Parkinson disease

and related comorbidities.

Ashoka Benedict Gomes. 10/11/16.

PHA5598
History of present illness:

JT is a 84 year caucasian male with history of overactive bladder (OAB), PD (Parkinson’s disease), HTN, DM2, OSA
(obstructive sleep apnea).
He reports that he is doing well with no recent falls but he gets confused and he feels like he forgets things. He recently had
urethritis due to UTI’s and had been hospitalized at which time his blood sugar was also low and hypertension was variable.
His chief complaint is that he still has continued urinary urgency. He reports that he takes his medication regularly and it helps
him but he also gets confused and he feels like he forgets things easily.

Past Medical History (PMH):

Parkinson's disease Jan 2013
Urinary inconsistency May 2014
Hypertension March 1998.
Diabetes May 2013.
Obstructive sleep apnea May 1998.

Current Medical Problem List:

1- Urinary inconsistency.
2- Diabetes uncontrolled.
3-Confusion and forgetfulness.
Family History/Social History:
Health Plan: Medicare part D (VA benefits).
Primary Provider: VA medical center.
Occupation: Retired VA.
Family History: No family history of diabetics or other chronic disease states.
Race: Caucasian.
Smoking: None
Alcohol: None
Illicit drug use: None
Hobbies: Watching TV.

Allergies: Cipro, Levofloxacin, Sulfa.

Adherence: patient is forgetful.
Immunization: uptodate.
Family History/Social History:
Health Plan: Medicare part D (VA benefits).
Primary Provider: VA medical center.
Occupation: Retired VA.
Family History: No family history of diabetics or other chronic disease states.
Race: Caucasian.
Smoking: None
Alcohol: None
Illicit drug use: None
Hobbies: Watching TV.

Allergies: Cipro, Levofloxacin, Sulfa.

Adherence: patient is forgetful.
Immunization: uptodate.
Current Medications:
Amlodipine 5 mg daily
Benazepril 20mg daily
Carbidopa- Levodopa 25-100 mg 2 tabs three times a day
Glipizide 5 mg daily
Vesicare 10 mg daily
Senna-s 8.6-50mg 1-2 tabs prn constipation
Tamsulosin (0.4mg) 1 cap at bedtime
Timolol (0.5%) ophthalmic 1 drop in both eyes every 12 hour
Vitamin B12 (1mg ) 1 tab daily

Review of Symptoms:
General: JT is a 84 year caucasian male; he is 5 feet 4 inches and weighs 186 lb, he reports urinary inconsistency,
forgetfulness and confusion, he is elderly and at risk for falls.
Vital signs: BP 145/72 mmHg. Standing BP 152/66 Pulse=56, RR=20.
HEENT: Head is atraumatic, normocephalic. PERL, EOMI (eye).
Neuro: Alert, oriented. Gait: small steps, slow, unstable, decreased elevation of feet.
Memory: Impaired.
Cardiovascular: RRR , no murmurs. Edema: 1+. TC=191, TG=75, HDL=63, LDL=102.
Renal: Scr=0.9. BUN=12 mg/dl (normal). Liver: AST=17, ALT=5.
Respiratory (OSA): unlabored, good effort, CTAB (no internal sounds).
Random blood sugar: 90 mg/dL (9/20/16)
A1c : 7.4 (on 8/24/16)
Identification of Drug Therapy Problems:

1- Indication for a drug but drug not prescribed properly. (vesicare is a muscarinic antagonist hence side effects can be
cognitive impairment constipation etc).

2- Indication for a drug but not prescribed properly. (glipizide can cause hypoglycemia).

3- No indication for a drug (vit B12/ hemoglobin levels are within range).

4- No indication for a drug (no diagnosis of eye problems).

Drug Therapy Problem #1:
Indication for a drug but drug not prescribed properly.

Vesicare is a competitive muscarinic m3 antagonist hence side effects can be cognitive impairment, constipation, salivary
problems and its levels are increased 20-25% in the elderly 60-80 years (Ref2).

