Pharmacy Blog – Dr Vibore

An isolated report describes acute hyperkalaemia and cardiovascular collapse when dantrolene was given to a patient taking verapamil,but not when he was subsequently given nifedipine. Animal studies have found similar effects with combination of dantrolene and verapamil or diltiazem, but not with nifedipine oramlodipine.

Clinical evidence,mechanism, importance and management

A case report describes a 60-year-old man with insulin-dependent diabetes undergoing a right hemicolectomy. Due to inoperable coronary artery disease,which was causing angina pain he was taking verapamil 80mg three times daily. On morning of surgery he was given verapamil 80mg with his pre-operative sedation and then, 2 hrs later at start of surgery, he was given intravenous dantrolene 220mg over 30 minutes, because he was known to have previously had malignant hypertension. After surgery,when he was on ITU, it was found that his potassium had risen from 4.6 mmol/L before surgery to 6.1 mmol/L at end of surgery (about 90 minutes after dantrolene infusion). He was given 10 units of insulin,but an hour later his potassium was 7.1 mmol/L. He was given more insulin,but then developed metabolic acidosis and some cardiac depression, which resolved when he was given bicarbonate and hetastarch 5%. He received three further doses of dantrolene without incident (See reference number 1).

The authors of report attributed effects seen to an interaction between verapamil and dantrolene. They note that hyperkalaemia has been seen following dantrolene infusions, but case they cite was in response to suxamethonium, and UK and US manufacturers of dantrolene do not include hyperkalaemia as an adverse effect (See reference number 2,3). Nevertheless, overall picture is that hyperkalaemia, of whatever cause, can apparently increase myocardial depression caused by verapamil (See reference number 4,5). This case seems to be only report of an interaction between verapamil, and several factors do not make this a clear-cut case of an interaction. However,hyperkalaemia and cardiovascular collapse have been seen in pigs and dogs given dantrolene and verapamil,(See reference number 6-8) and so an interaction cannot be completely ruled out. The manufacturers of dantrolene contraindicate its use in patients taking verapamil (See reference number 2,3). One animal study suggests that diltiazem may interact similarly,(See reference number 9) and combination of diltiazem and dantrolene may also cause ventricular arrhythmias (See reference number 10). The manufacturers of diltiazem similarly contraindicate concurrent use (See reference number 10). Studies suggest that amlodipine(See reference number 4) and nifedipine(See reference number 9) do not interact and they may therefore be safer alternatives. In case above(See reference number 1) patient later underwent further surgery while taking nifedipine, without any significant adverse effect (although potassium was moderately raised to 5.4 mmol/L).

Rubin AS,Zablocki AD. Hyperkalemia, verapamil, and dantrolene. Anesthesiology (1987)66, 246–9.

Dantrium Intravenous (Dantrolene sodium). Procter & Gamble Pharmaceuticals UK Ltd. UKSummary of product characteristics,April 2005.

Dantrium Intravenous (Dantrolene sodium). Procter & Gamble Pharmaceuticals. US Prescribing information,May 2001.

Freysz M,Timour Q, Bernaud C, Bertrix L, Faucon G. Cardiac implications of amlodipinedantrolene combinations. Can J Anaesth (1996) 43, 50–5.

Jolly SR,Keaton N, Movahed A, Rose GC, Reeves WC. Effect of hyperkalemia on experimental myocardial depression by verapamil. Am Heart J (1991) 121, 517–23.

Lynch C,Durbin CG, Fisher NA, Veselis RA, Althaus JS. Effects of dantrolene and verapamil on atrioventricular conduction and cardiovascular performance in dogs. Anesth Analg (1986) 65, 252–8.3954091

San Juan AC,Port JD, Wong KC. Hyperkalemia after dantrolene administration in dogs. Anesth Analg (1986) 65, S131.

Saltzman LS,Kates RA, Corke BC, Norfleet EA, Heath KR. Hyperkalemia and cardiovascular collapse after verapamil and dantrolene administration in swine. Anesth Analg (1984) 63, 473–8.

Saltzman LS,Kates RA, Norfleet EA, Corke BC, Heath KS. Hemodynamic interactions ofdiltiazem-dantrolene and nifedipine and nifedipine-dantrolene. Anesthesiology (1984) 61, A11.

Tildiem Retard (Diltiazem hydrochloride). Sanofi-Aventis. UK Summary of product characteristics,April 2004.

Chenodeoxycholic acid and ursodeoxycholic acid reduce bioavailability of nitrendipine

Clinical evidence,mechanism, importance and management

In a single-dose study,6 healthy subjects were given nitrendipine 10mg with or without either chenodeoxycholic acid 200mg or 600 mg, or ursodeoxycholic acid 50 mg. Ursodeoxycholic acid reduced peak plasma level and AUC of nitrendipine by 54 % and 75%, respectively. Chenodeoxycholic acid 200mg decreased peak plasma level and AUC of nitrendipine by about 20%, but 600mg dose reduced peak plasma level and AUC of nitrendipine by 54 % and 68%, respectively. The reduction in bioavailability of nitrendipine was possibly due to effects of bile acids on tablet disintegration or more probably on drug solubilisation. The clinical importance of interaction is not known (See reference number 1).

1. Sasaki M,Maeda A, Sakamoto K-I, Fujimura A. Effect of bile acids on absorption of nitrendipine in healthy subjects. Br J Clin Pharmacol (2001) 52, 699–701.

