Psychopharmacology: Anxiolytics

Updated on 26-01-2010

INTRODUCTION

There has been exponential increase in the number of medications

demonstrated to be effective for the treatment of anxiety and anxiety
disorders. Beginning in the late 19 the century, there was a progression
from alcohol, bromides and opiates to barbiturates developed in the early
20th century. Barbiturates were effective in decreasing anxiety, but they
were addictive in and lethal in overdose. There was continued
advancement in the development of anxiolytics like meprobmate and the
antihistamine hydroxyzine. The major advancement in the field of
anxiolytics in the 1960 s was the development and approval of
benzodiazepines. Also there was a cascade of anxiolytic research in the
1990 s.

INDICATION

Anti anxiety drugs are also called anxiolytcs and minor tranquilizers. They
are used in the treatment of anxiety disorders, anxiety symptom, acute
alcohol withdrawal, skeletal muscle spasms, convulsive disorders, status
epileptics and preoperative sedation. Their use and efficacy for periods
greater than 4 months have not been evaluated.

MECHANISM OF ACTION

Anti anxiety drugs depress the sub cortical levels of CNS, particularly the
limbic system and reticular formation. They may potentiate the effect of
powerful inhibitory neurotransmitter GABA in the brain thereby producing
a calming effect. All levels of CNS depression can be affected ,from mild
sedation to hypnosis to coma .

EXCEPTION

Buspirone does not depress the CNS .Although its action is unknown , the
drug is believed to produce the desired effects through interactions with
serotonin, dopamine, and other neurotransmitter receptors.

CLASSIFICATION

1. Barbiturates.

Barbiturates can be divided into 4 main groups.

* a) Long acting; Duration of action is more than 8 hours. Eg.

Phenobarbital.
* b) Intermediate acting- duration of action is 5-8 hours. Eg;
amobarbital and pentobarbital.
* c) Short acting- duration of action is 1-5 hours. Eg; secobarbital .
* d) Ultra short acting- duration of action is less than 1 hour. eg:
thiopentone and methohexital.

The barbiturates are no longer used commonly as anti-anxiety agents.

They produce multiple side effects like excessive sedation, respiratory and
circulatory depression, hepatic enzyme induction, dependence,
withdrawal symptoms, rebound increase in REM sleep on withdrawal, and
potential for use in suicide.

2. Non-barbiturate , nonbenzodiazepine antianxiety agents

These can be further divided into following categories.

A) Carbamates-not used commonly because of potentials of abuse and

dependence. Eg: meprobamate, tybamate and carisoprodol.

B) Piperidinediones- this too use not used now due to dependence

potential. Eg; gluethimide.

C) Alcohols- these drugs are highly dependence producing . eg: ethanol,

chloral hydrate, and ethchlorvynol.

D) Quinazoline derivatives- eg;methaqualone. It had become a street drug

or drug of abuse . So it was discontinued as an ant anxiety agent and a
hypnotic.

E) Anti-Histaminics-eg; diphenhydramine, hydroxycine, and promethazine.

Diphenhydramine is usually combined with methaqualone or diazepam .

They may be used as hypnotic-sedative , but their use as antianxiety

agent is minimal and probably not effective.

F) Cyclic ethers- Not used commonly as it is very effective and is

dependency producing.

G) Others- antipsychotic (eg; thioridazine) and antidepressants (eg:

doxepine) are sometimes used for treatment of severe intractable
anxiety. However they are not the drugs of first choice and should be
used with discretion, when all other rugs have failed to benefit.

H) Beta blockers- eg: propanolol. This is particularly effective in

treatment of peripheral somatic manifestations of anxiety. It is also used
as the drug of first choice of anticipatory anxiety and situational anxiety.

* Propanolol can be used either alone or along with benzidiazepines.

The role of this in the treatment of psychic manifestations of anxiety is
still in research. It is contraindicated in patients of bronchial asthma and
cardiac conditions.

