Transcript Neuroleptics

Medical University of Sofia, Faculty of Medicine
Department of Pharmacology and Toxicology
Neuroleptics
Anxiolytics
(Abstract)
Assoc. Prof. Ivan Lambev
e-mail: [email protected]
Psychotropic drugs
influence on the psyche (mentality)
and behaviour of patients.
• Neuroleptics
• Anxiolytics
• Mood stabilizers
• Antidepressants
• Psychostimulants
• Nootropics
(cognition enhancers) etc.
NEUROLEPTICS
(Antipsychotics,
Antischizophrenic drugs)
I. Typical (classical) antipsychotics
(with extrapyramidal motor symptoms)
• Phenothiazines
• Thioxanthenes
• Butyrophenones etc.
II. Atypical antipsychotics
(lack of extrapyramidal motor symptoms in rats)
Schizophrenia is a particular kind of psychosis
(mental disorder) characterized mainly by a clear
sensorium but a marked thinking disturbance.
Key symptoms include hallucinations, delusions,
and abnormal experiences, such as the perception
of loss of control of one’s thoughts.
Patients lose empathy with others, become withdrawn,
and demonstrate inappropriate or blunted mood.
Schizophrenic symptoms have been divided into two
major categories – positive and negative symptoms.
Positive symptoms can be regarded as an abnormality
(e.g., incoherent speech, agitation).
Negative symptoms indicate a loss or decrease
in function, such as poverty of speech or
blunted affect. Negative signs are more chronic
and persistent and less responsive to treatment.
The dopamine (DA) hypothesis for schizophrenia
is basis for rational drug therapy. Several lines
of circumstantial evidence suggest that excessive
DA-ergic activity plays a role in this psychosis:
(1) many antipsychotic drugs strongly block postsynaptic D2 receptors in the CNS, especially
in the mesolimbic-frontal system;
(2) drugs that increase DA-ergic activity, such as
levodopa (a precursor), amphetamines (releasers
of DA), and apomorphine (a direct DA-ergic agonist),
either aggravate schizophrenia or produce psychosis
de novo in some patients;
(3) DA receptor density has been found postmortem
to be increased in the brains of schizophrenics who
have not been treated with antipsychotic drugs;
(4) positron emission tomography (PET) has shown
increased DA receptor density in both treated and
untreated schizophrenics when compared with such
scans of nonschizophrenic persons;
(5) successful treatment of schizophrenic patients
has been reported to change the amount of homovanillic acid (HVA), a metabolite of DA, in the
cerebrospinal fluid, plasma, and urine.
Neuroleptics – mechanism of action
Several important DA-ergic systems or pathways are
now recognized in the brain:
(1) The first pathway (the one most closely related
to behavior) is the mesolimbic-mesocortical
pathway, which projects from cell bodies near the
substantia nigra to the limbic system and neocortex.
(2) The second system (the nigrostriatal pathway)
consists of neurons that project from the substantia
nigra to the caudate and putamen; it is involved in
the coordination of voluntary movement.
(3) The third pathway (the tuberoinfundibular
system) connects arcuate nuclei and periventricular
neurons to the hypothalamus and posterior pituitary.
DA released by these neurons physiologically
inhibits prolactin secretion.
(4) The fourth DA-ergic system (the medullaryperiventricular pathway) consists of neurons in
the motor nucleus of the vagus whose projections
are not well defined. This system may be involved
in eating behavior.
Five DA receptors have been described, consisting
of two separate families – the D1- and D2-like groups:
(1) The D1 receptor is coded by a gene on chromosome 5, increases cAMP by Gs-coupled activation
of adenylyl cyclase, and is located mainly in the putamen, nucleus accumbens, and olfactory tubercle.
The second member of this family, D5, is coded
by a gene on chromosome 4, also increases cAMP,
and is found in the hippocampus and hypothalamus.
The therapeutic potency of antipsychotic drugs
does not correlate with their affinity for binding
the D1 receptor, but for most, correlates
strongly with D2 affinity.
(2) The D2 receptor is coded on chromosome 11,
decreases cAMP (by Gi-coupled inhibition of
adenylyl cyclase), and inhibits calcium channels
but opens potassium channels. It is found both preand postsynaptically on neurons in the caudateputamen, nucleus accumbens, and olfactory tubercle.
A second member of this family, the D3 receptor,
also coded by a gene on chromosome 11, is
thought to decrease cAMP and is located in the
frontal cortex, medulla, and midbrain.
