Drug Safely 13 (6): 359-370. 1995 0114-591 6/95/001 2-0359/ 506.00/0
DRUG EXPERIENCE
© Adis International lim ited. All rights reserved.
P-Blockers Drug Interactions of Clinical Significance Ira Blaufarb, Tracy M. Pfeifer and William H. Frishman Division of Cardiology, Department of Medicine, The Albert Einstein College of Medicine, Bronx, New York, USA
Contents Summary . . . . . . . . . . .. .. .. . . .. . 1. Cardiovascular Drugs . . . . . . . . . . . . . . 1.1 Antihypertensive and Antianginal Drugs 1.2 Inotropic Agents . . . . 1.3 Antiarrhythmic Agents . 2. Noncardiovascular Drugs . 2.1. NSAIDs ...... . 2.2 Psychotropic Drugs . 2.3 Anti-Ulcer Medications. 2.4 Anaesthetic Agents .. 2.5 HMG-CoA Reductase Inhibitors. 2.6 Warfarin . . . . . . . . . . . . . . 2.7 Rifampicin (Rifampin), Cigarette Smoking and Alcohol (Ethanol) 2.8 Oral Hypoglycaemic Agents 3. Conclusion .... .... . . . . . . . . . . . . . . . . . . .... , ..
Summary
359 360 360 363 364 365 365 365 365 366 366 366 366 366 367
The clinician prescribing P-blockers for his or her patients is faced with an often difficult situation. There are many P-blockers, each with its own pharmacological profile. Patients are often taking multiple medications, thus increasing the risk of both anticipated and unexpected drug interactions. Reports of drug interactions are frequently anecdotal. The prescriber may not be aware of the patient's other medications or lifestyle habits. Pharmacokinetic and pharmacodynamic drug interactions involving P-blockers are documented in the literature, but these studies often examine small numbers of patients. For these reasons, it is difficult for the practitioner to distill guidelines for the administration of P-blockers in conjunction with other medication. In general, P-blockers are well tolerated, and symptomatic drug interactions are relatively infrequent. It is incumbent upon the clinical practitioner to have knowledge of his or her patient's drug profile and to be aware of the various drug interactions as well as each patient's unique pathophysiological profile when prescribing any medication, including P-blockers. p-Blockers may interact with a large number of commonly prescribed drugs, including antihypertensive and antianginal drugs, inotropic agents, antiarrhythmics, NSAIDs, psychotropic drugs, anti-ulcer medications, anaesthetics, HMG-CoA reductase inhibitors, warfarin, oral hypoglycaemics and rifampicin (rifampin).
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The wide diversity of diseases for which ~ blockers are employed raises the likelihood of their concurrent administration with other drugs. The list of commonly used drugs with which ~-blockers can interact is extensive (table I). Most of the reported interactions have been described with propranolol, the most comprehensively studied of the ~-blockers.
Drug interactions can be divided into 2 subgroupS.!I.3] The first are pharmacokinetic interactions, in which one drug can interfere with the absorption, protein binding, metabolism or excretion of the other drug. For example, there are drugs which can influence the first-pass metabolism of the lipid-soluble ~-blockers, metoprolol and propranolol.[4,5] The activity of the cytochrome P450 system in the liver can be enhanced by both alcohol (ethanol) consumption[6] and cigarette smoking;!?] this can increase the first-pass hepatic metabolism of orally ingested metoprolol and propranolol,[8.11] thereby decreasing ~-blocker bioavailability.!12] Accordingly, those ~-blockers which are predominantly excreted unchanged by the kidney (atenolol, nadolol and sotalol) would not be influenced by drug-induced changes in the hepatic cytochrome P450 system.l IO ,12] The second group of drug interactions are called pharmacodynamic interactions. These occur when the therapeutic or toxic effect of one drug is potentiated or enhanced by the pharmacological actions of another drug. An example would be the enhanced depression of both atrioventricular (AV) nodal conduction and left ventricular function when verapamil is coadministered with propranoloUI3] In this article the pharmacokinetic and pharmacodynamic interactions which include ~-blocking drugs will be reviewed.
