chapter
Antiparkinson’s drugs
Pages 12

Warn patient of this additive effect

AMANTADINE 1. ANTIEMETICS – metoclopramide 2. ANTIPSYCHOTICS 3. CENTRALLY ACTING ANTIHYPERTENSIVES – methyldopa 4. TETRABENAZINE

↓ efficacy of amantadine Antagonism of antiparkinson’s effect; these drugs have extrapyramidal side-effects

Use with caution; avoid in patients 20 years

AMANTADINE 1. ANTIPARKINSON’S DRUGS – dopaminergics 2. ANTIDEMENTIA DRUGS – memantine 3. DRUG DEPENDENCE THERAPIES – bupropion

≠ CNS side-effects Additive effects Monitor more closely for confusion and gastrointestinal side-effects. Initiate therapy with bupropion at the lowest dose and ≠ it gradually. Manufacturers recommend avoiding co-administration of amantadine and memantine

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Effect Mechanism Precautions

pramipexole

≠ ↓ renal excretion Monitor closely for confusion, disorientation, headache, dizziness and nausea

ANTIMUSCARINICS

ANTIMUSCARINICS ADDITIVE ANTICHOLINERGIC EFFECTS

ANTIMUSCARINICS 1. ANALGESICS – nefopam 2. ANTIARRHYTHMICS – disopyramide, propafenone 3. ANTIDEPRESSANTS – TCAs 4. ANTIEMETICS – cyclizine 5. ANTIHISTAMINES – chlorphenamine, cyproheptadine, hydroxyzine 6. ANTIPARKINSON’S DRUGS – dopaminergics 7. ANTIPSYCHOTICS – phenothiazines, clozapine, pimozide 8. MUSCLE RELAXANTS – baclofen 9. NITRATES – isosorbide dinitrate

≠ risk of antimuscarinic sideeffects. NB å efficacy of sublingual nitrate tablets

Additive effect; both drugs cause antimuscarinic sideeffects. Antimuscarinic effects å saliva production, which å dissolution of the tablet

Warn patient of this additive effect. Consider changing the formulation to a sublingual nitrate spray

ATROPINE, GLYCOPYRRONIUM

ALCOHOL ≠ sedation Additive effect Warn patients about this effect and advise them not to drink while taking these antimuscarinics

ANTIMUSCARINICS ANALGESICS – PARACETAMOL Atropine, benzatropine, orphenadrine, procyclidine and trihexyphenidyl may slow the onset of action of intermittentdose paracetamol

Anticholinergic effects delay gastric emptying and absorption

Warn patients that the action of paracetamol may be delayed. This will not be the case when paracetamol is taken regularly

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NERVOUS SYSTEM DRUGS ANTIPARKINSON’S DRUGS Antimuscarinics

Anticholinergic effects delay gastric emptying and absorption

May slow the onset of action of the first dose of mexiletine, but is not of clinical significance for regular dosing (atropine does not ↓ total dose absorbed)

TOLTERODINE ANTIBIOTICS – CLARITHROMYCIN, ERYTHROMYCIN

≠ tolterodine levels Inhibition of CYP3A4mediated metabolism

Avoid co-administration (manufacturers’ recommendation)

DARIFENACIN ANTICANCER AND IMMUNOMODULATING DRUGS – CICLOSPORIN

≠ levels of darifenacin Ciclosporin inhibits P-gp and CYP3A4, which results in ↓ clearance of darifenacin

Avoid co-administration

ANTIMUSCARINICS ANTIDEMENTIA DRUGS – MEMANTINE

Possible ≠ efficacy of antimuscarinics

Additive effect; memantine has weak antimuscarinic properties

Warn patients of this effect

ANTIMUSCARINICS ANTIDEPRESSANTS

DARIFENACIN, PROCYCLIDINE

PAROXETINE ≠ levels of these antimuscarinics

Inhibition of metabolism Watch for early features of toxicity

IPRATROPIUM, TIOTROPIUM

MAOIs ≠ occurrence of antimuscarinic effects such as blurred vision, confusion (in elderly people), restlessness and constipation

