chapter
Anxiolytics and hypnotics
Pages 11

Watch for poor response to these BZDs; consider increasing the dose, e.g. diazepam or nitrazepam 2-3-fold

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NERVOUS SYSTEM DRUGS ANXIOLYTICS AND HYPNOTICS Benzodiazepines

These BZDs are metabolized primarily by CYP3A4, which is inhibited moderately by ciclosporin

Warn patients about ≠ sedation. Consider using alternative drugs, e.g. flurazepam. Warn about activities requiring attention ➣ For signs and symptoms of CNS depression, see Clinical Features of Some Adverse Drug Interactions, Central nervous system depression

BZDs ANTIDEPRESSANTS

BZDs MAOIs Additive depression of CNS ranging from drowsiness to coma and respiratory depression

Synergistic depressant effects on CNS function

Necessary to warn patients, particularly regards activities that require attention, e.g. driving or using machinery and equipment that could cause self-harm

BZDs MIRTAZAPINE ≠ sedation Additive effect Warn patients about this effect BZDs TCAs Possible ≠ plasma

concentrations of diazepam Inhibition of CYP2C19-mediated metabolism of diazepam. The clinical significance of this depends upon whether diazepam’s alternative pathways of metabolism are also inhibited by co-administered drugs

Watch for excessive sedation with diazepam

ALPRAZOLAM, DIAZEPAM, MIDAZOLAM

SSRIs – FLUOXETINE, FLUVOXAMINE, PAROXETINE

≠ in plasma concentrations of these BZDs. Likely ≠ sedation and interference with psychomotor activity

Alprazolam, diazepam and midazolam are subject to metabolism by CYP3A4. Fluvoxamine, fluoxetine and possibly paroxetine are inhibitors of CYP3A4; sertraline is a weak inhibitor

Warn patients about risks associated with activities that require alertness. Consider use of alternatives such as oxazepam, lorazepam and temazepam, which are metabolized by glucuronidation ➣ For signs and symptoms of CNS depression, see Clinical Features of Some Adverse Drug Interactions, Central nervous system depression

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Mechanism Precautions

CARBAMAZEPINE, PHENYTOIN

Induction of metabolism Watch for poor response to these antiepileptics

ALPRAZOLAM, CHLORDIAZEPOXIDE, DIAZEPAM, LORAZEPAM, MIDAZOLAM, OXAZEPAM, TEMAZEPAM

ANTIFUNGALS – ITRACONAZOLE, KETOCONAZOLE, VORICONAZOLE

≠ plasma concentrations of these BZDs with ≠ risk of adverse effects. These risks are greater following intravenous administration of midazolam compared with oral midazolam

Itraconazole and ketoconazole are potent inhibitors of phase I metabolism (oxidation and functionalization) of these BZDs by CYP3A4. In addition, the more significant ≠ in plasma concentrations following oral midazolam – 15 times compared with 5 times following intravenous use – indicates that the inhibition of P-gp by ketoconazole is important following oral administration

Aim to avoid co-administration. If coadministration is necessary, always start with ↓ dose and monitor the effects closely. Consider the use of alternative BZDs, which predominantly undergo phase II metabolism by glucuronidation, e.g. flurazepam, quazepam. Fluconazole and posaconazole are unlikely to cause this interaction

BZDs ANTIHYPERTENSIVES AND HEART FAILURE DRUGS – CLONIDINE AND MOXONIDINE

Clonidine and moxonidine may exacerbate the sedative effects of BZDs, particularly during initiation of therapy

Uncertain Warn patients of this effect and advise them to avoid driving or operating machinery if they suffer from sedation

BZDs ANTIPARKINSON’S DRUGS – LEVODOPA

Risk of ↓ effect of levodopa Uncertain Watch for poor response to levodopa and consider increasing its dose. If severe antagonism of effect, stop the BZD

