Ebook Drugs in use (4E): Part 2

(BQ) Part 2 book “Drugs in use” has contents: Parkinson’s disease, substance misuse, symptom control in palliative care, anticoagulant therapy, colorectal surgery, medicines management, managing medicine risk, dementia, schizophrenia,… and other contents.

18 Epilepsy

Ben Dorward

Case study and questions

Day 1 Miss SL, a 19-year-old student who had recently moved away from

home to university, was witnessed ‘having a fit’ by her friends and wastaken to the local A&E department The fit had stopped by the time shearrived and Miss SL had no recollection of the event She was sent homefrom hospital with paracetamol for the resulting headache, and referred

to a ‘faints and fits’ clinic at the local neurology department

At the neurology clinic she commented that she had been encing jerking movements for several years, most notably in the morn-ing, and that these had occasionally led to her dropping her breakfast.Her friends had also commented to her that she was prone to daydream-ing On questioning she stated that initially she had found the transition

experi-to university life quite stressful She admitted experi-to taking full advantage ofthe social opportunities, and to feeling very tired due to having to get upearly for lectures after late nights out

The neurologist made a diagnosis of juvenile myoclonic epilepsy(JME) Miss SL was prescribed lamotrigine 25 mg once daily, increasing to

50 mg once daily after 14 days, and was referred to an epilepsy nursespecialist

Q1 What is epilepsy?

Q2 Is the history of stress significant?

Q3 Do you agree with the choice of lamotrigine for Miss SL?

Q4 Is the dose of lamotrigine appropriate?

Q5 Outline a pharmaceutical care plan for Miss SL What advice would youoffer her if she asked about contraception?

Q6 What is the role of the epilepsy nurse specialist?

Month 3 Miss SL presented a prescription for lamotrigine Her dose was

now 50 mg in the morning and 50 mg at night On receiving the

prescription Miss SL commented that the tablets did not look the same asthose she was given at the hospital On further questioning you realiseshe was previously dispensed a generic brand of lamotrigine and thegeneral practitioner (GP) has prescribed the Lamictal brand

Q7 Is there a significant difference between the different brands ofantiepileptic drugs (AEDs)?

Month 4 Miss SL developed a bad chest infection As she was known to

be allergic to penicillin (previous urticarial rash to amoxicillin) the GPprescribed ciprofloxacin 500 mg twice daily for 7 days

Q8 Is the choice of ciprofloxacin appropriate?

Month 5 The lamotrigine dose had been slowly titrated up to 150 mg

twice daily but Miss SL was not responding to treatment, and now stantly felt quite tired The myoclonic jerks continued and she had hadseveral further tonic–clonic seizures The frequency of seizures wasincreasing, and this was particularly noticeable in the 2–3 days before herperiod

con-Q9 What term is used to describe epilepsy that worsens around the time ofmenstruation, and how common is it?

Q10 What drug treatments are available for this form of epilepsy?

After discussion with Miss SL and her epilepsy nurse specialist, the logist decided to change the lamotrigine to levetiracetam She was pres-cribed 250 mg twice daily and instructed to increase the dose to 500 mgtwice daily in 2 weeks’ time If she did not experience a reduction inseizure frequency after 2 weeks at 500 mg twice daily, then she was tofurther increase the dose to 750 mg twice daily At the same time she wasinstructed to reduce the morning and evening doses of lamotrigine by

Month 8 Unfortunately, Miss SL had had to withdraw from her

univer-sity studies She had become very low in mood but was not keen to take

‘antidepressants’ She had read that St John’s wort can be effective for lowmood and came to seek your advice

Q13 What advice can you offer about St John’s wort?

Q14 If indicated, what is the appropriate drug treatment for depression inpeople with epilepsy?

Month 10 Miss SL experienced a particularly bad cluster of seizures and

injured herself on falling She was admitted to a neurological ward forobservation and assessment The consultant neurologist prescribed 10 mg

of buccal midazolam to be used when required to terminate tonic–clonicseizures lasting longer than 5 minutes

Q15 What are the advantages and disadvantages of using buccal midazolamover rectal diazepam?

Month 22 Levetiracetam had been gradually titrated upwards to a dose of

1500 mg twice daily and her seizures had become well controlled Miss SLhad started a career in accounting and met a partner They had discussedstarting a family and wanted to know more about how Miss SL’s epilepsywould affect this

Q16 What are the issues concerning pregnancy in women with epilepsy?

Q17 What drug should epileptic women who wish to become pregnant take,and at what dose?

Answers

What is epilepsy?

A1 Epilepsy is a neurological disorder characterised by a tendency towards epileptic seizures An epileptic seizure is the result of abnormal electrical activity in the brain The manifestation of an epileptic seizure depends on the area of the brain affected by the abnormal electrical activity

There are two main seizure types:

(a) Generalised seizures are a result of electrical activity spreadingthrough the entire cerebral cortex They can be secondary to a focalseizure or idiopathic (see below) Absence, myoclonic and tonic–clonic (grand mal) seizures are forms of generalised seizure

(b) Partial (focal) seizures are a result of a localised electrical disturbanceand are often the result of functional changes caused by braintumours or congenital structural abnormalities such as focal corticaldysplasia Partial seizures can be further subdivided into simple–partial and complex–partial, based on whether there is an impair-ment of consciousness (complex–partial) or not (simple–partial)

There are a large number of epilepsy syndromes that can be terised by the pattern of seizure type, age of onset and response to drugtreatment Many of the generalised epilepsy syndromes have a geneticbasis The diagnosis of epilepsy is largely a clinical one An accurateeyewitness account of the seizures is one of the most useful pieces ofinformation in making a diagnosis.

charac-JME is a form of idiopathic generalised epilepsy and is one of themost common epilepsy syndromes It is characterised by myoclonicjerks and generalised tonic–clonic seizures, often shortly after waking.Many patients also have absence seizures People with JME can be photo-sensitive, i.e myoclonic and tonic–clonic seizures can be precipitated byflashing or flickering light

Is the history of stress significant?

A2 Tiredness and a lack of sleep can increase the number of seizures, particularly myoclonic seizures in JME

Also, a significant number of people presenting to a neurology clinic withpossible epilepsy will be diagnosed with non-epileptic attack disorder(NEAD) Such seizures can be called non-epileptic seizures, pseudo-seizures, functional seizures, or non-organic seizures, and although theycan look very much like epileptic seizures, during an attack an electro-encephalogram (EEG) will show no abnormal electrical brain activity.This is one of the reasons why it is very important that a person withsuspected epilepsy should be referred to a suitably trained neurologist.NEAD can often be a reaction to stress To complicate matters fur-ther, some patients with epilepsy may have non-epileptic as well asepileptic seizures There is no specific drug treatment for NEAD

Do you agree with the choice of lamotrigine for Miss SL?

A3 Sodium valproate and lamotrigine are considered first-line treatments for JME; however, sodium valproate is no longer recommended as a first-line treatment in women of childbearing potential, for a number of reasons:

(a) Teratogenicity There is a 2–3% incidence of fetal abnormalitiesamong the general population The UK Epilepsy and Pregnancy

Register (see A16b) records a major malformation rate of 5.9% for

babies born to mothers treated with sodium valproate duringpregnancy

(b) Side-effects can include weight gain, hair loss and menstrual bances, all of which are particularly undesirable in young women.The SANAD trial was a large-scale practice-based randomised controlled

distur-trial comparing the long-term outcomes of the newer antiepileptic drugs(AEDs) against the older ones One arm of the study compared valproate

to lamotrigine in the treatment of generalised epilepsy syndromes andconcluded that sodium valproate was more effective but lamotrigine wasbetter tolerated Overall, sodium valproate was the most cost-effectivetreatment for generalised epilepsy

It is generally recommended that preventative drug treatment forepilepsy should only be considered after a person experiences a secondseizure, but in certain epilepsy syndromes treatment may be warrantedbefore a second seizure occurs Miss SL’s history indicates she had alreadyexperienced absence and myoclonic seizures prior to her presentation

at A&E Many people diagnosed with JME will require lifelong drugtreatment

Is the dose of lamotrigine appropriate?

A4 Yes It is very important to adhere to the recommending starting regimen for lamotrigine, which depends on whether it is pre- scribed as monotherapy or in combination with other anti- epileptics Rapid dose escalation is associated with the development of rash, including cases of toxic epidermal necroly- sis and Stevens–Johnson syndrome, which are severe, potentially fatal hypersensitivity reactions For this reason, people started on lamotrigine should be counselled to seek medical attention immediately if they develop a rash

Lamotrigine is metabolised hepatically by glucuronidation The inducing AEDs, which include carbamazepine and phenytoin, canaccelerate the metabolism of lamotrigine, whereas sodium valproateinhibits lamotrigine glucuronidation It is therefore very important tocheck the patient’s concomitant medication to ensure the dose is appro-priate, as the starting dose and titration regimen are dependent onwhether lamotrigine is prescribed as monotherapy, in combination withsodium valproate, or in combination with enzyme-inducing AEDs

enzyme-Outline a pharmaceutical care plan for Miss SL What advice would youoffer her if she asked about contraception?

A5 The pharmaceutical care plan should ensure that her treatment is prescribed at an appropriate dose, monitored correctly, and that Miss SL receives all the information she needs about her treat- ment Checks should be made on whether Miss SL is taking any other medicines, particularly oral contraception

Before offering specific counselling to Miss SL it is important to checkwhether or not she is taking any other medication Concomitant therapy

may affect the starting dose of lamotrigine (see A4 and below).

