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Pharmacology > Anxiolytics and Hypnotics > Flashcards

Anxiolytics and Hypnotics Flashcards

1
Q

……

A
  • GABA is the most important inhibitory NT in the brain
  • Glial cells envelope the synapse and surround them
  • One of the functions of glial cells is to ‘mop up’ NTs
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2
Q

What is GABA made from?

A

GABA is synthesised from glutamate (precursor for GABA)

Strangely, glutamate is the single most important excitatory NT in the brain

It is acted on by GAD (glutamate decarboxylase): glutamate -> GABA.

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3
Q

What does GABA bind to on post-synaptic neurones and what does this do?

A
  • GABA-A receptors
  • They are chloride ionophores
  • They are ion channel linked (chloride channel)
  • When stimulated by GABA, the ion channel changes conformation to transiently become a chloride ion
  • Chloride is negative, so they hyperpolarise the post-synaptic cell
  • If the cell has a very negative potential, it is harder to excite – this is how GABA dampens down activity
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4
Q

Where is GABA-B found and what is its role?

What type of receptor are they?

A

GABA-B receptors exist on the pre-synaptic terminals – these are type II receptors (G-protein coupled). They have a regulatory effect.

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5
Q

How does re-uptake of GABA occur?

A
  • GABA must first be taken up by the surround glial cells OR back into the pre-synaptic terminal
  • This reduces the synaptic concentration of GABA, but also allows for GABA metabolism
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6
Q

How is GABA metabolised?

A
  • GABA transaminase (GABA-T) is the first enzyme in metabolism (GABA -> succinic semialdehyde)
  • The second enzyme is succinic semialdehyde dehydrogenase (SSDH) to produce succinic acid
  • Succinic acid goes back into the TCA cycle in the cells
  • Glutamate also arises from the TCA cycle – this forms a GABA shunt
  • Around 10% of the activity of the TCA cycle is involved in generating GABA as a transmitter
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7
Q

Give examples of anti-convulsant/anti-epileptic drugs, what do they inhibit?

A

SODIUM VALPROATE (EPILIM): GABA -T and SSDH inhibitor + Na blocker

VIGABATRIN (SABRIL): GABA -T inhibitor

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8
Q

Where are GABA-T and SSDH found?

A

both mitochondrial enzymes

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9
Q

How can GABA be used to cause an anti-convulsant/anti-epileptic effect?

A
  • If we inhibit GABA metabolism, we can produce large increases in brain GABA levels
  • This enhances the release of GABA in the CNS -> anticonvulsant/anti-epileptic effects
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10
Q

What are the 4 main proteins making up the GABA-A receptor?

A
  • GABA receptor protein
  • Benzodiazepine receptor protein
  • Barbiturate receptor protein
  • Chloride channel protein
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11
Q

What happens to the GABA-A receptor when GABA binds?

A
  • When GABA binds to the GABA-A receptor, it binds to the GABA receptor protein
  • When this happens, GABA receptor protein and benzodiazepine receptor protein link together
  • This is mediated by a peptide called GABA modulin
  • The result is a momentary opening of the chloride channel protein -> hyperpolarisation
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12
Q

What is a competitive antagonist for the GABA-A receptor?

A

Bicuculline - competes with GABA to bind to the GABA receptor protein

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13
Q

What do benzodiazepines bind to and what does this do (2 effects)?

A
  • Benzodiazepine binds to the benzodiazepine receptor protein

This has two main effects on GABA neurotransmission:

  • Facilitate GABA mediated opening of the Cl- channel
  • Facilitate GABA binding to its own receptor (this is reciprocated)
    I.e. in the presence of GABA binding we get a facilitation of benzodiazepine binding
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14
Q

What is Flumezanil?

A
  • Competitive benzodiazepine antagonist

- It competes with benzodiazepine for its binding site

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15
Q

What do barbiturates bind to?

What 3 effects does this have?

A
  • Barbiturates binds to the barbiturate receptor protein

This has three main effects on GABA neurotransmission:

  • Facilitate GABA mediated opening of the Cl- channel
  • Facilitate GABA binding to its receptor but this is not reciprocated

At higher concentrations, barbiturates can have a direct action on the chloride channel

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16
Q

Can barbiturates and benzodiazepines work alone on the GABA receptor?