BZDs ANTIPLATELET AGENTS – ASPIRIN

↓ requirements of midazolam when aspirin (1 g) is co-administered

Uncertain at present Be aware of possible ↓ dose requirements for midazolam

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NERVOUS SYSTEM DRUGS ANXIOLYTICS AND HYPNOTICS Benzodiazepines

Additive effect Warn patients and carers of this effect. Particular care should be exercised when parenteral doses are given, e.g. for emergency sedation

BZDs ANTIVIRALS

DIAZEPAM, MIDAZOLAM NNRTIs – EFAVIRENZ ≠ efficacy and ≠ adverse effects, e.g. prolonged sedation

↓ CYP3A4-mediated metabolism of diazepam and midazolam

1. Monitor more closely, especially sedation levels. May need ↓ dose of diazepam or alteration of timing of dose 2. Avoid co-administration with midazolam

BZDs NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS – ZIDOVUDINE

≠ adverse effects including ≠ incidence of headaches when oxazepam is co-administered with zidovudine

Uncertain Monitor closely

BZDs PROTEASE INHIBITORS ≠ adverse effects, e.g. prolonged sedation

Inhibition of CYP3A4-mediated metabolism of BZDs and buspirone

Watch closely for ≠ sedation; ↓ dose of sedative as necessary. Some recommend considering substituting long-acting for shorter-acting BZDs with less active metabolites (e.g. lorazepam for diazepam)

BZDs ANXIOLYTICS AND HYPNOTICS – SODIUM OXYBATE

Risk of CNS depression – coma, respiratory depression

Additive depression of CNS Avoid co-administration. Caution even with relatively non-sedating antihistamines (cetrizine, desloratidine, fexofenadine, levocetirizine, loratidine, mizolastine) as they can impair the performance of skilled tasks

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Mechanism Precautions

Additive hypotensive effect; anxiolytics and hypnotics can cause postural ↓ BP

Watch for ↓ BP. Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.)

DIAZEPAM BETA-BLOCKERS May occasionally cause ≠ sedation during metoprolol and propranolol therapy

Propranolol and metoprolol inhibit the metabolism of diazepam

Warn patients about ≠ sedation

BZDs BRONCHODILATORS – THEOPHYLLINE

↓ therapeutic effect of BZDs BZDs ≠ CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors

Larger doses of diazepam are required to produce the desired therapeutic effects such as sedation. Discontinuation of theophylline without ↓ dose of BZD ≠ risk of sedation and of respiratory depression

BZDs CALCIUM CHANNEL BLOCKERS – DILTIAZEM, VERAPAMIL

Plasma concentrations of midazolam and triazolam are ≠ by diltiazem and verapamil

Diltiazem and verapamil inhibit CYP3A4-mediated metabolism of midazolam and triazolam

↓ dose of BZD by 50% in patients on calcium channel blockers; warn patients not to perform skilled tasks such as driving for at least 10 hours after the dose of BZD

ALPRAZOLAM, DIAZEPAM CARDIAC GLYCOSIDES – DIGOXIN

Alprazolam and possibly diazepam may ≠ digoxin levels, particularly in the over-65s

Uncertain at present; possibly ↓ renal excretion of digoxin

Monitor digoxin levels; watch for digoxin toxicity

BZDs CNS STIMULANTS

DIAZEPAM MODAFINIL May cause moderate ≠ plasma concentrations of diazepam

Modafinil is a reversible inhibitor of CYP2C19 when used in therapeutic doses

Be aware

TRIAZOLAM MODAFINIL May ↓ triazolam levels Uncertain Be aware

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NERVOUS SYSTEM DRUGS ANXIOLYTICS AND HYPNOTICS Benzodiazepines

Inhibited metabolism Warn patients of risk of excessive sedation

BZDs LOFEXIDINE ≠ sedation Additive effect Warn patients of risk of excessive sedation

ALPRAZOLAM, DIAZEPAM, MIDAZOLAM – ORAL

GRAPEFRUIT JUICE Possibly ≠ efficacy and ≠ adverse effects, e.g. sedation, CNS depression

