Module 3 Section 1 (Anxiety and Insomnia)

Question 1

True or false: excessive CNS excitation of the central nervous system (CNS; brain and spinal cord) can lead to a variety of deleterious effects for an individual, including anxiety, insomnia, and even seizures.

Answer 1

True

Question 2

How do drugs work to treat excessive CNS excitation (ex: anxiety)?

Answer 2

Drugs used to treat these conditions often work by decreasing the amount of excitation in the brain, with variable effect.

Question 3

Explain the neurochemistry of the brain.

Answer 3

Brain neurochemistry is dependent on the balance between the excitatory and inhibitory signals. These signals come from the excitatory and inhibitory neurotransmitters in the brain:

• Glutamate is the primary excitatory neurotransmitter
• Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter.

Among other factors, it is the balance between these two neurotransmitters that controls and modifies the activity of the brain.

Question 4

What is the appropriate treatment for sleep disorders (insomnia) and anxiety?

Answer 4

Appropriate treatment for these disorders can include behavioural changes, such as stress reduction and physical exercise, as well as prescription medications, such as sedative-hypnotic agents.

Question 5

What are sedative-hypnotic agents? What do they treat/produce?

Answer 5

Sedative-hypnotic agents are CNS depressants and produce dose-dependent depression of the CNS, ranging from:

• Anti-anxiety effect: used to treat anxiety disorders such as obsessive-compulsive disorder.
• Sedation: used to relieve anxiety, decrease activity, moderate excitement, and generally calm the individual.
• Hypnosis (sleep): used to produce drowsiness and aid in the onset and maintenance of sleep.
• General Anesthesia: used to induce general anesthesia, which is a state of unconsciousness with an absence of pain sensation.

Question 6

What anxiety disorders do sedative-hypnotic drugs treat? (5)

Answer 6

• generalized anxiety disorder
• obsessive compulsive disorder
• panic disorder
• post-traumatic stress disorder
• a number of phobias

Question 7

What are the mechanisms by which sedative-hypnotic drugs work?

Answer 7

This class of drugs controls CNS excitation by reducing the amount of glutamate-induced neural excitation.

One mechanism through which this can be accomplished is by increasing the GABA inhibitory signaling in the brain. Most of the sedative-hypnotic drug classes work in this manner:

1) Most brain activity involves excitatory neurons. These excitatory neurons release the neurotransmitter glutamate, which binds and activates glutamate receptors. Neurons “fire” when the excitatory inputs exceed the inhibitory inputs.
2) GABA binds to its receptor on the chloride channel and initiates its inhibitory effect. Most sedative-hypnotic agents will also bind to the chloride channel and mimic the inhibitory effects of GABA. The increased inhibitory signals in the presence of sedative-hypnotic agents slows excitatory CNS transmission.
3) The inhibitory signals eventually exceed the excitatory signals, and the glutamate nerves cease to fire.

Question 8

What is the definition of drug classes? Provide an example

Answer 8

A class of drugs is a group of drugs that have the same mechanism of action and similar pharmacological properties.

Ex: thiopental, secobarbital, and phenobarbital are all drugs that fall under the barbiturate class of drugs.

Question 9

How does GABA induce its inhibitory effects?

Answer 9

GABA binds to the chloride ion channel on the membrane of neurons in the brain and spinal cord. Binding causes the channel to open and allows negatively charged chloride ions to flow into the cell, resulting in an inhibitory effect.

In essence, drugs that bind the chloride channel enhance the inhibitory effect of GABA.

Question 10

Where do sedative-hypnotic agents bind to?

Answer 10

Sedative-hypnotic agents also bind to the chloride channel, however, each class of sedative-hypnotic agent binds to a different site on the chloride channel.

The result is an increase in synaptic inhibition, and thus a dampening of neuronal responses.

Question 11

What are the 3 main classess of of sedative-hypnotic drugs that elicit their pharmacological actions by binding to the chloride ion channel?

Answer 11

1) Benzodiazepines
2) Barbiturates
3) The “Z” Drug

Question 12

True or false: the benzodiazepines are among the most widely prescribed drugs in the world.

Answer 12

True

Ten percent of Canadians use a benzodiazepine at least once a year for medical reasons.

