Pharmacy Blog – Dr Vibore

Clinical evidence,mechanism, importance and management

A woman who had previously had bilateral lumbar sympathectomy for Raynaud’s disease developed total urinary incontinence when given methyldopa 500mg to 1.5 g with phenoxybenzamine 12.5mg daily,but not when she was taking either drug alone. This would seem to be outcome of additive effects of sympathectomy and two drugs on sympathetic control of bladder sphincters (See reference number 1). Stress incontinence has previously been described with these drugs. The general importance of this interaction is probably small.

1. Fernandez PG,Sahni S, Galway BA, Granter S, McDonald J. Urinary incontinence due to interaction of phenoxybenzamine and :5.5pt; font-weight:normal; color:#000000″>α-methyldopa. Can Med Assoc J (1981) 124, 174.

Grapefruit juice inhibits metabolism of ivabradine

Clinical evidence,mechanism, importance and management

Grapefruit juice increases exposure to ivabradine exposure twofold. This interaction probably occur because grapefruit inhibits cytochrome P450 isoenzyme CYP3A4 in intestine, by which ivabradine is metabolised. This leads to increased levels, which increases risks of adverse effects such as profound bradycardia The manufacturers recommend that intake of grapefruit juice by patients also taking ivabradine is restricted (See reference number 1). However, note that they contraindicate use of other drugs that increase ivabradine levels by a similar amount, and so it would seem that concurrent use is best avoided.

1. Procoralan (Ivabradine hydrochloride) Servier Laboratories Ltd. UK Summary of productcharacteristics,March 2007.

Clinical evidence,mechanism, importance and management

Ten patients with a low probability of coronary artery disease underwent dobutamine echocardiography. Five were given dobutamine alone, while other 5 were given a low intravenous dose of dipyridamole with maximal dose of dobutamine, to see whether sensitivity of test could be improved. Four of patients given both drugs experienced severe hypotension while no hypotension was seen in control group. The conclusion was reached that this combination of drugs can be hazardous and should not be used in patients suspected of coronary heart disease (See reference number 1). Note that,although both of these drugs are commonly used in stress echocardiography, they are not given together.

1. Shaheen J,Rosenmann D, Tzivoni D. Severe hypotension induced by combination of dobutamine and dipyridamole. Isr J Med Sci (1996) 32, 1105–7.

The effects of adrenaline (epinephrine), noradrenaline (norepinephrine) and other directly-acting sympathomimetics are slightlyincreased in presence of reserpine.

Pretreatment with phenylephrine 10 % eye drops caused a blood pressure increase of 30/12 mmHg in 11 patients taking reserpine,whereas no significant increase in blood pressure occurred in 176 patients who were given phenylephrine eye drops and who were not taking reserpine (See reference number 1). After 7 healthy subjects took reserpine 0.25 to 1mg daily for 2 weeks increase in blood pressure response to noradrenaline (norepinephrine) was increased by 20 to 40 % (See reference number 2). A man taking reserpine who became hypotensive while undergoing surgery failed to respond to an intravenous injection of ephedrine, but did so after 30 minutes treatment with noradrenaline, presumably because stores of noradrenaline at adrenergic neurones had become replenished (See reference number 3). The mydriatic effects of ephedrine have also been shown to be antagonised by pretreatment with reserpine (See reference number 4). However,in contrast, one report claimed that ephedrine 25mg given orally or intramuscularly, once or twice daily, proved to be an effective treatment for re-serpine-induced hypotension and bradycardia in schizophrenic patients (See reference number 5).

Studies in dogs have demonstrated that adrenaline (epinephrine),noradrenaline (norepinephrine) and phenylephrine (all sympathomimetics with direct actions) remain effective vasopressors after treatment with reserpine, and their actions are enhanced to some extent (See reference number 6-8). Metaraminol has also been successfully used to raise blood pressure in reserpine-treated patients (See reference number 9).

