L16 Benzodiazepines + Antiolytics

Question 1

Learning Outcomes (for general perusal)

Answer 1

• Describe the essential features of the main mental illnesses in which BDZ are indicated
• Describe the location and function of the principal neurotransmitters involved in the action of benzodiazepines.
• Describe the mechanisms of action, desired effects and principal adverse effects of benzodiazepines (BDZ): anxiolytics and hypnotics
• Relate the mechanisms of tolerance and dependence of anxiolytics to restrictions of their clinical use.

Question 2

What is anxiety?

Answer 2

A feeling of worry, nervousness, or unease about something with an uncertain outcome (normal)

A nervous disorder marked by excessive uneasiness and apprehension. (pathological)

Question 3

What are the symptoms of anxiety?

Answer 3

• Cognitive Beliefs -inability to cope with stress, unrealistic ideas of danger
• Emotional - feelings of fear, apprehension, irritability, low mood
• Somatic Symptoms -hyperventilation, retrosternal constriction, muscle tension, autonomic overactivity
• Behavioural - reduced purposeful activity, increased purposeless activity, avoidance.
• Arousal - increased alertness, hypervigilance, restlessness

Question 4

What are the different types of anxiety?

Answer 4

• Normal
• Trait Anxiety
• Anxiety Disorders
• Situational Anxiety
• Secondary to drug withdrawal
• Secondary to drug use
• Secondary to other psychiatric illness
• Secondary to physical illness

Question 5

How does anxiety show Psychic/Somatic interaction?

Answer 5

Cannon (1915) considered the emotional experience to be primary, i.e. the bodily change is caused by the emotion.

• An example is the ‘fight or flight’ response to a threat.
• In this a major role is subserved by the autonomic nervous system in preparing the organism to respond.

Papez (1937) identified a ‘circuit’ of brain regions which subserve emotional expression. These are part of the limbic system.

Question 6

What are the Biological Theories of Anxiety Disorders?

Focus on last one

Answer 6

BRAIN AREAS

• Periaqueductal grey area
• Medial hypothalamus
• Amygdala
• Septo-hippocampal system; -Temporal Cortex

NORADRENALINE

• LC stimulation in animals
• Effects of β-adrenoceptor antagonists
• Effects of α2 antagonists (yohimbine).

SEROTONIN

• Involved in brain aversion system
• benefits from 1A partial agonists & SSRIs.

GABA

• agonists reduce anxiety
• antagonists increase anxiety (e.g. pentylenetetrazol)
• gamma-2 knockout mice.

Question 7

Name the drugs used in the treatment of anxiety disorders

Answer 7

• BENZODIAZEPINES
• BETA-ADRENOCEPTOR ANTAGONISTS
• SSRI ANTIDEPRESSANTS
• 5-HT-1A AGONISTS
• LOW DOSE ANTIPSYCHOTICS
• NEW APPROACHES (antagonists for CCK-B, CRF and Substance P; pre-gabalin)

Question 8

Benzodiazepines

1. Where is the specific binding site for BDZs?
2. What does GABA act as in the CNS?
3. What is the mode of action of BDZs?
4. What occurs if GABA is absent or the R is blocked?

Answer 8

1. In the GABA-A receptor in the GABA-BDZ Receptor Complex. (Junction between G2 and A1)
2. An inhibitory transmitter
3. When a BDZ occupies its own receptor it enhances the action of GABA at its receptor resulting in greater flow of ‘negative’ Clˉ ions into the neurone.
   
   1. Act on RAS -reticular activating system
   2. Act on limbic system of cortex – emotion
4. BDZ on it’s own will have no effect

Question 9

What are the clinical effects of BDZs?

Answer 9

• anxiolytic e.g. anxiety disorders, premedication,
• hypnotic e.g. sleep disorders
• anti-convulsant e.g. epilepsy
• muscle relaxant e.g. musclespasticity, myoclonus

Question 10

BDZ : Pharmacokinetics

1. How can they be given?
2. When is peak plasma concentration reached?
3. In what form are they in the blood?
4. What causes them to accumulate in body fat?
5. What are they metabolised to?
6. What are they conjugated with in the liver?

Answer 10

1. Well absorbed when given orally (almost complete bioavailability with oral dose), can also be given IV, IM, PR
2. Within 1 hour (oxazepam absorbed more slowly)
3. Bind strongly to plasma proteins
4. High lipid solubility
5. Active metabolites so half life doesn’t ways reflect the duration of action (e.g. diazepam - active metabolite n-desmethyldiazepam which has a half life of 60 hours) - must be careful not to overdose
6. glucuronic acid

Question 11

BDZs

Can be split into (short, med and long acting)

Give an example of each of the following, and a clinical use:

1. Short-Acting BDZ
2. Long-Acting BDZ
3. BDZs which have anticonvulsant activity

Answer 11

1. temazepam, lorazepam - hypnotics, reduced hangover effects
2. diazepam, chlordiazepoxide - anxiolytic, anticonvulsant
3. Rectal diazepam, IV diazepam

Question 12

Name some general problems of BDZ use

Answer 12

• tolerance to the effects
• physical dependence
• psychological dependence
• active metabolites - prolonged effects

Question 13

BDZ : Adverse Effects

1. What are the toxic effects from BDZ overdose
2. What are the unwanted effects during normal therapeutic range?
3. When will tolerance and dependence begin to become evident? Why?

