1) Pathophysiology and clinical manifestations

Parkinson’s disease (PD) is a progressive condition of the nervous system in which parts of the brain deteriorate gradually. It is marked by both motor symptoms (i.e. bradykinesia, rigidity, postural instability) and non-motor symptoms (i.e. excessive daytime sleepiness, orthostatic hypotension). The pathological features involve neuronal loss in the brainstem leading to dopamine deficiency in the striatum which results in abnormal brain activity and PD symptoms. Genetic predisposition (i.e. mutation in α-synuclein protein) along with some environmental factors (i.e. air pollution) can cause PD (Whittlesea and Hodson, 2018). PD is clinically diagnosed based on UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria (NICE, 2017). It is monitored by symptoms improvement which are measured by different assessment tools (i.e. Unified Parkinson’s Disease Rating Scale, PDQ-39 questionnaire). Patient’s quality of life is affected as PD can restrict an individual’s day to day activities. Currently 1% of the population in UK aged over 65 and 2% over the age of 80 have PD (Whittlesea and Hodson, 2018).

2) Therapeutic management

	Treatment: Table 1 Therapeutic management of Parkinson’s disease in adults (adapted from NICE, 2017)	Role in Parkinson’s disease management	Dosing:		Measure/Monitoring:
					What?		When?
Pharmacological management of motor symptoms First line treatment	Levodopa with a dopa-decarboxylase inhibitor (e.g.co-careldopa)	Used in early stages of PD if motor symptoms impact on quality of life.	Initially 25/100mg 3 times daily; maintenance up to 200/200mg daily in divided doses.		Hepatic function, monitor side effects of co-careldopa e.g. Skin reactions, vision disorders.		Hepatic function is measured before starting therapy; manufacture advises to avoid in decompensated hepatic function.
	Dopamine agonist          (e.g. rotigotine)	For early stages of PD if motor symptoms do not impact on quality of life.	Patch: Initially 2mg/24 hours; maximum dose 8mg/24 hours.		Hepatic function, monitor vision complications (ophthalmic testing).		Hepatic function test before initiation, avoid in severe impairment; ophthalmic testing required if vision problems reported.
	Monoamine oxidase type B (MAO-B) inhibitors      (e.g. rasagiline)	For early stages of PD if motor symptoms do not impact on quality of life.	1mg daily.		Hepatic function, monitor side effects e.g. abdominal pain, urinary urgency.		Hepatic function is measured before starting therapy; caution in mild impairment.
Adjuvant treatment	Levodopa with dopamine agonists or MAO-B inhibitors or COMT inhibitors (e.g. Stalevo)	If dyskinesia or motor fluctuations develop despite optimal levodopa therapy.	Stalevo 100/25/200 (levodopa with carbidopa and entacapone): 1 tablet OD, maximum 10 tablets daily.		Monitor side effects e.g.  sudden onset of sleep.		Patients starting the treatment should be warned of the risk of sudden sleepiness when driving and operating machinery.
Managing impulse control disorder	Impulse control disorder can develop at any stages of the disease with dopaminergic therapy. Risk is higher with dopamine agonist therapy and having a history of previous impulsive behaviours along with alcohol consumption or smoking. If impulse control behaviour is developed, then modify dopaminergic therapy by gradually reducing dopamine agonist. Offer cognitive behaviour therapy if modifying dopaminergic therapy is not effective (under specialists). Withdrawing treatment will be considered as a last resort. Note: Be aware; impulse control disorder can also develop while taking dopaminergic therapies other than dopamine agonist.
Pharmacological management of non-motor symptoms	Modafinil	To treat excessive daytime sleepiness.	Initially 200mg daily in 2 divided doses; adjust according to response.	Renal function, hepatic function and ECG are required.		Renal and hepatic function along with ECG are measured before initiation; 50% dose reduction is required in severe renal impairment.
	Melatonin	For rapid eye movement sleep behaviour disorder.	2mg once daily up to 13 weeks.	Hepatic function; monitor for side effects e.g. anxiety, headaches, pain etc.		Hepatic function test when initiating; avoid in impairment as risk of decreased clearance.
	Midodrine	To treat orthostatic hypotension.	Initially 2.5mg 3 times daily; increased up to 10 mg TDS.	Hepatic and renal function; monitor for side effects e.g. supine hypertension.		Measure hepatic and renal function at regular interval; stop treatment if supine hypertension is not controlled on dose reduction.
Pharmacological neuroprotective therapy	Use of neuroprotective therapy is restricted to clinical trials only. Do not use vitamin E, co-enzyme Q10, dopamine agonist or MAO-B inhibitors as a neuroprotective therapy in people with PD. The aim of this therapy is to restore the level of dopamine in the striatum which will prevent or delay the degeneration of dopamine and resolve PD symptoms.
Non-pharmacological management of motor and non-motor symptoms	Physio, occupational, speech and language therapies.	Physiotherapy can help patients experiencing balance or motor function problems; occupational therapy is beneficial for patients experiencing difficulties with daily living activities; speech and language therapy should help patients experiencing problems with communication, swallowing or saliva. Consider referring people to these services who are in early stages of Parkinson’s disease for assessment, advice and support.
Advanced treatment options	Deep brain stimulation : Offer best medical therapy in advanced PD with apomorphine injection. Consider deep brain stimulation if symptoms uncontrolled with best medical therapy. Levodopa-carbidopa intestinal gel : Used for advanced levodopa responsive PD with severe motor fluctuations and administered with a portable pump into duodenum or jejunum.
Palliative care	Advanced care planning and the prognosis of the condition should be discussed with the family members and the carers. Treatment termination can also be discussed at this stage.
Referral	Patients can be referred at any stages of the Parkinson’s disease to the palliate care team to give them and the family members the opportunity to discuss the care.