(a) Monitoring It is not necessary to monitor serum levels of

lamo-trigine, and therapeutic dose monitoring generally has limitedapplications in monitoring AED therapy Other monitoringincludes:

i(i) Response to treatment: patients may keep a seizure diary.(ii) For adverse effects, especially rash

Women taking oral contraception should be advised to report anybreakthrough vaginal bleeding, as this suggests contraception isinadequate

(b) Contraception Although lamotrigine is not an enzyme-inducing

drug, recent evidence suggests it can reduce levels of progestogensand women taking lamotrigine need to be aware that oral contra-ceptives may not be fully effective In addition, combined oralcontraceptives can reduce lamotrigine levels Starting or stopping anoral contraceptive may thus require adjustment of the lamotriginedose The Summary of Product Characteristics recommends thatwomen’s contraceptive needs should be reviewed if lamotrigine is to

be prescribed, and they should be advised to use effective alternativenon-hormonal contraception

The efficacy of oral contraceptives is also reduced in womentaking the enzyme-inducing antiepileptics phenytoin, carba-mazepine, oxcarbazepine, phenobarbital, primidone and topira-mate, all of which enhance metabolism of the female sex hormones.The following recommendations are made for oral contraception inwomen taking enzyme-inducing AEDs:

ii(i) Enzyme-inducing AEDs are likely to render progesterone-onlycontraceptives ineffective

i(ii) Women wishing to take combined oral contraceptives shouldstart on a daily ethinylestradiol dosage of at least 50 micro-grams In practice this can be achieved by doubling the dose ofpreparations containing 30 micrograms of ethinylestradiol(iii) If breakthrough bleeding occurs then the daily ethinylestradioldose can be further increased to 75 or 100 micrograms Analternative option is to consider taking three consecutive pillpackets without a break, followed by a 4-day break, ratherthan the usual 7 (‘tri-cycling’) Non-hormonal methods ofcontraception may also be considered

(c) General counselling points that should be covered with Miss SLinclude:

iii(i) Explaining the name of the drug and the aim of treatment, i.e.

to prevent and hopefully stop further seizures The drug maynot have an instant effect, and the dose will be graduallyincreased to minimise the risk of side-effects

ii(ii) Lamotrigine needs to be taken regularly at the same time ofthe day and evenly spaced out during the day, i.e take eachdose approximately 12 hours apart for a twice-daily regimen.Written information is also beneficial for people with compli-cated treatment regimens, and for those with epilepsy whohave learning difficulties

i(iii) The potential side-effects of lamotrigine should be explained,including the importance of reporting any new rash.Gastrointestinal side-effects such as nausea can occur, as well

as tiredness and headache As with many AEDs, particularlythe older drugs, lamotrigine is associated with a risk of haema-tological toxicity and patients should be advised to seek med-ical advice if they develop symptoms suggestive of anaemia(fatigue, breathlessness etc); low platelets (bruising or bleed-ing); or infection (because of potential neutropenia)

i(iv) Miss SL needs to ensure her medication does not run out andthat doses are not missed, and needs to know where to getfurther supplies In some parts of the UK shared care protocolsfor epilepsy exist where hospitals are responsible for supplyingnewly prescribed medication until the patient is stabilised onthe new treatment Omission of doses or sudden discontinu-ation of AEDs can lead to worsening seizures, possibly statusepilepticus, and are thought to be a factor associated withsudden unexplained death in epilepsy (SUDEP) This term isused when people with epilepsy die suddenly and no obvious

cause is found at post mortem The exact cause of SUDEP is not

(vii) Miss SL could be advised of local and national support groupsfor patients with epilepsy

In developed countries with ready access to AEDs the overall nosis for people with epilepsy is good: up to 70% will have theirseizures controlled with drug treatment.

prog-What is the role of the epilepsy nurse specialist?

A6 Epilepsy clinical nurse specialists perform a vital role in providing practical and emotional support to people with epilepsy and their carers They may be based in hospital or primary care settings, and can be very useful contacts for patient-specific medication enquiries

Is there a significant difference between the different brands of AEDs?

A7 Generic versions of medicines are often significantly cheaper than branded ones Although the prescribing of generic medicines is recommended to reduce drug costs, this practice is somewhat controversial in relation to the prescribing of AEDs; however, Miss

SL can be reassured if the neurologist and GP feel it is acceptable

to switch brands, her response to lamotrigine therapy should not

be affected

The pharmacist has an important role in listening to patients’ concernsabout the appearance of their tablets and providing reassurance whenappropriate

Many of the older AEDs, such as carbamazepine and phenobarbital,have narrow therapeutic indices In the case of phenytoin, its metabolism

is saturable This means that small dose increases, such as those caused by

a switch to a slightly more bioavailable formulation, may produce a proportionate increase in the serum concentration of drug and result intoxicity There are published case reports and series describing loss of, orworsening, seizure control or side-effects after switching to an alternativebrand of AED

dis-The newer AEDs generally have more predictable pharmacokineticsand broader therapeutic indices In the case of generic lamotrigine the UKDepartment of Health has advised that there is no compelling evidence

to suggest that swapping to a generic alternative will have an adverse ical outcome More research is required into brand switching of AEDs toidentify patient groups who may be at risk

clin-In testing generic medicines, the European Agency for theEvaluation of Medicinal Products (EMEA) stipulates that to prove bio-equivalence between a generic and branded medicinal product, thebioavailability must be within 80% and 125% The pharmacokineticparameters used for comparison include the maximal concentration(Cmax) and area under the curve (AUC) A potential variation of up to25% may seem significant, but the limits of 80% and 125% are statistical

ones: they represent the 90% confidence intervals when calculating theratios of pharmacokinetic parameters between the generic and thebranded medicinal product There are some limitations of bioequivalencestudies:

(a) Bioequivalence studies are usually performed in young healthyvolunteers who are taking no other, potentially interacting, drugs.Extrapolating results from studies in healthy volunteers to anelderly population with comorbidities and concomitant drugtherapy, or to paediatric populations, may not be accurate

(b) The studies compare generic medicines to their branded equivalentbut not against other generic brands

One AED commonly associated with prescribing and administrationerrors is modified-release carbamazepine, which is often prescribed forepilepsy and has several advantages over the standard tablet formula-tions, such as less fluctuation in plasma levels, thereby reducing side-effects and improving seizure control; and twice-daily administration,which may encourage patient adherence Pharmacists should activelyclarify prescriptions for twice-daily regimens of carbamazepine if themodified-release formulation is not prescribed Occasionally, however, inpatients exquisitely sensitive to carbamazepine, the modified-releasetablets are prescribed three times a day

Is the choice of ciprofloxacin appropriate?

A8 No Ciprofloxacin is a quinolone antibiotic associated with an approximately 1% risk of seizures Quinolone antibiotics are thought to inhibit membrane receptor binding of the inhibitory neurotransmitter gamma-amino butyric acid (GABA)

A macrolide antibiotic such as erythromycin would be appropriate forMiss SL However, it is important to remember that erythromycin is astrong inhibitor of the cytochrome P450 3A4 isoenzyme and can interactwith a number of the older, hepatically metabolised AEDs, notablycarbamazepine Concomitant erythromycin therapy can increasecarbamazepine levels resulting in intoxication

What term is used to describe epilepsy that worsens around the time ofmenstruation, and how common is it?

A9 Catamenial epilepsy affects approximately 10% of women of childbearing age.

The definition of catamenial epilepsy is not an exact one, but around 10%

of women with epilepsy experience a worsening of seizures around the

time of menstruation Seizures may also worsen mid-cycle, around thetime of ovulation Catamenial seizures are thought to result from thechanging levels of sex hormones that occur throughout the menstrualcycle, in particular the reduction of serum progesterone prior to the onset

of menstruation

What drug treatments are available for this form of epilepsy?

A10 Clobazam, a benzodiazepine, is often prescribed in short courses for catamenial epilepsy.

Clobazam at a dose between 5 and 30 mg/day (sometimes higher inrefractory cases) may be prescribed to be taken on the days it is anti-cipated that seizures will be worse Clobazam is prescribed in addition tothe patient’s regular AEDs

Acetazolamide has also been used intermittently for catamenialepilepsy This is a relatively fast-acting antiepileptic that can be initiated

at a therapeutic dose Its use is based on expert opinion

Levetiracetam is not licensed as a monotherapy for generalised seizures.What is your opinion of the neurologist’s choice?

