Alzheimer Disease and Depression Flashcards
1
Q
What neuronal changes do we see with AD
A
Reduced acetylcholine (ACh) Reduced acetylcholinesterase (AChE)
2
Q
Pharmacotherapy outlines for AD
A
Raise cortical acetylcholine
Decrease glutamate mediated neuronal cell death
3
Q
Pharmacotherapy caveat of AD
A
No cure of slowing of the disease
4
Q
Goals of pharmacotherapy for AD
A
Minimize behavioral disturbances
Improve sx
5
Q
How many drugs are FDA approved for managing AD
A
4
6
Q
FDA approved Acetylcholinesterase inhibitors for AD
A
Donepezil (Aricept)
Rivastigmine (Exelon)
Galantamine (Razadyne)
7
Q
FDA approved NMDA antagonists for AD
A
Memantine (Namenda)
8
Q
Acetylcholinesterase inhibitors summary
A
Most effective in treating AD
Typically result in small improvement in sx
Most studies involve mild-moderate sx
May reduce behavior disturbances (aggression)
May improve cognition and behavior
A switch can be made easily after stopping initial therapy
9
Q
Adverse effects of AChE inhibitors
A
Increase ACh
GI tract issues
Severity of AE dose dependent
10
Q
Increase ACh effects
A
Depression Headache Anxiety Dizziness Insomnia Stomach pain
11
Q
GI tract AChE inhibitor AE
A
Nausea Vomiting Diarrhea Dehydration Decreased appetite Weight loss Stomach ulcers
12
Q
Dose dependent AChE inhibitor AE
A
Ptx < 50 kg (110 lbs) and elderly have increased incidence
Minimized by starting low and dose titration
Some may require drug discontinuation (D/C)
13
Q
Donezepil for AD
A
Approved for SEVERE AD
First agent approved
Give w/ or w/o food
14
Q
Donezepil starting dosing for AD
A
5 mg (long half life)
15
Q
Donezepil secondary dosage for AD
A
10 mg daily after 4-6 weeks
16
Q
Donezepil final dosing for AD
A
23 mg daily after 3 months
For pts w/ mod-severe AD
17
Q
Donezepil dosing forms
A
Generic = 5 & 10 mg IR tabs Brand = 5 & 10 mg orally disintegrating tabs Brand = 23 mg extended release tabs
18
Q
Galantamine
A
For mild-moderate AD
19
Q
Galantamine IR tabs or solution dosing
A
Initially bid w/ breakfast or dinner
4,8, or 12 mg tablets (generic)
20
Q
Galantamine ER capsule dosing
A
Daily w/ breakfast
21
Q
MOA of Galatamine
A
Inhibits AChE and stimulates nicotinic receptors
Stimulates at non-ACh site (allosteric modulation)
22
Q
Renal adjustments of Galatamine
A
Moderate renal impairment: 16 mg/day = MAX
DO NOT USE IN SEVERE RENAL IMPAIRMENT
23
Q
Conversion to galantamine
A
Poor tolerability when switching from donepezil or rivastigmine
(wait until SE subside or allow 7 day washout period to galantamine)
No intolerance to donepezil or rivastigmine (begin galantamine the day after stopping)
24
Q
Rivastigmine
A
TD patch is approved for severe AD
25
Oral dosing of Rivastigmine
Initial = 1.5 mg bid
Increase by 3 mg/day q2 weeks (pending tolerability)
Max dose = 6 mg bid
26
Advantages of Rivastigmine TD patch
Less NVD than oral forms
(But still bradycardia and syncope)
Immediately theraputic
27
Dosing forms of oral Rivastigmine
1.5, 3, 4.5, and 6 mg capsules (generic)
28
Dosing forms of transdermal Rivastigmine
Apply once daily and rotate
4. 6mg/24 hours (initial 4 weeks; then up to 9.5 mg/24 hours)
9. 5 mg/24 hours (for 4 weeks then 13.3 mg/24 hours)
13. 3 mg/24 hours (then back down to 9.5 mg/24 hours)
29
Caveat of oral Rivastigmine
Not immediately theraputic
30
MOA of Rivastigmine
Pseudo-irreversible
| Inhibits G1 AChE > G4 AChE
31
Metabolism/Elimination of Rivastigmine
Results in fewer drug-drug interactions
32
Exelon Patch (EP)
```
May cause allergic dermatitis
Be sure to rotate
Don't use same site for 14 days
Smart phone app to track
Recommended sites: upper/lower back
Alternate sites: chest/upper arm
```
33
High dosing on EP
High dose oral rivastigmine (> 6 mg/d):
| Switch directly to 9.5 mg/24h patch
34
Low dosing on EP
Lower dose oral rivastigmine (< 6 mg/d):
| Start on 4.6 mg/24h patch
35
Switching from donepezil or galantamine to EP
Start on 4.6 mg/24h patch
36
AD Cholinesterase Inhibitors benefits are...