Following 3 drugs have been chosen and justified for this therapeutic framework using evidence-based research.

Co-careldopa

is chosen because levodopa with a dopa decarboxylate inhibitor are recommended by NICE as a first line treatment in early stages of PD for motor symptoms (NICE, 2017). Mao and Modi (2016) conducted a randomized, placebo-controlled fixed dose study comparing carbidopa-levodopa extended release capsule (IPX066) with placebo. The study included 171 patients treated with either 3 doses of IPX066 (145mg, 245mg or 390mg) or placebo. After 30 weeks, IPX066 showed a huge improvement in symptoms measured by Unified Parkinson’s Disease Rating Scale compared to placebo (76.7% compared to 23%, ARR= 53.7%, NNT=2, P˂0.05). One limitation of the study is that the disease progression over time could affect these results as the study was only for 30 weeks.

Rotigotine

is chosen because dopamine agonists are recommended by NICE in early stages of PD patients whose motor symptoms have no impact on their quality of life (NICE, 2017). Zhang et al., (2017) carried out a randomized, double blind placebo-controlled study in PD patients inadequately controlled on levodopa (≥200mg/day). 346 patients having ≥2.5 h/day “off” time (symptoms returning) were randomized to receive rotigotine patch maintaining a maximum dose of 4-16 mg/24h or placebo for 12 weeks. They found rotigotine significantly reduced “off” time (primary efficacy) from base line to end of maintenance according to patient diaries (48.8% compared to 36.9%, ARR=11.9%, NNT=9, P=0.0269). Safety variables such as adverse effects were reported more in patients with rotigotine patch compared to placebo (59.2% VS 50%) where the most common adverse effects (≥5%) were dizziness, nausea, pruritus and dyskinesia.

Rasagiline

is chosen as MAO-B inhibitors are recommended by NICE as a first line treatment in early stages of PD or as adjunct to levodopa/dopamine agonists for patients developing motor fluctuations despite optimal levodopa therapy (NICE, 2017). Hauser et al., (2014) conducted a randomised controlled trial of rasagiline 1mg/day as an add-on therapy to dopamine agonists (ropinirole ≥ 6 mg/day or pramipexole ≥ 1.0 mg/day) in patients whose PD was not adequately controlled. They found a significant improvement in total Unified Parkinson’s Disease Rating Scale from baseline to week 18 in rasagiline group compared to placebo expressed in mean improvement (-3.6 +/- 0.68 in rasagiline and -1.2 +/- 0.68 in placebo, P˂0.05). They also concluded that rasagiline 1mg/day was well tolerated compared to placebo with dizziness being the most common adverse effects (7.4% compared to 6.1%, ARI=1.3%, NNH=77, P˂0.05).

