Complex Cases-Neurology_handout

Complex Cases In
Neurology: The
Essentials You Need
to Know
Michele A. Faulkner, PharmD
Creighton University Schools of Pharmacy and Medicine
Jacquelyn Bainbridge, PharmD
University of Colorado Skaggs School of Pharmacy and
Pharmaceutical Sciences
2
Disclosures
•Target Audience: Pharmacists
• Michele Faulkner declares the following disclosures:
• Upsher-Smith – senior editor, Epilepsy Certificate
Program initiative
•ACPE#: 0202‐0000‐16‐019‐L01‐P
• Jacquelyn Bainbridge declares the following disclosures:
• UCB Pharma – investigator initiated study in the
•Activity Type: Application‐based elderly and Advisory Board
• Sunovion – Advisory Board
• Upsher-Smith – Epilepsy Certificate Program Initiative
The American Pharmacists Association is accredited by the Accreditation
Council for Pharmacy Education as a provider of continuing pharmacy
education.
3
Learning Objectives
1. Recommend an appropriate plan for the initiation, titration, monitoring, and altering of pharmacotherapy for cognitive, functional, and psychiatric symptoms in patients with Parkinson’s disease.
2. Implement an appropriate plan for the initiation, titration, monitoring, and altering of pharmacotherapy for cognitive, functional, and psychiatric symptoms in patients with Alzheimer’s disease.
3. Compare and contrast appropriate pharmacologic therapies in the treatment and prophylaxis of migraine in patients for whom first‐line therapies have failed.
4. Discuss the role of recently approved treatment approaches in the management of seizures and formulate a monitoring plan for a given patient receiving antiepileptic therapy.
4
The most appropriate therapy to
initiate treatment in a newly
diagnosed Parkinson’s disease
patient with moderate symptoms and
a relatively short treatment horizon is
•
•
•
•
Benztropine
Carbidopa/Levodopa
Carbidopa/Levodopa/Entacapone
Rasagiline
5.Describe reasonable expectations and limitations of available therapies for the treatment of patients with complex neurologic conditions including seizures, migraines, Parkinson’s disease, and Alzheimer’s disease.
5
© 2016 by the American Pharmacists Association. All rights reserved.
6
When initiating treatment for a
patient with mild Alzheimer’s
disease, that frequently has skin
eczema and bouts of nausea, which
therapy is appropriate to begin with?
•
•
•
•
Which of the following is the best
option for a patient who has failed
treatment of acute migraine
headache with oral sumatriptan?
•
•
•
•
Memantine
Donepezil
Rivastigmine
Galantamie
Intranasal sumatriptan
Subcutaneous sumatriptan
Rizatriptan
Oxycodone/acetaminophen
7
When initiating an antiepileptic drug
(AED) in a patient which is newly
diagnosed with complex partial
seizures and a strong history of nonadherence. Which AED might be a
good first choice?
•
•
•
•
8
Recommend an appropriate plan for the initiation, titration, monitoring, and altering of pharmacotherapy for cognitive, functional, and psychiatric symptoms in patients with Parkinson’s disease.
Lacosamide
Rufinamide
Ezogabine
Eslicarbazepine
9
Prevalence of Parkinson’s Disease in
the United States (2003)
10
Parkinson’s Disease Burden
• Second most common neurodegenerative disorder
• Affects 1 to 1.5 million Americans
– 60,000 diagnosed annually
• 7-10 million persons worldwide
• Affects 1% of persons > 60 years of age
– 4% of persons > 80 years of age
• Affects Men > Women (1.5:1)
• Lifetime risk of being diagnosed is 1 in 40
Neuroepidemiology. 2010;34(3):143-151.
© 2016 by the American Pharmacists Association. All rights reserved.
11
Am J Manag Care. 2010;16:s87-s93
http://www.pdf.org/en/parkinson_statistics
12
Risk Factors Associated with
Parkinson’s Disease
Parkinson’s Disease Pathology
• Degenerative disorder of the central nervous system resulting in
• Pesticide exposure/Rural Living/Agricultural Occupation
destruction of dopaminergic neurons in the substantia nigra pars
compacta.
• Heavy metals
• Resulting dopamine deficiency in the basal ganglia results in increased
inhibitory output causing suppression of movement.
• Consumption of well water
• Relative overactivity of acetylcholine in the basal ganglia results in
spontaneous misfiring leading to tremor.
• Prior head injury
• Deposition of Lewy bodies (made up of misfolded α-synuclein protein)
is found throughout the central and peripheral nervous systems.
• Genetics
13
Things to Consider When Initiating
Treatment
Clinical Presentation
Motor signs
• Tremor at rest
• Bradykinesia
• Rigidity
• Postural impairment
14
Non-motor signs
• Depression
• Dementia
• Psychosis
• Orthostatic hypotension
• Sleep dysfunction
• Gastrointestinal
dysfunction
• Erectile dysfunction
• Drooling
• Age of patient
• Overall physical health/degree of
disability
• Concurrent diseases
• Work status
• Presence of non-motor symptoms
• Adherence
15
16
Parkinson’s Disease Case
Parkinson’s Disease Case
HB is a 66 year old female who is retired from her job as a
dental assistant. She has a small internet-based business
that allows her to sell the handmade jewelry she creates as a
hobby. She took up running when she retired, and is getting
ready to complete her first half-marathon next month.
Past Medical History
CC: “I’ve noticed some shaking in my left hand recently. It
used to come and go, but it seems to be getting worse.”
Medications
–
–
–
–
17
© 2016 by the American Pharmacists Association. All rights reserved.
–
–
–
–
Osteopenia
Chronic constipation (diagnosed with irritable bowel syndrome)
Hypertension x 4 years
Depression
Calcium citrate 600mg po daily
Polyethylene glycol 17gm po daily prn no bowel movement
Hydrochlorothiazide 25mg po daily
Lisinopril 5mg po daily
18
Parkinson’s Disease Case
Parkinson’s Disease Case
Social and family history
Vital signs/demographic information
–
–
–
–
–
–
Lives at home with husband
Gravida 3, Para 3
Non-smoker
Social drinker (1-2 per week)
Mother died of breast cancer (age 57)
Father died of an MI, diagnosed with Parkinson’s disease at age
67)
– 4 siblings, one with Parkinson’s disease (age of diagnosis 59)
–
–
–
–
–
BP 141/86
Pulse 66
Height 68 inches
Weight 144lb (65.3kg)
BMI 21.9
Recent labs
– CBC, CMP within normal limits
19
20
Parkinson’s Disease Case
Parkinson’s Disease Case
Review of Systems (continued)
– Genito-Urinary Superficial bleeding from external hemorrhoid. No urinary
symptoms noted.
Review of Systems
– Eyes PERRLA
– Female Reproductive Menopausal (age 54).
– Ears/Nose/Throat Non-contributory
– Musculoskeletal Non-contributory. Normal strength bilaterally.
– Mouth / Dental Non-contributory
– Breast No reported symptoms. Annual mammogram negative for pathology.
– Neurological Mild bilateral tremor L > R. Normal gait, slightly diminished arm swing
on left. Mild rigidity of upper L limb.
– Cardiovascular No SOB, chest pain. RRR
– Skin Non-contributory.
– Respiratory Non-contributory
– Endocrine Non-contributory.
– Gastrointestinal Constipation (last bowel movement 48 hours ago)
– Psychiatric Denies depression, but appears intermittently tearful during encounter.
Husband believes she is depressed.
21
22
Let’s Revisit the Things to
Consider…
Question #1
A diagnosis of Parkinson’s disease is confirmed. Should
pharmacologic therapy be initiated for the treatment of HB’s
Parkinson’s disease at this time?
• Age of patient
– Older chronologically (i.e. not young onset), but what about physiologically?
• Overall physical health/degree of disability
– Very active with regular exercise
A. Yes. The disease is interfering with her quality of life.
• Concurrent diseases
B. Yes. Some medications are neuroprotective, and if used early
they may produce a better outcome by delaying disability.
– IBS-C
• Work status
C. No. HB is an active individual, potentially with a long treatment
horizon, so therapy should be delayed to delay long-term side-effects.
– Retired-hobby requires dexterity
• Presence of non-motor symptoms
– Constipation
D. No. HB is still very active, and does not need treatment at this
time.
• Adherence
– No obvious concerns
23
© 2016 by the American Pharmacists Association. All rights reserved.
24
Question #2
Carbidopa/Levodopa
The decision is made to initiate drug therapy. What is/are the best
options?
