Other Warnings/Precautions

• May exacerbate asthma or other pulmonary disease

• Increased gastric acid secretion may increase the risk of ulcers

• Bradycardia or heart block may occur in patients with or without cardiac impairment

✽ Severe vomiting with esophageal rupture may occur if rivastigmine therapy is resumed without retitrating the drug to full dosing

• Individuals with low body weight may be at greater risk for adverse effects

• Certain transdermal patches containing even small traces of aluminum or other metals in the adhesive backing can cause skin burns if worn during MRI, so warn patients taking the transdermal formulation about this possibility and advise them to disclose this information if they need an MRI

Do Not Use

• If there is a proven allergy to rivastigmine or other carbamates

RIVASTIGMINE: SPECIAL POPULATIONS

Renal Impairment

• Dose adjustment not necessary; titrate to point of tolerability

Hepatic Impairment

• Dose adjustment not necessary; titrate to point of tolerability

Cardiac Impairment

• Should be used with caution

• Syncopal episodes have been reported with the use of rivastigmine

Elderly

• Some patients may tolerate lower doses better

• Use of cholinesterase inhibitors may be associated with increased rates of syncope, bradycardia, pacemaker insertion, and hip fracture in older adults with dementia

Children and Adolescents

• Safety and efficacy have not been established

Pregnancy

• Risk Category B [animal studies do not show adverse effects; no controlled studies in humans]

✽ Not recommended for use in pregnant women or women of childbearing potential

Breast Feeding

• Unknown if rivastigmine is secreted in human breast milk, but all psychotropics assumed to be secreted in breast milk

✽ Recommended either to discontinue drug or bottle feed

• Rivastigmine is not recommended for use in nursing women

RIVASTIGMINE: THE ART OF PSYCHOPHARMACOLOGY

Potential Advantages

• Theoretically, butyrylcholinesterase inhibition centrally could enhance therapeutic efficacy

• May be useful in some patients who do not respond to or do not tolerate other cholinesterase inhibitors

• Later stages or rapidly progressive Alzheimer disease

Potential Disadvantages

• Theoretically, butyrylcholinesterase inhibition peripherally could enhance side effects

Primary Target Symptoms

• Memory loss in Alzheimer disease

• Behavioral symptoms in Alzheimer disease

• Memory loss in other dementias

Pearls

• Dramatic reversal of symptoms of Alzheimer disease is not generally seen with cholinesterase inhibitors

• Can lead to therapeutic nihilism among prescribers and lack of an appropriate trial of a cholinesterase inhibitor

✽ Perhaps only 50% of Alzheimer patients are diagnosed, and only 50% of those diagnosed are treated, and only 50% of those treated are given a cholinesterase inhibitor, and then only for 200 days in a disease that lasts 7–10 years

• Must evaluate lack of efficacy and loss of efficacy over months, not weeks

✽ Treats behavioral and psychological symptoms of Alzheimer dementia as well as cognitive symptoms (i.e., especially apathy, disinhibition, delusions, anxiety, lack of cooperation, pacing)

• Patients who themselves complain of memory problems may have depression, whereas patients whose spouses or children complain of the patient’s memory problems may have Alzheimer disease

• Treat the patient but ask the caregiver about efficacy

• What you see may depend upon how early you treat

• The first symptoms of Alzheimer disease are generally mood changes; thus, Alzheimer disease may initially be diagnosed as depression

• Women may experience cognitive symptoms in perimenopause as a result of hormonal changes that are not a sign of dementia or Alzheimer disease

• Aggressively treat concomitant symptoms with augmentation (e.g., atypical antipsychotics for agitation, antidepressants for depression)

• If treatment with antidepressants fails to improve apathy and depressed mood in the elderly, it is possible that this represents early Alzheimer disease and a cholinesterase inhibitor like rivastigmine may be helpful

• What to expect from a cholinesterase inhibitor:

• Patients do not generally improve dramatically although this can be observed in a significant minority of patients

• Onset of behavioral problems and nursing home placement can be delayed

• Functional outcomes, including activities of daily living, can be preserved

• Caregiver burden and stress can be reduced

• Delay in progression in Alzheimer disease is not evidence of disease-modifying actions of cholinesterase inhibition

• Cholinesterase inhibitors like rivastigmine depend upon the presence of intact targets for acetylcholine for maximum effectiveness and thus may be most effective in the early stages of Alzheimer disease

• The most prominent side effects of rivastigmine are gastrointestinal effects, which are usually mild and transient

✽ May cause more gastrointestinal side effects than some other cholinesterase inhibitors, especially if not slowly titrated

• At recommended doses, transdermal formulation may have lower incidence of gastrointestinal side effects than oral formulation

• Use with caution in underweight or frail patients

• Weight loss can be a problem in Alzheimer patients with debilitation and muscle wasting

• Women over 85, particularly with low body weights, may experience more adverse effects