The rauwolfia alkaloids (e.g. reserpine) cause adrenergic neurones to lose their stores of noradrenaline (norepinephrine),so that they can no longer stimulate adrenergic receptors and transmission ceases. Indirectly-acting sympathomimetics, which work by stimulating release of stored noradrenaline, may therefore be expected to become ineffective. In contrast, effects of directly-acting sympathomimetics should remain unchanged. However, their effects may be enhanced (as described above) because when receptors are deprived of stimulation by noradrenaline for any length of time they can become supersensitive. Drugs with mixed direct and indirect actions, such as ephedrine, should fall somewhere between two, although reports cited seem to indicate that ephedrine has predominantly indirect activity (See reference number 3,4).

These are established interactions, but paucity of clinical information suggests that in practice they do not present many problems, perhaps because effects of these vasopressors are so closely monitored, and titrated to effect. If a pressor drug is required,a directly-acting drug such as noradrenaline (norepinephrine) or phenylephrine may be expected to be effective. The receptors may show some supersensitivity so that a dosage reduction may be required. table 1 below, gives a classification of sympathomimetics.

Kim JM,Stevenson CE, Mathewson HS. Hypertensive reactions to phenylephrine eyedrops inpatients with sympathetic denervation. Am J Ophthalmol (1978) 85, 862–8.

Abboud FM,Eckstein JW. Effects of small oral doses of reserpine on vascular responses totyramine and norepinephrine in man. Circulation (1964) 29, 219–23.

Ziegler CH,Lovette JB. Operative complications after therapy with reserpine and reserpinecompounds. JAMA (1961) 176, 916–19.

Sneddon JM,Turner P. Ephedrine mydriasis in hypertension and the response to treatment.Clin Pharmacol Ther (1969) 10, 64–71.

Noce RH,Williams DB, Rapaport W. Reserpine (Serpasil) in the management of the mentallyill. JAMA (1955) 158, 11–15.

Stone CA,Ross CA, Wenger HC, Ludden CT, Blessing JA, Totaro JA, Porter CC. Effect of :5.5pt; font-weight:normal; color:#000000″>αmethyl-3,4-dihydroxyphenylalanine (methyldopa), reserpine and related agents on some vascular responses in the dog. J Pharmacol Exp Ther (1962) 136, 80–8.

Eger EI,Hamilton WK. The effect of reserpine on the action of various vasopressors. Anesthesiology (1959) 20, 641–5.

Moore JI,Moran NC. Cardiac contractile force responses to ephedrine and other sympathomimetic amines in dogs after pretreatment with reserpine. J Pharmacol Exp Ther (1962) 136, 89–

96.

9. Smessaert AA,Hicks RG. Problems caused by rauwolfia drugs during anesthesia and surgery.N Y State J Med (1961) 61, 2399–2403.

Table 1 A categorisation of some sympathomimetic drugs
Drug	Receptors stimulated
Direct stimulators of alpha and beta receptors
Adrenaline (Epinephrine)	Beta more marked than alpha
Mainly direct stimulators of alpha receptors
Phenylephrine	Predominantly alpha
Metaraminol	Predominantly alpha
Methoxamine	Predominantly alpha
Noradrenaline (Norepinephrine)	Predominantly alpha
Mainly direct stimulators of beta-1 receptors
Dobutamine	Predominantly beta-1, some beta-2 and alpha
Dopamine	Predominantly beta-1, some alpha
Direct stimulators of beta-1 and beta-2 receptors (beta-agonist bronchodilators)
Bambuterol	Predominantly beta-2
Fenoterol	Predominantly beta-2
Formoterol	Predominantly beta-2
Isoetharine	Predominantly beta-2
Isoprenaline (Isoproterenol)	Beta-1 and beta-2
Orciprenaline	Predominantly beta-2
Pirbuterol	Predominantly beta-2
Reproterol	Predominantly beta-2
Rimiterol	Predominantly beta-2
Ritodrine	Predominantly beta-2
Salbutamol (Albuterol)	Predominantly beta-2
Salmeterol	Predominantly beta-2
Terbutaline	Predominantly beta-2
Tulobuterol	Predominantly beta-2
Direct and indirect stimulators of alpha and beta receptors
Ephedrine	Alpha and beta
Etefedrine	Alpha and beta
Phenylpropanolamine	Alpha and beta
Pseudoephedrine	Alpha and beta
Mainly indirect stimulators of alpha and beta receptors
Amfetamine (Amphetamine)	Alpha and beta – also central stimulant
Mephentermine	Alpha and beta – also central stimulant
Methylphenidate	Alpha and beta – also central stimulant
Tyramine	Alpha and beta

