chapter
Selective phosphodiesterase inhibitors
Pages 9

Monitor BP closely as unpredictable responses can occur. Advise patients to drink only in moderation and avoid large variations in the amount of alcohol drunk

SELECTIVE PHOSPHODIESTERASE INHIBITORS

ENOXIMONE, MILRINONE ANAGRELIDE Risk of adverse effects Additive effect; anagrelide has phosphodiesterase inhibitory activity

Avoid co-administration

ENOXIMONE BRONCHODILATORS – THEOPHYLLINE

Theophylline may ↓ efficacy of enoximone

Possibly competitive inhibition of selective phosphodiesterases

Be aware; watch for poor response to enoximone

SYMPATHOMIMETICS

SYMPATHOMIMETICS ANAESTHETICS – GENERAL

DIRECT ANAESTHETICS – GENERAL 1. Risk of arrhythmias when inhalational anaesthetics are coadministered with epinephrine or norepinephrine 2. Case report of marked ≠ BP when phenylephrine eye drops given during general anaesthesia

1. Inhalational anaesthetics seem to sensitize the myocardium to beta-adrenoceptor stimulation 2. Uncertain

1. Use epinephrine in the smallest possible dose (when using 1 in 100 000 infiltration to ↓ intraoperative bleeding, no more than 10 mL per 10 minutes and less than 30 mL/hour should be given) 2. Use alternative mydriatic drops during general anaesthesia

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2. Case report of ↓ sedative effect of midazolam and ketamine from methylphenidate

1. Uncertain; it is possible that inhalational anaesthetics sensitize the myocardium to sympathetic stimulation 2. Uncertain at present

Avoid giving methylphenidate on the day of elective surgery

INDIRECT ANALGESICS Dexamfetamine and methylphenidate ≠ the analgesic effects and ↓ the sedation of opioids when used for chronic pain

Uncertain; complex interaction between the sympathetic nervous system and the opioid receptors

Opioid requirements may be ↓ when patients also take indirect sympathomimetics

SYMPATHOMIMETICS ANTACIDS – SODIUM BICARBONATE

Possibly ≠ ephedrine/ pseudoephedrine levels

Alkalinising urine ↓ excretion of these sympathomimetics

Watch for early features of toxicity

SYMPATHOMIMETICS ANTIBIOTICS

SYMPATHOMIMETICS LINEZOLID Risk of ≠ BP when linezolid is co-ingested with either direct or indirect sympathomimetics

Linezolid causes accumulation of norepinephrine at the nerve ends; sympathomimetics stimulate the release of these ≠ reserves of norepinephrine, which in turn causes vasoconstriction and a rise in BP

Monitor BP closely; watch for ≠ BP. Warn patients taking linezolid not to take OTC remedies containing sympathomimetics

DIRECT VANCOMYCIN Vancomycin levels are ↓ by dobutamine or dopamine

Uncertain at present Monitor vancomycin levels closely

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Mechanism Precautions

PROCARBAZINE

metaraminol, methylphenidate, phenylephrine or pseudoephedrine (including nasal and ophthalmic solutions) with procarbazine may cause a prolongation and ≠ intensity of the cardiac stimulant effects and effects on BP, which may lead to headache, arrhythmias, hypertensive or hyperpyretic crisis

The metabolism of sympathomimetics is impaired due to an inhibition of MAO

It is recommended that sympathomimetics not be administered during and within 14 days of stopping procarbazine. Do not use any OTC nasal decongestants (sprays or oral preparations) or asthma relief agents without consulting the pharmacist/doctor

INDIRECT CICLOSPORIN Methylphenidate may ≠ ciclosporin levels

Uncertain at present Watch for ciclosporin toxicity; ↓ levels as necessary and monitor levels if available

INDIRECT CORTICOSTEROIDS Ephedrine may ↓ dexamethasone levels

Uncertain at present Watch for poor response to dexamethasone; uncertain at present if other corticosteroids are similarly affected

