Transcript Unit 3: Drug Therapy and Neurologic Drugs

Unit 3: Drug Therapy and
Neurologic Drugs
11 days
February 19th and 24th: Drugs that
Depress Brain Function
Sedative-hypnotics
• CNS depressants affect neurons and alter the
brain’s functioning
• The observed behaviors are dose related
• Resulting in the relief of anxiety, release from
inhibitions, sedation, sleep, unconsciousness,
general anesthesia, coma, and eventually
death from respiratory and cardiac depression
Sedative-hypnotics
• Most of these drugs have a high potential for
toxicity, dependency, and/or abuse
• The terms sedative, tranquilizer, anxiolytic,
and hypnotic can be applied to any CNS
depressant
Sedative-hypnotics
• CNS depressants have a uniformity of action,
and therefore any CNS depressant will
potentiate the effects of any other CNS
depressant
• Sometimes the depressant effect can be
supra-additive
• Depressant drugs should never be used in
combination for this reason
Sedative-hypnotics
• All sedative-hypnotic drugs carry the potential
for physiological dependence, psychological
dependence, and tolerance
– Physiological dependence is characterized by
withdrawal signs and symptoms when the drug is
withheld
– Psychological dependence is due to positive
reinforcement effects of taking the drug
– Tolerance occurs as a result of increased
metabolism by the liver and adaptation of
neurons in the brain
Sedative-hypnotics
• A large amount of cross-tolerance can occur
which is where tolerance to one drug results
in lessened response to another similar drug
• Cross-dependence may also be exhibited, in
which one drug can prevent the withdrawal
symptoms of another drug
• This is used to help moderate alcohol
withdrawal symptoms with benzodiazepines
Ethyl Alcohol
• In the English language the term alcohol is
used to refer to ethyl alcohol or ethanol
• Ethyl alcohol is unique of all the sedativehypnotic drugs because it is used primarily for
recreational purposes, and has virtually no
medicinal uses in modern medicine
• It is the 2nd most widely used drug (after
caffeine) and has created a multitude of
individual and societal problems
Pharmacokinetics of Alcohol
Absorption:
•Rarely drunk in its pure form
•~12% in wines, ~3-5 in beers, and ~40-50 in
hard liquors
•Expressed in ‘proof’ which is twice the alcohol
percent by volume (i.e. 40 proof = 20% abv)
Pharmacokinetics of Alcohol
• Alcohol is soluble in both water and fat, and
diffuses easily within the body
• It crosses all biological membranes
• After it is drunk, it completely and rapidly
absorbed through the gastrointestinal tract
• The maximum blood concentration occurs
between 30 and 90 minutes after alcohol is
drunk
Pharmacokinetics of Alcohol
• Alcohol can be directly absorbed from the
stomach
• Food quantity in the stomach may slow the
absorption of alcohol into the blood stream
Pharmacokinetics of Alcohol
Distribution:
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Alcohol is distributed to all body tissues evenly
It easily crosses the blood-brain barrier
It easily crosses the placental barrier
A fetus’s blood alcohol level is virtually the
same as the mother’s
• This can lead to Fetal Alcohol Syndrome
Pharmacokinetics of Alcohol
Metabolism and Excretion:
• ~95% of the alcohol a person drinks is
metabolized by alcohol dehydrogenase
• The other ~5% is excreted unchanged,
primarily through the lungs
• Alcohol quantity in exhaled air compared to
blood has a ratio of 1:2300
Pharmacokinetics of Alcohol
• ~85% of alcohol metabolism occurs in the liver
• The other ~15% is processed by gastric alcohol
dehydrogenase (this is an example of first pass
metabolism)
• Drinking on an empty stomach increases
gastric emptying time, which reduces the
amount of time the alcohol is susceptible to
first pass metabolism, which ultimately
increases the blood alcohol level
Pharmacokinetics of Alcohol
• Women are also more susceptible to alcohol
for 3 main reasons:
– They have ~50% less gastric metabolism due to a
lower level of enzymes – which results in ~7%
higher BAC (blood alcohol concentration)
– They have a higher body fat ratio, which has little
vascularization, so men have more blood, and
therefore the alcohol is diluted more
– They concentrate the alcohol into their plasma, as
opposed to their body tissues (fatty)
Pharmacokinetics of Alcohol
• The breakdown of alcohol is a 3 step process:
1.
3.
2.
Pharmacokinetics of Alcohol
– 1. alcohol dehydrogenase functions to convert
alcohol to acetaldehyde. NAD is required as a
coenzyme. The availability of NAD is the ratelimiting step, and because of this the maximum
amount of alcohol that can be metabolized in
24hrs is 170 grams.
– 2. the enzyme aldehyde dehydrogenase converts
acetaldehyde to acetic acid.
– 3. Acetic acid is broken down into CO2 and H2O
which releases energy (calories).
Pharmacokinetics of Alcohol
• An average person can metabolize between 6
and 8 grams of pure alcohol per hour
• This rate does not change depending on the
BAC or the genetic variation of the individual
– This is called a zero-order metabolism because it is
concentration independent
– Virtually all other drugs are 1st order, and their
rate changes based on the amount of drug
present
Pharmacokinetics of Alcohol
• An average person will process the following
in 1 hour:
– 1 ounce glass of 80-proof liquor
– 4 ounce glass of wine
– 12 ounce bottle of 3.5% beer
– 6 ounce glass of 7% microbrew beer
• These quantities can be used by most people
to predict level of drunkenness as well as time
after drinking until the alcohol has cleared the
body
Pharmacokinetics of Alcohol
• Most states define a BAC of 0.08 grams
percent (g%) as intoxication
• Driving above this level is prohibited
• This does not mean that a person with 0.07g%
is a safe driver, since the effects of alcohol are
not all-or-none
• Like all sedatives the symptoms progressively
impair a person’s ability to function
Pharmacokinetics of Alcohol
• A BAC of 0.15g%
makes a person
25 times more
likely to be
involved in a
serious
automobile
accident
Pharmacodynamics of Alcohol
• The exact mechanism was not fully
understood for a long time
• It was thought to be a general depressant on
nerve membranes and synapses
• This would result in a nonspecific and indirect
depression of neuronal function
Pharmacodynamics of Alcohol
• This explains the high-dose or anesthetic
properties of alcohol, but new research
indicates that there are other mechanism at
work as well
• Alcohol may disturb the synaptic activity of
various neurotransmitters (especially
glutamate and GABA)
• May suppress calcium ion currents, and alter
ATP-activated ion channels
Glutamate Receptors:
• Ethanol is a potent inhibitor of NMDA type
glutamate receptors
• Reduces the glutamate release, and results in
compensatory up-regulation of NMDA
receptors
• Therefore, upon withdrawal, these excess
excitatory receptors may result in symptoms
such as seizures
GABA Receptors:
• Ethanol activates the GABA-mediated increase
in chloride ion flow, resulting in neuronal
inhibition
• Results are sedation, muscle relaxation, and
inhibition of cognitive and motor skill
• Helps alleviate panic and the anxiety
associated with panic , and abuse is commonly
seen in people with panic disorders
GABA Receptors:
• Chronic alcohol abuse can affect gene
expression
• This causes several other neurotransmitter
systems to be affected
• Dependent people and their offspring may
demonstrate a deficit in brain opioid activity
• Ethanol may induce opioid release and trigger
brain dopamine reward systems
Pharmacological Effects
• The graded, reversible depression of CNS
function is the main pharmacological effect of
alcohol
• Respiration is depressed and this depression is
typically the cause of death at very high doses
• Seizure activity peaks approximately 8 to 12
hours after the last drink
Pharmacological Effects
• The effects of alcohol are additive with other
sedative-hypnotic compounds
• Alcohol dilates the blood vessels in the skin,
causing a warm flush and decrease in body
temperature
• Long-term use is also associated with disease
of the heart tissue which can result in heart
failure
Pharmacological Effects
• Small quantities of alcohol consumed daily
may reduce the risk of coronary artery disease
• This effect is lost on people who also smoke
cigarettes
Pharmacological Effects
•1 to 2 drinks per day
have also been
shown to reduce the
risks of ischemic
strokes, but greater
than 5 drinks per day
increased this stroke
risk
Pharmacological Effects
• Alcohol exerts a diuretic effect on the body by
increasing the excretion of fluids as a result of
its effects on renal function
• It does not appear to harm the structure or
function of the kidneys
Pharmacological Effects
• Alcohol is NOT an aphrodisiac
• It causes behavioral inhibition, which may
increase sexual activity, but actually impairs
motor function and sexual performance
• “It provokes the desire, but it takes away the
performance.” MacBeth Shakespeare
Psychological Effects
• In low doses the effect of alcohol on the CNS
leads to a mixture of stimulant and depressant
behaviors
• This is determined largely by the individual,
his or her mental expectations, and the
environment
• At high doses the effect becomes increasingly
standardized and sedative
Psychological Effects
• Alcohol intoxication with its resulting
disinhibition plays a major role in a large
percentage of violent crimes
• More than 50% of crimes and highway
accidents are alcohol related
• More than 10 million people in the U.S. suffer
from alcohol abuse
• Also, more than 10 million people in the U.S.
