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.

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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.