Myrbetriq pharmacokinetics are not affected by age and it is a B3 adrenergic receptor agonist with less adverse effects better
tolerated in patients.
Pathophysiology:
Parkinson's disease (PD) is thought to be due to the loss of cells in the substantia nigra of the brain. Dopamine is secreted in
this area and a reduction in its secretion causes motor effects mainly through the basal ganglia. The reasons for the
development of PD in humans is unknown and can be genetic or environmental (possible chemicals=agent orange, MPTP,
some herbicides).

The diagnosis of PD is a clinical decision by an experienced doctor based on the presentation of signs or symptoms, a PD
patient usually presents with a board (flat) like demeanor, stiffness (bradykinesia) and possibly tremors or involuntary
movements. Confirmation using a CT scan can be done but is not conclusive.

A common problem with PD patients is urinary incontinence (27-39%) or overactive bladder (OAB) as the urinary bladder is
controlled by brain signals and elderly patients have slow movements and take time to reach the bathroom.
Intervention to resolve drug therapy problem: for #1
Discontinuation of vesicare and starting Myrbetriq (mirabegron) 50 mg daily.
Rationale for intervention: Based on the diabetes guidelines for this patient and looking at the benefits (per american geriatric society
recommendations) for the selected alternative medication (mirabegron).

Pharmacology of mirabegron: Mirabegron is a b3 adrenergic receptor(b3-AR) agonist used for treating overactive bladder
(OAB), it works on b3 adrenergic receptors which have been shown to have a high density in GI and urinary smooth muscle
tissue (the detrusor muscle), specifically the b3 subtype shows 97% mRNA of the b3 subtype in the urothelium of the human
bladder (5) and hence its likely that B3 adrenergic receptors are likely to have clinical effects in OAB, though b3-AR agonists
do not cause clear recovery.

Mirabegron is indicated for urge incontinence, frequency and urgency, it has been shown in 3 double blind placebo-controlled
trials to have better tolerance than antimuscarinic medications.

Pharmacokinetics/dynamics of mirabegron:
Mirabegron is approximately 25% renally eliminated unchanged and rest is excreted in the feces. Mirabegron is also
metabolized in the liver(3). Cmax is achieved in about 3.5 hours after oral dosing and steady state is achieved in 7 days. There
is no need to adjust dosing in geriatric patients (3).

Preparation/administration/stability/cost of mirabegron: Mirabegron is available as a brand name tablet. Its cost is high.
Scientific/Expert opinion: #1
1- Oral pharmacotherapy for overactive bladder (OAB) in older patients: mirabegron as a potential alternative to antimuscarinics. Wagg A,
Nitti VW, Kelleher C, Castro-Diaz D, et al. Curr Med Res Opin. 2016;32(4):621-38.

Objective: The authors evaluated the side effect profiles of antimuscarinic agents and mirabegron.
Methods: 3 trials of 12 weeks duration and a 1 year trial were analysed for tolerability data (most prospective randomized, double blind,
placebo).

Results: Anticholinergic side effects of dry mouth occurred 6 fold higher in tolterodine er 4mg v/s mirabegron x12 weeks and 3 fold
higher x1 year. Constipation was higher in antimuscarinic agents and mirabegron had low incidence of CNS effects.
Adherence is a problem with treating OAB and mirabegron has showed 77% v/s 32-49% 6 months continuation rates v/s antimuscarinic
medicines and patients >65 years were 38% less likely to stop.
A study in the US has shown a reduction in costs and resource utilization because of continued use of mirabegron in pts aged >65years.
Also antimuscarinic medicines are not recommended for older patients at risk for glaucoma (4).

Conclusion: Based on the results it was concluded that older patients treated with a B3-adrenoceptor agonist (mirabegron) would help
with adherence (for longer periods) and have less antimuscarinic adverse effects.
While both antimuscarinic and B3-adrenoceptor agonists will be clinically effective in treating OAB.
Scientific/Expert opinion: #2
2- The efficacy and safety of mirabegron in treating OAB: a systematic review and meta-analysis of phase III trials. Cui Y, Zong H, Yang C,
Yan H, Zhang Y. Int Urol Nephrol. 2014 Jan;46(1):275-84.