Additive antimuscarinic effects Warn patients and carers, particularly those managing elderly patients

ANTIMUSCARINICS ANTIDEPRESSANTS – MAOIs ≠ occurrence of antimuscarinic effects such as blurred vision, confusion (in elderly people), restlessness and constipation

Additive antimuscarinic effects Warn patients and carers, particularly those managing elderly patients

ANTIMUSCARINICS ANTIEMETICS – DOMPERIDONE, METOCLOPRAMIDE

↓ efficacy of domperidone on gut motility by antimuscarinics

Some effects of metoclopramide are considered to be due to ≠ release of ACh and ≠ sensitivity of the cholinergic receptors to ACh. Antimuscarinics prevent the effects on muscarinic receptors

The gastrointestinal effects of metoclopramide will be impaired, while the antiemetic effects may not be. Thus, concurrent use with antimuscarinics is not advised because of effects on the gastrointestinal system

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Mechanism Precautions

KETOCONAZOLE

tolterodine levels

1. ↓ absorption 2. Inhibited metabolism

1. Watch for poor response to ketoconazole 2. Avoid co-administration of itraconazole, ketoconazole and these antimuscarinics. The US manufacturer of darifenacin recommends that its dose should not exceed 7.5 mg/day

PROTEASE INHIBITORS ANTIVIRALS

SOLIFENACIN PROTEASE INHIBITORS ≠ adverse effects with nelfinavir and ritonavir (with or without lopinavir)

Inhibition of CYP3A4-mediated metabolism of solifenacin

Limit maximum dose of solifenacin to 5 mg daily

TOLTERODINE PROTEASE INHIBITORS Possibly ≠ adverse effects, including arrythmias, with protease inhibitors

Inhibition of CYP2D6-and 3A4mediated metabolism of tolterodine

Avoid co-administration

ANTIMUSCARINICS ANTIPARKINSON’S – AMANTADINE

≠ risk of antimuscarinic side-effects Additive effect; both drugs cause antimuscarinic side-effects

Warn patients of this additive effect

IPRATROPIUM BRONCHODILATORS – SALBUTAMOL

A few reports of acute angle closure glaucoma when nebulized ipratropium and salbutamol were co-administered

Ipratropium dilates the pupil, which ↓ drainage of aqueous humour, while salbutamol ≠ production of aqueous humour

Warn patients to prevent the solution to mist or enter the eye. Extreme caution in co-administering these bronchodilators by the nebulized route in patients with a history of acute closed-angle glaucoma

DARIFENACIN CALCIUM CHANNEL BLOCKERS – VERAPAMIL

≠ darifenacin levels Inhibition of CYP3A4-mediated metabolism of darifenacin

Avoid co-administration (manufacturers’ recommendation)

PROPANTHELINE CARDIAC GLYCOSIDES – DIGOXIN

≠ digoxin levels (30-40%) but only with slow-release formulations

Slowed gut transit time allows more digoxin to be absorbed

Use alternative formulation of digoxin

ANTIMUSCARINICS PARASYMPATHOMIMETICS ↓ efficacy of parasympathomimetics

Parasympathomimetics and antimuscarinics have opposing effects

Avoid co-administration where possible

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NERVOUS SYSTEM DRUGS ANTIPARKINSON’S DRUGS Dopaminergics

drops during eye surgery

Atropine abolishes the cholinergic response to phenylephrineinduced vasoconstriction

Use a lower concentration of phenylephrine

DOPAMINERGICS

DOPAMINERGICS DRUGS WITH ANTIMUSCARINIC EFFECTS

DOPAMINERGICS 1. ANALGESICS – nefopam 2. ANTIARRHYTHMICS – disopyramide, propafenone 3. ANTIDEPRESSANTS – TCAs 4. ANTIEMETICS – cyclizine 5. ANTIHISTAMINES – chlorphenamine, cyproheptadine, hydroxyzine 6. ANTIMUSCARINICS – atropine, benzatropine, cyclopentolate, dicycloverine, flavoxate, homatropine, hyoscine, orphenadrine, oxybutynin, procyclidine, propantheline, tolterodine, trihexyphenidyl, tropicamide 7. ANTIPSYCHOTICS – phenothiazines, clozapine, pimozide 8. MUSCLE RELAXANTS – baclofen 9. NITRATES – isosorbide dinitrate

