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Drugs 05: Caffeine, Nicotine, and Alcohol
Transcript of Drugs 05: Caffeine, Nicotine, and Alcohol
Mechanism of Action:
Tolerance and Dependence:
Caffeine: most commonly consumed psychoactive drug in the world
Consumed by 80% of adults in U.S.
Average caffeine content (mg) for familiar sources:
Cup of coffee (5 oz): 100
Cup of tea (5 oz): 50
Can of soda (12 oz): 40
Chocolate: up to 25 per oz.
Caffeine is rapidly and completely absorbed. Blood levels increase within 30-45 min. and peak around 120 min.
Equal distribution throughout liquid environment of body
Takes place in the liver.
Half-life is 2.5-10 hours depending on individual
... until they try to quit
Enzymes that metabolize caffeine are inhibited by certain SSRIs, making patients taking those antidepressants particularly sensitive to caffeine
Increased heart rate and respiratory rate
More alert and competent
Faster, clearer flow of thought
Adverse effects at higher doses
Risk for caffeinism:
tachycardia, hypertension, cardiac arrhythmias, and GI disturbances
Lots of individual variability in susceptibility to caffeinism
Mechanism of Action
Ok, so caffeine activates adenosine receptors, right?
Caffeine binds to adenosine receptors and blocks adenosine action: it is an adenosine antagonist
Activation of adenosine receptor
Blockade of adenosine action
Pregnant women drinking > 8 cups/day showed increased risk of stillbirth (4/1000 v. 12/1000)
In general, moderate caffeine has a small effect on growth resulting in smaller babies at full term, larger doses slightly increase the risk of miscarriage
Tolerance and Dependence
Chronic use, even at low doses, is associated with habituation and tolerance. Quitting often results in withdrawal symptoms, including: headache, drowsiness, fatigue, negative mood state.
Increasing doses of drug are necessary to achieve similar effect
One of the most widely used psychoactive drugs
No therapeutic applications
1100 deaths/day in USA
4.3 million people die prematurely worldwide
900,000 people in USA begin smoking each year
Cigarettes (~1mg nicotine/cigarette)
Chewable tobacco (highly variable)
Dissolvable tobacco (~1-4mg/packet)
Nicotine is readily absorbed from every possible administration site on the body, including lungs, buccal and nasal mucosa, skin, and GI tract
Absorption into the brain occurs within 20-30 seconds
Only about 20% of inhaled nicotine is absorbed into blood stream. The rest is rapidly metabolized by the liver enzyme CYP-2A6
Individuals with naturally low levels of CYP-2A6, or those taking other medications that lower CYP-2A6 experience higher blood nicotine levels
Tobacco smoking is a complex but highly regulated behavior that has as its goal the maintenance of steady-state brain levels of the highly addictive psychoactive agent nicotine. Smokers "self-regulate" the level of nicotine in their system to produce desired effects (e.g. relaxation, increased concentration) and to avoid unpleasant adverse effects associated with getting too high (e.g. dizziness) or too low concentrations (e.g. desire to smoke or withdrawal). -Sellers (1998) JAMA
Once nicotine is metabolized to cotinine by the liver, it can be efficiently excreted by the kidneys
Early stages: nausea and vomiting due to stimulation of brain stem
Induces release of antidiuretic hormone from hypothalamus, which results in fluid retention
Reduced activity of afferent fibers coming from the muscles, results in relaxation effect
Reduced appetite by altering taste bud sensitivity
Increases in psychomotor activity, cognitive functioning, sensorimotor performance, attention, and memory consolidation
Increased blood flow to CNS structures mediating reward and motivation
Addictive properties of nicotine may be maintained in the insula
Source of several social emotions (e.g. lust and disgust, pride and humiliation, guilt and atonement)
Receiving zone that reads the physiological state of the entire body and then generates subjective feelings that can bring about actions, like eating, that keep the body in a state of internal balance
"Somatic marker hypothesis": rational thinking cannot be separated from feelings and emotions, with the insula playing a central role in the integration
Simple body states or sensations are recast as social emotions (e.g. bad taste or smell is sensed in the frontal insula as disgust)
Also important for processing events that have yet to happen
When an addict is confronted with sights, sounds, smells, situations or other stimuli associated with drug use, the insula is activated before using the drug
Smoking and depression
Hamilton Rating Scale for depression in 10 depressed patients before, during, and after administration of nicotine patches
Likelihood of depression recurrence among depressed patients that either (solid line) continued to smoke, or (dotted line) quit smoking.