Oral indometacin abolished hypotensive effects of intravenous hydralazine in one study, but no effect was found in another.In patients with pulmonary hypertension, intravenous indometacin reduced effects of intravenous hydralazine, and in patients with hypertension, intravenous diclofenac reduced theeffects of intravenous dihydralazine.

Clinical evidence,mechanism, importance and management

In 9 healthy subjects, oral indometacin 50mg every 6 hrs for 4 doses abolished hypotensive response to intravenous hydralazine 150 micrograms/kg, and subjects only responded when given another dose of hydralazine 30 minutes later (See reference number 1). A study in 7 patients with pulmonary hypertension given indometacin 50mg and hydralazine 350 micrograms/kg, both intravenously, either alone, or concurrently, also found that effects of hydralazine (reduction in systemic arterial pressure, heart rate, cardiac index) were reduced by indometacin (See reference number 2). In contrast,another study in 9 healthy subjects(See reference number 3) found that oral indometacin 25mg four times daily for 2.5 days did not affect hypotensive response to a single 200-microgram/kg intravenous dose of hydralazine.

Thus it is not clear if indometacin interacts with intravenous hydralazine,and it is uncertain if an interaction occurs when hydralazine is given orally.

On other hand, a single-dose study in 4 hypertensive subjects found that actions of intravenous dihydralazine (effects on blood pressure, urinary excretion, heart rate and sodium clearance) were reduced by intra

NSAIDs can cause increases in blood pressure due to their effects on sodium and water retention. Various NSAIDs have been reported to reduce efficacy of other antihypertensive drug classes, for example see ACE inhibitors + NSAIDs interaction. It would therefore be prudent to monitor concurrent use of hydralazine and NSAIDs.

Cinquegrani MP,Liang C-S. Indomethacin attenuates the hypotensive action of hydralazine.Clin Pharmacol Ther (1986) 39, 564–70.

Adnot S,Defouilloy C, Brun-Buisson C, Piquet J, De Cremoux H, Lemaire F. Effects of indomethacin on pulmonary hemodynamics and gas exchange in patients with pulmonary arteryhypertension, interference with hydralazine. Am Rev Respir Dis (1987) 136, 1343–9.

Jackson SHD,Pickles H. Indomethacin does not attenuate the effects of hydralazine in normalsubjects. Eur J Clin Pharmacol (1983) 25, 303–5.

Reimann IW,Ratge D, Wisser H, Fröhlich JC. Are prostaglandins involved in the antihypertensive effect of dihydralazine? Clin Sci (1981) 61, 319S–321S.

The effect of sublingual glyceryl trinitrate was not altered by pretreatment with nifedipine in two studies. Nifedipine and intravenous glyceryl trinitrate had additive vasodilator effects in onestudy, but preliminary results of another study found that patients undergoing coronary artery bypass surgery and takingnifedipine 20mg twice daily required more intravenous glyceryltrinitrate than those taking nifedipine 10mg twice daily or thosenot taking nifedipine.

Clinical evidence,mechanism, importance and management

In 9 patients with stable chronic angina,there was no significant haemodynamic interaction between sublingual glyceryl trinitrate and a single-dose of nifedipine, or nifedipine three times daily for 5 days (See reference number 1). In another study in healthy subjects, venodilatory effect of sublingual glyceryl trinitrate was not altered by pretreatment with nifedipine 10mg (See reference number 2). No special precautions are required during concurrent use.