A11 AEDs are sometimes prescribed outside of their licence tions, and levetiracetam monotherapy is a reasonable choice for Miss SL

indica-The use of leveiracetam as monotherapy is reasonable in this patient.Sodium valproate is not an ideal therapeutic option because of its adverseeffect profile and teratogenicity risk Carbamazapine can exacerbatemyoclonic and absence seizures Topiramate and zomisamide are othertherapeutic options for JME

There are a number of reasons for prescribing outside licensedindications These include:

(a) Exceeding the maximum dose recommended in the Summary ofProduct Characteristics The general principle when prescribingAEDs is to start at a low dose to minimise adverse effects and thenincrease the dose until seizures are controlled or side-effects becomeunacceptable For many AEDs central nervous system (CNS) side-effects such as drowsiness and somnolence are dose related andbecome the limiting factor in dose escalation Many of the moresevere side-effects of hepatic and haematological toxicity areidiosyncratic reactions, and the incidence is not related to the drugdose; rash from lamotrigine is an exception to this

(b) Prescribing for an indication not listed in the Summary of ProductCharacteristics, e.g for use as monotherapy when it is licensed as anadjunctive therapy only Most of the newer AEDs gained marketing

authorisation as adjunctive therapy in epilepsy These tions were granted based on the results of trials using the drug asadjunctive therapy in refractory epilepsy It would be ethically verydifficult to justify a drug trial in epilepsy where a patient would begiven a placebo monotherapy, i.e no treatment Given the hetero-geneity of epilepsy and the often tight inclusion and exclusion cri-teria of drug trials, applying results from these trials to every daypractice can have limitations

authorisa-Specialist epilepsy centres may occasionally use AEDs unlicensed in the

UK for refractory cases One example is felbamate, a drug associated with

a risk of hepatic failure and aplastic anaemia People prescribed felbamaterequire close monitoring of liver function and full blood count (FBC)

Levetiracetam is one of the newer antiepileptic drugs What are theiradvantages over the older drugs?

A12 The newer AEDs include gabapentin, levetiracetam, pine, pregabalin, topiramate and zonisamide The properties of each drug should be checked individually, but generally speaking the newer AEDs have advantages over the older AEDs, including: (a) Linear pharmacokinetics which provide a more predicable dose–response relationship.

oxcarbaze-(b) Low protein binding, hence less potential to displace and be displaced by other drugs.

(c) Metabolism independent of the cytochrome P450 system, thus reducing drug interactions, particularly with oral con- traceptives.

(d) A wider therapeutic index.

(e) More acceptable side-effect profiles.

Newer AEDs are invariably more expensive than older agents In the UKnewer AEDs can be used in people who have not responded to, or areintolerant of, the older agents, or in those for whom the use of olderagents is unsuitable In women of childbearing potential the older AEDsare usually considered unsuitable because of their teratogenic risk andpotential interactions with oral contraceptives

When taking into account the factors above, and individual patientfactors, newer AEDs are sometimes used as first-line therapy

What advice can you offer about St John’s wort?

A13 In the UK St John’s wort is not recommended to be used comitantly with any AEDs

con-St John’s wort is derived from the plant Hypericum perforatum and has

antidepressant actions that are not fully understood but which may beexerted through the inhibition of neurotransmitter reuptake

St John’s wort has been shown to induce metabolism of cytochromeP450, notably the 3A4 isoenzyme, and thus has the potential to interactwith drugs metabolised by this pathway and reduce their effectiveness.Carbamazepine is metabolised by CYP 3A4

St John’s wort can also induce p-glycoprotein, a transport proteinimplicated in drug resistance in epilepsy by the mechanism of activelyexpelling drugs from neurons There are case reports of reduced efficacywhen St John’s wort has been added to AEDs not metabolised bycytochrome P450 Miss SL should thus be advised to avoid it, eventhough there is no direct interaction between this product and herprescribed therapy

If indicated, what is the appropriate drug treatment for depression inpeople with epilepsy?

A14 The tricyclic and selective serotonin reuptake inhibitor (SSRI) antidepressants all have potential to lower the seizure threshold and their use in epilepsy is cautioned against If depression in a person with epilepsy becomes severe enough to warrant drug therapy then the decision to treat with antidepressants is a clini- cal one, weighing up the risks and benefits of treatment

SSRI antidepressants are considered first-line treatment for depression inthe general population Citalopram has been advocated as an appropriatedrug to use in people with epilepsy as it is thought to confer a lower risk

of inducing seizures

Recent evidence has shown a small increased risk of suicide with theAEDs Patients need to be aware of this and know to seek medical advice

if they develop mood changes or suicidal thoughts

What are the advantages and disadvantages of using buccal midazolamover rectal diazepam?

A15 A number of benzodiazepines are used to terminate epileptic seizures Rectal diazepam (as a solution, not suppositories) has historically been used, but its use is associated with the stigma and inconvenience of having to remove clothing to enable administration.

The use of buccal midazolam as an alternative to rectal diazepam isbecoming more widespread Midazolam is sufficiently lipophilic at phys-iological pH to rapidly cross the buccal mucosa Controlled trials, mainly

in children and adolescents with severe epilepsy, have shown buccalmidazolam to be as least as effective as rectal diazepam in terminatingepileptic seizures

Buccal administration represents an unlicensed route of midazolamadministration The injection formulation can be administered buccally

or a 10 mg/mL buccal formulation (made as a pharmaceutical special inthe UK) can be used An important counselling point is to administer thedrug buccally: oral administration would put a fitting patient at risk ofchoking The drug should be given using an oral syringe positionedbetween the gum and the cheek and by splitting the dose between bothsides of the mouth A usual adult dose would be 5–10 mg, which is0.5–1 mL of a 10 mg/mL formulation With such a small volume the risk

of accidental swallowing is low

There are concerns over the risk of respiratory depression whenusing benzodiazepines outside a hospital setting, but they are relativelysafe in carefully selected patients when carers are properly trained in how

to administer and when to use them and, importantly, are clear on when

to get further help

What are the issues concerning pregnancy in women with epilepsy?

A16 There are several issues for women with epilepsy wishing to become pregnant.

(a) Fertility Fertility rates are reduced in women with epilepsy

compared to age-matched controls The possible causes of this aremultiple and probably not just purely biological

(b) Teratogenicity of AEDs In utero exposure to AEDs is associated with

a higher risk of congenital malformations Accurately assessing therisk of individual drugs is difficult because women are not alwaystreated with monotherapy; however, sodium valproate is associatedwith the highest risk of congenital malformations The teratogenicrisk of AEDs has to be balanced against the risk to mother and babyfrom uncontrolled seizures

The UK Epilepsy and Pregnancy Register was created in 1996with the aim of collecting data on pregnancy outcomes fromwomen with epilepsy taking AEDs, particularly the newer agents In

2006 data were published on pregnancy outcomes with in utero

exposure to levetiracetam Although no congenital malformationswere reported from monotherapy, it is too early to assess accuratelythe relative safety of levetiracetam in pregnancy

(c) Altered pharmacokinetics of AEDs in pregnancy In the third

trimester the serum levels of a number of AEDs, including ine, phenytoin, carbamazepine and sodium valproate, can reduce as

lamotrig-a result of lamotrig-a vlamotrig-ariety of phlamotrig-armlamotrig-acokinetic mechlamotrig-anisms Regullamotrig-armonitoring of drug levels may be required to guide clinical care

What drug should women with epilepsy who wish to become pregnanttake, and at what dose?

A17 Ideally pregnancy should be planned and drug therapy reviewed

to optimise treatment at the lowest possible doses Folic acid should be prescribed at a dose of 5 mg/day for women with epilepsy who wish to become pregnant, and should be continued throughout pregnancy

Folic acid supplementation has been shown to reduce neural tube defects

in the general population Women with epilepsy may be deficient in folicacid owing to the effects of drug therapy, and so should be prescribed ahigher dose than the general population There are anecdotal reports offolic acid exacerbating seizures, but the benefits of therapy outweigh therisk

Acknowledgement

The author would like to thank Dr Stephen Howell (ConsultantNeurologist, Sheffield Teaching Hospitals NHS Foundation Trust) forreviewing and commenting on this chapter

Mack CJ, Kuc S, Grünewald RA Errors in prescribing, dispensing and

admin-istration of carbamazepine: a case report and analysis Pharm J 2000;

265: 756–760.

Marson AG, Al-Kharusi AM, Alwaidh M et al The SANAD study of

effective-ness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, ortopiramate for treatment of partial epilepsy: an unblinded randomised

controlled trial Lancet 2007; 369: 1000–1015.

Marson AG, Al-Kharusi AM, Alwaidh M et al The SANAD study of

effective-ness of valproate, lamotrigine, or topiramate for generalised andunclassifiable epilepsy: an unblinded randomised controlled trial

Lancet 2007; 369: 1016–1026.

MHRA St John’s wort: interactions with all antiepileptics Drug Safety Update

2007; 4: 7.

National Institute for Health and Clinical Excellence TA76 Newer Drugs for

Epilepsy in Adults NICE, London, 2004.

National Institute for Health and Clinical Excellence TA79 Newer Drugs for

Epilepsy in Children NICE, London, 2004.

National Institute for Health and Clinical Excellence CG20 The Epilepsies:

The Diagnosis and Management of the Epilepsies in Adults and Children in Primary and Secondary Care NICE, London, 2004.

Perucca E Role of therapeutic drug monitoring in epilepsy Hosp Pharm Eur

19 Parkinson’s disease

Stuart Richardson

Case study and questions

Day 1 Mr LN, a 67-year-old retired bookmaker, was admitted to the

neurology ward His presenting complaints included difficulty in getting

up from chairs and initiating walking

Eighteen months earlier he had noticed that his self-winding watch,which he wore on his right wrist, was consistently losing time Whenmoved to his left wrist, the watch kept perfect time Friends had pointedout that he had developed a limp, dragging his right foot These symp-toms had worsened over the previous 18 months, and he had also devel-oped a resting tremor in his right hand and leg He had noticed changes

in his bowel habits many years previously

His general practitioner (GP) suspected Parkinson’s disease andreferred Mr LN to a neurologist for confirmation of the diagnosis

Q1 What are the main symptoms of Parkinson’s disease?

