[Web Module] Nervous System - Drugs for Anxiety and Insomnia

What is anxiety?

Disproportionate state of tension, apprehension, or uneasiness that stems from the anticipation of danger - the source of which is largely unknown or unrecognized, although the patient can usually identify factors that bring on symptoms

What is situational anxiety?

Normal response to a stressful situation at home, work, school, or social activities - often beneficial and usually lasts 2-3 weeks

Treatment should be especially focused on non-pharmacological treatment compared to use of benzodiazepines

What is an anxiety disorder?

Severe or prolonged anxiety that impairs a person's ability to engage in normal day to day functions

What are 6 different types of anxiety disorders?

1. Separation anxiety disorder - separation from attachment figures which is developmentally inappropriate

2. Selective mutism - failure to speak in social situations where it is expected

3. Specific phobia - particular situation

4. Social Anxiety Disorder - Social interactions and situations

5. Panic Disorder - immediate apprehension, terror, or impending doom accompanied by increased ANS activity

6. Agoraphobia - fear of open/public spaces

Which two hormones are involved in the pathophysiology of anxiety?

GABA - Inhibitory NT, lowered in anxiety disorders

Norepinephrine - Excitatory NT, increased in anxiety disorders

What is the normal human response to a threat? What occurs to this response in anxiety?

A threat is perceived and a signal is sent to the locus coeruleus, which releases norepinephrine and signals the limbic system and cerebral cortex, producing symptoms of panic, restlessness, palpitations, and hyperventilation

In anxiety, this response is overexaggerated

How is the stress response involved in anxiety?

Stress response is mediated by the HPA axis. The hypothalamus releases CRH, which signals the anterior pituitary and the locus coeruleus. Signaling of the locus coeruleus causes release of norepinephrine and results in symptoms of anxiety

How are mood disorders involved in anxiety?

Exact mechanism unclear, however, increased serotonin levels in mood disorders is thought to increase anxiety as SSRIs are an effective treatment for anxiety disorders

What is the role of the cerebral cortex in anxiety?

Thinking or conscious part of the brain, processes sensory inputs, regulates voluntary muscle action, and responsible for higher brain functions

What is the role of the locus ceruleus in anxiety?

A brain stem nucleus that contains noradrenergic neurons which have extensive projections to the limbic system, cerebral cortex, and cerebellum

What is the role of the limbic system in anxiety?

Area in middle of brain responsible for emotional expression, learning, and memory - includes the amygdala

What is the role of the hypothalamus in anxiety?

Responsible for unconscious responses to stress, such as elevated bp, respiratory rate, and dilated pupils

How does GABA act as an inhibitory neurotransmitter?

GABA binds to receptors on chloride channels, which results in influx of chloride ions and hyperpolarization of the neuron, resulting in the neuron being less sensitive to the effects of excitatory neurotransmitters - such as norepinephrine

How does norepinephrine act as an excitatory neurotransmitter?

Increased norepinephrine results in an exaggerated response to normal stimuli, causing symptoms of anxiety

What is the role of the reticular activating system in regulating sleep and wakefulness?

Once activated by the hypothalamus, signals the cerebral cortex to cause feelings of arousal and alertness

Hyperactivation of the RAS can cause insomnia

What is the role of the hypothalamus in regulating sleep and wakefulness?

Once activated, the hypothalamus signals the RAS, causing increased arousal and alertness, signals the limbic system, causing fever and anxiety, and signals that locus cerelus by releasing CRF, activating the stress response.

This is how insomnia and anxiety are correlated with each other

What is the role of the cerebral cortex in regulating sleep and wakefulness?

Once activated by the RAS, causes symptoms of arousal and alertness

What is insomnia?

Characterized by a dissatisfaction of sleep quantity or quality, associated with difficulties of either initiating sleep, maintaining sleep, or early-morning awakenings. May be secondary to another condition

What is episodic/behavioral insomnia?

Insomnia attributed to normal stressors or specific activities (meals + caffeine). Symptoms of insomnia can last for 1-3 months.

Treatment should be especially focused on non-pharmacological treatment compared to use of benzodiazepines

What is long-term/persistent insomnia?