• Gold standard
• Dopamine replacement therapy
A. Carbidopa/Levodopa
– Highly effective for all medication-responsive motor symptoms
B. Monoamine oxidase inhibitor / MAO-I (e.g. rasagiline, selegiline)
C. Dopamine agonist (e.g. pramipexole, ropinirole, rotigotine)
• Risk of development of dyskinesia
– 50% at 5 years, >90% at 5 years if diagnosed before the age of 40
– Several trials indicate initiation of treatment with a different drug class
resulted in fewer motor complications,1-4 while higher cumulative
doses of levodopa5-6 and longer treatment duration7-9 have been
associated with dyskinesias
D. Amantadine
E. Anticholinergic (e.g. trihexyphenidyl, benztropine)
25
1. JAMA 2000; 284:1931-8 2. N Engl J Med 2000;342:1484-91. 3. N Engl J Med 2004;351:2498-508.
4. Cochrane Database syst Rev 2008;CD006564. 5. Arch Neurol 2006;63:1756-60.
6. Mov Disord 2013;28;1064-71. 7. Clin Neuropharmacol 1997;20:52330.
8. J Neurol 1999;246:1127-33. 9. Brain 2000;123:2297-305.
26
MAO-Is
• Irreversible, selective inhibition of dopamine metabolism
– Monoamine oxidase is an enzyme that catalyzes the oxidation of
monoamine neurotransmitters including dopamine, norepinephrine
and serotonin, as well as biogenic amines (e.g., tyramine)
• Four year multicenter study
– 91 Parkinson’s disease patients in Ghana and 2,282 patients in Italy
– Nested matched subgroups used to compare clinical variables
– Outcomes:
• Though levodopa was initiated later in patients in Ghana (4.2 + 2.8 vs. 2.4 +
2.1 years, p<0.001), Parkinson’s disease duration at time of dyskinesia onset
was similar
• Disease duration and daily levodopa dose (mg/kg) were associated with
dyskinesia onset
Brain 2014;137:2731-42
27
• Effective as monotherapy for mild-moderate motor symptoms
• Drug interactions
– Less likely when used at approved doses
– Concomitant use with tricyclic antidepressants and selective
serotonin reuptake inhibitors is not recommended, nor are
cyclobenzaprine, methadone or tramadol
J Clin Pharmacol 2012;52:620-8
Expert Opin Drug Saf 2014;13(8):1055-69
28
MAO-Is and neuroprotection
Study
• Survey of neurologists
Trial Components
Primary Outcome
Measure
Results
Conclusion
DATATOP (1993)
Selegiline vs. placebo
Delay to levodopa
Delay to levodopa
greater with
selegiline
Inconclusive:
selegiline
neuroprotection
vs. symptomatic effect;
no lasting effects at
35 months
TEMPO (2004)
Rasagiline vs. placebo
plus delayed-start
rasagiline
Change in UPDRS
Better overall UPDRS
at 12 months
Potential disease
modification with
rasagiline
ADAGIO (2008)
Rasagiline vs. placebo
plus delayed-start
rasagiline
Change in UPDRS;
slope
superiority to week 36;
non-inferiority weeks
48-72
72-week outcomes
better in early-start
group; all endpoints
met
Potential disease
modification with
rasagiline
– 75% response rate
• Estimated number of patients treated with selegiline + any
antidepressant : 4,568
• Number of patients identified with symptoms consistent
with serotonin toxicity: 11
– 2 patients with symptoms considered “serious”
Neurology 1997;48:1070-7
© 2016 by the American Pharmacists Association. All rights reserved.
29
http://www.uspharmacist.com/continuing_education/ceviewtest/lessonid/105986/
30
Dopamine Agonists
• Direct stimulation of D2 receptors in the CNS
– Stimulation of and affinity for other dopamine receptor types varies
by agent
• Effective as monotherapy for mild-moderate symptoms
– Works for all medication-responsive motor symptoms, but less
robust than carbidopa/levodopa
– Levodopa sparing as an adjunctive agent
• Less likely to induce motor fluctuations than levodopa
monotherapy
N Engl J Med 2009;361:1268-78.
31
Int J Neurosci 2012;122:345-53
CNS Drugs 2013;27:259–72
Mov Disord. 2007;22(16):2409–17
32
Parkinson’s disease and depression
• Depression in Parkinson’s disease is prevalent1
–
–
–
–
• 29 trials
– 5,247 patients
Major depression: 17%
Minor depression: 22%
Dysthymia: 13%
Clinically relevant symptoms without formal diagnosis: 35%
• Depression in Parkinson’s disease is underdiagnosed
• Randomization to a dopamine agonist resulted in fewer dyskinesias
– Approximately ½ are undiagnosed by neurologists2
– Of those diagnosed, ½ are undertreated3
(p<0.0001), dystonias (p=0.0002), and motor fluctuations (p=0.002)
compared to those who initiated therapy with levodopa
• Risk factors (predictive for major depression in 75% of
sample in study)4
• Randomization to dopamine agonists resulted in discontinuation of
–
–
–
–
–
therapy due to adverse events more often than with levodopa
(p<0.00001)
• Symptom control reported to be less robust with dopamine agonists
Stowe R, Ives N, Clarke CE, van Hilten, Ferreira J, Hawker RJ, Shah L, Wheatley
K, Gray R. Dopamine agonist therapy in early Parkinson's disease. Cochrane
Database of Systematic Reviews 2008, Issue 2. Art. No.: CD006564. DOI:
10.1002/14651858.CD006564.pub2.
33
1.
2.
3.
4.
Female sex
Previous diagnosis of depression
Family history
Advanced age
Somatic comorbidity (other than PD)
Mov Disord 2008;23(2):183-9.
Parkinsonsim Relat Disord 2002;8(3):193-7.
J Geriatr Psychiatry Neurol 2003;16(3):178-83.
Acta Psychiatr Scand 2002;106:196-201.
34
Amantadine
Dopamine agonists and depression
• Antiviral agent approved for the prophylaxis and treatment of
influenza
• Dopaminergic deficiency is established in the mesolimbic
– Secondarily approved for use in the treatment of Parkinson’s disease
and mesocortical pathways
– Involved in reward mechanism and mood regulation
– Area is rich with D3 receptors
• Mechanism in controlling symptoms is unclear
– Mild antimuscarinic effects
– Enhances pre-synaptic dopamine release
– NMDA glutamate receptor antagonist
• Useful for levodopa-induced dyskinesia
• Movement Disorder Society evidence based review1
– Pramipexole deemed efficacious for depression
• The highest binding affinity for D3 receptor subtype
– Data on other agonists is conflicting/lacking
• Not very useful as monotherapy
– Tachyphylaxis vs. limited efficacy
– May be used to delay initiation of levodopa
1.
Movement Disorders 2011;26(Suppl 3):S42-S80.
© 2016 by the American Pharmacists Association. All rights reserved.
35
Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD003468. DOI:
10.1002/14651858.CD003468
Br Med J 1970;4:24-6
Mov Disord 2011;26(Suppl 3):S2–S41
36
Anticholinergics
• Corrects disequilibrium between dopamine and acetylcholine
– Primarily effects tremor
• Community-based Parkinson’s disease cohort
– 235 patients (>40% on anticholinergic medications at baseline)
• Anticholinergic effects not well tolerated by older individuals
– Assessed using MMSE at baseline, 4 and 8 years
– Medications were rated according to anticholinergic load
– Many drug-disease interactions (BPH, glaucoma, arrhythmias)
• May exacerbate non-motor symptoms of Parkinson’s disease
– Dementia
– Constipation
• Decline in score was greater in patients exposed to anticholinergic
medications
– 6.5 points vs. 1 point (p=0.025)
• Anticholinergic load and duration of use were associated with cognitive
decline (adjusted for age, baseline cognition and depression)
• Some evidence that anticholinergic use increases risk for
– Load: p=0.04
permanent cognitive decline
Psychiatr Danub 2009;21:114-18
Drugs 1981;21:341-53
– Duration: p=0.032
37
Parkinson’s disease case continued…
After 3 years, HB’s symptoms are increasing in severity. She now has a
constant left hand tremor with intermittent tremor on the right, and significant
cogwheeling on the left. Her speech is soft. She demonstrates no arm swing
on the left and diminished swing on the right when walking, she walks on the
balls of her feet and turns en-bloc with 4 steps. Her depression is controlled.
However, she is having difficulty sleeping through the night because she has
difficulty re-positioning herself.
Medications include
–
–
–
–
–
–
J Neurol Neurosurg Psychiatry 2010;81:160-65.
38
Question #3
What is the best strategy to address HB’s advancing Parkinson’s
disease at this time?
A. Add rasagiline 1mg po daily
B. Add carbidopa/levodopa 25/100mg po tid
C. Change to monotherapy with carbidopa/levodopa
50/200 po tid
Calcium citrate 600mg po daily
Polyethylene glycol 17gm po daily prn no bowel movement
Hydrochlorothiazide 25mg po daily
Lisinopril 5mg po daily
Mirtazapine 15mg po q hs
Pramipexole 1.5mg po tid
D. Add levodopa/carbidopa/entacapone
18.75mg/75mg/200mg po tid
39
40
COMT-Is
• Inhibits metabolism of levodopa and dopamine
• Designed to see if limiting pulsatile stimulation of dopamine receptors would
– Entacapone acts peripherally, tolcapone acts peripherally and
centrally
– Place in therapy is as an adjunct to carbidopa/levodopa
decrease the risk of developing dyskinesias
– Prospective, double blind, 134-week trial
– 747 patients
– QID dosing at 3.5 hour intervals
• Helps compensate for overactivity of COMT resulting from
decarboxylase inhibition by carbidopa
• At study end the number of patients receiving entacapone with dyskinesias
was higher than those not using a COMT-I (42% vs. 32%, p=0.02).
• Place in therapy (early vs. late) is controversial
Clin Neuropharmacol 2007;30:287-94
Neurology 1994;44:913-19
© 2016 by the American Pharmacists Association. All rights reserved.