The rewarding (i.e. dopamine-mediated) effects of nicotine help to prevent recurrence among previously depressed patients. As individuals become chronic smokers and nicotine addiction is established, the midbrain dopamine release decreases, especially without nicotine.
Increased heart rate
Increased blood pressure
Increased risk of myocardial infarction
Lung tissue damage (smoking)
Oral cancers (chew)
Mechanism of Action
Nicotine activates nicotinic acetylcholine receptors
Substantia nigra: source of dopamine
Locus coeruleus: source of serotonin
Activation of nicotinic receptors in these nuclei can cause the release of dopamine and serotonin. These neurotransmitters likely induce the addictive properties of nicotine.
Tolerance and Dependence
Nicotinic receptors are also located at the junction between peripheral motor neurons and muscle fibers. These sites are responsible for the shakiness associated with elevated doses of nicotine.
No evidence for biological tolerance, even in chronic nicotine users.
However, evidence for addictive properties of nicotine is overwhelming
Freud smoked ~20 cigars per day. Despite oral and bone cancer, likely as a result of the cigars, he was unable to quit smoking
2nd most widely consumed psychoactive substance in the world
51.5% of adults (18 or older) in US are classified as regular consumers (at least 12 drinks/year)
15,990 deaths due to alcohol-induced liver diseases
25,692 deaths due to alcohol (excluding fatal accidents and homicides)
10 (women) to 20 (men) percent of adults drink at least 3-4 times per week
Beer industry is a $223 billion per year industry
63% of 12-20 year-olds get their alcohol from adults such as parents, guardians, other family members or unrelated adults
Absorption: alcohol is most commonly administered via beverages that are consumed. Alcohol content in beverages can vary drastically.
Distribution: Alcohol is water and fat soluble, which means it can cross any biological membrane. Time from consumption to maximal absorption is 30-90 minutes.
Metabolism and Excretion:
Approximately 95% of ingested alcohol is metabolized by the enzyme alcohol dehydrogenase in the liver. Two other steps complete the metabolism of alcohol before it is excreted via the kidneys.
The remaining 5% is exhaled in its un-metabolized form.
Affects on Glutamate Receptors:
Disruption of glutamatergic transmission by depressing responsiveness of NMDA receptors to glutamate.
Affects on GABA Receptors:
Activation of the GABA-mediated increase in chloride ion flow into the cell, resulting in neuronal inhibition.
Cognitive and motor inhibition
Overall impaired neural functioning, general sedative effect throughout central nervous system.
In cerebellum this means impaired balance
In basal ganglia this means reduced motor coordination
In sensory cortex (e.g. visual, auditory, somatosensory) this means increased reaction time
Alcoholism associated with several diseases of the heart muscle
Alcohol dilates blood vessels in the skin, producing a warm flush and decreasing body temperature.
The liver metabolizes alcohol, but chronic alcohol consumption can result in cirrhosis
Kidney function can by impaired by chronic alcoholism, resulting in inability to maintain optimal electrolyte concentrations.
When heavy drinkers suddenly stop or significantly reduce their alcohol consumption, the neurotransmitters previously effected by alcohol are no longer enhanced (GABA) or inhibited (glutamate)
Elevated glutamate and decreased GABA result in a phenomenon known as brain hyperexcitability
The effects associated with alcohol withdrawal -- anxiety, irritability, agitation, tremors, seizures, and delirium tremens -- are the opposite of those associated with alcohol consumption
Alcohol enhances the effect of GABA, the neurotransmitter which produces feelings of relaxation and calm
Chronic alcohol consumption
activity so over time,
less GABA is produced
by the neurons
Chronic alcohol consumption
To maintain equilibrium, the glutamate system responds by producing
Metabolic Tolerance: liver increases metabolic enzymes
Tissue Tolerance: neurons in the brain adapt to the amount of alcohol present (previous example)