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Chapter 7
Depressants and Inhalants
Depressants


These drugs all have a widespread
effect in the brain that can be summed
up as decreased CNS activity.
Why are CNS depressants problematic?
 Usually prescribed under physician
direction
 Second most frequently abused prescription
drug and sometimes contributes to death
due to accidental overdoses
 Can cause very alarming and dangerous
behavior if not closely monitored
 Most problems associated with these drugs
due to inadequate professional supervision
Depressants

As a group, also called sedativehypnotics

Sedatives treat anxiety (current examples of
popular sedatives include Xanax and Ativan)

Hypnotics treat insomnia (sleeping pills: Ambien
and Lunesta)

Widely used depressants include:


Alcohol
Benzodiazepines (prescription) - Benzodiazepines possess
sedative, hypnotic, anxiolytic, anticonvulsant, muscle relaxant,
and amnesic actions, which are useful in a variety of indications
such as alcohol dependence, seizures, anxiety, panic, agitation
and insomnia. (source)
DISCUSSION
In your small group, discuss why you think
physicians may be careless when prescribing
depressants for patients suffering from anxiety.
Discuss what you believe are the dangers of this
practice and what other alternate therapies may
exist
History: Before Barbiturates

Chloral hydrate

Synthesized in 1832 - It was discovered through the
chlorination of ethanol in 1832; chloral hydrate was not used
clinically until about 1870.

In the early 1900s a Chicago bartender named Mickey Finn
became briefly famous when he was prosecuted for adding chloral
hydrate to the drinks of some of his customers, after which they
would become incapacitated and be robbed by one of his “ house
girls.” The term “ Mickey Finn” entered our language as
slang for a drug added to someone’s drink without his
knowledge.

Chloral hydrate is rapidly metabolized to
trichloroethanol, which is the active hypnotic agent.
When taken orally, chloral hydrate has a short onset
period ( 30 minutes), and one to two grams will induce
sleep in less than an hour.
History: Before Barbiturates

Paraldehyde

Synthesized in 1829; used clinically in 1882

Effective with a wide safety margin and was soon found to
be an effective anticonvulsant, hypnotic and sedative

Today, paraldehyde is sometimes used to treat status epilepticus.
Unlike diazepam and other benzodiazepines, it does not suppress
breathing at therapeutic doses and so is safer when no
resuscitation facilities exist or when the patient's breathing is
already compromised.

Paraldehyde has an extremely noxious taste and an odor
that permeates the breath of the user.
History: Before Barbiturates

Bromides

Widely used as a sleep agent in patent
medicines

Bromides accumulate in the body, and
the depression they cause builds up
over several days of regular use.

Serious toxic effects follow repeated
hypnotic doses of these agents.

Bromides remained in OTC drugs
through the 1960s

In the early 1900’s, bromides were
replaced by Barbiturates.
Barbiturates

Background



First introduced in 1903, the barbiturates became so
important that eventually over 2,500 different
examples of this chemical class were synthesized
Examples of once-popular barbiturates include
phenobarbital, amobarbital, and secobarbital.
Barbiturates are grouped according to time of onset and
their duration of action (See Table 7.1, next slide). The
short- acting barbiturates begin to produce effects in as little as
15 minutes, and have effects lasting only 2 or 3 hours, whereas
the long- acting drugs may take an hour to produce effects, but
they may last for 8 hours or more.
BARBITURATES
Grouped based on the time of
onset and duration of activity
Short-acting and rapid onset: used
to induce sleep and often
prescribed in high doses
Long-acting and delayed onset:
used to reduce anxiety and often
prescribed in low doses
See written description of grouping
examples on next slide…
Examples of Barbiturates

Short-acting




Intermediate-acting




Pentobarbital, Secobarbital
Time of onset: 15 minutes
Duration of action: 2 to 3 hours
Amobarbital, Butabarbital
Time of onset: 30 minutes
Duration of action: 5 to 6 hours
Long-acting



Mephobarbital, Phenobarbital
Time of onset: 1 hour
Duration of action: 8 hours or longer
Concerns About Barbiturates

