The Pharmaceutical Journal Vol 262 No 7041 p547-551
April 17, 1999 Continuing education

DRUG INTERACTIONS THAT MATTER

(5)ANTIHYPERTENSIVES

By Heather Lucas, BPharm, MRPharmS

Other articles in this series include:
Antiarrhythmics (PJ, July 3, 1999, pp28-31)
Anticonvulsants (PJ, March 6, 1999, pp325-7)

In 1995, a survey carried out by the Office of Population Censuses and Surveys found that the prevalence of hypertension among adults in England was 22 per cent. Of this population, 14 per cent were receiving antihypertensive medication.¹ Although this survey was conducted some time ago, the situation is unlikely to have changed greatly. Therefore, given the large number of prescriptions issued for antihypertensive drugs, it is important that pharmacists understand and know how to manage interactions with other drugs. Additionally, drug interactions involving antihypertensive agents are of interest because:

• It is important that reductions in blood pressure are well controlled and, therefore, any interaction which may alter this situation is undesirable
• Adequate control of blood pressure may often require the use of more than one antihypertensive agent
• Hypertension may often coexist with other disease states requiring treatment with drugs that may interact with antihypertensives

The aim of this article is to discuss the management of clinically significant drug interactions that may occur with antihypertensive agents. Those discussed in the article are diuretics, beta-blockers, calcium channel blockers, drugs affecting the renin-angiotensin system, centrally-acting antihypertensives, alpha blockers and vasodilator antihypertensives.

INTERACTIONS WITH DRUGS THAT AFFECT BLOOD PRESSURE

Before moving on to discuss individual groups of drugs it is worth noting that any drug that affects blood pressure will interact pharmacodynamically with antihypertensive agents, ie, if it lowers blood pressure it will enhance the antihypertensive effect and if it raises blood pressure it will antagonise the effect.

Potentiation of the antihypertensive effect may or may not be considered desirable. When lowering of a patient’s blood pressure is not required, it may result in the patient feeling faint or dizzy or, if more profound, may result in cardiovascular collapse and renal failure.² Conversely, it is often the case that patients are deliberately prescribed another antihypertensive agent in order to lower their blood pressure to an acceptable level. It should be noted, however, that it is inadvisable to use some antihypertensive agents together and these combinations will be discussed under the individual drug group headings.
Where antagonism of the antihypertensive effect occurs, it follows that the preventative action of the antihypertensive agent against stroke, cardiovascular and renal disease will be reduced.
It is important that blood pressure is monitored regularly if drugs known to have an effect on blood pressure are given with antihypertensives. Panel 1 lists non-antihypertensive drugs that can affect blood pressure.

DIURETICS

Thiazides are the diuretics usually used to treat hypertension. They are either given alone or in combination with a potassium-sparing diuretic, to prevent hypokalaemia. Loop diuretics are less potent as antihypertensive agents but are indicated when there is concomitant cardiac or renal failure.

Mechanisms of diuretic drug interactions The significant interactions observed with diuretics are related to the adverse effects they may have on potassium, sodium, glucose and calcium levels in the blood. For example, diuretics may induce hypokalaemia, so caution should be exercised when using them in combination with drugs that are associated with prolongation of the QT interval on the electrocardiogram (ECG). If the QT interval is prolonged, this indicates that the time taken for ventricular repolarisation is lengthened, which may precipitate serious ventricular arrhythmias such as torsades de pointes.⁴ This interaction is discussed further in the case study (see p549).
Cautious use of diuretics is necessary with drugs that are also known to cause potassium loss, as hypokalaemia itself may result in muscle weakness and cardiac arrhythmias (Panel 2).²