In 7 patients with severe congestive heart failure,a single-dose of oral nifedipine increased stroke volume, with a peak effect at 30 minutes. The addition of intravenous glyceryl trinitrate at 2 hrs further increased stroke volume and increased cardiac index (See reference number 3). Therefore addition of glyceryl trinitrate enhanced vasodilator action of nifedipine. Conversely, in preliminary findings of a comparative study of 3 groups of patients undergoing coronary bypass graft surgery, those taking nifedipine 20mg twice daily needed initial doses of intravenous glyceryl trinitrate (to reduce cardiac workload, maintain graft patency and control blood pressure) that were about 40 % higher than those in other 2 groups; one taking nifedipine 10mg twice daily for hypertension, and other a control group of normotensive patients. Moreover, these higher doses had little effect on initial mean systolic blood pressure of half of group taking nifedipine 20mg twice daily, and they needed an additional infusion of nitroprusside (See reference number 4). It was suggested that since glyceryl trinitrate is converted to nitric oxide to elicit its vasodilator effect, it is possible that nifedipine inhibits enzymic production of nitrous oxide. This appears to be only study to suggest a negative interaction, and clinical relevance of its findings is unclear. Note that this study was non-randomised, and there may have been other important differences between patients in each group that would account for effects seen.

Boje KM,Fung H-L, Yoshitomi K, Parker JO. Haemodynamic effects of combined oral nifedipine and sublingual nitroglycerin in patients with chronic stable angina. Eur J Clin Pharmacol (1987) 33, 349–54.

Gascho JA,Apollo WP. Effects of nifedipine on the venodilatory response to nitroglycerin. Am J Cardiol (1990) 65, 99–102.

Kubo SH,Fox SC, Prida XE, Cody RJ. Combined hemodynamic effects of nifedipine and nitroglycerin in congestive heart failure. Am Heart J (1985) 110, 1032–4.

Key BJ,Wilkes MP, Keen M. Reduced responsiveness to glyceryl trinitrate following antihypertensive treatment with nifedipine in man. Br J Clin Pharmacol (1993) 36, 499P.

An isolated case report suggests that hypotensive effects of therapid infusion of vancomycin may occur more readily in thosewho are already vasodilated with nifedipine, but it seems likelythat effects seen were due to rapid infusion alone.

Clinical evidence,mechanism, importance and management

A man with severe systemic sclerosis was hospitalised for Raynaud’s phenomenon and dental extraction. After being started on nifedipine 40mg daily,he was given intravenous vancomycin 1 g in 200 mL of dextrose 5 % over 30 minutes. After 20 minutes he experienced a severe headache and was found to have a marked macular erythema on upper trunk, head, neck and arms. His blood pressure fell to 100/60 mmHg and his pulse rate was 90 bpm. He recovered spontaneously (See reference number 1). The authors of report acknowledge possibility of red-man syndrome caused by vancomycin, and suggest that it may occur more readily in those already vasodilated with nifedipine. However, given that this is an isolated report, and vancomycin was given over 3 times faster than recommended rate, it seems likely that this is purely an adverse effect of vancomycin.

1. Daly BM,Sharkey I. Nifedipine and vancomycin-associated red man syndrome. Drug Intell Clin Pharm (1986) 20, 986.

Combined oral contraceptives are associated with increasedblood pressure and may antagonise efficacy of antihypertensive drugs. However, effects are far greater with high-dosecontraceptives that were used historically, and risks appear tobe smaller with newer low-dose contraceptives.