• Patients receiving entacapone developed dyskinesias sooner than those on
carbidopa/levodopa monotherapy (p=0.04)
– Increases on time
– May increase levodopa half life by up to 80%
• Patients receiving dopamine agonists at baseline were at higher risk for
dyskinesia development
41
Ann Neurol 2010 Jul;68(1):18-27
42
Parkinson’s disease case continued…
After an additional two years, the clinic receives a call from the patient’s husband stating
that she keeps telling him that her mother (who has been deceased for 11 years) has
been visiting her in the evenings. HB is very distressed by these visits, and becomes
upset that her mother does not answer her when she initiates conversation. Her motor
symptoms have progressed, but she and her husband are both satisfied with her current
functionality, and are not interested in increasing her medications or adding additional
drugs for Parkinson’s disease at this time.
Medications include
– Calcium citrate 600mg po daily
-- Carbidopa/Levodopa 50/200mg po qid
– Polyethylene glycol 17gm po daily prn -- Pramipexole 1.5mg po tid
no BM
– Hydrochlorothiazide 25mg po daily
– Lisinopril 10mg po daily
– Mirtazapine 30mg po q hs
Question #4
What is the best strategy for addressing HB’s new onset of
psychotic symptoms?
A. Gradually titrate the carbidopa/levodopa off
B. Add Olanzapine 5mg po daily
C. Add Quetiapine 6.25mg po at bedtime
D. Don’t treat it since antipsychotics tend to
exacerbate motor symptoms (risk outweighs benefit)
43
Parkinson’s Disease and Psychosis
(PDP)
44
Treatment of PDP
• Not all patients need to be treated
– Treat if symptoms are distressing for patient
– Treat if symptoms put patient or caregivers at risk
• Will occur in up to 60% of Parkinson’s patients
– Most commonly visual hallucinations
• Up to 20% report auditory hallucinations
– Delusions in 10-20%
• Usually persecutory in nature
• Antipsychotic therapy has been associated with an
increased risk of mortality in Parkinson’s disease patients1
– Study of pimavanserin in Parkinson’s patients with (66) and without
(357) additional atypical antipsychotic use
– 18.8 deaths vs. 4.5 deaths per 100 person years
• Initial approach is to rule out infection and metabolic abnormalities
• Unnecessary medications should be discontinued
• Avoid traditional antipsychotics
• Attempts to taper Parkinson’s medications may be undertaken in the
– D2 receptor blockade will exacerbate symptoms
– Atypical antipsychotics with D2 receptor affinity may also make
motor symptoms worse (e.g. olanzapine, risperidone)
following order: Anticholinergics, MAO-Is, amantadine, dopamine
agonists, entacapone and carbidopa/levodopa
45
1. J Am Med Dir Assoc 2015 Oct 1;16(10):898.e1-7
Dosing: Motor symptoms of
Parkinson’s disease
Treatment of PDP
• Drugs of choice (off-label use)
– Clozapine
Medication
• Affinity for D1 and 5HT-2A/2C receptors
• Consistently found to be efficacious in randomized, controlled trials1-3
• Limited use due to risk of neutropenia and monitoring requirements
– Quetiapine
• Structurally similar to clozapine
• Most widely used antipsychotic in Parkinson’s disease despite conflicting
efficacy data
• Doses used are lower than in schizophrenia4
Carbidopa/Levodopa
Dosing Guideline
25/100mg po tid, maximum 600mg (levodopa component
Dopamine Agonists
Rotigotine patch
2-8mg topically daily
Pramipexole
IR 0.125mg po tid; ER 0.375mg po daily
Titrate either to max 4.5mg daily
Ropinirole
0.25mg po tid; XL 2mg po daily
Titrate either to max 24mg daily
MAO-Is
Selegiline
Rasagiline
– Clozapine 6.25-50mg daily, Quetiapine 12.5-150mg at night
Amantadine
Anticholinergics
Benztropine
• Emerging therapy
– Pimavanserin5
• Being studied specifically for the treatment of PDP
• Inverse agonist at 5HT-2A receptors
• No worsening of motor symptoms noted in clinical trials
1. Mov Disord 2001;16:135-9
2. Clin neuropharmacol 2006;26:331-7.
3. Neurol Sci 2002;23(Suppl2):S89-90. 4. Curr Treat Options Neurol 2014;16:281
5. Drugs Today (Barc) 2015 Nov;51(11):645-52
© 2016 by the American Pharmacists Association. All rights reserved.
46
Trihexyphenidyl
COMT-Is
Tolcapone
Entacapone
47
IR 5mg po bid (dose before 1:00PM);
ODT 1.25mg po daily (titrate to max 2.5mg daily)
0.5mg po daily (when initiated with levodopa); 1mg po daily
(monotherapy)
100mg po daily-bid
1-6mg po daily (divide higher doses)
1-10mg po daily (divided tid-qid)
100-200mg po tid
100-200mg po with each dose of levodopa (maximum
1600mg/day)
48
Key Points
• Since no medication has been proven to slow disease progression,
initiation of treatment should be based on the current needs of the
patient.
• The physiologic age, rather than the chronologic age of the patient
should be utilized for treatment decisions.
• Postponing the initiation of carbidopa/levodopa for appropriate patients
can delay the complications of dyskinesias.
• Depression in Parkinson’s patients is common, and underdiagnosed
possibly contributing to negative outcomes.
• The treatment of Parkinson’s disease psychosis is not necessary for all
affected patients.
Sinemet CR® [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; 2014
Rytary ® [package insert]. Hayward, CA: Impax Laboratories, Inc; 2015
49
Implement an appropriate plan for the initiation, titration, monitoring, and altering of pharmacotherapy for cognitive, functional, and psychiatric symptoms in patients with Alzheimer’s disease.
50
Types of Dementia
• Alzheimer’s Disease: 60-80%
• Vascular dementia
• Lewy body dementia
• Frontotemporal dementia (Pick’s)
• Mixed
• Reversible causes
51
Reversible Causes of Dementia
52
Drug Induced Cognitive Impairment: Beers
List Drugs to Avoid in Patients with
Dementia
Drugs/Depression
Eyes/ears
• Anticholinergics
Metabolic – hypoxia, B12/folate deficiency, TSH
Endocrine – DM, hypercalcemia
• Benzodiazepines
Normal pressure hydrocephalus (NPH)
• H2-receptor antagonists
Trauma/tumor - subdural
Infection – syphilis, HIV
• Zolpidem
Alcohol
• Antipsychotics
53
© 2016 by the American Pharmacists Association. All rights reserved.
54
Alzheimer’s Disease Pathophysiology
Extracellular amyloid plaques
• Chronic imbalance between production
and clearance of beta-amyloid peptide
• Excessive amounts interfere with signaling
at neuronal synapses
Pathophysiology
Intracellular neurofibrillary tangles
• Twisted strands of protein tau
• Microtubules collapse (transportation and
skeletal support system of neurons)
• Now thought to spread from neuron to
neuron like infectious process
Neuronal Loss
Cerebral Atrophy
55
Biochemical Changes of Alzheimer’s
Disease
56
Case Discussion
• A 74 y/o female diagnosed with AD approx 6 yrs ago
• Meds: Donepezil 10 mg po at bedtime, Vitamin E 400 IU po once daily,
• Most prominent = cholinergic abnormalities
• Associated with memory impairment
• Similar memory impairment with anticholinergics
•
•
• Diminished levels of:
• Norepinephrine
•
• Serotonin
• Dysregulated glutamate activity causing cell injury
Lisinopril 10 mg po once daily, Simvastatin 20 mg po every evening, Aspirin 81
mg po once daily, Oxybutynin 5 mg po twice daily (×2 months), Tylenol for
pain as needed
MMSE score today = 16/30; 2 years ago = 24/30.
She lives alone at home but her daughter is looking for a SNF to place her
mother in.
Daughter states “Mom has become apathetic and tearful in the last month. She
complains that someone is stealing from her and she is not always cooperative.
She lives on her own, but I am considering moving her to a nursing home.”
What nondrug therapies might be useful for this patient?
What feasible pharmacotherapeutic agents are available for treatment of the
cognitive deficits of AD?
57
58
Clinical Management of Alzheimer’s Disease
Pharmacologic Management of AD
No cure, only supportive care
• Cholinesterase Inhibitors
• Discontinue/change medications that might be
•
– FDA-approved for mild to moderate AD
contributing
Nonpharmacologic interventions
– Donepezil also approved for severe AD
– Rivastigmine also approved for PD dementia
– Patient/family/caregiver support
– Anticholinergics may negate effects
– Education and discussion of goals, legal decisions, QOL
• NMDA antagonists
– Refer to Alzheimer’s Association (www.alz.org)
– FDA-approved for moderate to severe AD in monotherapy or
combination therapy with AChE-I
• Cognitive “enhancing” medications
• Behavioral management
• Full benefit of meds typically takes 6mo
• Data for treatment > 1 year is lacking
– Nonpharmacological
– Pharmacological
59
© 2016 by the American Pharmacists Association. All rights reserved.