≠ risk of antimuscarinic sideeffects. Also, possibly ↓ levodopa levels. NB å efficacy of sublingual nitrate tablets

Additive effect. Delayed gastric emptying may cause more levodopa to be metabolized within the wall of the gastrointestinal tract. Antimuscarinic effects å saliva production, which å dissolution of the tablet

Warn patients of this additive effect. Consider increasing the dose of levodopa. Consider changing the formulation to a sublingual nitrate spray

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Mechanism Precautions

AGENTS

Uncertain Monitor EGC and BP closely. Consider using intravenous agents for maintenance of anaesthesia

DOPAMINERGICS ANALGESICS

DOPAMINERGICS NEFOPAM ≠ anticholinergic effects Additive effects Warn patients about these effects RASAGILINE, SELEGILINE OPIOIDS – PETHIDINE,

TRAMADOL 1. Risk of neurological toxicity when pethidine is co-administered with rasagiline 2. Risk of hyperpyrexia when pethidine and possibly tramadol is co-administered with selegiline

Unknown 1. Avoid co-administration; do not use pethidine for at least 2 weeks after stopping rasagiline 2. Avoid co-administration

DOPAMINERGICS PARACETAMOL Amantadine, bromocriptine, levodopa, pergolide, pramipexole and selegiline may slow the onset of action of intermittent-dose paracetamol

Anticholinergic effects delay gastric emptying and absorption

Warn patients that the action of paracetamol may be delayed. This will not be the case when paracetamol is taken regularly

DOPAMINERGICS ANTIBIOTICS

BROMOCRIPTINE, CABERGOLINE

ERYTHROMYCIN ≠ bromocriptine and cabergoline levels

Inhibition of metabolism Monitor BP closely and watch for early features of toxicity (nausea, headache, drowsiness)

ROPINIROLE CIPROFLOXACIN ≠ ropinirole levels Inhibition of CYP1A2-mediated metabolism

Watch for early features of toxicity (nausea, drowsiness)

DOPAMINERGICS ANTICANCER AND IMMUNOMODULATING DRUGS

BROMOCRIPTINE CYTOTOXICS – PROCARBAZINE

May cause ≠ serum prolactin levels and interfere with the effects of bromocriptine

Uncertain Watch for ↓ effect of bromocriptine

BROMOCRIPTINE HORMONE ANTAGONISTS – OCTREOTIDE

≠ bromocriptine levels Uncertain Be aware

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NERVOUS SYSTEM DRUGS ANTIPARKINSON’S DRUGS Dopaminergics

Uncertain at present Monitor INR at least weekly until stable

MEMANTINE

dopaminergics

Memantine has some agonist activity at dopamine receptors

Be aware. May be used therapeutically

DOPAMINERGICS ANTIDEPRESSANTS

LEVODOPA, SELEGILINE, POSSIBLY RASAGILINE, ENTACAPONE, TOLCAPONE

MAOIs Risk of adrenergic syndrome – hypertension, hyperthermia, arrhythmias – and dopaminergic effects with selegiline

Levodopa and related drugs are precursors of dopamine. Levodopa is predominantly metabolized to dopamine, and a smaller proportion is converted to epinephrine and norepinephrine. Effects are due to inhibition of MAOI, which breaks down dopamine and sympathomimetics

Avoid concurrent use. Onset may be 6-24 hours after ingestion. Carbidopa and benserazide, which inhibit dopa decarboxylase that converts L-dopa to dopamine, is considered to minimize this interaction. However, MAOIs should not be used in patients with Parkinson’s disease on treatment with levodopa. Imipramine and amitriptyline are considered safer by some clinicians

RASAGILINE, SELEGILINE SSRIs, VENLAFAXINE Risk of severe hypertensive reactions and of serotonin syndrome ➣ For signs and symptoms of serotonin toxicity, see Clinical Features of Some Adverse Drug Interactions, Serotonin toxicity and serotonin syndrome

