Caffeine Caffeine Brian J. Piper, Ph.D.
Nov 11, 2014
CaffeineCaffeineBrian J. Piper, Ph.D.
Goals
• Structure of different xanthines• Pharmacokinetics• Psychological and Physiological
Effects• Pharmacodynamics
http://en.wikipedia.org/wiki/Caffeine
Botany
• Coffea aribica: grown in Brazil, 10 m tall, 7 years to mature
• Coffea robusta (Coffea canephora): grown in Vietnam,
< 1 year to mature, 2 x caffeine
● Camellia sinensis: grown in China, 2 m tall, leaves = 4% caffeine
● Theobroma cacoa: grown in Mexico, 6 m tall, contains theobromine, dogs
Coffea aribica
http://www.ico.org/botanical.asp
Coffea robusta
Camellia sinensis
http://en.wikipedia.org/wiki/Camellia_sinensis
Theobroma cacao
Structure
• Xanthine: group of mild stimulants, Xanthine forms backbone
• Methly Group: a Carbon & 3 Hydrogens (CH3)
• Theobromine: Xanthine + two methyl groups (3,7)
• Theophylline: Xanthine + two methyl groups (1,3)
• Caffeine: Xanthine + three methyl groups (1,3,7)
Structure
• Caffeine: Xanthine + three methyl groups (1,3,7)
• CYP1A2: removes methyl groups
Energy Drinks Serving Size
(oz.)
Caffeine (mg)
Spike Shooter 8.4 300
Cocaine 8.4 280
Monster Energy 16 160
Full Throttle 16 144
Rip It, all varieties 8 100
Enviga 12 100
Tab Energy 10.5 95
SoBe 8 83
Red Bull Sugarfree 8.3 80
Rockstar Energy Drink 8 80
SoBe Adrenaline Rush 8.3 79
Amp 8.4 74
Glaceau Vitamin Water Energy Citrus 20 50
SoBe Essential Energy, Berry or Orange 8 48
http://www.cspinet.org/new/cafchart.htm Accessed 3/15/08
http://anrcatalog.ucdavis.edu/pdf/8265.pdf
Seizures?• Rats that were genetically prone
to convulsions received different doses (umol/kg) of methylxanthines.
• Behavior was rated for 6 hours: – 0 = no response– 2 = tremor– 4 = forelimb clonus– 6 = falling down– 8 = tonic-clonic seizures/death
De Sarro et al. (1997) Naunyn-Schmiedeberg’s Arch Pharmacol, 356, 48-55.
*Clonus (Gr: violent, confused motion), large involontary movements
Seizures?• Rats that were genetically prone
to convulsions received different doses (umol/kg) of methylxanthines.
De Sarro et al. (1997) Naunyn-Schmiedeberg’s Arch Pharmacol, 356, 48-55.
*Clonus (Gr: violent, confused motion), large involontary movements
Sex Differences in Caffeine PK
• Women and men received 100 mg caffeine capsules.
• Women (open circles) had higher caffeine levels than men (open-squares).
• Sex differences were apparent in both plasma and saliva.
• Smoking: increases CYP1A2• Oral Contraceptives: inhibit CYP1A2
Carrillo et al. (2000).Ther Drug Monitor, 22, 409-417.
<-women, non-smoking
<-men, non-smokingmen, smoking ->
Smoking Difference in Caffeine PK
• Smoking: increases CYP1A2
• Oral Contraceptives: inhibit CYP1A2
Carrillo et al. (2000).Ther Drug Monitor, 22, 409-417.
<-women, non-smoking
<-men, non-smokingmen, smoking ->
Caffeine-Melatonin CYP1A2 Interaction
Plasma melatonin levels in humans after melatonin administer either alone (circles)or preceeded by 3 x 200 mg or caffeine (squares).
Hartter (2003). Brit J Clin Pharmacology, 56, 679-682.
Caffeine increased: Cmax 2.4 AUC 2.2
Effects
• Psychological– Increased alertness– Improved attention– Euphoria (slight)– Nervousness (High
Doses)
• Physiological– Constricts blood
vessels in brain and eyes.