60
Donepezil
Cholinesterase Inhibitors: Summary of Efficacy
• Indicated for mild-moderate disease
• Dosing
• Very modest improvement/stabilization in symptoms
• ADAS-cog (range 0-70)
–
–
–
–
–
– 4 pt improvement 25-50% with treatment vs. 15-25% with placebo
– 7 pt improvement 12-20% with treatment vs. 2-6% with placebo
• Behaviors NPI (range 0-120)
– Improvements inconsistent – as low as 0 to as high as 5.6 pts vs.
placebo
Available as generic tablets, ODT
Initial: 5 mg daily
May increase to 10 mg QD after 4-6 weeks
May increase to BRAND 23 mg after 3 months
Minimum effective dose: 5mg daily
• Side effects
– Donepezil not effective for agitation: NEJM 2007;357:1382-1392
• Delay in Nursing Home Placement
– Some studies do suggest, but few data available powered and controlled
to formally look at this
–
–
–
–
Up to 10 mg: nausea (6%), vomiting (5%), diarrhea (9%)
23 mg: nausea (12%), vomiting (9%), diarrhea (8%)
Metabolized by CYP450 2D6 and 3A4
Warnings in patients with COPD/asthma, PUD, sick-sinus syndrome
– AD2000 study – no benefit
Lancet 2004; 363:2105-2115: no benefit
61
62
Galantamine
Rivastigmine
• Indicated for mild-moderate disease
• Dosing
– Available as generic capsules; BRAND oral soln & patch
– Caps/soln: 1.5 mg BID → 3mg BID → 4.5mg BID → 6mg BID after 4wks
at each dose
– Patch: 4.6mg patch once daily → 9.5mg patch once daily after 4 wks →
13.3 mg patch once daily
– Minimum effective dose: 3mg BID; 9.5mg patch daily
• Side effects
– Caps/soln: N/V 50%, diarrhea 17%, anorexia 20%
– Patches: N/V 7%, diarrhea 6%, anorexia 3%; increased with 13.3mg
patch
• Not appreciably metabolized in the liver, therefore low risk of drug interactions
• Must also be used with caution COPD/asthma, PUD, sick-sinus/bradycardia
• Indicated for mild-moderate disease
• Dosing
– Available as generic IR tablets, ER capsules, oral solution
– IR: 4mg BID → 8mg BID → 12mg BID after 4 wks at each dose
– ER: 8mg once daily → 16mg once daily → 24 mg once daily after 4 wks
at each dose
– Minimum effective dose: 16mg/day
• Side effects:
– Nausea 17%, vomiting 10%, diarrhea 12%, anorexia 9%
• Metabolized by 2D6 and 3A4 in the liver
• Renal excretion: max dose 16mg/d for moderate renal
impairment
• Similar cautions in COPD, PUD, SSS
63
Memantine
Memantine
• Consider mono-therapy or adjunct therapy in moderate to
•
•
•
•
severe disease
Moderate affinity, noncompetitive NMDA receptor
antagonist
Does not impair physiologic function of NMDA receptor
Helps to maintain function—modest results
Can be used in combination with cholinesterase inhibitors
65
© 2016 by the American Pharmacists Association. All rights reserved.
64
Dosing
IR tablets
• 5mg daily x 1 week  5mg BID x1 week  10mg AM and 5mg PM x 1
week  10mg BID
XR capsules
• 7,14,21,28 mg XR tabs
• 7mg daily x 1 week  14mg daily x 1 week  21mg daily x 1 week 
28mg daily
• Minimum effective dose: 10mg BID or 28mg daily
• Maximum dose for CrCl <30: 5mg BID or 14mg daily
66
Gingko Biloba
• Contains flavenoids and terpinoids that may have anti-oxidative
•
•
•
•
and anti-inflammatory effects/specific extracts
Mixed results in clinical studies
Unregulated and not recommended
Risk of bleeding
Cochrane review 4/09: …appears to be safe, but the evidence
…is inconsistent and unreliable.
Vitamin E: 1000 units BID
• 1997 study: majority female, mean age 73 yrs
– Delayed endpoint of death/institutionalization/loss of ADLs/severe
dementia by 145-215 days
– ↑ survival by 230 days vs PBO
– ↑ risk of falls/syncope with vit E
• 2014 study: men w/mild-moderate AD on AChEIs, mean age 78 yrs
– ↓ functional decline on ADCS-ADL by 19% / yr compared to PBO
– Non-significant ↓ in mortality compared to PBO (7.3% vs 9.4% / yr)
• High-dose Vitamin E ↑ all cause mortality
NEJM 1997;336:1216-1222; JAMA 2014;311(1):33-44.
67
Ann Int Med 2005;142:37-46; JAMA 2007;297:842-57
68
CNS Drugs 2002;16:811-24; JAMA 1997;278:1327-32; JAMA 2002;288:835-40; Birks J, Evans JG. Cochrane Review 4-09.
Behavioral Therapy of AD
Back to the Case
• Cholinesterase inhibitors have mixed data as behavioral therapy
• Depression
• A 74 y/o female diagnosed with AD approx 6 yrs ago
• Meds: Donepezil 10 mg po at bedtime, Vitamin E 400 IU po once daily,
•
•
•
Lisinopril 10 mg po once daily, Simvastatin 20 mg po every evening, Aspirin 81
mg po once daily, Oxybutynin 5 mg po twice daily (×2 months), Tylenol for
pain as needed
MMSE score today = 16/30; 2 years ago = 24/30.
She lives alone at home but her daughter is looking for a SNF to place her
mother in.
Daughter states “Mom has become apathetic and tearful in the last month. She
complains that someone is stealing from her and she is not always
cooperative. She lives on her own, but I am considering moving her to a
nursing home.”
What feasible pharmacotherapeutic agents are available for treatment of the behavioral
abnormalities in this patient?
69
Behavioral Therapy of AD
Psychotic symptoms
• Typical antipsychotics
OFF-LABEL THERAPY
• Atypical antipsychotics
• Use of antipsychotics requires risk/benefit documentation
Risks
• Side effects: orthostatic hypotension, EPS
• DART-AD (typicals/atypicals): increase in total mortality
• CATIE-AD (atypicals) subgroup analysis: weight gain, ↓HDL
• OBRA regulations - inappropriate for unsociability, wandering,
uncooperativeness, poor self-care
Benefits
• Some positive studies for risperidone, olanzapine, and aripiprazole but
only 17-18% of patients respond
• CATIE-AD (atypicals) demonstrated no overall benefit vs PBO
71
JAMA 2011; 306(12):1359-1369. AHRQ Comparative Effectiveness Review No. 43, 2011; Lancet Neurol 2009; Am J Psychiatr 2009; NEJM 2006;355:1525-38;
© 2016 by the American Pharmacists Association. All rights reserved.
• SSRIs and SNRIs – mixed results
• TCAs NOT recommended
• Inappropriate/disruptive behavior (anxiety, aggression,
agitation)
• No clear “drug of choice”
• SSRIs
• Benzodiazepines
• Buspirone
• Carbamazepine
• Valproic acid
• Estrogen: aggressive/sexually aggressive behavior
JAMA 2005;293:596-608; Arch Int Med 1995;155:250-60; NEJM 2006;355:1525-38
70
Antipsychotic Therapy in AD Black Box
Warning
WARNING: INCREASED MORTALITY IN ELDERLY
PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
See full prescribing information for complete boxed warning.
Elderly patients with dementia-related psychosis treated with
antipsychotic drugs are at an increased risk of death.
NOTE: This BBW applies to ALL antipsychotics
72
Initiating Antipsychotic Therapy
Antipsychotics and Beers List
All antipsychotics should be avoided in a person with
dementia or cognitive impairment
Doses much lower than for schizophrenia
• Haloperidol 0.25mg/d up to 1-3mg/d
• Olanzapine 2.5mg/d up to 5-10mg/d
• Quetiapine 25mg/d up to 100-300mg/d
• Risperidone 0.25mg/d up to 0.75-2mg/d
• Ziprasidone 20mg/d up to 40-160mg/d
• Aripiprazole 2mg/d up to 15mg/d
• Avoid for behavioral problems unless non-pharmacologic options have failed
and patient is a threat to themselves or others
• Increased risk of cerebrovascular accidents and mortality in persons with
dementia
• Must monitor for symptom control and if none within 1-2 months,
discontinue
• If continuous treatment, reevaluate at regular intervals
– Also monitor for weight gain, diabetes, and movement disorders
http://onlinelibrary.wiley.com/doi/10.1111/jgs.13702/abstract
73
J Am Geriatr Soc 63:2227-2246, 2015
74
Migraine burden
Compare and contrast appropriate pharmacologic therapies in the treatment and prophylaxis of migraine
in patients for whom first‐line therapies have failed.
• More than 28 million migraine headache sufferers in the
United states
• Affects Women > Men (3:1)
• Prevalence peaks between ages 25-55
• Diagnosis of 20% of all patients seeking care by a
neurologist in the outpatient setting
– More common than asthma and diabetes combined
75
Migraine headache triggers
One Year Prevalence of Common Headache
Disorders
41%
45%
76
• Hormonal changes in women
– Menstrual migraine
40%
• Foods
40%
– Chocolate, aged cheeses
– Skipping meals
35%
30%
25%
18%
• Drinks
20%
15%
6%
10%
5%
– Alcohol
– Highly caffeinated beverages
2.80%
•
•
•
•
•
5%
0%
Migraine
Episodic
Tension
Female
Chronic Daily
Male
Headache 2001;41(7):646-657
JAMA 1998;279:381-383
Headache 1998;38:497-506
© 2016 by the American Pharmacists Association. All rights reserved.