Objective: A meta analysis of 4 studies were analyzed for efficacy and safety of mirabegron in treating OAB.
Methods: Medline, EMBASE and cochrane trials register databases were searched for phase3 randomized double blinded controlled trials.
4 trials were selected for meta analysis.

Results: The efficacy was assessed by the mean number of incontinence episodes in 24hrs with SMD (standardized mean difference) -
0.44(95%=-0.59 to -0.29 (p<0.00001) v/s placebo. Other outcomes were also looked at and mirabegron was statistically more effective.
Safety of mirabegron was compared to placebo by measuring the frequency of adverse events and was found to have similar incidences (no
statistical difference in safety).

Conclusion: The meta analysis found that mirabegron was an effective and safe treatment for OAB with low side effects (similar side
effects as placebo).
Drug Therapy Problem#2:
Indication for a drug but not prescribed properly. (Glipizide can cause hypoglycemia).

Rationale for intervention: Based on the diabetes guidelines for this patient and looking at the benefits (per american geriatric society
recommendations) for the selected alternative medication (mirabegron).

Intervention to resolve drug therapy problem: for #2

Discontinuation of Glipizide and starting Metformin 500 mg twice a day.
Pathophysiology of diabetes:
In diabetic mellitus 2 (DM2) patients; insulin which is secreted by the beta cells of the pancreas is deficient and there is peripheral insulin
resistance (i.e even though there is levels of blood insulin there is no drop in sugar levels).
According to the ADA the tests to confirm DM2 in patients are 1- Fasting (no eat for 8hrs) plasma glucose level of >=126 mg/dl, 2- 75 gm
oral glucose tolerance test (OGTT) followed 2hrs later by plasma glucose level of >=200mg/dl or 3-A1c >=6.5 or 4-Random plasma glucose
of 200 mg/dl in pts with symptoms of hyperglycemia.
Signs of DM2 include blurred vision, excessive urine volume(polyuria), thirst(polydipsia), eating(polyphagia), weight loss, yeast infections.

Pharmacology of Metformin: Metformin is a biguanide not related to sulfonylureas its effects on glucose levels are due to
inhibition of liver gluconeogenesis(primarily), decreased gut glucose absorption and increased peripheral glucose uptake and
usage(6). Insulin secretion does not change and hence there is less chance of hypoglycemia v/s sulfonylureas, it does not
cause weight gain and actually can cause some weight loss (hence ideal for obese patients).

Pharmacokinetics/dynamics of Metformin: Metformin is quickly distributed to peripheral tissues and mainly to the GI tract. Most
of the drug (90%) is excreted via the kidneys with a plasma t1/2=6.5hours. In elderly patients with poor renal function there
may be accumulation.

Preparation/administration/stability/cost of Metformin: Metformin is available as a tablet and liquid. It is available as a

multisource generic and its cost is low.
Scientific/Expert opinion: #1
1- Sulfonylurea monotherapy and emergency room utilization among elderly patients with type 2 diabetes. Swapnil NR , Chunmay F,
Kimberley B, Samuel Se, Pamela CH. Diabetes Res Clin Pract. 2015 Sep;109(3):507-12.

OBJECTIVE: The study looked to compare the ER visits of elderly patients(>65 years) on sulfonylureas (SU) v/s non-SU monotherapy.
METHODS: A retrospective cohort study using a claims database was looked at for 1 year from 2010-2011 for ER use of patients on SU
monotherapy (glyburide=37.9%, glipizide=36.6%, glimepiride=24.9% and non-SU=78.4% metformin). A baseline history of the 2 groups
were performed to compare age, sex, disease conditions, medications used.

