive heart failure (see the section in this chapter), or β-adrenergic antagonists in patients with myocardial infarction (see the section in this chapter). Appropriate drug choices have been demonstrated in controlled trials to improve the outcome of the coexisting problem. In many settings, choice of a specific antihypertensive drug may have favorable symptomatic benefit in patients with other diseases. For example, in patients with angina, either β-adrenergic receptor antagonists or calcium-entry blockers can decrease episodes of chest pain. Patients with essential tremor or with recurrent migraine may benefit from specific, generally nonselective, β-adrenergic receptor antagonists. Men with benign prostatic hyperplasia may get marked improvement with an α1-adrenergic receptor antagonist used to treat hypertension.
Principles
Search out indications other than primary uses for an agent in a patient who has more than one treatable medical problem; that is, try to get “two for the price of one.”
On the other hand, certain antihypertensive drugs may adversely alter the course of other coexisting diseases. For example, reactive airway diseases such as asthma may be fatally exacerbated by concomitant use of a β-adrenergic antagonist. Heart block may be increased by β-adrenergic antagonists or some calcium-entry blockers. Mental depression may be worsened or precipitated in susceptible patients taking drugs such as β-adrenergic antagonists, clonidine-like drugs, or reserpine. In some settings, the risk is so great (e.g., β-adrenergic antagonists in asthmatics) that the offending drug is generally contraindicated. On the other hand, the potential adverse effect may be readily detected and reversible should it occur, leaving much more scope for clinical judgment (e.g., diuretics in patients with mild dyslipidemias).
Other special patient considerations
Special considerations in selecting the initial drug also may be influenced by factors other than coexisting diseases. Although certain drugs have been heavily marketed as better at preserving quality of life in patients with hypertension on average, evidence to support this contention is modest. Indeed, all drugs recommended for initial treatment of hypertension are generally well tolerated. In any case, if any particular drug has an adverse impact on quality of life in an individual patient, the drug can be discontinued or the dose adjusted as appropriate.
Principles
Although knowing about average effects of drugs in large populations is potentially important, the capacity to individualize therapy based on the actual responses in your patient may be much more significant in guiding therapeutic decisions.
There is some evidence that African-American hypertensive patients on average are more likely to respond to diuretics and calcium-entry blockers than to β-adrenergic antagonists or Angiotensin-converting enzyme inhibitors. On the other hand, particularly if either a β-adrenergic receptor antagonist or an Angiotensin-converting enzyme inhibitor is otherwise preferred because of a coexisting disease, such as myocardial infarction or congestive heart failure respectively, it is appropriate to use drugs in these classes in African-American patients. It may be necessary to use higher doses or encourage salt restriction to achieve the desired efficacy in some of these patients.
Cost of therapy should remain a major consideration in the choice of drugs. Many patients are not insured for the cost of drugs and will not even fill prescriptions for expensive agents. The cost of medication for those who are insured is shared by society as a whole in taxes, insurance rates, and so forth. The determination of the price of a drug in any given geographical area or practice plan is complex and not uniform. However, as a general rule, generic formulations and “older” drugs are cheaper.
Principles
When the efficacy of therapy can be easily monitored, there is little disadvantage in choosing the cheapest preparation of a given chemical entity or class.
The physician and patient should consider prior antihypertensive drug therapy and current antihypertensive drug therapy in choosing modifications in drug therapy. If at all possible, two drugs that are synergistic should be used, and two drugs that have additive adverse effects should be avoided. This commonsensical principle is very useful in guiding multiple-drug therapy. An example can be drawn from the step-care concept, whereby addition of a vasodilator to a β-adrenergic antagonist-plus-diuretic regimen is rational, because the diuretic will counter the vasodilator-induced salt retention and the β-adrenergic blocking agent will inhibit the reflex sympathetic actions on the heart and venous systems. Other potentially favorable drug pairs include diuretic–Angiotensin-converting enzyme inhibitor, diuretic–angiotensin II receptor antagonist, and minoxidil–loop diuretic. Indeed, there may be some justification in the use of fixed drug combination tablets in the treatment of hypertension because this may simplify a patient’s drug regimen, possibly having a favorable impact on patient compliance with medical treatment in some cases. However, it is generally advisable to define treatment requirements one drug at a time.
There are combinations of antihypertensive drugs that probably should not be used together as pairs. For example, combinations of two drugs from the same family or class generally makes little sense. Drugs that may share common or overlapping targets may exacerbate adverse drug effects. For example, some drugs may potentially have additive effects in terms of slowing resting heart rate: the combination of a β-adrenergic receptor antagonist that blocks catecholamine-mediated activation of the sinus node (such as atenolol) and a centrally acting α2-adrenergic receptor agonist (such as clonidine) that decreases sympathetic outflow to the heart and may enhance vagally mediated cardiac slowing can occasionally cause marked bradycardia. In terms of risk of postural hypotension, the combination of an α1-adrenergic receptor antagonist (such as prazosin) with a drug like clonidine may impair the capacity of smooth muscle in veins to contract because of blockade of the α1-adrenergic receptors (prazosin) coupled with inhibition of sympathetic activation of these receptors (clonidine).
To summarize the very important issue of choice of initial therapy, it is worth noting that, in practice, there is no way to predict the response of a given individual to a given drug. Therefore, the physician chooses a candidate drug based on many considerations, including personal experience, drug cost, and coexisting disease, and submits it to an empirical trial starting at low doses. The anticipated adverse effects in the individual (both short- and long-term) are a far greater consideration, because all antihypertensive drugs used as monotherapy produce similar degrees of blood pressure reduction when directly compared in large populations.
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