Transcript Zzzzzzz…. - The Cambridge MRCPsych Course

Zzzzzzz….
Benzodiazepines, ‘Z-drugs’
and tranquillisation
Dr David Middleton (ST4)
Introduction
• Anxiety
• Classification of anxiolytic and hypnotic
medications
• Benzodiazepines
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–
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action
uses
pharmacokinetics
adverse effects
• Alternatives to benzodiazepines
• Tranquillisation
• Exam questions
Anxiety
• Normal fear response to threatening
stimuli:
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autonomic reflexes (e.g. sweating)
arousal
corticosteroid secretion
emotional responses
behavioural responses (e.g. fight or flight)
Anxiety
• Becomes ‘abnormal’ when responses
occur independent of external stimuli
– anticipation
– spectrum between ‘normal’ and ‘pathological’
– becomes a disorder when it interferes with
functioning
• Important neurotransmitter systems:
– GABA, 5-HT and noradrenaline
Anxiety disorders
• Generalised anxiety disorder
– enduring anxiety state without clear precipitant
• Phobias
– specific fear of objects or situations
• Panic disorder
– discrete attacks of anxiety with somatic
symptoms
• Post-traumatic stress disorder
– recall of distressing experiences
• Obsessive compulsive disorder
– rituals driven by irrational anxiety
Classification of anxiolytic and
hypnotic drugs
• Benzodiazepines
– used as anxiolytic and hypnotic agents
• Buspirone
– 5-HT1A receptor partial agonist
– non-sedating
• β-adrenoceptor antagonists
– e.g. propranolol
– good for prominent physical symptoms
– block peripheral sympathetic responses
Classification of anxiolytic and
hypnotic drugs
• Zolpidem
– acts like a benzodiazepine
– used as hypnotic, minimal anxiolytic action
• Barbiturates
– rarely used except in anaesthesia/epilepsy
• Others
– chloral hydrate, rarely used
Benzodiazepines - history
• Identified in 1957 during systematic
screening of muscle-relaxants
• ‘taming’ effect on test animals
• Chlordiazepoxide in 1960, diazepam in
1962
• Began to replace barbiturates
• Physical dependence thought to be only in
high dose but later (1981) in therapeutic
doses
Benzodiazepines - structure
• Seven-membered ring fused to an aromatic ring
• Four substituent groups
• Some variation in pharmacological activity
– e.g. anticonvulsant>sedation
• Differences in pharmacokinetics are more
important clinically
Benzodiazepines - action
• Selective action on GABAA receptors (fast
inhibitory synaptic transmission in CNS)
• Open GABA-activated chloride channels in
the presence of GABA (c.f. barbiturates)
• Bind specifically to regulatory site of the
receptor not at the GABA-binding site
• Allosteric action i.e. increase affinity of
GABA for the receptor
• Do not affect glycine or glutamate
receptors
GABAA receptor
GABAA receptor structure
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Pentameric assembly of subunits
,  and  subunits
Three or more isoforms of each
Commonest type (50% of total): two 1 ,
two 2 and one 2
• 1 subunit: sedative, amnesic and
anticonvulsant effects
• 2 subunit: anxiolytic and muscle relaxant
effects
• Selective benzodiazepines in the future?
GABAA receptor subunits
Benzodiazepine receptors
• Benzodiazepine binding site lies between
1 and 2 subunits
• Type I benzodiazepine receptors:
– cerebellum
– induction and maintenance of sleep
• Type II benzodiazepine receptors:
– spinal cord and limbic regions
– muscle relaxant, anxiolytic and anticonvulsant
effects
Diazepam - pharmacokinetics
Bioavailability
Almost complete orally
Peak concentration
30-90 minutes
Protein binding
90-95%
Renal excretion
Negligible for unchanged drug
Metabolism
Phase I to active metabolite,
desmethyldiazepam
Phase II for inactivation of
metabolites
Elimination half-life
•Young adults
20 hours
•Elderly
30-100 hours
•Desmethyldiazepam 30-90 hours
Diazepam - pharmacokinetics
• Absorption following IM erratic
• Highly lipid soluble
– diffuses into CNS rapidly
– found in breast milk
– crosses placenta
• Newborn infants metabolise
benzodiazepines slowly, can accumulate
to cause respiratory depression
• Reports of cleft lip and cleft palate
Benzodiazepines - metabolism
• Phase I
– functional groups altered e.g. hydroxylation
– produces active metabolite in some cases e.g.
