CENTRAL NERVOUS SYSTEM DEPRESSANTS
This is a group of drugs with diverse chemical structures that induce a
behavioral depression. This desired effect produces relief from anxiety,
inhibitions, induces relaxation, sleep, unconsciousness, general anesthesia,
and coma. The predominant tendency of
all these drugs is to inhibit the excitability of neurons.
Be aware that not all these drugs result in the direct inhibition of
neurons. When a neuron that functions to inhibit another neuron is itself inhibited,
then the neuron it is supposed to inhibit will fire more. This is the pattern
of logic used to put hyperactive children on stimulants where the hope is that
the neurons that inhibit will be stimulated to provide this function.
The terms sedative, tranquilizer, hypnotic, and anxiolytic can be
applied to any central nervous system depressants.
The inducement of sleep is referred to as an hypnotic effect. This is very different from what happens in
hypnosis but the term was coined at a time when people believed hypnosis
induced a sleep-like trance.
Sedative-hypnotics include alcohol (ethanol), barbiturates, and
non-barbiturate hypnotics (Quaalude).
Anxiolytics are anti-anxiety drugs used for treating anxiety. The
unfortunate term minor tranquilizers
is often used but only refers to the fact that these drugs are used to treat
milder symptoms than those labeled major tranquilizers.
In general, anxiolytics are the most commonly used psychotropic
medications. The vast majority are prescribed by non-psychiatrists (less than
20% are prescribed by psychiatrists).
For the past 30 years the barbiturates were replaced by the
benzodiazapines that are less addictive and have less abuse potential.
Benzodiazapines account for 90% of the anxiolytic market.
Recently BuSpar has proven to be an effective anxiolytic with even less
abuse and addiction potential than the benzodiazapines.
BARBITUATES: The name is said to have been coined either because the
urine of a girl named Barbara was used to derive the compound or because it was
synthesized on St. Barbara's Day. Saint Barbara’s Day is Dec 4th.
She is the Patroness of miners and was martyred in 235 or 238. She was the
daughter of a wealthy heathen and upon professing the faith was martyred with
St. Juliana.
These have rapidly become the dinosaur of drugs. A anxiolytics, they
have pretty much been displaced by benzodiazapines. The effects of these drugs
are quite similar to ethanol. The main advantage to these is they are cheap
because the patent has expired.
Barbituates differ from each other primarily in terms of how quickly
the drugs act, the intensity of action and the duration of action. The
differences between these properties are the main consideration in deciding
what these drugs are used for.
Clinical uses include treatment of epileptic seizures, alleviation of
migraine headaches, and as a component of anesthesia.
They used to be used more for insomnia but induce sedation to the point
where a person may not hear a smoke alarm or similar sounds and they disrupt
REM sleep and discontinuation results in REM rebound
MECHANISM: mechanism of action is not clearly understood. They do
decrease the excitability of neurons throughout the nervous system and inhibit
polysynaptic responses. The dominant action is to hyperpolarize numerous types
of neurons.
Hyperpolarizations inhibit
the production of action potentials. They are synonymous with inhibitory
post-synaptic potentials. The mechanism of action seems related to chloride
channels and potassium channels (although calcium channels are implicated in
IPSP). The barbituates hyperpolarize numerous types of neurons by facilitating
the inflow of negatively charged ions through the ion channels. Negatively
charged ions then hyperpolarize the cell.
The neurons in the reticular activating system are particularly
sensitive to barbiturate drugs. In addition, sites of action include the
cerebellar pyramidal cells (fine movement), the substantia nigra (motor
skills), and the thalamus (sensory information).
CONTRAINDICATIONS: severe respiratory disease, liver impairment (can't
metabolize then) or concomitant use of other CNS depressants because
barbiturates seem to enhance the binding action of other CNS depressants.
COMMON SIDE EFFECTS: Sleepiness (disruption of REM), ataxia (loss of
muscle coordination) CNS depression, respiratory depression, may cause blood
disorders (agranulocytosis).
