Methylxanthines Flashcards
coffee
botanical preparation
infusion of complex chemicals from a plant fruit
identification of new chemicals
extraction
purification
predictions
characterization
experiments for psychoactive chemicals
animal behaviour
physiological measures
biochemical assays
primary actives in caffeine
methylxanthines
methylxanthines
heterocyclic alkaloids
purine base nucleus
= 2 rings with N
2 carboxyls
chlorogenic acids
induce liver enzymes
(phase II transferases like GST)
dihydrocaffeic acid
anti-inflammatory with vascular benefits
promotes NO production
Kahweol and cafestol
diterpenes
increase phase II enzymes
induce anti stress genes
elevate cholesterol
most common anti-oxidant sources
coffee and tea
synthetic xanthines
aminophylline
IBMX
pentoxifylline
propentofylline
medical indications for caffeine
respiratory stimulation in premature infants
2nd most commonly rxed NICU drug
asthma → bronchodilator
migraines → reduces cranial blood flow
respiratory stimulation
PDE4 inhibition increases [cAMP] in rhythmogenic preBotC complex
most commonly consumed psychoactive substance
caffeine
absorption
ingestion
small intestine
45 min to peak
distribution
amphipathic (small molecule)
rapid
widely distributed
metabolism
no first pass
CYP1A2 → demethylation
caffeine → theophylline, theobromine, paraxanthine
paraxanthine
84%
increases blood glycerol/fatty acids via lipolysis
theobromine
12%
dilates vessels
increases urine volume
theophylline
4%
inhibits PDE → increases [cAMP]
relaxes smooth muscle
excretion
kidney
cellular drug actions
non-selective adenosine receptor antagonists
non-selective phophodiesterase (PDE) antagonists
[receptors are expressed broadly in the body]
targets Ca2+ release, GABA receptors
adenosine receptors
A1, A2a, A2b, A3
presynaptic receptors - limit NT release
receptors form extensive pairs
A1-D1, 2 A2a + 2 D2, A1 + A2
AR signaling
antagonist of all 3 types
effects primarily by A1 and A2a
A1
pre- and post-synaptic
Gi = inhibits AC, reduced cAMP
inhibition of NT release
caffeine increases NT release
expressed in reward circuit, hippocampus
A2
pre- and post-synaptic
Gs = activates AC, increased cAMP
activation of NT release
caffeine decreases NT release
expressed in DA-rich regions + olfactory bulb; GABA-ergic neurons
acute effects of caffeine
general stimulant effects
similar to cocaine, AMPH - milder
physiological mechanisms
increase NE, glu, DA release
constriction of cranial vessels - treat headaches
diuretic → increases kidney blood flow, promotes micturition, prevents reabsorption of water/salt by kidneys
heart effects
high cAMP levels → relaxation of smooth muscle (vasodilation) but central vasoconstriction
biphasic effect on hr
low dose = ↓ hr
high dose = ↑ hr, bp
endurance mechanisms
increases intracellular concentration of calcium by increasing activation of calcium channels
= increase work capacity of muscles
reinforcing mechanisms
dopamine release in NAc (2x baseline)
due to blocking pre-synaptic A1 on DAergic VTA→NAc neurons
presynaptic A1 signal via Gi/o
increases glu release in NAc
wakefulness
metabolism of ATP in neurons → adenosine
levels increase during waking
stimulation of A2a receptors in hypothalamus → triggers GABA release = inhibits arousal systems
caffeine facilitation of wakefulness
disrupts adenosine signaling
prevents adenosine binding to A2a receptors → prevents GABA release = prevents inhibition of arousal systems = wakefulness
parkinson’s disease
strong inverse relationship between caffeine and parkinson’s
CYP1A2 polymorphisms
*1A = fast metabolic rate (need two copies)
*1F = slow metabolic rate (at least one copy)
slow metabolizers show increased dose dependent risk of heart attack
tolerance
develops quickly
to elevated heart rate/bp (CV + resp effects) and sleep
not to mood effects
withdrawal
headache, fatigue, decreased energy, irritability, thirst
dependence
develops quickly
mild
long term risks
osteoporosis
increased risk of panic attacks - stimulant effects
osteoporosis
due to increased calcium elimination and reduced dietary Ca2+ absorption
anti-depressants
adenosine receptor antagonists
due to regulating synaptic NT levels
use during pregnancy
effects on fetus are inconclusive
nootropic
cognitive enhancers
caffeine - memory
positive effect on learning and memory
acute doses increase BDNF and TrkB activation in hippocampus
BDNF - linked to LTP
taurine
in energy drinks
anxiolytic - glycine receptor activation and increased IPSPs
nootropic examples
taurine
herbs
nicotine
AMPH - adderall
ritalin
-afinil family
herbs
ginko biloba
panax ginseng
bacopa monnieri
ritalin
benzylpiperidine
-afinil family
modafinil
adrafinil
armodafinil
