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.
- Generalized anxiety disorder, adjustment disorder with anxious mood.
- Panic disorder, agoraphobia, and school phobia (particularly alprazolam and clonazepam)
- Agitated depression, (added to antidepressants for first 1-2 week); alprazolam probably has an antidepressant effect.
- Insomnia
- Stage 4 NREM sleep disorders like enuresis, somnambulism, (diazepam reduces duration of stage 4 NREM sleep).
- Nightmares (diazepam also reduces REM sleep duration)
- Premedication in anaesthesia (intravenous lorazepam, midazolam or diazepam).
- Anticonvulsant use (drugs of choice for status epilepticus, myoclonic seizures, and certain infantile spasms).
- To produce skeletal muscle relaxation ( eg: in tetanus, cerebral palsy)
- Treatment of alcohol and other drug withdrawal syndromes.
- Ffor minor surgical, endoscopic or obstetric procedures.
- Acute mania (clonazepam, either alone or with lithium)
- Antipsychotic induced akathisia
- Emergency management of acute psychoses ( iv lorazepam , along with parenteral antipsychotics)
- Narcoanalysis or abreaction (IV diazepam)
- Treatment resistant schizophrenia (experimental use in High doses)
- 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.
- BDZ receptor 1, which is linked with GABA ( Gamma –Amino Butyric – Acid)
- 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
- Risk for injury related to seizures; panic anxiety, abrupt withdrawal after long term use, effects of intoxication and overdose.
- Risk for activity intolerance related to side effects of sedation and lethargy.
- Risk for acute confusion related to action of the medication on CNS.
BIBLIOGRAPHY
Books
- Gail W Stuart , Michele T Laraia. Principles and practice of Psychiatric Nursing .8th edn. Missouri. Mosby publications. 2005.
- Mary C Townsend. Psychiatric Mental Health Nursing . 5th edn. Philadelphia. FA D avis company.
- Cacelia Monat Taylor. Essentials of Psychiatric Nursing .5th edn. Missouri. Mosby publications . 2002
- Niraj Ahuja. A Short Textbook of Psychiatry.5th edn. New Delhi.Jaypee publications .2002.
- Deborah Antai Otong.Psychiatric Nursing. Biological and Behavioural Concepts.U.S. North Texas Health Care System. 2003.
Journals
- Paul PD. Trends in the Pharmacologic Management of Insomnia.J Clin Psychiatry 2006; 67: suppl 13: 5-8.
- Milton KE. Influence of Pharmacokinetic profiles on safety and efficacy of Hypnotic medications.J of Clin Psychiatry. 2006; 67: suppl 13: 9-12.
0 comments:
Post a Comment