Alzheimer's Disease

Front 1

prevalence of Alzheimer’s Disease

Back 1

• >5M adults affected in USA
• ~5% of men and women between ages of 65-74 are affected
• ~50% of those age L 85 YO are affected
• The number of people with disease doubles for every 5 years after age 65

Front 2

signs and symptoms of AD

Back 2

• Increasing forgetfulness and mild confusion
• Memory loss gets worse
• Disorientation
• Difficulty with thinking and reasoning skills:
• Planning and performing familiar tasks: cooking, dressing themselves, bathing
• Behavioral changes: depression, anxiety, social withdrawal, mood swings,distrust, aggressiveness, wandering, sleep changes

Front 3

DSM-IV diagnosis for AD.

Back 3

1. Memory impairment
2. One (or more) of the following cognitive disturbances:Aphasia (language disturbance),Apraxia (impaired motor activities,Agnosia (failure to recognize or identify,Disturbance in executive functioning
cognitive deficits not due to disease

Front 4

risk factors for AD, pay particular attention to the effects of age and
environmental factors that result in increased or decreased risk of AD.

Back 4

A. Genetic Factors, gene mutations (5%)
B. Age
C. Environmental Factors:• Lack of Exercise • Smoking • High BP and cholesterol • Poorly controlled diabetes

Front 5

Decreased risk for AD

Back 5

• Higher levels of education
• A stimulating job
• Mentally-challenging leisure activities: reading, playing games,
playing a musical instrument
• Frequent Social Interactions

Front 6

neurological deficits in brains of AD patients.

Back 6

Alzheimer’s disease leads to nerve cell death and tissue loss throughout the brain. Over time, the brain shrinks dramatically, affecting nearly all its function and disrupts both the way electrical charges travel within cells and the activity of neurotransmitters.

Front 7

key pathological changes .Define “plaques” and “tangles” and how they may relate to disease

Back 7

Plaques: deposits of extracelluar, insoluble beta-amyloid protein that may result in damage to nerve cells and cell-to-cell signaling.
Tangles: comprised of tau protein that normally supports cellular microtubule structure. Threads of tau protein twist together to form intracellular tangles and disruption of cellular transport mechanisms that may result in cell death.

Front 8

Cholinergic Hypothesis of AD:

Back 8

neurotransmitter levels are changed, cholinergic neurons are lost, primarily due to destruction of the cell bodies within the Nucleus Basalis of Meynert. acetylcholine, muscarinic and nicotinic receptors,Choline Acetyltransferase (ChAT) and high affinity choline uptake is reduced. are reduced;

Front 9

Scopolamine

Back 9

a centrally-active muscarinic antagonist, can produce “amnesia”
or loss of recent memory in patients after acute administration

Front 10

Glutamate Hypothesis in AD

Back 10

Beta amyloid oligomers have been shown to block Glutamate reuptake in Glial cells elevating extracellular glutamate. Beta amyloid oligomers may interfere with cell signaling. excess glutamate can activate NMDA receptors resulting in excitotoxicity and destruction of cholinergic neurons in Nucleus Basalis of Meynert

Front 11

Donepezil

Back 11

Central Cholinesterase Inhibitors (Aricept) Alzheimer’s dementia mild to severe. “Reversible”, but covalent, Carbamylating Agents (or not?) Listed as a Piperidines.
metabolized primarily by CYP; Long T1/2 ~70 hrs

Front 12

Galantamine

Back 12

Central Cholinesterase Inhibitors (Razadyne, Reminyl) mild to moderate Alzheimer’s dementia. Competitive Antagonists
multiple CYPs involved in metabolism

Front 13

Rivastigmine

Back 13

Central Cholinesterase Inhibitors (Exelon, patch) mild to moderate Alzheimer’s dementia. Only one for Parkinson’s Dementia. “Reversible”, but covalent, Carbamylating Agents
metabolized by cholinesterase.Cholinesterase inhibition is much longer (~10 hrs)

Front 14

Describe peripheral, mechanism-based adverse effects of cholinesterase inhibitors

Back 14

CV effects: bradycardia predominates
GI: N/V, diarrhea most common AEs
Eye: some vision disturbances Why?
Urinary tract: urinary urgency/incontinence
Muscle cramps: Why?
CNS effects: dizziness, sleep disturbances, headache most common; convulsions, coma
in toxicity

Front 15

Describe key pharmacodynamic interactions for cholinesterase inhibitors

Back 15

• Neuromuscular Blockers
• Other Cholinesterase Inhibitors
• Anticholinergic agents

Front 16

Memantine

Back 16

(Namenda) NMDA antagonists
has low to moderate affinity for NMDA receptor, results in inhibition of NMDA receptor-activated Ca2+ influx (ligand-gated channels) that results in neurotoxicity, effects at other glutamate receptor
subtypes are spared.

Front 17

Memantine pharmacokinetics

Back 17

Long T1/2 in plasma of 60-80 hrs; Large VD of 9-11 L/kg implies extensive tissue distribution; 60-80% excreted by kidney as unchanged drug. Acidification of the
urine may increase renal elimination.

Front 18

Memantine adverse effects

Back 18

Relatively low incidence of reported AEs (most were near placebo incidence).
CV: BP changes; QT prolongation
Derm: some rash
CNS: dizziness (fall risk), confusion, fatigue, agitation
GI: constipation