D4 receptor also decrease cAMP.
The activation of D2 receptors by a variety of direct
or indirect agonists (eg, amphetamines, levodopa,
apomorphine) causes increased motor activity and
stereotyped behavior in rats, a model that has been
used for antipsychotic drug screening. When given
to humans, the same drugs aggravate schizophrenia.
The antipsychotic agents block D2 receptors
stereoselectively for the most part, and their
binding affinity is very strongly correlated with
clinical antipsychotic and extrapyramidal potency.
Continuous treatment with antipsychotic drugs
produce a transient increase in levels of a DA
metabolite, homovanillic acid (HVA), in the
cerebrospinal fluid, plasma, and urine.
These findings have been incorporated into the
DA hypothesis of schizophrenia. However, many
questions have not been satisfactorily answered.
For example, DA receptors exist in both high- and
low-affinity forms, and it is not known whether
schizophrenia or the neuroleptics alter the
proportions of receptors in these two forms.
Of most importance, newer atypical neuroleptics
(clozapine, olanzapine, quetiapine, and aripiprazole)
do not have very high affinity for the D2 receptor,
which suggests that additional actions are critical
to their antipsychotic effects.
The key steps in the synthesis and degradation of dopamine
and the sites of action of various psychoactive substances at the
dopaminergic synapse
It has not been convincingly demonstrated that
antagonism of any DA receptor other than the D2
receptor plays a role in the action of antipsychotic
drugs. Selective D3-receptor antagonists may
prove therapeutic effect but are not yet available.
Most of the newer “atypical” antipsychotics and
some of the traditional ones have significant
affinity for the 5-HT2A receptor, suggesting
an important role for the serotonin system.
Participation of glutamate, GABA, and ACh
receptors in the pathophysiology of schizophrenia
has also been proposed. Agents targeted at
glutamatergic and cholinergic systems are just
beginning to be evaluated in schizophrenia.
(5-HT)
(NE)
(DA)
The effects of DA, 5-HT and NE on the brain functions
Blocking activity
of neuroleptics on monoamine
and cholinergic receptors
Chlorpromazine: α1 = 5-HT2A > D2 > D1
Haloperidol: D2 > α1 > D4 > 5-HT2A > D1 > H1
Clozapine: D4 = α1 > 5-HT2A > D2 = D1
Olanzapine: 5-HT2A > H1 > D4 > D2 > α1 > D1
Aripiprazole: D2 = 5-HT2A > D4 > α1 = H1 >> D1
Quetiapine: H1 > α1 > M1,3 > D2 > 5-HT2A
Basic & Clinical Pharmacology – 10th Ed. (2007)
Main effects
(1) CNS. In normal individuals antipsychotics produce
neuroleptic syndrome – indifference to surroundings,
paucity of thought, psychomotor slowing, emotional
quietening, reduction in initiative etc.
In psychotic patients neuroleptics reduce
irrational behaviour, agitation and aggresiveness.
They control psychotic symptomatology. Disturbed
thought and behaviour are gradually normalized,
anxiety is relieved. Hyperactivity, hallucinations
and delusions are suppressed.
The sedative effect is produced immediately
while antipsychotic effect take week to develop.
Tolerance develops only to the sedative effect.
Temperature control is knocked off at relative higher
doses, because the thermoregulatory centre is turn off,
rendering the patient poikilothermic (body temperature falls of surroundings are cold and contrary …
The medullary, respiratory and other vital centres
are not affected, except of very high doses. It is very
difficult to produce coma with neuroleptics.
Antiemetic effect is exerted through the CTZ. Almost
all neuroleptics, except thioridazine, have this effect.
However, they are ineffective in motor sickness.
In animal antipsychotic agents produce a state of
rigidity and immobility (catalepsy).
(2) ANS. Neuroleptic have varying degrees of alphaadrenergic blocking activity and produced hypotension
(primarily postural). The hypotensive effect is more
marked after parenteral administration and parallels
the alpha-adrenergic blocking potency. Anticholinergic
(atropine-like) property of neuroleptics is weak.
The phenothiazines have weak H1-antihistaminic and
anti-5-HT actions as well. Promethazine has strong
sedative and H1-antihistaminic action.
(3) Endocrine system. Neuroleptics consistently
increase prolactin release by blocking the inhibitory
action of DA on pituitary lactotropes. This may result
in galactorrhea and gynecomastia. They reduce
gonadotropins, ACTH, GH and ADH secretion.
