Download Panic Disorder

ANXIETY
DISORDERS
Definition
Anxiety is an unpleasant feeling of apprehension or fearful
concern.
It can be :
-Normal, reasonable and expected response to a
stressful situation or perceived danger (adaptive purposes)
or
It may be:
-An excessive, irrational state that signifies a mental
disorder (maladaptive)
Clinical subtypes of anxiety include:
•Generalized anxiety disorder (GAD)
•Panic disorder (PD)
•Obsessive-compulsive disorder (OCD)
• Posttraumatic stress disorder (PTSD)
•Social phobia (SP)
Epidemiology
The prevalence of anxiety disorders in the general
population is about 10-20%
There is a high rate of co-morbidity with depressive
disorders.
The overall female to male ratio is nearly 2:1.
The age of onset of most anxiety disorders is in young
adulthood (twenties and thirties)
The maximum prevalence of generalized anxiety and
agoraphobia-panic in the general population is in the 50-64
year age group.
Pathophysiology
Neurotransmitter systems involved in anxiety generation
include:
1) The GABAA-benzodiazepine receptor complex
2) The serotonin (5HT1A/5HT2C) receptor group
3) The noradrenergic system
These brain receptor systems mediate the effects of the three
main classes of drugs used for treating neurotic disorders
Patients with anxiety disorders, particularly PD, exhibit
symptoms of peripheral autonomic hyperactivity including:
Tremulousness, palpitations, and hyperventilation
According to the noradrenergic model:
The autonomic nervous system of patients with anxiety
disorders becomes oversensitive to various stimuli,
responding with:
excess amount of noradrenaline.
GABA (Gamma-aminobutyric acid) is the major inhibitory
neurotransmitter
Attenuation of the effects of GABA causes:
Increased arousal
Enhanced memory
Anxiety
Restlessness
Insomnia
Exaggerated reactivity (startle)
Convulsions
The indolamine neurotransmitter serotonin (5HT) has been
proposed to play a role in anxiety disorders
The hypothalamic-pituitary-adrenal axis (HPA) also plays a
role in anxiety disorders
Perceived threat or stress activates the HPA axis and one of
its components, corticotrophin-releasing factor (CRF)
Evidence suggests that CRF is responsible for integrating
the endocrine, autonomic, and behavioral responses of an
organism to stress
Clinical presentation and diagnosis
It is important to exclude organic causes such as:
•Thyrotoxicosis
•Excessive use of stimulant drugs such as caffeine
•The possibility of alcoholism or withdrawal effects from
benzodiazepines
Unnecessary investigations should be avoided if possible
It is also important to determine whether the anxiety is
situational anxiety (usually last 2-3 weeks) or an anxiety
disorder
A variety of medical conditions may cause anxiety
symptoms
In this case the anxiety may be labeled as anxiety disorder
due to a general medical condition
Anxiety symptoms may be associated with almost all major
psychiatric illnesses such as:
•Schizophrenia
•Major depression
•Dysthymia
•Mania
•Delirium
•Dementia
•Substance-related disorders
Medical disorders associated with anxiety
Cardiovascular
Arrhythmias, Angina
MI, HTN, CHF
Mitral valve prolapse
Respiratory
COPD, PE, Pneumonia
Hyperventilation
Endocrine
Hyperthyroidism
Hypothyrodisim
Hypoglycemia
Pheochrmocytoma
Metabolic
B12 deficiency, Porphyria
Gastrointestinal
Ulcerative colitis
Peptic ulcer disease
Irritable bowel syndrome
Inflammatory
Rheumatoid arthritis
Lupus erythematosus
Neurologic
Neoplasms
Encephalitis
Miscellaneous
Chronic infections
Malignancies
Several pharmacologic agents are known to produce anxious
symptoms
Anxiety associated with the use of these agents is seen when
they are abruptly discontinued after chronic use
Some pharmacologic agents known to produce anxious
symptoms
CNS stimulants
Albuterol,
Amphetamines,
Cocaine,
Fenfluramine,
Isoproterenol,
M ethylphenidate
CNS depressants
Alcohol,
Narcotic analgesics
Barbiturates,
Meprobamate,
BZDs
Nonprescription drugs
Caffeine,
Nicotine,
Decongestants:
(ephedrine,
pseudo
ephedrine,
oxymetazoline,
naphzoline.....)