diazepam to desmethyldiazepam
– causes ‘hangover’ effect if used as hypnotics
– affected by age, liver disease or enzymeinducing drugs
• Phase II
– functional groups added to drug or metabolite
– conjugation (e.g. combining with sulphate or
glucuronic acid) usually inactivates compound
– phase II only preferable in hypnotics
Pharmacological properties of anxiolytics and
hypnotics
Drug
Absorption
t1/2 of
drug
Metabolic t1/2 of
phases
metabolites
Diazepam
Rapid
20-100
I + II
30-90
Chlordiazepoxide Intermediate 5-30
I + II
30-90
Alprazolam
Intermediate 5-15
I + II
Low concn
Lorazepam
Intermediate 10-20
II only
None
Nitrazepam
Intermediate 24
I + II
30-90
Flurazepam
Rapid
2
I + II
36-120
Temazepam
Slow
10
II only
None
Zolpidem
Rapid
2
II only
None
Zaleplon
Rapid
1
II only
None
Zopiclone
Rapid
3-4
I + II
3-6
Diazepam – adverse effects
Common
Occasional
Rare
Drowsiness
Dry mouth
Amnesia
Dizziness
Blurred vision
Restlessness
Psychomotor
impairment
Gastrointestinal
upset
Ataxia
Headache
Reduced BP
Skin rash
Benzodiazepines - uses
• Reduction of anxiety
– mainly generalised anxiety disorder or acute
anxiety states
– better response:
• somatic and psychological symptoms, clear
stressors and short duration
– poorer response:
• depressive, phobic and hypochondriacal
symptoms
– use for shortest possible duration
– smallest effective dose
– not more than 4 weeks
Benzodiazepines - uses
• Sedation and sleep
– decrease time taken to get to sleep and
increase total sleep
– effect declines if taken regularly for >2 weeks
– minimal long-term reduction in REM sleep (but
reduces from 25% to 10-15% in first two weeks’
use)
– rebound increase in REM if stopped
(nightmares)
– reduce slow-wave sleep
– best used for acute stress or jet-lag, not chronic
insomnia
Benzodiazepines - uses
• Alcohol withdrawal
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reduce withdrawal symptoms
prevent seizures
long half-life better e.g. chlordiazepoxide
reducing dose over 5-10 days
Benzodiazepines - uses
• Psychosis
– high doses in acute psychotic states can reduce
severe agitation
– tolerance can develop, therefore limit to a few
days
– antipsychotics better in agitated depression
– Note: risk of paradoxical increase in agitation
possible (triazolam withdrawn due to this).
Probably part of withdrawal syndrome in shortacting benzodiazepines
Benzodiazepines - uses
• Other uses:
– muscle relaxation
– anticonvulsant
– anterograde anmesia (minor surgical
procedures)
Benzodiazepines - tolerance
• “the need for larger doses to achieve the same
effect with repeated administration”
• Less marked than barbiturates (induction of drugmetabolising enzymes)
• Relatively quickly (days-weeks):
– sedative, hypnotic, anticonvulsant and muscle
relaxant effects
• Slowly (months):
– anxiolytic effects
• Rarely:
– amnesic effects
Benzodiazepines - tolerance
•
Mechanisms of tolerance:
1. Pharmacokinetic factors (body’s effect on drug)
•
not important in benzodiazepine tolerance
2. Pharmacodynamic factors (drug’s effect on body)
•
most important mechanism, affects sensitivity to
drug:
1. reduction in BDZ receptors
2. uncoupling of links between BDZ and GABA
receptors
3. Cognitive factors
Benzodiazepines - dependence
• Occurs secondary to tolerance
• Adaptive changes left unopposed in
absence of drug
• Rebound hyperexcitability causes a
withdrawal syndrome
• Suppressed by recommencing drug,
hence chronic use and dependence
• REM sleep rebound on cessation of
hypnotics is particularly prominent
Benzodiazepines – withdrawal symptoms
Anxiety
symptoms
Perceptual
disturbances
Severe
(but rare,<5%)
Anxiety
Dysphoria
Tremor
Muscle pains
Sleep disturbance
Headache
Nausea
Anorexia
Sweating
Fatigue
Hypersensitivity to
stimuli
Abnormal bodily
sensations
Abnormal sense of
movement
Depersonalisation
Visual disturbances
Paranoid
psychosis
Depressive
episode
Seizures
Confusion
Hallucinations
Benzodiazepines - withdrawal
• Occurs in approximately 45% of patients
using benzodiazepines for >6 months
• Symptoms in first week, last 7-10 days
• Short-acting benzodiazepines cause more
acute withdrawal effects (rapid drop in
plasma concentrations)
• Triazolam:
– very short-acting
– no longer in use due to withdrawal effect within
hours of single dose
– early morning insomnia and daytime anxiety if
used as a hypnotic
Benzodiazepines – managing
withdrawal
• Usually can be done as outpatient (unless
previous seizures on withdrawal)
• Short half-life drugs changed to long halflife drugs
• Gradual reduction (approx 2mg diazepam
or 25% daily dose), every 1-2 weeks over
4-16 week period
• β-blockers can reduce severity of
symptoms but not outcome
• Education and support are important
• Anxiety management, relaxation therapy
Benzodiazepines - antagonists
• Competitive antagonists useful to reverse
effects of benzodiazepines
• Flumazenil often used in benzodiazepine
overdose or for treatment of comatose
patient suspected of overdose
• 200µg IV over 15 seconds
• Further 100µg IV over 10 seconds after
one minute if no response. Max 1mg.