I. Typical antipsychotics
Phenothiazines
Phenothiazines are classified on the basis of their
chemistry, pharmacological actions, and potency.
Chemical classifications include the aliphatic,
piperidine, and piperazine subfamilies.
The piperazine derivatives are generally more
potent and pharmacologically selective than
the others.
Type 1 (aliphatic side chain)
Chlorpromazine, Promazine,
Levomepromazine, Promethazine
Type 2 (piperidine side chain)
Thioridazine
Type 3 (piperazine side chain)
Trifluoperazine,
Prochlorperazine, Fluphenazine
Thioxanthenes
R
They are a three-ring compound structurally related
to phenothiazine but having the nitrogen atom at
position 10 replaced by a carbon atom with a
double bond. Thioxanthenes have nearly
equivalent potency with phenothiazines.
•Chlorprothixene
•Flupenthixol
•Zuclopenthixol
Butyrophenones
•Droperidol
•Benperidol
•Haloperidol:
The butyrophenones are structurally distinct from
the phenothiazines and thioxanthenes. They offer
greater potency and fewer autonomic side effects.
II. Atypical antipsychotics
•Clozapine
•Olanzapine
•Quetiapine
•Risperidone
•Ziprasidone
•Amisulpride
•Zotepine
•Sertindole
The dibenzodiazepine clozapine
bears some structural resemblance
to the phenothiazine group but
causes little extrapyramidal toxicity.
The benzisoxazole risperidone is
representative of many of the
newer agents in having a better
side effect profile.
Psychiatric indications of neuroleptics
Schizophrenia is the primary indication for neuroleptics.
Unfortunately, many patients show little response and
virtually none show a complete response.
Antipsychotics are also indicated for schizoaffective
disorders, which share characteristics of both
schizophrenia and affective disorders. The psychotic
aspects of the illness require treatment with
antipsychotic drugs, which may be used with other
drugs such as antidepressants, lithium, or valproates.
Whilst a classical antipsychotic drug should
provide adequate treatment of positive symptoms
including hallucinations and delusions in at least
60% of cases, patients are often left with
unresolved negative symptoms such as
apathy, flattening of affect and alogia. Evidence
suggests that clozapine and the newer atypicals
have a significant advantage over classical drugs
against negative symptoms.
The manic phase in bipolar affective disorder often
requires treatment with neuroleptics (chlorpromazine,
haloperidol), though lithium or valproic acid
supplemented with high-potency benzodiazepines (eg,
lorazepam or clonazepam) may suffice in milder cases.
Recent controlled trials support the efficacy of
monotherapy with atypical antipsychotics in the
acute phase (up to 4 weeks) of mania, and
olanzapine has been approved for this indication.
Nonmanic excited states may also be managed
by antipsychotics, often in combination with
benzodiazepines.
Other indications for the use of antipsychotics
include disturbed behavior in patients with
Alzheimer's disease, and, with antidepressants,
psychotic depression.
Antipsychotics are not indicated for the treatment
of various withdrawal syndromes, eg, opioid
withdrawal. In small doses antipsychotics have
been promoted (wrongly) for the relief of anxiety
associated with minor emotional disorders, but
the anxiolytic agents are preferred.
Nonpsychiatric indications
Most older antipsychotics, with the exception of
thioridazine, have a strong antiemetic effect.
This action is due to D2 receptor blockade,
both centrally (in the chemoreceptor trigger zone
of the medulla) and peripherally (on receptors in
the stomach). Some drugs, such as prochlorperazine
are promoted only as antiemetics.
Phenothiazines with shorter side chains have considerable H1-receptor-blocking action and used for
relief of pruritus or, in the case of promethazine,
as preoperative sedatives. The butyrophenone
droperidol is used in combination with an opioid,
fentanyl, in neurolept-anesthesia (-analgesia).
Adverse reactions
Behavioral effects
The older typical antipsychotic drugs are unpleasant
to take. Many patients stop taking these drugs
because of the adverse effects, which may be
mitigated by giving small doses during the day and
the major portion at bedtime. A “pseudodepression”
that may be due to drug-induced akinesia usually
responds to treatment with antiparkinsonian drugs.
Other pseudodepressions may be due to higher
doses; the decreasing the dose may relieve the
symptoms. Toxic-confusional states may occur
with very high doses of drugs that have
prominent antimuscarinic actions.