Calcium-channel blockers in current clinical usage affect slow L-type channel. They are usually classified by their chemical structure, which determines their selectivity for vascular smooth muscle over myocardium, and hence their potential to slow heart rate (negative inotropic activity) see table 1 below,(below). Interactions due to additive inotropic effects will therefore apply only to benzothiazepine (diltiazem) and phenylalkylamine-type (verapamil) calcium-channel blockers, and usually not to dihydropyridine-type (e.g. nifedipine) calcium-channel blockers. All three types of calcium-channel blocker will have additive hypotensive effects with other drugs with blood-pressure lowering activity.

Calcium-channel blockers also undergo interactions due to altered metabolism. Both verapamil and diltiazem are principally metabolised by cytochrome P450 isoenzyme CYP3A4, and also inhibit this enzyme (see table 2 below,). They are therefore affected by drugs that induce or inhibit CYP3A4,and also themselves interact with drugs metabolised by CYP3A4.

Many of dihydropyridine-type calcium-channel blockers are also metabolised by CYP3A4, and are affected by inducers or inhibitors of this isoenzyme. However,they do not generally inhibit CYP3A4, or other isoenzymes to a clinically relevant extent. The exception is perhaps nicardipine,which may cause a clinically relevant inhibition of CYP3A4 (see table 2 below,).

This section is primarily concerned with those interactions where activity of calcium-channel blockers is changed by presence of another drug. Where calcium-channel blocker is affecting agent, relevant monograph is usually categorised under heading of affected drug.

Mibefradil is a calcium-channel blocker that acts on fast T-type calcium channel. It was thought that practical problems of implementing all warnings relating to these interactions were too difficult and risky

Amlodipine,Barnidipine, Benidipine, Felodipine, Isradipine, Lacidipine, Lercanidipine, Manidipine, Nicardipine, Nifedipine, Nilvadipine, Nimodipine,† Nisoldipine, Nitrendipine

Gallopamil,Verapamil

†Nimodipine crosses blood-brain barrier and therefore affects cerebral blood vessels, and is used for cerebral ischaemia.

Table 1 Classification of calcium-channel blockers that act on slow L-type channels
Class	Rate limiting?	Effect on AV or SA node	Examples
Dihydropyridine	No	Little or none	Amlodipine, Barnidipine, Benidipine, Felodipine, Isradipine, Lacidipine, Lercanidipine, Manidipine, Nicardipine, Nifedipine, Nilvadipine, Nimodipine,† Nisoldipine, Nitrendipine
Benzothiazepine	Yes	Depression (negative inotropic activity)	Diltiazem
Phenylalkylamine	Yes	Depression (negative inotropic activity)	Gallopamil, Verapamil

Table 2 Drugs affecting or metabolised by isoenzyme CYP3A4		the cytochrome P450
Inhibitors	Aprepitant Azoles Itraconazole Ketoconazole Voriconazole Cimetidine Delavirdine Diltiazem Grapefruit juice Imatinib	Macrolides Clarithromycin Erythromycin Troleandomycin Nefazodone Nicardipine Protease inhibitors SSRIs Fluoxetine Verapamil

Table 3 Drugs affecting or metabolised by isoenzyme CYP3A4		the cytochrome P450
Inhibitors	Aprepitant Azoles Itraconazole Ketoconazole Voriconazole Cimetidine Delavirdine Diltiazem Grapefruit juice Imatinib	Macrolides Clarithromycin Erythromycin Troleandomycin Nefazodone Nicardipine Protease inhibitors SSRIs Fluoxetine Verapamil

There is evidence that most NSAIDs can increase blood pressurein patients treated with antihypertensives, although some studieshave not found increase to be clinically relevant. In varioussmall studies, indometacin appeared not to reduce hypotensive effects of amlodipine, felodipine, nicardipine, nimodipine orverapamil, but it did in one of two studies with nifedipine, and onestudy with nitrendipine. Similarly, ibuprofen caused a small reduction in antihypertensive effects of amlodipine. Diclofenacand sulindac appear not to interact with nifedipine,nor ibuprofen, naproxen, piroxicam or sulindac with verapamil, nor naproxen with nicardipine. Low-dose aspirin did not alter theantihypertensive effect of felodipine or nifedipine in one study,and long-term aspirin did not alter cardiovascular benefits ofnitrendipine in another. Diclofenac reduces verapamil serum levels and raises those of isradipine,but these changes are probablyunimportant. Two reports describe abnormal bruising and prolonged bleedingtimes in two patients and one healthy subject taking verapamilwith aspirin. There are conflicting reports as to whether or notgastrointestinal bleeding is increased by giving NSAIDs with calcium-channel blockers.

Various large epidemiological studies and meta-analyses of clinical trials have been conducted to assess effect of NSAIDs on blood pressure in patients treated with antihypertensives, and findings of these are summarised in table 1 below,(below). In these studies, NSAIDs were not always associated with an increase in blood pressure, and maximum increase was 6.2 mmHg. The effect has been shown for both COX-2 inhibitors and non-selective NSAIDs. In two meta-analyses,(See reference number 1,2) effects were evaluated by NSAID. The confidence intervals for all NSAIDs overlapped, showing that there was no statistically significant difference between NSAIDs, with exception of comparison between indometacin and sulindac in one analysis (See reference number 2). Nevertheless, an attempt was made at ranking NSAIDs based on means. In one analysis,(See reference number 1) effect was greatest for piroxicam, indometacin, and ibuprofen, intermediate for naproxen, and least for sulindac and flurbiprofen. In other meta-analysis,(See reference number 2) effect was greatest for indometacin and naproxen, intermediate for piroxicam, and least for ibuprofen and sulindac. An attempt was also made to evaluate effect by antihypertensive in one analysis (See reference number 1). The mean effect was greatest for beta blockers,intermediate for vasodilators (includes ACE inhibitors and calcium-channel blockers), and least for diuretics. However, differences between groups were not significant.