A
  • Benzodiazepines and barbiturates have no activity alone (allosteric action)
  • If you take GABA out of the equation then these drugs have no activity on their own
  • They are working to enhance the action of GABA, they are not direct GABA agonists by themselves
  • They bind to GABA-A receptor but also bind to their own binding sites (not GABA receptor protein)
17
Q

How do barbiturates and benzodiazepines work?

A

Barbiturates and benzodiazepines have slightly different mechanisms:

  • Benzodiazepines: increase the frequency of chloride channel opening
  • Barbiturates: increase the duration of the chloride channel opening
  • Barbiturates also reduce excitatory transmission (some antagonist action at glutamate receptors)
  • This contributes to their anxiolytic and hypnotic effects
  • Barbiturates also have other membrane effects (e.g. direct action on Cl channel at higher concentrations)
18
Q

Compare the selectivity of barbiturates and benzodiazepines and what this means

A
  • Barbiturates are less selective than benzodiazepines

This reduced selectivity may explain:

  • Induction of surgical anaesthesia (we can’t do that with benzodiazepines)
  • Barbiturates are less safe than the benzodiazepines
19
Q

What are the clinical uses of barbiturates and benzodiazepines?

A
  • Anaesthetics (barbiturates only: thiopentone)
  • Anticonvulsants – barbiturates (diazepam, clonazepam) and barbiturates (phenobarbital)
  • Anti-spastics (diazepam) – action in spinal cord and reduces AP propagation in alpha motor neurones
  • Anxiolytics
  • Sedatives/hypnotics
20
Q

What are anxiolytics, sedatives and hypnotics?

A

ANXIOLYTICS: Remove anxiety without impairing mental or physical activity (“minor tranquillisers”)

SEDATIVES: Reduce mental and physical activity without producing loss of consciousness

HYPNOTICS: Induce sleep

21
Q

What must anxiolytics, sedatives and hypnotics ideally do/not do?

A
  • Have wide margin of safety
  • Not depress respiration
  • Produce natural sleep (hypnotics)
  • Not interact with other drugs
  • Not produce ‘hangovers’
  • Not produce dependence
22
Q

Structure of barbiturates

A
  • Barbiturates all have a six-membered ring in the middle – they differ in their substituent groups
  • It has four carbons and two nitrogens (different barbiturates have different groups at specific sites)
23
Q

Give an examples of a barbiturate and its use

A

AMOBARBITAL: useful in severe intractable insomnia, t½ 20-25 hours

**Barbiturates were once our front line sedative/hypnotic drugs – but they have many unwanted effects

24
Q

What are the unwanted effects of barbiturates?

A
  • They possess low safety margins (depress respiration -? overdosing lethal)
  • Alter natural sleep (decrease REM sleep) -> hangovers and irritability
  • Enzyme inducers – barbiturates induce microsomal enzymes – so avoid co-administration
  • Potentiate effect of other CNS depressants (e.g. Alcohol)
  • Tolerance
  • Dependence: withdrawal syndrome: insomnia, anxiety, tremor, convulsion and death
25
Q

Give examples of benzodiazepines

A

DIAZEPAM, OXAZEPAM, TEMAZEPAM

26
Q

Structure of benzodiazepines and what do they all act on? Compare potencies and mechanism of action

A
  • The structure is tricyclic: classic three-ring structure (2 six-membered and 1 seven-membered)
  • There are around 20 available – but they all act at GABAA receptors
  • They all have similar potencies & profiles, and have the same mechanism
  • Pharmacokinetics of different types largely determine use
27
Q

How are benzodiazepines:

  • administered?
  • distributed?
  • metabolised?
  • excreted?
  • duration of action?
A

Administration

  • Well absorbed orally
  • Peak plasma concentration is reached after about 1 hour
  • Sometimes IV – used in the treatment of status epilepticus (continuous seizure activity)

Distribution

  • Bind plasma proteins strongly
  • Highly lipid soluble - large volume of distribution in the body

Metabolism
- Usually extensively metabolised in the liver

Excretion
- Excreted in the urine as glucuronide conjugates

Duration of Action

  • Varies a lot
  • This allows classification of the drugs as short-acting or long-acting
  • Long-acting either has slower metabolism or generates active metabolites
28
Q

Which benzodiazepines are short/long acting?