Neurologic effects
Extrapyramidal reactions occurring early during
treatment with older agents include typical
Parkinson's syndrome, akathisia (uncontrollable
restlessness), and acute dystonic reactions
(spastic retrocollis or torticollis). Parkinsonism can
be treated, with conventional antiparkinsonian
drugs of the antimuscarinic type or, in rare cases,
with amantadine. Parkinsonism may be self-limiting,
so that an attempt to withdraw antiparkinsonian
drugs should be made every 3–4 months.
Akathisia and dystonic reactions also respond to
such treatment, but many prefer to use a sedative
antihistamine with anticholinergic properties,
eg, diphenhydramine.
Tardive dyskinesia
Persistent involuntary movements of mouth, tongue
or face.
Autonomic nervous system effects
Antimuscarinic (atropine-like) adverse effects:
urinary retention, dry mouth, midriasis.
Alpha-blockade: Orthostatic hypotension or impaired
ejaculation should be managed by switching to drugs
with less marked adrenoceptor-blocking actions.
Ocular complications
Deposits in the anterior portions of the eye (cornea
and lens) are a common complication of chlorpromazine therapy. They may accentuate the normal
processes of aging of the lens. Thioridazine is the
only antipsychotic drug that causes retinal deposits,
which in advanced cases may resemble retinitis
pigmentosa. The deposits are usually associated
with "browning" of vision. The maximum daily dose
of thioridazine has been limited to 800 mg/d to
reduce the possibility of this complication.
Metabolic and endocrine effects
Weight gain is very common, especially with
clozapine and olanzapine, and requires monitoring
of food intake, especially carbohydrates.
Hyperglycemia may develop.
Hyperprolactinemia in women results in the
amenorrhea – galactorrhea syndrome and infertility;
in men, loss of libido, impotence, and infertility
may result.
Toxic or allergic reactions
Agranulocytosis, cholestatic jaundice, and skin
eruptions occur rarely with the high-potency
antipsychotic drugs currently used.
Neuroleptic malignant syndrome
This life-threatening disorder occurs in patients who
are extremely sensitive to the extrapyramidal effects
of antipsychotics. The initial symptom is marked
muscle rigidity. If sweating is impaired, as it often
is during treatment with anticholinergic drugs,
fever may ensue, often reaching dangerous levels.
The stress leukocytosis and high fever associated
with this syndrome suggest an infectious process.
Autonomic instability, with altered blood pressure
and pulse rate, is often present. Creatine kinase
isoenzymes are usually elevated, reflecting
muscle damage.
This syndrome is believed to result from an excessively
rapid blockade of postsynaptic DA receptors. A severe
form of extrapyramidal syndrome follows. Early in
the course, vigorous treatment of the extrapyramidal
syndrome with antiparkinsonian drugs is worthwhile.
Muscle relaxants, particularly diazepam, are often
useful. Other muscle relaxants, such as dantrolene,
or DA agonists, such as bromocriptine, have been
reported to be helpful. If fever is present, cooling
by physical measures should be tried.
ANXIOLYTICS
(antianxiety drugs)
•Benzodiazepines
Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)
•Azapirones (buspirone)
•Benzoxazines (etifoxine)
•Sedative H1-blockers
(hydroxyzine)
•Nonselective
beta-blockers
•SSRIs
Gamma aminobutyric acid (GABA) is probably
the most important inhibitory transmitter in
the CNS. GABA-ergic neurones are distributed
widely in the CNS. GABA controls the state of
excitability in all brain areas and the balance
between excitatory inputs (mostly glutamatergic)
and the inhibitory GABA-ergic activity. If the balance
swings in favour of GABA, then sedation, amnesia,
muscle relaxation and ataxia appear and nervousness and anxiety are reduced. The mildest reduction
of GABA-ergic activity elicits arousal, anxiety, restlessness, insomnia and exaggerated reactivity.
Most drugs used in insomnia act as agonists
at the GABAA-receptor
and have effects other than their direct
sedating action, including muscle relaxation,
memory impairment, and ataxia, which can impair
performance of skills such as driving. Clearly those
drugs with onset and duration of action confined to
the night period will be most effective in insomnia
and less prone to unwanted effects during the day.
Those with longer duration of action are likely to
affect psychomotor performance, memory and
concentration; they will also have enduring
anxiolytic and muscle-relaxing effects.
Benzodiazepines (BDZs)
When GABA binds with the GABAA-receptor,
the permeability of the central
pore of the receptor to chloride ions increases,
allowing more ions into the neurone and decreasing
excitability. Classical benzodiazepines in clinical
use enhance the effectiveness of GABA by
lowering the concentration of GABA required for
opening the channel. These drugs are agonists at
the receptor and the flumazenil (antagonist)
prevents agonists from binding at the receptor site.