3) Pharmacist’s contribution to patient care

A side effect of co-careldopa is dyskinesia (BNF, 2018). This happens when levodopa causes the dopamine in the brain to spike suddenly resulting in involuntary jerky movements. Chaudhuri, Jenner and Antonini, (2019) found that levodopa resulted in dyskinesia of up to 36% of patients within 5 years and 88% within 10 years. Therefore, pharmacist should advise patients to report dyskinesia symptoms (i.e. rapid blinking, sticking out the tongue) to their GP who can review their treatment.

Co-careldopa is cautioned in diabetes mellitus (BNF, 2018). Patients with PD have abnormal glucose tolerance which can be further exacerbated by levodopa therapy (Rasanu, 2019). Pharmacists can provide life style advice and diabetes self-management education as part of the MUR and monitor patients HbA1c regularly.

Clozapine interacts with co-careldopa to decrease the effect of levodopa (BNF, 2018). This is because the absorption of levodopa is decreased by clozapine which can trigger the fluctuations of motor functions. Hence, pharmacist should discuss how this interaction can be managed with the prescriber (discuss any suitable alternatives) as manufacture advises to avoid this combination.

Patients should be advised that initiation of co-careldopa can cause sudden onset of sleep at daytime as it causes a calming effect in the nervous system (BNF, 2018). Hence, Pharmacists should counsel patients on improving sleep behaviours and advise them to stay away from driving or operating machines.

Rotigotine can cause impulse control disorder (ICD) as a side effect (BNF, 2018). Antonini et al, (2016) found 9% of 786 people treated with rotigotine experienced ICD where 2.5% reported having compulsive sexual behaviour, 2.3% buying disorder and 2% compulsive gambling. If patients develop these symptoms, pharmacists should refer them to their GP for a dose reduction or cognitive behaviour therapy if dose reduction not effective (NICE, 2017).

Rotigotine is contraindicated in breast feeding as it can suppress lactation (BNF, 2018). Pharmacists should advise appropriate female patients to avoid breastfeeding and resort to a suitable infant formula milk if possible as manufacturer found this drug to be present in milk in animal studies.

Rotigotine interactswith amlodipineto increase the risk of hypotension (BNF, 2018). These two drugs reduce blood pressure by venous and arterial dilation. Pharmacists should counsel patients on self blood pressure monitoring and advise them to visit GP for review if BP falls below 90/60 mmHg.

Pharmacists should be aware of dopamine dysregulation syndrome which can develop with rotigotine because of the addictive pattern of dopamine (BNF, 2018). Patients and the carer should be advised to report symptoms like craving, addiction or other self-control problems like gambling and abnormal sexual behaviour to their GP for an appropriate review.

An important side effect of rasagiline is dysphagia which occurs when neurological problem affects the nerves.  Ludolph et al., (2018) described dysphagia as a common adverse effect in a randomised controlled trial on safety and efficacy of rasagiline (1mg/day for 36 months vs placebo) (25% compared to 19%, ARI=6%, NNH=17, P˂0.05). Pharmacists should refer patients to their GP immediately for review if dysphagia symptoms (i.e. drooling, food sticking in the throat, choking) occur.

Rasagiline iscontraindicated in moderate to severe hepatic impairment because of increased risk of exposure (BNF, 2018). Pharmacists should request GP to carry out liver function tests before initiating treatment with rasagiline.

Rasagilineinteracts with pseudoephedrine to cause severe hypertensive crisis (BNF, 2018). This happens because smaller blood vessels of the body narrow causing excessive pressure against the vessel walls. Therefore, pharmacists should avoid selling over the counter decongestants containing pseudoephedrine and offer alternatives (i.e. saline, nasal strips).

Pharmacists must advise patients and the carers not to stop rasagiline abruptly as it can cause neuroleptic malignant syndrome or acute akinesia because of dysfunction in the autonomic nervous system (BNF, 2018). Hence, patients should be advised to talk to their GP for any concern about rasagiline before deciding to stop suddenly.