Insomnia that is often associated with mood disorders, such as depression, anxiety, bipolar disorder , or chronic pain due to illness

Non pharmacological therapies should be prioritized for which type of insomnia?

Episodic/behavioral insomnia

Nor pharmacological therapies should be prioritized for which type of anxiety?

Situational anxiety

What is the recommended first-line treatment for anxiety + insomnia?

Non pharmacological therapies

Can include meditation, lifestyle, exercise, or diets

Pharmacological therapies should only be recommended if the patient resists pharmacological therapies or if the condition is severe enough to interfere with ADLs

What drug class is prescribed for short term treatment of anxiety and insomnia?

Selective central nervous system depressants - benzodiazepines

Long term use is associated with worsening outcomes and physical + psychological dependence

What drug class is prescribed for long term treatment of anxiety and insomnia?

Antidepressant drugs

-> SSRIs (Anxiety)

-> Tricyclic antidepressants (anxiety, insomnia)

-> nonbenzodiazepine anxiolytics (insomnia), can still cause dependence and rebound effects

What are benzodiazepines? (Use, Mechanism of Action, Pharmacokinetics - Absorption, Distribution, Metabolism, Half life; Dosing, Adverse Effects, Contraindications)

Use

Used for short term treatment of anxiety and insomnia after non pharmacological therapies have been used

Mechanism of Action

Binds to GABA receptors, enhancing the effect of GABA and allowing more chloride ions into the neuron, causing increased hyperpolarization

Pharmacokinetics

Half life - two types -> short half life and long half life

Absorption - Well absorbed; lipid soluble

Distribution - Highly binds to plasma proteins

Metabolism - Short half life -> no active metabolites, only glucuronidation// Long half life -> active metabolites, oxidation via CYP 450 and glucoronidation

Dosing

Start at lower effective dose, PRN - avoid daily use

For anxiety, if prescribed antidepressants, benzodiazepines can be used before antidepressant therapy is effective

Adverse Effects

-Oversedation

-Dizziness

-Confusion

-Impaired mobility

-Withdrawal - abrupt discontinuation of drug, should be slowly tapered off

-Physical dependence - prolonged use

Contraindications

Especially for long half life benzodiazepines

-Elderly patients (low metabolism + excretion)

-Liver disease

-Drugs that inhibit liver oxidation

What are long half life benzodiazepines?

Benzodiazepines that have a long half life and produce active metabolites - resulting in plasma accumulation

Recommended to be prescribed to patients with anxiety - associated with longer stabilized mood

When should long half life benzodiazepines be and not be prescribed?

Should be prescribed for treatment of anxiety - longer stabilized mood

Should not be prescribed for elderly patients, patients with liver dysfunction or for insomnia due to risk of increased daytime drowsiness

What are short half life benzodiazepines?

Benzodiazepines that have a short half life and do not produce active metabolites - less likely to result in plasma accumulation

Recommended to be prescribed to patients with insomnia due to reduced risk of daytime drowsiness

When should short half life benzodiazepines be and not be prescribed?

Should be prescribed for treatment of insomnia - reduced risk of daytime drowsiness

Should not be prescribed for treatment of anxiety - increased bouts of anxiety between benzodiazepine doses

What is the mechanism of action of benzodiazepines?

Binds to GABA receptors, enhancing the effect of GABA and allowing more chloride ions into the neuron, causing increased hyperpolarization of the neuron

Describe the absorption and distribution of benzodiazepines

Highly lipid soluble - well absorbed through oral administration - also available to be administered via IV

Highly bound to plasma proteins

How are long half life benzodiazepines metabolized?

Metabolized by CYP450 enzymes via oxidation reaction (Phase I). Then converted into a water soluble inactive metabolite through glucuronidation (Phase II) and excreted via the kidneys

This is why long half life benzos are contraindicated in patients with liver dysfunction

How are short half life benzodiazepines metabolized?

Metabolized through glucuronidation (Phase II) into a water soluble inactive metabolite. Short half life benzos do not have to go through Phase I reactions as it does not produce active metabolites

What is the recommended dosing regimen for prescription of benzodiazepines?