A model of the GABAA
receptor-chloride ion
channel macromolecular complex
Basic & Clinical
Pharmacology –
10th Ed. (2007)
Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)
BDZs enhance GABA-ergic inhibition.
Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)
Benzodiazepines (BDZs)
GABAAbenzodiazepine
receptor
complex
Adapted from Bennett and Brown
Clinical Pharmacology – 9th Ed. (2003)
+
GABAAsite
+
+
Cl+ Barbitu-
rate sate
Ethanol
Barbiturates
The most used
BENZODIAZEPINES
•Bromazepam
(t1/2 20 h)
•Flurazepam
(t1/2 > 40 h)
•Flunitrazepam
(t1/2 15 h)
•Nitrazepam
(t1/2 26 h
tab. 5 mg)
•In anaesthiology
•Diazepam (long t1/2)
•Midazolam
(t1/2 2 h)
•Triazolam
(t1/2 3 h)
Advantages of BDZs
BDZs have a high therapeutic index. In hypnotic doses
they do not affect respiration and cardiovascuar
functions. BDZs have practically no action on other
body systems. Only in i.v. injection the blood pressure
may fall. BDZs cause less distortion of sleep
architecture. They do not alter disposition of other
drugs by microsomal enzyme induction.
They have lower abuse liability: tolerance is mild,
psycholgical and physical dependence and
withdrawal syndrome are less marked.
A selectve BDZs antagonist flumazenil can be used
in case of poisoning.
CNS action and classification of BDZs
The action of all BDZs is qualitatively similar, but there
are prominent differences in selectivity and time
course of effect: different members of BDZs are used
for different therapeutic purposes.
In contrast to barbiturates BDZs exert relatively selective
anxiolytic (antianxiety), hypnotic (euhypnotic), muscle
relaxant and anticonvulsant (antiepileptic) effects.
Anxiolytic effect have all BDZs:
Alprazolam, Bromazepam (Lexotan – tab. 3 mg),
Chlordiazepoxide, Diazepam, Lorazepam,
Мedazepam, Nordiazepam etc.
Hypnotic (euhypnotic) effect
Bromazepam, Flurazepam, Flunitrazepam
Nitrazepam, Midazolam, Triazolam etc.
Anticonvulsive (antiepileptic) BDZs
Clonazepam, Clorazepate, Diazepam,
Lorazepam, Nitrazepam
Central muscle relaxants
Diazepam, Tetrazepam
Pharmacokinetics
BDZs are effective after administration
by mouth but enter the circulation at very different
rates that are reflected in the speed of onset of
action, e.g. alprazolam is rapid, oxazepam is slow.
The liver metabolizes them, usually to inactive
metabolites, but some compounds produce active
metabolites, some with long t1/2 which greatly
extends drug action, e.g. chlordiazepoxide,
clorazepate and diazepam.
Biotransformation of benzodiazepines
Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)
Biotransformation of benzodiazepines
Uses
•Benzodiazepines are used for: insomnia;
anxiety; alcohol withdrawal states; muscle spasm
(tetrazepam, diazepam) due to a variety of causes,
including tetanus and cerebral spasticity;
epilepsy (clonazepam, lorazepam, diazepam);
anaesthesia and sedation (midazolam, triazolam)
for endoscopies and cardioversion.
•Potent BDZs alprazolam and lorazepam injected
i.m. have adjuvant role in management of acutely
psychotic and manic patients.
•The choice of drug as hypnotic and anxiolytic
is determined by their pharmacokinetic properties.
Tolerance to the anxiolytic effects does not seem
to be a problem. In sleep disorders the situation is not
so clear; studies of subjective sleep quality show
enduring efficacy but about half of the objective
(EEG) studies indicate decreased effects after
4–8 weeks, implying that some tolerance develops.
The necessity for dose escalation in sleep disorders
is rare.
Withdrawal of BDZs should be gradual after
as little as 3 weeks' use but for long-term users
it should be very slow, e.g. about 6–12 weeks. Withdrawal should be slowed if marked symptoms occur
and it may be useful to substitute a long t1/2 drug (e.g.
diazepam) to minimize rapid fluctuations in plasma
concentrations. In difficult cases withdrawal may be
assisted by concomitant use of an antidepressant.
