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Year 2 LCRS > Pharmacology 26 - Anxiolytics and Sedatives > Flashcards

Pharmacology 26 - Anxiolytics and Sedatives Flashcards

1
Q

Describe GABA metabolism

A
  • GABA to succinic semialdehyde via GABA transaminase
  • Succinic semialdehyde to succinic acid via succinic semialdehyde dehydrogenase
  • Use of mitochondrial enymes
  • GABA shunt (producing and removing GABA via TCA cycle)
  • Inhibition causes large increase in brain GABA
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2
Q

Compare receptor actions of benzodiazepines and barbituates

A
  • No activity alone, they enhance GABA so are not agonists (allosteric action - bind to different sites to GABA)
  • Different binding sites and mechanisms (BZs increase frequency of openings of the ion channel, while BARBs increase the duration of openings)
  • BARBs less selective than BZs and can also decrease glutamate mediated excitatory transmission as well as other membrane effects (may explain induction of anaesthesia and low margin of safety)
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3
Q

List clinical uses of benzodiasepines and barbituates

A
  • Anaesthetics (BARBs only - thiopentone)
  • Anticonvulsants (diazepam, clonazepam, phenoarbital)
  • Anti-spastics (diazepam)
  • Anxiolytics
  • Sedatives/ hypnotics
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4
Q

Define anxiolytic

A

Remove anxiety without impairing mental or physical activity (previously called minor tranquillisers)

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5
Q

Define sedatives

A

Reduce mental and physical activity without producing loss of consciousness (grouped with hypnotics)

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6
Q

Define hypnotics

A

Induce sleep (grouped with sedatives)

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7
Q

List characteristics of anxiolytics, sedatives and hypnotics

A
  • Wide margin of safety
  • Not depress respiration
  • Produce natural sleep (hypnotics)
  • Not interact with other drugs
  • Not produce hangovers
  • Not produce dependence
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8
Q

List uses of barbituates

A
  • Sedative/hypnotic

- Amobarbital used in severe intractible insomnia half life 20-25h

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9
Q

List unwanted effects of barbituates

A
  • Low safety margins (depress respiration, overdosing is lethal)
  • Alter natural sleep by decreasing REM, resulting in hangovers/ irritability
  • Enzyme inducers
  • Potentiate effect of CNS depressants (eg. alcohol)
  • Tolerance
  • Dependence
  • NOT FIRST CHOICE DRUGS
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10
Q

What is seen in withdrawal from barbituates?

A
  • Insomnia
  • Anxiety
  • Tremor
  • Conxulsions
  • Death
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11
Q

Describe pharmacokinetics of benzodiazepines

A
  • Act on GABAa receptors
  • Well absorbed orally, peaks in plasma after 1 hour (can be given IV in status epilepticus)
  • Binds to plasma proteins strongly - highly lipid soluble with wide distribution
  • Extensive metabolism (liver)
  • Excreted in urine as glucoronide conjugates
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12
Q

Describe duration of action of benzodiazapenes

A
  • Varies greatly
  • May be short acting (sedative/ hypnotics)
  • Or long acting with slower metabolism or generate active metabolites (slow metabolism and/or active metabolites- anxiolytics)
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13
Q

Give examples of long acting and short acting benzodiazepines

A
  • Long acting benzodiazepines (diazepam)

- Short acting benzodiazepines (lorezepam)

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14
Q

List anxiolytic benzodiazepines

A
  • Diazepam (used only during crisis)
  • Chloradizepoxide
  • Nitrazepam
  • Oxazepam (used in hepatic impairment, short acting drug unlike the others)
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15
Q

List sedative/ hypnotic benzodiazepines

A
  • Temazepam (used in insomnia treatment)
  • Oxazepam
  • Nitrazepam (long duration of action, used when suffering with early morning waking)
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16
Q

List advantages of benzodiazepines

A
  • Wide margin of safety
  • Overdose results in rousable prolongued sleep (flumazenil is an antagonist, used in overdose or to reverse effect)
  • Mild effect on REM sleep
  • Do not induce liver enzymes
17
Q

List unwanted effects of benzodiazepines

A
  • Sedation, confusion, amnesia, ataxia (impaired manual skills)
  • Potentiate other CNS depressants
  • Tolerance (less than barbs)
  • Withdrawal similar to barbituates but less intense, therefore slowly withdrawn
  • Increased concentration free in plasma following displacement from plasma proteins by aspirin and heparin
18
Q

What is zopiclone?