Generalized Anxiety Disorder
The essential feature of GAD is excessive and unrealistic
worry about several life situations that has been present for
6 months or longer
The anxiety must be accompanied by at least three of the
following six symptoms:
•Restlessness
•Fatigability
•Difficulty concentrating
•Irritability
•Muscle tension
•Disturbed sleep
Many patients with GAD also experience somatic symptoms
(e.g., headache, irritable bowel syndrome) and depressive
symptoms
Panic Disorder:
A Panic attack is a discrete period of intense fear or discomfort
that is accompanied by at least four somatic or cognitive
symptoms
Palpitations or tachycardia
Sweating
Trembling or shaking
Sensations of shortness of
breath or smothering
Feeling of choking
Chest pain
Nausea or abdominal distress
Feelings of dizziness, lightheadedness, or fainting
Feelings of unreality, or feelings
of being detached from oneself
Fear of losing control or going crazy
Fear of dying
Numbness or tingling sensations
Chills or hot flashes
Panic attacks occur in the context of several different anxiety
disorders and it is separate from the disorder
The essential criterion of Panic Disorder (PD)is
•Recurrent, unexpected panic attacks (without specific
stimulus)
•Followed by at least one month of persistent concern with
the possibility of experiencing further attacks,
•Worry about the possible implications or consequences of
the episodes, or
•A significant change in the patient’s behavior secondary to
the attacks
Obsessive-Compulsive Disorder:
The essential feature of OCD is recurrent obsessions or
compulsions
•That cause marked distress,
•Are time consuming, or
•Interfere significantly, with normal
functioning, social activities, or relationships
occupational
Posttraumatic Stress Disorder:
PTSD may develop when a person experiences or witnesses
an event that involves actual or threatened death or serious
injury, or a threat to the physical integrity of self or others
As a response to the event, the person reacts with intense
fear, helplessness, or horror
Social Phobia:
SP is characterized by a persistent fear of social or
performance situations in which embarrassment may occur
TREATMENT
•Drugs provide only symptomatic treatment of anxiety and do
not cure the underlying disorder
•They may temporarily help patients to cope with stress and
provide a short-term cover
•This will allows time for more specific treatments to take
effect
•Effective treatment in the long term is by nonpharmacological interventions including:
-Counseling
-Psychotherapy
-Behavioral and cognitive methods
-Relaxation and anxiety management training
Pharmacotherapy
Commonly used antianxiety medications include:
BZDs
Buspirone
β-blockers
TCAs
MAOIs,
SSRIs
Benzodiazepines
Currently available BZD antianxiety agents are
Alprazolam (Xanax®)
Chlordiazepoxide (Librium®)
Clonazepam (Rivotril®)
Diazepam (Valium®)
Lorazepam (Ativan®)
Oxazepam (Serax®)
•Still the most commonly prescribed drugs for anxiety
•Have potent anxiolytic effects which are exerted at low
doses that produce minimal sedation
•In subjects with low trait anxiety and in non-stressful
conditions BZDs may paradoxically increase anxiety and
impair psychomotor performance
The major site of anxiolytic action is the limbic system
The effect is mediated by a primary action at GABAA
receptors, resulting in enhancement of inhibitory GABA
activity
Secondary suppression of noradrenergic and/or serotonergic
pathways may be of particular importance in relation to
anxiolytic effects
The most common indication for BZD therapy is GAD
Alprazolam has the efficacy of as an antipanic agent
2 to 6 mg/day usually is sufficient for most patients with PD
taking alprazolam
The total daily BZD dosages in PD tend to be much higher
than those in GAD
Patients experiencing interdose symptom breakthrough:
switch from alprazolam to clonazepam (anticonvulsant)
Clonazepam has longer half life
Patients who do not respond to one BZD may respond to
another
The high-potency BZD are effective for SP, with onset of
response occurring within 2 weeks.
Clonazepam was reported to significantly improve patients
with long-term treatment in dose of 1.5 to 2 mg/day
Alprazolam is another BZD considered effective for SP at 3
mg/day.
Choice of BZD in anxiety
BZD can be valuable in the short term management of
anxiety because of their anxiolytic efficacy and rapid onset
of action.
Pharmacokinetic characteristics affect the choice of an
appropriate BZD
Potent BZDs such as lorazepam have been widely used for
anxiety disorders but are probably inappropriate.