Possibly ≠ bioavailability, ↓ presystemic metabolism. Constituents of grapefruit juice irreversibly inhibit intestinal CYP3A4. Transport via P-gp and MRP-2 efflux pumps is also inhibited

Avoid concomitant use. Be particularly vigilant in elderly patients or those with impaired liver function. Consider alternative, e.g. temazepam

BZDs (NOT LORAZEPAM OR TEMAZEPAM)

H2 RECEPTOR BLOCKERS – CIMETIDINE, RANITIDINE

≠ efficacy and adverse effects of BZD, e.g. sedation

Cimetidine is an inhibitor of CYP3A4, CYP2D6, CYP2C19 and CYP1A2

Not clinically significant for most patients. Conflicting information for some BZDs. Monitor more closely, and ↓ dose if necessary

BZDs MUSCLE RELAXANTS

BZDs BACLOFEN, TIZANIDINE ≠ hypotensive effect Additive hypotensive effect Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.)

BZDs BACLOFEN, METHOCARBAMOL, TIZANIDINE

≠ sedation Additive effect Warn patients

BZDs NITRATES ≠ hypotensive effect Additive hypotensive effect Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.)

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Mechanism Precautions

with oral contraceptives

Uncertain The clinical significance is uncertain. It would seem to be wise to advise patients to use an alternative form of contraception during and for 1 month after stopping BZDs

BZDs PERIPHERAL VASODILATORS

BZDs CILOSTAZOL Midazolam ≠ cilostazol levels Midazolam inhibits CYP3A4mediated metabolism of cilastazol

Avoid co-administration

BZDs MOXISYLYTE ≠ hypotensive effect Additive hypotensive effect Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.)

BZDs POTASSIUM CHANNEL ACTIVATORS

≠ hypotensive effect Additive effect Avoid co-administration of nicorandil with phosphodiesterase type 5 inhibitors. For other drugs, monitor BP closely

BZDs PROTON PUMP INHIBITORS – OMEPRAZOLE/ ESOMEPRAZOLE

≠ efficacy and adverse effects, e.g. prolonged sedation

Inhibition of metabolism via CYP450 (some show competitive inhibition via CYP2C19)

Monitor for ≠ side-effects, and ↓ dose as necessary. Likely to delay recovery after procedures for which BZDs have been used. Consider alternative proton pump inhibitor, e.g. lansoprazole or pantoprazole

BUSPIRONE

BUSPIRONE ANTIBIOTICS

BUSPIRONE MACROLIDES ≠ buspirone levels Inhibition of CYP3A4-mediated metabolism

Warn patients to be aware of additional sedation

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NERVOUS SYSTEM DRUGS ANXIOLYTICS AND HYPNOTICS Buspirone

Induction of CYP3A4-mediated metabolism

Watch for poor response to buspirone; consider increasing the dose

BUSPIRONE ANTICANCER AND IMMUNOMODULATING DRUGS – PROCARBAZINE

Risk of elevation of blood pressure Additive effect; buspirone acts at serotonin receptors; procarbazine inhibits the breakdown of sympathomimetics

Avoid concurrent use

BUSPIRONE ANTIDEPRESSANTS – MAOIs

Cases of hypertension Uncertain Monitor BP closely

BUSPIRONE ANTIFUNGALS – ITRACONAZOLE, KETOCONAZOLE

≠ buspirone levels Inhibition of CYP3A4-mediated metabolism

Warn patients to be aware of additional sedation

BUSPIRONE ANTIVIRALS – PROTEASE INHIBITORS

≠ adverse effects, e.g. prolonged sedation

Inhibition of CYP3A4-mediated metabolism of BZDs and buspirone

Watch closely for ≠ sedation; ↓ dose of sedative as necessary. Some recommend considering substituting long-acting for shorter-acting BZDs with less active metabolites (e.g. lorazepam for diazepam)

