Anxiety

The normal fear response to threatening

stimuli include
defensive behaviors
autonomic reflexes
arousal and alertness
corticosteroid secretion
negative emotions
In anxiety states, these reactions occur in
an anticipatory manner, independently of
external events
Manifestations of anxiety
Verbal complaints The patient says he/she
is anxious, nervous, edgy
Somatic and autonomic effects The
patient is
restless and agitated
has tachycardia
increased sweating
weeping
gastrointestinal disorders
Social effects Interference with normal
productive activities
Pathological Anxiety
Generalized anxiety disorder (GAD)
People suffering from GAD have general
symptoms of motor tension, autonomic
hyperactivity, etc. for at least one month
Phobic anxiety
Strong fears of specific things or situations,
e.g. snakes, open spaces, flying, social
interactions
Post-traumatic stress disorder
Anxiety triggered by insistent recall of past
stressful experiences
Pathological Anxiety
Panic disorders
Attacks of overwhelming fear occurring in
association with marked somatic symptoms,
such as sweating, tachycardia, chest pains,
trembling, choking
Genetic?

Obsessive-compulsive behaviors
These patients show repetitive ideas
(obsessions) and behaviors (compulsions)
Pathology of anxiety
The stress response in humans involves a
cascade of hormonal events

release of corticotropin-releasing factor (CRF)

release of corticotropin

release of the stress hormones from the adrenal
cortex (glucocorticoids and epinephrine)

glucocorticoids exert negative feedback to the
hypothalamus

decreasing the release of CRF
Corticotropin-releasing factor, - key mediator of
autonomic, behavioral, immune, and endocrine
stress responses
The peptide appears to be anxiogenic,
depressogenic, and proinflammatory and leads
to increased pain perception
GABA inhibits CRF release
Benzodiazepines facilitate GABA
neurotransmission and therefore can improve
anxiety

Prolonged exposure of the CNS to glucocorticoid
hormones eventually depletes norepinephrine
levels in the locus ceruleus
As norepinephrine is an important
neurotransmitter involved in attention, vigilance,
motivation, and activity, the onset of depression
may subsequently occur
Anxiolytic drugs
Benzodiazepines
5-HT
1A
-receptor
agonists: Buspirone
-adrenoceptor
antagonists
Others - Hydroxyzine,
Methaqualone,
Chloral hydrate
Barbiturates
Classes of anxiolytic drugs
Benzodiazepines- used for treating both anxiety
states and insomnia

5-HT
1A
-receptor agonists - anxiolytic activity with
little sedation

-adrenoceptor antagonists - reduce physical
symptoms of anxiety (tremor, palpitations, etc.); no
effect on the affective component

Methaqualone, chloral hydrate - still used
occasionally to treat insomnia

Barbiturates - obsolete as anxiolytic/sedative
agents
Classes of anxiolytic drugs
Benzodiazepines: Diazepam,
Chlordiazepoxide, Oxazepam, Lorazepam,
Alprazolam

Azapirones: Buspirone, Gepirone,

- blocker: Propranolol

Sedative antihistaminics: Hydroxyzine
BZDs in anxiety
Minimal effects on other body
systems
Lower dependence producing liability
Safe in gross overdosage
Chlordiazepoxide
Slow oral absorption
Long lasting effects
t
1/2
:5-15 hrs

Diazepam
Dose: 5-30 mg

Oxazepam
Preferred in elderly and patients with
liver disease as hepatic metabolism is
negligible
Lorazepam
Shorter t
1/2
: 10-20 hrs
Very sedative and marked amnesia
OCD, tension syndromes

Alprazolam
High potency anxiolytic
Mood elevating action in mild
depression
t
1/2
: 12 hrs

Adverse effects of BZDs in
anxiolytic doses
Sedation
Lightheadedness
Psychomotor or cognitive impairment
Vertigo
Increased appetite and weight gain
Alteration in sexual function
Failure in ovulation
Dependence
Buspirone
Used in various anxiety disorders
Ineffective in controlling panic attacks
No significant sedation
No cognitive/ functional impairment
Doesn't interact with BDZ receptor or modify
GABAergic transmission
Doesn't produce tolerance or physical
dependence
No muscle relaxant activity
No anticonvulsant activity
Analogs: Ipsapirone, gepirone, tandospirone
Buspirone: MOA
Buspirone is a partial agonist at presynaptic
5-HT
1A
receptors - inhibitory autoreceptors that
reduce the release of 5-HT and other mediators

5-HT
1A
subtype is important in the brain in relation
to mood and behaviour

Inhibition of the activity of noradrenergic locus
coeruleus neurons - interferes with arousal
reactions

Weak D
2
blocking action: No mood elevation, EPS

Buspirone takes days or weeks to produce its
effect in humans
Pkinetics
Rapid absorption
Extensive first pass metabolism (BA<5%)
One active metabolite
Excretion: urine and faeces

Side-effects
Less troublesome than with BDZs
They include
Dizziness
Nausea
Headache
-adrenoceptor Antagonists
Used mainly to reduce physical symptoms of
anxiety due to sympathetic overactivity
tremor, palpitations, rise in BP

Effectiveness depends on block of peripheral
sympathetic responses rather than on any
central effects

They have no effect on the affective
component