The findings of individual clinical and pharmacological studies that have studied effects of aspirin or specific NSAIDs on specific calcium-channel blockers are outlined in subsections below

Felodipine. In Hypertension Optimal Treatment (HOT) study, 18 790 treated hypertensive patients, about 82 % of whom received a calcium-channel blocker, usually felodipine alone or in combination, were also given either aspirin 75mg daily or placebo for an average of 3.8 years. It was found that long-term low-dose aspirin does not interfere with blood pressure-lowering effects of antihypertensive drugs studied (See reference number 3).

Nifedipine. In a small study in 18 patients, low-dose aspirin 100mg daily for 2 weeks did not alter blood pressure lowering effect of nifedipine 30 to 60mg daily, given as a modified-release preparation (See reference number 4).

Nitrendipine. A post-hoc analysis of Syst-Eur trial of nitrendipinebased antihypertensive treatment found no difference in cardiovascular outcome between 861 patients who were also using long-term aspirin (700 patients) and/or other NSAIDs (161) and 2882 patients who had never taken aspirin or NSAIDs. Patients in this trial were randomised to receive nitrendipine,which could be combined or replaced by enalapril, hydrochlorothiazide, or both (See reference number 5).

Unnamed calcium-channel blockers. In a randomised study, use of low-dose aspirin 100mg daily for 3 months did not alter blood pressure control in patients taking calcium-channel blockers or ACE inhibitors, when compared with placebo (See reference number 6).

Hypertensive subjects taking slow-release verapamil 240mg daily had a 26 % reduction in AUC of verapamil when they took diclofenac 75mg twice daily (See reference number 7). The AUC of isradipine 5mg twice daily for a week was unaffected in 18 healthy subjects by a single 50mg dose of diclofenac but maximum serum levels were raised by about 20%

2 Summary of epidemiological studies and meta-analyses of effect of NSAIDs on blood pressure in patients taking antihypertensive drugs

Other NSAID or celecoxib therapy not associated with difficulty in controlling blood pressure,but rofecoxib was (odds ratio 1.38).

antagonised all antihypertensives,but only beta blockers

Among

NSAIDs, only effect of piroxicam was statistically

significant, with piroxicam, indometacin and ibuprofen causing greatest increase, and sulindac and flurbiprofen least.

Hydrochlorothiazide,

furosemide,methyldopa, propranolol

significant) in those on NSAIDs,but DBP did not differ. Findings same if indometacin users removed.

NSAID use was associated with a 29 % increased risk of hypertension in those on antihypertensives,but not in those not on antihypertensives.

mmHg,naproxen 3.7,piroxicam 0.5,decrease in mean arterial pressure with ibuprofen 0.8,sulindac 0.16. The difference between indometacin and sulindac was statistically significant.

Sheridan R,Montgomery AA, Fahey T. NSAID use and BP in treated hypertensives: a retrospective controlled observational study. J Hum Hypertens (2005) 19,445–50.

Wolfe F,Zhao S, Pettitt D. Blood pressure destabilization and edema among 8538 users of celecoxib,rofecoxib, and nonselective nonsteroidal antiinflammatory drugs (NSAID) and nonusers of NSAID receiving ordinary clinical care. J Rheumatol (2004) 31,1143–51.

Johnson AG,Nguyen TV, Day RO. Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis. Ann Intern Med (1994) 121,289–300.

Chrischilles EA,Wallace RB. Nonsteroidal anti-inflammatory drugs and blood pressure in an elderly population. J Gerontol (1993) 48,M91–M96.

Johnson AG,Simons LA, Simons J, Friedlander Y, McCallum J. Non-steroidal anti-inflammatory drugs and hypertension in elderly: a community-based cross-sectional study. Br J Clin Pharmacol (1993) 35,455–9.

Pope JE,Anderson JJ, Felson DT. A meta-analysis of effects of nonsteroidal anti-inflammatory drugs on blood pressure. Arch Intern Med (1993) 153,477–84.

was unaffected and pharmacokinetics of diclofenac were unchanged (See reference number 8)

A study in elderly women with hypertension found that diclofenac sodium 25mg three times daily for one week had no effect on control of their blood pressure with nifedipine (See reference number 9)

Fifty-three hypertensive patients had no changes in their blood pressure control with verapamil 240 or 480mg daily when they also took ibuprofen 400mg three times daily for 3 weeks (See reference number 10). However, another study in 12 patients with mild or moderate essential hypertension controlled with amlodipine 10mg daily, found that ibuprofen 400mg three times daily for 3 days increased mean blood pressure by 7.8/3.9 mmHg (See reference number 11).

Indometacin 100mg daily for a week did not significantly affect hypotensive effects of nifedipine 20mg twice daily in 10 patients with mild to moderate essential hypertension (See reference number 12). In contrast, in another study, indometacin 100mg in divided doses over 24 hrs was found to raise mean arterial pressure by 17 to 20 mmHg in 5 out of 8 hypertensive patients taking nifedipine 15 to 40mg daily (See reference number 13).