Lorazepam is moderately rapidly eliminated and needs to be
taken several times daily.
Declining blood concentrations may lead to inter-dose
anxiety as the anxiolytic effect of each tablet wears off.
A slowly eliminated BZD such as diazepam is more
appropriate in most cases.
Diazepam has a rapid onset of action, and its slow
elimination ensures a steady blood concentration.
It should be prescribed in the minimal effective dosage to
avoid cumulative effects
It can also be used as a hypnotic, thus avoiding the need for a
separate hypnotic drug.
Patients with hypoalbuminemia may have greater free
fraction of BZDs that are highly protein bound.
For these patients, lorazepam or alprazolam would be a
rational choice because of its lower percentage of protein
binding.
Patients should be started on low dosages and titrated
upward to the lowest effective dosage.
The anxiolytic use of BZDs should generally be limited to
short-term (2 weeks) or intermittent use.
Parenteral administration of lorazepam or diazepam may
occasionally be indicated for severely agitated psychiatric
patients.
Profile of some drugs used in anxiety disorders
Drug
Benzodiazepines
Alprazolam
Chlordiazepoxide
Clonazepam
Diazepam
Lorazepam
Oxazepam
Buspirone
β
Atenolol
Propranolol
Tricyclic antidepressants
Amitriptyline
Clomipramine
Imipramine
SSRIs
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline
Citalopram
MAOIs
Moclobemide
Phenelzine
a d r e n o c e p t o r
Elimination half-life (h)
Anxiolytic dosage
Maximum dosage
12-15
5-30
20-50
20-100
10-18
4-15
2-11
0.25-0.5 mg TID
15-30 mg TID
0.5 mg BID
2-5 mg TID
1 mg TID
10-30 mg TID
5-10 mg TID
1 mg QID
100 mg QHS
3 mg BID
40 mg QHS
5 mg BID
30 mg TID
20 mg TID
6-7
2-4
25 mg QAM
40 mg BID
100 mg QAM
120 mg TID
10-25
16-20
4-18
25-50 mg QHS
25 mg QHS
25-50 mg QHS
300 mg QHS
250 mg QHS
300 mg QHS
20 mg QAM
100 mg QHS
20 mg QAM
50 mg QAM
10-20 mg QAM
80 mg QAM
150 mg BID
50 mg QAM
200 mg QAM
40 mg QAM
300 mg daily
15 mg TID
300 mg BID
30 mg TID
a n t a g o n i s t
2-3 days
15
20
26
33
1-4
1
Adverse effect of anxiolytic use
Tolerance
Tolerance to the anxiolytic effects of BZDs seems to
develop more slowly than to the hypnotic effects.
Most patients reporting initial drowsiness find that it wears
off in a few days while the anxiolytic effects remains for
some weeks.
BZDs are usually no longer effective in the treatment of
anxiety after 1-4 months of regular use.
Psychomotor impairment
Long-term use of BZDs results in psychomotor impairment
and has adverse effects on memory
Many patients on long-term BZDs complain of poor
memory, and incidents of shoplifting have been attributed to
memory lapses caused by BZDs use.
Additive effects with other CNS depressants including
alcohol occur, and may contribute to traffic and other
accidents
Disinhibition, paradoxical effects
Occasionally, BZDs produce paradoxical stimulant effects.
These effects are most marked in anxious subjects and
include: Excitement
Increased anxiety
Irritability
Outbursts of rage
Increased daytime anxiety can occur with rapidly
eliminated BZDs, such as lorazepam, and is probably a
withdrawal effect.
Affective reactions
Chronic use of BZDs:
•Can aggravate depression and provoke suicide in
depressed patients
•Can cause depression in patients with no previous history
of depressive disorder.
•Some patients on long-term BZDs complain of
‘emotional anesthesia’ with inability to experience either
pleasure or distress.
•In some patients, BZDs induce euphoria, and they are
increasingly used as drug of abuse when taken in high
doses or self administered intravenously
Dependence
The greatest drawback of chronic BZD use is the
development of drug dependence.
The regular use of therapeutic doses of BZDs for more than
a few weeks can give rise to dependence
Withdrawal symptoms on cessation of drug use occur in
over 40% of patients.
Abuse
Patients with a history of alcohol or other drug abuse are at
greatest risk of becoming BZD abusers.