Question 13

How do benzodiazepines work?

Answer 13

Benzodiazepines bind to the chloride channel at a different receptor than GABA, called the benzodiazepine receptor.

Upon binding, benzodiazepines increase the frequency of the opening of the chloride channel, enhancing the effect of GABA and producing CNS depression.

Question 14

How are benzodiazepines taken?

Answer 14

Benzodiazepines are usually taken as a capsule or tablet, but some are available for intravenous use.

Benzodiazepines have different durations of action, which are determined by the rate of liver metabolism and formation of, or lack of formation of, pharmacologically active metabolites.

Question 15

There are five different classes of drugs – agonist, partial agonist, allosteric activator, competitive antagonist, and non-competitive agonist. Which class do benzodiazepines fall into?

a) Agonist
b) Partial agonist
c) Allosteric activator
d) Competitive antagonist
e) Non-competitive antagonis

Answer 15

d) Competitive antagonist

Question 16

List the various pharmacological properties of benzodiazepines. (8)

Answer 16

• They possess a very high therapeutic index.
• They relieve anxiety.
• They produce sedation and amnesia.
• They can decrease aggression.
• Some members of this group are effective hypnotics.
• They produce minimal suppression of rapid-eye-movement (REM)-type sleep.
• They produce skeletal muscle relaxation (e.g. diazepam).
• They have anticonvulsant action (e.g. diazepam).

Question 17

How do the clinical effects of benzodiazepines differ from short-term to long-term use?

Answer 17

Short-term use: the desirable short-term effects are relaxation, calmness, and relief from anxiety or tension.

• Adverse effects may include drowsiness, lethargy, impairment of thinking and memory, nausea, and constipation.
• Moderate doses of all benzodiazepines can impair motor coordination and driving. Patients taking these drugs during the day should refrain from driving or operating dangerous machinery.

These responses are exaggerated as the dose is increased.

Long-term use: it varies. Some individuals can take large amounts of benzodiazepines for long periods of time without any major evidence of intoxication, while others will demonstrate the symptoms of chronic sedative-hypnotic intoxication. These are:

• impaired thinking, poor memory and judgement
• disorientation, incoordination
• slurred speech

Question 18

What populations are more likely to experience adverse effects for benzodiazepines

Answer 18

Elderly: Benzodiazepines can produce cognitive dysfunction in the elderly; they should be used with caution, if at all, in this age group.
- In addition, the elderly metabolize benzodiazepines more slowly than young adults, often leading to over-sedation, falls, and injury.

Pregnant/Breastfeeding: Benzodiazepines freely cross the placenta and distribute into the fetus.

• When administered in the first trimester, benzodiazepines are associated with a small but significant risk for fetal abnormalities.
• Benzodiazepines are also secreted into the milk, exposing nursing infants to therapeutic or toxic doses of the drug, and can result in sedation or death.

Question 19

True or false: the benzodiazepines are among the drugs most commonly involved in overdose.

Answer 19

True

Question 20

What is Flumazenil? What can it be used for?

Answer 20

Flumazenil is a benzodiazepine receptor antagonist that blocks the effect of the benzodiazepines.

As such, it can be used as an antidote for benzodiazepine poisoning.

Question 21

What is the abuse potential for Benzodiazepines?

Answer 21

Benzodiazepines have a low abuse liability, as they have weaker reinforcing properties than barbiturates, alcohol, opioids, and stimulants. The inherent harmfulness is also low since it doesn’t depress respiration at therapeutic doses.

Question 22

What is the substance dependence potential for Benzodiazepines?

Answer 22

Tolerance does not appear to be a problem for the clinical use of these drugs. A high degree of cross-tolerance occurs among the benzodiazepines and other sedative-hypnotic drugs, such as barbiturates and alcohol, as they all modulate the chloride ion channel in the CNS.

The risk of dependence is low for short-term use (i.e. up to a few months). However, if use is chronic (i.e. one year or more), sudden discontinuation of the drug may lead to withdrawal symptoms such as agitation, paranoia, seizures, and delirium.

Question 23

What are barbiturates? What is their duration of action?