1. Cardiovascular Drugs 1.1 Antihypertensive and Antianginal Drugs , . 1. 1 Nifedipine and Other Dihydropyridines
Nifedipine is a dihydropyridine calcium antagonist whose primary action is to cause both coronary and peripheral arterial vasodilatation. It does, © Adis International Limited. All rights reserved.
however, have some direct negative inotropic effects.[14] Nifedipine is often prescribed with a ~ blocker for treatment of patients with angina pectoriS[15,16] and/or hypertension.l 17] Occasional cases of severe hypotension and heart failure have been reported when nifedipine is used with either atenolol or propranolol[18] in patients with severe left ventricular dysfunction.[I9,20] Pharmacokinetic interactions occurring between nifedipine and the ~-blockers propranolol, metoprolol and atenolol have also been reported.!21] The most significant one discussed is the interaction between propranolol and nifedipine, in which the time to peak concentration of oral propranolol is decreased, and the peak serum concentration and bioavailability of propranolol is increased.[22] Similar effects have been observed with felodipine and nicardipine. Other investigators[23] found either no change or a 40% decrease in blood concentrations of propranolol when administered with nifedipine. The different outcomes observed in these trials could be explained by differences in hepatic blood flow which can often influence ~-blocker metabolism in the liver. ,. 1.2 Verapamil
Verapamil is a calcium channel antagonist with considerable negative chronotropic and inotropic actions which can have significant additive pharmacodynamic interactions with ~-blockade. There are reports of hypotension, haemodynamically significant bradycardia and heart failure, as well as haemodynamic collapse associated with the concurrent use of verapamil and ~-blockade.[24-27] Marked bradycardia has even been described in patients receiving timolol eye drops and oral verapamil. [28,29]
In terms of pharmacokinetic interactions, there are conflicting reports. Warrington et al.[30] reported no interaction of verapamil in combination with atenolol, metoprolol or propranolol. However, other investigators[31] have noted that blood concentrations of propranolol and metoprolol,[32] and the area under the plasma concentration-time curve (AUC) of atenolol are increased with the concurrent use of verapamiJ.l33] Propranolol decreased Drug Safety 13 (6) 1995
Drug Interactions with
~-Blockers
Table I. Drug interactions that may occur with Drug
361
~-blocking
drugs
Pharmacokinetic interactions
a-Blockers
Pharmacodynamic interactions
Precautions
Increased risk for first-dose hypotension
Use with caution
ACE inhibitors
None
Enhanced blood pressure effects and bronchospasm
Monitor response
Alcohol (ethanol)
Enhanced first-pass hepatic degradation
None
May need increased doses of lipid-soluble agents
None
Clinical efficacy rarely altered
Aluminum hydroxide gel Decreased ~-blocker absorption Aminophylline
Mutual inhibition
Amiodarone
Reduced hepatic clearance of metoprolol
Ampicillin
Impaired GI absorption leading to decreased ~-blocker bioavailability
Angiotensin II receptor blockers (Iosartan)
None
Antiarrhythmics (type I)
Propafenone and quinidine Disopyramide is a potent negative decrease clearance of lipid-soluble inotropic and chronotropic agent
Antidiabetics
Both enhanced and blunted responses seen
Calcium
Decreases ~-blocker absorption
Calcium antagonists
Decreased hepatic clearance of lipid-soluble and water-soluble ~-blockers ; decreased clearance of calcium antagonists
Potentiation of AV nodal negative inotropic and hypotensive responses
Avoid use if possible, although few patients show adverse effects
Cimetidine
Decreased hepatic clearance of lipid-soluble ~-blockers
None
Combination should be used with caution
Clonidine
None
Nonselective agents exacerbate clonidine withdrawal phenomenon
Use only ~, -selective agents or labetalol
Potentiation of bradycardiac and AV blocks
Observe patient's response; interactions may benefit angina patients with abnormal ventricular function
Epinephrine (adrenaline) None
Severe hypertension and bradycardia
Administer epinephrine cautiously; cardioselective ~-blocker may be safer
Ergot alkaloids
Severe hypertension and peripheral artery hyperperlusion have been seen, although ~-blockers are commonly coadministered
Observe patient'S response; few patients show adverse effects
Observe patient's response Enhanced negative inotropic and chronotropic effects
May need to increase ~-blocker dose Enhanced blood pressure effects and bronchospasm
~-blockers
Diazepam
Diazepam metabolism reduced
Digoxin
None
None
Use with caution
None
Monitor response Cautious co-prescription; use with sotalol can be dangerous because of additive effects on ECG QT interval Monitor for altered diabetic response May need to increase ~-blocker dose
Observe patient's response
Erythromycin
Reduced metabolism of ~-blockers May increase ~-blocker effect
Monitor clinical response
Glucagon
Enhanced clearance of lipid-soluble ~-blockers
Monitor for reduced response
None
Observe for impaired response to
Halofenate
~-blockade
Hydralazine
Decreased hepatic clearance of lipid-soluble ~-blockers
Enhanced hypotensive response
Cautious coadministration
Indomethacin and ibuprofen
None
Reduced efficacy in treatment of hypertension
Observe patient's response
Isoprenaline (isoproterenol)
None
Cancels pharmacological effect
Avoid concurrent use or choose selective 13,-blocker
© Adis International Limited. All rights reserved.