77
Stress
Sensory stimuli
Changes in wake/sleep pattern
Changes in barometric pressure
Vasodilating medications
78
Migraine cascade
Cephalalgia 2007;27(5):394-402
79
Typical clinical presentation of
“common migraine”
80
Other migraine features
• Localized in frontotemporal and ocular area of head
Prodrome
Aura
• Premonitory symptoms that occur • Neurologic symptoms that precede
• Duration of 4-72 hours (untreated)
• Unilateral
in up to 60% of patients
• Throbbing, pulsatile pain
– Comes on gradually over 1-2 hours
• Moderate to severe pain
At least two of
these must be
present to fulfill
diagnostic criteria
• Pain intensifies with movement or physical activity
• Nausea/vomiting
• Phonophobia/photophobia
At least one of these must be present
to fulfill diagnostic criteria
– Heightened sensitivity to light, sound,
and odors
– Lethargy or uncontrollable yawning
– Food cravings
– Mental and mood changes (eg,
depression, anger, euphoria)
– Excessive thirst and polyuria
– Fluid retention
– Anorexia
– Constipation or diarrhea
or accompany headache in ~10% of
patients
– Visual field defects
– Scintillating scotoma
– Paresthesia
• May be followed by numbness
– “Heavy” limbs without weakness
– Speech/language disturbance
81
Migraine Headache Case
Migraine Headache Case
EM is a 27 year old female who arrives at the neurology clinic with severe
migraines that are present nearly every day. When attacks first started 4
years ago, she tried to treat them with OTC NSAIDS, but within the last year
she has visited the emergency room on several occasions due to refractory
headache symptoms. The last time she went to the ER about three months
ago, she says they gave her a shot that made her go to sleep, and gave her a
prescription for some pain medication which she has been taking at a
frequency of every other day to twice daily. She denies aura. She
characterizes her current pain level at 6/10. She requests the shades on the
window be closed.
CC: “My headaches are happening more and more often, and I’m afraid I’m
going to lose my job because I keep missing work.”
83
© 2016 by the American Pharmacists Association. All rights reserved.
82
Past Medical History
– Patellar tendinitis
Medications
– Oxycodone 5mg/APAP 325mg, 1-2 tablets po q4 hours as needed
for headache pain
– Multivitamin 1 po daily
Social and family history
–
–
–
–
Lives with 2 roommates
Non-smoker
Denies alcohol use
Mother with hypertension
84
Migraine Headache Case
Migraine Headache Case
Review of Systems
– Eyes PERRLA
Vital signs/demographic information
–
–
–
–
–
– Ears/Nose/Throat Non-contributory
BP 149/92
Pulse 70
Height 65 inches
Weight 184 lbs (83.5 kg)
BMI 30.6
– Mouth / Dental Non-contributory
– Cardiovascular No SOB, chest pain. RRR. Elevated blood pressure (untreated
hypertension)
– Respiratory Non-contributory
– Gastrointestinal Nausea without vomiting
Recent labs and diagnostic tests
– CBC, CMP within normal limits
– CT (obtained in ER) is non-contributory
– Neurological Unilateral, temporal pulsating pain radiating to jaw on left present for >24
hours.
– Psychiatric Non-contributory.
85
86
Medication overuse headache
Question #1
• Secondary cause of chronic daily headache/transformed
What is the most likely cause of the increasing frequency of
EM’s headache?
migraine
– Formerly referred to as rebound headache
• Can occur with virtually all acute migraine therapies
A. The patient is of the age where heightened
prevalence is common
–
–
–
–
B. Lack of sleep caused by headache pain
C. An underlying pathology (e.g. a tumor, or bleed)
Opioids and butalbital-containing analgesics
Triptans
Ergotamine derivatives
Simple analgesics and NSAIDS
• Exception is plain ASA
• Headache characteristics
– Occur > 15 days/month
– Regular overuse of a medication for > 3 months
D. Medication overuse
87
Consequences of chronic opioid use
for migraine headache
Opiate use for migraine headache
• Most widely used medications for acute migraine treatment
in North American emergency
rooms1
– Repeat ER visitors more likely to use opioids for migraine
– Those receiving opioids as treatment more likely to return to same
ER within 7 days
Managed Care Benchmark Database2
– Opioids prescribed for diagnosed migraine patients 59% of the
time
• Triptans prescribed 41%
© 2016 by the American Pharmacists Association. All rights reserved.
• Upregulation of calcitonin gene-related peptide (CGRP) in
primary affarent neurons
• Increased levels of substance P noted with repeat
morphine administration
– Animal models1,2
• Increase spinal cord dynorphin
– Pro-nociceptive
– May promote release of CGRP
– Activates NMDA glutamate receptors
• Opiate tolerance
• Increased cortical excitability
• International Healthcare Information Services National
1. Emerg Med Clin North Am 2009;27:71-79.
2. Headache Pain 2006;17:11-17.
88
• Changes ultimately result in paradoxical hyperalgesia
– Changes persist long after opiate therapy is withdrawn3
89
1. Life Sci 2003;73:783-800
2. Biopolymers 2005;80:319-324
3. Cephalalgia 2009;29:1277-1284
90
Effect of opioids on other migraine
medications
• Post-hoc pooled
• Jakubowski et al1
– 28 subjects
receiving either
sumatriptan +
ketorolac IV or
ketorolac IV
alone
– 9/9 nonresponders had a
recent history of
opioid treatment
– 1/19 responders
had a recent
history of opioid
treatment
Where do opioids fit in migraine
treatment?
analysis of 9
rizatriptan studies2
1. Headache 2005;45:850-861
2. Headache 2009;49:395-403
• No study with pain-free status as the primary outcome has
shown efficacy of opioids
– No effect on pathophysiology of migraine
• No treatment guideline for migraine headache
recommends use of opiates or barbiturates as first-line
treatment
– Use for only the most refractory headaches (rescue)
– Consider need for use a directive to modify other therapies
91
Question #2
92
Migraine prophylaxis
An opiate tapering schedule is developed for EM. She treats most of her
headaches with NSAIDS, and while they don’t alleviate her pain entirely, they
usually diminish it to the point that she can participate in daily activities (except
for the most severe headaches). What changes to therapy should be made at
this time?
A.
Begin treatment with a triptan immediately for acute headache pain not
relieved by NSAIDS
B.
Begin an antihypertensive therapy along with an agent for migraine
headache prophylaxis
C.
Initiate therapy with DHE nasal spray and use it in place of the previous
opiate dose during the taper
D.
Don’t add anything at this time to allow the patient’s baseline headache
frequency to emerge after the taper is complete
• When is prophylaxis indicated?
– Frequent migraines
• May put patient at risk for overuse headaches
– Significant disability with individual attacks
– Contraindications to medications used for acute migraine pain
– Need for treatment of migraine more than 2 times per week
• Choice of agent
– Base on co-existing medical conditions
– Consider pregnancy risk
93
94
Classification of preventive therapies
for episodic migraine
Prophylaxis “pearls”
• Established
Efficacy
• Start with low dose and titrate
• Continue well-tolerated medications for at
least 2-3 months at a therapeutic level
before labeling treatment failure
• Probably
Effective
– Divalproex
sodium/sodium
valproate
– Amitriptyline
– Topiramate
– Atenolol
– Metoprolol
– Nadolol
– Venlafaxine

Possibly
Effective
-- Lisinopril
-- Guanfacine
-- Candesartan
-- Carbamazepine
• Communicate expectations of prophylaxis
to patient
– Propranolol
-- Nebivolol
-- Nicardipine
– Timolol
Neurology 2012;78:1337-45
95
© 2016 by the American Pharmacists Association. All rights reserved.
96
Cardiovascular risks with acute
migraine therapy
Headache case continued…
• First-line (triptans) and second-line (dihydroergotamine tartrate
(DHE)) prescription medications for the treatment of acute,
episodic migraine pain are 5HT-1B/1D agonists
– Potent vasoconstrictors
• Produces the meningeal vasoconstriction and trigeminal
inhibition of pro-inflammatory neuropeptide release
EM describes her severe headaches as having a gradual onset, with peak pain
about an hour after they begin. She has been using sumatriptan 100mg orally
with the option to repeat the dose in 2 hours if necessary. After 1 ½ months of
use, she says it provides little relief, and she continues to miss work due to pain
and nausea.
• Serious events are extremely rare (<1/million)
– Medication-associated chest pain is rarely due to ischemia1,2
• Vasospasm, esophageal motility difficulties, activation of pain
fibers in periphery?
– Contraindications for use include
• Ischemic disease (cardiac, peripheral vascular, cerebral)
• Uncontrolled hypertension
1.
2.
Headache 2004;44(Suppl 1):S20-30
Lancet 2001;358:1668-75
97
98
When one triptan fails, try, try again…
Question #3
• Accurate assessment of efficacy should only be done after a
triptan has been used for at least three headaches.
What is the best therapy option for EM at this time?
– Patients should be instructed to take the medication at the first sign
of headache, and before the pain reaches maximum intensity
– Triptans do not show consistent efficacy when taken during an
aura
A. Continue sumatriptan as EM hasn’t used it long
enough to determine efficacy
• Evidence suggests non-responders to one triptan may respond
B. Change to the injectable form of sumatriptan
to another1
– Overall response rate for any triptan is 70%, while combining all
triptans results in a response rate of 90%
C. Begin a different triptan
• All triptans are similar in efficacious and tolerability in the
D. Change to a combination of sumatriptan and
naproxen
general population2
– Characteristics of an individual’s headaches should be used to
determine the best option for initiation of therapy
99
– Speed of headache onset, duration of headache, presence of
nausea/vomiting, severity of pain
Ultra fast acting
Fast acting
Almotriptan

Eletriptan

– NSAIDS (ibuprofen, naproxen, aspirin)
– Acetaminophen/aspirin/caffeine
• Acetaminophen/isometheptene/dichloralphenazone
– Original formulation removed from the market
– Available at some compounding pharmacies

Naratriptan
100
• OTC medications
Slow acting/Long
lasting
Frovatriptan
1. Cephalalgia 2004;23(6):463-71
2. Cochrane Database Syst Rev 2003;(3):CD002915
Other options for acute migraine
headache pain
Choosing the right triptan
• Considerations

Rizatriptan

Sumatriptan oral

Sumatriptan nasal

Sumatriptan SQ
EM was successfully tapered off oxycodone/apap and her blood pressure is
controlled. She is currently receiving metoprolol tartrate 25mg po bid. Her
headaches have decreased in frequency (usually one per week, but sometimes
she has two). However, she is unable to attain complete pain control with
NSAIDS, and occasionally still has a severe, disabling headache requiring the
use of a triptan (approximately 3x/month).