Clinical evidence,mechanism, importance and management

Early after introduction of combined oral contraceptives it was realised that they can cause increases in blood pressure and clinical hypertension (See reference number 1,2). One study,(See reference number 3) from 1970s, in 83 women found that average rise in blood pressure was 9.2/5 mmHg, and that it was about twice as likely to occur as in those not on pill. Additionally,cases were noted where antihypertensives (at that time, commonly guanethidine and/or methyl-dopa) were not that effective in women with hypertension on combined oral contraceptives (See reference number 2,4). Although modern combined oral contraceptives are lower dose,they are still associated with a small increased risk of elevated blood pressure (See reference number 5). A UK study found that combined oral contraceptives were associated with a 2.6/1.8 mmHg rise in blood pressure,whereas progestogen-only oral contraceptives did not affect blood pressure (See reference number 5). Furthermore, in a study in 24 postmenopausal women with hypertension taking enalapril 10mg twice daily use of enalapril with drospirenone/estradiol 3/1 mg (12 women) produced a significant decrease in blood pressure of 9/5 mmHg after 14 days of treatment, when compared with placebo group (12 patients). No serious adverse effects were reported (See reference number 6). Note that drospirenone is an analogue of spironolactone,and shares some of its effects, including its blood pressure-lowering effects.

This is only a very brief review of this subject, but risks of hypertension with combined hormonal contraceptives appear to be modest. Nevertheless, they need to be considered in context of other possible cardiovascular risk factors. Where possible,blood pressure should be monitored before and during contraceptive use.

Wallace MR. Oral contraceptives and severe hypertension. Aust N Z J Med (1971) 1,49–52.

Woods JW. Oral contraceptives and hypertension. Lancet (1967) iii,653–4.

Weir RJ,Briggs E, Mack A, Naismith L, Taylor L, Wilson E. Blood pressure in women takingoral contraceptives. BMJ (1974) 1, 533.

Clezy TM. Oral contraceptives and hypertension: the effect of guanethidine. Med J Aust (1970) 1,638–40.

Dong W,Colhoun HM, Poulter NR. Blood pressure in women using oral contraceptives: results from the Health Survey for England 1994. J Hypertens (1997) 15, 1063–8.

Preston RA,Alonso A, Panzitta D, Zhang P, Karara AH. Additive effect of drospirenone/17ß-estradiol in hypertensive postmenopausal women receiving enalapril. Am J Hypertens (2002) 15, 816–22.

Clinical evidence,mechanism, importance and management

A study in 8 healthy subjects found that sulfinpyrazone 800mg daily for a week, increased clearance of a single oral dose of verapamil by about threefold, possibly due to an increase in its liver metabolism (See reference number 1). The clinical importance of this is uncertain,but be alert for reduced verapamil effects. It seems probable that dosage may need to be increased.

1. Wing LMH,Miners JO, Lillywhite KJ. Verapamil disposition—effects of sulphinpyrazone andcimetidine. Br J Clin Pharmacol (1985) 19, 385–91.

The plasma levels of diltiazem, isradipine and nifedipine areincreased by cimetidine and it may possibly be necessary to reduce dosages of these calcium-channel blockers. High doses ofcimetidine may increase bioavailability of lercanidipine. Although studies suggest no important interactions occur betweennicardipine or nisoldipine and cimetidine, manufacturers advise caution. Plasma felodipine,lacidipine, nimodipine, and nitrendipine levels are also increased by cimetidine, but thisseems to be clinically unimportant. Cimetidine does not interactwith amlodipine. It is uncertain whether cimetidine interacts significantly with verapamil. Ranitidine appears to interact onlyminimally with calcium-channel blockers,if at all. Famotidinedoes not interact pharmacokinetically with nifedipine.

A crossover study in 12 healthy subjects found that cimetidine 400mg twice daily for 14 days had no effect on pharmacokinetics of amlodipine 10mg (See reference number 1)

Cimetidine 300mg before meals and at bedtime for a week increased AUC of a single 60mg oral dose of diltiazem by 50 % in 6 healthy subjects and increased peak plasma levels by 57%. Ranitidine 150mg twice daily for a week increased AUC of diltiazem by 15%, but this was not statistically significant (See reference number 2). Increases in serum levels and AUC of diltiazem of 40 % and 25 to 50%, respectively, were seen in another study using ci

Cimetidine 1 g daily increased AUC of felodipine 10mg by 56%, and raised peak serum level by 54 % in 12 subjects. There was a short lasting effect on their heart rates but clinical effects were minimal (See reference number 4).