Additive inhibitory effect on serotonin the reuptake with SSRIs. Venlafaxine inhibits the reuptake of both serotonin and norepinephrine. Due to impaired metabolism of these amines, there is an accumulation of serotonin and norepinephrine in the brain and at peripheral sites. These dopaminergics are MAO-B inhibitors

Avoid co-administration. Rasagiline and selegiline should not be started for at least 2 weeks after stopping SSRIs (5 weeks after fluoxetine). Do not start selegiline or rasagiline for at least 1 week after stopping venlafaxine. Conversely, SSRIs and venlafaxine should not be started for at least 2 weeks after stopping rasagiline and selegiline

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Mechanism Precautions

≠ tions of TCAs, with risk of toxic effects. ≠ risk of serotonin syndrome and of adrenergic syndrome with older MAOIs. Clomipramine may trigger acute confusion in Parkinson’s disease when used with selegiline

TCAs are believed to also act by inhibiting the reuptake of serotonin and norepinephrine, increasing the risk of serotonin and adrenergic syndromes. The combination of TCAs and antidepressants can ≠ risk of seizures

Very hazardous interaction. Avoid concurrent use and consider the use of an alternative antidepressant. Be aware that seizures occur with overdose of TCAs just before cardiac arrest

ROPINIROLE SSRI – FLUVOXAMINE ≠ ropinirole levels Inhibition of CYP1A2-mediated metabolism

Watch for early features of toxicity (nausea, drowsiness)

RASAGILINE, SELEGILINE ANTIDIABETIC DRUGS – INSULIN, SULPHONYLUREAS

≠ risk of hypoglycaemic episodes These drugs are MAO-B inhibitors. MAOIs have an intrinsic hypoglycaemic effect and are considered to enhance the effect of hypoglycaemic drugs

DOPAMINERGICS ANTIEMETICS

DOPAMINERGICS METOCLOPRAMIDE ↓ efficacy of dopaminergics Metoclopramide is a centrally acting antidopaminergic

Use with caution, avoid in patients 20 years. Manufacturers recommend avoiding co-administration of metoclopramide with ropinirole or rotigotine

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NERVOUS SYSTEM DRUGS ANTIPARKINSON’S DRUGS Dopaminergics

Domperidone and metoclopramide are associated with prolactin secretion

Use alternative antiemetics when bromocriptine and cabergoline are being used to treat prolactinomas. Domperidone has minimal central antidopaminergic effect and may therefore be used when bromocriptine and cabergoline are administered as treatments for Parkinson’s disease

LEVODOPA ANTIEPILEPTICS – PHENYTOIN

Possibly ↓ levodopa levels Uncertain Watch for poor response to levodopa and consider increasing its dose

DOPAMINERGICS ANTIHYPERTENSIVES AND HEART FAILURE DRUGS

LEVODOPA ANTIHYPERTENSIVES AND HEART FAILURE DRUGS

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

LEVODOPA CENTRALLY ACTING ANTIHYPERTENSIVES

1. Clonidine may oppose the effect of levodopa/carbidopa 2. Methyldopa may ↓ levodopa requirements, although there are case reports of deteriorating dyskinesias in some patients

1. Uncertain at present 2. Uncertain at present

1. Watch for deterioration in control of symptoms of Parkinson’s disease 2. Levodopa needs may ↓; in cases of worsening Parkinson’s control, use an alternative antihypertensive

PERGOLIDE ACE INHIBITORS Possible ≠ hypotensive effect Additive effect; a single case of severe ↓ BP with lisinopril and pergolide has been reported

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

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Additive effects Monitor more closely for confusion, gastrointestinal side-effects. Initiate therapy with bupropion at the lowest dose and ≠ gradually. Manufacturers recommend avoiding co-administration of amantadine and memantine

PRAMIPEXOLE AMANTADINE ≠ side-effects ↓ renal excretion Monitor closely for confusion, disorientation, headache, dizziness and nausea

DOPAMINERGICS ANTIPSYCHOTICS ↓ efficacy of dopaminergics Antipsychotics may cause extrapyramidal side-effects, which oppose the effect of antiparkinson’s drugs. The atypical antipsychotics cause less effect than the older drugs