are alcohol dependent
Psychological Effects
• Alcohol has lots of calories but few nutrients
• Alcoholism leads to vitamin deficiencies and
nutritional diseases
• It also leads to a wide variety of issues with a
wide variety of organ systems
• About 10% of the U.S. population is affected
by alcoholism in one way or another
Tolerance
• Tolerance to alcohol develops in a similar
manner to other CNS depressants
• Moderate of infrequent use does not lead to
tolerance
• Heavy and frequent use leads to marked
tolerance in individuals
Tolerance
• 3 Types:
– Metabolic tolerance, the liver increases its amount
of drug metabolizing enzymes (~25% of tolerance)
– Tissue or functional tolerance, neurons in the
brain adapt to the amount of alcohol present (can
have a BAC 2x higher than what would be
behaviorally predicted)
– Associative, contingent, or homeostatic tolerance,
which are environmental manipulations that
counter the effects of alcohol
Dependence
• When physical dependence develops,
withdrawal of alcohol results within several
hours
• Alcohol abuse is one of the most common
causes of adult onset seizures
• ~10% of adults in alcohol withdrawal exhibit
seizures, these seizures usually last for a
period less than or equal to 6 hours
• Alcohol withdrawal is the only drug
withdrawal that can be fatal
Side Effects and Toxicity
• Many side effects occur with alcoholism:
– Disorientation
– Impaired insight
– Impaired judgment
– Antegrade amnesia (black outs)
– Diminished intellectual capabilities
– Delusions
– Hallucinations
– Confabulations
Side Effects and Toxicity
• Liver damage:
– Most serious long term physiological consequence
– Irreversible
– Changes in both structure and function
• ~75% of alcoholic deaths are due to cirrhosis
• Cirrhosis is the 7th most common cause of
death in the U.S.
Side Effects and Toxicity
• May cause destruction of nerve cells:
– Permanent brain syndrome
– Dementia
– Korsakoff’s Syndrome
• Digestive system:
– Pancreatitis
– Chronic gastritis
– Peptic ulcers
Side Effects and Toxicity
• Alcoholism is a major risk factor for cancer:
– Ethanol is not itself carcinogenic
– May be a co-carcinogen or tumor promoter
– Metabolism of ethanol leads to acetaldehyde and
free radical production
• Shown to promote tumor growth
• Stomach, intestines, and oral pharynx
• Has an immunosuppressive effect
• Augments the effects of other cancer causing
agents (like cigarettes)
Teratogenic Effects
• Birth defects
• Both a physical and behavioral teratogen
• Alterations occur in brain structure and/or
function
• Fetal Alcohol Syndrome (FAS) affects as many
as 30 to 50% of babies born to alcoholic
women
• About 5 in every 1,000 births (and increasing)
Teratogenic Effects
• Exact amount of alcohol required to cause FAS
is unknown
• Generally believed that more than 3 ounces of
absolute alcohol per day
• Especially high rates associated with binge
drinking
• No ‘safe’ level of alcohol consumption during
pregnancy has been established
Teratogenic Effects
• FAS:
– CNS dysfunction
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Low intelligence
Microcephaly (reduced cranial circumference)
Mental retardation
Behavioral abnormalities
– Hyperactivity
– Difficulty with social integration
– Retarded body growth rate
Teratogenic Effects
• FAS:
– Facial abnormalities
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Short palpebral fissures
Short nose
Wide-set eyes
Small cheekbones
– Other anatomical abnormalities
• Congenital heart defects
• Malformed eyes
• Malformed ears
Teratogenic Effects
• ~2.6 million babies are born annually with
significant intrauterine alcohol exposure
• Birth defects range from FAS to more mild
symptoms (ARND)
• About 9 out of 1,000 births have alcoholrelated neurodevelopmental disorder (ARND)
• 3rd leading cause of birth defects with mental
retardation – the only one that is preventable
Teratogenic Effects
• Structural and growth effects are well
documented and described, but the behavioral
and cognitive effects are often underappreciated
• Affected aspects include:
– Intelligence (IQ), activity, attention, learning,
memory, language, and motor activities
• Also sensory problems involving:
– Ocular, auditory, and speech and language
development
Teratogenic Effects
• The mechanism responsible for FAS and ARND
are unclear
• One hypothesis involves the interaction of
vitamin A and ethanol
• Another involves the production of reactive
oxygen species (free radicals) that cause lipid
peroxidation
• All women who are, could be, or are trying to
become pregnant should ABSTAIN from alcohol
Pharmacological Treatment
• The recognition of alcoholism as a disease is
relatively recent
• In 1935 Alcoholics Anonymous was founded
and treats patients based of a moral model of
alcoholism
• Offers spiritual and behavioral framework for
understanding, accepting, and recovering
from the compulsion to use alcohol
Pharmacological Treatment
• In the late 1950’s the AMA recognized
alcoholism as a medical illness
• In the mid-1970’s alcoholism was redefined as
a ‘chronic, progressive, and potentially fatal
disease’
Pharmacological Treatment
• Inherent genetic factors may make certain
individuals more susceptible to alcoholic
behaviors
• Many scientists and doctors feel that most
alcoholics do not have ‘primary alcoholism’
but rather begin drinking due to some other
psychopathology
– Addiction to other drugs
– Depression
– Anxiety disorders
– Etc.
Pharmacological Treatment
• Often ‘dual diagnosis’ or ‘comorbid illness’
must be assumed until proven otherwise
• This means that the patient has multiple
issues
• Of the 160 million Americans who are old
enough to drink legally 112 million do so
• As many as 14 million Americans may have
serious alcohol problems
Pharmacological Treatment
• 30 to 50% of alcoholics meet criteria for major
depression
• 33% have a coexisting anxiety disorder
• Many have antisocial personalities
• Some are schizophrenic
• 36% are addicted to other drugs
Pharmacological Treatment
• In a study conducted analyzing the long term
effect of alcohol abuse the researcher looked
at 2 groups of men who abused alcohol at a
young age.
