Pharmacy Blog – Dr Vibore

Antipsychotics,Anxiolytics and Hypnotics 737

Clinical evidence,mechanism, importance and management

Saw palmetto 320mg daily, given to 12 subjects for 16 days, did not affect pharmacokinetics of a single 2mg dose of alprazolam given on day 14 day (See reference number 1). In another study in 12 healthy subjects who took saw palmetto,160 mg twice daily for 28 days,there was no change in metabolic ratio of a single 8mg dose of midazolam (See reference number 2). These findings suggest that saw palmetto does not alter activity of cytochrome P450 isoenzyme CYP3A4, and no dosage adjustments of these benzodiazepines would be expected to be needed on concurrent use.

Markowitz JS,Donovan JL, DeVane L, Taylor RM, Ruan Y, Wang J-S, Chavin KD. Multipledoses of saw palmetto (Serenoa repens) did not alter cytochrome P450 2D6 and 3A4 activity in normal volunteers. Clin Pharmacol Ther (2003) 74, 536–42.

Gurley BJ,Gardner SF, Hubbard MA, Williams DK, Gentry WB, Carrier J, Khan IA, EdwardsDJ, Shah A. In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes: Citrus aurantium, Echinacea purpurea, milk thistle, and saw palmetto. Clin Pharmacol Ther (2004) 76, 428–40.

Intravenous, but not oral, metoclopramide increases rate ofabsorption of diazepam and raises its maximum plasma levels.Metoclopramide increases rate of absorption of zopiclone.

Clinical evidence,mechanism, importance and management

Intravenous metoclopramide increased peak plasma levels of diazepam by 38 % and increased rate of absorption (peak levels occurred at 30 minutes instead of 60 minutes),(See reference number 1) but in 6 healthy subjects oral metoclopramide 10mg did not increase rate of absorption of oral diazepam

0.2 mg/kg (See reference number 2). The reason is not understood. The clinical importance of this interaction is not known,but it is probably small.

The rate of absorption of a single 7.5mg dose of oral zopiclone was increased by metoclopramide 10mg given intravenously to 12 healthy subjects. This was presumably because these drugs alter gut motility. Metoclopramide increased mean plasma levels of zopiclone, from 22.7 to 44.4 nanograms/mL at 1 hour,and from 49.3 to 59.6 nanograms/mL at 2 hrs (See reference number 3). The clinical importance of these findings is not known.

Gamble JAS,Gaston JH, Nair SG, Dundee JW. Some pharmacological factors influencing theabsorption of diazepam following oral administration. Br J Anaesth (1976) 48, 1181–5.

Chapman MH,Woolner DF, Begg EJ, Atkinson HC, Sharman JR. Co-administered oral metoclopramide does not enhance the rate of absorption of oral diazepam. Anaesth Intensive Care (1988) 16, 202–5.

Elliott P,Chestnutt WN, Elwood RJ, Dundee JW. Effect of atropine and metoclopramide onthe plasma concentrations of orally administered zopiclone. Br J Anaesth (1983) 55, 1159P– 1160P.

Diclofenac reduces dose of midazolam needed to produce sedation and hypnosis. Diazepam has a small effect on pharmacokinetics of diclofenac, ibuprofen and naproxen. Diazepam andindometacin appear not to interact adversely,although feelings ofdizziness may be increased. Zaleplon and ibuprofen appear not tointeract.

Clinical evidence,mechanism, importance and management

Diclofenac. In a study in 8 healthy subjects, diazepam increased AUC of diclofenac by 60 % while clearance was reduced by 36 % (See reference number 1). The effects of diazepam on diclofenac appeared to depend on time of administration and may reflect time-dependent effects of diazepam on gastrointestinal function. More study is needed.

Ibuprofen. A study in 8 healthy subjects investigating effects of diazepam on ibuprofen pharmacokinetics found that ibuprofen half-life was increased from 2.39 to 3.59 hrs and clearance was reduced by about one-third when diazepam and ibuprofen were given at 10 pm, but no effect was seen with morning dosing (See reference number 2). The clinical importance of this is uncertain.