3) Benzodiazepines

Since the discovery of chlordiazeopoxide in 1957 by Sternbach,

benzodiazepines have replaced other anti-anxiety drugs. Presently
benzodiazepines are the drugs of first choice in treatment of anxiety and
for the treatment of insomnia.

* The benzodiazepines are thought to reduce anxiety because they are

powerful potentiators (receptor agonists) of the inhibitory
neurotransmitter GABA. A post synaptic receptor site specific for the
benzodiazepine molecule is located next to GABA receptor. The BZ
molecule and GABA bind to each other at the GABA receptor site. The
result is an enhancement of the actions of GABA, resulting in an inhibition
of neurotransmission (a decrease in the firing rate of neurons), resulting in
a clinical decrease in the person’s level of anxiety.
* The benzodiazepines are classified according to their elimination half
lives.

Class and drug

Elimination half live

Usual hypnotic dose

Oral dose

1.Very short acting

· Triazolam

· Midazolam

2-5

2-5

.125-.25

____

2.Short acting

· oxazepam

· lorazepam

· temazepam

· alprazolam

estazolam

5-15
10-20

10-20

6-20

8-24

15-30

0.5-2

15-30

not used

1-2

15-120

2-6

15-30

0.5-6

1-2

3. Long acting

· chlordiazepoxide

· diazepam

· flurazepam

· chlorazepate

· nitrazepam

· prazepam

· halazepam

· clonazepam

· quazepam
25-48

14-90

30-100

30-100

20-60

30-60

30-60

20-40

40-160

10-25

2-10

15-30

7.5-30

5-10

10-20

20-40

7.5-30

15-100

2-60

15-60

7.5-60

5-20

20-60
40-160

0.5-20

7.5-15

INDICATIONS

The indications for the use oef benzodiazepines are as follows.

1. Generalized anxiety disorder, adjustment disorder with anxious mood.

2. Panic disorder, agoraphobia, and school phobia (particularly
alprazolam and clonazepam)
3. Agitated depression, (added to antidepressants for first 1-2 week);
alprazolam probably has an antidepressant effect.
4. Insomnia
5. Stage 4 NREM sleep disorders like enuresis, somnambulism,
(diazepam reduces duration of stage 4 NREM sleep).
6. Nightmares (diazepam also reduces REM sleep duration)
7. Premedication in anaesthesia (intravenous lorazepam, midazolam or
diazepam).
8. Anticonvulsant use (drugs of choice for status epilepticus, myoclonic
seizures, and certain infantile spasms).
9. To produce skeletal muscle relaxation ( eg: in tetanus, cerebral palsy)
10. Treatment of alcohol and other drug withdrawal syndromes.
11. Ffor minor surgical, endoscopic or obstetric procedures.
12. Acute mania (clonazepam, either alone or with lithium)
13. Antipsychotic induced akathisia
14. Emergency management of acute psychoses ( iv lorazepam , along
with parenteral antipsychotics)
15. Narcoanalysis or abreaction (IV diazepam)
16. Treatment resistant schizophrenia (experimental use in High doses)
17. Psychosomatic disorders

Whenever administered, benzodiazepines should not be ordinarily used

for more than 6 weeks at one time. Otherwise the risk of dependence is
high, and tolerance occurs.

MECHANISM OF ACTION

Exact mechanism of action of benzodiazepines is not clear. The recent

discovery (1977) of benzodiazepine receptors has shed some light on the
mode of action.

There are presently 2 known benzodiazepine receptors.

1. BDZ receptor 1, which is linked with GABA ( Gamma –Amino Butyric –

Acid)
2. BDZ receptor 2, which is alone and is probably involved in cognition
and motor control.

Thus benzodiazepines probably act by enhancing GABA transmission in

brain.