Caution with co-administration; consider using atypical antipsychotics, and use antimuscarinic drugs if extrapyramidal symptoms occur. Manufacturers recommend avoiding co-administration of amisulpride with levodopa, and co-administration of antipsychotics with pramipexole, ropinirole and rotigotine. Clozapine can be coadministered with Sinemet and pergolide

LEVODOPA ANXIOLYTICS AND HYPNOTICS – BZDs

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

LEVODOPA BETA-BLOCKERS ≠ hypotensive effect Additive hypotensive effect; however, overall, adding beta-blockers to levodopa can be beneficial (e.g. by reducing the risk of a dopaminemediated risk of arrhythmias)

Monitor BP at least weekly until stable

LEVODOPA CALCIUM CHANNEL BLOCKERS

≠ 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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NERVOUS SYSTEM DRUGS ANTIPARKINSON’S DRUGS Dopaminergics

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

DOPAMINERGICS – ENTACAPONE, TOLCAPONE

DOPAMINERGICS – SELEGILINE

Possible risk of severe hypertensive reactions

Theoretical risk due to additive inhibitory effect on dopamine metabolism

Manufacturers recommend limiting the dose of selegiline to a maximum of 10 mg

LEVODOPA DRUG DEPENDENCE THERAPIES – BUPROPION

≠ CNS side-effects Additive effects Initiate therapy with bupropion at the lowest dose and ≠ gradually

PRAMIPEXOLE, ROPINIROLE

H2-RECEPTOR BLOCKER – CIMETIDINE

≠ efficacy and adverse effects of pramipexole

↓ renal excretion of pramipexole by inhibition of cation transport system. Inhibition of CYP1A2mediated metabolism of ropinirole

Monitor closely; ↓ dose of pramipexole may be required. Adjust dose of ropinirole as necessary or use alternative acid suppression, e.g. H2 antagonist proton pump inhibitor (not omeprazole or lansoprazole)

ENTACAPONE, LEVODOPA

IRON – ORAL ↓ entacapone levels Iron chelates with entacapone and levodopa, which ↓ their absorption

Separate doses as much as possible. Consider increasing the dose of antiparkinson’s therapy

LEVODOPA MUSCLE RELAXANTS – BACLOFEN

Reports of CNS agitation and ↓ efficacy of levodopa

Uncertain Avoid co-administration

APOMORPHINE NITRATES Risk of postural ↓ BP when apomorphine is given with nitrates

Additive effect; apomorphine can cause postural ↓ BP

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

ROPINIROLE, SELEGILINE OESTROGENS ≠ levels of ropinirole and selegiline

Inhibition of metabolism (possibly N-demethylation)

Watch for early features of toxicity (nausea, drowsiness) when starting oestrogens in a patient stabilized on these dopaminergics. Conversely, watch for poor response to them if oestrogens are stopped

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MOXISYLYTE

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

SELEGILINE PROGESTOGENS ≠ selegiline levels Inhibition of metabolism Watch for early features of toxicity (nausea, drowsiness) when starting progestogens in a patient stabilized on these dopaminergics. Conversely, watch for poor response to them if progestogens are stopped

DOPAMINERGICS SYMPATHOMIMETICS

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

Likely additive effect; both can cause ≠ BP

Monitor BP closely; watch for ≠ BP

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

Likely additive effect; both can cause ≠ BP

Monitor BP closely; watch for ≠ BP

RASAGILINE SYMPATHOMIMETICS Risk of adrenergic syndrome Due to inhibition of MAOI, which breaks down sympathomimetics

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

SELEGILINE DOPAMINE 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

LEVODOPA VITAMIN B6 ↓ efficacy of levodopa (in the absence of a dopa decarboxylase inhibitor)

A derivative of vitamin B6 is a cofactor in the peripheral conversion of levodopa to dopamine, which ↓ the amount available for conversion in the CNS. Dopa decarboxylase inhibitors inhibit this peripheral reaction

Avoid co-administration of levodopa with vitamin B6; co-administration of vitamin B6 with co-beneldopa or co-careldopa is acceptable