• For patients with intolerable side effects, generally allow a washout period with resolution of side effects prior to switching to another cholinesterase inhibitor

• Cognitive improvement may be linked to substantial (>65%) inhibition of acetylcholinesterase

• Rivastigmine may be more selective for the form of acetylcholinesterase in hippocampus (G1)

✽ More potent inhibitor of the G1 form of acetylcholinesterase enzyme, found in high concentrations in Alzheimer patient’s brains, than the G4 form of the enzyme

• Butyrylcholinesterase action in the brain may not be relevant in individuals without Alzheimer disease or in early Alzheimer disease; in the later stages of the disease, enzyme actively increases as gliosis occurs

• Rivastigmine’s effects on butyrylcholinesterase may be more relevant in later stages of Alzheimer disease, when gliosis is occurring

✽ May be more useful for later stages or for more rapidly progressive forms of Alzheimer disease, when gliosis increases butyrlylcholinesterase

✽ Butyrylcholinesterase actively could interfere with amyloid plaque formation, which contains this enzyme

• Some Alzheimer patients who fail to respond to another cholinesterase inhibitor may respond when switched to rivastigmine

• Some Alzheimer patients who fail to respond to rivastigmine may respond to another cholinesterase inhibitor

• To prevent potential clinical deterioration, generally switch from long-term treatment with one cholinesterase inhibitor to another without a washout period

✽ May slow the progression of mild cognitive impairment to Alzheimer disease

✽ May be useful for dementia with Lewy bodies (DLB, constituted by early loss of attentiveness and visual perception with possible hallucinations, Parkinson-like movement problems, fluctuating cognition such as daytime drowsiness and lethargy, staring into space for long periods, episodes of disorganized speech)

• May decrease delusion, apathy, agitation, and hallucinations in dementia with Lewy bodies

✽ May be useful for vascular dementia (e.g., acute onset with slow stepwise progression that has plateaus, often with gait abnormalities, focal signs, imbalance, and urinary incontinence)

• May be helpful for dementia in Down’s syndrome

• Suggestions of utility in some cases of treatment-resistant bipolar disorder

• Theoretically, may be useful for ADHD, but not yet proven

• Theoretically, could be useful in any memory condition characterized by cholinergic deficiency (e.g., some cases of brain injury, cancer chemotherapy-induced cognitive changes, etc.)

Suggested Reading

Bentue-Ferrer D, Tribut O, Polard E, Allain H. Clinically significant drug interactions with cholinesterase inhibitors: a guide for neurologists. CNS Drugs 2003;17:947–63.

Birks J, Grimley Evans J, Iakovidou V, Tsolaki M, Holt FE. Rivastigmine for Alzheimer’s disease. Cochrane Database Syst Rev 2009;15(2):CD001191.

Dhillon S. Rivastigmine transdermal patch: a review of its use in the management of dementia of the Alzheimer’s type. Drugs 2011;71(9):1209–31.

Jones RW. Have cholinergic therapies reached their clinical boundary in Alzheimer’s disease? Int J Geriatr Psychiatry 2003;18(Suppl 1): S7–13.

SELEGILINE

SELEGILINE: THERAPEUTICS

Brands

• EMSAM

• Eldepryl

see index for additional brand names

Generic?

Yes (oral only)

Class

• Transdermal: tissue selective monoamine oxidase (MAO) inhibitor (MAO-A and MAO-B inhibitor in brain and relatively selective MAO-B inhibitor in gut)

• Oral: selective MAO-B inhibitor

Commonly Prescribed for

(bold for FDA approved)

• Major depressive disorder (transdermal)

• Oral: Parkinson’s disease or symptomatic parkinsonism (adjunctive)

• Treatment-resistant depression

• Panic disorder (transdermal)

• Social anxiety disorder (transdermal)

• Treatment-resistant anxiety disorders (transdermal)

• Alzheimer disease and other dementias (oral)

How the Drug Works

• Transdermal selegiline (recommended doses): in the brain, irreversibly inhibits both MAO-A and MAO-B from breaking down norepinephrine, serotonin, and dopamine, which presumably boosts noradrenergic, serotonergic, and dopaminergic neurotransmission

• Transdermal selegiline (recommended doses): in the gut, is a relatively selective irreversible inhibitor of MAO-B (intestine and liver), reducing the chances of dietary interactions with the MAO-A substrate tyramine

• Oral: at recommended doses, selectively and irreversibly blocks MAO-B, which presumably boosts dopaminergic neurotransmission

• Oral: above recommended doses, irreversibly blocks both MAO-A and MAO-B from breaking down norepinephrine, serotonin, and dopamine while simultaneously blocking metabolism of tyramine in the gut

• Thus, high dose oral administration is not tissue selective and is not MAO-A sparing in the gut, and may interact with tyramine-containing foods to cause hypertension