Q2 Is it possible to make a definitive diagnosis of IPD?

Q3 What biochemical defects are thought to be present in a patient such as

Mr LN?

Q4 Outline a pharmaceutical care plan for Mr LN

Q5 Which drugs are usually considered for the initial treatment of patientswith IPD and what are their modes of action?

Day 2 Mr LN was started on ropinirole

Q6 Do you agree with this choice?

Q7 How should Mr LN’s ropinirole therapy be adjusted to optimise hisresponse?

Day 13 Mr LN was discharged on ropinirole 500 micrograms three times

daily and instructed to titrate the dose as directed Mr LN’s GP was sent a

letter describing his recent admission and advice on how to further titratethe dose of ropinirole

Month 18 Mr LN was admitted for reassessment Despite never

com-pletely abating, Mr LN’s symptoms of bradykinesia and rigidity hadtemporarily improved following initiation and up-titration of ropinirole;however, recently Mr LN had experienced a worsening of these symp-toms, and his wife reported that he had become rather obsessive aboutcleaning out the garden shed, performing this task on an almost dailybasis On admission he was taking ropinirole 6 mg three times daily

Q8 What recommendations would you make with regard to Mr LN’s drugtherapy?

It was decided to start Mr LN on Sinemet Plus 125 mg three times dailyand to simultaneously reduce the dose of his dopamine agonist

Q9 How can the adverse effects of levodopa be minimised?

Month 18, Day 8 Mr LN was discharged He was now stabilised on

Sinemet Plus, two tablets three times daily, and ropinirole 4 mg threetimes daily and had experienced a significant improvement in his motorfunction

Month 66 Mr LN was again admitted for reassessment His therapy and

symptoms had remained stable on the Sinemet and ropinirole untilrecently, when he had started to notice his arms shaking about 1 hourafter each dose of Sinemet Plus This lasted for about 45 minutes beforestopping Mr LN also complained of painful dystonic cramps at night,which caused him to wake early most mornings He had attempted tocounter this by taking an extra Sinemet Plus tablet shortly before going

to bed, which sometimes helped His wife added that he was becomingprofoundly immobile up to 2 hours before his Sinemet doses were dueduring the day

On examination he was found to have a mask-like face and a ing tremor in both hands and legs ‘Cog-wheel’ rigidity was found in allfour limbs He had difficulty initiating speech and his voice was veryquiet He struggled to rise from his chair, and had a characteristic ‘parkin-sonian shuffle’ when walking When his shoulders were pulled forwardfrom standing he staggered forward and had to be supported to stop himfalling

rest-Mr LN complained of occasional falls and was not confident to leavethe house He relied on his wife to do everything for him He admitted tobeing depressed about his condition.

There was no other medical history of note All routine laboratorytests were within normal ranges His drug therapy was ropinirole 4 mgthree times daily plus two Sinemet Plus tablets at 8 am, 2 pm and 7 pmand, occasionally, one Sinemet Plus tablet at 11 pm

Q10 Which of the long-term complications of levodopa therapy is Mr LNsuffering from?

Q11 What alterations to Mr LN’s drug therapy would you recommend in order

to try to minimise these effects?

Q12 How could you monitor and assess Mr LN’s response to these changes?

Q13 Can you suggest any non-drug management that might benefit Mr LN?

Mr LN’s drug therapy was changed to one Madopar dispersible 62.5 mgtablet on waking around 7 am, and one Sinemet Plus tablet at 10 am,

1 pm, 4 pm and 7 pm In addition, he was prescribed one Sinemet CRtablet at 10 pm The nursing staff were asked to complete an hourly

‘on–off’ chart Parts of the chart for days 1 and 5 are shown in Table 19.1

Month 66, Day 6 Mr LN’s mobility and dyskinesias were improved;

however, he remained depressed about his condition

Q14 Would Mr LN benefit from an antidepressant?

Q15 If so, which would you choose?

Month 66, Day 8 Mr LN had noticed a significant reduction in the

shak-ing of his arms followshak-ing his recent regimen change; however, he was stillbecoming considerably immobile about 1 hour before his dose of

Table 19.1

Sinemet His sleep had improved so that he was getting at least 6 uous hours’ sleep and no longer woke in pain from cramps

contin-The consultant neurologist recommended commencing entacapone

Q16 Why has the consultant neurologist recommended entacapone, and doesthis necessitate the adjustment of Mr LN’s other IPD therapy?

Q17 What counselling points would you highlight to a patient commencingentacapone?

Month 66, Day 11 During the ward round, you noted that Mr LN’s

morn-ing medication was still on his bedside table His medication nowcomprised one Madopar dispersible 62.5 mg tablet on waking around

7 am, one Sinemet Plus tablet at 10 am, 1 pm, 4 pm and 7 pm, and aSinemet CR tablet at 10 pm In addition, he was taking one entacaponetablet alongside each dose of Sinemet Plus and 3 mg ropinirole threetimes a day (made up of a 1 mg and a 2 mg tablet for each dose) Hisregimen thus comprised a total of 16 tablets per day

On questioning, Mr LN informed you that although he was feelingbetter, he was concerned at the number of tablets he was taking andfeared that he would have problems remembering to take them all when

he returned home He also found the new tablet quite hard to swallowbecause of its size

Q18 In view of MR LN’s concerns, what options are there for rationalising hismedications?

Month 75 Mr LN was admitted as an emergency by his GP, having

devel-oped visual and auditory hallucinations over the previous week He washearing voices talking about him, threatening to kill him He was alsoseeing insects crawling up the walls and burrowing into his skin Onexamination he was clearly distressed and very frightened His medica-tion on admission was one Madopar dispersible tablet on waking, oneStalevo 100/25/200 tablet four times daily, one Sinemet CR tablet at nightand one ropinirole XL tablet 8 mg daily

Q19 Which drugs might have contributed to Mr LN’s symptoms?

Q20 What adjustments would you recommend be made to Mr LN’s

medication?

Month 75, Day 7 The recommendations had been carried out Mr LN’s

visual hallucinations had improved, but he was still experiencing tressing auditory hallucinations and the control of his symptoms haddeteriorated, such that he was experiencing frequent ‘off’ periods

dis-Q21 What course of action would you suggest to improve Mr LN’s symptoms?

Mr LN was started on rivastigmine 1.5 mg twice daily The dose wasincreased over the next 10 days to 4.5 mg twice daily His dopaminergictherapy was adjusted to one Stalevo 100/25/200 tablet five times daily,one Sinemet CR tablet at night and one Madopar 62.5 mg dispersibletablet upon waking His ropinirole XL therapy was discontinued Hishallucinations resolved and acceptable control of his Parkinson’ssymptoms was achieved He was discharged on this regimen

Q22 What is the long-term outlook for Mr LN?

Answers

What are the main symptoms of Parkinson’s disease?

A1 The main symptoms in patients with Parkinson’s disease are tremor, rigidity, bradykinesia (slowness of movement), akinesia (loss of movement) and postural abnormalities.

The onset of Parkinson’s disease is usually insidious and progression slow.Many patients first notice a resting tremor This usually initially affectsthe hands and may be unilateral The tremor disappears on movementand during sleep, and may be worse under stress The patient is usuallyover 50 years old on presentation

Rigidity manifests as an increased resistance to passive movementand is classically termed ‘cog-wheel’ rigidity, with a ratchet-like phenom-enon felt at the wrist on passive movement of the hand

Bradykinesia manifests as a general slowness in movement Togetherwith the rigidity, it is responsible for the typical abnormalities of gait: dif-ficulty in starting and finishing steps, resulting in shuffling; a stoopedhead; flexed neck, upper extremities and knees; and a lack of normal armswing

A wide range of non-motor symptoms (NMS) have also beendescribed in Parkinson’s disease, all of which can have a significantimpact on quality of life These include bowel and bladder problems,fatigue, pain, sleep disorders and autonomic dysfunction, in addition todifficulty in swallowing and speech alteration, drooling of saliva andolfactory disturbance Loss of postural reflexes leads to postural imbal-ance and sometimes to frequent falls NMS are common and can occur

at all stages of Parkinson’s disease, including long before diagnosis.Symptoms increase in number and severity as the disease progresses

Until recently, there has been a tendency for healthcare professionals tooverlook these features in favour of the more apparent motor symptoms

Is it possible to make a definitive diagnosis of idiopathic Parkinson’sdisease (IPD)?

A2 At present the only way of making a definite diagnosis of IPD is

by postmortem study of the brain.