4) Conclusion

PD can have detrimental effects on patients quality of life as well reducing life expectancy due to related complications. Pharmacological treatment with co-careldopa, rotigotine and rasagiline aims to improve motor symptoms of PD taking into account individual’s symptoms and co-morbidities. Therefore, the role of the pharmacists is essential in ensuring effective management of PD, whilst prioritising patient safety.

References

• Antonini, A., Chaudhuri, K., Boroojerdi, B., Asgharnejad, M., Bauer, L., Grieger, F. and Weintraub, D. (2016). Impulse control disorder related behaviours during long-term rotigotine treatment: a post hoc analysis.
  
  European Journal of Neurology
  
  , 23(10), pp.1556-1565.
• Chaudhuri, K., Jenner, P. and Antonini, A. (2019). Should there be less emphasis on levodopa‐induced dyskinesia in Parkinson’s disease?
  
  Movement Disorders,
  
  1(1), pp.2-3.
• Hauser, R., Silver, D., Choudhry, A., Eyal, E. and Isaacson, S. (2014). Randomized, controlled trial of rasagiline as an add-on to dopamine agonists in Parkinson’s disease.
  
  Movement Disorders
  
  , 29(8), pp.1028-1034.
• Joint Formulary Committee (2018).
  
  British National Formulary
  
  . 76
  
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  edition. London: BMJ group and Pharmaceutical Press.
• Ludolph, AC., Schuster, J., Dorst, J., Dupuis, L., Dreyhaupt, J., Weishaupt, JH., Kassubek, J., Weiland, U., and Petri, S (2018). Safety and efficacy of rasagiline as an add-on therapy: a randomised, double-blind, parallel-group, placebo-controlled, phase 2 trial.
  
  The Lancet Neurology
  
  , 17(8), pp.681-688.
• Mao, Z. and Modi, N. (2016). Dose-Response Analysis of the Effect of Carbidopa-Levodopa Extended-Release Capsules (IPX066) in Levodopa-Naive Patients With Parkinson Disease: a randomized, placebo‐controlled, fixed‐dose, parallel‐arm phase 3 study.
  
  The Journal of Clinical Pharmacology
  
  , 56(8), pp.974-982.
• NICE (2017)
  
  Parkinson’s disease in adults | Guidance | NICE
  
  . [online] Available at: https://www.nice.org.uk/guidance/ng71 [Accessed 13 Jul. 2019].
• Rasanu, I. (2019). The Relation Between Type 2 Diabetes Mellitus and Parkinson Disease Up to Date.
  
  Romanian Journal of Diabetes Nutrition and Metabolic Diseases
  
  , 26(1), pp.79-84.
• Whittlesea, C. and Hodson, K. (2018).
  
  Clinical Pharmacy and Therapeutics 6E
  
  . [S.I]: Churchill Livingstone, pp.pg 507-516.
• Zhang, Z., Liu, C., Tao, E., Shao, M., Liu, Y., Wang, J., Asgharnejad, M., Xue, H., Surmann, E. and Bauer, L. (2017). Rotigotine transdermal patch in Chinese patients with advanced Parkinson’s disease: A randomized, double-blind, placebo-controlled pivotal study.
  
  Parkinsonism & Related Disorders
  
  , 44, pp.6-12.