INDIRECT ANTICOAGULANTS Methylphenidate may ≠ efficacy of warfarin

Uncertain at present Monitor INR closely

SYMPATHOMIMETICS ANTIDEPRESSANTS

DIRECT MAOIs Risk of adrenergic syndrome – see above. Unlikely to occur with moclobemide and selegiline. This is likely with some OTC medications, which may contain some of these sympathomimetics

Due to inhibition of MAOI, which breaks down sympathomimetics. Moclobemide is involved in the breakdown of serotonin, while selegiline is mainly involved in the breakdown of dopamine

Avoid concurrent use. Onset may be 6-24 hours after ingestion. Do an ECG; measure electrolytes, FBC, CK and coagulation profile. Before prescribing/dispensing, enquire about the use of MAOI antidepressants and related drugs such as linezolid

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2. Case reports of psychiatric disturbances when methylphenidate was given with sertraline and phenylpropanolamine co-administered with phenylpropanolamine

1. Uncertain; postulated that it is an additive effect of the inhibition of serotonin reuptake by citalopram with the release of serotonin by venlafaxine 2. Uncertain

1. Avoid co-administration of dexamfetamine and citalopram 2. Warn patients to watch for early signs such as anxiety

INDIRECT TCAs 1. Methylphenidate ≠ TCA levels, which may improve their efficacy, but cases of toxicity with imipramine have been reported 2. TCAs possibly ↓ efficacy of indirect sympathomimetics

1. Uncertain; postulated to be due to inhibition of the hepatic metabolism of TCAs 2. Indirect sympathomimetics cause release of norepinephrine from the nerve endings; this is blocked by TCAs

1. Warn patients to watch for early signs of ≠ TCA efficacy such as drowsiness and dry mouth 2. Watch for poor response to indirect sympathomimetics

DIRECT TCAs ≠ efficacy of norepinephrine, epinephrine or phenylephrine when co-administered with TCAs; risk of ≠ BP and tachyarrhythmias

TCAs block reuptake of norepinephrine into the nerve terminals, which prolongs its activity

Monitor PR, BP and ECG closely; start inotropes at a lower dose. It would be advisable to monitor PR and BP even when using local anaesthetics containing epinephrine, although there is no evidence of significant toxicity

INDIRECT OTHER – VENLAFAXINE Case report of serotonin syndrome when dexamfetamine was coadministered with venlafaxine

Uncertain; postulated to be an additive effect of the inhibition of serotonin reuptake by venlafaxine and the release of serotonin by venlafaxine

Avoid co-administration

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Mechanism Precautions

Epinephrine causes the release of glucose from the liver and is an important defence/homeostatic mechanism. Hyperglycaemia may occur due to an antagonistic effect

Larger doses of antidiabetic therapy may be needed during the period of epinephrine use, which is usually in the short term or in emergency situations

SYMPATHOMIMETICS ANTIHYPERTENSIVES AND HEART FAILURE DRUGS

SYMPATHOMIMETICS ACE INHIBITORS, ADRENERGIC NEURONE BLOCKERS

↓ hypotensive effect. Note there is a risk of interactions even with topical sympathomimetics (eye and nose drops)

Adrenergic neurone blockers act mainly by preventing release of norepinephrine. Sympathomimetics ≠ cardiac output and/or cause vasoconstriction

Monitor BP at least weekly until stable

DIRECT ADRENERGIC NEURONE BLOCKERS

For patients on guanethidine, ≠ pressor effects have been reported with the administration of norepinephrine and metaraminol, as has a lower threshold for arrhythmias with norepinephrine. Prolonged mydriasis has been reported when eye drops were given to patients on guanethidine

Guanethidine blocks the release of norepinephrine from adrenergic neurones; this causes a hypersensitivity of the receptors that are normally stimulated by norepinephrine, and leads to the ≠ response when they are stimulated by directly acting sympathomimetics