Five other studies, two in healthy subjects(See reference number 14,15)and 3 in patients with hypertension(See reference number 16-18)found that indometacin did not alter blood pressure-lowering effects of amlodipine,(See reference number 18)felodipine,(See reference number 14,16)nicardipine(See reference number 15) or verapamil (See reference number 17). Similarly, haemodynamic effects of nimodipine 30mg three times daily were not affected to a clinically relevant extent by indometacin 25mg twice daily in 24 healthy elderly subjects, although AUC of nimodipine and its maximum plasma levels were slightly increased (See reference number 19). However,indometacin 25mg three times daily raised systolic and diastolic blood pressure by a mean of 4 mmHg in 15 patients taking nitrendipine 5 to 20mg twice daily (See reference number 20).

Naproxen 375mg twice daily had no effect on pharmacokinetics of verapamil in hypertensive subjects (See reference number 7)

A placebo-controlled study in 100 patients taking nicardipine 30mg three times daily found that naproxen 375mg twice daily caused no clinically relevant changes in control of their blood pressure (See reference number 21)

A study in hypertensive patients given up to 440mg of verapamil daily found that piroxicam 20mg once daily for 4 weeks did not significantly alter antihypertensive effects of verapamil (See reference number 22)

A study in elderly women with hypertension found that sulindac 100mg three times daily for one week had no effect on control of their blood pressure with nifedipine (See reference number 9)

A study in hypertensive patients given up to 440mg of verapamil daily found that sulindac 200mg twice daily for 4 weeks did not significantly alter antihypertensive effects of verapamil (See reference number 22)

The bruising ceased when verapamil was stopped

4.5 minutes while she was taking verapamil,and to 9 minutes while she was taking verapamil and aspirin. A healthy subject taking same dose of verapamil and aspirin observed appearance of new petechiae and her bleeding time rose from a normal 4.5 minutes to more than 15 minutes in presence of both drugs (See reference number 23). An 85-year-old man taking enteric-coated aspirin 325mg daily developed widespread and serious ecchymoses of his arms and legs and a retroperitoneal bleed about 3 weeks after starting verapamil 240mg daily (See reference number 24).

A prospective cohort study(See reference number 25)in 1636 elderly hypertensive patients and a case-control study(See reference number 26) found that calcium-channel blockers were associated with an increased risk of gastrointestinal bleeding compared with beta blockers; in one of studies, verapamil had highest rate of bleeding, followed by diltiazem and nifedipine (See reference number 25). Two studies indicated that gastrointestinal bleeding was not increased by calcium-channel blockers (See reference number 27,28). A post-hoc analysis of Syst-Eur data found that there was no interaction between chronic NSAID intake (81% aspirin) and antihypertensive therapy based on nitrendipine in terms of incidence of gastrointestinal bleeding. Further, results suggested that chronic NSAID therapy tended to be associated with a lower incidence of bleeding in patients taking nitrendipine-based therapy than those on placebo (See reference number 5).

There is some evidence that NSAIDs may increase blood pressure in patients treated with antihypertensives. Possible explanations for this include inhibition of vasodilator and natriuretic prostaglandins in kidney and/or a decrease in vascular or endothelial prostaglandin synthesis resulting in salt retention and vasoconstriction (See reference number 29). In contrast, low-dose aspirin appears not to affect blood pressure-lowering effects of calcium-channel blocker-based antihypertensive therapy (See reference number 3).

The prolonged bleeding times noted with verapamil(See reference number 23)are probably a result of inhibition of platelet aggregation, because calcium-channel blockers interfere with movement of calcium ions through cell membranes, which can affect platelet function. This appears to be additive with effects of other antiplatelet drugs. It was suggested that vasodilation produced by calcium-channel blockers in conjunction with inhibition of platelet aggregation may increase risk of bleeding, or at least prevent normal vasoconstrictive response to bleeding,(See reference number 25) although a protective effect of beta blockers rather than an adverse effect of calcium-channel blockers may also be reason (See reference number 27).

Although several studies exist, evidence for an interaction between calcium-channel blockers and NSAIDs or aspirin is still somewhat inconclusive. Some consider that use of NSAIDs should be kept to a minimum in patients on antihypertensives. The effects may be greater in elderly and in those with blood pressures that are relatively high, as well as in those with high salt intake (See reference number 30). However, others consider that clinical importance of an interaction between NSAIDs and antihypertensives is less than has previously been suggested (See reference number 31). While their findings do not rule out a 2/1 mmHg increase in blood pressure with NSAIDs in treated hypertensives,they suggest that if patients in primary care have inadequate control of blood pressure, other reasons may be more likely than any effect of concurrent NSAIDs (See reference number 31). There is insufficient data at present to clearly differentiate between NSAIDs. Further study is needed.

There is some limited evidence that interaction of NSAIDs with calcium-channel blockers is less than with ACE inhibitors (See reference number 4,16,18)

For effects of NSAIDs on other antihypertensive drug classes see ACE inhibitors, , beta blockers, and thiazide diuretics, .

Johnson AG,Nguyen TV, Day RO. Do nonsteroidal anti-inflammatory drugs affect bloodpressure? A meta-analysis. Ann Intern Med (1994) 121, 289–300.

Pope JE,Anderson JJ, Felson DT. A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure. Arch Intern Med (1993) 153, 477–84.

Zanchetti A,Hansson L, Leonetti G, Rahn K-H, Ruilope L, Warnold I, Wedel H. Low-doseaspirin does not interfere with the blood pressure-lowering effects of antihypertensive therapy. J Hypertens (2002) 20, 1015–22.