APPENDIX




Summary Therapeutic Framework Information for 3 chosen drugs

Therapeutic management of Parkinson’s disease in adults
Drug Name	Co-careldopa (Levodopa-Carbidopa)	Rotigotine	Rasagiline
Drug Group	(Dopaminergic drug) Levodopa- Central nervous system agent Carbidopa- Dopa decarboxylate inhibitor	Non ergoline dopamine agonist	Monoamine oxidase type B (MAO-B) inhibitors
Legal Classification	POM	POM	POM
How the drug works in the condition	Levodopa is converted into a neurotransmitter called dopamine once in body that helps to restore the level of dopamine in the brain and carbidopa prevents the breaking down of dopamine before it reaches the brain. Thus, it helps to alleviate the motor symptoms of PD.	Once in the bloodstream, rotigotine stimulates the dopamine receptors in the brain which mimics the action of dopamine. As a result of this, the normal level of dopamine is maintained in the brain of PD patients.	Monoamine oxidase B is an enzyme that normally breaks down dopamine. MAO-B inhibitors prevent the breaking down of dopamine in the brain making more dopamine available. Therefore, this drug also alleviates the motor symptoms of PD.
The usual adult dose (route, dose, frequency)	By mouth Initially 25/100mg 3 times a day, then increased gradually by 12.5/50mg once daily or increased in steps of 25/100mg once daily or on alternate days. Dose can be increased until 800mg of levodopa along with 200mg of carbidopa reached which is given daily in divided doses. Maintenance up to 200/200mg daily.	By transdermal application using patches Initially 2mg/24 hours, then increased if required by 2mg/24 hours every week; maximum 8mg/24hours.	By mouth 1mg daily.
Patient monitoring to check that the drug is working	Disease control, symptom improvement i.e. alleviation of symptoms can be measured using Unified Parkinson’s Disease Rating Scale (UPDRS), Hoehn and Yahr Scale or by using PDQ-39 questionnaire.	Improvement in motor symptoms (i.e. tremor, rigidity etc) can be seen taking this drug. PD NMS questionnaire and NMS survey can be used to measure the treatment outcome. Patients monitoring is needed for visual problems or history of retinal disease (ophthalmic testing).	This drug can be effective in reducing “off” time (returning of motor and non- motor symptoms) when given along levodopa. Parkinson’s Disease Composite Scale and patient’s survey can be used to measure this.
Important side-effects caused by the drug and monitoring for these side-effects	Dyskinesia-check for symptoms such as rapid blinking, sticking out the tongue, random movement of the lips etc. Sleep disorders- check for daytime fatigue, lack of concentration, irritability etc. Seizure-check for unusual behaviours or feelings that occur hours to days before a seizure.	Impulse control disorder- check for binge eating, pathological gambling and hypersexuality. If the patient develops this, treatment should be withdrawn or dose reduction is needed. Psychotic disorder- check for mental status by observing the patients. Monitor by MRI or CT scans by specialists if needed. Sexual dysfunction-monitor with blood tests, urine tests, ultrasound and physical exam.	Dysphagia- Monitor for dysphagia symptoms such as choking on food, pain when swallowing, drooling, food sticking on throat etc. Constipation-check for risk factors such as infrequent stools, difficulty defecation etc. Urinary urgency- Monitor by uncomplicated self monitoring techniques such as monitoring the timing and amount of fluid and caffeine intake. Postural hypotension-monitor blood pressure while standing and sitting to compare the measurements.
Important drug interactions	Clozapine – it decreases the effect of levodopa. Manufacturer advises to avoid or monitor worsening of parkinsonian symptoms. Haloperidol – effects of levodopa is decreased with haloperidol. Phenelzine – levodopa increases the risk of hypotensive crisis when given with it.	Rotigotine – Rotigotine increases the risk of hypotension with amlodipine, amitryptaline, atenolol, aripiprazole, baclofen and bisoprolol (moderate interaction).	Rasagiline- it causes severe hypertensive crisis when given with pseudoephedrine, ephedrine, salbutamol, salmeterol and xylometazoline (severe interaction).
Important disease interactions (Contra-indications and Cautions)	Cautions : diabetes mellitus, cushing’s syndrome, hyperthyroidism, osteomalacia. Contra-indication: impulse control disorder.	Contra-indication: breast feeding Cautions :  avoid exposure of rotigotine patch to heat, remove aluminium containing patch before cardioversion.	Contra-indication : avoid in moderate to severe hepatic impairment. Cautions : pregnancy, breastfeeding, hepatic impairment.
What the patient should be told about their medicine	Patients starting the treatment should be warned of the risk of excessive daytime sleepiness. Patients experiencing excessive sedation should be advised to refrain from driving and operating machines. Patients should be counselled on improving sleep behaviour.	There is an increased risk of developing dopamine dysregulation syndrome with dopamine agonist like rotigotine. Patients and the carer should be advised to report symptoms like addiction, craving or other self-control problems like gambling and abnormal sexual behaviour.	Patients and the carer should be advised not to stop this medication abruptly due to poor absorption (for example- gastroenteritis) or any other reasons (i.e. side effects) to avoid the risk of acute akinesia or neuroleptic malignant syndrome.