• By 60 years of age 23% had died, 20.5% were
abstinent, 11.5% were controlled drinkers,
45% were still abusing alcohol
Pharmacotherapies for Alcohol
Withdrawal
• Benzodiazepines are the drugs of choice for
the treatment of acute alcohol withdrawal
• They lessen symptoms and reduce seizures
• This effectively replaces a short acting drug
(alcohol) with a long acting one
(benzodiazepine)
• This is still an addictive drug, but can be
weaned gradually
Pharmacotherapies for Alcohol
Withdrawal
• Antipsychotic drugs can alleviate delirium and
hallucinosis
• However, they lower the seizure threshold and
can increase the likelihood of withdrawal
seizures
February 25th: Inhalants of Abuse
Inhalants of Abuse
• Inhalant abuse is the intentional inhalation of
a volatile substance for the purpose of
achieving a euphoric state
• Beginning with children as young as 6 it is an
often under recognized form of substance
abuse with a significant morbidity and
mortality
Inhalants of Abuse
• Chemicals that are volatile at room
temperature, readily vaporize into gasses from
liquids, can be inhaled when exposed to air
• Effects include:
– Euphoria
– Delirium
– Intoxication
– Alterations in mental status
Examples of Inhaled Substances
• Anesthetics – nitrous oxide and halothane
• Industrial or household solvents – paint
thinner, degreasers, and solvents in glue
• Art and office supply solvents – typewriter
correction fluid and marker pen solvents
• Household aerosol propellants – paint,
hairspray, and fabric protector spray
Why Inhalants are Abused
• Researchers studied rats and found behaviorreinforcing properties of glue vapor
• At low to moderate concentrations the motor
activity of the rats increased
• Increasing vapor concentration suppressed
the activation of the brain reward systems and
brought on behavioral depression
• These effects are similar to ether, nitrous
oxide, chloroform, and other medically used
anesthetics
Who Abuses Inhalants
• The extent of solvent abuse is greater than
most people acknowledge
• Currently inhalant abuse is one of the most
pervasive but least recognized drug problems
• In the U.S. inhalants are the 4th most abused
type of drug after marijuana, alcohol, and
tobacco
• Peak use is documented between the ages of
14 and 15 years old
Who Abuses Inhalants
• About 20% of youths have tried inhalants by
the end of 8th grade
• Death can and often does occur in first time
users
• 70% of all inhalant deaths occur in people
between 13 and 22 years old
• 95% of deaths occur in males
• Gas fuels account for 46% of the fatalities
Acute Intoxication
• Death is relatively rare
• Does occur on occasion from: anoxia, cardiac
arrhythmias, aspiration of vomit, or trauma.
• The volatile hydrocarbons also sensitize the
heart to serious arrhythmias when a person is
startled or becomes too excited
• The sudden adrenaline surge can trigger these
fatal arrhythmias
Chronic Abuse
• Serious complications include: PNS and CNS
dysfunction, liver and/or kidney failure,
dementia, loss of cognitive or higher
functioning, gait disturbances, and loss of
coordination
• Also has been shown to cause teratogenic
effects, and has a named syndrome (Fetal
Solvent Syndrome)
March 2nd: Barbiturates, General
Anesthetics, & Antiepileptic Drugs
Historical Background
• Alcohol is the oldest sedative-hypnotic agent,
and has long been used to combat insomnia
and anxiety
• The opium alkaloids have also been used
historically to induce a somnolent effect
• The addictive potential of the opioids
combined with their lethal potential have
limited their use to smaller populations
Historical Background
• In the mid 19th century bromide and chloral
hydrate became available as safer and more
reliable alternatives to alcohol and opium
• In 1912 phenobarbital was introduced, and
was the first barbiturates
• Between 1912 and 1950 hundreds of
barbiturates were tested and around 50 were
marketed commercially
Historical Background
• The barbiturates were so successful that very
few other drugs were successfully marketed
• The first new drug to corner the market was
chlordiazepoxide (Librium) which was the first
available benzodiazepine tranquilizer
• Between 1960 and 1990 about 15
benzodiazepines were marketed, each with
different pharmacokinetic properties
Historical Background
• Now we have second generation anxiolytics
that are replacing even the benzodiazepines
• We are continuing to see progress in
producing better drugs with fewer side effects
and lower potential for abuse
Sites and Mechanisms of Action
• These compounds were presumed to cause
nonselective neuronal depression in both the
brain stem and the cerebral cortex
• Brain stem depression continues as dosage
increases, which explains the sedative effects
and potential resulting coma or death
• Today the actual mechanism is controversial –
and few people still feel the mechanism is
nonselective
Sites and Mechanisms of Action
• Barbiturates cause reduction in electrical and
metabolic activity in the brain
• This reduction is thought to be caused by
either reduction of excitatory activity or
augmentation of inhibitory activity
Sites and Mechanisms of Action
• Several studies that have been conducted also
seem to point to the role of GABAA receptors
in the anesthetic properties of these drugs
• This binding opens chloride channels and
causes an influx of chloride ions
Sites and Mechanisms of Action
• Barbiturates are also capable of opening the
chloride channels in the absence of GABA
• This accounts for the increased toxicity of
barbiturates compared to benzodiazepines
• Benzodiazepines only enhance the effect of
GABA, and cannot open chloride channels
independently
Barbiturate Use
• Use has declined in recent years because:
– They are lethal when overdosed
– Their therapeutic-to-toxic range is quite narrow
– They are highly likely to induce tolerance,
dependence, and abuse
– They have many dangerous drug interactions
Barbiturate Use
• Oral barbiturates have low selectivity, and are
dispersed rapidly to most body tissues
• Ultra-short acting barbiturates cross the blood
brain barrier easily, because they are very lipid
soluble
• They can induce sleep within seconds
Barbiturate Use
• Longer acting barbiturates are more water
soluble
• Sleep can be delayed for 20 to 30 minutes
• Often have more of a hangover effect
• Screening for barbiturate can be done with
urinalysis
• Barbiturates stay in the system for 30 hrs to
several weeks, depending on the drug
Barbiturate Use
• Barbiturates are not analgesics
• They do not cause sleep when the person is in
pain
• The reduce REM sleep, and therefore reduce
dreaming
• During withdrawal, dreaming can become
extremely vivid
• This may cause insomnia
Barbiturate Use
• Barbiturates are sedatives and depress
memory
• They are cognitive inhibitors
• Effects may persist for up to several days until
the compound has been eliminated from the
system
Barbiturate Use
• Combinations of barbiturates and alcohol are
VERY dangerous, since they both suppress
respiration
• Barbiturates have very little effect on other
body systems, until lethal doses are reached
• The liver synthesizes enzymes to metabolize
the drug, and therefore tolerance is often
produced
Psychological Effects
• Barbiturate use is similar to alcohol, and mild
use produces a wide range of behavioral
effects
• High doses lead to overall behavioral
depression and sleep
• Just like with alcohol; mental set, location, and
physical condition play a huge role in the
effects that are experienced
Adverse Reactions
• Drowsiness is one of the primary effects, and
is often the reason a person takes barbiturates
• Motor skill, intellectual performance, and
judgment are also impaired
Adverse Reactions
• There is no specific antidote to overdose
• Overdose is treated by supporting the
respiratory and cardiovascular systems until
the drug is metabolized
Adverse Reactions
• Tolerance is also an effect of barbiturate use
• Two main mechanisms:
– Induction of drug metabolizing enzymes by the
liver
– Adaptation of the neurons in the brain to higher
levels of drug
Adverse Reactions
• Physical dependence is often seen, primarily
as sleep difficulties in the absence of the drug
and during withdrawal attempts
• Withdrawal from high doses may also cause
hallucinations, restlessness, disorientation,
and even convulsions
Adverse Reactions
• Psychological dependence (the urge to use the
drug for its pleasurable effect) is also common
• All CNS depressants have this adverse effect,
because they reduce anxiety, cause euphoria,
and induce sedation
Use During Pregnancy
• Barbiturates, like all psychoactive drugs are
freely distributed to the fetus during
pregnancy
• There is limited data about what effects
exactly barbiturate use has on the fetus, but it
is thought that developmental abnormalities
may occur
Use During Pregnancy
• Many studies have failed to confirm the
teratogenic effects, however most doctors
agree that recreational barbiturate use during
pregnancy should be avoided
• However, they are not necessarily
contraindicated for mothers who need these
drugs as seizure control and prevention
Barbiturates, General Anesthetics, &
Antiepileptic Drugs
General Anesthetics
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•
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Potent CNS depressants
Loss of sensation
Unconsciousness
Are typically inhaled or injected
General Anesthetics
• Inhalation is caused by:
– Nitrous oxide (gas)
– Isoflurane (volatile liquid)
– Halothane (volatile liquid)
– Desflurane (volatile liquid)
– Enflurane (volatile liquid)
– Sevoflurane (volatile liquid)
General Anesthetics
• Anesthetic effect is caused by alteration of the
physiochemical processes of nerve
membranes
• As the anesthetics dissolve, the nerve
membrane is distorted, which alters the
function of the ion channels and membrane
proteins
General Anesthetics
• These inhaled anesthetics are commonly
abused
• Many can be found as carrier gases in
available canned products
• When mixed only with room air however,
hypoxia results
• This causes permanent brain damage
General Anesthetics
• Several injectable anesthetics are also available:
– Thiopenthal (Pentothal) – ultra-short acting
– Methohexital (Brevital) – ultra-short acting
– Propofol (Diprovan) – resembles GABA
– Etomidate (Amidate)
– Gamma-hydroxybutyric acid – not used in U.S.