Polónia J,Boaventura I, Gama G, Camões I, Bernardo F, Andrade P, Nunes JP, Brandão F, Cerqueira-Gomes M. Influence of non-steroidal anti-inflammatory drugs on renal functionand 24 h ambulatory blood pressure-reducing effects of enalapril and nifedipine gastrointestinal therapeutic system in hypertensive patients. J Hypertens (1995) 13, 925–31.

Celis H,Thijs L, Staessen JA, Birkenhäger WH, Bulpitt CJ, de Leeuw PW, Leonetti G, Nachev C, Tuomilehto J, Fagard RH for the Syst-Eur investigators. Interaction between nonsteroidal anti-inflammatory drug intake and calcium-channel blocker-based antihypertensivetreatment in the Syst-Eur trial. J Hum Hypertens (2001) 15, 613–18.

Avanzini F,Palumbo G, Alli C, Roncaglioni MC, Ronchi E, Cristofari M, Capra A, Rossi S,Nosotti L, Costantini C, Pietrofeso R. Collaborative Group of the Primary Prevention Progect(PPP)–Hypertension study. Effects of low-dose aspirin on clinic and ambulatory blood pressure in treated hypertensive patients. Am J Hypertens (2000) 13, 611–16.

Peterson C,Basch C, Cohen A. Differential effects of naproxen and diclofenac on verapamilpharmacokinetics. Clin Pharmacol Ther (1990) 49, 129.

Sommers DK,Kovarik JM, Meyer EC, van Wyk M, Snyman JR, Blom M, Ott S, Grass P,Kutz K. Effects of diclofenac on isradipine pharmacokinetics and platelet aggregation in volunteers. Eur J Clin Pharmacol (1993) 44, 391–3.

Takeuchi K,Abe K, Yasujima M, Sato M, Tanno M, Sato K, Yoshinaga K. No adverse effectof non-steroidal anti-inflammatory drugs, sulindac and diclofenac sodium, on blood pressurecontrol with a calcium antagonist, nifedipine, in elderly hypertensive patients. Tohoku J ExpMed (1991) 165, 201–8.

Houston MC,Weir M, Gray J, Ginsberg D, Szeto C, Kaihlenen PM, Sugimoto D, Runde M,Lefkowitz M. The effects of nonsteroidal anti-inflammatory drugs on blood pressures of patients with hypertension controlled by verapamil. Arch Intern Med (1995) 155, 1049–54.

Minuz P,Pancera P, Ribul M, Priante F, Degan M, Campedelli A, Arosio E, Lechi A. Amlodipine and haemodynamic effects of cyclo-oxygenase inhibition. Br J Clin Pharmacol (1995) 39, 45–50.

Salvetti A,Pedrinelli R, Magagna A, Stornello M, Scapellato L. Calcium antagonists: interactions in hypertension. Am J Nephrol (1986) 6 (Suppl 1), 95–99.

Thatte UM,Shah SJ, Dalvi SS, Suraokar S, Temulkar P, Anklesaria P, Kshirsagar NA. Acutedrug interaction between indomethacin and nifedipine in hypertensive patients. J Assoc Physicians India (1988) 36, 695–8.

Hardy BG,Bartle WR, Myers M, Bailey DG, Edgar B. Effect of indomethacin on the pharmacokinetics and pharmacodynamics of felodipine. Br J Clin Pharmacol (1988) 26, 557–62.

Debbas NMG,Raoof NT, Al Qassab HK, Jackson SHD, Turner P. Does indomethacin antagonise the effects of nicardipine? Acta Pharmacol Toxicol (Copenh) (1986) 59 (Suppl V), 181.

Morgan T,Anderson A. Interaction of indomethacin with felodipine and enalapril. J Hyper-tens (1993) 11 (Suppl 5), S338–S339.

Perreault MM,Foster RT, Lebel M, Du Souich P, Larochelle P, Cusson JR. Pharmacodynamic effects of indomethacin in essential hypertensive patients treated with verapamil. Clin Invest Med (1993) 16 (Suppl 4), B17.

Morgan TO,Anderson A, Bertram D. Effect of indomethacin on blood pressure in elderlypeople with essential hypertension well controlled on amlodipine or enalapril. Am J Hyper-tens (2000), 13, 1161–7.

Mück W,Heine PR, Schmage N, Niklaus H, Horkulak J, Breuel H-P. Steady-state pharmacokinetics of nimodipine during chronic administration of indometacin in elderly healthy volunteers. Arzneimittelforschung (1995) 45, 460–2.

Harvey PJ,Wing LM, Beilby J, Ramsay A, Tonkin AL, Goh SH, Russell AE, Bune AJ,Chalmers JP. Effect of indomethacin on blood pressure control during treatment with nitrendipine. Blood Pressure (1995) 4, 307–12.

Klassen DK,Jane LH, Young DY, Peterson CA. Assessment of blood pressure duringnaproxen therapy in hypertensive patients treated with nicardipine. Am J Hypertens (1995) 8, 146–53.

Baez MA,Alvarez CR, Weidler DJ. Effects of the non-steroidal anti-inflammatory drugs,piroxicam or sulindac, on the antihypertensive actions of propranolol and verapamil. J Hypertens (1987) 5 (Suppl 5) S563–S566.

Ring ME,Martin GV, Fenster PE. Clinically significant antiplatelet effects of calcium-channel blockers. J Clin Pharmacol (1986) 26, 719–20.

Verzino E,Kaplan B, Ashley JV, Burdette M. Verapamil–aspirin interaction. Ann Pharmacother (1994) 28, 536–7.

