ANXIETY

INTRODUCTION
• Anxiety is an emotional state commonly caused by the perception of real or perceived
danger that threatens the security of an individual. It allows a person to prepare for or
react to environmental changes.
• Everyone experiences a certain amount of nervousness and apprehension when faced
with a stressful situation. this is an adaptive response, and is transient in nature.
• Anxiety can produce uncomfortable and potentially debilitating psychological (e.g.,
worry or feeling of threat) and physiological arousal (e.g., tachycardia or shortness of
breath) if it becomes excessive.
• Some individuals experience persistent, severe anxiety symptoms and possess irrational
fears that significantly impair normal daily functioning. These persons often suffer from
an anxiety disorder
• To treat anxiety appropriately, the clinician must make a reliable diagnosis. It is
essential that the distinction between short-term symptoms of anxiety and
anxiety disorders be understood.
• Common or situational anxiety is a normal response to a stressful circumstance.
Although symptoms can be severe, they are temporary and usually last no more
than 2 or 3 weeks. While short-term, “as needed” treatment with an anxiolytic
agent such as a benzodiazepine is common and may provide some symptomatic
relief, prolonged drug therapy is unnecessary
 EPIDEMIOLOGY

• In United States, the 1-year prevalence rate for anxiety disorders was
13.3% in persons aged 18 to 54 years and 10.6% in those over age 55
years
• Anxiety disorders are a group of heterogeneous illnesses that
develop before age 30 and are more common in women, individuals
with social issues, and those with a family history of anxiety and
depression.
 ETIOLOGY
(1) Common Medical Illnesses Associated with Anxiety Symptoms
• Cardiovascular Neurologic
Dementia, Migraine, Parkinson’s
• Angina, Arrhythmias, Congestive Heart Failure, Ischemic Disease, Seizures, Stroke, Neoplasms,
Heart Disease, Poor Pain Control
• Myocardial Infarction Respiratory System
Asthma, Chronic Obstructive
• Endocrine And Metabolic
Pulmonary Disease, Pulmonary
• Cushing’s Disease, Hyperparathyroidism, Embolus,
Hyperthyroidism, Pneumonia
• Hypothyroidism, Hypoglycemia, Hyponatremia, Others
Hyperkalemia, Anemias, Systemic Lupus
Erythematosus, Vestibular
• Pheochromocytoma, Vitamin B12 Or Folate Deficiencies Dysfunction
 (2) DRUGS ASSOCIATED WITH ANXIETY SYMPTOMS
• Anticonvulsants: Carbamazepine
• Antidepressants: Selective Serotonin
Reuptake Inhibitors, Tricyclic
• Antidepressants
• Antihypertensives: Felodipine
• Antibiotics: Quinolones, Isoniazid
• Bronchodilators: Albuterol, Theophylline
• Corticosteroids: Prednisone
• Dopa Agonists: Levodopa
• Herbals: ma huang, ginseng, ephedra
• Nonsteroidal anti-inflammatory drugs:
ibuprofen
• Stimulants: amphetamines,
methylphenidate, caffeine, cocaine
• Sympathomimetics: pseudoephedrine
• Thyroid hormones: levothyroxine
• Toxicity: anticholinergics, antihistamines,
digoxin
• Withdrawal: alcohol, sedatives
 (3) PSYCHIATRIC DISEASES ASSOCIATED WITH ANXIETY

• Anxiety symptoms are extremely common in patients with mood

disorders, schizophrenia, delirium, dementia, and substance use
disorders.
• Most psychiatric patients will have two or more concurrent
psychiatric disorders (comorbidity) within their lifetime.
 PATHOPHYSIOLOGY
• The modulation of normal and pathologic anxiety states is associated with multiple regions of the
brain and abnormal function in several neurotransmitter systems, including norepinephrine (ne), γ –
aminobutyric acid (gaba), and serotonin (5-ht).
• current neuroanatomic models of fear (i.e., the response to danger) and anxiety (i.e., the feeling of
fear that is disproportionate to the actual threat) include some key brain areas.
• The amygdala, a temporal lobe structure, plays a critical role in the assessment of fear stimuli and
learned response to fear. The locus ceruleus (lc), located in the brain stem, is the primary ne-
containing site in the brain, with widespread projections to areas responsible for implementing
fear responses (e.g., vagus, lateral and paraventricular hypothalamus).
• The hippocampus is integral in the consolidation of traumatic memory, and along with the
entorhinal cortex, contextual fear conditioning that is involved in overgeneralization of the fear
response. The hypothalamus is the principal area for integrating neuroendocrine and autonomic
responses to a threat.
 NEUROCHEMICAL THEORIES

• NORADRENERGIC MODEL
• The autonomic nervous system of anxious patients is hypersensitive and overreacts
to various stimuli. Many anxious patients clearly display symptoms of peripheral
autonomic hyperactivity.
• In response to threat or fearful situations, the LC serves as an alarm center, activating
NE release and stimulating the sympathetic and parasympathetic nervous systems.
• Chronic central noradrenergic overactivity downregulates α2-adrenoreceptors in
patients with GAD. This receptor is hypersensitive in some patients with panic
disorder. Patients with SAD appear to have a hyperresponsive adrenocortical
response to psychological stress.
 Noradrenergic model continues……………..