Gamma-hydroxybutyric acid
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•
•
•
GHB
Naturally occurring in mammalian brains
Synthesized from GABA
4 Carbon molecule
Gamma-hydroxybutyric acid
• Used widely and increasingly by substance
abusers and athletes
• Thought to be a body building aid, euphoriant,
and sexual enhancer
• Often called “Nature’s Quaalude”
• Widely implicated as a date rape drug
• No evidence for any of the above claims – it is
a sedative and depressant
Gamma-hydroxybutyric acid
• Increases dopamine levels in the brain
• Has a cocaine-like effect
• Overdoses are characterized by stupor,
delirium, unconsciousness, and coma
• Seizures, respiratory depression, and vomiting
are common as well
• No antidote, supportive treatment offered
Antiepileptic Drugs
• Epilepsy refers to a CNS disorder that results in
recurring seizures that have a rapid onset
• Seizures are manifestations of electrical
disturbances in the brain
• Often associate with localized lesions in the
brain
Antiepileptic Drugs
• Drugs can suppress seizures by:
– Blocking the trans-membrane channels, and
limiting firing of neurons
– Enhancing the synaptic inhibition by reducing the
metabolism of GABA, enhancing the influx of
chloride ions, or facilitating GABA release from
nerve terminals
Antiepileptic Drugs
• Traditional antiepileptic drugs belong to either
the barbiturate or hydantoin classes
• New drugs resemble GABA or act on GABA
receptors to potentiate GABA
neurotransmission
• Development began in 1978 and has
continued
• Most of these antiepileptic drugs can also be
used to treat bipolar disorder
Gabapentin
• Structural analogue of GABA
• Used to treat anxiety and disorder
• Often used in demented elderly patients to
reduce agitation and aggressive behavior
Antiepileptics During pregnancy
• Rates of stillbirth and infant mortality are
higher for women with epilepsy
• Women treated with antiepileptics during
pregnancy have a 7%risk of birth defects (as
opposed to the 2-3% for the general population)
• This is a difficult decision to be made by
women and doctors
March 4th: Benzodiazepines
Benzodiazepines
• First introduced in the 1960’s, the
benzodiazepines quickly became the most
widely used class of drugs
• These drugs have anxiolytic, sedative,
anticonvulsant, amnestic, and relaxant
properties
Benzodiazepines
• Agonists of a GABA chloride receptor
• Facilitate influx of chloride ions
• Causes hyperpolarization of the postsynaptic
neuron, depressing its excitability
• Benzodiazepines have low toxicity and high
effectiveness in relieving anxiety
Benzodiazepines
• For over 40 years these are the drugs of
choice for treating anxiety disorders
• However, their use is typically limited to 3 or 4
weeks
• Because dependency can occur, long term
issues are more typically treated by
antidepressant drugs
Benzodiazepines
• Benzodiazepines are used only with great
caution in elderly patients and children
• Attitudes are varied and highly controversial
over whether these drugs should be used,
how frequently, and in what type of patient
Benzodiazepine Mechanism of Action
• The amygdala is involved in feelings of fear,
stress, anxiety, and panic
• A multitude of studies in mammals have
demonstrated that the amygdala can become
oversensitive to otherwise non-distressing
events, and essentially overreact with its panic
response
Benzodiazepine Mechanism of Action
• Benzodiazepines can
potentially reset the
threshold of the
amygdala to a more
normal level
Pharmacokinetics
• 15 benzodiazepine derivatives are available in
the U.S.
• Others are available in other countries
• Estazolam, has been found in an herbal
product called ‘Sleeping Buddha’
• It is not approved for use in the U.S., but is
being sold as an herbal alternative to
sedatives
Pharmacokinetics
• The different drugs differ in rates of
metabolism, pharmacologically active
intermediates, and plasma half-lives
• 14 are available orally, and 3 are available for
parenteral administration
Pharmacokinetics
• Like other drugs classes
we have studied,
benzodiazepines all
share a common
structural nucleus:
Absorption and Distribution
• Well absorbed orally
• Peak plasma levels are attained within about
an hour
• Some are metabolized in gastric juice and
completely absorbed
Metabolism and Excretion
• Remember that most psychoactive drugs are
metabolized into non-active water-soluble
compounds, and then excreted in urine
• Some benzodiazepines follow this pattern, but
others have active intermediate metabolites
Metabolism and Excretion
• Some intermediate metabolites have very long
half lives (up to 60 hours) and can therefore
build up to high levels in the body when taken
daily
• Elderly patients have reduced ability to
metabolize these drugs
• Some can have measurable amounts in their
system up to a month after a single dose
Metabolism and Excretion
• Elderly patients may also experience dementia
from these drugs, and therefore they should
be used in this population with extreme
caution
• Many patients who have used
benzodiazepines for years as an insomnia
treatment often begin to demonstrate drug
caused dementia as they age
Pharmacological Effects
• Benzodiazepines are GABA agonist, some are
complete and some are partial
• Different effects stem from the portion of the
brain that each compound affects
• It is hoped that modification of the side chains
will result in new drugs with specific effects
(i.e. anxiolysis without sedation)
Uses
• Indicated for patients experiencing debilitating
anxiety
• Also commonly used as hypnotics for the
treatment of insomnia
• Can also be used as muscle relaxants, because
the increased GABA activity inhibits neuronal
function
Uses
• Also benzodiazepines have amnesic effects,
and therefore suppress memory
• This can be good when dealing with surgery
• This can be bad when abused, such as in the
case of the date-rape drug flunitrazepam
(Rohypnol)
Uses
• Can also be used to treat panic attacks and
phobias
• Pros: rapid onset, anxiolysis, low level side
effects, and good patient acceptance
• Cons: impaired psychomotor performance,
impaired alertness, and the potential for
dependence and abuse
Uses
• Can be used for treating alcohol withdrawal
• Also help reduce the relapse of alcohol
abusers
• All benzodiazepines are antiepileptics as well,
but are not commonly used as the primary
treatment for seizure disorders
Side Effects and Toxicity
• Common side effects are extensions of the
intended actions
• Include disorientation, dementia, sedation,
lethargy, amnesia, and many other sedative
effects
Side Effects and Toxicity
• Respiration is rarely affected, even at high
doses
• Suicide attempts are rarely successful when
benzodiazepines are taken alone
Side Effects and Toxicity
• Cognitive and generalized intellectual
impairments are common when using
benzodiazepines
• These impairments tend to go away after drug
is discontinued
Tolerance and Dependence
• Benzodiazepines have a reputation for low
levels of dependence
• When discontinued, rebound increases in
insomnia, restlessness, agitation, irritation,
and unpleasant dreams gradually appear
Tolerance and Dependence
• Rare cases of seizures, hallucinations, and
psychoses have been reported
• Withdrawals symptoms typically subside
within 1 to 4 weeks
Tolerance and Dependence
• Typically benzodiazepines are only abused by
individuals who are also abusing other
substances
Effects in Pregnancy
• Benzodiazepines and their metabolites
accumulate in the fetal circulation, and reach
levels higher than that in the maternal
circulation
Effects in Pregnancy
• Benzodiazepines taken during the first
trimester can potentially cause birth defects
• When taken in the third trimester the baby
can be born with benzodiazepine dependency
(floppy baby syndrome)
Effects in Pregnancy
• Benzodiazepines are also excreted in breast
milk
• Accumulate in nursing baby
• Not recommended for breast feeding mothers
March 9th and March 11th: Drugs that
Stimulate Brain Function and
Psychostimulants
Drugs that Stimulate Brain Function
• Psychostimulants
• Increases the behavioral activity of an animal
• Elevates mood, increases motor activity,
increases alertness, allays sleep, and increases
the brain’s metabolic and neuronal activity
Psychostimulants
• The term psychostimulant includes a wide
array of drugs, that are different in
pharmacology, mechanisms of action,