Diazepam, followed by alprazolam and lorazepam, has
been judged to have the greatest potential for abuse among
the BZDs.
BZD withdrawal
Abrupt withdrawal in dependent subjects is dangerous, and
can induce acute anxiety, psychosis or convulsion.
BZDs should be discontinued gradually, by one-eighth to
one-fourth of the total dosage every few weeks to allow
careful monitoring and to reduce the risk of withdrawal
or rebound.
Substituting a long-half-life BZD for a short to
intermediate-half-life drug before downward tapering may
reduce the severity of withdrawal symptoms
Drug interactions with the BZD antianxiety agents
Drug
Antacids
β
-b lo ck er s
Cimetidine
Digoxin
Disulfiram
Ethanol
Hydantoins
Effect
Drug
Decreased rate of diazepam and Isoniazid
chlordiazepoxide absorption
Levodopa
in oxidative metabolism of diazepam
Decreased oxidative metabolism of Probenecid
most BZDs
↑digoxin serum concentrations Rifampin
with reported toxicity with addition
of alprazolam or diazepam
Decreased oxidative metabolism of Theophylline
BZDs
Inhibition of BZD metabolism; Valproic acid
additive or synergistic CNS
depression
↑&↓ phenytoin serum concent. Oral
reported with diazepam & contraceptives
chlordiazepoxide;
Increased oxazepam eelimination
P ro p ra n o l o l c a u se a sm a ll r e d u c ti o n
Effect
Decreased oxidative metabolism
of diazepam
Worsening of parkinsonian
symptoms
May increase lorazepam level by
decreasing clearance
Increased oxidative metabolism
of diazepam
Antagonism of CNS depressant
effects of BZDs
Decreased oxidative metabolism
of diazepam, protein binding of
diazepam may also be altered.
↓ clearance of chlordiazepoxide,
diazepam and alprazolam;
↑ metabolism of lorazepam and
oxazepam
Buspirone
Buspirone has a structure and mode of action completely
different from that of BZDs
It has mixed agonist/antagonist action at serotonergic
receptors that are thought to be involved in anxiety
It has anxiolytic effects comparable with those of BZDs, but
it is without sedative/hypnotic, anticonvulsant or muscle
relaxant effects
A major disadvantage is that anxiolytic effects are delayed
for up to 3 weeks, and in some patients buspirone produces
dysphoria and may actually increase anxiety
Concurrent use of buspirone and MAOIs is
recommended because blood pressure may increase
not
Buspirone may displace digoxin from plasma proteins.
Serum haloperidol may be increased by buspirone.
Unlike BZDs, buspirone does not produce
-Physical dependence
-Withdrawal symptoms
-Abuse
-Lacks interaction with alcohol
Buspirone does not usually alleviate anxiety associated with
BZD withdrawal.
Buspirone is recommended for short term use only and its
place in the treatment of anxiety is doubtful at present.
Antidepressant drugs
A number of tricyclic (TCAs) and other antidepressants
have additional sedative or anxiolytic effects
They appear to be as effective as BZDs in GAD and
superior in agoraphobia.
The efficacy of imipramine in treating PD is now well
established, and recently clomipramine has been reported to
be superior to imipramine in PD treatment.
Also, clomipramine is well-documented to be effective in
treating OCD.
The TCAs have the most solidly established efficacy in
treating core intrusive PTSD symptoms.
Imipramine and amitriptyline have produced positive results
in treating veterans with PTSD.
TCAs are also of value in depressive states associated with
anxiety and in anxiety/depression associated with BZD
withdrawal
Selective serotonin reuptake inhibitors (SSRIs) and
monoamine oxidase inhibitors (MAOIs) are also effective in
phobic states and panic disorders.
A disadvantage of all these drugs is:
•Their slow onset of action which may be delayed for 2-4
weeks
•They may initially exacerbate anxiety symptoms.
For this reason it is advisable to start with small doses.
The mode of action of these drugs is thought to be:
•An initial increase in central serotonergic and noradrenergic
activity
•This may cause further anxiety
•Followed by a down-regulation of adrenergic and
serotonergic receptors, accounting for the delayed anxiolytic
effect.
Another disadvantage of antidepressants is that:
•Some are toxic in overdose
•Have many adverse effects including anticholinergic
actions, cardiovascular actions, especially in the elderly
•Drug interactions, and interaction with certain foods.