Indometacin. Diazepam 10 to 15mg impaired performance of a number of psychomotor tests (digit symbol substitution, letter cancellation, tracking and flicker fusion) in 119 healthy medical students. It also caused subjective drowsiness,mental slowness and clumsiness. When indometacin 50 or 100mg was given effects were little different from diazepam alone, except that feeling of dizziness (common to both drugs) was increased and caused subjective clumsiness (See reference number 3).

Naproxen. A double-blind,crossover study failed to find any clinically important changes in mood or attention in healthy subjects given naproxen and diazepam (See reference number 4). A single-dose study in 10 healthy subjects found that peak serum concentrations of naproxen 500mg were reduced by 23%, time to peak concentration was increased (1.36 to 2 hours) and absorption rate constant was decreased (4.07 to 2.42 h(See reference number –1)) by diazepam 10 mg. Other pharmacokinetic parameters were not affected (See reference number 5). No special precautions appear to be necessary.

A clinical study found that diclofenac 75mg given intravenously to 10 patients reduced dose of intravenous midazolam needed to produce sedation and hypnosis by 35%, when compared with 10 control subjects not given diclofenac (See reference number 6). The clinical importance of this is uncertain.

For interactions of parecoxib with midazolam see NSAIDs; Parecoxib + Miscellaneous interaction

A randomised, single-dose study in 17 healthy subjects found that ibuprofen 600mg had no effect on pharmacokinetics of zaleplon 10mg (See reference number 7).

Mahender VN,Rambhau D, Rao BR, Rao VVS, Venkateshwarlu G. Time-dependent influenceof diazepam on the pharmacokinetics of orally administered diclofenac sodium in human subjects. Clin Drug Invest (1995) 10, 296–301.

Bapuji AT,Rambhau D, Srinivasu P, Rao BR, Apte SS. Time dependent influence of diazepamon the pharmacokinetics of ibuprofen in man. Drug Metabol Drug Interact (1999) 15, 71–81.

Nuotto E,Saarialho-Kere U. Actions and interactions of indomethacin and diazepam on performance in healthy volunteers. Pharmacol Toxicol (1988) 62, 293–7.

Stitt FW,Latour R, Frane JW. A clinical study of naproxen-diazepam drug interaction on testsof mood and attention. Curr Ther Res (1977) 21, 149–56.

Rao BR,Rambhau D. Influence of diazepam on the pharmacokinetic properties of orally administered naproxen. Drug Invest (1992) 4, 416–21.

Carrero E,Castillo J, Bogdanovich A, Nalda MA. El diclofenac reduce las dosis sedante e hipnótica de midazolam. Rev Esp Anestesiol Reanim (1991) 38, 127.

Garcia PS,Carcas A, Zapater P, Rosendo J, Paty I, Leister CA, Troy SM. Absence of an interaction between ibuprofen and zaleplon. Am J Health-Syst Pharm (2000) 57, 1137–41.

A man taking alprazolam became semicomatose a few days afterstarting to take kava,which was suggested to be due to additivesedation. The pharmacokinetics of midazolam were unaffected bykava.

Clinical evidence,mechanism, importance and management

A 54-year-old man taking alprazolam,cimetidine and terazosin was hospitalised in a lethargic and disorientated state 3 days after starting to take kava, which he had bought from a local health food store. He denied having overdosed with any of these drugs. The patient became alert again after several hrs (See reference number 1). The reason for what happened is not known, but suggested explanation is that kava :7.8pt; font-weight:normal; color:#000000″>α-pyrones might have had additive sedative effects with those of alprazolam (See reference number 1,2). This is an isolated case and its general importance is not known.