therapeutic properties, and potential for
abuse and dependency
Cocaine, Amphetamines, and Other
Behavioral Stimulants
• Powerful psychostimulants
• Markedly affect a person’s behavior and
mental functioning
• Augment the actions of several
neurotransmitters:
– Monoamines dopamine
– Norepinephrine
– Serotonin
Cocaine, Amphetamines, and Other
Behavioral Stimulants
• Also directly stimulate the nucleus accumbens
which is associated with behavioral
reinforcement, compulsive behavior, and drug
dependency
Cocaine, Amphetamines, and Other
Behavioral Stimulants
• Widely recognized as drugs of abuse
• Also have therapeutic usefulness in the
treatment of narcolepsy and ADHD
Cocaine, Amphetamines, and Other
Behavioral Stimulants
• In low doses these drugs produce an alerting,
arousing, behavior-activating response similar
to a normal reaction to an emergency or
stress
• Blood pressure and heart rate increase, pupils
dilate, blood flow shifts from skin and organs
to muscles, oxygen levels rise, and blood
glucose levels rise
Cocaine, Amphetamines, and Other
Behavioral Stimulants
• In the CNS these drugs produce positive and
attractive effects such as elevation of mood,
induction of euphoria, increased alertness,
reduced fatigue, a sense of increased energy,
increased appetite, improved task
performance, and a relief from boredom
Cocaine, Amphetamines, and Other
Behavioral Stimulants
• Negative effects include: anxiety, insomnia,
and irritability
• As dose increases, irritability and anxiety
become more intense, and psychotic behavior
may appear
• Intense dependence develops, which has no
widely successful treatment or rehabilitation
Cocaine History
• The leaves of Erythroxylon coca have been
used since ancient times in South America
• Have religious, social, mystical, euphoriant,
and medicinal purposes
• Most notably increases endurance, promotes
a sense of well being, reduce fatigue,
increases stamina, and alleviates hunger
Cocaine History
• Chewing the leaves
typically delivered a
total daily dose of
around 200 mg of
cocaine
Cocaine History
• The active alkaloid was isolated in 1855,
purified in 1860, and named cocaine
• First attempted to be used as an anesthetic for
surgery
• This was the only anesthetic used at the time,
and replaced unanaesthetized surgery and
surgery performed on drunk patients
Cocaine History
• Further research and experimentation was
done, and cocaine became widely used as a
topical anesthetic
• Also used for spinal anesthesia and nerve
blocks from 1884 until around 1918
• It was replaced by Novocaine at that time
Cocaine History
• In 1884 Sigmund Freud obtained cocaine,
studied its psychological effects, and used it
himself
• He also began prescribing it for his patients
• Used to treat depression and chronic fatigue
Cocaine History
• Freud described it as a magical drug, and used
it to ‘cure’ opioid addiction
• He did not realize until later the negative
effect of cocaine use, which are tolerance,
dependency, psychosis, and withdrawal
depression
• He later called it the “third scourge” of
humanity (after alcohol and heroin)
Cocaine History
• In the U.S. in the 1880’s there was no
regulation on cocaine, and it was incorporated
into many products
• These included Coca-Cola, which had around
60 mg of cocaine per 8 fl.oz. serving
• In 1914 the Harrison Narcotic Act banned the
incorporation of cocaine into patent
medicines and beverages
Cocaine History
• With enforcement of the Narcotic Act, cocaine
use decreased throughout the following
decades
• It was replaced by use of amphetamines,
which cost less and produced longer lasting
effects
• Cocaine essentially disappeared until the
1960’s
Cocaine History
• In the late 1960’s federal restrictions on
amphetamines cause cocaine to become
comparably priced and available once again
• Cocaine and amphetamines can be used more
or less interchangeably, so typically price and
availability determine the comparative
popularity of the two
Cocaine History
• In the 1970’s and 1980’s ‘crack’ cocaine
became available, and was/is inexpensive
• This cocaine epidemic continue today
• Cocaine has been used by ~50 million
Americans, and is used regularly by >6 million
Americans
Cocaine History
• Most regular users snort the water soluble salt
of cocaine
• Some smoke ‘crack’ cocaine
• A few inject cocaine hydrochloride
Cocaine History
• Cocaine dependent people are typically:
– Between the ages of 12 and 39
– Dependent on at least 3 drugs
– Male (75%)
– Have coexisting psychopathology
• 30% anxiety disorders
• 67% clinical depression
• 25% paranoia
– 85 – 90 % are alcohol dependent
Cocaine History
• Cocaine use is associated with a range of
violent and premature deaths including:
– Homicides
– Suicides
– Accidents
Forms of Cocaine
• The leaf of E. coca has about 0.5 - 1.0%
cocaine
• When the leaves are soaked and mashed
cocaine is extracted in the form of coca paste,
which is 60 – 80% cocaine
• This paste is usually treated with hydrochloric
acid to form the less potent water soluble salt
cocaine hydrochloride
Forms of Cocaine
• This cocaine hydrochloride is suitable for
injecting or snorting
• It is destroyed by heat though, and cannot be
smoked
Forms of Cocaine
• The cocaine base, which is insoluble in water,
can be smoked
• This is known as free-base or crack
• It is the cheapest, and also most popular form
of cocaine
Forms of Cocaine
• Cocaine hydrochloride (crystal or snow) gives
about a 25 mg dose per line
• Users may take in 50 to 100 mg pf cocaine at a
time
• Crack yields an average dose of 250 mg to 1 g
when smoked
• This is a significantly higher dose, with
significantly more drastic consequences
Pharmacokinetics
Absorption
• Absorbed from all sites of application
• Mucous membranes, stomach, and lungs
Absorption
• Taken intranasally cocaine acts as a
vasoconstrictor, and inhibits its own
absorption
• ~20 – 30% is absorbed into the blood, and
plasma levels peak 30 to 60 minutes after
administration
• Euphoric effect is prolonged because the drug
is absorbed slowly, and may persist in plasma
for up to 6 hours
Absorption
• When cocaine base is smoked absorption is
rapid and almost complete
• Onset of effect is within seconds and peaks at
~5 minutes
• High persists for around 30 minutes
• Only 6 – 32% of initial amount vaporized
reaches the plasma
Absorption
• Intravenous injection bypasses all absorptive
barriers and places 100% into the blood
stream
• Onset is within 30 – 60 seconds depending on
injection site
Absorption
• Cocaine can also be absorbed orally, however
this is not a typical route of administration
Distribution
• Penetrates the brain rapidly
• Brain concentrations typically exceed the
plasma concentrations
• Rapidly redistributed to all other tissues
• Freely crosses the placental barrier, causing
fetal levels equal to that of the mother
Metabolism and Excretion
• Biological half life in plasma of 30 – 90
minutes
• Rapidly and almost completely metabolized by
enzymes in the plasma and liver
• More slowly removed from the brain
• Can be detected for 8 or more hours after
initial use
Metabolism and Excretion
• Urine can test positive for up to 12 hours in
one time users
• The major metabolite being tested for
(benzoylecgonine) can be detected for about
48 hours (or much longer) in chronic users
• The drug tends to accumulate in the body
tissues of long term users
Metabolism and Excretion
• The metabolic interaction between cocaine
and alcohol is complex and interesting
• The liver enzymes that metabolize the two
drugs actually produces a combined
metabolite
• Cocaethylene is as pharmacologically active as
cocaine, and is actually more toxic than
cocaine
Metabolism and Excretion
• Cocaethylene:
– Exacerbates cocaine’s toxicity
– Increases the risk of dual dependency
– Potentiates the euphoric effects
– Increases the severity of withdrawal
– Has a longer half life (150 minutes) than cocaine
Mechanism of Action
• Pharmacologically cocaine has 3 actions:
– Local anesthetic
– Vasoconstrictor
– Psychostimulant with reinforcing qualities
Dopaminergic Actions
• Cocaine has been known to potentiate the
synaptic actions of dopamine, norepinephrine,
and serotonin for over 25 years
• Cocaine blocks active reuptake of these
neurotransmitters into the presynaptic nerve
terminals from which they were released
Dopaminergic Actions
• Currently it is thought that the blocking of