IPD is the most common cause of parkinsonism, accounting for imately 75% of cases presenting to neurologists Other causes includeother neurodegenerative diseases such as progressive supranuclear palsy(PSP) and multiple system atrophy (MSA), intoxication with heavymetals, treatment with therapeutic drugs (neuroleptics, metoclopramide),and chronic cerebrovascular disease

approx-The definitive diagnosis of Parkinson’s disease is based on istic neuropathological findings of Lewy bodies and neuronal loss in thesubstantia nigra and other brainstem nuclei Studies have shown thatonly 65–75% of patients diagnosed as having early Parkinson’s diseasehad the characteristic findings at postmortem

character-Current opinion and guidelines recommend that all patients with

a ‘suspected’ diagnosis of IPD must be referred untreated to a specialistwho can reliably differentiate between IPD and other parkinsoniansyndromes

Previously the response to a ‘challenge’ of levodopa or ergic agents has been used for diagnostic purposes; however the NICEguidance for Parkinson’s disease does not advocate that this be performedroutinely, although guidelines vary worldwide

dopamin-The use of imaging techniques is increasing in this field Singlephoton emission computed tomography (SPECT) with DatSCAN, a radio-labelled cocaine derivative, can be used to measure the amount ofdopamine-releasing neurons in the brain This type of imaging can aiddifferentiation between parkinsonian and non-parkinsonian syndromes,but it is unable to distinguish between IPD, MSA and PSP

What biochemical defects are thought to be present in a patient such as

In patients with Parkinson’s disease, dopamine concentrations in thethree major parts of the basal ganglia are reduced to a fraction of normal.Compensatory mechanisms operate and symptoms are not noted until asevere loss (80%) of dopaminergic neurons has occurred The severity ofsome symptoms, such as bradykinesia, has been found to correlate withstriatal dopamine levels; however, abnormalities of other neurotrans-mitters, including norepinephrine (noradrenaline), 5-hydroxytryptamine(serotonin) and gamma-aminobutyric acid, have also been reported Thefull relevance of these changes is unclear.

Outline a pharmaceutical care plan for Mr LN

A4 The goals of symptomatic drug treatment are to help the patient function independently for as long as possible, and to achieve this with the minimum of adverse effects.

Patients with Parkinson’s disease have a chronic deteriorating conditionwhich will result in lifelong drug therapy of increasing complexity

A long-term pharmaceutical care plan would include:

(a) Involving Mr LN in the choice of appropriate initial therapy.(b) Ensuring the development of appropriate treatment outcomemeasures and a suitable treatment monitoring programme

(c) Ensuring that the patient understands the role of drugs in the tomatic treatment of the disease and their possible adverse effects.(d) Ensuring that the patient and carers understand the importance ofadherence and timing of drug doses

symp-(e) Anticipating problems such as the potential for nausea and ing with levodopa preparations, and offering appropriate advice ontheir prevention

vomit-(f) Counselling the patient and carers about drugs that should beavoided in Parkinson’s disease These include medicines which act

as dopamine antagonists, such as metoclopramide and the olderantipsychotics (e.g chlorpromazine, haloperidol)

(g) As the disease progresses and more drugs are added to the regimen,medicine taking may become problematic and advice on methodsfor improving and maintaining adequate adherence should be given.(h) As most patients with IPD will be elderly, the general considerationsgiven to elderly patients should also be applied

As treatment may continue for many years and become increasingly plex, continuity of pharmaceutical care is an issue and considerationshould be given to a personal, individualised patient record that can beused by pharmacists at various stages of the disease

com-The Parkinson’s Disease Society (www.parkinsons.org.uk) publishes

a helpful booklet on drug use in IPD which is of value to patients andcarers and can be used as a counselling aid Patients with IPD now have alife expectancy near to normal, so treatment, help and support may benecessary for over 20 years Non-pharmacological considerations includeeducation on the disease itself, advice on diet, exercise programmes, andother areas such as driving, alcohol intake and recreational activities

Which drugs are usually considered for the initial treatment of patientswith IPD and what are their modes of action?

A5 Initial drug therapy as recommended by NICE guidelines for both early- and late-onset IPD will usually be chosen from the follow- ing: levodopa preparations; a dopamine agonist; or a monoamine oxidase B inhibitor (MAOBI)

There is still considerable debate about the best initial choice of therapyfor patients with IPD, and also when to start symptomatic treatment.Most experts now advocate early treatment to provide patients with max-imal clinical benefit at the start of their illness Most Parkinson’s diseasespecialists start treatment when a patient’s symptoms begin to interferewith their lifestyle What constitutes this will vary from patient topatient, but may include impairment of activities of daily living, threat-ened loss of employment, or gait disturbance with a risk of falling.When a decision is made to initiate treatment the age of the patient,the degree and type of symptoms and the patient’s expectations willinfluence drug choice Patients should be made aware that drug treatmentcan provide symptomatic relief, but that there is at present no way ofhalting the progression of the disease Levodopa is the most effective drug

in the symptomatic management of Parkinson’s disease, and virtually allpatients will experience meaningful benefit; however, it can cause signi-ficant short- and long-term adverse effects, and there is a growing body ofevidence and opinion among experts that most patients should initially

be started on a dopamine agonist instead

The rationale for early use of dopamine agonists is that they providesimilar benefits to levodopa in early disease, but are significantly lesslikely to lead to the development of motor complications, particularlydyskinesias Studies directly comparing levodopa with the dopamineagonists ropinirole, pramipexole and cabergoline as initial therapy forParkinson’s disease have been published and appear to confirm thistheory It is thus generally recommended to begin therapy with adopamine agonist in patients who require this but who still have relat-ively mild symptoms Patients with more severe symptoms, and those

over 70 (in whom the development of motor complications is less likely),should probably be started on a levodopa preparation.

Anticholinergic drugs are now rarely used for the treatment ofParkinson’s disease They provide some relief of tremor but are of littlevalue in the treatment of other features, such as rigidity and bradykinesia

In addition, adverse effects are common These include peripheral effectssuch as dry mouth, blurred vision and constipation, as well as potentiallyserious central effects including confusion and hallucinations Their use

is best reserved for younger patients (under 60), in whom resting tremor

is the predominant feature Anticholinergic drugs are thought to act

by correcting the relative central cholinergic excess brought about bydopamine deficiency

The MAOBIs selegiline and rasagiline selectively inhibit monoamineoxidase B, one of the enzyme systems which break down dopamine Theaction of endogenous dopamine is thus augmented Selegiline has a mildanti-parkinsonian effect and is sometimes used either alone in earlydisease, or later to potentiate the action of levodopa preparations It iswidely believed to possess neuroprotective properties in early disease, butthis has yet to be proved Selegiline is metabolised to amphetaminederivatives, so it may have an alerting effect, especially at night, when itcan cause insomnia, vivid dreams and nightmares Rasagiline, althoughvery similar in chemical structure, is not metabolised to amphetaminederivatives and so is potentially free of alerting side-effects

Dopamine deficiency cannot be rectified by the administration ofdopamine, because dopamine does not cross the blood–brain barrier.Levodopa does cross the blood–brain barrier and is converted to dopa-mine in the basal ganglia Levodopa is thus thought to act primarily byincreasing brain dopamine concentrations If levodopa is administeredalone, over 95% of a dose is decarboxylated to dopamine peripherally,which results in reduced amounts being available to cross the blood–brain barrier and problematic peripheral side-effects such as nausea,vomiting, and postural hypotension Levodopa is therefore now almostalways administered with a dopa-decarboxylase inhibitor, either carbidopa

or benserazide These dopa-decarboxylase inhibitors do not cross theblood–brain barrier and so smaller daily doses of levodopa can be admin-istered, thereby reducing the incidence of peripheral side-effects.Levodopa therapy is particularly helpful in controlling symptoms ofbradykinesia or akinesia

Do you agree with this choice?

A6 Yes The choice of initial therapy is based on many different tors that will vary from patient to patient The use of a dopamine agonist is indeed appropriate in this situation, as would be the use of levodopa.

fac-The dopamine agonists can be split into two different categories: ergotand non-ergot Ergot-derived dopamine agonists include the older gener-ation products bromocriptine, lisuride, pergolide and cabergoline Non-ergot-derived agonists include the newer agents pramipexole, ropinirole,and rotigotine

Use of the ergot-derived agonists has declined considerably over thelast few years as a result of increased concerns about long-term side-effects, specifically cardiac fibrosis There are clear monitoring guidelinesfor patients who remain on these agents

Critical appraisal of the literature evaluating the two derived oral agonists provides no evidence to prefer one over the other.Rotigotine, the transdermal patch formulation, although considered lesspotent than the other non-ergot-derived dopamine agonists, providescontinuous dopaminergic stimulation (CDS) over a 24-hour period.Although it is suggested that 24-hour continuous drug release moreclosely resembles endogenous dopamine release and may reduce the risk

non-ergot-of motor fluctuations and dyskinesias developing, there are at present nofirm clinical data to support this Ropinirole XL is also available as a once-daily preparation, but requires patients to be previously stablised on thethree times a day preparation before switching

How should Mr LN’s ropinirole therapy be adjusted to optimise hisresponse?

A7 Like any dopaminergic therapy, ropinirole must be started at a low dose and increased gradually in order to reduce the incidence

of side-effects and to establish the lowest effective dose

In order to facilitate gradual up-titration, ropinirole is available as a

‘starter pack’ that contains all the medication required for a stepwise dosetitration over a 4-week period A ‘follow-on’ pack allows further stepwisetitration over a similar period to a therapeutic dose This dose can then befurther increased as required and tolerated by the patient

Rotigotine patches are also available in a starter pack format.Pramipexole doses are often referred to in both the salt and the base form

It is important to be aware of this when referring to doses with patientsand other healthcare professionals; however, there are a number ofinformation materials available to aid patients and reduce confusion

What recommendations would you make with regard to Mr LN’s drugtherapy?