• Dihydroergotamine tartrate (DHE)
– Binds to serotonin receptors (same as triptans)
– Contraindicated in pregnancy
– Not as efficacious as triptans for episodic migraine (limited data)

Zolmitriptan oral

Zomitriptan nasal

© 2016 by the American Pharmacists Association. All rights reserved.
101
102
Headache case continued…
With titration of metoprolol to 100mg po bid, and education
about the appropriate way to use abortive therapy, EM now
experiences migraine headaches only rarely, and she has
used eletriptan only twice within the previous six months.
According to her headache diary, she has been headache
free for 112 days.
• Multinational, multicenter, randomized, double-blind,
double-dummy, crossover study
– 368 patients treating two attacks
– Sumatriptan nasal 20mg vs. DHE 1mg (option to repeat 1mg)
– Headache relief at 60 minutes
• 53% sumatriptan, 41% DHE, p < 0.001
– Relief of nausea at 60 minutes
• 64% sumatriptan, 49% DHE, p = 0.006
Int J Clin Pract 2000 Jun;54(5):281-6
103
104
Question #4
What is the best approach to EM and her use of metoprolol for
migraine prophylaxis?
A. Prophylaxis must be continued indefinitely to maintain
efficacy
• 50 patients with pain freedom of 90 days on prophylaxis
– 15.2% of eligible patients
• 40-44% had daily migraine prior to prophylaxis
B. Prophylaxis should be continued until EM is pain free for 6
months
– Time to pain freedom ranged from 6-48 months
– Group 1 maintained prophylaxis for 12 additional months
– Group 2 maintained prophylaxis for 24 additional months
C. Prophylaxis should be continued until EM is pain free for one
year
D. Prophylaxis should be continued until EM is pain free for two
years
• Number of headache days
annually after prophylaxis
discontinuation
Group 1
Group 2
5.1
0.4
After 2nd yr
6.5
1.1
0.002
After 3rd yr
8.6
2.1
0.004
105
Dosing: Migraine prophylaxis
Therapeutic
Category
ß-blockers
Antidepressants
Anticonvulsants
Drug
Propranolol
Timolol
10mg bid, max 30mg
qd
Metoprolol
25mg bid, max
300mg/day
Atenolol
50mg qd, max
100mg po qd
Nadolol
Venlafaxine
40mg qd, max
320mg/day
10-25mg hs, max
150mg/day (titrate q
wk by 10-25mg)
Divalproex/valproic
acid
(1Depakote®,
2Depakote ER®)
Begin with 37.5mg
qd, effective dose
75-225mg (may use
XR)
1 250mg bid, max
1500mg
2 500-1000mg/day
(single dose)
Amitriptyline
Topiramate
Eletriptan
Frovatriptan
20mg bid-tid, max
320mg qd (may use
LA)
Naratriptan
Rizatriptan
Sumatriptan
Dosing: Acute migraine
Therapeutic Category
NSAIDS
Drug
Aspirin
Ibuprofen
Naproxen sodium
Dose
325-650mg po q4h
200-800mg po q6-8h
250-500mg po q 12 hours
Ergotamine
Dihydroergotamine
Nasal: 1 spray ea. nostril,
repeat in 15min. (Max 4
sprays per attack, 6
sprays per day, 8 sprays
per wk)
Combination analgesic
Acetaminophen
250mg/aspirin
250mg/caffeine 65mg
1-2 tablets q6h, max 8
tablets/day
Acetaminophen
325mg/dichloralphenazone
100mg/isometheptene
65mg
1-2 capsules q4h, max 8
capsules/day
If on propranolol, 5mg po
(max 15mg/day)
25-100 mg po
May repeat every 2 h
(max 200mg/day)
5-20mg IN (spray in one
nostril)
May repeat q 2 hrs (max
40mg/day)
107
© 2016 by the American Pharmacists Association. All rights reserved.
Dose
6.25-12.5mg po
May repeat in 2 h x1
20-40mg po
May repeat in 2 h x1
2.5-5mg po
May repeat in 2 h (max
7.5mg/day)
1-2.5mg po
May repeat in 4 h
5-10mg po
May repeat in 2 h (max
30mg/day)
4-6mg SQ
May be repeat in 1 hour
x1
25mg hs, max 100mg
(div. bid)
0.001
106
Drug
Almotriptan
Dose
p-value
After 1st yr
Sumatriptan/Naproxen
85/500mg po
May repeat in 2 h (max 2
tablets/day)
Zolmitriptan
1.25-2.5mg po (5mg if
refractory)
May repeat in 2 h (max
10mg/day)
5mg IN (dispensed as 1x
use devices)
May repeat in 2h (max
10mg/day)
SQ: 1mg q1h, max
3mg/day
108
Key Points
• Opiates (and barbiturates) should not be routinely used in the
treatment of acute migraine headache.
• The failure of one drug from the triptan class does not rule out other
triptans as potentially affective agents.
• The choice to initiate prophylactic therapy for migraine headaches
should be based on the overall burden to the patient.
• A trial of 2-3 months is often necessary to determine the effectiveness
of prophylactic therapy.
Discuss the role of recently approved treatment approaches in the management of seizures and formulate a monitoring plan for a given patient receiving antiepileptic therapy.
• Prophylactic therapy should be continued for at least two years after a
patient achieves continuous headache-free status.
109
Incidence/100,000
Age-Related Incidence
Pediatric
perinatal & neonatal insults
genetic susceptibility
Adult
idiopathic
trauma
complex febrile seizures
status epilepticus
110
Treatment Considerations
Senior
idiopathic
cerebrovascular accidents
neurodegenerative disorders
tumor
1. Beydoun A, et al. Postgrad Med. 2002;111:69-70, 73-78, 81-82. 2. Bergey GK. Neurology. 2004;63(10 suppl 4):40-48. 3. Sirven JI. Mayo Clin Proc.
2002;77:1367-1375. 4. Ferrendelli JA, et al. Epilepsy Behav. 2003;4:702-709.
Age (yrs)
111
112
Modified from WA Hauser et al. Epilepsia 34:453, 1993
Success in AED regimens
What is the reality?
•First AED monotherapy fails in ~50% of patients with epilepsy
•Chance of seizure freedom with substitution monotherapy after
failure of initial AED is low (~13%)
•Many patients with epilepsy will require adjunctive therapy
•The rate of seizure freedom is ~26% with adjunctive therapy
•Adjunctive AED therapy may be more effective when initiated
immediately after failure of first AED
•Better efficacy and safety profiles of newer AEDs may translate
into combination therapy that improves seizure control without
increased toxicity
Kwan and Brodie N Engl J Med. 2000
© 2016 by the American Pharmacists Association. All rights reserved.
113
114
Common AEDs: New
•
•
•
•
•
•
•
•
Felbamate (FBM) 1993
Lamotrigine (LTG) 1993
Gabapentin (GBP) 1994
Topiramate (TPM) 1996
Tigabine (TGB) 1997
Oxcarbazepine (OXC) 1999
Levetiracetam (LEV) 1999
Zonisamide (ZNS) 2000
•
•
•
•
•
•
•
•
Levetiracetam
GH is a 65y/o F with new onset partial seizure’s, she is currently taking
warfarin for an unprovoked DVT and escitalopram for depression. Today
she presents to the pharmacy with a new prescription for levetiracetam.
Adding levetiracetam to GH’s medications will cause which of the
following drug interactions to occur:
Pregabalin (PGB) 2006
Vigabatrin (VGB) 2009
Lacosamide (LCM) 2009
Rufinamide (RFN) 2009
Ezogabine (EZG) 2011
A. Increased risk of bleeding due to inhibited warfarin metabolism
B. Increased risk of escitalopram toxicity due to inhibited metabolism
C. Increased risk of DVT due to decreased warfarin effect
D. None of the above
Clobazam (CLB) 2011
Perampanel (PMP)2011
Eslicarbazepine (ESL) 2013
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116
Levetiracetam
Levetiracetam
GH is a 65y/o F with new onset partial seizure’s, she is currently taking
warfarin for an unprovoked DVT and escitalopram for depression. Today
she presents to the pharmacy with a new prescription for levetiracetam.