Commonly there is a kind of psychological dependence based on the fact that the treatment works to
reduce patients' anxiety or sleep disturbance and
therefore they are unwilling to stop. If they do stop,
there can be relapse, where original symptoms return.
Adverse effects of BDZs
Common reactions:
Fatigue, drowsiness, ataxia.
Infrequently reactions:
Constipation, incontinence,
urinary retention,
dysarthria, blurred vision,
dipoplia, hypotension,
nausea, dry mouth, skin rash, tremor.
In addition to those, BDZs can affect
memory and balance. Hazards with car driving
or operating any machinery can arise from amnesia and impaired psychomotor function,
in addition to sleepiness (warn the patient).
Amnesia for events subsequent to administration
occurs with i.v. high doses, for endoscopy, dental
surgery (with local anaesthetic), cardioversion, and
in these situations it can be regarded as a blessing.
Women (1 in 200), may experience sexual fantasies,
including sexual assault, after large doses of BDZs
as used in some dental surgery, and have brought
charges in law against male staff.
Plainly a court of law has, in the absence of a witness,
great difficulty in deciding whom to believe.
Paradoxical behavior effects and perceptual disorders,
e.g. hallucinations, can occur.
Headache, giddiness, GI upset, skin rashes and
reduced libido can occur. Extrapyramidal reactions,
reversible by flumazenil, are rare.
The PRC of BDZs is D. BDZs cross the placenta and
can cause fetal cardiac arrhythmia and muscular
hypotonia, suckling hypothermia and respiratory
depression in the new born.
Interactions
All BDZs potentiate the effects of alcohol
and other central depressants, and all are likely
to exacerbate breathing difficulties where this is
already compromised, e.g. in obstructive sleep
apnoea. BDZs potentiate the action of analgetics too.
The fluoroquinolones block GABAA-receptors and
decrease the action of BDZs.
Overdose. Flumazenil (Anexate®) selectively
reverses benzodiazepine effects and is useful in
diagnosis and in treatment of intoxication with them.
Flumazenil is a competitive partial agonist.
Fluoroquinolones
Adapted from Bennett and Brown (2003)
Azapirones
Buspirone is a selective partial agonsist of precynaptic
5-HT1A receptors. By stimulating these receptors it reduces activity of dorsal raphe serotoninergic neurons.
Buspirone has week D2-blocking action without antipsychotic and extrapyramidal effects.
Buspirone relieves mild to moderate generalized
anxiety, but is ineffective in severe cases (panic
reactions and obsessive compulsive disorder).
Sedative H1-blockers
Hydroxyzine is a H1-blocker with sedative, antiemetic,
antimuscarinic and spasmolytic effects. It is effective
in pruritus and urticaria.
Nonselective beta-blockers
Many symptoms of anxiety (palpitations, rise in blood
pressure, shaking, tremor, GI hurrying)
are due to sympathetic overactivty and these
symptoms reinforce anxiety. Propranolol and other
nonselective beta-blockers cut the vicious cycle and
provide the symptomatic relief. They do not affect
psychologycal symptoms, such as fear, tension and
worry, but are valuable in acutely stessful situations
(examination fear, unaccustomed public appearance).
SSRIs (selective serotonin reuptake inhibitors)
are effective in obsessive compulsive disorder (OCD),
phobias, panic and many types of sever generalized
anxiety disorders.
Treatment of anxiety
Anxiety is an universal phenomenon, but if is
frequent and persists in a severe form, it may
cause distress and markedly impair performance.
The established drugs for treatment of excessive
anxiety are BDZs, which must be used in the smallest
possible dose. The usual practice is to give ½ to 2/3 of
DD at bed time to insure good nightly rest; the remaining part is divided in 2 to 3 doses, given at day time.
Though the plasma half life of BDZs, used in anxiety,
are longer, divided day time doses are required
to avoid high plasma peaks.
Buspirone is a nonsedating alternative to BDZs for
less severe form of generalized anxiety.
The tricyclic and especially SSRI antidepressants
are now being increasingly used in many forms of
severe anxiety disorders. They produce a delayed
but often gratifying response and combined with BDZs.
The SSRIs are now drugs of choice for treatment of
social anxiety in which BDZs though effective, carry
abuse potential on long term use. Patients with
arterial hypertension, peptic ulcer, ulcerative colitis,
irrhitable bowel, gastroesophageal reflux, thyrotoxicosis, angina pectoris are often given low doses
BDZs intermittently in addition to specific therapy,
though anxiety may not be a prominent manifestations.