Cognitive Enhancers

Question 1

amphetamines: MOA

Answer 1

DL-amphetamine, Dextroamphetamine, Methamphetamine
MOA:
1) substrate (competitive inhibitors) of neuronal monoamine uptake transporters NET and DAT
2) enter synaptic nerve ending and displace stored NE and DA (displacer effect)
3) interact with VMAT-2
4) NE and DA transported out via DAT and NET working in reverse
5) at high conc., inhibit MAO (normally breaks down DA and NE

Question 2

amphetamines: effects

Answer 2

DL-amphetamine, Dextroamphetamine, Methamphetamine
Effects:
1) release DA and NE from nerve terminals in brain
2) increase extracellular [NE] and [DA] near synapse
3) stimulant lasts a few hours, followed by depression and anxiety -locomotor/rewarding effects driven by DA
Prolonged use:
1) amphetamine psychosis -treat with antipsychotics (DA receptor antagonists)
2) drug stopped after few days: deep sleep followed by lethargy, depressed/anxious feelings (possibly suicidal), hunger

Question 3

amphetamines: pharmacokinetics

Answer 3

DL-amphetamine, Dextroamphetamine, Methamphetamine

Pharmacokinetics:

1) readily absorbed from GI tract
2) snorted/injected or smoked in crystal form
3) freely penetrate BBB
4) excreted mainly unchanged in urine
3) plasma half-life varies (5-30 hours, depending on urine flow)

Question 4

Methylphenidate (Ritalin): effect, MOA, pharmacokinetics, clinical use

Answer 4

effect: profound and sustained elevation of extracellular NE and DA

MOA: inhibit NET and DAT transporters (NOT substrate -doesn’t enter nerve terminal or facilitate NE/DA release)

pharmacokinetics: orally active, slowly absorbed via intestine and colon (peak level after 2 hrs)
- pre-systemic metabolism, so only 20% enters systemic circulation ADHD

Question 5

Modafinil: effects (and proposed MOA), pharmacokinetics, clinical uses

Answer 5

effects:
1) increase extracellular DA levels in striatum and nucleus accumbens (likely inhibits DA reuptake by binding to DAT)
2) enhanced release of 5HT, glutamate, and histamine
3) inhibition of GABA release
note: no euphoria when administered by mouth
4) wakefulness promoting agent (rather than classic amphetamine-like stimulant)
5) brightens mood
6) enhances cognitive performance (gaining pop. as “lifestyle drug”)

pharmacokinetics: well absorbed from gut, metabolized in liver, half-life = 10-14 hrs

clinical uses:

1) narcolepsy treatment (also shift work sleep disorder, excessive daytime sleepiness assoc. with obstructive sleep apnea)
2) adult ADHD (not kids b/c develop severe skin rash)

Question 6

Atomoxetine (Strattera)

Answer 6

used to treat ADHD

MOA:

1) highly selective NE reuptake inhibitor
2) elevates DA levels in PFC (but NOT in nucleus accumbens -mediates euphoric properities- or striatum)
- only ADHD medication with no abuse potential
- also approved to treat adult ADHD

Adverse effects:
nausea, vomiting, weight loss
sleep problems
liver damage

-less effective in reducing ADHD than stimulants

Question 7

donepezil, rivastigmine, galantamine

Answer 7

used to treat Alzheimer Disease 
cholinesterase inhibitors 
enhance cholinergic transmission
-slight improvements in tests of memory/cognition in AD pts -may be too small to be significant in terms of everyday life  
cholinergic side effects: 
-GI symptoms (nausea, diarrhea, cramps) 
-altered sleep with unpleasant/vivid dreams
-bradycardia (usually benign) 
-muscle cramps

Question 8

Memantine

Answer 8

used to treat AD

• weak antagonist at NMDA receptors
• orally active
• modest cognitive improvement in moderate or severe AD
• not neuroprotective

possible MOA:

• selective inhibition of excessive, pathological NMDA receptor activation
• preserves more physiological NMDA receptor activation
• long plasma half-life
• used in conjunction with cholinesterase inhibitors or by itself

-slows deterioration, decreases caregiver burden for pts with moderate to severe AD (not approved for mild AD)

Adverse effects:
-headache, dizziness, drowsiness, constipation, shortness of breath, hypertension, others