– Increases heart rate– Elevates urine
production– Increases breathing
rate
Cognitive Benefits
• Medical students (N=18) completed tests of vigilance or sleepiness at baseline, after placebo,150 mg caffeine, or caffeine + 2 g taurine.
• Both caffeine & caffeine + taurine improved performance
Aggarwal et al. (2011). Brit J Surgery, 98, 1666-1672.
Caffeine & Reinforcement
Patkina & Zvartau Eur J Neuropsychopharm, 8, 287-291.
----------------------------------
Preference
Aversion
Pharmacodynamics
• Adenosine antagonist
• Increases dopamine & glutamate
• Elevates adrenaline (epinephrine)
• Blocks antidiuretic hormone
For more details about neurobiological effects of caffeine, goto:http://images.google.com/imgres?imgurl=http://www.benbest.com/health/A_Recept.gif&imgrefurl=http://www.benbest.com/health/caffeine.html&h=288&w=429&sz=29&tbnid=yC5aX2S9XqKrbM:&tbnh=82&tbnw=123&hl=en&start=12&prev=/images%3Fq%3Dadenosine%26svnum%3D10%26hl%3Den%26lr%3D%26rls%3DCNDB,CNDB:2004-15,CNDB:en%26sa%3DN
Adenosine
• has 24 hour rhythm
Solinas, M. (2002). et al. J. Neurosci 22, 6321-6324
Neurochemistry
• Caffeine causes biphasic effects on nucleus accumbens neurotransmitters and behavior.
Caffeine Tolerance
• Caffeine abstaining humans (N=18) lived in a lab for two-weeks
– Day 1-3: all placebo
– Day 4-10: 250 mg caffeine or placebo
– Day 11-14: placebo
Robertson et al. (1981) J Clin Invest , 67, 1111-1117.
Tolerance to other Physiological Effects
Robertson et al. (1981) J Clin Invest , 67, 1111-1117.
<- Day 1
<- Day 7
Caffeine Tolerance
• Rats received caffeine (1.0, 0.25, or 0 mg/ml drinking water) for two-weeks.
• They were then dosed with caffeine, adenosine antagonists (CPT or MSX) or amphetamine.
• Motor activity was recorded.• How do you interpret this
data?
Karcz-Kubicha et al (2003) Neuropsychopharmacology, 28, 1281-1291.
Caffeine in Water for 2 weeks
Dose
Interpretation
• What information is provided by: – A versus B– B versus C– D versus E versus F– G versus H
A
B
C
D EFG
H
Interpretation
• In rats that were caffeine naïve, caffeine caused hyperactivity (A vs. B).
• Rats that regularly consumed caffeine were insensitive/tolerant to caffeine (B vs. C).
● There was no cross- tolerance to the hyperactivity caused by
amphetamine(D vs. E vs. F).● Adenosine is important for caffeine tolerance. Caffeine pre- exposed rats also showed a blunted hyperactivity to the A1 and A2A antagonists (G vs H). A
B
C
D EFG
H
Caffeine & Parkinson’s Disease (PD)?
• Dietary habits were obtained from middle aged men (N=8,000) in 1965.
• Subjects were monitored for 30 years for incidence of PD.
• Mechanisms– Antioxidant– 3rd variable
Ross, G. W. et al. (2000). JAMA, 283, 2674-2679.
Parkinson’s Symptoms (2 min):http://www.youtube.com/watch?v=_L_WF6gv5BI
Tri-methyl-xanthine Summary
• Pharmacokinetics (CYP1A2)
• Pharmacodynamics– Adenosine antagonist
• Risks (seizures?)• Benefits (Parkinson’s Disease?)
Self-test
• Jane drinks two large (12 oz) cups of instant coffee with breakfast, a Starbucks cafe latte in the afternoon, a Coke (12 oz) with dinner, and a decaf coffee (8 oz) while studying before bed.
• What was her total (mg) of caffeine consumption for the day? Please show how you reached this total using the chapter in Buzzed.