Hypokalaemia can also increase the sensitivity of the myocardium to the action of digoxin, resulting in symptoms of digoxin toxicity.⁵ Therefore, if digoxin and diuretics are used concurrently, potassium levels must be monitored and corrected as appropriate.
Hyperkalaemia may result from concurrent use of potassium-sparing diuretics with drugs that also increase potassium levels (Panel 2). This combination must, therefore, be avoided as it may result in cardiac arrest.²
Diuretics, in particular the thiazides, have also been associated with hyponatraemia.⁶ This can cause nausea and vomiting, lethargy, confusion and, ultimately, convulsions.² The concurrent use of thiazides with carbamazepine or chlorpropamide, two other drugs known to cause hyponatraemia, has been reported to potentiate this effect on rare occasions.^7,8 Although the reported incidence of this interaction is low, pharmacists should be aware that it may occur.
Diuretic-induced sodium loss is also responsible for the well-documented interaction between diuretics and lithium. This results in increased plasma lithium concentrations, which may lead to lithium intoxication. Compensatory reabsorption of lithium in response to increased sodium excretion is thought to be the mechanism by which this rise in lithium levels occurs. Of the diuretics available, it is the thiazide diuretics that are most likely to cause this effect and, therefore, their concurrent use with lithium should be avoided. Lithium levels must be regularly monitored if other diuretics are used concomitantly.⁵
Non-steroidal anti-inflammatory drugs should be used with caution in patients taking thiazides as they cause sodium and water retention, which antagonises the diuretic effect.
Thiazide diuretics are also known to cause increases in blood sugar levels and to reduce excretion of calcium.³ Thus, they may antagonise the effect of hypoglycaemic medication and, in combination with large doses of vitamin D or calcium preparations, may cause hypercalcaemia.⁵ Although none of these drug combinations need be avoided, patients should have their glucose or calcium levels monitored.

BETA-BLOCKERS

Since the introduction of propranolol in 1965, many other beta-blockers have been developed. Differences exist between these drugs which may affect the choice of treatment of particular diseases or individual patients. However, the two properties that are the most important in determining the likelihood of drug interactions with beta-blockers are whether they are hepatically metabolised, ie, lipid soluble, and their selectivity for beta₁-receptors.

Mechanisms of beta-blocker interactions Both pharmacokinetic and pharmacodynamic drug interactions have been reported with beta-blockers. The pharmacokinetic interactions, which affect the metabolism of beta-blockers, are usually less clinically significant. This is because of wide inter-individual differences in steady state plasma concentrations and lack of an association between plasma concentration and therapeutic effect or toxicity.⁹ Hence, although a drug may inhibit or induce the metabolism of a beta-blocker via the cytochrome P450 isoenzyme system, resulting in significantly increased or decreased drug levels, the actual clinical effect may be small (Panel 3). Only those beta-blockers which are hepatically metabolised, such as propranolol, metoprolol and bisoprolol, are reported to be affected by pharmacokinetic drug interactions. The clinical effect of beta-blockers should be monitored if they are used concurrently with these drugs to ensure that the dose of the beta-blocker does not need to be adjusted.
Propranolol is also reported to inhibit the cytochrome P450 isoenzyme CYP2D6.¹¹ This results in the reduced metabolism of some drugs, such as lignocaine, chlorpromazine and thioridazine, which are also metabolised by this enzyme. Concurrent use should be monitored, as doses of the affected drugs may have to be reduced. Pharmacodynamic drug interactions involving beta-blockers may occur as a result of additive or antagonistic effects. For example, an additive negative inotropic effect is observed when beta-blockers are used with drugs that also have this action (Panel 4). The combination may result in bradycardia and myocardial depression.^5,6,10 Although this effect may be desirable in some circumstances, such as in the control of atrial fibrillation, the effect of concurrent use on heart rate should be regularly monitored.

It should be remembered that systemic absorption may follow topical application of beta-blockers to the eye.⁶ Therefore, there is a possibility that this additive negative inotropic action may also occur with ophthalmic preparations of beta-blockers.
Examples of antagonistic pharmacodynamic drug interactions with beta-blockers include their concurrent use with hypoglycaemics and with sympathomimetics.
Non-selective beta-blockers prevent the mobilisation of glucose from the liver in response to hypoglycaemia. All beta-blockers can also prevent the adrenaline-induced increase in heart rate which normally acts as a warning sign of hypoglycaemia. Generally, concurrent use of hypoglycaemic agents and beta-blockers is safe and severe hypoglycaemia is rare. However, the following should be noted:

• The selective beta-blockers, ie, those that preferentially block beta₁-receptors, are safest
• There is a greater risk of prolonged hypoglycaemia with insulin-controlled patients
• Patients taking beta-blockers and hypoglycaemics should be monitored and hypoglycaemic dose adjustments made, as necessary
• Patients should be counselled that some of the warning signs of hypoglycaemia, ie, tachycardia and tremor, may not occur^5,10

The administration of adrenaline to patients taking non-selective beta-blockers can result in severe hypertension and bradycardia. This occurs because beta-blockade allows the adrenaline to produce unopposed alpha vasoconstriction. The interaction may be life-threatening, depending on the dose of adrenaline administered. Hence, it is recommended that patients on non-selective beta-blockers should be administered adrenaline in reduced doses. There are also reports that patients who suffer an anaphylactic reaction when taking non-selective beta-blockers do not respond to the bronchodilatory effects of adrenaline. A less marked effect is likely with the cardioselective beta-blockers as they have a much smaller effect on beta₂-receptors in the blood vessels and lungs.⁹ The manufacturer of the Epipen (an autoinjector form of adrenaline) recommends that patients who are prescribed adrenaline for administration in the event of an anaphylactic reaction should not be prescribed non-selective beta-blockers.
It is generally considered that any increases in blood pressure observed when beta-blockers are administered with other sympathomimetics are clinically insignificant.⁵

CALCIUM CHANNEL BLOCKERS

Calcium channel blockers used for treating hypertension can be conveniently divided into two groups on the basis of their predominant site of action:

• Verapamil and diltiazem, which predominantly act on myocardial cells
• The dihydropyridines, eg, nifedipine and amlodipine, which predominantly act on the cells of vascular smooth muscle.

The two main differences between these groups that influence their drug interaction profiles are that verapamil and diltiazem possess negative inotropic activity and are inhibitors of the cytochrome P450 system CYP3A4,⁹ whereas the dihydropyridines have neither of these effects.

Mechanisms of calcium channel blocker interactions As a consequence of the negative inotropic activity of verapamil and diltiazem, additive interactions can occur with drugs which have a similar action, to produce bradycardia and myocardial depression (Panel 4). Verapamil exhibits greater negative inotropic activity than diltiazem⁶ and therefore the clinical effect of its concurrent use tends to be more severe.
It should be noted that when digoxin is used in combination with verapamil or diltiazem, a significant increase in digoxin levels may be observed, in addition to the combined negative inotropic effect. This appears to be caused by inhibition of the renal and biliary clearance of digoxin by the calcium channel blocker.⁵

Pharmacokinetic drug interactions also result from the ability of verapamil and diltiazem to inhibit the CYP3A4 enzyme system.^5,10 This results in reduced metabolism of a number of drugs (Panel 5). Therefore, when these drugs are used in combination with verapamil or diltiazem it is important to monitor for increased clinical effect and/or toxicity. Dihydropyridines have also been reported to increase blood concentrations of some beta-blockers. They are thought to do this by increasing their bioavailability, either by increasing liver blood flow or by reducing clearance.¹²

Although there are clinical differences between the calcium channel blockers, they are all hepatically metabolised.⁹ Hence, their metabolism and, potentially, their clinical effect may be reduced or increased by some inhibitors and inducers of the cytochrome P450 isoenzyme systems (Panel 6). It is important to monitor patients on these drug combinations as the dose of the calcium channel blocker may need to be adjusted. Alternatively, it may in some cases be possible to use a non-interacting drug.

DRUGS AFFECTING THE RENIN-ANGIOTENSIN SYSTEM

Drugs that affect the renin-angiotensin system include:

• Angiotensin-converting enzyme (ACE) inhibitors
• Angiotensin-II receptor antagonists