Start alpha-and beta-1 agonists at a lower dose; monitor BP and cardiac rhythm closely

DIRECT CENTRALLY ACTING ANTIHYPERTENSIVES

Risk of ≠ BP when clonidine is given with epinephrine or norepinephrine

Additive effect; clonidine use is associated with ≠ circulating catecholamines

Monitor BP at least weekly until stable

INDIRECT CENTRALLY ACTING ANTIHYPERTENSIVES

1. Indirect sympathomimetics may ↓ the hypotensive effect of methyldopa 2. Methyldopa may ↓ the mydriatic effect of ephedrine eye drops

1. Uncertain 2. Uncertain Monitor BP at least weekly until stable; watch for poor response to methyldopa

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↓ hydralazine

Additive effect Avoid co-administration

SYMPATHOMIMETICS ANTIMUSCARINICS – ATROPINE

Reports of hypertension when atropine was given to patients receiving 10% phenylephrine eye drops during eye surgery

Atropine abolishes the cholinergic response to phenylephrineinduced vasoconstriction

Use a lower concentration of phenylephrine

SYMPATHOMIMETICS ANTIPARKINSON’S DRUGS

INDIRECT BROMOCRIPTINE Case reports of severe, symptomatic ≠ BP when coadministered with indirect sympathomimetics

Likely additive effect; both can cause ≠ BP

Monitor BP closely; watch for ≠ BP

INDIRECT ENTACAPONE Cases of severe, symptomatic ≠ BP when co-administered with indirect sympathomimetics

Likely additive effect; both can cause ≠ BP

Monitor BP closely; watch for ≠ BP

SYMPATHOMIMETICS RASAGILINE Risk of adrenergic syndrome – see above

Due to inhibition of MAOI, which breaks down sympathomimetics

Avoid concurrent use. Onset may be 6-24 hours after ingestion. Do ECG; measure electrolytes, FBC, CK and coagulation profile

DIRECT SELEGILINE Case report of ≠ hypertensive effect of dopamine when it was given to a patient already taking selegiline

Selegiline inhibits metabolism of dopamine

Titrate dopamine carefully

SYMPATHOMIMETICS ANTIPSYCHOTICS

SYMPATHOMIMETICS ANTIPSYCHOTICS Hypertensive effect of sympathomimetics are antagonized by antipsychotics

Dose-related ↓ BP (due to vasodilatation) is a side-effect of most antipsychotics, particularly phenothiazines

Monitor BP closely

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Mechanism Precautions

methylphenidate 2. Case report of acute dystonias with haloperidol and dexamfetamine 3. ↓ efficacy of chlorpromazine when dexamfetamine was added

1. Additive anticholinergic effect 2. Uncertain; possibly due to ≠ dopamine release 3. Uncertain

1. Watch for signs of altered bowel habit 2. Warn patients of this rare interaction 3. Avoid co-administration

SYMPATHOMIMETICS ANTIVIRALS – PROTEASE INHIBITORS

1. Risk of serotonin syndrome when dexamfetamine is administered with ritonavir 2. Indinavir may ≠ phenylpropanolamine levels

1. Protease inhibitors inhibit CYP2D6-mediated metabolism 2. Likely inhibition of phenylpropanolamine metabolism

1. Avoid co-administration 2. Monitor BP closely; watch for marked ≠ BP

SYMPATHOMIMETICS BETA-BLOCKERS

DIRECT BETA-BLOCKERS 1. Severe ≠ BP and bradycardia with non-cardioselective betablockers (including reports of severe ≠ BP in patients given infiltrations of local anaesthetics containing epinephrine and one case of a fatal reaction with phenylephrine eye drops) 2. Patients on beta-blockers may respond poorly to epinephrine when it is given to treat anaphylaxis

1. Unopposed alpha stimulation causes vasoconstriction, which results in a rise in BP. Beta-2 receptors, when stimulated, cause vasodilatation, which counteracts the alpha action; non-selective beta-blockers antagonize beta-2 receptors