PHARMACOKINETICS: Rapidly and completely absorbed and distributed to
most body tissues. The ultra-short-acting barbituates are lipid soluble, cross
the blood-brain barrier quickly and can induce sleep in seconds.
EXAMPLES:
Thiopental - fast acting with ultra-short duration (15 minutes)
and used primarily as an anesthetic.
secobarbitol - short duration (1 1/2 hours) used as a sleep inducer.
pentobarbitol - short to intermediate duration (4 hours) used for sleep
inducing qualities.
phenobarbitol - long actin (6 hours) drug used for sedative or
anti-convulsant.
METABOLISM: The main metabolic pathway is the liver and greatly
increase metabolizing enzymes in the liver.
NON-BARBITUATE ALTERNATIVES: these are so similar to barbituates in
everything except molecular structure that we will omit lengthy discussion of
them here.
The important part of their story is that they stimulated research that
led to the benzodiazapine revolution. In 1945 a Czechoslavakian pharmacologist
Frank Berger, attempting to develop anti-bacterial agents stumbled onto
Meprobemate which roughly acted like a barbiturate but did not induce sleep as
readily. He noted that it seemed to induce “tranquilization.” It was marketed
with much fanfare in 1955. Its primary success was that it allowed people to
remain awake while reducing anxiety.
Meprobamate and other non-barbiturate alternatives hold the same
desirable and undesirable qualities as barbiturates. Some like Quaaludes have
been taken off the market because of their recreational use and abuse
potential.
BENZODIAZAPINES: This is the prototypic anxiolytic. Following up on
research begun by Berger, Leo Sternbach, a Polish chemist, first synthesized
Librium and Valium at Roche Drug Co. in
In trying to learn how Meprobamate acted at a molecular level,
Sternbach was sythesizing chemicals called quinazolines and screening them for
anti-anxiety properties. He screened 19 out of 20 with no success and moved on.
A year-and-a-half later while cleaning his lab he found the 20th
compound and decided to have it screened. It turned out to be quite active. It
turned out that the final steps of its synthesis completely altered its
chemical properties from a quinazoline to what we now call a benzodiazapine.
Benzodiazapines are effective in reducing anxiety-related symptoms in
70-80% of people. This must be seen in light of the fact that the symptoms vary
considerably across time and go into remission with a placebo in 25-30% of
clients.
BZP's also serve as sedatives, muscle relaxants, intravenous
anesthetics, and anti-convulsants.
Versed is a BZ used in twilight anasthesia.
Benzodiazapines facilitate GABAa induced increases in chloride
conductance which inhibits synaptic action. The BZ actually bind on the GABA
receptor and, in the absence of GABA, have no activity in and of themselves.
BZs may block stress-induced increases in NE, ST, and DA and other
transmitters whose neurons have GABA receptors.
In the presence of GABA, BZs also exert an influence on second
messenger systems that serve to hyperpolarize cells.
When GABA is present, they act in a
potentiating way (1+0=2) GABA = 1, BZ=0.
Although the benodiazapines do not effect REM sleep like the
barbituates they do interfere with deeper stages of sleep and this may be just
as disruptive to rest. The shorter acting the benzodiazapine, the fewer daytime
side-effects (lethargy, decreased coordination).
There are three families or subclasses of BZs. The more drug metabolism
that takes place in the liver, the more the drug will interfere with other
medications due to moderate metabolic tolerance (more the first class).
·
2-keto Most lipophilicitous of the three. Oxidized
primarily in the liver and this process is slower so they have longer
half-lives (up to 60 hours). Many have multiple metabolites to so longer half
lives. For example Valium is a prodrug meaning, it starts inactive and through
anabolism becomes active. It acts as a precursor for methyldiazepam which is
further metabolized to oxazapam. Examples include valium,diazepam,
Tanxene/clorazapate, and Paxipam/halazaepam.