The manufacturer of isradipine(See reference number 5) notes that cimetidine increases bioavailability of isradipine by about 50%

A single 800mg dose of cimetidine increased maximum plasma level of a single 4mg dose of lacidipine by 59 % and increased AUC by 74 % in one study in healthy subjects

Cimetidine 800mg daily causes no significant alteration in plasma levels of lercanidipine but manufacturer says that bioavailability of lercanidipine and its hypotensive effects may be increased by higher doses of

No adverse interaction was seen in 22 patients given calcium-channel blockers,including nicardipine, with oral famotidine for 6 to 8 weeks (See reference number 8). No changes in pharmacokinetics or pharmacodynamics of a 12-hour intravenous infusion of nicardipine 24mg were seen in 12 healthy subjects given intravenous cimetidine 300mg every 6 hrs for 48 hrs (See reference number 9).

Cimetidine 1 g daily for a week increased AUC of nifedipine 40mg daily by about 60 % and increased maximum plasma levels by about 90%. Ranitidine 150mg twice daily for a week caused an insignificant rise of about 25 % in maximum nifedipine plasma levels and AUC (See reference number 10). Seven hypertensive patients had a fall in mean blood pressure from 127 to 109 mmHg after taking nifedipine 40mg daily for 4 weeks,and a further fall to 95 mmHg after they also took cimetidine 1 g daily for 3 weeks. When they took ranitidine 300mg instead of cimetidine,there was an insignificant fall in blood pressure (See reference number 10,11).

Other studies clearly confirm that cimetidine causes a very significant rise in plasma nifedipine levels and an increase in its effects,whereas ranitidine interacts only minimally (See reference number 12-18).

A study found no pharmacokinetic interaction between nifedipine and famotidine, but famotidine reversed effects of nifedipine on systolic time intervals and significantly reduced stroke volume and cardiac output (See reference number 19,20). No adverse interaction was seen in 22 patients given calcium-channel blockers,including nifedipine, with famotidine for 6 to 8 weeks (See reference number 8).

Cimetidine 1 g daily for 7 days increased bioavailability of nimodipine 30mg three times daily in 8 healthy subjects by 75%, but haemodynamic effects were unchanged. Ranitidine did not interact (See reference number 21).

A study in 8 healthy subjects found that taking cimetidine 1 g in divided doses on day before study and then three 200mg doses every 4 hrs on study day, increased bioavailability of a single 10mg dose of nisoldipine by about 50%, but haemodynamic effects of nisoldipine were unaltered (See reference number 22). Ranitidine does not interact with nisoldipine (See reference number 23).

Cimetidine 800mg given before, and 400mg in divided doses given after, a single 20mg dose of nitrendipine was found to increase its bioavailability by 154 % but haemodynamic effects were unchanged (See reference number 24). Another study found that ranitidine increased AUC of oral nitrendipine 20mg daily for 1 week by about 50 % and decreased its clearance, but there were no changes in haemodynamic measurements (systolic time intervals, impedance cardiography) (See reference number 25,26). A further study found that ranitidine increases AUC of nitrendipine by 89%, but this does not appear to be clinically significant (See reference number 27).

A study in 8 healthy subjects found that cimetidine 300mg every 6 hrs for 8 days did not affect pharmacokinetics of a single 10mg intravenous dose of verapamil, but bioavailability of a 120mg oral dose of verapamil was increased from 26 to 49%. A small insignificant change in clearance occurred but no change in AUC. The changes in PR interval caused by verapamil were unaltered in presence of cimetidine (See reference number 28). Another study found that cimetidine 300mg four times daily for 5 days reduced clearance of a single intravenous dose of verapamil by 21 % and increased its elimination half-life by 50 % (See reference number 29). Cimetidine 400mg twice daily for a week increased bioavailability of verapamil from 35 to 42 % and its clearance was reduced by almost 30 % in another study (See reference number 30). A further study found a small increase in bioavailability of both enantiomers of verapamil (See reference number 31). In contrast, other studies have found that pharmacokinet

It is believed that cimetidine increases nifedipine levels by inhibiting its oxidative metabolism by liver. Like ranitidine, it may also increase bioavailability of nifedipine by lowering gastric acidity (See reference number 14). The mechanisms of other interactions are probably similar.