Adding levetiracetam to GH’s medications will cause which of the
following drug interactions to occur:
• MOA: Enhances SV2A function to inhibit abnormal bursting in epileptic
circuits
• Indications: Adjunctive treatment of PS, myoclonic, and GTCS
• Metabolism: Enzymatic hydrolysis, 66% unchanged in urine, t½: 6 to 8
hours
A. Increased risk of bleeding due to inhibited warfarin metabolism
B. Increased risk of escitalopram toxicity due to inhibited metabolism
C. Increased risk of DVT due to decreased warfarin effect
D. None of the above
• Dosage forms: 250, 500, 750, and 1000mg tablets, 100mg.ml solution,
100mg/ml IV solution
– Keppra XR: 500 and 750mg tablets dosed once daily
– Dose: 1000 to 3000mg/day
– Blood levels: 5 to 50mcg/ml
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Levetiracetam
Vigabatrin
• Side effects:
TM is a 47y/o female patient with refractory generalized epilepsy is
currently taking levetiracetam 1500mg BID, lacosamide 200mg BID and
carbamazepine 400mg BID. TM has failed to tolerate several other AEDs
and her seizures are still poorly controlled, her neurologist would like to
start vigabatrin. Which of following drug interactions will occur:
–
Somnolence, fatigue, incoordination (Resolve after 1st month)
–
Behavioral changes, dizziness
–
Sedation, mental disturbances
• Drug interactions:
–
Not metabolized by CYP450 pathways
–
No clinically significant drug-drug interactions
A. Lack of efficacy of vigabatrin due to carbamazepine’s enzyme
induction
• Other uses:
–
Migraine, pain spasticity
–
Bipolar?
B. Carbamazepine toxicity due to inhibition of metabolism by vigabatrin
C. Vigabatrin toxicity due to carbamazepine’s enzyme inhibition
D. Levetiracetam toxicity due to vigabatrins inhibition of renal excretion
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© 2016 by the American Pharmacists Association. All rights reserved.
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Vigabatrin
Vigabatrin
TM is a 47y/o female patient with refractory generalized epilepsy is
currently taking levetiracetam 1500mg BID, lacosamide 200mg BID and
carbamazepine 400mg BID. TM has failed to tolerate several other AEDs
and her seizures are still poorly controlled, her neurologist would like to
start vigabatrin. Which of following drug interactions will occur:
A. Lack of efficacy of vigabatrin due to carbamazepine’s enzyme
• MOA: GABA-transaminase inhibitor
• Indications:
–
Adjunctive therapy for refractory complex partial seizures in adults
–
Infantile spasm
• Pharmacokinetics:
induction
B. Carbamazepine toxicity due to inhibition of metabolism by
–
Absorption not affected by food
vigabatrin
C. Vigabatrin toxicity due to carbamazepine’s enzyme inhibition
D. Levetiracetam toxicity due to vigabatrins inhibition of renal excretion
–
Renally eliminated (adjust dose for CrCl < 60ml/min)
–
CYP2C9 inducer
• Dosage forms: 500mg powder, tablet
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Vigabatrin
Vigabatrin
• Dosage: (Seizure)
Monitoring
• Ophthalmologic examinations: testing recommended at baseline, every
•
•
–
Adults: 1gm/day starting dose; 2-4gm/day maintenance
Children: 40mg/kg/day in two divided doses starting
dose; 80-100mg/kg/day maintenance
Infantile spasm: 50-100mg/kg/day, divided twice daily
• Side effects:
–
Irreversible visual field defects, drowsiness, fatigue, hyperactivity
in children
• Drug interactions:
–
–
3 months during treatment and 3-6 months following discontinuation,
complete ophthalmic examinations in patients 2 years of age or
younger
• Scr: especially in elderly patients
• Anemia workup
• New onset or worsening of depression, suicidal thoughts, or unusual
changes in mood or behavior
Inhibits carbamazepine metabolism (Major)
Induces phenytoin and fosphenytoin (Moderate)
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Lacosamide
Lacosamide
JL is a 27y/o F with new onset partial seizures, which of the following
medications are FDA approved for monotherapy in this patient:
JL is a 27y/o F with new onset partial seizures, which of the following
medications are FDA approved for monotherapy in this patient:
1. Topiramate
2. Ezogabine
3. Lacosamide
1. Topiramate
2. Ezogabine
3. Lacosamide
A.
I and II
A.
I and II
B.
I and III
B.
I and III
C.
I only
C.
I only
125
© 2016 by the American Pharmacists Association. All rights reserved.
126
Lacosamide
Lacosamide
• MOA: Sodium channel blockade (slow and selective)
• Dosage forms:
• Indication: Adjunct therapy for partial-onset seizures in
patients with epilepsy in patients > 17 years old, received
approval for monotherapy indication in August 2014
–
Tablet: 50, 100, 150, and 200mg
–
Solution: 10mg/ml
–
IV solution: 200mg/20ml single-use vial
• Dosage:
–
• Pharmacokinetics:
–
–
Not affected by food
Renally eliminated; 300mg/day max for CrCl< 30ml/min and mildmoderate liver disease
– IV formulation: pH 3.5-5 (possible interface at y-site)
–
Oral: 50mg twice daily, increase weekly by 100mg/day in two divided doses up to
200 to 400mg/day
IV: Same as oral, infuse over 30 to 60 minutes
• Controlled substance: Schedule V
• Side effects: Headache, nausea, diplopia, PR interval increase (minimal)
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Lacosamide
128
Rufinamide
HG is a 38 year old female with LGS that has been well
controlled with rufinamide and clobazam. She additionally
has an 11 year history of poorly controlled T2DM and CKD
and is here today with her caretaker for her annual visit. You
notice her CrCl is now 27ml/min. Your recommendation for
dose adjustment is:
Monitoring
• ECG: prior to treatment and after titration in patients with known
cardiac conduction problems who receive concomitant
medications that prolong the PR interval, and in patients with
severe cardiac disease
• New onset or worsening of depression, suicidal thoughts, or
unusual changes in mood or behavior
• Toxicity: in patients with mild to moderate hepatic impairment or
coexisting renal and hepatic impairment
A. Clobazam dose needs to be decreased.
B. No dose adjustments are needed.
C. Rufinamide dose needs to be decreased by 25%
D. Rufinamide dose needs to be decreased by 50%
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130
Rufinamide
Rufinamide
HG is a 38 year old female with LGS that has been well
controlled with rufinamide and clobazam. She additionally
has an 11 year history of poorly controlled T2DM and CKD
and is here today with her caretaker for her annual visit. You
notice her CrCl is now 27ml/min. Your recommendation for
dose adjustment is:
• MOA: Prolongation of the inactive state of sodium channels
A. Clobazam dose needs to be decreased.
B. No dose adjustments are needed.
C. Rufinamide dose needs to be decreased by 25%
D. Rufinamide dose needs to be decreased by 50%
131
© 2016 by the American Pharmacists Association. All rights reserved.
• Indications: Adjunct treatment of seizures associated with LGS in adults and
children >4 years old
• Pharmacokinetics:
–
Food increases bioavailability
–
Protein bound: 34%
–
Metabolized via enzymatic hydrolysis (not CYP450 dependent)
–
Elimination is 85% renal
–
Plasma half-life is 6-10 hours
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Rufinamide
Rufinamide
• Dosage forms: 100, 200, and 400mg tablets
Monitoring
• New onset or worsening of depression, suicidal thoughts, or
• Dosage:
–
Children: 10mg/kg/day in two divided doses. Increase by 10mg/kg every
other day to a target dose of 45mg/kg/day given in two equally divided doses
–
Adults: 400-800mg/day in two equally divided doses. Increase by 400-800mg
every other day to a target dose of 3200mg/day in two equally divided doses
–
Should be taken with food
–
Dose adjustment not necessary for CrCl < 30ml/min
unusual changes in mood or behavior
• Rash: may indicate multi-organ hypersensitivity reactions (fever,
elevated LFTs, hematuria, lymphadenopathy)
• Side effects:
–
Shortened QT interval, headache, somnolence
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Ezogabine
Ezogabine
FS is a 47y/o M with refractory generalized epilepsy, he is currently taking
levetiracetam 1500mg BID and topiramate 150mg BID, he has failed to tolerate
oxcarbazepine, phenytoin, lamotrigine and lacosamide. His neurologist would like
to start ezogabine. Which of the following are important monitoring parameters:
FS is a 47y/o M with refractory generalized epilepsy, he is currently taking
levetiracetam 1500mg BID and topiramate 150mg BID, he has failed to tolerate
oxcarbazepine, phenytoin, lamotrigine and lacosamide. His neurologist would like
to start ezogabine. Which of the following are important monitoring parameters:
1. Retinal abnormalities
2. Urinary retention
3. CBC
1. Retinal abnormalities
2. Urinary retention
3. CBC
A. I only
A. I only
B. I and III
B. I and III
C. I and II
C. I and II
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Ezogabine
136
Ezogabine
• MOA: Activates voltage-gated potassium channels
• Indication: Adjunct therapy for partial-onset seizures in adults (>18 years) who
have responded inadequately to several alternative treatments and benefits
outweigh the risk of retinal abnormalities and potential decline in visual acuity
• Dosage forms: 50, 200, 300, and 400mg tablet
• Dosage: 100mg TID, increase by max of 150mg/day every week
until at maintenance dose of 200-400 TID
• Side effects:
–
• Pharmacokinetics:
–
Not affected by food
–
Renally eliminated; 600mg/day max for CrCl < 50ml/min
–
Moderate liver disease (Child-Pugh 7-9) max 750mg/day
–
Severe liver disease (Child-Pugh >9) max 600mg/day
•
Rare: Urinary retention, prolonged QT interval
• Black box warning:
–
137
© 2016 by the American Pharmacists Association. All rights reserved.