dopamine reuptake is the most important for
causing cocaine’s effects
Serotoninergic Actions
• In 1998 Rocha and co-workers studied cocaine
effects in mice which lacked the dopamine
transporter
• The drug was still a reinforcer, and therefore
must act on other pathways besides the
dopamine ones previously studied
Serotoninergic Actions
• Rocha concluded that the serotonin system
may provide a secondary pathway for
reinforcement
Low-Dose Use
• Relatively mild effects are experienced
• Difficult to maintain, because cocaine
promotes further use of cocaine and tolerance
develops
Affects on Sexual Function
• High doses are sometimes described as
orgasmic, but cocaine is not an aphrodisiac
• Sexual dysfunction is common in heavy users
• Social isolation is also typical of cocaine users
Organ-Specific Complications
• CNS:
–
–
–
–
Ischemic or hemorrhagic strokes
Seizures
Movement disorders
Intracranial hemorrhage
• Cardiac Complications:
–
–
–
–
–
–
Acute myocardial infarction
Cardiac arrhythmias
Sudden cardiac arrest and death
Heart failure
Myocarditis (infections of the heart)
Ruptured aorta
Organ-Specific Complications
*The effects of cocaine on the cardiovascular
system are often the most obvious and life
threatening
– Typically a heart attack or heart failure in a person
under the age of ~35 is considered to be caused
by cocaine until proven otherwise
– These symptoms can appear in young people due
to congenital defects, but cocaine use is by far the
most common cause
Organ-Specific Complications
• Pulmonary Complications:
–
–
–
–
–
Nasal septal perforations
Inhalation injuries
Immunity-related diseases
Pulmonary edema, hemorrhage
Bronchiolitis (inflammation of bronchial tree)
• Gastrointestinal Complications:
– Ulcers
– Bowel ischemia (lack of oxygen)
– Intestinal infarction
• Renal Complications:
– Renal failure
– Renal ischemia
Organ-Specific Complications
• Maternal:
–
–
–
–
Spontaneous abortion
Placental abruption
Placenta previa
Stillbirth
• Fetal:
–
–
–
–
Growth retardation
Premature delivery
Congenital anomalies
Cerebral infarction and/or hemorrhage
• Neonatal:
– Drug withdrawal
– Seizure disorders
– Cardiovascular system complications
High-Dose Use
• Toxic symptoms including: anxiety, sleep
deprivation, hypervigilance, suspiciousness,
and paranoia
• The person can have an altered perception of
reality, and can become aggressive or
homicidal
• This is called Toxic Paranoid Psychosis
High-Dose Use
• Also, interpersonal conflicts are common
• As is depression, dysphoria, and bizarre and
violent psychotic disorders that can last for
days or weeks after the cessation of the drug
• Many users experience vivid visual, auditory,
and tactile hallucinations
Comorbidity
• Chronic cocaine use produces psychiatric
symptoms:
– Mania
– Depression
– Schizophrenia-like syndromes
– Personality disorders
– Etc.
Comorbidity
• Chronic cocaine use also produces
neuropsychological symptoms:
– Depression
– Anxiety
– Bipolar disorder
– Antisocial personality
– PTSD
– ADHD
– Etc.
Cocaine During Pregnancy
• There is no defined ‘cocaine fetal syndrome’
• Rather cocaine produces a wide array of effect
on the fetus and newborn baby
• The vasoconstriction properties often lead to
reduction of blood flow to the placenta, which
can cause growth retardation of any/all organ
systems or the baby as a whole
Cocaine During Pregnancy
• One of the most classic outcomes of cocaine
use during pregnancy is premature labor
• Babies born early have low birth weights and
may or may not have completed development
Cocaine During Pregnancy
• Placental abruption (the placenta prematurely
detaching from the uterine wall during
pregnancy) is typically considered to be a
result of cocaine use until proven otherwise
• It can occur with trauma, or for a few other
reasons, but the most common cause by far is
maternal cocaine use
Cocaine During Pregnancy
• Between 50,000 and 100,000 babies are born
each year to mothers who have used cocaine
during pregnancy
• This is equivalent to about 11% of pregnant
women
• Another study found that between 15 and
25% of babies are born in this country with
cocaine in their system
• Cocaine also passes through breast milk
Cocaine During Pregnancy
• The rates of cocaine use during pregnancy are
much higher among low-income and innercity women
Pharmacological Treatments
• Several different approaches have been tried
for cocaine abuse treatment
• There is no consensus, and no specific
successful treatment plan
• Not only does the drug have intense physical
addictive properties, but also a degree of
mental and social addiction
Pharmacological Treatments
• Furthermore most cocaine abusers also have
other co-dependences or psychological
disorders
• Rarely is cocaine addiction the only problem
needing to be addressed
Pharmacological Treatments
• There are three main areas of need for
pharmacological intervention:
– Antiwithdrawal agents, used to ameliorate
withdrawal depression
– Anticraving agents, to break the reinforcing desire
to use cocaine
– Treatment of comorbid psychological disorders, to
reduce the drive to self-medicate with cocaine
Pharmacological Treatments
• No replacement drug is known that
adequately replaces cocaine during
withdrawal
• Ritalin was attempted, but was not effective
enough to ameliorate symptoms
Psychosocial Interventions
• Since pharmacological interventions tend to
fail, the most effective approach so far in
cocaine abuse treatment are psychosocial in
nature
• These include: step programs, interventions,
group drug therapy, individual drug therapy,
cognitive behavioral therapy, supportiveexpressive psychodynamic therapy, and
behavioral reinforcement methods
March 12th: Amphetamine
Amphetamines
• Structurally defined group of drugs that affect
the CNS and the autonomic nervous system
• Mimic the actions of adrenaline
• Produce vasoconstriction, hypertension,
tachycardia, and other signs of normal alerting
response
• Negative effects include tremor, restlessness,
increased motor activity, agitation, insomnia,
and loss of appetite (anorexia)
History of Amphetamines
• Between 1935 and 1946 a list of conditions
that amphetamines could treat was developed
• This list included schizophrenia, morphine
addiction, tobacco smoking, heart block, head
injury, radiation sickness, hypotension,
seasickness, severe hiccups, and caffeine
dependence
History of Amphetamines
• Used by soldiers during WWII to enhance
performance and fight fatigue
• These uses led to wider use, which eventually
led to large-scale abuse of orally ingested
tablets in the late 1940’s
• Amphetamines continued to be used and
abused as appetite suppressants (even though
this effect only last for the first few weeks)
and alertness increasers
History of Amphetamines
• In the late 1960’s injectable forms of
amphetamines were marketed, and widely
abused
• These injectable forms have been
discontinued by pharmacological companies
and in medicinal use
Amphetamines Today
• Today amphetamines are used for treating
narcolepsy and attention deficit disorders
• They are also abused, especially
methamphetamine
Mechanisms of Action
• Exert effects by releasing newly synthesized
norepinephrine and dopamine from
presynaptic storage sites
• The PNS effects likely result from increased
norepinephrine levels
• The behavioral effects seem to come from the
effects on the mesolimbic system
Mechanisms of Action
• Some adults experience increased aggressive
behavior when using amphetamines
• They show increases in repetitive behaviors
• In children, amphetamines are used to reduce
aggressive behaviors and actions typical of
ADHD
• Behavioral calming can also occur
Pharmacological Effects
• The release of dopamine and norepinephrine
are responsible for the effects seen by
amphetamine use
• This is similar the how cocaine works
• Both drugs have the net result of increasing
the amount of dopamine available, even
though they use different mechanisms
Pharmacological Effects Low Dose
• At low dose all amphetamines increase blood
pressure, slow heart rate, relax bronchial
muscles, and produce other alerting
responses
• Amphetamine is a psychomotor stimulant,
producing alertness, euphoria, excitement,
wakefulness, reduced fatigue, loss of appetite,
mood elevation, increased motor activity,
increase speech activity, and a feeling of
power
Pharmacological Effects Low Dose
• Task performance may improve, but dexterity