• By administering drugs that have a relatively specific effect on the LC,

researchers have further explored the NE theory of anxiety and panic disorder.
Drugs with anxiogenic effects (e.g., yohimbine [an α2-adrenergic receptor
antagonist]) stimulate LC firing and increase noradrenergic activity.
• NE in turn increases glutamate release (an excitatory neurotransmitter). This
produces subjective feelings of anxiety and can precipitate a panic attack in
those with panic disorder, but not in normal volunteers or those with other
psychiatric illnesses.
• Drugs with anxiolytic or antipanic effects (e.g., benzodiazepines,
antidepressants, and clonidine) inhibit LC firing, decrease noradrenergic activity,
and block the effects of anxiogenic drugs.
 GABA RECEPTOR MODEL
• There are two superfamilies of GABA protein receptors: GABAA and GABAB. Drugs to
reduce anxiety and produce sedation target the GABAA receptor.
• The GABAB receptor is a G-protein coupled receptor postulated to be involved in the
presynaptic inhibition of GABA release. GABAA receptors are ligand-gated ion
channels. The opening of the channel is composed of five peptide subunits (i.e., α, β, γ
, δ, or ρ subunits) that surround a central pore that crosses the neuronal cell
membrane and is permeable to chloride.
• Benzodiazepine ligands either enhance or diminish the inhibitory effects of GABA.
GABA, the major inhibitory neurotransmitter in the CNS, has a strong regulatory or
inhibitory effect on the 5-HT, NE, and dopamine (DA) systems. When GABA binds to
the GABAA receptor, the chloride ion channel opens and permits the influx of
negatively charged chloride ions; this results in hyperpolarization of the cell
membrane and decreases nerve cell excitability.
• The specific role of the GABA receptors in anxiety disorders has not been
established. The number of GABAA receptors can change with alterations in the
environment (e.g., chronic stress) and the subunit expression can be altered by
hormonal changes. In patients with GAD, benzodiazepine binding in the left
temporal lobe is reduced.
• Abnormal sensitivity to antagonism of the benzodiazepine binding site and
decreased binding was demonstrated in panic disorder. This is consistent with the
suggestion that panic disorder is secondary to a lack of central inhibition that
results in uncontrolled elevations in anxiety during panic attacks.
 SEROTONIN MODEL
• The 5-HT system is dysregulated in patients with anxiety disorders. 5-HT is primarily an
inhibitory neurotransmitter that is used by neurons originating in the raphe nuclei of the
brain stem and projecting diffusely throughout the brain (e.g., cortex, amygdala,
hippocampus, and limbic system).
• The diverse actions of 5-HT are regulated by at least 14 different postsynaptic receptor
subtypes. Abnormalities in serotonergic functioning through release and uptake at the
presynaptic autoreceptors (5-HT1A/1D), the serotonin reuptake transporter site (SERT), or
effect of 5-HT at the postsynaptic receptors (e.g., 5-HT1A, 5-HT2A, and 5-HT2C) may play a
role in anxiety disorders.
• Preclinical models suggest that greater 5-HT function facilitates avoidance behavior;
however, primate studies show that reducing 5-HT increases aggression. It is postulated that
greater 5-HT activity reduces NE activity in the LC, inhibits defense/escape response via the
periaqueductal gray region, and reduces hypothalamic release of corticotropin-releasing
factor.
• The selective serotonin reuptake inhibitors (SSRIs) acutely increase 5-HT levels by
blocking the SERT to increase the amount of 5-HT available postsynaptically, and are
efficacious in blocking the manifestations of panic and anxiety. The precise role of 5-HT
in panic disorder is unclear; however, 5-HT may play a role in the development of
anticipatory anxiety. Low 5-HT activity may lead to a dysregulation of other
neurotransmitters.
• NE and 5-HT systems are closely linked, and interactions between the two are reciprocal
and vary. NE may act at presynaptic 5-HT terminals to decrease 5-HT release, and its
activity at postsynaptic receptors can cause increased 5-HT release.
• Stimulation of the postsynaptic 5-HT2A receptors in the limbic system results in anxiety
and avoidance behavior.
 CLINICAL PRESENTATION
• Anxiety disorders into several categories:
• GAD,
• panic disorder (with or without agoraphobia),
• agoraphobia,
• SAD,
• specific phobia,
• obsessive-compulsive disorder,
• posttraumatic stress disorder, and
• acute stress disorder
 PRESENTATION OF GENERALIZED ANXIETY DISORDER
• PSYCHOLOGICAL AND COGNITIVE SYMPTOMS IMPAIRMENT
• Excessive anxiety Social, occupational, or other important