Dosing - start with lowest effective dose and increase based on patient's response

What is the recommended dosing regimen for prescription of benzodiazepines in patients with insomnia?

For insomnia, benzodiazepines should be taken PRN and not daily to avoid dependence or worsening insomnia; benzodiazepine therapy becomes ineffective after 2-4 weeks of daily use

Dosing should be reassessed after 3 weeks of lack of sleep improvement as it may indicate that the insomnia is caused by an underlying condition.

What is the recommended dosing regimen for prescription of benzodiazepines in patients with anxiety?

Often initiated on antidepressant therapy, however, usually takes 4-6 weeks to be effective.

Benzodiazepine therapy can thus be initiated during this period, and after antidepressant therapy becomes effective, benzodiazepine use should be slowly discontinued

What are the adverse effects of benzodiazepines?

Oversedation

Dizziness

Confusion

Impaired mobility

Agitation

-Especially common in elderly patients due to impaired metabolism and excretion

Why should there be cautions when prescribing benzodiazepines for elderly patients?

Elderly patients have impaired metabolism and excretion, which makes adverse effects more common in this population, such as increased agitation and confusion.

As a result, there is a need for close monitoring

What is rebound insomnia/anxiety?

Symptoms of insomnia and anxiety worsening after discontinuation of benzodiazepine therapy, can cause increased risk of dependence for the drug

Prevented by slowly tapering off the dose

What is the use, mechanism of action, and adverse effects of flumazenil - benzodiazepine antagonist?

Use

Used to treat adverse effects associated with benzodiazepine overdose - does not reverse respiratory depression

Mechanism of Action

Competes with benzodiazepines for GABA receptors

Adverse Effects

-Dysphoria

-Agitation

-Anxiety

-Cardiac arrhythmias

-Seizures

-> Need for caution while using the drug

What is benzodiazepine dependence?

Prolonged or high dose regimens causing the cells of the body functioning as though it is normal for the drug to be continually present - resulting in withdrawal effects once the drug is discontinued abruptly

What is the pathophysiology of benzodiazepine withdrawal?

Theorized that abrupt cessation causes decrease in GABA neurotransmitters, resulting in less inhibition of the CNS and symptoms of hyperarousal - leading to insomnia and anxiety

What are causes and symptoms of benzodiazepine withdrawal?

Causes

-Mostly associated with abrupt cessation of short half life benzodiazepines

-Can also occur with abrupt cessation of long half life benzodiazepines - symptoms may appear 4-5 days after cessation

Symptoms

-Increased HR

-Loss of appetite

-Tremors

-Abdominal and muscle cramps

-Vomiting

-Sweating

-Insomnia

-Agitation

-Anxiety + Panic

Symptoms can often persist for 2-4 weeks

Why is benzodiazepine dependence often misdiagnosed in elderly patients?

Elderly patients do not fit the common stereotype associated with physical dependence

DSM 5 criteria

- Failure to fill role obligations at school, work, or home

x Elderly patients often do not go to school or work

x Requirement of home visits or report from close associate to learn about role obligations at home

-Physical hazardous situations with legal consequences

x Elderly patients often do not drive

-Recurrent social or interpersonal problems

x Elderly patients often live alone

Which sex most commonly experiences benzodiazepine dependence?

Females -> often misdiagnosed as symptoms of anxiety, depression, or stress, leading to renewed benzodiazepine prescription and worsening dependence

What is the DSM-5 criteria for substance dependence?

Recurrent substance use that results in:

-Failure to fulfill role obligations at school, work, or home

-Physically hazardous situations

-Substance related legal problems

-Recurrent social or interpersonal problems

What is the nursing role in benzodiazepine therapy?

Nurses often have the highest level of interaction with the patient and are the first to observe signs of adverse reactions to medications

-Monitor and educate patient about drug regimen

-Assess patient's needs

-Identify precipitating factors for patient's anxiety or insomnia (factors + coping)

-Take a drug history

-Assess likelihood for drug abuse or dependence

-Assess patient for side effects

-Ensure patient is taking lowest possible dose