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 New Jersey.

 

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 Davis Temple and Michael Eison of Bristol-Myers Co. It was first synthesized in 1968 in an effort to find a better anti-psychotic. Chemically, BuSpar resembles a butyrophenone anti-psychotic more than any anti-depressant or anxiolytic.

 

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.