In a study in 6 subjects who regularly took 7 to 27 g of kavalactones weekly as an aqueous kava extract, there was no change in metabolism of a single 8mg oral dose of midazolam before or after they stopped kava for 30 days (See reference number 3). Similar results were found in a study in 12 healthy subjects given kava kava root extract 1 g twice daily for 28 days before receiving a single 8mg dose of oral midazolam (See reference number 4). In contrast to some in vitro data, these studies show that kava has no effect on cytochrome P450 isoenzyme CYP3A4, of which midazolam is a probe substrate (See reference number 4). It is possible that kava levels achieved clinically are insufficient to affect CYP3A4. The findings of these studies suggest that it is unlikely that kava will alter pharmacokinetics of other substrates of CYP3A4 (see table 1 below,, for a list).

Almeida JC,Grimsley EW. Coma from the health food store: interaction between kava and alprazolam. Ann Intern Med (1996) 125, 940–1.

Jussofie A,Schmiz A, Hiemke C. Kavapyrone enriched extract from Piper methysticum as modulator of GABA binding site in different regions of rat brain. Psychopharmacology (Berl) (1994) 116, 469–74.

Russman S,Lauterburg BH, Barguil Y, Choblet E, Cabalion P, Rentsch K, Wenk M. Traditional aqueous kava extracts inhibit cytochrome P450 1A2 in humans: protective effect againstenvironmental carcinogens? Clin Pharmacol Ther (2005) 77, 453–4.

Gurley BJ,Gardner SF, Hubbard MA, Williams DK, Gentry WB, Khan IA, Shah A. In vivoeffects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2,2D6, 2E1, and 3A4/5 phenotypes. Clin Pharmacol Ther (2005) 77, 415–26.

Table 1 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

Isoniazid reduces clearance of both diazepam and triazolam

A study in 9 healthy subjects found that isoniazid 90mg twice daily for 3 days increased half-life of a single 5- or 7.5mg dose of diazepam from about 34 to 45 hours, and reduced total clearance by 26 % (See reference number 1). A study in 6 healthy subjects found that isoniazid 90mg twice daily for 3 days, increased half-life of a single 500 microgram dose of triazolam from 2.5 to 3.3 hours, increased AUC by 46 % and reduced clearance by 43 % (See reference number 2).

A study in 9 healthy subjects found that isoniazid 90mg twice daily for 3 days had no effect on pharmacokinetics of a single 30mg oral dose of oxazepam (See reference number 2). Similarly, in another study, pharmacokinetics of clotiazepam were not altered by isoniazid (See reference number 3).

What is known suggests that isoniazid acts as an enzyme inhibitor, decreasing metabolism and loss of diazepam and triazolam from body, thereby increasing and prolonging their effects. Oxazepam which is metabolised by glucuronidation would be unlikely to interact.

Information is limited but interactions appear to be established. Their clinical importance is uncertain but be alert for need to decrease dosages of diazepam and triazolam if isoniazid is started. There seems to be no direct information about other benzodiazepines,but those undergoing high first-pass extraction and/or liver microsomal metabolism may interact similarly. Oxazepam and clotiazepam appear not to interact.

Ochs HR,Greenblatt DJ, Roberts G-M, Dengler HJ. Diazepam interaction with antituberculosis drugs. Clin Pharmacol Ther (1981) 29, 671–8.

Ochs HR,Greenblatt DJ, Knüchel M. Differential effect of isoniazid on triazolam oxidation and oxazepam conjugation. Br J Clin Pharmacol (1983) 16, 743–6.

Ochs HR,Greenblatt DJ, Verburg-Ochs B, Harmatz JS, Grehl H. Disposition of clotiazepam:influence of age, sex, oral contraceptives, cimetidine, isoniazid and ethanol. Eur J Clin Pharmacol (1984) 26, 55–9.

An isolated report describes temazepam toxicity due to disulfiram. The serum levels of chlordiazepoxide and diazepam areincreased by use of disulfiram and some patients may possiblyexperience increased drowsiness. Alprazolam,oxazepam and lorazepam are either not affected, or only minimally affected, by disulfiram.

A man taking disulfiram 200mg daily developed confusion,drowsiness, slurred speech and an unsteady gait within a few days of starting to take temazepam 20mg at night. This was interpreted as temazepam toxicity. The symptoms disappeared when both drugs were stopped (See reference number 1).