• t1/2 1-2 hours, so drowsiness may return
• Side effects: anxiety, agitation, nausea,
convulsions
Buspirone
• 5-HT1A partial receptor agonist
• Also binds to dopamine receptors but this
action less important in anxiety
• 5-HT1A receptors are inhibitory
autoreceptors that reduce release of 5-HT
and other mediators
• Also inhibit NA in locus coeruleus neurons
so reduce arousal
• Buspirone takes days-weeks to have an
effect (?more complex action)
• Ineffective in panic attacks or severe
anxiety states
Buspirone
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Non-sedating
Does not cause motor incoordination
No withdrawal effects
Main side-effects:
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nausea
dizziness
headache
restlessness
Barbiturates
• Diethylbarbituric acid (1903),
phenobarbital (1912)
• t1/2 : 30-90 hours
• Hepatic metabolism
• Induce cytochrome P450 and conjugating
enzymes…drug interactions
• Enhance action of GABA at its receptors
and produce depressant activity on CNS:
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hypnotic
sedative
anxiolytic
anticonvulsant
Barbiturates
• Adverse effects:
– impairment of psychomotor function
– chronic cognitive impairment and paradoxical
hyperactivity in children
– vertigo
– nausea
– vomiting
– diarrhoea
• Tolerance and dependence
• Overdose:
– respiratory and cardiovascular depression
– cross-potentiation with alcohol
Rapid tranquillisation
• Nice guidelines on management of
violence and aggression:
http://www.nice.org.uk/nicemedia/pdf/cg02
5_SPC_chart_for_press.pdf
• Lecture in MRCPsych Paper III course
Rapid tranquillisation
Medication
Time to peak
plasma
concentration
Half-life
Haloperidol IM
15-60 mins
10-36 hours
Haloperidol liquid
2-6 hours
10-36 hours
Haloperidol tablet
2-6 hours
10-36 hours
Lorazepam IM
60-90 mins
12-16 hours
Lorazepam tablet
2 hours
12 hours
Olanzapine disp
5-8 hours
32-50 hours
Olanzapine IM
15-45 mins
32-50 hours
Risperidone disp
1-2 hours
24 hours
Risperidone liquid
1-2 hours
24 hours
Risperidone tablet
1-2 hours
24 hours
Rapid tranquillisation (Maudsley)
1. De-escalation, time out, placement
2. Offer oral treatment
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haloperidol 5mg or
olanzapine 10mg or
risperidone 1-2mg
with or without lorazepam 1-2mg
repeat every 45-60 minutes
3. Consider IM treatment
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lorazepam 1-2mg
haloperidol 5mg
olanzapine 5-10mg (NB not with BDZ)
repeat up to two times at 30-60 minutes
Rapid tranquillisation
4. Consider IV treatment (very very rare!)
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diazepam 10mg over >5 minutes
repeat after 5-10 minutes if needed up to three
times
5. Seek expert advice (if not already
done…)
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amylobarbital 250mg IM
paraldehyde 5-10 ml IM
very, very rare!
Please read full NICE/Trust guidelines
Accuphase (zuclopenthixol
acetate)
• Not used for rapid tranquillisation
• Considered if repeated injections of
antipsychotics/benzodiazepines required
in acutely psychotic patient
• 50-150mg (max 400mg in 2 weeks)
• Sedative effects after 2 hours, peak at 12
hours
• Effects up to 72 hours
Accuphase (zuclopenthixol
acetate)
• Should not be used if patient is:
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accepting oral medication
neuroleptic naïve
sensitive to EPSE
unconscious
pregnant
suffering renal/hepatic impairment
suffering from cardiac disease
• It is not a ‘chemical straightjacket’
• Best used in those with previous good
response
Exam questions
A 24-year old with anxiety and depression
presents following an overdose of 30
diazepam tablets. She is drowsy and poorly
compliant with examination. Which of the
following is true regarding diazepam?
A. Blood levels are useful in deciding if ventilation
is required
B. The half-life of its sedative effects is 2-3 hours
C. Only active after metabolic activation
D. Is water-soluble and predominantly renally
excreted
E. Its sedative effects are exaggerated by alcohol
Exam questions
A man is admitted for alcohol detoxification.
He has tender hepatomegaly but refuses
transfer to a medical ward. The treatment
choice for detox would be:
A. Diazepam
B. Clobazam
C. Alprazolam
D. Chlordiazepoxide
E. Nitrazepam
Exam questions
Which of the following is not a common
symptom of benzodiazepine withdrawal
syndrome?
A. Stiffness
B. Tinnitus
C. Blurred vision
D. Hypertension
E. Headache
Exam questions
Which of the following regarding buspirone is
false?
A. It is a 5-HT1A partial agonist
B. Effects are usually evident after 8-10
hours
C. It can cause galactorrhoea
D. Dysphoria has been reported
E. It has no significant withdrawal
syndrome
Exam questions
Which of the following regarding
benzodiazepines is false?
A. Oxazepam and lorazepam are shortacting
B. Diazepam is 95% protein-bound
C. They are ineffective in phobic states
D. They initially increase REM sleep
E. Withdrawal can cause rebound insomnia