5. Caffeine

Question 1

What is caffeine?

Answer 1

• Naturally occurring compound –> over 60 known plants!
• Most widely used psychoactive drug worldwide
• Member of the methylxanthine family
• adenosine receptor antagonist

Question 2

What are the primary caffeine effects?

Answer 2

• Stimulant effect on central nervous system
  
  • Decreased fatigue (keep awake longer)
  • Increased mental alertness and concentration
  • Improved performance on motor and memory tasks

Question 3

What are the other caffeine effects?

Answer 3

• Stimulates acid release from gastric mucosa
• Constricts cerebral blood vessels
  
  • Headache relief: if headache is due to excess pressure in the brain because of extra fluid in the blood vessels. By constricting blood vessels —> squeezes plasma out of central nervous system —> less fluid in the brain —> relief
• Increased heart rate and blood pressure
  
  • Tremors at higher doses
• Mild diuretic effect
  
  • Rapid tolerance develops to this effect
• Not relevant when consumed as a beverage (refer to slide 6)

Question 4

Refer to slide 8-10 for explanation on our body and energy –> caffeine PD

Answer 4

other side!

Question 5

What sort of interaction with adenosine receptors would lead to the principle physiological effects associated with caffeine?

Answer 5

• activactor/agonist
  
  • we know caffeine is a very strong central nervous simulate. We can recognize it as it is acting on these cells/receptors as an antagonist. By blocking the ability of adenosine to “whisper” cell to slow down —> allows cell to keep going.
• —> caffeine: adenosine receptor antagonist; blocking the ability of adenosine to tell the cell to slow down
  
  • reduced ATP levels (inc adenosine) does not stimulate cell to slow down, so cells continues to deplete energy stores, neurons continue to fire

Question 6

What kind of effects can we expect from a single cup of coffee?

Answer 6

• Drug effects are a function of plasma concentration
  
  • The specific conversion factor will vary depending on many factors…
    
    • Individual variability (genetics)
    • Temporal variability (time of day, regular user, empty stomach, etc.)
• …BUT, as an approximation… refer to slide 13

Question 7

What is the first tangible effect of caffeine? What does increase caffeine consumption lead to?

Answer 7

• Adenosine receptor antagonism is the first tangible effect of caffeine
  
  • Most potent concentration-response relationship
• Increased caffeine consumption –> increased adenosine block…
• …BUT, not without side effects as other systems are affected… refer to slide 14

Question 8

What are the side effects of caffeine? (hint: areas of the body)

Answer 8

• central (brain)
  
  • irritability
  • anxiety
  • restlessness
  • confusion
  • delirium
  • headache
  • insomnia
  • sleep deprivation
• visual
  
  • seeing flases
• ears
  
  • ringing

skin
- inc sensitivity to touch or pain

• muscular
  
  • twitching
  • trembling
  • overextension

heart
- rapid heartbeat
- irregular rhythm

• respiratory
  
  • rapid breathing
• gastric
  
  • abdominal pain
  • nausea

Question 9

Explain the 3 mechanisms of action for the explanation of caffeine side effects.

Answer 9

• Phosphodiesterase inhibition –> prevents termination of sympathetic stimulation
• GABAA antagonism –> impedes CNS inhibition, leading to hyperexcitability
• Ca2+ release –> increased cardiac and smooth muscle contractility

*Individuals will differ in susceptibility to side effects!

Question 10

Where does toxic dose lie/begin?

Answer 10

• Toxic dose is generally cited as being where these effects are introduced
  
  • Lethal dose ~10 grams of caffeine, equivalent to over 100 cups of coffee!

*please refer to slide 19

Question 11

How is caffeine absorbed and distributed?

Answer 11

• Absorption
  
  • Primary route of administration: Oral
  • Peak blood concentration (Cmax) within 15 minutes to 2 hours (Tmax)
• Distribution
  
  • Hydrophobic, distributes throughout body
  • Crosses blood-brain barrier readily (obviously…)

Question 12

How is caffeine metabolized and excreted?

Answer 12

• Half-life of ~3-7 hours
  
  • Longer in neonates, with oral contraception, and in pregnancy
  • Shorter with chronic smoking
• CYP450 enzymes in liver
• Predominately CYP1A2 enzyme
  
  • (subtype within larger Cytochrome P450 family)
• ~5% excreted unchanged (via urine)

Question 13

Why do people react differently to coffee or caffeine-containing products?

Answer 13

• Pharmacodyamics; adenosine receptor variations have been shown to…
  
  • …affect sensitivity to caffeine
  • …correlate with anxiogenic effects of caffeine
• Pharmacokinetics; CYP 450 isozyme 1A2 (CYP 1A2) variations have been shown to…
  
  • …affect caffeine metabolism (“fast” or “slow” metabolizers), influencing likelihood of insomnia
  • …alter the interaction between enzyme effects induced by smoking, and caffeine metabolism
  • …affect the risk of spontaneous abortion in pregnant women, correlated to metabolism rate

Question 14

Is Caffeine Addictive?

Answer 14

• Dependence can certainly occur, but in contrast to “street drugs”…
  
  • …doesn’t threaten physical, social or economic well-being
  • …very few users report losing control of caffeine intake
    
    • i.e. “drug seeking behavior” typically associated with street drugs 
• Not presently classified as an addictive substance
• Withdrawal certainly can occur
  
  • As little as 1-2 cups per day
    
    • Fatigue
    • Irritability
    • Headache
  • Generally alleviated by caffeine intake
  • 2-3 day period in most people

Question 15

Is Caffeine Beneficial or Harmful?