may decrease
• Metabolites are excreted in the urine and are
typically detectable for 48 hours
Pharmacological Effects Moderate Dose
• Additional effects at moderate doses of
amphetamines include stimulation of
respiration, slight tremors, restlessness,
insomnia, and agitation
Pharmacological Effects High Dose
• Stereotypical behaviors of chronic high dose
use include:
– Continual, purposeless, repetitive acts
– Sudden outbursts of aggression and violence
– Paranoid delusions
– Severe anorexia
– Psychosis and abnormal mental conditions
– Skin sores
– Overall neglected health
Pharmacological Effects High Dose
• Typically users experience a deterioration of
the social, personal, and occupational affairs
• Also typical is psychotic episodes that usually
require hospitalization
Pharmacological Effects
• Overdoses are unpredictable, and low doses
can have severe effects at times
• On the other hand, first time users can survive
extremely high doses
Pharmacological Effects
• Use during pregnancy has not been well
studied
• There is some consensus that infants born to
users have growth retardation and low birth
weight
• No pattern of congenital anomalies has been
described
• Some long-term behavioral problems have
been seen
Dependence and Tolerance
• Dependence does develop, and the cessation
of the drug leads to withdrawal
• However, the withdrawal symptoms are
relatively mild when compared to other
classes of drugs
• Characterized by sleepiness, increased
appetite, and weight gain
Dependence and Tolerance
• Tolerance also readily develops
• This causes increased use and higher doses
• Often periods of prolonged binging are
observed
• Tolerance and drug-induced highs leads to
further drug intake and social withdrawal
ICE
• A free-base form of methamphetamine
• More potent than dextroamphetamine
• Considered an illicit drug, no longer used for
legitimate medical treatment
• Readily made from easily obtainable
chemicals
• ‘ice’ is the smokable form, but other names
used interchangeably between amphetamines
are ‘speed’, ‘go’, ‘crystal’, and ‘crank’
ICE
• Similar to cocaine, only one form of
methamphetamine (ICE) can be smoked
• ICE is the amphetamine equivalent of crack to
cocaine
• However, methamphetamine has a much
longer half life than cocaine, and therefore
gives a prolonged drug high
Pharmacokinetics
• Methamphetamine is metabolized in the liver,
and the end products are excreted by the
kidneys
• About 40% of the drug is excreted by the
kidneys unchanged
Effects and Toxicity
• Repeated high doses cause violent behavior
and paranoid psychosis
• This causes long-lasting decreases in
dopamine and serotonin in the brain
• These changes appear to be irreversible
• Fatalities have occurred from cardiac toxicity
which manifests itself as pulmonary edema or
heart failure
March 17th: Caffeine
Caffeine
• Most commonly consumed psychoactive drug
in the world
• In the U.S. it is consumed daily by around 80%
of the adult population
• Found in coffee, tea, cola drinks, chocolate,
and cocoa
Caffeine
• The average intake is between 80 and 400 mg
per person per day (about 3 to 5 cups of
coffee)
• Regulatory agencies impose no restrictions of
caffeine
• Caffeine use is not considered drug use by
most people
Caffeine Effects
• Positive effects include alertness, increased
energy, and a sense of well being
• Caffeine is reinforcing
Pharmacokinetics
• Taken orally
• Rapidly and completely absorbed
• Significant blood levels are reached after 30 –
45 minutes
• Complete absorption occurs over 90 minutes
• Plasma levels peak after about 2 hours, and
decrease after
Pharmacokinetics
• Equally distributed throughout the total body
water
• Crosses to the fetus
• Crosses to the brain
• Mostly metabolized by the liver before being
excreted by the kidneys
• About 10% is excreted unchanged
Pharmacokinetics
• The half life is about 3.5 to 5 hours in adults
• This can cause nighttime wakefulness in some
people
• This half life is longer in infants, pregnant
women, and the elderly
Pharmacokinetics
• During the latter part of pregnancy the half
life can be as long as 10 hours
• Caffeine is readily excreted in breast milk
Pharmacokinetics
• In smokers, the half life is shortened, but
when smoking stops the half life increases
• This can compound smoking withdrawal
symptoms
Pharmacokinetics
• People with anxiety disorders or who are
prone to panic attacks often show higher
sensitivity to caffeine symptoms
• Use of this drug can cause increased anxiety
and other negative effects
• Also, toxicity may occur at lower doses than
expected
Pharmacological Effects
• Caffeine is a CNS stimulant with cardiac,
respiratory, and diuretic effects
• Has been used to treat asthma, narcolepsy,
migraines, and other pain syndromes like
headaches
Pharmacological Effects
• Heavy intake of caffeine can have adverse
effects such as agitation, anxiety, tremors,
rapid breathing, and insomnia
• The lethal dose is around 100 grams (100 cups
of coffee)
• Death from caffeine is unusual, and rare
Pharmacological Effects
• Caffeinism is a clinical syndrome produced by
the overuse or overdoses of caffeine
• CNS symptoms include increases in anxiety,
agitation, insomnia, and mood changes
• Peripheral symptoms include tachycardia,
hypertension, cardiac arrhythmias, and
gastrointestinal disturbances
Pharmacological Effects
• Caffeine dilates coronary vessels, providing
more oxygen to the harder working heart
• It constricts blood vessels in the brain,
decreasing blood flow by around 30% and
reducing pressure in the brain
• This is responsibly for the reduction in
headaches and migraines
Pharmacological Effects
• Caffeine dose increase dopamine release in
the prefrontal cortex, which is similar to the
effects of cocaine and amphetamines, but in a
different part of the brain
• This causes caffeine’s reinforcing properties,
but does not act on the dopaminergic
structures related to reward, motivation, and
addiction (like cocaine and amphetamines)
Reproductive Effects
• Caffeine is consumed by 75% of pregnant
women
• The safety of this habit is unresolved
• In 1980 the FDA cautioned pregnant women
about caffeine use
• However, many studies have had difficulty
implicating caffeine as a genotoxin
Reproductive Effects
• Data are conflicting and controversial
• In 1993 the Journal of the American Medical
Association published two studies, which
arrived at contradictory conclusions
Reproductive Effects
• The first article reported that caffeine was
relatively safe in moderate doses (under 300
mg per day)
• In higher doses, fetal growth retardation was
seen
Reproductive Effects
• The second study showed that at low doses
during the first trimester, fetal growth
retardation was seen
• At higher doses, even in the month before
pregnancy, increased risk of spontaneous
abortion (miscarriage) was seen
• This risk was nearly double that of noncaffeine using mothers
Reproductive Effects
• A recent study concluded that the
consumption of large amounts of caffeine (6 –
10 cups of coffee per day) is associated with
and increased risk of miscarriage
• However, moderate consumption does not
increase the risk
• Caffeine itself is not a teratogen, and does not
affect the course of normal labor and delivery
Tolerance and Dependence
• Chronic use is often associated with
habituation and tolerance
• Discontinuation may produce withdrawal
symptoms
• Symptoms of withdrawal include headache,
drowsiness, fatigue, and overall negative
mood
March 19th: Nicotine
Nicotine
• Together with caffeine and ethyl alcohol,
nicotine is one of the three most widely used
drugs in society
• Nicotine has little to no therapeutic effects in
medicine
• Its potency, widespread use, and toxicity make
it of extreme importance in any discussion of
pharmacology
Nicotine
• Nicotine and other ingredients in tobacco are
responsible for a wide variety of health
problems
• This includes the death of more than 1,100
Americans each day
Cigarettes
• From WWII to the 1960’s cigarette smoking
was considered stylish
• Today it is shunned as unhealthy and unwise
• Every day about 6,000 American teenagers try
their first cigarette, and 3,000 children
become regular smokers
• 1,000 of them will eventually die from
smoking related illness
Cigarettes
• 9 in 10 smokers become addicted before the
age of 21
• Over 3 million adolescents are smokers in the
U.S.