The interactions of cimetidine with diltiazem and nifedipine are established. Concurrent use need not be avoided but increase in calcium-channel blocker effects should be taken into account. It has been suggested that dosage of diltiazem should be reduced by 30 to 50%(See reference number 34,35) and that of nifedipine by 40 to 50 % (See reference number 34,35). The interaction between verapamil and cimetidine is not well established, but monitor effects until more is known. It has been suggested that verapamil dose may need to be reduced by 50 % (See reference number 35). Monitoring is advised if isradipine is given with cimetidine and a reduction in isradipine dose may be required (See reference number 5).

Similarly, high doses of cimetidine may increase hypotensive effects of lercanidipine and caution is advised (See reference number 7). The evidence available suggests that, although cimetidine increases serum levels of felodipine, lacidipine, nimodipine, and nitrendipine, haemodynamic changes are unimportant. However,this needs confirmation. The manufacturer of nisoldipine warns that antihypertensive effect may be potentiated by cimetidine,(See reference number 23) but study available suggests that this is not significant, Although some studies indicate no interaction between nicardipine and cimetidine, manufacturer notes that cimetidine increases nicardipine plasma levels and monitoring is recommended (See reference number 36). Amlodipine and cimetidine do not interact.

Ranitidine does not interact significantly with diltiazem,nimodipine, nisoldipine or nifedipine, and is possibly a non-interacting alternative for cimetidine with other calcium-channel blockers. Note that nitrendipine AUC was increased by 50 % and 89 % by ranitidine, although this was not considered clinically relevant.

Quoted as unpublished data,Pfizer Central Research by Abernethy DR. Amlodipine: pharmacokinetic profile of a low-clearance calcium antagonist. J Cardiovasc Pharmacol (1991)17 (Suppl 1), S4–S7.

Winship LC,McKenney JM, Wright JT, Wood JH, Goodman RP. The effect of ranitidine andcimetidine on single-dose diltiazem pharmacokinetics. Pharmacotherapy (1985) 5, 16–19.

Mazhar M,Popat KD, Sanders C. Effect of cimetidine on diltiazem blood levels. Clin Res (1984) 32, 741A.

Janzon K,Edgar B, Lundborg P, Regårdh CG. The influence of cimetidine and spironolactone on the pharmacokinetics and haemodynamic effects of felodipine in healthy subjects.Acta Pharmacol Toxicol (Copenh) (1986) 59 (Suppl 4), 98.

Prescal (Isradipine). Novartis Pharmaceuticals UK Ltd. UK Summary of product characteristics,February 2002.

Dewland PM. A study to assess the effect of food and a single 800mg oral dose of cimetidineon the pharmacokinetics of a single 4mg oral dose of calcium-channel inhibitor,GR43659X(lacidipine). Boehringer Ingelheim report GMH/88/030.

Zanidip (Lercanidipine hydrochloride). Recordati Pharmaceuticals Ltd. UK Summary ofproduct characteristics,October 2004.

Chichmanian RM,Mignot G, Spreux A, Jean-Girard C, Hofliger P. Tolérance de la famotidine. Étude du réseau médecins sentinelles en pharmacovigilance. Therapie (1992) 47, 239–

43.

Lai C-M,McEntegart CM, Maher KE, Bell VA, Turlapaty P, Quon CY. The effects of iv cimetidine on the pharmacokinetics (PK) and pharmacodynamics (PD) of iv nicardipine in man. Pharm Res (1994) 11 (Suppl 10), S386.