Similar for all 3
| Chose based on pt factors
37
What line of treatment are AD Cholinesterase Inhibitors (AChEIs) for AD
First line agents
38
When should you start tx w/ AChEIs?
On diagnosis of AD
39
When are AChEIs therapeutic?
Immediately
| PS responses are dose dependent
40
Side effects of AChEIs
NV (MC)
| Bradycardia (under-reported) that could lead to syncope
41
How do we manage the side effects of AChEIs?
Slow dose titration
42
What is Memantine?
N-methyl D-aspartate (NMDA) antagonist
| Recently approved for moderate-severe AD
43
Is Memantine a stand alone drug?
Not really. Usually add to AChI's and see cognitive improvement
44
Initial dosing of Memantine IR tabs
5 mg daily
45
How often do you increase Memantine dosing
1 week intervals
46
Second tier dosing of Memantine
5 mg bid
47
Third tier dosing of Memantine
10 mg Q AM and 5 mg Q PM
48
Final dosing of Memantine
10 mg BID (max of 20 mg daily)
49
Switching form Memantine IR tabs to ER
May switch 10 mg BID pts to 28 mg ER tab daily
OR
Start with 7 mg ER tab daily, then increase to 28 mg daily
50
Memantine side effects?
Infrequent
| Mild
51
Memantine dosage in renal impairment
Mild-moderate: no adjustment
| Severe: 5 mg bid max
52
Etiology and pathophysiology of depression
```
Sx reflect changes in brain monoamine neurotransmitters
Ex:
norephinephrine (NE)
Serotonin (5-hydroxytryptamine; 5-HT)
Dopamine
```
53
Biogenic amine hypothesis of depression
Agents blocking reuptake/metabolism of these amines are effective antidepressants
54
Medical conditions that can cause depression
```
Hypothyroidism
Addison or Cushing disease
Pernicious anemia (B12 deficiency)
Severe anemia
HIV/AIDS
```
55
Drugs that cause depression
Antihypertensives (clonidine; diuretics)
Oral contraceptives
Steroids
ACTH
56
Suicide risk evaluation
1) Evaluate major depression pts for suicidal thoughts
2) Evaluate factors increasing risk
3) Immediately refer if high risk
57
Risk factors for suicide in increasing order
```
Feelings of hopelessness
Inpatient status
Single or living alone
Male (females attempt more often; males succeed more often)
Suicidal plan/attempt
```
58
General approach to depression treatment
3 phases:
1) Acute phase -> 3 months
2) Continuation phase -> 4-9 months
3) Maintenance phase: 12-36 months
* **Duration of therapy depends on risk of recurrence***
59
Acute phase treatment
Evaluate weekly or biweekly
Continue until substantial improvement occurs
Start med doses low, increase gradually
Keep an eye on side effects
If <50% improvements at 4 weeks, change meds
Do NOT prescribe a lot of meds to seriously depressed out-pt patients
60
Continuation phase treatment
4-9 months
All pts should get 3 months of acute phase treatment and 4 minimum of continuation phase
Residual sx may indicate recurrence, early relapse, or chronic course
Continuation until sx resolve
61
Maintenance phase tx
```
Maintenance for 12-36 months decreases recurrence by 2/3
Indicated for pts w/:
1) yearly episodes
2) impairment from mild residual sx
3) chronic major depression
4) severe episodes
5) high risk of suicide
```
62
Discontinuation of depressive tx
If no recurrence or relapse during continuation phase
Most pts qualify 7 months (minimum length of therapy)
Early discontinuation increases risk of relapse
Taper meds down over several weeks
63
Non-pharmacotherapy for depression
Psychotherapy for those willing (might be first line for mild-mod depression)
64
Are all antidepressants equal?
Pretty much
| Similar efficacy when given at comparable doses
65
How do we chose what antidepressant to use?
```
Previous response history
Pharmacogenetics (hx of familial response)
Presenting sx (fatigue vs. agitation)
Side effect profile
Pt preference
Cost
```
66
Selective Serotonin Reuptake Inhibitors (SSRIs)
Superior to other antidepressants for major depression
67
Why are SSRIs first line?
Overdose safety
| Tolerability
68
SSRI side effects
Mild and short
| Decreased libido
69
What happens if you abruptly stop taking your SSRI?
Withdrawal sx or discontinuation
70
Which SSRI has less of a chance of withdrawal sx happening if stopped abruptly
Fluoxetine
71
When are SSRIs contraindicated
Pts that were recently (5-6 weeks) taken off of MAOIs -> causes serotonin syndrome
72
Fluoxetine
First SSRI FDA approved for kids
| Only SSRI w/ consistent efficacy in children and adolescents
73
Fluoxetine black box warning
Increased suicidal ideation in kids and adolescents
74
Does fluoxetine have a longer or shorter half-life than its counterparts?