A8 Mr LN should at this stage be commenced on a low dose of odopa as an adjunct to the dopamine agonist The dopamine agonist dose should be reduced in view of his history of punding (the obsessive and repetitive perfomance of a useless task) The levodopa dose should be gradually increased, with decisions based on symptom relief and adverse effects.

lev-Levodopa and dopa-decarboxylase inhibitors are marketed in the UK asSinemet (levodopa plus carbidopa: co-careldopa) and Madopar (levodopaplus benserazide: co-beneldopa) There are six Madopar preparations andsix Sinemet preparations available in a variety of levodopa strengthsand formulations (standard, dispersible and controlled release) Thepotential for confusion among clinicians and pharmacists is considerable,and care must be taken to ensure that the patient receives the intendedpreparation

At the start of levodopa therapy the effects of a dose usually last for4–8 hours, so the tablets may be prescribed three times daily The doseshould be increased by one tablet every 2–3 days until optimum effectsare seen or adverse effects occur If daily doses of <70 mg carbidopa areused, the peripheral decarboxylase will not be saturated and Mr LN will

be more likely to suffer from nausea and vomiting For this reason thereare low levodopa Sinemet preparations containing 25 mg carbidopa plus

100 mg levodopa There are also preparations containing 10 mg dopa plus 100 mg levodopa that are suitable when higher levodopa dosesare needed This is not a problem with benserazide preparations Mostpatients are initially controlled on 400–800 mg levodopa daily

carbi-Mr LN is beginning to display symptoms of ‘punding’ This is acterised by repetitive pointless behaviours carried out for long periods oftime at the expense of all other activities, and is associated with excessivedopaminergic stimulation Although it has a relatively low incidence(5%) it can cause considerable distress to the patient, their family andfriends, and should be carefully monitored

char-Punding is managed by reducing and discontinuing ergic stimulatory agents, predominantly dopamine agonists, althoughlevodopa is also implicated In view of Mr LN’s worsening motor function

dopamin-it is reasonable to reduce his dopamine agonist to manage the side-effect

of punding, and to supplement this with (initially) low doses of levodopa

in view of its superiority in improving motor function Abrupt drawal of dopamine agonists has been associated with neuroleptic malig-nant syndrome and should therefore be avoided As there are no definedreduction regimens for these agents, the rate of withdrawal can vary In

with-the case of Mr LN, complete withdrawal may not be necessary and so slowreduction would be appropriate, depending on symptom control.Reducing the daily dose by 3 mg at 5-day intervals would be a reasonableregimen

How can the adverse effects of levodopa be minimised?

A9 The peripheral side-effects of levodopa are significantly reduced

by combining it with a dopa-decarboxylase inhibitor (see A5); however, peripheral side-effects may still occur.

Levodopa therapy is therefore best started at a low dose and increasedgradually In addition, ensuring that the drug is taken with or after foodcan reduce the incidence of nausea and vomiting still further Usingdomperidone, a dopamine antagonist that does not cross the blood–brainbarrier, can also reduce nausea and vomiting Doses of 10–20 mg dom-peridone 1 hour before levodopa preparations are effective

Which of the long-term complications of levodopa therapy is Mr LNsuffering from?

A10 End-of-dose akinesia and dyskinesias.

Initial treatment with levodopa leads to sustained improvement out the day Most patients will show a slow improvement in response dur-ing the first 18–24 months of treatment Symptoms are then adequatelycontrolled for 3–5 years Unfortunately, after long-term treatment(>5 years) only about 25% of patients continue to have a good, smoothresponse The main complications that develop are fluctuations inresponse, dyskinesias, psychiatric side-effects and partial or substantialloss of efficacy

through-Fluctuations in response initially consist of end-of-dose tion or end-of-dose akinesia End-of-dose akinesia is the term used whenthe therapeutic effects of a dose of levodopa are lost This commonlyoccurs first thing in the morning (after the longest dosage interval) or justbefore or after a dose during the day, when the effect of the previous dosewears off and before the next one is taken or becomes effective Patientsmay become immobilised and unable to do anything except wait for thenext dose After prolonged treatment, gradual deterioration in symptomsmay begin between 1 and 3 hours after a dose

deteriora-Long-term levodopa therapy is also associated with the ‘on–off’phenomenon The patient develops a sudden loss of effectiveness (off),when ‘freezing’ occurs, which may last for only a minute or for up toseveral hours before normal function returns (on)

Dyskinesias (abnormal movements) can occur in 60–90% of patientsand are usually dose related They are generally worse when the response

to a dose is maximal, and have been correlated with high levodopaplasma levels They are therefore commonly seen after a dose has beentaken Symptoms include grimacing, gnawing and involuntary rhythmicjerking movements

What alterations to Mr LN’s therapy would you recommend in order totry to minimise these effects?

A11 Increase the frequency of levodopa administration to 3-hourly and reduce the amount given with each dose.

The most common approach to response fluctuation is to reduce eachindividual dose of levodopa and to increase the frequency of administra-tion This can reduce end-of-dose akinesia, but care must be taken toensure a clinical response is maintained

End-of-dose bradykinesia or akinesia is thought to be caused by aprogression of the underlying disease or an unexplained occurrence ofsymptoms of dopamine deficiency after an initial response to each dose.Although there is no change in the plasma half-life of levodopa, itappears that the pharmacological half-life is reduced End-of-dose akin-esia has been shown to be corrected by levodopa infusion; however, this

is not a genuine therapeutic option, as levodopa must be infused in largevolumes, owing to its acidity, and it also commonly causes throm-bophlebitis The initial approach taken to minimise the end-of-dose effect

is therefore to try to reduce the dosage interval

Modified-release versions of careldopa (Sinemet) and beneldopa (Madopar) are available which result in a more prolonged andconstant plasma level of levodopa Both preparations lead to delayedaction and lower peak concentrations than standard levodopa, but therisk of dose failure may be higher Patients may still need to takecontrolled-release preparations every 3 or 4 hours, and may need doses ofstandard preparations to produce optimal clinical effects, especially withthe first dose of the day

co-Dyskinesias may occur at the time of peak benefit, at the beginning

or end of a dose, or both (diphasic), or during ‘off’ periods A reduction

in levodopa dose may reduce peak dose dyskinesias, as may the partialreplacement of levodopa with a dopamine agonist Diphasic dyskinesiasmay also be helped by partially replacing levodopa with dopamineagonists ‘Off’ period dyskinesia may be improved by administering a fast-acting (e.g dispersible) preparation or, for those occurring in the earlymorning, a controlled-release preparation last thing at night

How could you monitor and assess Mr LN’s response to thesechanges?

A12 By charting his mobility regularly.

Some neurology wards use mobility charts on which an indication of apatient’s mobility can be recorded at suitable intervals Such charts can be

a valuable aid to the manipulation of drug administration in order tooptimise therapy One version of a scoring system is described in Table19.2 In addition to a score, a brief description of the patient’s conditionmay be added

Can you suggest any non-drug management that might benefit Mr LN?

A13 Mr LN may benefit from some remedial therapy, such as speech and language therapy, physiotherapy or occupational therapy This should be available to patients with IPD and has been endorsed in NICE guidance for IPD.

The role of these therapies is to maintain the maximum level of tional mobility and capacity to perform activities of daily living (ADL).Early therapeutic intervention cannot reverse the course of Parkinson’sdisease, but it can delay potential deformity and functional decline.Physiotherapy for Parkinson’s disease patients addresses the func-tional limitations caused by rigidity and bradykinesia It may include anexercise programme that focuses on maintaining flexibility, balance andstrength

func-Occupational therapy focuses on finding solutions to difficultiespatients encounter with ADLs Specialist adaptive equipment may beprovided if necessary

Mr LN and his relatives should also be made aware of the existence

of the Parkinson’s Disease Society, which can provide education andgeneral advice

Table 19.2

Unable to mobilise or only with assistance

On with dyskinesia No rigidity, mobilising but with involuntary

movements

Would Mr LN benefit from an antidepressant?

feel-Ensuring adequate treatment for Parkinson’s disease should be thefirst step before considering more specific antidepressant therapy Thishas been achieved in Mr LN, so a trial of an antidepressant would bereasonable

If so, which would you choose?

A15 A tricyclic antidepressant (TCA) or selective serotonin reuptake inhibitor (SSRI) could be prescribed for Mr LN.

At present, there is insufficient evidence to recommend one sant/antidepressant class over another This lack of data is also high-lighted in the NICE guidance Clinical practice, as well as trial data,supports the use of some TCAs (e.g amitriptyline, nortriptyline) inParkinson’s disease; however, they are often associated with anticholin-ergic effects and orthostatic hypotension, which may limit their useful-ness

antidepres-The SSRIs (e.g fluoxetine, sertraline, citalopram) have also beenshown to be effective in Parkinson’s disease They are free of the anti-cholinergic effects associated with the tricyclics, and theoretical concernsthat they may worsen parkinsonian symptoms have not been borne out

Entacapone is a catechol-O-methyltransferase (COMT) inhibitor and

works in synergy with Sinemet and Madopar preparations, resulting in a30–50% increase in levodopa half-life

Entacapone works by inhibiting the peripheral metabolism of dopa by the enzyme COMT, thereby increasing its availability to thebrain Entacapone is licensed for use as an adjunct to levodopa in

levo-Parkinson’s disease Studies have shown that its use can significantlyreduce ‘off’ time and increase ‘on’ time in patients with ‘wearing-off’episodes It should be given at a dose of 200 mg with each dose of levo-dopa, up to 10 times daily The introduction of entacapone to a regimencan cause a new-onset or worsening of existing dyskinesias In order tominimise this, the daily dose of levodopa should be reduced by about10–30% by extending the dosing intervals and/or by reducing theamount of levodopa per dose In practice, the choice varies from patient

to patient

Tolcapone, the only other commercially available COMT inhibitor,differs from entacapone in that it also blocks central COMT Tolcaponewas withdrawn in 1998 after a number of cases of hepatitis, but has sincebeen relaunched with strict monitoring parameters and guidance on use

What counselling points would you highlight to a patient commencingentacapone?