Benzodiazepine receptor antagonists (eg: flumazenil) are anxiety

provoking agents. The benzodiazepines have no significant clinical
advantage over each other, although differences in half life can be
clinically useful. For eg; patients with persistent high level of anxiety
should take a drug with a long half life. Patients with fluctuating anxiety
might do better with either a short acting drug or drug with a sustained
release formulation ( alprazolam, chlorazepate , diazepam and
adinazolam ) . Sustained release BZP blunt the peaks of toxicity and the
troughs of symptom breakthrough and are becoming a popular
alternative to the original formulations .

In addition the lipid solubility of each BBZP determines the rapidity of

onset and the intensity of effect, and this should be considered when
selecting a BZP. FOR eg; the diazepam is more lipid soluble than
lorazepam , thus is more readily move into and out of the central nervous
system (CNS) .and is more extensively distributed toperipheral sites
particularly to fat cells.

The rate of absorption of different BZP from the gastrointestinal tract

varies considerably, thus affecting this rapidity and intensity of onset of
their acute effects. Antacids and food in the stomach slow down this
process when these drugs are taken by mouth.

The injectable BZP (lorazepam, and midazolam) have been proven reliable
when administered in the deltoid muscle. Diazepam results in predictable
and rapid rises in the blood level when used intravenously .
Concentrations of BZP in the blood have not been firmly correlated to
clinical effects, so blood level measurements are not clinically helpful.

Some patients need to take anti anxiety drugs for extended periods.
Because of the potential disadvantage of BZP, they should be always used
along with nonpharmacological treatments for the patient with chronic
anxiety or insomnia. Psychotherapy, behavioural technique,
environmental changes, stress management, sleep hygiene, and an
ongoing therapeutic relationship continue to be important in the
treatment of anxiety disorders and insomnia.

In general the treatment of BZP should be brief and used during a time of
specific stress or for a specific indication. The patient should be observed
frequently during the early days of treatment to assess target symptom
response and monitor side effects so that the dose can be adjusted as
needed. Some patients, such as those with [panic disorder, may require
daily dosing and long term BZP treatment.

SIDE EFFECTS

The side effects are common, dose related, usually short term and almost
always harmless. It include nausea, vomiting , weakness , epigastric pain ,
diarrhoea, vertigo, blurring of vision , body aches , urinary
incontinence( rare), impotence., lassitude, sedation, increased reaction
time ,ataxia ( in high doses ) , dry mouth retrograde amnesia ( rare) ,
impairment of driving skills , severe effects when administered with
alcohol, irritability ( particularly with flurazepam and (chlordiazepoxide) ,
disinhibited behaviour ( particularly with diazepam ) .

Tolerance can develop to the sedative effect of BZP which in some ways
is an advantage , but is unclear whether tolerance also develop to
induced sleep or antianxiety effects. These drugs should be tapered to
minimize withdrawal symptoms and rebound symptoms of insomnia and
antianxiety. If these symptoms occur the dose should be raised until
symptoms are gone and then tapering is resumed at a slower rate.

Withdrawal syndromes include agitation, anorexia, anxiety, autonomic

arousal, dizziness, generalized seizures, hallucinations, headache,
hyperactivity, insomnia, irritability, nausea and vomiting, sensitivity to
light and sounds, tinnitus and tremulousness.

Elderly patients are more vulnerable to side effects because the aging
brain is more sensitive to sedatives, Dosing ranges from one-half to one-
third of the usual daily dose used for adults. The BZP with no active
metabolites are less affected by liver disease, the age of the patient, or
drug interactions.

BZP are more successfully used in children to treat sleep waking ,in single
dose to allay anticipatory anxiety , and to treat panic , generalized
anxiety disorder , and avoidant personality disorder but in general they
can increase anxiety and produce or aggravate behaviour disorders
,especially ADHD.

BZP during pregnancy have been associated rarely with palate

malformations and intrauterine growth retardations especially when used
during the first trimester. When used in late trimester or during breast
feeding, these drugs are associated with floppy infant syndrome, neonatal
withdrawal symptoms and poor sucking reflex. Hence they are not
recommended.

