methylxanthines and Nootropics

Question 1

what are three most common drug categories that contain caffeine?

Answer 1

Stimulants

analgesics (pain killers) –> uses caffeines vasoconstrictive properties to target headaches and migranes

Diuretics –> drug that increases urine volume and decreases blood pressure

Question 2

what is caffeine classified as?

Answer 2

a methylxanthine

Question 3

What are some of the side effects of caffeine (4) what major drug class is it most similar to?

Answer 3

1. motor activation
2. arousal
3. increased concentration
4. wakefulness

potentiates dopamine system similar to psychostimulants like cocaine and amphetamines but its obviously not as strong

Question 4

what is a methyxanthine found in coffee?

Answer 4

caffeine

Question 5

what is the methylxanthine found in tea?

Answer 5

theophylline

Question 6

what is the methylxanthine found in chocolate?

Answer 6

theobromine

Question 7

what are 5 general physiological effects of caffeine?

Answer 7

1. increases release of NT including adrenaline
2. activation of cortex in EEG studies
3. it dilates local blood vessels and in the brain it constricts the blood vessels (thats why it stops migrants in some people)
4. relaxes smooth muscle, and stimulates skeletal muscle
5. 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

Question 8

In what ways can caffeine be a cognitive enhancer?

Answer 8

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

Question 9

What is adenosine?

Answer 9

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

Question 10

what effect does caffeine have on adenosine receptors?

Answer 10

caffeine prevents all of the inhibitory and calming effects that adenosine has on the brain by preventing adenosine from binding to its receptors

Question 11

What kind of an effect does caffeine have on adenosine receptors?

Answer 11

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

Question 12

what are the 4 main adenosine receptor types? and which ones are most important for caffeine effects?

Answer 12

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

Question 13

what are the properties of the adenosine A1 receptor? (location in synapse, effect on second messenger, effect on NT release and distribution)?

Answer 13

• 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

Question 14

what are the properties of the adenosine A2A receptor? (location in synapse, effect on second messenger, effect on NT release and distribution)?

Answer 14

• 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)

Question 15

how does adenosine modulate sleep?

Answer 15

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

Question 16

what effect does caffeine have on sleep?

Answer 16

caffeine prevents adenosine binding to the A2A receptors of the hypothalamus therefore it prevents the release of GABA therefore inhibiting sleep

Question 17

What are 3 other effects of caffeine on neurotransmitters at higher doses?

Answer 17

1. 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
2. it inhibits GABA-A receptors
3. Increases calcium channel function –> increases intracellular concentration of calcium by increasing activation of calcium channels which is thought to increase work capacity of muscles

Question 18

What is the most important target for caffeine in the brain?

Answer 18

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

Question 19

where is caffeine metabolized in the body?

Answer 19

in the liver

Question 20

what are the three primary metabolic products of caffeine?

Answer 20

1. 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
2. theobromine (12%) –> dilates blood vessels and increases urine volume
3. theophylline (4%) –> relaxes airway smooth muscle

paraxanthine is the only naturally occurring product

Question 21

is Caffeine a drug of abuse?

Answer 21

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

Question 22

What are some health risks with caffeine?

Answer 22

caffeine can cause anxiety, agitation, muscle twitch, heart palpitations, and increase temperature

abruptly terminating caffeine use can lead to withdrawal symptoms

Question 23

what is the lethal dose of caffeine?

Answer 23

lethal dose is 100 cups of coffee (10g) and death occurs from conclusion and respiratory arrest

Question 24

what is the dose limit for caffeine in energy drinks?

Answer 24

180mg or 400mg/litre

Question 25

what did the study examining the speed of metabolism of caffeine and cardiovascular risk in subjects less than 50 years old show?

Answer 25

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

Question 26

what are 2 other health issues of caffeine?

Answer 26

1. osteoporosis –> negative effects on bone density bc caffeine increases urinary excretion of calcium and inhibits absorption from diet
2. increase risk of panic attacks due to stimulant effects but mostly in those with a specific mutation in the A2A receptor (the inhibitory one)

Question 27

What are the effects of caffeine on Parkinsons?

Answer 27

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

Question 28

What are nootropics?

Answer 28

drugs that are thought to be cognitive enhancers

noos in greek means mind and troppein means towards

Question 29

what are some examples of nootropics?

Answer 29

includes medicines for ADHD like Ritalin and some are used as part of the therapy for diseases such as Alzheimer’s, stroke and dementias

Question 30

what is memantine? what is the effect?

Answer 30

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

Question 31

what are the side effects of memantine?

Answer 31

confusion, dizziness, headache, constipation and body aches

Question 32

what is Rivastigmine?

Answer 32

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)

Question 33

what are the side effects of Rivastigmine?

Answer 33

diarrhea and other GI complaints, confusion, dizziness, hallucinations, seizures, irregular heartbeat, severe nausea