Continued over page
Drug Safety 13 (6) 1995
Blaufarb et al.
362
Table I. Contd Drug
Pharmacokinetic interactions
Levodopa
Pharmacodynamic interactions
Precautions
Antagonism of hypotensive and positive inotropic effects of levodopa Enhanced lidocaine toxicity
Monitor for altered response; interaction may have favourable results Combination should be used with caution ; use lower doses of lidocaine Monitor response; titrate dose to desired lipid levels Monitor for hypertensive episodes Manufacturer of propranolol considers concurrent use contraindicated
Lidocaine (lignocaine)
Decreased hepatic clearance of lidocaine by lipid-soluble
Lovastatin and pravastatin Methyldopa Monoamine oxidase inhibitors
20% decrease in AUC
None
Uncertain
Hypertension during stress Enhanced hypotension
Naproxen
None
None
Nitrates
None
Enhanced hypotension
Monitor response
Omeprazole
None
None
None
Phenobarbital (phenobarbitone) Phenothiazines
Increased hepatic metabolism of Additive hypotensive response
May need to increase lipid-soluble ~-blocker dose Monitor for altered response; especially with high doses of phenothiazine
~-blockers
~-blockers
Increased phenothiazine and blood concentrations
~-blocker
Phenylpropanolamine
Severe hypertensive reaction
Phenytoin
Additive ventricular depressive effects None
Avoid use, especially in hypertension controlled by both methyldopa and ~-blockers
Ranitidine Reserpine
Not marked
Rifampicin (rifampin)
Enhanced hepatic clearance of propranolol
Selective serotonin reuptake inhibitors Smoking
Decreased hepatic clearance of propranolol (enzyme inhibition) Enhanced first-pass metabolism
May increase ~-blocker effect (enhanced AV block) None
Sulindac Thyroxine
None Enhanced clearance of
None Reduced
Depression; possible enhanced sensitivity to ~-adrenergic blockade
~-blockers
Use with caution Observe response Monitor closely
May need to increase dose of propranolol
~-blocker
effect
Use with caution May need to increase dose of lipid-soluble ~-blockers Monitor clinical response to ~-blocker
Tricyclic antidepressants
Inhibits negative inotropic and chronotropic effects; enhanced hypotension Enhanced neuromuscular blockade
Tubocurarine
Wartarin
Decreased clearance of wartarin
None
Use cautiously with sotalol because of additive effects on ECG QT interval Observe response in surgical patients, especially after high doses of propranolol Monitor response
Abbreviation: AV =atrioventricular.
the AVC and the maximum plasma concentration (C max ) of verapamiI.l34] Again, differential blood flow patterns to the organs where drug clearance occurs may be responsible. © Adis International Limited. All rights reserved.