Answer 23

The barbiturates are potent CNS depressants and are classified according to their duration of action:

• Long-acting (1-2 days), e.g. phenobarbital.
• Short-acting (3-8 hours), e.g. secobarbital.
• Ultrashort-acting (20 minutes), e.g. thiopental.

Question 24

How do barbiturates work? What occurs during activation?

Answer 24

Barbiturates bind to the chloride channel at a separate and distinct receptor than GABA – the barbiturate receptor.

Activation of the barbiturate receptor increases the duration of the opening of the chloride channel, increasing the effects of GABA.

Question 25

True or false: the duration of action for a barbiturate determines its medical use.

Answer 25

True

Ex: an ultra-short acting agent can be used to induce anesthesia for surgery

Ex: a short to intermediate acting may be used to induce sleep

Ex: a long-acting agent can be used for pain/migraine relief.

Question 26

True or false: the barbiturates possess a low therapeutic index and suppress REM-type sleep.

Answer 26

True

Question 27

What is the risk for taking barbiturates?

Answer 27

Lethality is common, especially when combined with alcohol, and a specific antidote for barbiturate poisoning does not exist.

Death can also result during barbiturate withdrawal.

Question 28

What are the clinical uses of barbiturate?

Answer 28

The clinical uses for barbiturates are limited, especially since they have been replaced with safer alternatives.

Ultrashort acting and short-acting barbiturates can be used to induce anesthesia, and phenobarbital (a long-acting agent) is used as an anti-seizure drug.

Question 29

Describe the patterns of use for barbiturates?

Answer 29

Barbiturates are prescribed much less frequently now than 40 years ago. However, illicit use continues to be a problem.

Barbiturates are sometimes combined with other drugs such as heroin, amphetamines, and alcoho

Question 30

What is the abuse potential of barbiturates?

Answer 30

The abuse liability of the barbiturates is equal to or greater than alcohol.

The pleasurable effects of some of the barbiturates give a significant degree of reinforcement. The inherent harmfulness of the barbiturates is very high. These drugs should be avoided

Question 31

What is the substance dependence potential for barbiturates?

Answer 31

Tolerance develops very rapidly to the sleep induction and mood effects of barbiturates, often within a few weeks of nightly administration.

However, tolerance to the anticonvulsant actions develops much more slowly and does not appear to be a major problem clinically.

A high degree of cross-tolerance exists between barbiturates and other sedatives (e.g. benzodiazepines).

Question 32

What is the addiction potential for barbiturates?

Answer 32

The cravings often persist long after used has stopped.

A withdrawal syndrome occurs after discontinuation of chronic use.

Symptoms initially appear as tremors, anxiety, weakness, and insomnia, and may progress to include seizures, delirium, and visual hallucinations.

The withdrawal syndrome can be fatal and therefore dependent individuals must be withdrawn slowly under medical supervision.

Question 33

How do “Z” drugs work? What occurs during activation?

Answer 33

Zolpidem, zopiclone, and similar drugs (that usually begin with the letter Z) bind to a subset of the GABA receptors, causing sedation.

They have advantages over the benzodiazepines as a hypnotic, as they disturb sleep patterns (REM sleep) even less than the benzodiazepines.

Drugs in this class appear to have more “sedative” effects as compared to anxiolytic effects.

Question 34

Using what you have learned about benzodiazepines, why should the “Z” drugs be used with caution in the elderly?

Answer 34

As with the benzodiazepines, these drugs should be used with caution in the elderly.

The “Z” drugs, similar to the benzodiazepines, can produce cognitive dysfunction in the elderly. Additionally, the elderly metabolize these drugs slower than younger adults, which can lead to over-sedation, falls, and injury. Therefore, these drugs should be used with caution in this population.

Question 35

Which one of the statements correctly applies to the benzodiazepines?

a) The benzodiazepines, when taken in large doses, often cause lethality.
b) The benzodiazepines do not exhibit cross-tolerance with barbiturates.
c) Tolerance occurs to the sedative and hypnotic effects of the benzodiazepines
d) The benzodiazepines have strong reinforcing properties compared to the barbiturates.

Answer 35

c) Tolerance occurs to the sedative and hypnotic effects of the benzodiazepines