Somnolence, dizziness, confusion
Retinal abnormalities
–
Retinal pigment dystrophies
–
Baseline and every 6 month eye exam
138
Ezogabine
Clobazam
Monitoring
JS is a 22 y/o male with generalized seizures following a closed head injury, his
seizures have improved on Topiramate 200mg BID and levetiracetam 1500mg
BID, but are still uncontrolled. During a recent hospitalization one of the
physicians asked JS’s father if they have tried clobazam. JS and his father are
in clinic with you today, his father asks you what you think about clobazam for
JS.
•
New onset or worsening of depression, suicidal thoughts, or unusual changes in
mood or behavior
•
Systematic visual monitoring at baseline and every 6 months
•
Urologic symptoms, especially in patients with other risk factors for urinary
retention
•
Appearance of confusion, psychotic symptoms or hallucinations
•
QT-interval: in patients with known prolonged QT-interval, congestive heart
failure, ventricular hypertrophy, hypokalemia or hypomagnesaemia
•
Baseline LFTs, Scr, BUN: repeat annually
A. Clobazam has the same properties as any other benzodiazepine.
B. Clobazam is not appropriate for JS because of the serious drug interaction
potential with levetiracetam.
C. Clobazam may have less sedation associated with its use than other
benzodiazepines.
D. Clobazam does not cause sedation like other benzodiazepines because of
its 1,5 structure.
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140
Clobazam
Clobazam
JS is a 22 y/o male with generalized seizures following a closed head injury, his
seizures have improved on Topiramate 200mg BID and levetiracetam 1500mg
BID, but are still uncontrolled. During a recent hospitalization one of the
physicians asked JS’s father if they have tried clobazam. JS and his father are
in clinic with you today, his father asks you what you think about clobazam for
JS.
A. Clobazam has the same properties as any other benzodiazepine.
B. Clobazam is not appropriate for JS because of the serious drug interaction
potential with levetiracetam.
C. Clobazam may have less sedation associated with its use than other
benzodiazepines.
D. Clobazam does not cause sedation like other benzodiazepines because of
its 1,5 structure.
• MOA: Enhances GABA via enhanced Cl- conductance through GABAA receptors
• Indication: Adjunct therapy for partial-onset seizures in age > 12 years
• Pharmacokinetics:
» Food does not affect extent, but slows absorption
» Highly protein bound (95-96%)
» Substrate of 3A4/5, oxidative metabolism and sequential glucuronidation
» 22% eliminated by kidney, and 48% by feces
141
Clobazam
Clobazam may have lower affinity
for GABA-A receptor subtype
associated with sedation, and
higher selectivity for the subtype
associated with anxiolytic and antiseizure effects
142
Clobazam
Diazepam
(1,4-)
Clobazam
(1,5-)
• Dosage form: 5, 10, 20mg tablet
• Dosage:
– < 30kg: 2.5 twice daily, increase to 5mg twice daily in one week,
then 10mg twice daily at week two
 30kg: 5mg twice daily, increase to 10mg twice daily in one week, then
20mg twice daily at week two
GABA-A ω1 (sedation):
clobazam < diazepam
• Side effects: Somnolence (perhaps less than other
benzos), fever, drooling, lethargy
GABA-A ω2 (anxiolytic,
anticonvulsant):
clobazam > diazepam
Nakajima 2001
© 2016 by the American Pharmacists Association. All rights reserved.
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144
Perampanel
Perampanel
HR is a 35y/o F with LGS, her parents are her caretakers and feel she is
having too many seizures. She is currently taking clobazam, valproic acid
and topiramate, her neurologist wishes to add perampanel. Which
adverse effects should HR’s parents be counseled about before starting
parampanel?
• MOA: Non-competitive antagonist of AMPA
A. Potentially fatal rash
B. Hyponatremia
C. Increased hostility and aggression
D. All of the above
• Indication: Adjunct therapy for LGS
• Pharmacokinetics:
–
Not affected by food
–
Renally-eliminated; mild to moderate renal impairment. No dose adjustments
–
Moderate liver disease (Child-Pugh 5-9)
• 5mg QD initially
• Max of 20-40mg/day based on weight
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Perampanel
Perampanel
• Dosage forms: 2, 4, 6, 8, 10, 12mg tablets
• Dosage:
Monitoring
– Without enzyme inducing AEDs: 2mg QHS initially, increase by 2mg/day
weekly up to 4-8mg QHS
• New onset or worsening of depression, suicidal thoughts, or unusual
– With enzyme inducing AEDs: 4mg QHS initially, increase by 2mg/day weekly
up to 8012mg QHS
changes in mood or behavior
• Psychiatric and behavioral reactions, especially during titration and for 1
month after the last dose
– Dose titration every two weeks in elderly
– Max dose of 6mg in mild hepatic impairment, 4mg in moderate hepatic
impairment, avoid in severe impairment (Renal or hepatic)
• Gait disturbances
• Weight gain
• Side effects: Hostility, aggression (12-20% of patients at 8-12mg),
• Baseline CBC, LFTs, Scr, then annually
homicidal ideation, dizziness, sleepiness, fatigue
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148
Eslicarbazepine
Eslicarbazepine
TJ is a 69 y/o F with well controlled partial seizures, she has been
controlled for many years on carbamazepine. Recently at her annual
check up her sodium was 123mEq. Her primary care physician wishes to
switch the patient to eslicarbazepine and would like to know your opinion.
TJ is a 69 y/o F with well controlled partial seizures, she has been
controlled for many years on carbamazepine. Recently at her annual
check up her sodium was 123mEq. Her primary care physician wishes to
switch the patient to eslicarbazepine and would like to know your opinion.
A. Eslicarbazepine is associated with hyponatremia, but is less likely to
A. Eslicarbazepine is associated with hyponatremia, but is less
cause this than carbamazepine.
B. Eslicarbazepine is not associated with hyponatremia.
C. Eslicarbazepine demonstrates the same incidence of hyponatremia
as carbamazepine.
D. Eslicabazepine is associated with more hyponatremia than
carbamazepine.
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© 2016 by the American Pharmacists Association. All rights reserved.
likely to cause this than carbamazepine.
B. Eslicarbazepine is not associated with hyponatremia.
C. Eslicarbazepine demonstrates the same incidence of hyponatremia
as carbamazepine.
D. Eslicabazepine is associated with more hyponatremia than
carbamazepine.
150
Eslicarbazepine
Eslicarbazepine
• MOA: Unknown, but thought to involve sodium channel blockade
• Dosage forms: 200, 400, 600, 800mg tablets
• Dosage:
• Indication: Adjunct treatment of partial-onset seizures, received
–
monotherapy indication in August 2015
–
• Pharmacokinetics:
400mg QD, increase to 800mg after one week. Max dose of 1200mg
Moderate to severe renal impairment: 200mg QD. Increase to
400mg after two weeks. Max dose of 600mg.
• Side effects:
–
Not affected by food
–
Metabolized via hydrolytic 1st pass metabolism
–
Renal elimination
–
t1/2: 13-20 hours
Sunovion Pharmaceuticals, Aptiom package insert, 2013
–
Dizziness, somnolence, N/V, headache, diplopia, fatigue, vertigo,
ataxia, blurred vision, tremor
–
Suicidal behavior/ideation, dermatologic reactions (SJS)- contains
the same aromatic ring as carbamazepine and oxcarbazepine.
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152
Eslicarbazepine
Eslicarbazepine
• Hyponatremia: Eslicarbazepine (0.6-2%)
Monitoring
– Sunovian pharmaceuticals adjunctive data shows significant
hyponatremia (sodium <125 mEq/L) in 1.0% of the patients treated
with 800mg and in 1.5% of the patients treated with 1200mg.
– Hyponatremia has been seen with both adjunct and monotherapy.
– These effects are dose related and are generally seen within the first 8
weeks (as early as 3 days)
– Measurement of serum sodium and chloride levels should be
considered during maintenance therapy
• Serum sodium and chloride levels during maintenance therapy
• Baseline CBC, BMP, LFTs and Scr, then annually
• Neurological events, including gait and coordination disturbances,
nystagmus, balance, and ataxia
• New onset or worsening of depression, suicidal thoughts, or unusual
changes in mood or behavior
• Compare to incidence of hyponatremia with:
– Carbamazepine (4-21%)
– Oxcarbazepine (1-5%)
Sunovion Pharmaceuticals, Aptiom package insert, 2013
153
154
The most appropriate therapy to
initiate treatment in a newly
diagnosed Parkinson’s disease
patient with moderate symptoms and
a relatively short treatment horizon is
•
•
•
•
•
•
•
•
Benztropine
Carbidopa/Levodopa
Carbidopa/Levodopa/Entacapone
Rasagiline
155
© 2016 by the American Pharmacists Association. All rights reserved.
When initiating treatment for a
patient with mild Alzheimer’s
disease, that frequently has skin
eczema and bouts of nausea, which
therapy is appropriate to begin with?
Memantine
Donepezil
Rivastigmine
Galantamie
156
When initiating an antiepileptic drug
(AED) in a patient which is newly
diagnosed with complex partial
seizures and a strong history of nonadherence. Which AED might be a
good first choice?
Which of the following is the best
option for a patient who has failed
treatment of acute migraine
headache with oral sumatriptan?
•
•
•
•
Intranasal sumatriptan
Subcutaneous sumatriptan
Rizatriptan
Oxycodone/acetaminophen
•
•
•
•
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© 2016 by the American Pharmacists Association. All rights reserved.
Lacosamide
Rufinamide
Ezogabine
Eslicarbazepine
158