Overdose Deaths



Abuse and dependence




Intentional and accidental
the cause of death is typically respiratory depression
(breathing slows and eventually stops) and in a great many
cases this is due to the combined effects of alcohol and a
depressant drug.
Reinforcing effects of a drug are related to the rapidity of
onset of effects
Short-acting drugs are more likely to lead to psychological
dependence
Physical dependence ( withdrawal symptoms) are more
likely to occur when a drug leaves the body quickly
Concerns led to search for safer medications concerns about overdoses, psychological
dependence, and physical dependence led to a
search for safer CNS depressants
Meprobamate


Meprobamate ( Milltown) was patented in
1952
psychological dependence, and
physical de-pendence led to a bad
reputation for all bar-bituratesWidely
prescribed beginning in the 1950s



Used as an anxiolytic
Like barbiturates, can produce
psychological and physical
dependence
Still available as a prescription drug
Meprobamate


Meprobamate ( Milltown) was patented in
1952, the FDA approved its use in
1955.
like the other barbiturates, produced
both psychological and physical
dependence
 In
1970, meprobamate became a
Schedule IV controlled substance,
and although it is still available for
prescriptions under several brand
names, the benzodiazepines have
largely replaced it.
Methaqualone

Other names:



Brand = Quaalude or Sopor
Slang = “ludes” or “sopors”
Despite problems in other countries, drug
was introduced in the U.S. (1965)
Package insert read “Addiction potential not established”
Physicians overprescribed, thinking the drug was a safe
alternative to barbiturates
 Widely misused and abused - Physicians were
overprescribing a hypnotic drug that they believed to be
safer than the barbiturates.



Scheduling history:


1973: Schedule II
1985: Schedule I
Benzodiazepines

First introduced in 1960:

The first of the benzodiazepines was
chlordiazepoxide, which was marketed under the
trade name Librium ( possibly because it “
liberates” one from anxieties).

Reduces anxiety without inducing sleep Chlordiazepoxide enabled the treatment of emotional
disturbances without a loss of mental acuity or alertness

Much larger safety margin than barbiturates

Physical dependence and overdose was rare (only
when combined with other depressants like
alcohol)

Diazepam (Valium) became the best seller among
all prescription drugs
Benzodiazepines


As these drugs became widely used, reports again
appeared of psychological dependence, occasional
physical dependence, and over-dose deaths.
Dose level and time course are critical
factors




Overdose deaths more likely for drugs sold in higher
doses
Psychological dependence more likely with drugs that
have a rapid onset of effects
Physical dependence more likely with drugs that have a
short duration of action - one way to reduce the severity
of withdrawal symptoms is to reduce the dose of a drug
slowly over time.
Are benzodiazepines safer than
barbiturates?

More differences among drugs within each class
Benzodiazepines: Rohypnol

A 1990s version of a “Mickey Finn” Rohypnol ( flunitrazepam), a benzodiazepine sold as a hypnotic
in many countries around the world but not in the United
States, hit the news when reports surfaced of its being put into
the drinks of unsuspecting women by their dates.


Produces profound intoxication when mixed
with alcohol during which the woman would be
highly suggestible and unable to remember
what had happened to her.
Reportedly used as a “date-rape”
drug


Slipped into drinks
1997 change in the formulation causes a
distinctive color when dissolved in a drink
Nonbenzodiazepine Hypnotics


The most recent additions to the class of
depressant drugs do not have the
chemical structure of the
benzodiazepines, but they have similar
effects.
“Z-drugs” (Zopiclone)


Similar to benzodiazepines but with a different
chemical structure
Zolpidem
(Ambien) became the most widely
prescribed hypnotic


Short duration
Rapid onset
Nonbenzodiazepine Hypnotics

“Z-drugs”

Although many initially hoped that the
nonbenzodiazepines would be more
specific and avoid some of the problems
of earlier drugs, there have been
reports of withdrawal reactions and
other complications with them as well.
They are listed, along with the
benzodiazepines, in Schedule IV, one
step below the Schedule III
classification of the barbiturates.
Mechanism of Action

Benzodiazepines and barbiturates




Bind with receptors on GABA receptor complex
Separate binding site for barbiturates and
benzodiazepines
Enhances the normally inhibitory effects of GABA
Nonbenzodiazepine hypnotics


Drug companies quickly began developing new drugs
based on their ability to bind to these sites, leading to
the development of the entire class of
nonbenzodiazepine hypnotics.
Thus the nonbenzodiazepine hypnotics were an
entirely new class of drugs designed to selectively
bind to different sites on the GABA receptor complex
Beneficial Uses

As Anxiolytics

Sedatives often prescribed to reduce anxiety
Most physicians used to accept the widely held view that various types
of dysfunctional behavior ( e.g., phobias, panic attacks, obsessivecompulsive disorders psychosomatic problems) result from various
forms of psychological stress that can be lumped under the general
classification of “ anxieties.”