Antidepressants more suitable for long term use than BZDs,
and can be continued for several months.
They are often effective in low to moderate doses and do not
cause cognitive impairment.
Some patients have difficulty in stopping these drugs
because of withdrawal symptoms, which include:
•Rebound excessive cholinergic activity
•Increased anxiety or depression.
Withdrawal should therefore be carried out gradually.
β adrenoceptor blockers
Some somatic symptoms of anxiety such as palpitations and
tremor are due to excessive sympathetic activity acting on
peripheral β adrenoceptors
These symptoms can be alleviated by β adrenoceptor
blockers such as propranolol
These drugs, when used in small doses which do not induce
hypotension, can be of value in acutely stressful situations
or panic attacks where physical symptoms dominate the
picture
They have little effect on subjective symptoms
If used regularly, withdrawal should be gradual to prevent
rebound tachycardia and return of palpitations.
Antipsychotic drugs
Some antipsychotic drugs such as chlorpromazine and
haloperidol have sedative and anxiolytic effects
They may, on occasion, be of short term use in severe
anxiety disorders associated with panic.
They have a rapid onset of action (within 1 hr) but should
be used in minimal dosage and only short-term since they
carry a risk of dyskinesias and other adverse effects.
Anxious patients may have withdrawal problems after
regular use.
The growing tendency to prescribe these drugs as
alternatives to BZDs is to be deprecated.
Rational use of drugs in anxiety
It is clear that drugs do not provide a long-term solution for
anxiety.
In acute anxiety states, often precipitated by stress, shortterm BZDs may help to cop with the immediate situation
as they have high efficacy and a rapid onset of action.
Diazepam is probably the drug of choice.
A single dose may be sufficient, and it should not be
continued regularly for more than 1 or 2 weeks
It can be given intermittently and intermittent courses can
be repeated if necessary
Potent, short acting BZDs such as alprazolam and lorazepam
should be avoided
BZDs are not recommended in bereavement because their
amnesic actions may interfere with subsequent adjustment
If longer-term treatment is required in GAD,
anxiety/depression or phobic states, sedative TCAs or SSRIs
are preferred
These drugs are efficacious, can be used for several months
and do not interfere with non-pharmacological treatment
MAOIs are effective in panic and phobic disorders
β adrenoceptor blockers are effective in controlling somatic
symptoms such as palpitations and tremor
The most effective long-term treatment of anxiety is by
psychological methods, which can include:
•Self-help groups
•Counseling
•Behavioral and cognitive techniques
•Anxiety management training
•Psychotherapy
Common therapeutic problems in the management of anxiety
Problem
BZD overdose
Contributing factors
BZD often taken with other
drugs including
antidepressants,
paracetamol, alcohol and
opiates
Management
Flumazenil (a competitive antagonist at BZD
receptors) may be administered cautiously.
It may precipitate withdrawal reactions in
BZD-dependent patients. Flumazenil is shortacting, repeated administration may be required
if long-acting BZD has been taken in overdose.
Patients wishing to
withdraw from
lorazepam or other
potent, relatively shortacting BZDs
Lorazepam is 10 times
potent than diazepam.
If BZD withdrawal is indicated, it is usually
advisable to switch to the equivalent diazepam
dose then withdrawal can be carried out
gradually at the rate of 1-2 mg diazepam every
2-4 weeks
Patients taking a
combination of a BZD
and an antidepressant
drug
An antidepressant may have
been prescribed for
depression caused by
chronic BZD use, or for
patients with anxiety/depression, although this is not
recommended.
Gradual withdrawal from BZD may be
indicated. In this case, the patient should
continue on the antidepressant drug until BZD
withdrawal is complete.
The advisability of continuing or slowly
withdrawing the antidepressant can then be
considered
Patients attending
pharmacies for several
months to obtain repeat
prescriptions for BZDs
A considerable proportion of
these patients are likely to be
dependent and to be at risk
of adverse effects, especially
if elderly
The pharmacist may approach the prescriber
and suggest methods of withdrawal and help in
supervision of withdrawal.
BZD abuse
Illicit BZD abuse is common
among polydrug users,
alcoholic, and psychiatric
patients.
The source of most illicitly obtained BZDs is
stolen prescriptions. Reduction in BZD
prescribing would help to alleviate this
problem.