A
  • Short acting sedative/ hypnotic
  • Acts at BZ receptors (GABA enhancement action - but they are not benzodiazepines but cyclopyrolones)
  • Similar efficacy to BZs
  • Minimal hangover effects but dependency is still a problem
19
Q

List other anxiolytics (other than BARBs and BZs)

A
  • SSRIs (less sedation and dependence, used long-term with delayed effect)
  • Antiepileptic drugs (valproate, tiagapine)
  • Antipsychotic drugs (olanzapine, quetiapine)
  • Propanolol (improves physical symptoms, eg. tachycardia and tremor)
  • Busiprone
20
Q

What is busiprone?

A
  • 5HT 1A agonist
  • Anxiolytic
  • Fewer side effects (less sedation)
  • Slow onset of action (days/weeks)
21
Q

Describe the GABA-ergic synapse

A
  • GABA released from vesicles by calcium influx following arrival of the action potential
  • Diffuses across the cleft
  • Binds to postsynaptic chloride ionopore receptors (GABAa receptors - type 1), generally on the short axon interneurons (damps down hyperactivity)
  • Reuptake into the presynaptic terminal, as well as uptake into glial cells
  • GABA autoreceptors on the presynaptic nerve terminals regulate the release of GABA (negative feedback to the presynaptic nerve - GABAb receptors)
22
Q

Describe GABA synthesis

A
  • Glutamate to GABA

- Catalysed by glutamate decarboxylase

23
Q

Which drugs inhibit GABA metabolism?

A
  • Sodium valproate (epilim - inhibits GABA-T and SSDH, as well as multi-sensitive sodium channels)
  • Vigabatrin (sabril - inhibits GABA-T)
  • Cause large increases in brain GABA
24
Q

Describe the GABAa receptor complex

A
  • Central chloride channel protein
  • GABA receptor protein
  • Benzodiazepine receptor protien
  • Barbituate receptor protein
25
Q

Describe physiological function of GABAa receptor

A
  • When GABA binds linking to benzodiasepine receptor protein by GABA modulin
  • Causes influx of chloride
  • This reduces resting membrane potential, making the postsynaptic cell more difficult to excite (hyperpolarisation - inhibitory)
26
Q

How do benzodiazepies interact with GABAa receptor complex

A
  • Binds to Benzodiazepine receptor protein
  • Enhances chloride influx into the postsynaptic cell
  • Enhances binding of GABA to the GABA receptor protein (reciprocal response, as GABA enhances benzodiazepine binding)
27
Q

How do barbituates interact with GABAa receptor complex?

A
  • Bind to barbituate receptor
  • Enhances influx of chloride into postsynaptic cell
  • Increase affinity of GABA binding (not reciprocated - no effect on barbituate binding by GABA binding to GABA receptor protein)
  • Higher concentrations can directly open the chloride channel
28
Q

How do biculline and flumazenil work?

A
  • Flumazenil blocks the benzodiazepine receptor protein (competitive antagonist)
  • Biculline competes with GABA to bind to GABA receptor protein (antagonist)
29
Q

Why are benzodiazepines normally avoided in elderly patients and those with a history of drug abuse

A
  • Avoided because CNS active drugs have a greater effect in elderly people. Depression of neuronal excitability can cause falls and psychomotor impairment in older patients
  • Benzodiazepines have an issue with dependency, and 35% of patients taking them for more than 4 weeks will develop dependence. High dose, regular continuous use and dependent personality are at the strongest risk factors
30
Q

How can the MOA of diazepam be briefly described?

A

Positive allosteric modulation

Year 2 LCRS (128 decks)

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