1. 1.3 Dilfiazem
In patients with coronary disease, the use of both diltiazem and propranolol have been associated with bradycardia, hypotension, high degree heart Drug Safety 13 (6) 1995
Drug Interactions with P-Blockers
block, and heart failure.[35] However, its use with most ~-blockers is generally well tolerated. Diltiazem decreases the clearance of propranolol and metoprolol by about 25%;[36] this does not occur with atenoloJ.l37] 1.1.4 ACE Inhibitors and Angiotensin /I Receptor Antagonists
When combined with a ~-blocker, ACE inhibitors can cause hypotension, especially in the setting of acute myocardial infarction. Additionally, the concomitant use of ~-blockers and captopril has been associated with increased bronchial hyperactivity,l38] an effect which should not be seen with angiotensin II receptor antagonists. However, the combination of ~-blockers and ACE inhibition is a well tolerated and efficacious therapy for patients with combined chronic left ventricular dysfunction and coronary artery disease. As a class of drugs, the ACE inhibitors and angiotensin II receptor blockers have not been associated with any pharmacokinetic interactions with ~-blockers.l39-41] 1. 1.5 Hydralazine
Hydralazine is a direct arterial vasodilator whose effect on afterload is attenuated by propranolol but not by atenoloLf 42 1In addition, the use ofhydralazine with propranolol or metoprolol can result in dramatically increased plasma concentrations of active P-blocker. [43,44] The mechanism for this phenomenon most likely involves the creation of a functional hepatic shunt.[45] The metabolism of aten0101 and of the long-acting preparation of propranolol is not affected by hydralazine. This is possibly related to renal clearance of atenolol, and in the case of slow release propranolol, to a slowed presentation of substrate to the liver.[46] 1.1.6 Clonidine
The nonselective P-blockers have a propensity to antagonise the actions of clonidine.l 47 ] In both animal and human studies, the addition of nonselective ~-blockers may attenuate the antihypertensive effect of clonidine,[48] and can exacerbate the clonidine withdrawal phenomenon.[49] Atenolol has not been found to do this. However, in cases of clonidine withdrawal, atenolol will also not prevent © Adis International Limited. All rights reserved.
363
rebound hypertension.[50] Labetalol, an (X- and Pblocking agent, can be useful in preventing and treating the clonidine withdrawal phenomenon.l 51 ] 1.1.7 Prazosin, Doxazosin and Terazosin
Prazosin, an (Xl-blocker, is a direct arterial vasodilator that can cause first-dose hypotension, and is associated with more prolonged episodes of firstdose hypotension in the presence of P-blockers.[52] Postural hypotension has been reported in a limited number of patients taking both P-blockers and terazosin or doxazosin. In general, both terazosin and doxazosin are well tolerated by patients taking P-blockers.[53-57] 1.1.S Reserpine
Reserpine was one of the first effective drugs used on a large scale in the treatment of hypertension. Reserpine can be used in the presence of a P-blocker with the following precautions. Firstly, reserpine, as well as the lipid-soluble P-blockers, have been associated with depression.[58] Secondly, the antihypertensive effect observed with the use of both P-blockade and reserpine may be severe. Thirdly, reserpine has been shown to upregulate Padrenergic receptors in the kidney,[59] and has been associated with supersensitivity in the heart to adrenergic agents unrelated to' a change in receptor affinity.l60] It is, therefore, possible that an upregulation in the number of p-receptors observed in the kidney is occurring in the heart and other tissues, which may enhance the sensitivity of patients pretreated with reserpine to the effects of ~-blockade. 1.1.9 Nitrates
Nitrates are vasodilators which decrease preload and afterload, and increase coronary blood flow. The potential for hypotension when used with intravenous or oral P-blockers does exist; however, their concomitant use is widespread and well tolerated. There are no reported pharmacokinetic interactions.l 61 ] 1.2 Inotropic Agents 1.2. 1 Epinephrine (Adrenaline)
The use of epinephrine (adrenaline) in the presence of P-blockade is not common since their Drug Safety 13 (6) 1995
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Blaufarb et al.