Kirch W,Janisch HD, Heidemann H, Rämsch K, Ohnhaus EE. Einfluss von Cimetidin und Ranitidin auf Pharmakokinetik und antihypertensiven Effekt von Nifedipin. Dtsch Med Wochenschr (1983) 108, 1757–61.

Kirch W,Rämsch K, Janisch HD, Ohnhaus EE. The influence of two histamine H2-receptorantagonists, cimetidine and ranitidine, on the plasma levels and clinical effect of nifedipineand metoprolol. Arch Toxicol (1984) (Suppl 7), 256–9.

Kirch W,Hoensch H, Ohnhaus EE, Janisch HD. Ranitidin-Nifedipin-Interaktion. Dtsch Med Wochenschr (1984) 109, 1223.

Smith SR,Kendall MJ, Lobo J, Beerahee A, Jack DB, Wilkins MR. Ranitidine and cimetidine: drug interactions with single dose and steady-state nifedipine administration. Br J Clin Pharmacol (1987) 23, 311–15.

Adams LJ,Antonow DR, McClain CJ, McAllister R. Effect of ranitidine on bioavailabilityof nifedipine. Gastroenterology (1986) 90, 1320.

Kirch W,Ohnhaus EE, Hoensch H, Janisch HD. Ranitidine increases bioavailability of nifedipine. Clin Pharmacol Ther (1985) 37, 204.

Schwartz JB,Upton RA, Lin ET, Williams RL, Benet LZ. Effect of cimetidine or ranitidineadministration on nifedipine pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther (1988) 43, 673–80.

Renwick AG,Le Vie J, Challenor VF, Waller DG, Gruchy B, George CF. Factors affectingthe pharmacokinetics of nifedipine. Eur J Clin Pharmacol (1987) 32, 351–5.

Khan A,Langley SJ, Mullins FGP, Dixon JS, Toon S. The pharmacokinetics and pharmacodynamics of nifedipine at steady state during concomitant administration of cimetidine orhigh dose ranitidine. Br J Clin Pharmacol (1991) 32, 519–22.

Kirch W,Halabi A, Linde M, Ohnhaus EE. Negativ-inotrope Wirkung von Famotidin. Schweiz Med Wochenschr (1988) 118, 1912–14.

Kirch W,Halabi A, Linde M, Santos SR, Ohnhaus EE. Negative effects of famotidine on cardiac performance assessed by noninvasive hemodynamic measurements. Gastroenterology (1989) 96, 1388–92.

Mück W,Wingender W, Seiberling M, Woelke E, Rämsch K-D, Kuhlmann J. Influence ofthe H2-receptor antagonists cimetidine and ranitidine on the pharmacokinetics of nimodipinein healthy volunteers. Eur J Clin Pharmacol (1992) 42, 325–8.

Van Harten J,van Brummelen P, Lodewijks MTM, Danhof M, Breimer DD. Pharmacokinetics and hemodynamic effects of nisoldipine and its interaction with cimetidine. Clin Pharmacol Ther (1988) 43, 332–41.

Syscor MR (Nisoldipine). Forest Laboratories UK Ltd. UK Summary of product characteristics,August 1998.

Soons PA,Vogels BAPM, Roosemalen MCM, Schoemaker HC, Uchida E, Edgar B, LundahlJ, Cohen AF, Breimer DD. Grapefruit juice and cimetidine inhibit stereoselective metabolismof nitrendipine in humans. Clin Pharmacol Ther (1991) 50, 394–403.

Kirch W,Nahoui R, Ohnhaus EE. Ranitidine/nitrendipine interaction. Clin Pharmacol Ther (1988) 43, 149.

Halabi A,Nahoui R, Kirch W. Influence of ranitidine on kinetics of nitrendipine and on noninvasive hemodynamic parameters. Ther Drug Monit (1990) 12, 303–4.

Santos SR,Storpirtis S, Moreira-Filho L, Donzella H, Kirch W. Ranitidine increases the bioavailability of nitrendipine in patients with arterial hypertension. Braz J Med Biol Res (1992) 25, 337–47.

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