Pharmacology of Meds Used to Treat Dementia

Question 1

NonPharm Treatment of AD

Answer 1

 Behavioral symptoms
 Calm environment
 Removal of stressors or triggers
 Education, communication and planning

Question 2

Successful pharm treatment of AD =

Answer 2

short term improvement of symptoms and less decline in behavioral, functional and cognitive abilities over a longer period of time

Question 3

AD Pathophysiology

Answer 3

 Loss of cholinergic neurons esp muscarinic and nicotinic
 Loss of cholinergic activity correlates with severity of AD
• Up to 90% reduction in cholinergic markers (ACh)
 Loss of nicotinic receptors
• Presynaptic nicotinic receptors control the release of ACh and other NT important for memory and mood

Question 4

Even though there is a loss of cholinergic transmission:

Answer 4

• Increasing cholinergic transmission does not improve memory because cell loss is caused by the disease and not what causes the disease

Question 5

Define M1

Answer 5

Excitatory on postsynaptic

Activation increases cognitive function!

Question 6

Define M2

Answer 6

Inhibitory on presynaptic

Limits excess release of ACh

Question 7

M1 and M2 in AD

Answer 7

M1 is preserved but M2 are reduced

Question 8

Nicotinic Receptors MOA

Answer 8

Enhance release of DA and NE which have cognition-enhancing properties

Question 9

Nicotinic Receptors in AD

Answer 9

Beta-amyloid bind them and reduce function and they indirectly cause damage through oxidative species (ROS)
So, they are reduced

Question 10

Muscarinic ACh receptors agonists Drugs

Answer 10

Arecoline and Xanomeline

Question 11

Cholinesterase Inhibitors Drugs

Answer 11

Tacrine (Cognex)
Donepezil (Aricepf)
Rivastagmine (Exelon)
Galantamine (Razadyne)

Question 12

Cholinesterase Inhibitor MOA

Answer 12

Prevent the hydrolysis of ACh, which increases the concentration of ACh in the synaptic cleft; BuChE also hydrolyzes ACh (increased in AD)

Question 13

Cholinesterase Inhibitor Side Effects

Answer 13

GI disturbances
Muscle Cramps
Weird dreams

Question 14

Cholinesterase Inhibitor Things to Remember

Answer 14

• Abrupt discontinuation should be avoided
• Not with other anticholinergic agents
• Only 1/3 of patients show clear improvement
• Doses must be titrated in and out

Question 15

Advantages to Cholinesterase Inhibitor

Answer 15

More natural
Activate receptors all over the brain
Both muscarinic and nicotinic transmission is enhanced

Question 16

Disadvantags to Cholinesterase Inhibitor

Answer 16

Inactive in advanced AD

Question 17

Tacrine (Cognex)

Answer 17

• Reversible, non-selective (AChE and BuChE)
• Acts upon M1 and M2
• WITHDRAWN

Question 18

Donepezil (Aricepf)

Answer 18

• Specific and reversible inhibitor of AChE
• Highly lipophilic
• Well tolerated
• Long half-life (3 days)

Question 19

Rivastigimine (Exelon)

Answer 19

• Inhibits BuChE and AChE
Pseudo-irreversible inhibitor (stays bound for a really long time)
Lots of GI side effects

Question 20

Galantamine (Razadyne)

Answer 20

• Reversible and selective AChE inhibitor(Enhances action of ACh on nicotinic receptors- allosteric modulator of nicotinic receptors but no difference in effectiveness)
Metabolized 3A4 and 2D6
Well tolerated

Question 21

BuCHE Inhibition in AD

Answer 21

 Neuronal AChE disappears during Alzheimer’s disease progression
 Inhibition of BuChE might be effective in late-stage Alzheimer’s disease

Question 22

NMDA Receptor Antagonists Drug

Answer 22

Memantine (Namenda)

Question 23

Normal MOA of NMDA Receptors

Answer 23

Glutamate major excitatory NT in the hippocampus and cortex
o Plays an essential role in learning and memory by triggering NMDA receptors to let a controlled amount of calcium into a nerve cell
o Excess glultamate overstimulates NMDA receptors leading to increased Intracellular Ca and free radicals → toxic
o Usually Mg blocks the receptor from excess Ca influx

Question 24

AD MOA of NMDA Receptors

Answer 24

• There is increased Ca influx → progressive deficit in cognitive functions → leads to neuronal death
• Blocking the NMDA receptor will decrease activity of glutamate in the synapse

Question 25

Memantine

Answer 25

``` NaMenDA • Blocks glutamatergic NT by antagonizing NMDA receptor (more effective than Mg) Urine excretion 60-80 hour half life Wel tolerated Monotherapy or combo with AChE inhibitor ```

Question 26

What is Namzaric?

Answer 26

Memantine ER + Donepezil

Question 27

Ginkgo Biloba MOA

Answer 27

o Increased blood flow by decreasing blood viscosity o Inhibits MOA oxidase o Anti-infective properties o Prevents ROS damage

Question 28

Ginkgo Biloba Use and caution

Answer 28

* May increase M receptors and serum levels of ACh and NA * CAUTION WITH ANTICOAGULANTS, ANTIPLATELETS, OR NSAIDS * Guidelines do NOT recommend use in AD

Question 29

Hyperzine A use in AD

Answer 29

• MOA: reversible AChE inhibitor o Symptomatic treatment • NOT with other AChE inhibitor • Safety issue

Question 30

Vitamin E use in AD

Answer 30

• Antioxidant properties • Adjunctive treatment o Mixed evidenced o Said to not benefit cognition (selegiline too)

Question 31

What should you monitor for brain vascular health?

Answer 31

High BP High cholesterol Glucose levels

Question 32

Lipid lower agents in AD

Answer 32

* Only use if the pt has another reason for taking statins * There is some evidence showing a correlation between elevated mid-life cholesterol and AD * Mixed results

Question 33

Estrogen in AD

Answer 33

* Promoting neuronal growth and preventing oxidative damage | * Post menopause = lower incidence of AD with estrogen replacement but also increase CV risk

Question 34

NSAIDs in AD

Answer 34

* Long treatment (2 years) lowers the risk of AD maybe…? | * NSAIDs and prednisone are NOT recommended

Question 35

Antipsychotics in AD for non-cognitive symptoms

Answer 35

* Adverse effects offset the usefulness | * Modest expectation of benefit

Question 36

Antidepressants in AD for non-cognitive symptoms

Answer 36

* 50% of AD pts exhibit depression * SSRI (sertraline, citalopram, fluoxetine, paroxetine) * SNRI (venlafaxine) * NOT TCA’s

Question 37

What should never be used in AD

Answer 37

Benzodizepines

Question 38

Encenicline in AD

Answer 38

ACh co-agonist MOA: Sensitizes alpha 8 nicotinic receptors and makes it possible for smaller amounts of naturally occurring ACh to activate the receptor • MEMORY DEFICITS CAN BE MINIMIZED OR ENTIRELY REVERSED