·
3-hydroxy
compounds Metablized through liver and
direct joining with endogenous compounds which brings about more rapid
oxidation (negative charging and water solubility) and thus a shorter half life
(10-15 hours). Examples include Serax/oxazapam and Ativan/lorazapam,
Restoril/Temazepam.
·
Triazolo
family also more quickly oxidized with
fewer metabolites (although a few more than the 3-hydroxy gp). Short half lives
(15 hours). Example is Xanax/alprazolam.
PHARMACOKINETICS: well absorbed. The majority of shorter-acting BZP's
have no active metabolites and thus are excreted more quickly. The rest are metabolized first into active
metabolites and then have to go through further metabolization taking longer to
be excreted from the body.
In elderly people the only BZP recommended is Oxazapam (Serax). The
dose should be one-third to one-half the dose for younger people (starting dose
7.5 mg no more than 3x a day).
TOLERANCE & DEPENDENCE: If taken for long periods of time, a
pattern of tolerance and dependence can develop. Studies indicate that only a
small minority of clients on such medications abuse them.
Chronic use is not correlated with cognitive impairment on mental
tests.
Withdrawals include a return of
the symptoms for which the drug was prescribed, insomnia rebound, restlessness,
agitation, irritability, and muscle
tension. Syndrome usually only lasts 48-72 hours.
Although the BZPs do not induce the much change in the production of
hepatic drug-metabolizing enzymes there is receptor adaptation in the form of
down-regulation or a decrease in the sensitivity of the receptors.
FLUMAZANIL: BZP derivative that binds with high affinity to BZP
receptors on the GABAa complex with no intrinsic activity after binding. As a
result it blocks the binding of active BZPs (antagonist). Used for BZP
overdose.
BUSPAR: BuSpar was developed by
Although ineffective in alleviating symptoms of psychosis, BuSpar did
seem to have anti-anxiety properties.
BuSpar does not interact with GABA receptors. It does interact with DA
and ST receptors. It interacts in agonist and antagonist ways in DA receptors -
unclear.
BuSpar is believed to have its
anti-anxiety effect as a serotonin antagonist. It acts on the noradrenergic
system to increase firing of locus coeruleus. Whereas this would usually
increase anxiety, the effect seems to be offset by BuSpar's blocking of serotonin
receptors. These seem to overide the effects on the LC.
The actions of the drug on serotoning (5 transmembrane, slow
transmitter) seem to account for the length of time it takes to work.
Although BuSpar has no direct effect on benzodiazapine or GABA
receptors but has been shown to increase benzodiazapine binding. BuSpar’s onset
of action may take up to 7 weeks. During this time a benzodiazapine may be used
without contraindication with the BuSpar. BuSpar is useful in GAD and
depression.
BuSpar is extensively metabolized in the liver with active metabolites.
DIFFERENCES BETWEEN BUSPAR AND BZPs:
1) lacks hypnotic, anti-convulsant, and muscle relaxant properties.
2) takes 1-2 weeks of daily Tx before onset of effects.
3) much less likely to induce drowsinesss and fatigue
4) does not impair psychomotor or cognitive function
5) minimal potential for abuse and dependence
6) no synergistic effect with alcohol
7) lacks affinity for benzodiazapine receptors and does not appear to
act via GABA mechanisms
8) is not cross-tolerant with BZPs
MECHANISM OF ACTION: High affinity for serotonin receptors resulting in
their blocking and down regulation. Also enhances dopaminergic and
noradrenergic cell firing.
COMMON SIDE EFFECTS: dizziness, nausea, headache, insomnia,
tachacardia, palpitations, nervousness, drowsiness.
CONTRAINDICATIONS: MAOI therapy.
BuSpar can be withdrawn without withdrawal effects.
NORADRENERGIC AGENTS
A second biological substrate for anxiety is the norepinephrine neuron.
Quite a few in the brain stem structure LOCUS COERULEUS. Cell bodies based in
brain stem and project through the brain. Activation of these results in
increased vigilance
SO WHAT HOW DO YOU THINK AN ANTI-ANXIETY MED WOULD AFFECT THEM?