pharmacodynamic actions are opposite. Epinephrine increases the heart rate and blood pressure, while ~-blockade lowers the heart rate and blood pressure. Additionally, when a patient on long term oral therapy with a nonspecific ~-blocking agent is given epinephrine (possibly subcutaneously as part of local anaesthesia), uncontrolled hypertension may result as a consequence of unopposed (lreceptor stimulation by epinephrine)62] This phenomenon has been described with propranolol, but could occur with ~I-selective blockers as well.[62.63] 1.2.2 Glucagon
Glucagon increases hepatic blood flow, and results in increased clearance of propranolol.[64] It is one of the therapies used to treat overdose with propranolol and other ~-blockers.[65] 1.2.3 Isoprenaline (Isoproterenol) and Dobutamine ~-Blockers are competitive inhibitors of isoprenaline (isoproterenol) and dobutamine, and it would be unusual to ever combine them in clinical practice except for reversing ~-blocker overdose.[66] However, dobutamine is being used in stress echocardiography for diagnosing myocardial ischaemia in patients receiving ~-blockers. By lowering the peak cardiac workload and inotropic response during dobutamine stress echocardiography, ~ blockade has the potential to influence the sensitivity of this test.[67]
1.2.4 Digoxin
Digoxin is a sodium/potassium ATPase pump blocker which has negative chronotropic effects on AV nodal conduction, but whose inotropic effect is not blunted by the addition of ~-blockade.[68] Digoxin and ~-blockers can have additive inhibiting effects on AV node activity. 1.3 Antiarrhythmic Agents 1.3. 1 Disopyramide
Disopyramide is a type I antiarrhythmic agent with marked negative inotropic and chronotropic effects.[69] When both ~-blockers and disopyramide have been given together, severe bradycardia, asystole and heart failure have resulted.[69,70] Aten© Adis International Limited. All rights reserved.
0101 has been reported to decrease the clearance of disopyramide by about 15%, and to increase its plasma concentration slightly)71] Additionally, caution should be used if concomitant administration with sotalol is contemplated, as both drugs can prolong the QT interval and result in fatal arrhythmia.[72] 1.3.2 Propafenone
Propafenone is a type I antiarrhythmic agent with its own ~-blocking properties that can be additive to those of concomitant ~-blockade. In addition, propafenone decreases hepatic clearance of the lipidsoluble ~-blocking agents, resulting in increased plasma concentrations and clinical activity.P 3] The AUC of propafenone is increased by more than 200% by propranolol.[74] Sotalol should not be used with propafenone because of potential additive effects on the ECG QT intervaU 72 ] 1.3.3 Quinidine
Quinidine is a type I antiarrhythmic agent that has been noted to cause postural hypotension when prescribed with propranolol or atenolol.[75-77] Pharmacokinetic interactions have been reported. Quinidine reduces the metabolism of propranolol through inhibition of the 4-hydroxylation pathway, resulting in increased ~-blocker blood concentrations[77] and greater degrees of clinical ~-blockade.[78] Additionally, type I antiarrhythmic agents often prolong the QT interval, and sotalol should be coadministered only with great caution (if at all) as sotalol also prolongs the QT interval and has been associated with torsade de pointes.[72] 1.3.4 Amiodarone
Amiodarone is a type III antiarrhythmic agent with negative chronotropic properties. Some significant pharmacodynamic or pharmacokinetic interactions with ~-blockers have been describedP9] The negative chronotropic properties of amiodarone are additive to those seen with clinical ~ blockade)80] Sotalol should not be used with amiodarone because of potential additive effects on the ECG QT intervaJ.l72] Drug Safety 13 (6) 1995
Drug Interactions with
~-Blockers
7.3.5 Udocaine (Ugnocaine)
There are numerous reports of lidocaine (lignocaine) toxicity when this agent is co-prescribed with propranolol,l81-83) However, the data regarding some of the other ~-blockers are contradictory. Lysbo Svendsen et al,[83] reported no effect on the disposition of lidocaine in patients given metoprolol, atenolol or pindolol. Miners et al,[84] showed that healthy volunteers on oral preparations of either metoprolol or atenolol were able to metabolise a single intravenous dose of lidocaine normally. Deacon et al.,l85] however, reported varied degrees of inhibition of lidocaine clearance/metabolism. The mechanism is presumed to be the same as that for propranolol, which decreases hepatic blood flow by 25% and results in a 25% increase in lidocaine concentrations. [86] There is also evidence that propranolol and the other lipid-soluble agents alter systemic clearance by inhibiting lidocaine metabolism directly through the cytochrome P450 system.[82]
2. Noncardiovascular Drugs 2.1. NSAIDs
2. 7. 7 Indomethacin When administered alone, indomethacin can cause hypertension[87,88] as a result of reductions in the levels of vasodilator prostaglandins)89] When given with a variety of ~-blockers, this effect persisted.[89,90] In addition, when given with propranolol, heart rate reduction as well as efficacy in the treatment of premature ventricular contractions were reduced.[9I ,92) In animals, the mechanism for this effect might be a reduction in the number of ~-receptors found in the heart and presumably vascular smooth muscle .[92] 2. 7.2 Ibuprofen Ibuprofen may interfere with ~-blocker efficacy for the treatment of hypertension. 2.7.3 Sulindac, Naproxen and Aspirin
Sulindac, naproxen and aspirin, when administered in commonly prescribed dosages, do not interfere with the antihypertensive effects of either atenolol or propranolol. © Adis International Limited. All rights reserved.
