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Flashcards in Alzheimer Disease and Depression Deck (111):
1

What neuronal changes do we see with AD

Reduced acetylcholine (ACh)
Reduced acetylcholinesterase (AChE)

2

Pharmacotherapy outlines for AD

Raise cortical acetylcholine
Decrease glutamate mediated neuronal cell death

3

Pharmacotherapy caveat of AD

No cure of slowing of the disease

4

Goals of pharmacotherapy for AD

Minimize behavioral disturbances
Improve sx

5

How many drugs are FDA approved for managing AD

4

6

FDA approved Acetylcholinesterase inhibitors for AD

Donepezil (Aricept)
Rivastigmine (Exelon)
Galantamine (Razadyne)

7

FDA approved NMDA antagonists for AD

Memantine (Namenda)

8

Acetylcholinesterase inhibitors summary

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

Adverse effects of AChE inhibitors

Increase ACh
GI tract issues
Severity of AE dose dependent

10

Increase ACh effects

Depression
Headache
Anxiety
Dizziness
Insomnia
Stomach pain

11

GI tract AChE inhibitor AE

Nausea
Vomiting
Diarrhea
Dehydration
Decreased appetite
Weight loss
Stomach ulcers

12

Dose dependent AChE inhibitor AE

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

Donezepil for AD

Approved for SEVERE AD
First agent approved
Give w/ or w/o food

14

Donezepil starting dosing for AD

5 mg (long half life)

15

Donezepil secondary dosage for AD

10 mg daily after 4-6 weeks

16

Donezepil final dosing for AD

23 mg daily after 3 months
For pts w/ mod-severe AD

17

Donezepil dosing forms

Generic = 5 & 10 mg IR tabs
Brand = 5 & 10 mg orally disintegrating tabs
Brand = 23 mg extended release tabs

18

Galantamine

For mild-moderate AD

19

Galantamine IR tabs or solution dosing

Initially bid w/ breakfast or dinner
4,8, or 12 mg tablets (generic)

20

Galantamine ER capsule dosing

Daily w/ breakfast

21

MOA of Galatamine

Inhibits AChE and stimulates nicotinic receptors
Stimulates at non-ACh site (allosteric modulation)

22

Renal adjustments of Galatamine

Moderate renal impairment: 16 mg/day = MAX
DO NOT USE IN SEVERE RENAL IMPAIRMENT

23

Conversion to galantamine

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

Rivastigmine

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