Pahor M,Guralnik JM, Furberg CD, Carbonin P, Havlik RJ. Risk of gastrointestinal haemorrhage with calcium antagonists in hypertensive persons over 67 years old. Lancet (1996) 347, 1061–5.

Kaplan RC,Heckbert SR, Koepsell TD, Rosendaal FR, Psaty BM. Use of calcium channelblockers and risk of hospitalized gastrointestinal tract bleeding. Arch Intern Med (2000) 160, 1849–55.

Suissa S,Bourgault C, Barkun A, Sheehy O, Ernst P. Antihypertensive drugs and the risk ofgastrointestinal bleeding. Am J Med (1998) 105, 230–5.

Kelly JP,Laszlo A, Kaufman DW, Sundstrom A, Shapiro S. Major upper gastrointestinalbleeding and the use of calcium channel blockers. Lancet (1999) 353, 559.

Beilin LJ. Non-steroidal anti-inflammatory drugs and antihypertensive drug therapy. J Hypertens (2002) 20,849–50.

Johnson AG. NSAIDs and blood pressure. Clinical importance for older patients. Drugs Aging (1998) 12,17–27.

Sheridan R,Montgomery AA, Fahey T. NSAID use and BP in treated hypertensives: a retrospective controlled observational study. J Hum Hypertens (2005) 19, 445–50.

Table 1 Summary of epidemiological studies and meta-analyses of the effect of NSAIDs on blood pressure in patients taking antihypertensive drugs
Study type	Patients	Antihypertensives	NSAIDs	Findings	Refs
Case-control (2005)	184 cases 762 controls (UK primary care)	Not stated. Median of 2 different drugs.	Ibuprofen (78 cases) Diclofenac (60) Other (25)	BP control in treated hypertensives was not affected by use of NSAIDs. No evidence that either SBP or DBP differed according to type of NSAID.	1
Retrospective analysis (2004)	8538 patients with rheumatic disease and hypertension	Not stated	NSAID (1164 patients) Celecoxib (654) Rofecoxib (417)	Other NSAID or celecoxib therapy not associated with difficulty in controlling blood pressure, but rofecoxib was (odds ratio 1.38).	2
Meta-analysis	50 randomised	Beta blockers (15)	Indometacin (33 trials)	NSAIDs elevated mean supine BP by 5 mmHg. NSAIDs	3
(1994)	controlled trials in 771	Vasodilators (18)	Sulindac (7)	antagonised all antihypertensives, but only beta blockers
	patients or healthy	Diuretics (12)	Ibuprofen (5)	was statistically significant (6.2 mmHg). Among the
	subjects		Piroxicam (4)	NSAIDs, only the effect of piroxicam was statistically
			Flurbiprofen (4)	significant, with piroxicam, indometacin and ibuprofen causing the greatest increase, and sulindac and flurbiprofen the least.
Case-control	133 cases	Hydrochlorothiazide,	Ibuprofen (30% of	SBP was about 5 mmHg higher (not statistically	4
(1993)	133 controls	furosemide, methyldopa, propranolol	cases) Indometacin (22%) Naproxen (18%) Sulindac (13%)	significant) in those on NSAIDs, but DBP did not differ. Findings the same if indometacin users removed.
Cross-sectional cohort (1993)	2800 elderly (12% on both an NSAID and antihypertensives)	Not stated	Not stated	NSAID use was associated with a 29 % increased risk of hypertension in those on antihypertensives, but not in those not on antihypertensives.	5
Meta-analysis	54 studies with 108	Not stated	Indometacin (600	Increase in mean arterial pressure with indometacin 3.6	6
(1993)	NSAID treatment arms in 1213 hypertensive patients		patients) Naproxen (72) Piroxicam (51) Ibuprofen (55) Sulindac (277)	mmHg, naproxen 3.7, piroxicam 0.5, decrease in mean arterial pressure with ibuprofen 0.8, sulindac 0.16. The difference between indometacin and sulindac was statistically significant.

Morphine may moderately raise serum levels of esmolol, butthis is unlikely to be clinically important. The fatal doses of morphine and propranolol are markedly reduced by concurrent usein animals, but clinical relevance of this in man is uncertain.

Clinical evidence,mechanism, importance and management

In a study in 10 healthy men a 3mg injection of morphine sulfate increased steady-state levels of a 300 microgram/kg per minute infusion of esmolol, given over 4 hours. However, increases were only statistically significant in 2 of subjects (increase of 46%), and were considered to be of no clinical importance. The pharmacokinetics of morphine were unchanged (See reference number 1).

Studies in animals have shown that median fatal dose of propranolol was reduced two to sevenfold by morphine in mice(See reference number 2) and median lethal dose of morphine was reduced fifteen to sixteenfold by propranolol in rats.(See reference number 3) The same interaction has also been seen in dogs (See reference number 3). There do not appear to be any published reports of synergistic toxicity involving morphine and propranolol, so clinical relevance of this is uncertain.

Lowenthal DT,Porter RS, Saris SD, Bies CM, Slegowski MB, Staudacher A. Clinical pharmacology, pharmacodynamics and interactions with esmolol. Am J Cardiol (1985) 56, 14F–18F.

Murmann W,Almirante L, Saccani-Guelfi M. Effects of hexobarbitone, ether, morphine, andurethane upon the acute toxicity of propranolol and D-(-)-INPEA. J Pharm Pharmacol (1966) 18, 692–4.