A17 Entacapone can discolour the urine reddish brown Patients should also be advised that nausea and vomiting can occur due to augmentation of levodopa, and that diarrhoea is a common adverse effect.

The large size of the tablets may cause problems for patients withswallowing difficulties

In view of Mr LN’s concerns, what options are there for rationalising hismedications?

A18 The use of combination products and alternative formulations could be considered.

In the literature it has been noted that approximately 20% of patientswith IPD are non-adherent with their medication Younger patients andthose with complex regimens are associated with the highest levels ofnon-adherence

A number of pharmaceutical companies have recently developedcombined preparations and modified-release preparations in an attempt

to reduce the patient’s ‘pill burden’

Stalevo is a combined preparation of levodopa, carbidopa andentacapone formulated into one tablet A Stalevo tablet is smaller than atablet of entacapone alone and is thus also helpful in patients with swal-lowing difficulties who require therapy Stalevo is available in a number

of strengths, although dose titration is more limited than with the vidual components Mr LN could be started on Stalevo in place ofSinemet and entacapone

indi-The transdermal patch rotigotine and the oral formulation irole XL are both designed for once-daily administration At the time ofwriting, pramipexole, the remaining non-ergot dopamine agonist is inthe process of being developed as a once-daily formulation that isexpected to come to market

ropin-There are therefore a number of options for the rationalisation of MrLN’s medication regimen A reasonable option would be to convert eachdose of levodopa/carbidopa and entacapone to one tablet of Stalevo100/25/200 Ropinirole could also be converted to the XL preparation, asrecommended in the Summary of Product Characteristics (SPC) to one

8 mg tablet daily These changes would more than halve the number oftablets taken by Mr LN from 16 per day to seven

Which drugs might have contributed to Mr LN’s symptoms?

A19 All the drugs prescribed for Mr LN can cause the psychiatric complications described.

Levodopa causes a variety of psychiatric symptoms, including tions Dopamine agonists such as ropinirole can cause central nervoussystem effects such as hallucinations and confusion These psychiatriccomplications are especially common in elderly patients In addition,progression of the disease itself may contribute to these symptoms

hallucina-What adjustments would you recommend be made to Mr LN’smedication?

A20 Gradually reduce his dose of ropinirole XL and stop if necessary.

The psychiatric complications of most anti-parkinsonian drugs are doserelated and often respond to a reduction in dosage

It is generally recommended to reduce or eliminate parkinsonian drugs in the following order, corresponding to their relativepropensity to cause psychiatric problems versus degree of anti-parkinsonian activity: anticholinergics, amantadine, MAOBI, dopamineagonist, levodopa

anti-Mr LN’s dose of ropinirole should be reduced to the point ofimproving his hallucinations without drastically worsening his parkin-sonism, if possible It should be reduced gradually, as sudden withdrawal

of dopaminergic agents may precipitate a neuroleptic malignant drome The levodopa dose should only be reduced if hallucinationspersist after elimination of all other anti-parkinsonian agents

syn-What course of action would you suggest to improve Mr LN’ssymptoms?

A21 Add a low dose of an ‘atypical’ antipsychotic drug, or consider a cholinesterase inhibitor.

Haloperidol and chlorpromazine are effective antipsychotics but are notrecommended for Parkinson’s patients because of their capacity to blockstriatal dopamine D2receptors and exacerbate parkinsonism

The newer ‘atypical’ antipsychotics (e.g clozapine, olanzapine,risperidone, quetiapine) are relatively free of D2-receptor-blocking poten-tial, and in principle should improve psychotic features without worsen-ing parkinsonism The best-studied of these is clozapine, which has beenshown to reduce hallucinations without worsening parkinsonism.However, the potential for clozapine to cause agranulocytosis (1–2% ofpatients) and the consequent rigorous monitoring requirements oftendeter its use Olanzapine and risperidone have proved less effective thanclozapine in comparative studies, and have also worsened parkinsonism.The early work with quetiapine was more hopeful; however, morerecent controlled studies have been negative When quetiapine is consid-ered, a starting dose of 12.5 mg at bedtime is recommended and the doseshould be titrated upwards at 3–5-day intervals until the desired effect isachieved

The cholinesterase inhibitors rivastigmine, galantamine anddonepezil, which were developed primarily for Alzheimer’s disease, havebeen shown to reduce psychotic features and improve cognition in somepatients with Parkinson’s disease dementias Rivastigmine is the onlyagent licensed for use in Parkinson’s disease dementias A relative cholin-ergic excess is already present in the striatum of Parkinson’s diseasepatients, and thus the use of an agent likely to further support thisimbalance should only be undertaken under specialist supervision

What is the long-term outlook for Mr LN?

A22 It is likely that Mr LN’s condition will continue to deteriorate with time, and that he will experience more ‘off’ time and increasing dyskinesias His cognitive function may also decline further.

Amantadine has been used for the management of dyskinesias based onits antiglutamate activity; however, its side-effects (confusion, hallucina-tions) would preclude its use in Mr LN Other side-effects of amantadineinclude ankle swelling and livedo reticularis

A small number of other therapies can be used at this stage inpatients with Parkinson’s disease, but their risks and financial implica-tions are considerable

The use of apomorphine, a potent dopamine agonist licensed forthe treatment of refractory motor fluctuations (‘off’ periods) in IPD, is apossibility in patients who deteriorate despite maximum tolerated oraltherapy The drug cannot be given orally and must be administered sub-cutaneously It may be given as a continuous subcutaneous infusion or assingle injections It causes severe nausea and vomiting, so 3 days’ pre-treatment with domperidone (20 mg three times daily) is used to min-imise this Domperidone therapy may be continued until tolerance tothis side-effect develops Apomorphine is effective within 5–10 minutes,and patients may remain in the ‘on’ state for up to 60 minutes Duringthis time an oral dose of medication should have taken effect Manypatients are helped by up to five injections a day, although up to 10 may

be needed in some patients If the number of injections needed is high,then continuous infusions of apomorphine should be considered If thenausea and vomiting can be overcome, apomorphine therapy is generallywell tolerated Bruising, nodules or abscesses may form at the site of aninfusion, so the site should be changed daily As Mr LN has had psychoticfeatures in the past that resolved following discontinuation of hisdopamine agonist, the use of apomorphine may not be appropriate andmay further exacerbate this symptom

The use of surgical techniques such as subthalamic deep brainstimulation (STN-DBS) may also be precluded in Mr LN by his previouspsychotic symptomatology The relatively high morbidity and mortalityrate associated with lesioning operations such as thalamotomy andpallidotomy has recently made STN-DBS more favourable STN-DBSinvolves the placement of tiny wires into the subthalamic nucleus (STN).These emit continuous electrical impulses from a neurostimulator, which

is similar to a heart pacemaker This stimulation can have a positive effect

on the brain activity involved in controlling movement, and can improvetremor, stiffness, slowness and dyskinesia In addition, with improvement

in these symptoms medication can be reduced, thereby further reducingdyskinesias

Mr LN may, however, be an appropriate candidate for Duodopa, agel formulation of levodopa/carbidopa that is infused directly into theduodenum Duodopa is designed to mimic the pharmacokinetic profile ofendogenous dopamine release The technique, albeit initiated using anasogastric tube, requires a percutaneous gastrostomy tube for long-termadministration Such a procedure in patients with advanced Parkinson’sdisease can be hazardous

It is estimated that the cost of intraduodenal levodopa therapy is inthe region of £30,000 per patient per annum, which compares witharound £10,000 for apomorphine and £6000 for STN-DBS

Although there have been many recent advances in the ment of IPD, there is still no cure Ongoing research is targeted at neuro-protection strategies: interventions to protect or rescue vulnerabledopaminergic neurons, and to slow down or stop disease progression.Gene therapy trials are also currently under way.

Chaudhuri KR, Healy D, Schapira AHV The non-motor symptoms of

Parkinson’s disease Diagnosis and management Lancet Neurol 2006; 5:

235–245

Clarke CE, Guttman M Dopamine agonist monotherapy in Parkinson’s

disease Lancet 2002; 360: 1767–9.

Deane KHO, Spieker S, Clarke CE Catechol-O-methyltransferase Inhibitors Versus

Active Comparators for Levodopa-induced Complications in Parkinson’s Disease Cochrane Database of Systematic Reviews 2004, Issue 4

Emre M, Aarsland D, Albanese A Rivastigmine for dementia associated with

Parkinson’s disease N Engl J Med 2004; 351: 2509–2518.

Fernandez HH, Friedman JH, Jacques CC et al Quetiapine for the treatment

of drug-induced psychosis in Parkinson’s disease Mov Disord 1999; 14:

484–487

Friedman JH, Factor SA Atypical antipsychotics in the treatment of

drug-induced psychosis in Parkinson’s disease Mov Disord 2000; 15: 201–211.