BUSPIRONE ANXIOLYTICS AND HYPNOTICS – SODIUM OXYBATE

Risk of CNS depression – coma, respiratory depression

Additive depression of CNS Avoid co-administration

BUSPIRONE CALCIUM CHANNEL BLOCKERS

Plasma concentrations of buspirone are ≠ by diltiazem and verapamil

Diltiazem and verapamil inhibit CYP3A4-mediated metabolism of buspirone

Start buspirone at a lower dose (2.5 mg twice a day is suggested by the manufacturers) in patients on calcium channel blockers

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Mechanism Precautions

depression

Possibly ≠ bioavailability, ↓ presystemic metabolism. Constituents of grapefruit juice irreversibly inhibit intestinal CYP3A4. Transport via P-gp and MRP-2 efflux pumps is also inhibited

Avoid concomitant use. Be particularly vigilant in elderly patients or those with impaired liver function. Consider an alternative, e.g. temazepam

CHLORAL HYDRATE

CHLORAL HYDRATE ANTIDEPRESSANTS

CHLORAL HYDRATE MAOIs Case report of fatal hyperpyrexia and cases of hypertension

Uncertain Avoid co-administration

CHLORAL HYDRATE SSRIs Case of excessive drowsiness Uncertain; possibly additive effects, possibly displacement of chloral hydrate from proteinbinding sites

Warn patients to be aware of additional sedation

CHLORMETHIAZOLE

CHLORMETHIAZOLE H2 RECEPTOR BLOCKERS – CIMETIDINE

≠ efficacy and adverse effects, e.g. sedation, ‘hangover’ effect

Inhibition of metabolism Monitor closely; ↓ dose may be required

MEPROBAMATE

MEPROBAMATE OESTROGENS, PROGESTERONES

Reports of breakthrough bleeding when meprobamate is co-administered with oral contraceptives

Uncertain The clinical significance is uncertain. It would seem to be wise to advise patients to use an alternative form of contraception during and for 1 month after stopping meprobamate

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NERVOUS SYSTEM DRUGS ANXIOLYTICS AND HYPNOTICS Zaleplon, zolpidem, zopiclone

3. ANTIDEPRESSANTS – TCAs 4. ANTIEPILEPTICS – barbiturates 5. ANTIHISTAMINES 6. ANTIPSYCHOTICS 7. ANXIOLYTICS AND HYPNOTICS – BZDs, buspirone

Additive depression of CNS Avoid co-administration. Caution even with relatively non-sedating antihistamines (cetrizine, desloratidine, fexofenadine, levocetirizine, loratidine, mizolastine) as they can impair the performance of skilled tasks

ZALEPLON, ZOLPIDEM, ZOPICLONE

ZALEPLON, ZOLPIDEM, ZOPICLONE

ANTIBIOTICS – RIFAMPICIN ↓ levels of these hypnotics Induction of CYP3A4-mediated metabolism

Watch for poor response to these agents

ZOLPIDEM ANTIDEPRESSANTS – FLUOXETINE, PAROXETINE, SERTRALINE, VENLAFAXINE

Cases of agitation hallucinations Uncertain Avoid co-administration

ZALEPLON, ZOLPIDEM, ZOPICLONE

ANTIEPILEPTICS – CARBAMAZEPINE, RIFAMPICIN

↓ levels of these hypnotics Induction of CYP3A4-mediated metabolism

Watch for poor response to these agents

ZALEPLON, ZOLPIDEM, ZOPICLONE

ANTIFUNGALS – KETOCONAZOLE

≠ zolpidem levels reported; likely to occur with zaleplon and zopiclone

Inhibition of CYP3A4-mediated metabolism

Warn patients of the risk of ≠ sedation

ZOLPIDEM, ZOPICLONE ANTIPSYCHOTICS – CHLORPROMAZINE

Risk of sedation Additive effect; uncertain why this occurs more with chlorpromazine

Warn patients of this effect

ZOLPIDEM DRUG DEPENDENCE THERAPIES – BUPROPION

Cases of agitation hallucinations Uncertain Avoid co-administration