Longer
| Allows for once daily dosing
75
Precautions with fluoxetine and bipolar disorder
One metabolite may persist for weeks
| May aggravate the manic state
76
Fluoxetine dosing
Increase by 20 mg/day each week over several weeks to 80 mg/day max
77
Paroxatine
SSRI
Blocks serotonin reuptake at lower doses
Blocks dopamine reuptake at higher doses
78
Paroxetine dosing
Max of 50 mg/day
79
Sertraline
Blocks serotonin reuptake at lower doses
Blocks dopamine reuptake at higher doses
Might contribute to anti-depressive action
80
Sertaline dosing
Max of 200 mg/day
81
Fluvoxamine
Oldest SSRIs
May cause or worsen sexual dysfunction
300 mg/day MAX
82
Citalopram
FDA approved to treat sx of major depression
| FDA warning in 2011 -> 40 mg/day might prolong QT interval
83
When to avoid citalopram
Congenital long QT syndrome
Other drugs causing QT prolognation are already taken
Risk for Torsade des Pointes
84
Citalopram dosing
Increase by 20 mg after at least one week to max 40 mg/day
| *originally at 60 mg/day*
85
Escitalopram
S isomer of citalopram
May reduce frequency of hot flashes in perimenopausal women
20 mg/day max
86
Mixed 5-HT/NE reuptake inhibitors
Newer
2nd generation
Block monoamines more selectively than TCAs
No cardiac conduction effects like TCAs
87
Other names for mixed 5HT/NE reuptake inhibitor
Serotonin NE reuptake inhibitors (SNRIs)
OR
Dual action antidepressants
88
Mixed 5HT/NE reuptake inhibitor agents
Venlafaxine
Duloxetine
Desvenlafaxine
89
Venlafaxine
Superior for severe depression than SSRIs or TCAs
Effective for chronic pain
May DOUBLE risk for miscarriage
90
Desvenlafazine
Metabolite of venlafaxine
10xs more effective at blocking serotonin than NE uptake
Higher rates of discontinuation syndrome
Not really needed for treating major depressive disorder
91
What is Duloxetine FDA approved for
Major depressive disorder
Neuropathic pain
Fibromyalgia pain
92
Duloxetine
No need to choose w/ so many other options
Not recommended w/
1) CrCL < 30 minutes
2) w/ hepatic impairment
93
Wellbutrin
Inhibits NE and dopamine reuptake
No action on serotonin
Similar efficacy to TCAs and SSRIs
Less nausea, diarrhea, somnolence, and sexual dysfunction than SSRIs
Effective alternative of adjunctive therapy for SSRI non-responders
94
Tricyclic antidepressants (TCAs)
Mixed serotonin/NE reuptake inhibitors
| Effective for all depressive subtypes
95
TCA SE
```
*Limits use*
Anticholinergic effects
Sedation
Orthostatic hypotension
Seizures
Cardiac conduction abnormalities
```
96
TCAs have:
Tertiary amines
Secondary amines
and higher risk of death with overdose
97
Monoamine oxidase inhibitors (MOIs)
Older, first generation agents
Irreversibly, non-selective binding MAO A&B
Similar effects to TCA
98
Why are MAOIs no longer first line tx
Serotonin syndrome and drug-drug interactions
99
MAOI agents
Phenelzine
| Selegiline
100
Serotonin syndrome (SS)
Potentially life threatening adverse drug reaction
101
When can SS happen
W/ therapeutic drug use with SSRIs
Intentional self-poisoning w/ SSRIs
Drug interactions (SSRI and another drug)
Tyramine containing foods while on MAOIs
102
Why is pt counseling critical for SS
Gives dietary and med restrictions for MAOIs
| Early sx recognition for pts AND clinicians
103
SS triad
Mental status change
Autonomic hyperactivity
Neuromuscular abnormalities
104
How frequent is SS in SSRI overdoses
14-16%
105
Presentation of SS
Autonomic findings:
1) shivering, diaphoresis, mydriasis
2) labile BP/HTN
3) Hyperthermia (>41 C is critical)
106
Tx of SS
STOP PRECIPITATING AGENT
| 5-HT2A antagonist; cyproheptadine
107
Tx of SS if fever > 41 C
Immediate sedation with benzodiazepines (diazepam)
Neuromuscular paralysis (vercuronum -> non-depolarizing)
Orotracheal intubation
Monitor and treat hypotension
108
Triazolopyridines
New, mixed action agents
Less sexual, sleep, and anticholinergic SE
Similar to TCas
Black box warning of possible liver failure
109
Mirtazapine
Similar efficacy to TCAs and SSRIs
110
Trazadone
Alpha 1
Not associated w/ increased appetite or weight gain
Limited by dizziness, orthostatic hypotension, and sedation
Less anticholinergic effects (dry mouth, constipation, tachycardia)
Less sexual effects than TCAs
111
Aripiprazole
FDA approved for adjunctive depression in 2007
| Originally approved as an atypical anti-psychotic agent
