principles of drug action Alzheimer exam 3

Question 1

DEMENTIA AND ALZHEIMER’S DISEASE definition

Answer 1

Group of symptoms related to loss or impairment of thinking, memory, and reasoning that is severe enough to interfere with a person’s daily functioning

Genetic factors are important in all forms of dementia
 Early onset dementia: dementia with an onset before the age of 65 years
 Late onset dementia: after age 6

Question 2

DEMENTIA

Answer 2

Dementia is the general term for a group of brain disorders that cause memory problems and make it hard to think clearly

What symptoms does dementia cause? — The symptoms of dementia often start off very mild and get worse slowly. Symptoms can include:

 ●Forgetting all sorts of things

 ●Confusion

 ●Trouble with language (for example, not being able to find the right words for things)

 ●Trouble concentrating and reasoning

 ●Problems with tasks such as paying bills or balancing a

checkbook
 ●Getting lost in familiar places

Question 3

Alzheimer disease

Answer 3

lzheimer disease is the most common cause of dementia. It is a disorder in which brain cells slowly die over time.

Question 4

Vascular dementia

Answer 4

Vascular dementia happens when parts of the brain do not get enough blood. This can happen when blood vessels in the brain get blocked with blood clots or damaged by high blood pressure or aging. This form of dementia is most common among people who have had strokes or who are at risk for strokes.

Question 5

Parkinson disease dementia

Answer 5

Parkinson disease is a brain disorder that affects movement. It causes trembling, stiffness, and slowness. As Parkinson disease gets worse, some people develop dementia

Question 6

alzheimers disease

clinical and pathophsiolgy

Answer 6

Clinical:

 Characterized by deficits in short-term memory, language, visuospatial and executive functioning, resulting in global cognitive impairment, with a mean disease duration of 5–15 years

Pathology: Typical characteristics of AD brains at autopsy include:

 Proteinacious neural plaques comprised of toxic aggregates of AB 42 peptides

 produced by cleavage of the amyloid-beta precursor protein by b- and y- secretases instead of by a-secretase

Neurofibrillary tangles comprised hyperphosphorylated tau protein

Question 7

ALZHEIMER’S AND AGGREGATION OF ABERRANT PROTEINS

Answer 7

step 1 : cleavge by either a or b secretase

step 2: cleavge by y secretase [presenilins involved in this process]

Question 8

AD PATHOLOGY-AMYLOID PLAQUES

Answer 8

Abnormally processed polypeptides are toxic (A1–42 )
•Extracellular aggregates can “stick” to AMPA, NMDA receptors and Ca2+ ion

channels, increasing Ca2+ influx (excitototoxicity)
•The polypeptides also initiate an inflammatory response, with production of

intracellular tangles

Question 9

EVIDENCE OF CHOLINERGIC DYSFUNCTION

Answer 9

Long term effect on CNS cholinergic function

• Alzheimer’s disease likely involves inappropriate accumulation of misfolded oligomeric aggregates of β-amyloid peptide leads to the dysfunction of cholinergic neurons and pathways in the brain

Eventually cholinergic neurons from the basal forebrain cholinergic system are killed (Nucleus basalis)

Question 10

What pharmacotherapeutic options are available to treat Alzheimer’s

Answer 10

Drugs that can boost CNS cholinergic function

Clinical effectiveness of AChE inhibitors supports cholinergic

dysfunction and may be useful in slowing disease progression

Question 11

REVERSIBLE CHOLINESTERASE INHIBITORSMAINSTAY OF DRUG TREATMENT for alzheimer

Answer 11

• physostigmine
• neostigmine

pyridostigmine

rivastigmine

edrophonium

tacrine

donepezil

galantamine

Question 12

DONEPEZIL (ARICEPT)

Answer 12

Non-competitive inhibitor of AChE
 Treatment of mild, moderate, or severe dementia

 100% bioavailable

 In long-term studies delayed symptomatic progression of the disease for periods up to 55 weeks

 good CNS penetration, long duration of action (~70 hours-once-a-day dosing)

More selective CNS cholinesterase inhibitor than tacrine with no hepatotoxocity

Question 13

RIVASTIGMINE (EXELON)

Answer 13

Non-competitive (pseudo-irreversible) inhibitor of AChE

 Treatment of mild to moderate dementia

 Treatment for dementia associated with Parkinson’s

 Oral and patch

 Short (24-52 weeks) and long term efficacy in SLOWING cognitive and behavioral decline

 No hepatic metabolism

 Short half-life (2-3 hours) requires twice-a-day dosing, but _______________

Question 14

GALANTAMINE (RAZADYNE)

Answer 14

MOA

 Competitive, reversible centrally-acting cholinesterase inhibitor AND nAChR agonist

Elevates acetylcholine in cerebral cortex by slowing the degradation of acetylcholine

 Modulation of presynaptic nAChRs to increase ACh release from surviving presynaptic terminals

 Improves cognitive function and appears to delay disease progression

Question 15

SUMMARY-ADRS CHOLINESTERASE INHIBITORS

Answer 15

Generally well tolerated and usually exhibit few cholinomimetic side effects

Central nervous system: Insomnia (2% to 14%) Headache (3% to 10%), pain (3% to 9%), fatigue (1% to 8%), dizziness (2% to 8%),

Gastrointestinal: Nausea (3% to 19%; dose related), diarrhea (5% to 15%; dose related)

Cardiovascular: Hypertension (3%), chest pain (2%), hemorrhage (2%), syncope (2%), hypotension, atrial fibrillation, bradycardia, ECG abnormal, edema, heart failure, hot flashes, peripheral edema, vasodilation

Question 16

SUMMARY-DRUG INTERACTIONS CHOLINESTERASE INHIBITORS

Answer 16

Acetylcholinesterase Inhibitors (Central): may diminish the therapeutic effect of anti-cholinergics. If the anticholinergic action is a side effect of the agent, the result may be beneficial

All used in mild to moderate disease, and in combination with memantine (donepezil)

Question 17

MEMANTINE-MOA

Answer 17

Excessive receptor activation prevents magnesium from reentering and blocking the NMDA channel pore

results in a chronically open state and excessive calcium influx

 Memantine binds to the magnesium biding site, and functions as an effective receptor blocker under conditions of excessive stimulation

 Memantine does not affect normal neurotransmission but regulates NMDA receptor activation, controls calcium influx and may prevent glutamate-induced toxicity

Question 18

MEMANTINE indications and disease concerns

Answer 18

Indications-Treatment of moderate-to-severe dementia of the Alzheimer’s type alone or in combinations with donepezil

 Disease related concerns:

 Cardiovascular disease: Use with caution in patients with cardiovascular disease; increased incidence of cardiac failure, angina, bradycardia, and hypertension

 Hepatic impairment: Use with caution in patients with severe hepatic impairment.

 Renal impairment: Use with caution in patients with severe renal impairment; dose adjustments may be required.

Question 19

MEMANTINE

ADRs:

Answer 19

Cardiovascular: Hypertension (4%), cardiac failure, cerebrovascular accident, syncope, transient ischemic attack

 Central nervous system: Dizziness (7%), confusion (6%), headache (6%), hallucinations (3%), pain (3%), somnolence (3%), fatigue (2%), aggressive reaction, ataxia, vertigo

 Gastrointestinal: Constipation (5%), vomiting (3%), weight loss

 Neuromuscular & skeletal: Back pain (3%), hypokinesia

Question 20

LIVEDO RETICULARIS

Answer 20

Livedo reticularis is a purplish or blue-reddish skin discoloration consisting of a mottled reticulated vascular pattern and most often localized in the lower extremities

Question 21

which agents are used for AD and dementia