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2,2 Psychotropic Drugs
2.2. 7 Diazepam and Oxazepam The lipid-soluble ~-blockers can inhibit the metabolism of diazepam, and result in increased blood concentrations of the drug and its active metabolites. The kinetics of oxazepam are not affected by concomitant ~-blockers.[93] 2.2.2 Phenothiazines
Steady-state propranolol blood concentrations are increased with concurrent chlorpromazine therapy. Chlorpromazine blood concentrations are also potentiated, which may explain the previous observations that ~-blockers are effective in schizophrenia.[94] 2.2.3 Antidepressant Drugs
Monoamine oxidase inhibitors and tricyclic antidepressants can both induce hypotension that can be aggravated by concomitant ~-blocker treatment. These antidepressants may also interfere with the hypotensive effects of ~-blockers because of their inhibitory effects on catecholamine reuptake.l 95 ] Since the new selective serotonin reuptake inhibitors (SSRIs) can interfere with the hepatic metabolism of propranolol, ~-blocker dosages should be adjusted as necessary in patients who are concomitantly taking SSRIs. 2,3 Anti-Ulcer Medications 2.3. 1 Cimetidine and Ranitidine
Cimetidine increases blood concentrations of the lipid-soluble ~-blocking agents by inhibiting hepatic drug metabolism)96] This has been clearly shown for propranolol, but the results for metoprolol are not conclusive)97,98) Atenolol clearance is not affected by the coadministration of cimetidine. Symptoms resulting from elevated ~-blocker concentrations are rare. There are no expected pharmacodynamic interactions, although the adverse effect profiles may be additive. For example, both medications can cause nightmares which may not be apparent when either drug is used alone, but occur when both drugs are used together. Ranitidine does not significantly alter oxidative metabolism by the liver, and does not affect the metabolism Drug Safety 13 (6) 1995
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of lipid-soluble P-blockers. However, there are some reports of pharmacokinetic interactions between metoprolol and ranitidine. [99, I00] 2.3.2 Omeprazole
There are no reported pharmacokinetic or pharmacodynamic interactions between P-blockers and omeprazole. 2.3.3 Aluminum Hydroxide
There are no expected pharmacodynamic interactions between aluminum hydroxide suspensions and P-blockade. However, there have been pharmacokinetic interactions. Aluminum hydroxide reduces the absorption of atenolol, resulting in a 20% reduction in plasma concentrationsJIOI] The data for propranolol are conflicting, with some investigators noting a decrease in absorption and others noting no effect.[102] In all, the change in absorption seen with atenolol, and possibly with propranolol, does not result in a decrease in clinical efficacy. 2.4 Anaesthetic Agents
/3-Blocking agents should be continued through surgery in patients who undergo general or local anaesthesiaJl03] Caution is recommended with the use of nonspecific /3-blockers when the use of uvasoconstrictor agents (either associated with local anaesthetics or for their pressor effect) are contemplated. Though hypovolaemia and hypoxia may occur with surgical procedures, patients on P-blockers tend to do as well as untreated patients. The principal reason for this appears to be that untreated patients who receive general anaesthesia have marked impairment of their sympathetic response, and patients receiving P-blockers often behave in a similar fashion, not an exaggerated one. There are certain anaesthetic agents, however, which should not be used with P-blockade; these include cyclopropane, diethylether, fluroxene, trichloroethylene, methoxyflurane and enflurane. Methoxyflurane and trichloroethylene can reduce myocardial contractilityJlO4] © Adis International Limited. All rights reserved.
Blaufarb et al.