Answer 13

1. Respiratory depression, prolonged sleep
2. drowsiness, dizziness, dry mouth, blurred vision, ataxia, amnesia
3. after two weeks - due to a change at receptor level

Question 15

What are the features of BDZ withdrawal syndrome?

Answer 15

• Anxiety: sleep disturbance, sweating, tremor, dysphoria
• Disturbance of Perception: Hypersensitivity to stimuli, visual disturbance, depersonalisation, sense of body sway
• Rare: Paranoid Psychoses, Seizures, Depressive Illness

Question 16

Withdrawal from long-term BDZ treatment

Answer 16

Withdrawal Symptoms and Rebound Anxiety

Question 17

How is BDZ withdrawal mangaged?

Answer 17

• Gradual decrease in dose over 4 to 16 weeks.
• Transfer to longer half-life drug, e.g. diazepam.
• Beware of increased alcohol consumption.
• Outcome - most succeed initially, 1/3 relapse but later succeed and 1/3 fully relapse

Question 18

How can BDZs be carefully prescribed?

Answer 18

• Where possible, identify causes of anxiety or insomnia and treat these appropriately.
• Reserve BDZs for more severe symptoms.
• Use the lowest effective dose.
• Ideally only prescribe for 2 weeks and at most 4 weeks.
• Avoid ‘repeat’ prescriptions as far as possible (don’t let receptionists give out repeats)
• Warn patients about the possibility of *dependence*.

Question 19

BDZ antagonists and inverse agonists

1. What is Flumazenil?
2. What is it used for?
3. How is it given?
4. What is it’s duration of action?
5. What adverse effect could occur?

Answer 19

1. competitive antagonist of benzodiazepines
2. used to reverse the effect of benzodiazepine overdose if severe respiratory depression
3. IV
4. Acts quickly, 2 hour duration of action
5. Convulsions

Question 20

BETA-ADRENOCEPTOR ANTAGONISTS

1. What are they used for?
2. Where does the effect take place?
3. What is it useful to treat?
4. Give an example

Answer 20

1. To reduce the physiological symptoms of anxiety
2. The effect is probably largely peripheral, due to the effects on beta-adrenoceptors.
3. Useful in treating Situational anxiety or Generalised anxiety disorder

May help attenuate withdrawal symptoms in BDZ withdrawal

4. Atenolol (B₁ selective, Propanolol

Question 21

5-HT-1A AGONISTS

1. What is Buspirone?
2. What is it’s mechanism?
3. What is a benefit?
4. Why are they less effective than BDZs?
5. What are the adverse effects?

Answer 21

1. 5-HT-1A partial
2. Initial ↓ 5-HT release but later this returns to normal but have agonist effect at post-synaptic receptors.
3. No effects at GABA sites and therefore avoids the unwanted effects of the benzodiazepines.
4. Slower onset and may be less effective than BDZs. Particularly so for patients previously given a BDZ.
5. nausea, dizziness, headache

Question 22

What are the common presentations of an anxiety disorder?

Answer 22

• Acute anxiety related to stressful event: often support from GP and perhaps short-term BDZ
• Chronic Generalised Anxiety Disorder: Psychological support and short term use of BDZs for exacerbations. SSRIs may be helpful.
• Situational Anxiety: Beta-blockers often helpful.
• Panic Disorder: SSRIs and CBT

Question 23

What are the stages of sleep?

Answer 23

• I (5%) - drowsy, shallow sleep - slow rolling eye movements
• II (50%) - Asleep - no eye movements, decreased muscle tone, HR and RR
• III (8%) - Asleep (slow wave sleep) - As for stage II
• IV (12%) - Asleep (slow wave sleep) - As for stage II
• REM (25%) - Dreaming - Bursts of rapid eye movement, increased cerebral blood flow, HR, RR and BP are all very variable

Question 24

Which stage of sleep are we in for the longest?

Answer 24

Stage II (50%)

Asleep - no eye movements, decreased muscle tone, HR and RR

Question 25

BDZ as Hypnotics

1. What does insomnia involve?
2. What do hypnotics do?
3. What characteristics does drug-induced sleep have?
4. What to BDZ do?
5. What is a benefit?

Answer 25

1. initial insomnia and early morning wakening
2. induce sleep, treat insomnia in the short term if non pharmacological methods have failed
3. Reduced REM component
4. •BDZ reduce the time taken to get to sleep and increase the total duration of sleep in those who sleep <6 hours.

•Avoid hangover effect with those benzodiazepines with a short duration of action e.g. temazepam

5. Don’t cause REM rebound that occurs with other hypnotics (nightmares)

Question 26

1. What are Z-drugs?
2. What do they act upon?
3. Where does Zopiclone- cyclopyrrolone bind?
4. Where does Zolpidem- imadazopyridine bind?
5. Where does Zaleplon- pyrazolopyrimidine bind?

Answer 26

1. Hypnotics
2. GABA-BDZ receptor
3. a different site on the complex
4. relatively selective for BDZ Type 1 receptor
5. relatively selective for BDZ Type 1 receptor

Question 27

Give an example of a Z-drug

Answer 27

Zopiclone-cyclopyrrolone