• Worries that are difficult to control functional areas

• Feeling keyed up or on edge Poor coping abilities

• Poor concentration or mind going blank

• PHYSICAL SYMPTOMS
• Restlessness
• Fatigue
• Muscle tension
• Sleep disturbance
• Irritability
 SYMPTOMS OF A PANIC ATTACK
• PSYCHOLOGICAL SYMPTOMS PHYSICAL SYMPTOMS
• Depersonalization • Abdominal distress
• Derealization
• Chest pain or discomfort
• Fear of losing control
• Fear of going crazy • Chills
• Fear of dying • Dizziness or light-headedness
• Feeling of choking
• Hot flushes
• Palpitations
• Nausea
• Paresthesias
• Shortness of breath
• Sweating
• Tachycardia
• Trembling or shaking
 PRESENTATION OF SOCIAL ANXIETY DISORDER
• FEARS
• Physical symptoms
• Being scrutinized by others
• Blushing
• Being embarrassed • “Butterflies in the stomach”
• Being humiliated • Diarrhea
• Sweating
• SOME FEARED SITUATIONS • Tachycardia
• Addressing a group of people • Trembling
• Types
• Eating or writing in front of others
• Generalized type: fear and avoidance extend to a wide
• Interacting with authority figures range of
• Speaking in public • social situations
• Nongeneralized type: fear is limited to one or two
• Talking with strangers
situations
• Use of public toilets
 TREATMENT: GENERALIZED ANXIETY DISORDER
• The short-term goals of therapy in the acute management of GAD are to reduce the severity and
duration of the anxiety symptoms and to improve overall functioning.
• The long-term goal in GAD is remission with minimal or no anxiety symptoms and no functional
impairment. DRUG CHOICES FOR ANXIETY DISORDERS
 DRUG CHOICES FOR ANXIETY DISORDERS
• NONBENZODIAZEPINE ANTIANXIETY AGENTS FOR GENERALIZED ANXIETY DISORDER
 NONPHARMACOLOGIC THERAPY

• Psychoeducation,
• Short-term counseling,
• Stress management,
• Psychotherapy,
• Meditation, or
• Exercise.
 PHARMACOLOGIC THERAPY

• The benzodiazepines are the most effective, safe, and commonly prescribed
drugs for the rapid relief of acute anxiety symptoms.
• Because of the lack of dependency and tolerable adverse effect profile,
antidepressants have emerged as the treatment of choice for the long-term
management of chronic anxiety, especially in the presence of comorbid
depressive symptoms.
• Buspirone is an additional anxiolytic option in patients without comorbid
depression or other anxiety disorders (e.g., panic disorder and SAD).
 ANTIDEPRESSANT THERAPY

• Antidepressants are considered first-line agents in the long-term management

of GAD.
• Venlafaxine extended-release, paroxetine, and escitalopram are FDA-approved
antidepressants for GAD.
• Imipramine is considered when patients fail to respond to SSRIs or venlafaxine.
The antianxiety response of antidepressants is delayed by 2 to 4 weeks or
longer.
• Venlafaxine extended-release, a serotonin-norepinephrine reuptake inhibitor
(SNRI), alleviates anxiety in patients with and without comorbid depression.
Venlafaxine (dosed once daily) was effective at doses of 150 and 225 mg fThe
reduction in psychic symptoms of anxiety and tension is not accompanied by
significant reductions in somatic symptoms. or 2 months in patients with GAD,
and efficacy was maintained for an additional 6 months of therapy.
• Paroxetine was significantly more effective than placebo at achieving response
in 62% and 68% of patients at 20 and 40 mg daily, respectively, after 2 months.
Remission occurred in 30% and 36% of patients taking 20 and 40 mg of
paroxetine, respectively.
• Escitalopram was more efficacious than placebo in three 8-week trials in
patients with GAD. In a four parallel-group comparison, diazepam and trazodone
were found to be equivalent in anxiolytic activity (remission rates of 66% and
69%, respectively) compared with placebo (47% remission rate), but
imipramine’s rate of remission (73%) exceeded that of the other three
treatments
 MECHANISM OF ACTION