One subclass of noradrenergic receptors (alpha 2) act as autoreceptors
on the presynaptic membrane. By exerting an agonist action on these, you
decrease the noradrenergic activity here.
Beta-Blockers Propanodol/Inderal
Clonidine/Catapres
In recent years there has been renewed interest in using these drugs to
arrest anxiety because of their decreasing the activity in the sympathetic
NS. They have some use in generalized
anxiety but not much use in panic attacks.
They are widely believed to be useful before speaking in public but this
is not supported by research. There is more support for their use in milder
anxiety.
Clonidine has been used in treating hypertension, Tourettes, anxiety,
ADHD, detoxing from alcohol, heroin and BZs, and PTSD.
The mechanism of action is still largely unknown with the exception of
autoreceptor occupation. These drugs act on both the central and peripheral
nervous systems.
ANXIOLYTIC THERAPY BY DIAGNOSIS:
GENERALIZED ANXIETY DISORDER: BuSpar is drug of first choice since BZP
treatment over a long period can result in dependence and tolerance. BuSpar
requires 2-6 weeks before full therapeutic effects are noticed.
Major problem is premature discontinuation due to slow onset. Can be
prescribed with short-term doses of BZP to provide immediate relief.
Must be taken every day. If client is unresponsive and there is no
history of alcohol or other substance abuse, BZP can then be prescribed
Can also use a tricyclic AD or SSRI in combination with an initial dose
of BZ. Also must be taken every day.
Recently Paxil and Effexor have been approved for GAD
STRESS-RELATED ANXIETY: All BZP are effective in treating acute
stress-induced anxiety. Important considerations have to do with side effects
and half life.
Most common side effect is sedation. Use low sedation BZP for
decreasing daytime anxiety.
BZP's with a shorter half-life will have to be discontinued gradually.
PANIC DISORDER: two discrete phases
1) eliminate or reduce frequency or intensity of the panic attacks with anti-panic drugs (3
categories)
a. high potency benzodiazapines: very effective, works quickly and
reduces anticipatory anxiety BUT most clients require larger doses and sedation
can be a common problem. Very gradual discontinuation.
b. antidepressants: tricyclics and SSRI's
effective in reducing panic attacks. Can treat concurrent depression.
May experience an initial increase in attacks - can be managed well with short
term use of BZP but the BZP will enhance the effects of the SSRI.
c. MAO inhibitors
Very effective, can treat concurrent depression, can be used for
prolonged periods without risk of tolerance/dependence BUT have delayed onset
(2-3 weeks) and medication/dietary restrictions.
PHASE 2 - gradual re-exposure to feared situations accompanied by a
series of experiences without panic.
Some people can withdraw from meds after 6 months but others may need
them for years.
SOCIAL PHOBIA: Until recently, counseling was the treatment of choice
for social phobics.
2/3 of people with generalized social phobia resonded to the MAO
inhibitor Nardil.
As noted, Beta-Blockers (like Propanadol) can be helpful in diminishing
performance anxiety. Beta-blockers are B-adrenergic receptor antagonists
that block epinephrine sites.
Epinephrine is a hormone secreted in the medulla.
Prozac has shown to be successful with 2/3 of social phobics. Also BZP
are helpful for about 80% of social phobics. Therapy also recommended
concurrently.
Paxil is currently FDA approved for Social Phobia.
ANXIOLYTICS IN CHILDREN:
Despite the high prevalence of anxiety disorders in children (10-20%)
very few controlled medication trials have been conducted (only 9 since 1981).
This is partly due to the fact that children respond well to
non-medical interventions for anxiety disorders.
In all studies with benzodiazapines, the medication groups did no
better than placebo controls.
The two studies that did yield significant differences dealt with 1)
school refusers and 2) selective mutism and social phobia
The school refusers did better than controls when given
Tofranil/Imipramine, a tricyclic antidepressant.
The other study on selective mutism and social phobia showed that the
experimental subjects did better than controls when given Prozac.