Davis WM,Hatoum NS. Possible toxic interaction of propranolol and narcotic analgesics.Drug Intell Clin Pharm (1981) 15, 290–1.

Itraconazole markedly increased bioavailability of celiprololand only slightly affected pharmacokinetics of atenolol, without affecting heart rate or blood pressure These interactions arenot expected to be clinically relevant.

Clinical evidence,mechanism, importance and management

In a study in 10 healthy subjects itraconazole 200mg twice daily for 5 doses had only minor effects on pharmacokinetics of a single 50mg dose of atenolol and no effects on heart rate or blood pressure were seen (See reference number 1)

In a study in 12 healthy subjects itraconazole 200mg twice daily for 5 doses increased AUC of a single 100mg dose of celiprolol by 80%, without increasing half-life. However, itraconazole did not increase effect of celiprolol on heart rate or blood pressure (See reference number 2).

It was suggested that itraconazole probably increases absorption of celiprolol by inhibiting P-glycoprotein in intestinal wall (See reference number 2)

Although increase in plasma levels was marked, it was suggested that it is unlikely to be clinically relevant because celiprolol has a wide therapeutic range (See reference number 2).

Lilja JJ,Backman JT, Neuvonen PJ. Effect of itraconazole on the pharmacokinetics of atenolol.Basic Clin Pharmacol Toxicol (2005) 97, 395–8.

Lilja JJ,Backman JT, Laitila J, Luurila H, Neuvonen PJ. Itraconazole increases but grapefruitjuice greatly decreases plasma concentrations of celiprolol. Clin Pharmacol Ther (2003) 73, 192–8.

Clinical evidence,mechanism, importance and management

In a study 36 patients with mild hypertension were given either propranolol 80mg daily or fish oil 9 g daily (as capsules and equivalent to eicosapentaenoic acid 1.8 g and docosahexaenoic acid 1.1 g daily) for 36 weeks followed by placebo for 4 weeks. A further group of 16 patients were given propranolol 80mg daily for 12 weeks,propranolol plus fish oil 9 g daily for 12 weeks, propranolol plus fish oil placebo for 12 weeks, and finally propranolol placebo for 4 weeks. Fish oil alone decreased blood pressure to a similar extent to propranolol, and decreases in blood pressure with combination were greater than with either propranolol or fish oil alone (See reference number 1). A further similar study in 14 patients taking a beta blocker found that when they were also given 4 capsules of Omacor (equivalent to eicosapentaenoic acid 1.9 g and docosahexaenoic acid 1.5 g) daily for 6 weeks their blood pressure decreased by a further 3.3/1.9 mmHg (See reference number 2).

The mechanism is uncertain, but as fish oil seems to have a hypotensive effect of its own, it may enhance hypotensive effect of any beta blocker.

Singer P,Melzer S, Goschel M, Augustin S. Fish oil amplifies the effect of propranolol in mildessential hypertension. Hypertension (1990) 16, 682–91.

Lungershausen YK,Abbey M, Nestel PJ, Howe PRC. Reduction of blood pressure and plasmatriglycerides by omega-3 fatty acids in treated hypertensives. J Hypertens (1994) 12, 1041–5.

Although both colestyramine and colestipol can moderately reduce absorption of propranolol, this does not seem to reduceits effects. Colesevelam does not appear to affect absorption ofmetoprolol.

5 g did not cause a clinically relevant alteration in plasma levels of sustained-release metoprolol 100mg (See reference number 1)

When 6 healthy subjects took a single 120mg dose of propranolol with a 10-g dose of colestipol peak plasma propranolol levels were raised by 30%. However, if an additional 10 g dose of colestipol was taken 12 hrs before propranolol peak plasma levels were decreased by 36 % and AUC was reduced by about 30%. No changes in blood pressure or pulse rates were seen (See reference number 2).

When 6 healthy subjects took a single 120mg dose of propranolol with an 8-g dose of colestyramine peak propranolol plasma levels were reduced by almost 25 % and AUC was reduced by 13%. An additional dose of colestyramine 12 hrs before propranolol reduced AUC by 43%. However,no changes in blood pressure or pulse rate were seen (See reference number 2). Preliminary results of another study found that colestyramine (single unstated dose) caused no significant changes in blood levels of propranolol in 5 patients with type II hyperlipidaemia taking propranolol 40mg four times daily (See reference number 3).

Uncertain. It seems probable that both colestyramine and colestipol can bind to propranolol in gut, thereby reducing its absorption.

Information is limited. Even though both colestyramine and colestipol can apparently reduce absorption of a single dose of propranolol, no changes in its effects were reported,(See reference number 2) suggesting that interaction is of minimal clinical importance. There is therefore no obvious reason for avoiding concurrent use. However,note that it is usually recommended that other drugs are given 1 hour before or 4 to 6 hrs after colestyramine, and 1 hour before or 4 hrs after colestipol.

Donovan JM,Stypinski D, Stiles MR, Olson TA, Burke SK. Drug interactions with colesevelam hydrochloride, a novel, potent lipid-lowering agent. Cardiovasc Drugs Ther (2000) 14, 681–90.

Hibbard DM,Peters JR, Hunninghake DB. Effects of cholestyramine and colestipol on theplasma concentrations of propranolol. Br J Clin Pharmacol (1984) 18, 337–42.

Schwartz DE,Schaeffer E, Brewer HB, Franciosa JA. Bioavailability of propranolol followingadministration of cholestyramine. Clin Pharmacol Ther (1982) 31, 268.

Hydroxychloroquine and possibly chloroquine may increase theblood levels of metoprolol,but this is probably not clinically important.