1. Monitor BP closely. When using local anaesthetics with epinephrine, use small volumes of low concentrations (such as 1 in 200 000 epinephrine); avoid high concentrations (e.g. 1 in 1000 mixtures) 2. Look for failure of epinephrine therapy and consider using salbutamol or isoprenaline

INDIRECT BETA-BLOCKERS ↓ hypotensive efficacy of betablockers

The hypertensive effect of sympathomimetics opposes the hypotensive actions of beta-blockers

Monitor BP at least weekly until stable; watch for poor response to beta-blockers

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Alkalinizing urine ↓ the excretion of these sympathomimetics

Watch for early features of toxicity (tremor, insomnia and tachycardia)

INDIRECT THEOPHYLLINE ≠ incidence of side-effects of theophylline (without a change in its serum concentrations) when co-administered with ephedrine

Uncertain Warn patients to avoid OTC remedies containing ephedrine

DIRECT THEOPHYLLINE Case report of marked tachycardia when dobutamine was given to a patient already taking theophylline

Uncertain Carefully titrate the dose of dobutamine in patients taking dobutamine

DIRECT CALCIUM COMPOUNDS Parenteral calcium administration may ↓ the positive inotropic effects of epinephrine and dobutamine

Uncertain; postulated that calcium modulates the signal transmission from the receptor

Monitor BP closely; watch for poor response to these inotropes

SYMPATHOMIMETICS CNS STIMULANTS – MODAFINIL

May ↓ modafinil levels with dexamfetamine, methylphenidate

Due to delayed absorption Be aware

SYMPATHOMIMETICS DOXAPRAM Risk of ≠ BP Uncertain at present Monitor BP closely SYMPATHOMIMETICS DRUG DEPENDENCE THERAPIES

AMPHETAMINES BUPROPION 1. ≠ plasma concentrations of these substrates, with risk of toxic effects 2. ≠ risk of seizures. This risk is marked in elderly people, patients with a history of seizures, those with an addiction to opiates/ cocaine/stimulants, and those with diabetes treated with oral hypoglycaemics or insulin

1. Bupropion and its metabolite hydroxybupropion inhibit CYP2D6 2. Bupropion is associated with a dose-related risk of seizures. These drugs that lower seizure threshold are individually epileptogenic. They have additive effects when combined

1. Initiate therapy with these drugs, particularly those with a narrow therapeutic index, at the lowest effective dose. Interaction is likely to be important with substrates for which CYP2D6 is considered the only metabolic pathway (e.g. amphetamines) 2. Extreme caution. The dose of bupropion should not exceed 450 mg/day (or 150 mg/day in those with severe hepatic cirrhosis)

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Mechanism Precautions

Additive effects; these drugs interfere with dopamine metabolism

Caution with co-administration. Warn patients and carers to watch for early features

SYMPATHOMIMETICS ERGOT DERIVATIVES

SYMPATHOMIMETICS ERGOT DERIVATIVES Risk of ergot toxicity when ergotamine is co-administered with sympathomimetics

Uncertain Watch for early features of ergotamine toxicity (vertigo and gastrointestinal disturbance)

DIRECT ERGOT DERIVATIVES Case report of gangrene when dopamine was given to a patient on ergotamine

Thought to be due to additive vasoconstriction

Titrate dopamine carefully

SYMPATHOMIMETICS H2 RECEPTOR BLOCKERS ≠ efficacy and adverse effects of sympathomimetics

Unclear ≠ hypertensive response; dose reduction may be required. Monitor ECG for tachycardias

SYMPATHOMIMETICS OXYTOCICS Risk of ≠ BP when oxytocin co-administered with ephedrine, metaraminol, norepinephrine or pseudoephedrine

Additive vasoconstriction Monitor PR, BP and ECG closely; start inotropes at a lower dose