2.5 HMG-CoA Reductase Inhibitors
The effects of these agents are not modified by the coadministration of P-blockersJI05] Pharmacokinetic interactions with propranolol result in a 20% decrease in the AUC of both lovastatin and pravastatin.[106] 2.6 Warfarin
Conflicting data regarding warfarin and Pblocker interactions exist. In rats, P-blockers inhibited warfarin metabolism by the liver.[l07] Mantero et aI)108] however, reported no interaction in humans. Both Bax et al.[l09,11O] and Scott et al.[lII] showed increases in warfarin concentrations when either ate nolo I or propranolol were concomitantly given. Bax et aLl I10] showed an effect of this rise on measured clotting (an increase in the prothrombin time), while Scott et aLl III] did not. Neilson and Seldon[l12] reported a case of severe haemorrhage brought about by the addition of propranolol in a patient on a previously stable warfarin dosage regimen. Overall, the addition of propranolol appears to reduce warfarin clearance, and when added to a patient on a stable anticoagulant regimen, prothrombin time should be carefully monitored. 2.7 Rifampicin (Rifampin). Cigarette Smoking and Alcohol (Ethanol)
The above compounds act as hepatic enzyme inducers and increase hepatic clearance of those /3-blockers that are metabolised by the liver. [I 13,114] This results in a decrease in the systemic bioavailability of lipid-soluble P-blockers. Atenolol, nadolol and sotalol, which are not metabolised by the liver, are largely not affected. 2.8 Oral Hypoglycaemic Agents
P-Blockers are well known for their ability to blunt the physiologic response to hypoglycaemia. In diabetic patients, this blunted response can be dangerous. Patients concomitantly taking P-blockers and hypoglycaemic agents should be closely monitored to ascertain the effects on serum glucose levels. Metformin, unlike the other oral hypoglycaeDrug Safety 13 (6) 1995
Drug Interactions with
~-Blockers
mic agents, is uncommonly associated with hypoglycaemia. However, the manufacturer does caution its concomitant use with ~-blockers in critically ill patients in whom lactic acidosis is a concern.
3. Conclusion With the growing number of cardiovascular and noncardiovascular drugs being used today, and our increasing knowledge and sophistication about the interactions between these medications, an in-depth knowledge of drug interactions becomes increasingly important when ~-blockers are prescribed to patients. New antihypertensive drugs such as the angiotensin II antagonists, new antidepressants such as selective serotonin reuptake inhibitors, new drugs used in the treatment of peptic ulcer disease or gastric emptying such as omeprazole and domperidone, and new drugs used in the treatment of diabetes such as metformin, will be used frequently with ~-blockers. The clinician should therefore be alert to the potential for new drug interactions involving ~-blocking drugs, and report them as soon as they are observed.
References I. Beeley L. Drug interactions and beta-blockers. BMJ 1984; 289: 1330-1 2. McDevitt D G. Drug interactions involving beta-ad renoreceptor blocking drugs. Cardiovasc Respir Dis Ther 1980; I: 21-41 3. Wood AJJ. Feely J. Pharmacokinetic drug interactions with propranolol. Clin Pharmacokinet 1983; 8: 253-62 4. Heagerty AM. Donovan MA. Castleden CM. et al. Influence of cimetidine on pharmacokinetics of propranolol. BMJ 1981 ; 282: 1917-9 5. Kirch W. Kohler H. Spahn H. et al. Interaction of cimetidine with metoprolol. propranolol or atenolol. lancet 1981; ii: 531-2 6. Kater RMH. Roggin G. Tobboon F. et al. Increased rate of clearance of drugs from the circulation of alcoholics. Am J Med Sci 1969;258: 35-9 7. Jusko WJ. Role of tobacco smoking in pharmacokinetics. J Pharmacokinet Biopharm 1978; 6: 7-39 8. Deanfield J. Wright C. Krikler S. et al. Cigarette smoking and the treatment of angina with propranolol. atenolol. and nifedipine. N Engl J Med 1984; 310 (15): 951-4 9. Walle T. Walle UK. Cowart TD. et al. Selective induction of propranolol metabolism by smoking: additional effects on renal clearance of metabolites. J Pharmacol Exp Ther 1987; 241: 928-33
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Correspondence and reprints: Dr William H. Frishman, Jack D. Weiler Hospital of the Albert Einstein College of Medicine/Montefiore Medical Center, 1825 Eastchester Road, Bronx, NY 10461, USA.
Drug Safety 13 (6) 1995