Clinical evidence,mechanism, importance and management

Hydroxychloroquine 400mg daily for 8 days increased AUC and peak plasma levels of a single 100mg dose of metoprolol by 65 % and 72%, respectively, in 7 healthy subjects who were of extensive CYP2D6 metaboliser phenotype,(See reference number 1)see Genetic factors, . Hydroxychloroquine may inhibit metabolism of metoprolol by cytochrome P450 isoenzyme CYP2D6. The clinical significance of this interaction is unknown, but changes of this size in AUC of beta blockers have proved not to be clinically important. Other beta blockers that are extensively metabolised (see table 1 below,.) may behave like metoprolol, but those that are excreted unchanged in urine would not be expected to interact. In vitro study suggests that chloroquine may interact with metoprolol in same way as hydroxychloroquine (See reference number 2). More study is needed.

Somer M,Kallio J, Pesonen U, Pyykkö K, Huupponen R, Scheinin M. Influence of hydroxychloroquine on the bioavailability of oral metoprolol. Br J Clin Pharmacol (2000) 49, 549–54.

Lancaster DL,Adio RA, Tai KK, Simooya OO, Broadhead GD, Tucker GT, Lennard MS. Inhibition of metoprolol metabolism by chloroquine and other antimalarial drugs. J Pharm Pharmacol (1990) 42, 267–71.

The adrenoceptors of sympathetic nervous system are of two maintypes, namely alpha and beta. Drugs that block beta adrenoceptors(better known as beta blockers) are therapeutically exploited to reduce,for example, normal sympathetic stimulation of heart. The activityof heart in response to stress and exercise is reduced, its consumptionof oxygen is diminished, and in this way exercise-induced angina can bemanaged. Beta blockers given orally can also be used in managementof cardiac arrhythmias, hypertension, myocardial infarction, and heartfailure. They may also be used for some symptoms of anxiety and for migraine prophylaxis. Some beta blockers are used in form of eye dropsfor glaucoma and ocular hypertension.

Not all beta receptors are identical but can be further subdivided into twogroups,beta1 and beta2. The former are found in heart and latter in bronchi. Since one of unwanted adverse effects of generalised betablockade can be loss of normal noradrenaline-stimulated bronchodilation (leading to bronchospasm), cardioselective beta1-blockingdrugs (e.g. atenolol,metoprolol) were developed, which have less effecton beta2 receptors. However, it should be emphasised that selectivityis not absolute because bronchospasm can still occur with these drugs, particularly at high doses. table 1 below,(below) includes an indication of thecardioselectivity of commonly used systemic beta blockers. Some betablockers also have alpha1-blocking activity,which causes vasodilatation, and this is also indicated in table 1 below,(below). Some beta blockers,such as celiprolol and nebivolol,also have vasodilator activity but producethis by mechanisms other than blocking alpha1 receptors. Other betablockers also possess intrinsic sympathomimetic activity in that they canactivate beta receptors and are therefore partial agonists. Sotalol has additional class III antiarrhythmic activity,and therefore it has a range of interactions not shared by most other beta blockers.

Beta blockers may be lipophilic drugs (such as metoprolol) or hydrophilic (such as atenolol). The lipophilic beta blockers are more likelyto be involved in pharmacokinetic interactions than hydrophilic drugs.Many of lipophilic beta blockers are principally metabolised by cytochrome P450 isoenzyme CYP2D6 (see table 1 below’,(below)), anddrugs that are inhibitors or inducers of this isoenzyme (see table 4 below,) increase or decrease their levels. Propranolol is also metabolised inpart by CYP1A2 (see ‘Beta blockers + SSRIs).

This section is generally concerned with those drugs that affect activity of beta blockers. Where beta blocker is affecting drug, theinteraction is dealt with elsewhere.

Rapidly metabolised to an active metabolite after which about 50 % is excreted by liver and 50 % excreted in urine

Largely excreted unchanged in urine

50% hepatic metabolism and 50 % excreted unchanged in urine

Primarily metabolised by CYP2D6,although other isoenzymes do contribute.

Mostly excreted unchanged (only 1-3% metabolised) with 50 % excreted in bile and 50 % excreted in urine

Conjugated in liver

Largely excreted unchanged in urine

Extensively metabolised by liver

30 to 40 % excreted unchanged in urine, rest excreted by liver and kidney as inactive metabolites.

Largely excreted unchanged in urine

Mostly metabolised by liver, with some involvement from CYP2D6. 20 % excreted unchanged. Timolol and metabolites renally excreted.

Table 4 Drugs affecting or metabcytochrome P450 isoenzymes		olised by the CY	P2 family of
Isoenzyme	Inhibitors	Inducers	Substrates
CYP2B6	Thiotepa	Phenobarbital Phenytoin	Cyclophosphamide Ifosfamide
CYP2C8	Gemfibrozil Rifampicin Trimethoprim		Pioglitazone Repaglinide Rosiglitazone
CYP2C9	Amiodarone Azoles Fluconazole Miconazole Voriconazole Fluvastatin SSRIs Fluoxetine Fluvoxamine Sulfinpyrazone Ticlopidine Zafirlukast	Aprepitant Rifampicin	Irbesartan Losartan Nateglinide NSAIDs Celecoxib Diclofenac Etoricoxib Valdecoxib Phenytoin Statins Fluvastatin Rosuvastatin Sulphonylureas Glibenclamide Gliclazide Glimepiride Glipizide Tolbutamide* S-Warfarin*