Four benzodiazepines are among the top 100 most
commonly prescribed medications in the United
States
 Xanax
 Ativan
 Klonopin
 Valium
Concerns: Anxiolytics

Sedatives are not appropriate for all
anxiety disorders


Example: For specific phobias ( e.g., fear of spiders), behavior
therapy is a more effective treatment. And for obsessivecompulsive disorder and most of the official “anxiety
disorders”, certain antidepressant drugs seem to be most
effective.
Overprescribed…


Most sedatives are not prescribed by psychiatrists
Most patients do not have a clearly defined anxiety
disorder or physical ailment, and in any individual
case it may be impossible to know whether the patient
just enjoys getting a “ feel- good pill” or feels better
because of a specific antianxiety effect.
Beneficial Uses

As hypnotics

Insomnia is the term used to include several symptoms:
trouble falling asleep, trouble staying asleep, or waking
up too early.

Sedatives (at large enough doses) decrease sleep onset
time - This is essentially the principle on which hypnotic
drug therapy is based: a large enough dose is taken to
help you get to sleep more quickly.

About a third of American adults report trouble sleeping
- most people who are concerned about insomnia do not
take prescription hypnotic drugs, and there are effective
nonmedical ways of dealing with insomnia ( see
Targeting Prevention Box, p157).
Concerns: Hypnotics

Concerns about the nonbenzodiazepine
hypnotics include:
Sleepwalking
 Sleep-eating
 Driving while in a semi-waking state
 These concerns led the FDA to investigate such
reports, and in 2008 all hypnotic drugs were required
to attach a warning label about sleep- driving and
other dangerous behaviors that might occur after
taking these drugs.
If you or someone you know has trouble sleeping, before resorting
to the use of medication it would be wise to follow the suggestions
given in the Targeting Prevention Box. These tactics will probably
help most people deal with sleeplessness.


Beneficial Uses

As anticonvulsants



Barbiturates and benzodiazepines may be
prescribed for seizure disorders (epilepsies)
They are effective in reasonably low doses and
are often combined with other anticonvulsant
drugs for even better effectiveness.
Potential concerns


Tolerance can make it difficult to find a dose that
is effective but doesn’t cause excessive
drowsiness
Abrupt withdrawal is likely to cause seizures so
medication changes should be done carefully.
Causes for Concern –
Dependence Liability

Psychological dependence

Especially associated with short-acting sedatives:




Animals given the opportunity to press a lever that
delivers intravenous barbiturates will do so, and the
short- acting barbiturates work best for this.
Animals will also self- inject several of the
benzodiazepines, but at lower rates than with the shortacting barbiturates.
Experiments in humans yielded similar results
These experiments indicate that these sedative drugs can serve
as reinforcers of behavior but that the short- acting barbiturates
are probably more likely to lead to dependence than are any of
the benzodiazepines currently on the market.
Causes for Concern –
Dependence Liability

Physical dependence





Withdrawal syndrome is similar to alcohol and
potentially life-threatening
Barbiturate withdrawal symptoms:
 anxiety, insomnia, tremulousness, weakness,
nausea and vomiting, seizures, disorientation,
agitation, delusions, and visual and auditory
hallucinations
Benzodiazepine withdrawal is similar but less
severe
Because there is a cross- dependence among the
barbiturates, the benzodiazepines, and alcohol, it
is theoretically possible to use any of these drugs
to halt the withdrawal symptoms from any other
depressant.
Drug treatment is often used, and a general rule
is to use a long-acting drug, given in divided
Causes for Concern –
Acute Toxicity

Behavioral
 Behaviorally, all these drugs are capable of
producing alcohol- like intoxication with impaired
judgment and incoordination.
 Additive effects if combined with alcohol so that
the danger is further increased.