A

Short-Acting: OXAZEPAM and TEMAZEPAM

Long-Acting: DIAZEPAM

29
Q

How are oxazepam, temazepam and diazepam metabolised?

A

OXAZEPAM:
- Metabolised in the liver to its inactive glucuronide

TEMAZEPAM:
- Metabolised initially to oxazepam, which is then converted to the glucuronide conjugate

DIAZEPAM:
- Metabolised via temazepam and oxazepam to the glucuronide

**Some diazepam is metabolised through nordiazepam then oxazepam. So diazepam has slower metabolism than the other two and it also generates active metabolites

30
Q

Benzodiazepines as anxiolytics - which can be used and why?

What happens in hepatic impairment, which drug is used and why?

A
  • Benzodiazepines can be used as anxiolytics and sedative/hypnotics
  • Anxiolytics (generally the longer acting benzodiazepines)
  • DIAZEPAM – classic anxiolytic benzodiazepine
  • CHLORDIAZEPOXIDE (librium)
  • NITRAZEPAM

If the patient has hepatic impairment then the metabolism of the drug will be slowed so in this case you can use a shorter-acting benzodiazepine for its anxiolytic activity - the drug of choice is OXAZEPAM (t1/2 = 8 hours).

31
Q

Benzodiazepines as sedatives/hypnotics

Which are used, give examples and why?

What is an exception that can be used?

A
  • Sedative/Hypnotics (generally the shorter acting benzodiazepines)
  • TEMAZEPAM
  • OXAZEPAM
  • Exception: NITRAZEPAM (t1/2 = 28 hours) – can be used as a sedative/hypnotic (it also has a daytime anxiolytic effect)
32
Q

What are the advantages of benzodiazepines?

A
  • Benzodiazepines have largely superseded the barbiturates
  • They have a wider margin of safety – overdose -> prolonged sleep (this is rousable)
  • We can give an intravenous shot of flumazenil (competitive antagonist) to overcome this
  • Mild effect on REM sleep -> so do not induce the hangover effect
  • Do not induce liver enzymes
33
Q

What are the unwanted effects of benzodiazepines?

A
  • Sedation – when they are being used as anxiolytics the patients will feel a little drowsy
  • Confusion, ataxia (impaired manual skills)
  • Potentiate other CNS depressants (e.g. alcohol and barbiturates)
  • Tolerance (but less than barbiturates because of tissue tolerance only - no pharmacokinetic tolerance)
  • Dependence
    Associated with withdrawal syndrome (but less than barbiturates)
    Drugs should be withdrawn slowly
  • Free plasma concentration of benzodiazepines can be increased by giving aspirin and heparin –
    They are plasma protein bound and compete with benzodiazepines
34
Q

What is zopiclone?

A
  • Short acting (t½ is around 5 hours)
  • Acts at benzodiazepine receptor but it is NOT a benzodiazepine
  • It does enhance GABA-mediated neurotransmission by binding to the BZ binding site
  • But it is actually a cyclopyrrolone (not a benzodiazepine)
  • Sedative/hypnotic
  • Similar efficacy to benzodiazepines
  • Minimal hangover effects
  • Minimal hangover effects but dependency still a problem
35
Q

Give examples of anxiolytics

A
  • Some anti-depressants: SSRIs
    Less sedation & dependence/delayed response/long-term treatment
  • Some anti-epileptic drugs: Valproate, tiagabine
  • Some antipsychotic drugs:
    Olanzapine, quetiapine
  • Propranolol
    This is a non-selective beta-blocker
    It improves the physical symptoms of anxiety
    E.g. Tachycardia (b1) and Tremor (b2)
  • Buspirone
    5-HT1A agonist
    Has fewer side-effects (less sedation compared to benzodiazepines)
    Downside: slow onset of action

Pharmacology (26 decks)

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