Anxiety and Panic Disorder Drugs

Drugs Used in Anxiety and Panic Disorders

Objectives

By the end of this lecture, you will be able to:

  • Define different types of anxiety disorders.

  • Classify types of drugs used for the treatment of anxiety.

  • Understand the mechanism of action of the drugs, along with the indications and side effects.

Antianxiety Drugs

Anxiety is a normal psychological response that helps protect individuals from unpleasant or threatening situations. Mild to moderate anxiety can enhance performance and encourage appropriate action. However, excessive or prolonged anxiety may become debilitating, leading to severe distress and significant impairment in social functioning.

Symptoms of Anxiety

Emotional Symptoms

  • Irrational and excessive fear and worry

  • Irritability

  • Restlessness

  • Trouble concentrating

  • Feeling tense

Physical Symptoms

  • Sweating

  • Tachycardia

  • Shortness of breath

  • Stomach upset

  • Frequent urination or diarrhea

  • Sleep disturbances

  • Fatigue

  • Sensitivity to noise

  • Dry mouth

  • Difficulty in swallowing

  • Constriction in the chest

  • Difficulty inhaling

  • Feeling of breathlessness

  • Palpitations

  • Discomfort in the chest

  • Awareness of missed beats

  • Restlessness

  • Tremor

  • Aching muscles

  • Fearful anticipation

  • Irritability

  • Poor concentration

  • Worrying thoughts

  • Headache

  • Dizziness

  • Insomnia

  • Avoiding the situation/object

  • GI discomfort

  • Excessive wind

  • Frequent or loose motions

  • Frequent or urgent micturition

  • Failure of erection

  • Menstrual discomfort

  • Amenorrhea

Types of Anxiety Disorders

  • Generalized Anxiety Disorder (GAD): Patients are usually and constantly worried about health, money, and work with no apparent reasons.

  • Panic Disorder: A disorder in which people have sudden and intense attacks of anxiety in certain situations.

  • Obsessive-Compulsive Disorder (OCD): An anxiety disorder in which people cannot prevent themselves from unwanted thoughts or behaviors that seem impossible to stop (e.g., washing their hands).

  • Social Anxiety Disorder (Social Phobia): Intense fear of social situations.

  • Specific Phobias: Intense fear of specific objects or situations (e.g., spiders, heights).

  • Separation Anxiety Disorder: Excessive fear of separation from loved ones.

  • Post-traumatic Stress Disorder (PTSD): An anxiety disorder that affects people who have experienced a severe emotional trauma, such as rape, a dramatic car accident, or even war.

Treatment of Anxiety

Episodes of mild anxiety are common life experiences and do not warrant treatment. However, severe, chronic, and debilitating anxiety may be treated with antianxiety drugs. Because many antianxiety drugs also cause some sedation, they may be used clinically as both anxiolytic and hypnotic (sleep-inducing) agents.

Classification of Anxiolytic Drugs

  • Antianxiety drugs: Drugs that can relieve anxiety without interfering with mental or physical function.

  • Benzodiazepines (BDZ)

  • Antidepressants (Fluoxetine, Doxipine)

  • Non-sedating Anxiolytic Drugs

    • Partial 5HT1A agonists (Buspirone)

    • Beta-adrenergic blockers (Propranolol)

    • MAO inhibitors (Phenelzine)

Benzodiazepines

Benzodiazepines are a large group of drugs that have similar pharmacologic effects. They are so named because they share the common chemical structure of a benzene ring (benzo) joined to a seven-member ring containing two nitrogen molecules (diazepine).

Classification According to Duration of Action

  • Short-acting (3-8 hours):

    • Triazolam

    • Midazolam

  • Intermediate-acting (10-20 hours):

    • Alprazolam

    • Lorazepam

  • Long-acting (24-72 hours):

    • Chlordiazepoxide

    • Diazepam

Mechanism of Action

Benzodiazepines bind to specific sites on the GABA-A receptor. They do not directly activate the GABA-A receptor themselves. They enhance the response to GABA by facilitating the opening of GABA-activated chlorine channels and increasing the affinity of GABA for the receptor. Binding of GABA to its receptor triggers an opening of the central ion channel, allowing chloride through the pore. The influx of chloride ions causes hyperpolarization of the neuron and decreases neurotransmission by inhibiting the formation of action potentials.

Empty receptor is inactive, and the coupled chloride channel is closed.

Binding of GABA causes the chloride ion channel to open, leading to hyperpolarization of the cell.

Pharmacokinetics

They are lipid-soluble, well absorbed orally, and can be given parenterally. Chlordiazepoxide and Diazepam can be given intravenously (IV only, NOT IM). They are widely distributed and cross the placental barrier (causing fetal depression) and are excreted in milk (causing neonatal depression). They are metabolized in the liver to active metabolites (resulting in a long duration of action).