Physiological
 Respiratory depression
 Especially dangerous if combined with alcohol
 In the coroners’ reports, in almost every case the
culprit is the drug in combination with alcohol or
another drug, rather than the benzodiazepine
alone
Causes for Concern –
Patterns of Abuse


Almost all of the abuse of the sedative- hypnotic
agents has historically involved the oral use of
legally manufactured products.
Two types of typical abusers:
1) Older adults using prescription drugs who
develop tolerance and increase their dosage


Even though some of these individuals visit several
physicians to obtain prescriptions for enough pills
to maintain this level of use, many would
vehemently deny that they are “ drug abusers.” This
type of chronic use can lead to physical
dependence.
Causes for Concern –
Patterns of Abuse

Two types of typical abusers:


2) The other major group tends to be younger
and consists of people who obtain the drugs
simply to get high. These younger abusers tend
to take relatively large doses, to mix several
drugs, or to drink alcohol with the drug, all for
the purpose of becoming intoxicated.
With this type of use, the possibility of acute
toxicity is particularly high.
Inhalants

Examples of products that contain
inhalable solvents



gasoline, glue, paint, lighter fluid, spray cans, nail
polish, correction fluid
when inhaled, can have effects that are similar in an
overall way to the depressants.
High-dose exposure to these fumes makes users
intoxicated, often slurring their speech and causing
them to have trouble walking a straight line, as if they
were drunk on alcohol.
similar to alcohol and other depressants
Examples of InhalantsSee Table 7.3, next slide

Gaseous Anesthetics



Nitrites



Nitrous oxide, ether
Current and former medical anesthetics
Isoamyl, isobutyl
“Locker room,” “Rush,” “poppers”
Volatile solvents


Petroleum, acetone, toluene
Paint, paint thinner and remover, nail polish remover,
correction fluid, glues
TABLE 7.3 - SOME CHEMICALS ABUSED
BY INHALATION
Gaseous Anesthetics



One of the oldest, nitrous oxide, was first used in the
early 1800s and quite early acquired the popular
name “ laughing gas” because of the hilarity
exhibited by some of its users.
Nitrous oxide is still used for light anesthesia,
especially by dentists. It is also often used in
combination with one of the more effective inhaled
anesthetics, allowing the use of a lower
concentration
Used as a propellant for commercial and home
whipping-cream dispensers and is abused by
recreational users
Nitrites





Amyl nitrite was first introduced into
medicine in the mid- 1800s as a treatment for
chest pain. Inhaling the vapors of this drug
relaxes blood vessels, including the coronary
arteries.
Causes systemic vasodilation
Reduces blood pressure, pre-syncope
Used to treat cyanide poisoning
In addition to amyl nitrite, butyl, isopropyl, and
isobutyl nitrite produce similar effects. These
products have been used in various cleaning
products, and some users have inhaled those
products to achieve the same effect.
Volatile Solvents

The modern era of solvent abuse can be
traced back to 1959 investigative article




News articles and education programs demonstrated
how to abuse volatile solvents (see text p. 161-162)
Use may have spread due to increased publicity
In general, abuse tends to occur as
localized fads
Most users are very young


8% of 8th-graders reported past year use
3.6% of 12th-graders reported past year use
Dangers of Inhaling Solvents

Several solvents have been linked to:







Kidney damage
Brain damage
Peripheral nerve damage
Irritation of the respiratory tract
Severe headache
Death by suffocation
Laws to limit sales of these household solvents to minors or
to make it illegal to use them to become intoxicated have
been passed in some areas, but typically they have little
effect. Too many products are simply too readily available.
Gamma Hydroxybutyric Acid



GHB

Gamma hydroxybutyrate (GHB) occurs naturally in
the brain as well as in other parts of the body. Its
structure is fairly close to the inhibitory
neurotransmitter GABA. GHB has been known for
some time to be a CNS depressant, and has been
used in other countries as an anesthetic.

Structurally similar to the inhibitory neurotransmitter
GABA


Is a CNS depressant
Taking larger quantities of GHB alone, or combining
GHB with alcohol, produces a combined depressant
effect similar to what would be produced by
combining alcohol with any of the other depressants
In 2000, Congress directed that GHB be
placed on Schedule I.
Except for one formulation (Xyrem)
 Reduces frequency of cataplexy (affects roughly 70%
of people who have narcolepsy)
End of presentation