What are the three areas of ADHD indicators?
When do ADHD symptoms present? What percent of children? Adolescence? Adults?
usually before age 7
3-5% of children globally
of those, 60-80% persist into adolescence and 30-40% persist into adulthood
What are the american academy of pediatrics guidelines for an ADHD diagnosis/
at least 6 attention symptoms or 6 hyperactivity symptoms (with some before age 7)
symptoms must be present for at least 6 months
must be seen in at least 2 settings
not caused by another problem
symptoms have to be severe enough to cause difficulties in many settings, not just school
What two NTs are disrupted in ADHD?
NE and DA
Specifically, what pathway is involved with NE in ADHD?
from the locus soeruleus to the frontal and limbic cortices
it affects sustained and focused attention, mediates, energy and fatigue, working memory
What 3 pathways are involved with DA in ADHD?
1. susbantia nigra - striatum (motor hyperactivity)
2. tegmentum - frontal and limbic cortex (cognitive functions)
3. VTA - nucleus accumbens (euphoria)
What is the mode of action for all drugs used to treat ADHD?
to raise the levels of DA and NE
What are two classes of psychostimulants used in ADHD?
Amphetamines and Methylphenidate
What are the immediate-release and sustained-release forms of amphetamines used for ADHD>
immediate release = dexedrine
sustained = dexedrine spansules and adderrall XR
What ar ethe immediate release and sustained release version of methylphenidate used for ADHD?
Sustained: Concerta and Metadate CD
Why are the sustained released versions so helpful
they only need to be administered in the morning - never at school, so it removes the burden on schools to manage drug administrations
What do all the amphetamines and methylphenidates do? What added mechanism does d.l-amphetamine have?
they all enhance DA release and block reuptake
d,l-amphetamine also enhances NE release
Why are STIMULANTS effective for ADHD? You would think it'd be the opposite.
areas of the PFC and limbic cortex involved in focusing and maintaining attention and prioritizing behaviors are ACTIVATED at low (therapeutic) doses
What areas of the brain are stimulated at toxic doses?
areas involved in motor activity and arousal - euphoria
How do patients with ADHD respond to stimulants differently than non-ADHD patients?
stimulants have a calming effect on them
tolerance develops at a slower place
What group of people are at risk for "reverse tolerance" with stimulants, where they becomes psychotic with chronic use of the drug even without dose escalation?
people who have abused amphetamines like cocaine
What is the mechanism of atomoxetine?
it's a highly selective NE reuptake inhibitor
also elevates DA levels in the PFC (but not nucleus accumbens or the striatum)
Why is atomoxetine (strattera) the only first line ADHD drug with no abuse potential?
remember that it doesn't elevate DA levels in the nucleus addumbens, so you don't get the mesolimbic euphoric properties
How do cholinergic neurons impact ADHD?
there are cholinergic neurons in the cortical and subcortical regions of the brain that are implicated in vigilance, attention and workin gmemory
Tzavara was observed to increase ACh release from rat frontal cortex only under what conditions to improve attention and working memory?
alpha1 receptors had to be activated by NE and D1 receptors had to be activated by DA
so Tzavara given in combo with atomoxetine or methylphenidate improved attention and memory
What NT is largely affect in the neuropathology of AD?
How do tau proteins eventually lead to cell death in AD?
the tau tangles tend to surround neuron's microtubules
this interferes with the cell's ability to transport essential chemicals form the cell body to the axon terminal
How do the beta-amyloid plaques interfere with cognition?
in the nucleus basalis, they accumulate in the synapse and interfere with normal ACh transmission
What is the general time course of AD proression?
1. memory problems start with neuronal loss in the NBM
2. within about 3 years, cell damage to areas receiving ACh from the NBM causes loss of functional independence - early disenoasis of AD cna be made
3. 3-6 years after that, the neocortex becomes heavily involved in the disease process
4. usually die over the following 3 years
What drugs can you give to hopefully delay AD progression?
(delays cognitive deterioration by about one year in 20% of patients)
What are the side effects of the anticholinesterases and why?
nausea, anorexai, vomiting and diarrhea
they raise ACh levels thorughout the brain - not just in the areas where ACh is low
What are some examples of anticholinesterases used in AD?
Donepezil = aricept
galanatamine = razadyne
rivastigmine = exelon
tacrine = cognex
memantine = namenda
What cholinesterases does rivastigmine block?
both AChE and BuChE
(this means it causes more gastrointestinal problems and muscle weakness than the others)
Why is tacrine (cognex) a second line treatemtn for AD?
It has a short half life and needs to be given multiple times per day, so compliance is poor
there are also lots of drug interactions- esp with NSAIDs
may cause liver damage
What does Galantamine (Razadyne) do>
1. inhibits AChE
2. stimulates nicotinic cholinergic neurons to release more stored ACh
What drugs should Galantamine NOT be taken with?
antidepressants: paroxetine, amitriptyline, fluoxetine, and fluvoxamine
and other drugs with anticholinergic side effects
they can interfere with the elimination of galantamine
Why should people on cholinesterase inhibitors only use NSAIDs with great caution?
cholinesterase inhibitos increase the risk of stomach ulcers
Who is memantine (namenda) particularly useful for?
patients with moderate to severe AD
it can help patients in latera stages of the disease to maintain additiona independence
What is the mechanism of Memantine (Namenda)?
it is an antagonist at the NMDA receptor
What are nootropics?
memory enhancers, "smart drugs"
What are Eugeroics?
they are "wakefulness enhancers" like modafinil and armodafinil (provigil and nuvigil)
Is ginko biloba good for AD?
it may have a modest benefit for AD patients, but serious side effects have been found - bleeding, seizures, coma!