Mechanisms of ACE inhibitor and angiotensin-II receptor antagonist drug interactions Drug interactions involving this group of drugs primarily result from additive pharmacological effects. For example, concurrent use with any drug known to cause potassium retention (see Panel 2) may result in hyperkalaemia.⁶ Either use of the combination should be avoided or potassium levels should be checked regularly. Caution should also be exercised when using these drugs in patients with sodium depletion and hypovolaemia caused by diuretics. These patients are thought to be most at risk of developing acute hypotensive reactions and acute renal failure as a result of the combination.¹⁰ The hypoglycaemic effect of antidiabetic agents may, rarely, be enhanced by ACE-inhibitors.^5,10 Concurrent use need not be avoided but any hypoglycaemic episodes could be attributed to the combination. There are no reports of this occurring with angiotensin-II receptor antagonists.
In addition to pharmacodynamic interactions, this group of drugs has also been reported, in some patients, significantly to increase lithium concentrations.^13,14 The mechanism of this interaction is not fully understood but it may occur as a result of an increase in sodium excretion induced by a reduction in aldosterone secretion. This will cause increased reabsorption of lithium by the kidneys.¹³ Concurrent use of these drugs is not advised unless intensive lithium concentration monitoring is undertaken, as lithium intoxication can result.
Two reports of pharmacokinetic interactions involving chelation of the ACE-inhibitors captopril and fosinopril with antacids have also been published.⁵ They suggest that antacids may significantly reduce the absorption of these drugs. However, the clinical significance of these observations is not known, although the manufacturer of fosinopril recommends a two hour interval between doses of fosinopril and doses of antacids.

CENTRALLY ACTING ANTIHYPERTENSIVES

The drugs discussed under this heading are clonidine, methyldopa and moxonidine. Clonidine and methyldopa are now rarely initiated as standard therapy for hypertension; however, older patients may be maintained on them and methyldopa is often used for treating hypertension during pregnancy. Moxonidine tends to be used in resistant cases of hypertension.

Mechanisms of centrally acting antihypertensive drug interactionsIn common with all antihypertensive agents, these drugs may be antagonised or potentiated by drugs which affect blood pressure. Other than this, moxonidine is not reported to have any clinically significant drug interactions and the mechanisms of those reported with clonidine and methyldopa follow no pattern. For example, two clinically significant interactions reported with clonidine involve concurrent use with beta-blockers and concurrent use with tricyclic antidepressants. The mechanisms of the interactions are entirely different. The hypertension that may accompany rapid clonidine withdrawal is thought to result from increased catecholamine levels. If the patient is receiving a beta-blocker during withdrawal from clonidine, the beta-response of adrenaline (vasodilatation) would be blocked. This causes an exaggerated alpha-response (vasoconstriction) resulting in hypertension.^5,10 The tricyclic antidepressants reduce or abolish the effect of clonidine either by blocking its uptake into brain neurones or by desensitising alpha₂-receptors.^15,16
Drug interactions with methyldopa are also diverse and their mechanisms are often not understood. Reports include potentiation of the effects of levodopa when used with methyldopa. This has allowed reductions in levodopa dose and has enhanced control of Parkinson’s disease in some patients. The mechanism is not understood but may involve inhibition of peripheral levodopa destruction. There are also reports of worsening dyskinesias during concurrent use. This may be caused by the production of a false neurotransmitter from methyldopa, which opposes the effects of levodopa.^5,10 Reports of concurrent use with lithium have also been published.^5,10 These suggest that the combination should be avoided, as lithium toxicity can result. The mechanism is not understood.

ALPHA BLOCKERS

The alpha blockers used for hypertension - prazosin, doxazosin, terazosin and indoramin - are well documented as causing first dose hypotension.⁶ Therefore, although no specific drug interactions occur with this group of drugs, particular caution must be exercised when initiating them in patients taking other drugs known to lower blood pressure (see Panel 1).

VASODILATOR ANTIHYPERTENSIVES

Vasodilator antihypertensives include hydralazine, minoxidil and sodium nitroprusside. They are generally used for cases of resistant or severe hypertension.
No specific drug interactions exist but general guidance regarding concurrent use with drugs that affect blood pressure applies.

SUMMARY

It is important that pharmacists are aware of the clinically significant drug interactions reported with antihypertensive agents and know how to manage them. With this knowledge, pharmacists are well placed to ensure that patients do not receive drugs that may compromise their antihypertensive therapy or result in adverse effects.

ACKNOWLEDGMENTS I thank Dr Sarah Corlett (oncology pharmacist, Kent and Canterbury hospital) and Dr Paul Adams (drug information pharmacist, Gloucestershire Royal hospital) for their helpful comments on the content of this article.

Mrs Lucas is clinical services manager at Kent and Canterbury NHS Trust