4. Newer drugs

a) Buspirone

Buspirone is a new anti-anxiety drug which is not a BZP. It is an

azaspirodecane –Dione (azaspirone) derivative and is 5 HT partial agonist
and is a selective DA autoreceptor antagonist. It also inhibits the
spontaneous firing of 5HT neurons. It does not seem to act upon
BZPreceptors. It is anxioselective with no sedative action, no
anticonvulsant or muscle relaxant properties.

It is administered in a dose of 15-30 mg/day, in a thrice a daily schedule

due to short half life. As it has a slower and more gradual onset of action,
it usually takes about 2 weeks before the anti-anxiety effects of buspirone
are evident .It is not useful in the treatment of panic disorder. The side
effect includes dizziness, headache, light headedness and diarrhoea.

As it is anxioselective, and lack any risk of dependence, it may replace the

BZP as the drug of choice in GAD.

B) Zopiclone

Zopiclone belongs to a new class of BZP drugs , the cyclopyrrolones.

Cyclopyrrolone derivatives also act on the GABA receptors, but at a site
distinct from that of BZP.
Zopiclone has a short duration of action as well as shorter onset. After oral
administration it is observed rapidly, with peak plasma concentration
occurring in about 60 minute. The elimination half life is 4-6 hours.

The usual dose of zopiclone is 3.75-7.5 mg at bedtime ( lower dose in

elderly and in patients with severe hepatic failure) . The side effects
include bitter taste, dry mouth, drowsiness, nausea and headache. Its
safety in pregnancy, lactation and in children are not proven. It is clinically
superior to BZP in subjective awakening quality, well being and attention
span in the morning.

3) Zolpidem

It is an imidazopyridine derivative which I being marketed as a hypnotic.

It is administered in a dose of 5-10 mg for hypnotic use. It has a half life of
2-3 hours; therefore it is useful in the treatment of difficulty in initiation of
sleep.

The side effects include drowsiness, dizziness, headache, depression,

nausea, dry mouth and myalgia.It should not be used for more than 2
weeks at one time. Its safety in pregnancy, lactation and children is not
proven.

4) Zalpelon

Zalpelon is an pyrazylo-pyramidine derivative which is being marketed as

a hypnotic. Although a non BZP drug it acts on the omega -1 BZP
receptor located on the alpha sub unit of the GABA –A receptor complex
( causing sedation ) , with very little effect on omega 2 and omega 3
receptors.

Side effects include headache, drowsiness, dizziness nausea and

myalgia . It should not be used for more than 1 week at a time .Its safety
in pregnancy, children and lactation are not proven.

POSSIBLE NURSING DIAGNOSIS

1. Risk for injury related to seizures; panic anxiety, abrupt withdrawal

after long term use, effects of intoxication and overdose.
2. Risk for activity intolerance related to side effects of sedation and
lethargy.
3. Risk for acute confusion related to action of the medication on CNS.

BIBLIOGRAPHY

Books

1. Gail W Stuart , Michele T Laraia. Principles and practice of Psychiatric

Nursing .8th edn. Missouri. Mosby publications. 2005.
2. Mary C Townsend. Psychiatric Mental Health Nursing . 5th edn. Philadelphia.
FA D avis company.
3. Cacelia Monat Taylor. Essentials of Psychiatric Nursing .5th edn. Missouri.
Mosby publications . 2002
4. Niraj Ahuja. A Short Textbook of Psychiatry.5th edn. New Delhi.Jaypee
publications .2002.
5. Deborah Antai Otong.Psychiatric Nursing. Biological and Behavioural
Concepts.U.S. North Texas Health Care System. 2003.
Journals

1. Paul PD. Trends in the Pharmacologic Management of Insomnia.J Clin

Psychiatry 2006; 67: suppl 13: 5-8.
2. Milton KE. Influence of Pharmacokinetic profiles on safety and efficacy of
Hypnotic medications.J of Clin Psychiatry. 2006; 67: suppl 13: 9-12.