Results: The mean number (+/-SD) of ER visits in SU monotherapy was 0.56+/-1.28 (15,849pts) v/s non-SU monotherapy(13,895pts)
0.49+/-1.11 (p<0.0001) (for metformin specifically=0.45+/-1.04), the odds of SU therapy ER usage was higher. (multivariable analysis
LinearRegresion odds ratios of SU monotherapy v/s metformin=1.11(95%=1.05-1.17).
450 patients on SU had documented hypoglycemia ER visits vs 125 for non-SU pts. Comparing without documentation to those with
documented hypoglycemia, the mean number of ER visits (SD)=1.6(2.15) for documented vs 0.51 for undocumented (1.18,p<0.0001).
Multivariate LR odds ratio=2.25 for these 2 groups.

CONCLUSION: The authors concluded that in elderly patients monotherapy SU treatment resulted in higher ER visits over the 1 year
studied vs non-SU (metformin) use. And specifically documented hypoglycemia (which is more in SU treated patients) results in higher ER
visits.
Scientific/Expert opinion: #2
2- Comparison of Clinical Outcomes and Adverse Events Associated With Glucose-Lowering Drugs in Patients With Type 2 Diabetes: A
Meta-analysis. Palmer SC, Mavridis D, Nicolucci A,et al. JAMA. 2016 Jul 19;316(3):313-24.

Objective: The authors analyzed a comprehensive comparison of the effectiveness and safety of glucose drugs in addition to insulin.
Methods: A meta-analysis of data obtained from the cochrane library, Medline and embase was done. Comparisons were done against
metformin, sulfonylurea, TZD, DPP-4, SGLT2, GLP-1 agonist, insulin treatments, monotherapy and combinations and others. Endpoints for
adverse (safety) events were hypoglycemia and weight gain. 25 studies of monotherapy were evaluated.

Results: On primary outcome of CV death in monotherapy there was no significant differences between groups. Compared to metformin
the groups of sulfonylureas showed higher A1c’s (SMD=0.18 95%=0.1-0.34). Sulfonylurea treatments had bad associations with
hypoglycemia (absolute risk reduction(AAR) of 10% compared to metformin). And showed higher body weight while metformin monotherapy
showed less hypoglycemia and lower body weight.

Conclusion: Metformin treatment caused lower A1c’s or no differences between the other drug classes compared and is in agreement
with the ADA recommendations for initial metformin monotherapy for pts with DM2 considering other co-morbidities.
Scientific/Expert opinion: #2
2- Comparison of Clinical Outcomes and Adverse Events Associated With Glucose-Lowering Drugs in Patients With Type 2 Diabetes: A
Meta-analysis. Palmer SC, Mavridis D, Nicolucci A,et al. JAMA. 2016 Jul 19;316(3):313-24.

Objective: The authors analyzed a comprehensive comparison of the effectiveness and safety of glucose drugs in addition to insulin.
Methods: A meta-analysis of data obtained from the cochrane library, Medline and embase was done. Comparisons were done against
metformin, sulfonylurea, TZD, DPP-4, SGLT2, GLP-1 agonist, insulin treatments, monotherapy and combinations and others. Endpoints for
adverse (safety) events were hypoglycemia and weight gain. 25 studies of monotherapy were evaluated.

Results: On primary outcome of CV death in monotherapy there was no significant differences between groups. Compared to metformin
the groups of sulfonylureas showed higher A1c’s (SMD=0.18 95%=0.1-0.34). Sulfonylurea treatments had bad associations with
hypoglycemia (absolute risk reduction(AAR) of 10% compared to metformin). And showed higher body weight while metformin monotherapy
showed less hypoglycemia and lower body weight.

Conclusion: Metformin treatment caused lower A1c’s or no differences between the other drug classes compared and is in agreement
with the ADA recommendations for initial metformin monotherapy for pts with DM2 considering other co-morbidities.
Monitoring Plan:
Parameter Frequency

Blood sugar testing:Per ADA target for this When patient comes to the clinic.
patient will be A1c < 8 due to cognitive Monthly Target for the patient is A1c<8 and bedtime
impairment,age and comorbidities. Mean plasma glucose of 100-180 mg/dl per ADA guidelines.
glucose of 183 mg/dl

Number of urinary episodes per day Patient will record events daily Patient will record how often he goes to the
bathroom daily and bring to the next clinic visit.
Baseline will be previous visits reporting.