• The mechanism of action of antidepressants in anxiety disorders is not fully

understood. Research indicates that antidepressants modulate receptor
activation of neuronal signal transduction pathways connected to the
neurotransmitters 5-HT, DA, and NE. As a result these cascades modify the
expression of certain genes and the proteins that are produced (e.g., increase
messenger RNA for glucocorticoid receptors and brain-derived neurotropic
factor for trkB receptors, and reduce mRNA expression for corticotropin-
releasing hormone).
• It is theorized that by activating stress-adapting pathways, SSRIs and SNRIs
reduce the somatic anxiety symptoms and the general distress experienced by
patients.
 ADVERSE EFFECTS
• The most common adverse events of venlafaxine in patients with GAD were
nausea, somnolence, and dry mouth.
• Paroxetine was associated with a high rate of somnolence, nausea, abnormal
ejaculation, dry mouth, decreased libido, and asthenia compared with placebo.
• Escitalopram caused nausea, insomnia, fatigue, decreased libido, ejaculation
disorders, and decreased libido at a higher rate than placebo in patients with
GAD.
• The use of TCAs may be limited by troublesome adverse events (e.g., sedation,
orthostatic hypotension, anticholinergic effects, and weight gain) in some
patients and the risk of toxicity in overdose.
 BENZODIAZEPINE THERAPY
• The benzodiazepines are the most frequently prescribed drugs for treating anxiety.
Although all benzodiazepines possess anxiolytic properties, only 7 of the 13 currently
marketed agents have Food and Drug Administration (FDA) approval for the
treatment of GAD.
• Estazolam, flurazepam, temazepam, quazepam, and triazolam are marketed as
sedative-hypnotic agents.
• Clonazepam is marketed as an antipanic agent and anticonvulsant, and midazolam is
labelled for preoperative sedation.
• Alprazolam is indicated for the treatment of panic disorder with or without
agoraphobia, as well as GAD, and is also available in once-daily dosed extended-
release tablets
PHARMACOKINETICS OF BENZODIAZEPINE
ANTIANXIETY AGENTS
 PHARMACOLOGY AND MECHANISM OF ACTION
• The GABA receptor model of anxiety (described in the pathophysiology section) theorizes
that benzodiazepines ameliorate anxiety through potentiation of the inhibitory activity
ofGABA.
• The GABA receptor is composed of protein subunits arranged in a pentamer with a
chloride ion channel in the center. Benzodiazepines bind on the GABAA receptor at the
α1, α2, α3, and α5 sites; the anxiolytic effects of benzodiazepines are mediated at the α2
site.
• When benzodiazepines bind to the GABAA receptor, the frequency of the chloride ion
channels opening and the influx of chloride ions into the neuronal cell are increased.
• The resulting negatively charged hyperpolarized membrane prevents further
depolarization by excitatory neurotransmitters.
• Other neurotransmitters (e.g., 5-HT, NE, and DA) may be involved in benzodiazepine
activity.
 ADVERSE EFFECTS
• The most common adverse events associated with benzodiazepine therapy involve CNS
depression. This is manifested clinically as drowsiness, sedation, psychomotor impairment,
and ataxia. A transient mild drowsiness is experienced commonly by patients during the
first few days of treatment; however, tolerance often develops.
• Disorientation, depression, confusion, irritability, aggression, and excitement are reported.
• Impairment of memory and recall also may occur during benzodiazepine treatment. The
memory loss induced by the benzodiazepines typically is limited to events occurring after
drug ingestion (anterograde amnesia).
• Anterograde amnesia is secondary to disordered consolidation processes that store
information and is not impairment in the perception or retrieval of information.
• Benzodiazepines with high affinity for binding to the benzodiazepine receptor (e.g.,
lorazepam) appear to possess a higher potential for amnesia.
• ABUSE,
• DEPENDENCE,
• WITHDRAWAL, AND
• TOLERANCE
 BUSPIRONE THERAPY
• Buspirone is a nonbenzodiazepine anxiolytic that lacks anticonvulsant, muscle
relaxant, hypnotic, motor impairment, and dependence properties.
• It is considered to be a second-line agent for gad because of inconsistent reports
of efficacy, delayed onset of effect (i.e., 2 weeks or longer), and lack of efficacy
for other potential comorbid depressive and anxiety disorders (e.g., panic
disorder or sad)
• PHARMACOLOGY AND MECHANISM OF ACTION
• Buspirone’s anxiolytic mechanism of action is unknown. It is thought to exert its
anxiolytic effect through 5-HT1A partial agonist activity at the presynaptic 5-HT
receptors by reducing the firing of 5-HT neurons.
• Unlike benzodiazepines, buspirone is effective for the cognitive symptoms of
anxiety
• PHARMACOKINETICS
• After an oral dose, buspirone is absorbed rapidly and completely and undergoes
extensive first-pass metabolism. The mean elimination half-life is 2.5 hours and
it must be dosed 2 to 3 times daily, which adversely affects adherence to the
drug regimen.51
• ADVERSE EFFECTS
• A major advantage of buspirone is its lack of sedative properties.
• Adverse events include dizziness, nausea, and headaches.
ALGORITHM FOR THE PHARMACOTHERAPY OF GAD.