Answer 15

• Studies suggest both positive and negative effects to caffeine (typically coffee) consumption
• When individual studies are accumulated into meta-analysis (i.e. systematic reviews of the literature), aggregate literature generally suggests positive benefits to coffee consumption or, at worst, no effect
  
  • Cardiovascular Disease
  • Stroke
  • Heart Failure
  • Cancer
  • Liver Disease
  • Parkinson’s Disease
  • Alzheimer’s Disease
  • Type 2 Diabetes

Question 16

What is a Meta-analysis? What are it’s advantages and disadvantages?

Answer 16

• Attempt to combine results from several smaller, similar studies to find the “common truth”
  
  • Pooled analysis (or re-analysis) of data
• Advantages:
  
  • Increased sample size and statistical power
  • Increased precision and accuracy with more data
  • Generalization of smaller studies to a larger population
• Disadvantages:
  
  • Several smaller studies ≠ one large study
  • Increased “power” cannot compensate for poor design of individual studies
  • Conclusions are subject to publication bias or “cherry-picking” of studies

*please refer to slide 27

Question 17

What is the relationship between Coffee & Cardiovascular disease?

Answer 17

• Systematic review of 36 studies
  
  • ~48 000 cases of cardiovascular disease in nearly 1.3 million participants
• Negative correlation between coffee consumption and the relative risk of cardiovascular disease (CVD), coronary heart disease (CHD) and stroke
  
  • Dotted lines = 95% confidence intervals
    
    • refer slide 30

Question 18

What is the relationship between Coffee & Cancer disease?

Answer 18

• the more cups of coffee you drink = 3% reduction in risk of cancer
• Systematic review of 40 studies
  
  • ~34 000 cases of cancer in a pool of ~2.2 million participants
• Significant decrease in relative risk in all cancers
  
  • 0.87 (0.82-0.92) for regular drinkers compared to non-drinkers
    
    • Variation based on level of consumption, with a lower RR (Relative Risk) for high consumers
      
      • 1 cup/day –> 3% reduction in relative risk (0.96-0.98)
• Subdivision of data by cancer type showed more variability

*refer to slide 32

Question 19

What is the relationship between Coffee & Parkinson’s disease?

Answer 19

• Systematic review of 13 studies
  
  • ~4000 cases of Parkinson’s disease among just over 900 000 participants
  • Maximum protection (Relative Risk reduction) at 3 cups per day for coffee consumption, and continuing benefits for tea consumption

Question 20

What is the relationship between Coffee & Diabetes?

Answer 20

• the more coffee as well as decaf you drink = lesser chance of diabetes
  
  • so its not caffeine, its coffee
• Systematic review of 28 published studies
  
  • ~45 000 cases of Type 2 Diabetes out of 1.1 million participants
  • Compared to control group of no/rare coffee consumption, relative risk decreased by 8-33% for 1-6 cups/day consumed
  • Benefits also observed for decaffeinated coffee

Question 21

What are 4 caveats on caffeine & health? What is the conclusion on this?

Answer 21

• Most studies are lifestyle/questionnaire-based, or observational in nature; these are subject to:
  
  • Errors in self-reporting (intentionally or not)
  • Self-selection mechanisms
• Genetic variability
  
  • CYP1A2 genotype (fast or slow metabolizer), and other proteins
  • Disease incidences, causes and progressions
• Most studies look into coffee, as opposed to caffeine itself
  
  • Complicating factor, as it may be a different component of the drink conferring benefits
    
    • Or multiple components!
  • Many studies show similar benefits with drinking tea (lower caffeine) or decaf!
• Lack of proper control measures
  
  • 2 cups/day for 16 years? Every day?
  • Choices involved in consumption must also be factored in (milk, sugar?)
• conclusion: more coffee does not mean better health
  
  • Limited data in the form of randomized controlled trials (RCTs), the gold standard in research

*refer to slides 38- 46

Question 22

What are the medical uses of coffee? explain each one

Answer 22

• Headaches
  
  • Often included in over-the-counter analgesics
  • Does it help?
    
    • Systematic review of 19 studies (7238 participants)
      
      • 5-10% more patients report good analgesia benefit with
        medications containing 100 mg of caffeine or more
        
        • Small but significant effect
  • Mechanism?
    
    • Adjuvant (additive) properties not fully understood
      
      • Adenosine receptor block?
        
        • Used by some cells in body to trigger production of
          inflammatory mediators
    • Vasoconstriction?
• Newborn respiratory disorders
  
  • Apnea of prematurity
    
    • Cessation of breathing by premature infant, with hypoxia and/or bradycardia
    • Erenberg et al. 2000. Pharmacotherapy 20(6): 644
      
      • Randomized placebo-controlled trial on question of caffeine in treatment of apnea of prematurity
    • Further studies have demonstrated reductions in more long-term associated complications
      
      • Bronchopulmonary dysplasia, a frequent complication of artificial ventilation (Schmidtetal. 2006.NEJM354)
      • Rate of survival without neurodevelopmental disability (Schmidt et al. 2007. NEJM357)
    • Believed to work through stimulation of respiratory center, decreasing CO2 threshold
      
      • Also through increased skeletal muscle (diaphragm) tone and/or relaxation of bronchial smooth muscle?