Ghazi-Noori S, Chung TH, Deane KHO et al Therapies for Depression in

Parkinson’s Disease Cochrane Database of Systematic Reviews 2003,

Issue 3

Grosset KA, Bone I, Grosset DG Suboptimal medication adherence in

Parkinson’s disease Mov Disord 2005; 20: 1502–1507

Hibble JP Long-term studies of dopamine agonists Neurology 2002; 58:

S42–S50

National Institute for Health and Clinical Excellence CG35 Parkinson’s

Disease – Diagnosis and Management in Primary and Secondary Care NICE,

London, 2006

Nutt JG Continuous dopaminergic stimulation: is it the answer to the motor

complications of levodopa? Mov Disord 2007: 22; 1–9.

Nutt JG, Wooten GF Diagnosis and initial management of Parkinson’s disease

N Engl J Med 2005; 353: 1021–7.

Olanow CW, Obeso JA, Stocchi F Continuous dopamine receptor treatment

of Parkinson’s disease: scientific rationale and clinical implications

Lancet Neurol 2006; 5: 677–687

O’Sullivan SS, Evans AH, Lees AJ Punding in Parkinson’s disease Prac Neurol

2007; 7: 397–399

Schapira AHV Present and future drug treatment for Parkinson’s disease J

Neurol Neurosurg Psychiatr 2005; 76: 1472–1478.

Scherfler C, Schwarz J, Antonini A et al Role of DAT-SPECT in the diagnostic

work up of Parkinsonism Mov Disord 2007: 22; 1229–1238.

Shade R, Andersohn F, Suissa S et al Dopamine agonists and the risk of cardiac

valve regurgitation N Engl J Med 2007; 356: 29–38.

Singh N, Pillay, Choonara Y Advances in the treatment of Parkinson’s disease

Prog Neurobiol 2007; 81: 29–44.

Thanvi B, Lo N, Robinson T Levodopa-induced dyskinesia in Parkinson’s

dis-ease: clinical features, pathogenesis, prevention and treatment Postgrad

Med J 2007; 83: 384–388.

Walter BL, Vitek JL Surgical treatment for Parkinson’s disease Lancet Neurol

2004; 3: 719–728

Zanettini R, Antonini A, Gatto G et al Valvular heart disease and the use of

dopamine agonists for Parkinson’s disease N Engl J Med 2007; 356:

39–46

20 Depression

Stuart Gill-Banham

Case study and questions

Day 1 35-year-old Miss CT made an appointment to see her general

prac-titioner (GP) because she felt run-down and generally unable to cope Shesaid she felt tired all day long, yet at night she could not sleep Concen-trating on any task had become difficult, and she felt everything was get-ting on top of her Frequently she would be reduced to tears when facedwith a task and she dreaded having to go out, as she felt quite panickywhen she left the house She had not felt 100% for the last few months,since she had split up with her partner She denied ever having felt likethis in the past, although she had been extremely saddened by the sud-den death of her mother when she was 14 years old The GP prescribedfluoxetine 20 mg daily plus diazepam 2 mg twice daily for just 2 weeks

Q1 Are Miss CT’s presenting symptoms typical of depression?

Q2 Is this depressive episode purely a reaction to the end of her relationship,

or could it be due to other factors?

Q3 In what ways can depression be treated?

Q4 Is the combination of fluoxetine and diazepam appropriate?

Week 3 Miss CT had been concerned that she would become addicted to

the medication, so after 2 weeks she had stopped both the fluoxetine andthe diazepam as she was feeling slightly better However, her mood hadquickly deteriorated and so she returned to her GP

Q5 Are antidepressants addictive, and how long should they be prescribed for?

The GP persuaded Miss CT that antidepressants are not addictive and sherestarted the fluoxetine plus a further 2-week course of diazepam

Q6 Outline a pharmaceutical care plan for Miss CT

Week 12 Miss CT was still experiencing poor concentration and feeling

unable to cope with daily activities When her GP saw her he noticed thatshe had lost a considerable amount of weight and had an unkemptappearance Miss CT was adamant that she has been taking the fluoxetineregularly every day

Q7 What treatment options are available to the GP now?

The GP decided to try Miss CT on venlafaxine 37.5 mg twice daily

Q8 Was the starting dose of venlafaxine appropriate?

Q9 How should venlafaxine therapy be monitored?

Week 20 The dose of venlafaxine had reached 225 mg daily It had been

higher than this, but Miss CT could not tolerate the associated severenausea, so the dose had had to be reduced Miss CT described herself as50% better She was now able to leave her house without feeling panicky,and she no longer felt like crying as much as before However, she stilllacked motivation and her appetite remained poor

Q10 What options are there to improve Miss CT’s mood further?

The GP decided to try to augment her antidepressant therapy with lithium

Q11 Is augmentation with lithium appropriate?

Q12 What baseline checks need to be performed before lithium is started, andhow frequently should lithium levels be monitored?

Q13 What points should be covered when counselling Miss CT about herlithium therapy?

Q14 How long should treatment with lithium and venlafaxine be continued?

Q15 What other treatment options could be considered if Miss CT fails torespond to this therapy?

Answers

Are Miss CT’s presenting symptoms typical of depression?

A1 It is difficult to say exactly which symptoms of depression are typical because of the varied ways in which the illness can present; however, Miss CT does display some key symptoms of a depressive illness.

Depression is a syndrome characterised by persistent low mood, onia, a lack of interest in usual daily activities and a lack of energy In

anhed-addition to these key symptoms a wide range of accompanying toms can be present Accompanying symptoms can be psychological (e.g.anxiety, increased sense of guilt, pessimism or suicidal thoughts andplans), physical (e.g disturbed sleep, early morning wakening, tiredness,lack of energy, loss of appetite and increased sensitivity to pain), cognitive(e.g impaired concentration and memory) and psychomotor (e.g agita-tion, physical slowing or refusal of food and drink) In order to make adiagnosis of mild depression at least four symptoms, two of which need

symp-to be key, need symp-to have been present for at least the preceding 2 weeks.Moderate depression is diagnosed when six symptoms are present, two ofwhich must again be key Severe depression is diagnosed when eightsymptoms are present, at least three of which must be key symptoms.Depressive symptoms are more common than most people realise

Up to 10% of the population will experience some form of depressive ness at some time in their life Women are more than twice as likely asmen to develop depression, partly as a result of an increased readiness toadmit what their true feelings are

ill-The key symptoms displayed by Miss CT were low mood and lack

of energy accompanied by poor sleep, pessimism, lack of concentrationand severe anxiety, which together were impairing her daily routine.Frequently depression is not diagnosed when patients seek medical help,especially when they present with predominantly physical complaints.Depression ratings scales, which are formal sets of questions that can beused to give a numerical score to symptom severity, can be helpful in thediagnosis However, such scales should not be seen as providing a blackand white answer to the question of whether somebody is depressed:rather, they serve as a guide to indicate when an individual’s underlyingproblem might be depressed mood

Is this depressive episode purely a reaction to the end of Miss CT’srelationship, or could it be due to other factors?

A2 Although a depressive episode is frequently triggered by a ful life event, it is not possible to say that one event is solely responsible Several factors, such as genetic predisposition, previ- ous experiences and childhood upbringing, can influence how an individual handles life events, and in turn the likelihood of a stressful event leading to an episode of depression.

stress-The degree to which somebody has a predisposition to depression isdetermined by a combination of genetic factors along with their upbring-ing and previous life experiences Studies comparing rates of depression

in identical and non-identical twins have found depression to be almosttwice as likely in the brother or sister of an identical twin with depression

as in a non-identical twin Genetic predisposition could exert its ence on the biochemical structure of the brain, or its influence could besubtler, by altering individual character traits Along with genetic factors,early life experiences, particularly parental discord or abuse, can influencethe degree of predisposition faced by an individual.

influ-Regardless of an individual’s predisposition to depression, some lifeevents may be more likely than others to cause depression Events thatlead to feelings of entrapment or humiliation are thought to be particu-larly important

For Miss CT the break-up of her relationship was a significant factor,but it may not have been the cause of her depression In her personal his-tory she had coped with the loss of her mother at an early age It is imposs-ible to say how this influenced her upbringing, but it could have affectedthe way she coped with stressful events Although the relationship endedabout the same time as the depressive episode started, it might have beenthe emerging depressive illness that caused the relationship to end

In what ways can depression be treated?

A3 A range of options are available to treat depression, including psychological therapy, drug therapy and electroconvulsive ther- apy (ECT).

Deciding which treatment option is the most appropriate depends on theseverity of the depressive episode, and the preferences of both the doctorand the patient Drug therapy is not necessarily the best option for milddepressive episodes

The NICE clinical guideline No 23 (Depression: Management of

Depression in Primary and Secondary Care) introduces the concept of

stepped care for the management of depression This highlights the ferent needs of depressed individuals, depending on the characteristics oftheir depression and their personal and social circumstances The stepsrange from 1, with a focus on recognition and assessment, to 5, whichfocuses on the most severe presentations where the individual requirescomplex inpatient treatment in order to minimise risk to life or self-neglect

dif-Studies of mild depression frequently fail to demonstrate thatantidepressants have a significant effect, largely as a result of high placeboresponse rates Many patients prefer non-drug approaches: they particu-larly value practical support and problem-solving approaches Additionalnon-drug therapies may include dynamic psychotherapy, which exam-ines interpersonal dynamics and how these may contribute to an indi-vidual’s predisposition to experiencing depression; or cognitive therapy,