Therapeutic Uses of Benzodiazepines

  • Anxiety disorders:

    • Generalized anxiety disorder

    • Obsessive-compulsive disorder

    • Panic attack with depression (Alprazolam)

  • Sleep disorders (Insomnia):

    • Triazolam

    • Lorazepam

  • Other therapeutic uses:

    • Treatment of epilepsy (status epilepticus) - Diazepam, Lorazepam

    • In anesthesia:

      • Pre-anesthetic medication (diazepam).

      • Induction of anesthesia (Midazolam, IV)

    • Muscle Spasm

Adverse Effects

  • Drowsiness and confusion

  • Ataxia (motor incoordination)

  • Cognitive impairment

  • Respiratory & cardiovascular depression in large doses only (toxic effects).

  • Alcohol and other CNS depressants enhance the sedative and hypnotic effects of BDZs.

Drug Dependence

Psychological and physical dependence can develop if high doses of benzodiazepines are given for a prolonged period. All benzodiazepines are controlled substances. Abrupt discontinuation of these agents results in withdrawal symptoms, including confusion, anxiety, agitation, restlessness, insomnia, tension, and (rarely) seizures.

Contraindications

  • Absolute Contraindications

    • Severe Respiratory Depression

    • Acute Narrow-Angle Glaucoma

    • Myasthenia Gravis

    • Severe Hepatic Impairment

    • Pregnant women or breast-feeding.

  • Elderly

    • Dose reduction is recommended.

Benzodiazepine Antagonist

  • Flumazenil is a benzodiazepine antagonist that is used primarily to reverse the effects of benzodiazepines in cases of overdose or excessive sedation. It acts by competitively inhibiting benzodiazepine binding at the gamma-aminobutyric acid (GABA-A) receptor.

Buspirone

The drug is used in the treatment of chronic anxiety and produces an anxiolytic effect without causing marked sedation, amnesia, tolerance, dependence, or muscle relaxation.

Mechanism of Action

Buspirone is a partial agonist at serotonin 5-HT1A receptors and may exert its anxiolytic effect by activating presynaptic receptors. It can cause up-regulation of postsynaptic serotonin receptors. This effect takes time to develop and is consistent with the 3- to 4-week delay in the onset of the anxiolytic effect of buspirone. Buspirone also shows affinity for dopamine D2 receptors, acting as an antagonist.

Therapeutic Uses

It is used for mild anxiety & generalized anxiety disorders.

Disadvantages of Buspirone

  • Slow onset of action (delayed effect)

  • GIT upset, dizziness, drowsiness

  • Drug interactions with CYT P450 inducers and inhibitors

Nonbenzodiazepines (Zolpidem, Zaleplon, and Eszopiclone)

Like the BDZs, non-BDZs exert their effects by binding to and activating the benzodiazepine site of the receptor complex. Their actions are blocked and reversed by the BDZ receptor antagonist flumazenil. These drugs are widely used for short-term management of insomnia.

Zolpidem

Zolpidem is not structurally related to benzodiazepines, but it binds to GABAA, and their actions are blocked and reversed by the benzodiazepine antagonist flumazenil. These drugs are widely used for short-term management of insomnia.

Properties

Zolpidem has no anticonvulsant or muscle-relaxing properties at hypnotic doses. It shows few withdrawal effects, exhibits minimal rebound insomnia, and little tolerance occurs with prolonged use. Zolpidem is rapidly absorbed after oral administration. It has a rapid onset of action and short elimination half-life (about 2 to 3 hours). The drug provides a hypnotic effect for approximately 5 hours.

Beta Blockers

Drugs such as Propranolol reduce somatic symptoms of anxiety.

Antidepressants

Many antidepressants are effective in the treatment of chronic anxiety disorders and should be considered as first-line agents, especially in patients with concerns for addiction or dependence.

  • Doxepin, Imipramine: Used for anxiety, especially associated with depression; effective for panic attacks.

Monoamine Oxidase Inhibitors (MAOIs)

  • Phenelzine: Used for panic attacks and phobia.

Selective Serotonin Reuptake Inhibitors (SSRIs)

  • Fluoxetine: Used for panic disorder, OCD, depression, generalized anxiety disorders, and phobia.

Melatonin and Melatonin Receptor Agonists

Melatonin is a hormone secreted by the pineal gland that helps maintain the circadian rhythm, which underlies the normal sleep–wake cycle. At an oral dose of 80 mg, melatonin induces sleep; however, at lower doses of 2–10 mg, it slightly increases the propensity to fall asleep without causing central nervous system (CNS) depression.