After taking disulfiram 500mg daily for 14 to 16 days, plasma clearance of single doses of chlordiazepoxide and diazepam were reduced by 54 % and 41%, respectively, and half-lives were increased by 84 % and 37%, respectively. The plasma levels of chlordiazepoxide were approximately doubled. Oxazepam was also given following disulfiram treatment but changes in oxazepam pharmacokinetics were minimal. There was no difference in interaction between alcoholic subjects (without hepatic cirrhosis) and healthy subjects (See reference number 2).

Other studies show that pharmacokinetics of lorazepam and alprazolam are unaffected by disulfiram (See reference number 3,4)

Disulfiram inhibits initial metabolism (N-demethylation and oxidation) of both chlordiazepoxide and diazepam by liver so that an alternative but slower metabolic pathway is used. This results in accumulation of these benzodiazepines in body. In contrast, metabolism (glucuronidation) of oxazepam and lorazepam is minimally affected by disulfiram so that their clearance from body remains largely unaffected (See reference number 2,3). The possible interaction between disulfiram and temazepam is not understood, as temazepam is also mainly eliminated in urine as inactive glucuronide metabolite, and so its metabolism would not be expected to be affected by disulfiram.

There seems to be only one report (with temazepam) of a clinically significant interaction between disulfiram and benzodiazepines, and this report is unconfirmed, as patient did not take temazepam alone. The other reports only describe potential interactions that have been identified by single-dose studies. These do not necessarily reliably predict what will happen in practice. However,it seems possible that some patients will experience increased drowsiness, possibly because of this interaction, and because drowsiness is a very common adverse effect of disulfiram. Reduce dosage of benzodiazepine if necessary. Benzodiazepines that are metabolised by similar pathways to diazepam and chlordiazepoxide, may possibly interact in same way (e.g. bromazepam,clonazepam, clorazepate, prazepam, ketazolam, clobazam, flurazepam, nitrazepam, medazepam) but this needs confirmation. Alprazolam,oxazepam and lorazepam appear to be non-interacting alternatives.

Hardman M,Biniwale A, Clarke CE. Temazepam toxicity precipitated by disulfiram. Lancet (1994) 344, 1231–2.

MacLeod SM,Sellers EM, Giles HG, Billings BJ, Martin PR, Greenblatt DJ, Marshman JA.Interaction of disulfiram with benzodiazepines. Clin Pharmacol Ther (1978) 24, 583–9.

Sellers EM,Giles HG, Greenblatt DJ, Naranjo CA. Differential effects on benzodiazepine disposition by disulfiram and ethanol. Arzneimittelforschung (1980) 30, 882–6.

Diquet B,Gujadhur L, Lamiable D, Warot D, Hayoun H, Choisy H. Lack of interaction between disulfiram and alprazolam in alcoholic patients. Eur J Clin Pharmacol (1990) 38, 157–

60.

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Clinical evidence,mechanism, importance and management

2.5 mg to 15mg daily; 1 taking betamethasone 0.5mg daily; 1 taking methylprednisolone 48mg daily) and to 10 other patients not taking corticosteroids. In patients taking corticosteroids AUC of midazolam was decreased and clearance increased, when compared with patients not taking corticosteroids; however differences were not significant. The onset of anaesthesia between two groups was also not different. It was suggested that trend towards increased midazolam metabolism may be due to induction of cytochrome P450 isoenzyme CYP3A4 and/or UDP-glucuronosyltransferase. Although results with intravenous metabolism were not significant authors note that it is possible that metabolism of oral midazolam may be more markedly affected (See reference number 1).

1. Nakajima M,Suzuki T, Sasaki T, Yokoi T, Hosoyamada A, Yamamoto T, Kuroiwa Y. Effectsof chronic administration of glucocorticoid on midazolam pharmacokinetics in humans. Ther Drug Monit (1999) 21, 507–13.

