methylxanthines and Nootropics Flashcards
what are three most common drug categories that contain caffeine?
Stimulants
analgesics (pain killers) –> uses caffeines vasoconstrictive properties to target headaches and migranes
Diuretics –> drug that increases urine volume and decreases blood pressure
what is caffeine classified as?
a methylxanthine
What are some of the side effects of caffeine (4) what major drug class is it most similar to?
- motor activation
- arousal
- increased concentration
- wakefulness
potentiates dopamine system similar to psychostimulants like cocaine and amphetamines but its obviously not as strong
what is a methyxanthine found in coffee?
caffeine
what is the methylxanthine found in tea?
theophylline
what is the methylxanthine found in chocolate?
theobromine
what are 5 general physiological effects of caffeine?
- increases release of NT including adrenaline
- activation of cortex in EEG studies
- it dilates local blood vessels and in the brain it constricts the blood vessels (thats why it stops migrants in some people)
- relaxes smooth muscle, and stimulates skeletal muscle
- caffeine can be a diuretic after 300mg or more of consumption … it does this by increasing blood flow to the kidneys, and weakens bladder muscles (by relaxing smooth muscle) and inhibits resorption of water and sodium
In what ways can caffeine be a cognitive enhancer?
caffeine causes increased performance under sub-optimal alertness conditions i.e. boring tasks and will improve performance in fatigued subjects, however in normal conditions when a person is well-rested there has been on and off evidence for caffeine helping with cog. enhancement
What is adenosine?
it is a neuromodulator in the CNS so it controls other neurotransmitters
when released, adenosine has a calming effect on the brain and prevents neurotransmitters from being released
using adenosine receptors, adenosine acts presynaptically to PREVENT NT release and has depressant effects post synaptically
it reduces the rate of spontaneously firing neurons
what effect does caffeine have on adenosine receptors?
caffeine prevents all of the inhibitory and calming effects that adenosine has on the brain by preventing adenosine from binding to its receptors
What kind of an effect does caffeine have on adenosine receptors?
caffeine is an antagonist at the adenosine receptors and it blocks the effects of adenosine and takes away the accessibility of those receptors to adenosine
what are the 4 main adenosine receptor types? and which ones are most important for caffeine effects?
A1, A2A, A2B, and A3 receptors are the major ones
A1 and A2A seem to be the most important for caffeine effects but the theory behind this is somewhat controversial
what are the properties of the adenosine A1 receptor? (location in synapse, effect on second messenger, effect on NT release and distribution)?
- Location in synapse: mostly presynaptic
- Effect on second messengers: inhibits cAMP production
- Effect on Neurotransmitter release: inhibit s NT release
- Distribution: distributed throughout the brain
A1 - selective antagonist most closely mimic the effect of caffeine
what are the properties of the adenosine A2A receptor? (location in synapse, effect on second messenger, effect on NT release and distribution)?
- Location in Synapse: can be both pre and post synaptic
- effect on second messengers: stimulates cAMP production
- Effect on NT release: promotes NT release
- distribution: found mostly in brain area that includes the striatum (nucleus accumbens)
how does adenosine modulate sleep?
the concentration of extracellular adenosine increases during waking until a point is reached that triggers sleep (demonstrated by cat experiment) –> so us getting sleepy is due to our adenosine levels going down
- adenosine release is thought to come from metabolism of ATP in neurons –> the more we stay awake, the more ATP is metabolized up until a point where we feel sleepy so we can re-energize
- stimulation of A2A (presynaptic) receptors by adenosine in the hypothalamus triggers GABA release
- GABA release inhibits arousal systems
what effect does caffeine have on sleep?
caffeine prevents adenosine binding to the A2A receptors of the hypothalamus therefore it prevents the release of GABA therefore inhibiting sleep
What are 3 other effects of caffeine on neurotransmitters at higher doses?