• Most advertisements still appeal to children
Cigarettes
• Half of all people who have tried cigarettes
have quit
• In 1965 about 50% of American adults smoked
• In 1998 only 25% of American adults smoke
• About 1 million potential deaths have been
averted or postponed by people who have
successfully quit smoking
Cigarettes
• Nicotine is the primary active ingredient of
tobacco
• About 4,000 compounds are released by
burning a cigarette
• Nicotine is responsible for the
pharmacological effects and dependence of
cigarettes
• The adverse effects are produced by other
compounds
Pharmacokinetics
• Nicotine is readily absorbed from every site on
the body including the lungs, buccal and nasal
mucosa, skin, and gastrointestinal tract
• Nicotine is suspended in cigarette smoke in
tiny tar molecules
• It is absorbed relatively slowly into the blood
stream, but does provide an initial rush to the
brain
Pharmacokinetics
• Only about 20% of the nicotine is absorbed
into the blood
• The remainder is metabolized by liver
enzymes
Pharmacokinetics
• The user has very good control over the
amount of nicotine being taken in
• They can avoid acute toxicity by regulating
breath frequency, breath depth, the time the
smoke is held in the lungs, and the total
number of cigarettes smoked
Pharmacokinetics
• Smokers can self regulate, and often maintain
a steady state of drug in their blood stream to
maintain the desired effects
• Chewing tobacco gives levels of blood nicotine
similar to that of smoking cigarettes
Pharmacokinetics
• Nicotine is readily transported to all body
tissues
• It crosses the placental barrier, and is excreted
in breast milk
• There are no barriers in the body to nicotine
Pharmacokinetics
• Nicotine is broken down by the liver (80–90%)
and excreted by the kidneys
• The primary metabolite is called cotinine
Pharmacokinetics
• Recent studies have noted higher cotinine
levels in black smokers compared to white
smokers
• This means that black smokers are either
eliminating cotinine slower, or taking in more
nicotine per cigarette
• This may explain why black smokers often find
it harder to quit smoking than white smokers
Pharmacokinetics
• The elimination half life of nicotine in chronic
smokers is about 2 hours
• Often smokers will smoke 2 or 3 cigarettes
rapidly upon waking in the morning to resume
therapeutic blood levels
Pharmacological Effects
• Nicotine is the only pharmacologically active
drug in tobacco smoke, except for
carcinogenic tars
• It exerts its effects on the brain, spinal cord,
PNS, heart, and various other body structures
• Early stages of smoking often cause nausea
and vomiting
• Tolerance to this effect develops rapidly
Pharmacological Effects
• Nicotine causes fluid retention
• It also reduces the activity of afferent nerve
fibers, which reduces muscle tone
• Nicotine also reduces weight gain, probably by
reducing appetite
Pharmacological Effects
• Affects the CNS and increases psychomotor
activity, cognitive functioning, sensorimotor,
performance, attention, and memory
consolidation
• At high doses nicotine can induce
nervousness, tremors, and when overdosed,
seizures
• Cigarette smoking is also associated with
increased panic disorders and panic attacks
Pharmacological Effects
• Many adults with depression disorders are
also smokers
• Nicotine patches administered to non-smokers
who were depressed showed improvements in
mood
• This suggests that smoking may be an attempt
at self-medication
Pharmacological Effects
• Nicotine causes dilation of the coronary
vessels to compensate for the increased work
being done by the heart muscle
• In individuals with atherosclerotic coronary
arteries, the vessels cannot dilate, and cardiac
ischemia can result
• This can cause angina of myocardial infarction
Tolerance and Dependence
• Nicotine does not appear to induce any
biological tolerance
• It DOES induce physiological and psychological
dependence in the majority of smokers
• Only a small minority of smokers can quit
without intense withdrawal symptoms
Tolerance and Dependence
• In 1988 the Surgeon General of the U.S. made
the following conclusions:
– Cigarettes and other forms of tobacco are
addicting
– Nicotine is the drug in tobacco that causes the
addiction
– This addiction is similar to the addiction of heroin
and cocaine
– More than 300,000 Americans die each year as a
result of their nicotine addiction (today this is
more like 450,000)
Tolerance and Dependence
• Nicotine withdrawal symptoms include severe
craving, irritability, anxiety, anger, difficulty in
concentrating, restlessness, impatience,
increased appetite, weight gain, and insomnia
• The withdrawal period may last for many
months
Toxicity
• The pharmacological effects and withdrawal
symptoms are caused by the nicotine in
tobacco
• The tar in tobacco is mainly responsible for
the diseases associated with long-term
tobacco use
Toxicity
• Of the 450,000 annual deaths in the U.S.:
– 82,000 non-cancerous lung disease
– 115,000 lung cancer
– 30,000 other cancers
– More than 200,000 heart attack and vascular
disease
• On average, a person’s life is shortened by 14
minutes for every cigarette smoked
• 1 in 5 Americans will die from smoking related
causes
Cancer
• Nicotine itself is not carcinogenic, but other
chemicals found in tobacco products are
• Most common cancers are lungs, mouth,
throat, and voice box
• It also causes bladder and pancreatic cancers,
and doubles the risk of uterine and cervical
cancers
• 30% of annual cancer deaths are caused by
smoking
Effects of Passive Smoke
• About 4,000 people die annually in America
from lung cancer caused by second-hand
smoke
• 37,000 deaths per year occur from heart
disease contracted as a result of passive
smoke
Effects During Pregnancy
• Cigarette smoking adversely affects the
developing fetus
• Increased rates of spontaneous abortion,
stillbirth, early postpartum death, and
premature deliveries are seen in smoking
mothers
• Low birth weight and fetal growth retardation
have also been well documented
Effects During Pregnancy
• More than 2,000 infant deaths per year are
attributed to maternal smoking
Effects During Pregnancy
• Cigarette smoking reduced oxygen delivery to
the fetus
• This can result in long-term, irreversible
intellectual and physical deficiencies
• Many, many other behavioral, social, and
developmental disorders have greatly
increased likelihood in people who were born
to smoking mothers