Aprepitant inhibits metabolism of oral midazolam resulting inincreased plasma levels

In a randomised study 16 healthy subjects took either aprepitant 125mg on day 1 followed by 80mg daily for 4 days,or 40mg on day 1 followed by 25mg daily for 4 days, with a single 2mg oral dose of midazolam on days 1 and 5. The aprepitant 40/25 mg dosing schedule had no significant effect on pharmacokinetics of midazolam. However, aprepitant 125/80 mg dosing schedule increased AUC of oral midazolam by 126 % and 229 % on days 1 and 5, respectively, and increased maximum plasma levels of midazolam by 46 % and 94 % on days 1 and 5, respectively (See reference number 1).

In a randomised,placebo-controlled study, 24 healthy subjects were given aprepitant 125mg on day one then 80mg daily for a further 2 days. A single 2mg intravenous dose of midazolam was given on days 4,8 and 15. The 3-day aprepitant regimen increased midazolam levels slightly on day 4 (AUC increased by 25 % and clearance reduced by 20%),decreased midazolam levels slightly on day 8 (AUC decreased by 19 % and clearance increased by 24%) and had almost no effect by day 15, when compared to placebo (See reference number 2).

Aprepitant inhibits cytochrome P450 isoenzyme CYP3A4 by which midazolam is metabolised, resulting in increased midazolam levels. The pharmacokinetic effect on intravenous midazolam indicate effects of aprepitant on systemic rather than on intestinal CYP3A4 activity. Aprepitant is also a mild inducer of CYP3A4,(See reference number 2,3) however induction is transient, with maximal effect 3 to 5 days after end of treatment.

Based on way midazolam interacts with similarly potent inhibitors of CYP3A4, aprepitant may be expected to increased drowsiness and length of sedation and amnesia in patients given midazolam. Consider reducing midazolam dose in patients given aprepitant and monitor outcome of concurrent use carefully. The manufacturer notes that potential effects of increased levels of other benzodiazepines metabolised via CYP3A4, such as alprazolam and triazolam, should be considered if

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They also state that effects of aprepitant on plasma levels of intravenously administered CYP3A4 substrates are expected to be less than effects on orally administered substrates (See reference number 3)

1. Majumdar AK,McCrea JB, Panebianco DL, Hesney M, Dru J, Constanzer M, Goldberg MR,Murphy G, Gottesdiener KM, Lines CR, Petty KJ, Blum RA. Effects of aprepitant on cytochrome P450 3A4 activity using midazolam as a probe. Clin Pharmacol Ther (2003) 74, 150–

6.

Shadle CR,Lee Y, Majumdar AK, Petty KJ, Gargano C, Bradstreet TE, Evans JK, Blum RA.Evaluation of potential inductive effects of aprepitant on cytochrome P450 3A4 and 2C9 activity. J Clin Pharmacol (2004) 44, 215–23.

Emend (Aprepitant). Merck Sharp & Dohme Ltd. UK Summary of product characteristics,February 2007.

An isolated report describes clonazepam toxicity, which was attributed to concurrent use of amiodarone.

Clinical evidence,mechanism, importance and management

A 78-year-old man with congestive heart failure and coronary artery disease was taking furosemide,potassium, and calcium supplements, a multivitamin preparation, and amiodarone 200mg daily for sustained ventricular tachycardia. Two months after clonazepam 500 micrograms at night was added to treat restless leg syndrome he developed slurred speech,confusion, difficulty in walking, dry mouth and urinary incontinence. This was interpreted as clonazepam toxicity. The problems cleared when clonazepam was stopped. The authors of report suggest that amiodarone may have inhibited oxidative metabolism of clonazepam by liver, thereby allowing it to accumulate. They also point out that this patient may have been more sensitive to these effects because of a degree of hypothyroidism caused by amiodarone. Hypothyroidism is known to decrease metabolism of drugs that undergo oxidative metabolism by liver (See reference number 1).

1. Witt DM,Ellsworth AJ, Leversee JH. Amiodarone–clonazepam interaction. Ann Pharmacother (1993) 27, 1463–4.

1. D’Souza DL,Levasseur LM, Nezamis J, Robbins DK, Simms L, Koch KM. Effect of alosetron on the pharmacokinetics of alprazolam. J Clin Pharmacol (2001) 41, 452–4.