- inhibits phosphodiesterase (PDE) enzymes which metabolize cAMP producing high cAMP levels… this results in the relaxation of smooth muscles via vasodilation and increased contraction of heart muscle
- it inhibits GABA-A receptors
- Increases calcium channel function –> increases intracellular concentration of calcium by increasing activation of calcium channels which is thought to increase work capacity of muscles
What is the most important target for caffeine in the brain?
experiment on mice examine the concentrations where effects start to happen
after intake of 3 cups there is 1-10 micro molar of caffeine in plasma
adenosine type 1 and 2A receptors are the primary target and some suggest PDE as well
where is caffeine metabolized in the body?
in the liver
what are the three primary metabolic products of caffeine?
- paraxanthine (84%) –> increases lipolysis (break down of fat from storage and use for energy) leading to elevated glycerol and free fatty acids in blood plasma) might be cause for increased muscle strength
- theobromine (12%) –> dilates blood vessels and increases urine volume
- theophylline (4%) –> relaxes airway smooth muscle
paraxanthine is the only naturally occurring product
is Caffeine a drug of abuse?
there is a robust dopamine increase in the nucleus accumbens that seems to be due to the blocking of A1 receptors (the inhibitory ones) that normally inhibit dopamine release
also, caffeine blocks A1 receptors that normally inhibit glutamate release as well
Glutamate then stimulates dopaminergic neurons in the VTA onto the Nucleus accumbens
an experiment shows in vivo microdyalisis that at doses of caffeine that are really high theres an increase in dopamine release in the nucleus accumbens
What are some health risks with caffeine?
caffeine can cause anxiety, agitation, muscle twitch, heart palpitations, and increase temperature
abruptly terminating caffeine use can lead to withdrawal symptoms
what is the lethal dose of caffeine?
lethal dose is 100 cups of coffee (10g) and death occurs from conclusion and respiratory arrest
what is the dose limit for caffeine in energy drinks?
180mg or 400mg/litre
what did the study examining the speed of metabolism of caffeine and cardiovascular risk in subjects less than 50 years old show?
this study identified fast and slow caffeine metabolizers
- two copies of the *1A variant of the CYPA1A2 (caffeine metabolizing enzyme in the liver) = fast metabolizers
- a single copy of the *1F = slow metabolizers
odds of having a myocardial infarction (heart attack) are below one for the 1A/1A (fast) group indicating protection
slow metabolizers show increased risk with increased disease
with individuals who are 1F/1F or 1A/1F, the odds of having a heart attack in their lives increase as the number cups per day of caffeine increase
but for the fast metabolizers 1A/1A, there is a decrease in odds while having 1-3 cups per day (below 1) and overall decrease in odds of having caffeine
what are 2 other health issues of caffeine?
- osteoporosis –> negative effects on bone density bc caffeine increases urinary excretion of calcium and inhibits absorption from diet
- increase risk of panic attacks due to stimulant effects but mostly in those with a specific mutation in the A2A receptor (the inhibitory one)
What are the effects of caffeine on Parkinsons?
there is a strong inverse correlation between caffeine intake and Parkinson’s disease
effects are dose related
cuts risk almost five-fold
caffeine can lessen symptoms in animal models
so higher the caffeine intake, the lower chance of getting Parkinsons
What are nootropics?
drugs that are thought to be cognitive enhancers
noos in greek means mind and troppein means towards
what are some examples of nootropics?
includes medicines for ADHD like Ritalin and some are used as part of the therapy for diseases such as Alzheimer’s, stroke and dementias
what is memantine? what is the effect?
memantine is a low-affinity reversible NMDA receptor antagonist and a nootropic
in patients with neurodegeneration, it is used to stop excess activation of NMDA receptors which can kill neurons (except memory depends on NMDA receptors)
in healthy users, it is thought to decrease background glutamate “noise” which is what people think causes distractions and still allows receptors to be activated when glutamate is release from nerve endings
what are the side effects of memantine?
confusion, dizziness, headache, constipation and body aches
what is Rivastigmine?
it is an acetylcholinesterase inhibitor and a nootropic
inhibits the enzyme that breaks down aCH
clinically used as a cognitive enhancer in neurodegenerative disease (where aCH is lost)
what are the side effects of Rivastigmine?
diarrhea and other GI complaints, confusion, dizziness, hallucinations, seizures, irregular heartbeat, severe nausea