Blood pressure, pulse. monthly At time of clinic visit

Per JNC 8 guidelines goal BP= 140/90

Weight monthly At time of clinic visit. Goal will be to have a

reduction in weight from the previous baseline
visit and educate patient on the need to reduce
weight.

Dry mouth, constipation Patient will record events daily.

Alternative Drug Therapy:
1- Combination therapy of vesicare and mirabegron could be used but would still have antimuscarinic side effects of cognitive
impairment.
2- D/c glipizide and start Invokana (SGLT2)100 mg daily.
3- D/c glipizide and start Januvia (DPP4) 50mg daily.
References:
1- ADA guidelines 2016- Standards of medical care in diabetics 2016- Diabetes care, volume 39 supplement 1, Jan 2016, page s43.

2-Clinical pharmacology. http://www.clinicalpharmacology-ip.com/

3- Persistence and adherence with mirabegron, a new beta-3 receptor agonist, versus antimuscarinics in overactive bladder: early experience
in Canada. Wagg A, Franks B, Ramos B, et al. Can Urol Assoc J2015;9:343-50.

4- The pathophysiology and treatment of glaucoma: a review. Weinreb RN, Aung T, Medeiros FA. JAMA 2014;311:1901-11.

5- Beta3-adrenoceptors in urinary bladder. Yamaguchi O, Chapple CR. Neurourol Urodyn. 2007;26(6):752-6.

6- METFORMIN: ACTIONS AND INDICATIONS FOR USE IN NON-INSULIN-DEPENDENT DIABETES MELLITUS. Richard J. Mahler.
Endocrine Practice: November 1995, Vol. 1, No. 6, pp. 418-422.

7- Comparison of Therapeutic Efficacy and Urodynamic Findings of Solifenacin Succinate versus Mirabegron in Women with Overactive
Bladder Syndrome: Results of a Randomized Controlled Study. Vecchioli Scaldazza C, Morosetti C. Urol Int. 2016 Apr 20.
References (continued):
8-The efficacy and tolerability of mirabegron, a β3 adrenoceptor agonist, in patients with symptoms of overactive bladder. Thiagamoorthy G,
kotes S, Zacchè M, Cardozo L. Ther Adv Urol. 2016 Feb;8(1):38-46.

9- Mirabegron: a review of its use in patients with overactive bladder syndrome.

10- A drug safety evaluation of mirabegron in the management of overactive bladder.

11- The efficacy and tolerability of mirabegron, a β3 adrenoceptor agonist, in patients with symptoms of overactive bladder. Thiagamoorthy G,
Kotes S, Zacchè M, Cardozo L. Ther Adv Urol. 2016 Feb;8(1):38-46.

12- Mirabegron relaxes urethral smooth muscle by a dual mechanism involving β3 -adrenoceptor activation and α1 -adrenoceptor blockade.
Alexandre EC, Kiguti LR, Calmasini FB, Silva FH, et al. Br J Pharmacol. 2016 Feb;173(3):415-28.

13 - Tolterodine and Tamsulosin for Treatment of Men With Lower Urinary Tract Symptoms and Overactive Bladder. A Randomized
Controlled Trial. Kaplan SA, Roehrborn CG, Rovner ES, et al. JAMA. 2006 Nov 15;296(19):2319-28.

14- Early glycaemic control among patients with type 2 diabetes and initial glucose-lowering treatment: a 13-year population-based cohort
study. Thomsen RW, Baggesen LM, Svensson E, Pedersen l, Nørrelund H, Buhl ES, Haase CL, Johnsen SP. Diabetes Obes Metab. 2015
Aug;17(8):771-80.

15- Worry vs. knowledge about treatment-associated hypoglycaemia and weight gain in type 2 diabetic patients on metformin and/or
sulphonylurea. Lund A, Knop FK. Curr Med Res Opin. 2012 May;28(5):731-6.