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Year 2 LCRS Pharmacology > 26: Anxiolytics, Sedativs and Hypnotics > Flashcards

26: Anxiolytics, Sedativs and Hypnotics Flashcards

1
Q

Explain the Synthesis of GABA

A

Glutamate –Glutamate decarboxylase (GAD) –> GABA

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2
Q

Explain the effects of GABA on the postsynaptic memrane

A
  1. Binds to GABA(A) receptors causing
    1. hyperpolerisation via Cl- influx
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3
Q

How is GABA in the synaptic cleft inhibited?

A

Via reupttake

  • into presynaptic cell
  • into ajacent Glial cells
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4
Q

What are the targets of GABA once it is in the synaptic cleft?

A
  1. Postsynaptic GABAA receptors
  2. Autorecepors on presynaptic membrane
    • negative feedback to reduce GABA release
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5
Q

Explain the Metabolism of GABA

A

Happens in Mitochondria after uptake

  1. Either directly recycled into vesicles
  2. or: GABA– GABA Transaminase (GABA T) –> Succinic Semialdehyde — Succinic Semialdehyde dehydrogenase –> Succinig acid (goes back to TCA cycle)
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6
Q

What happens when you inhibit GABA metabolism?

When is this therapeutically useful?

A
  • leads to large increase in GABA and GABA release
    • used as Anti-convulsants (e.g. sodium valporate)
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7
Q

Explain the structure of a GABA A receptor compex

A
  1. There are 4 (5) Subunits
    1. GABA receptor protein
      1. if GABA is bound linked by GABA modulin to:
    2. Benzodiazepine receptor protein
    3. Barbiturate receptor protein
    4. All three surround: Chloride Channel protein
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8
Q

Where does GABA on the GABAA receptor complex bind to?

What happens/changes with binding?

A
  1. GABA binds to GABA receptor protein
    • causes GABA modulin to link GABA receptor protein linking with Benzodiazepine receptor protein
    • Causes Cl- channel opening
  • Also enhances binding of Benzodiazepines
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9
Q

Explain the MOA of Benzodiazepines

A
  1. Bind to Benzodiazepine Receptor protein on GABA receptor unit
    • enhances effect of GABA on receptor
    • cause increased GABA binding (bidirectional) leading to
      • Increased frequency of Cl- channel binding
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10
Q

What is a PAM?

A

Positive allosteric modulator

  • drugs that enhance the binding protein at the receptor (bind to different target site)
    • In example of GABA receptors: Benzodiazepines and Barbiturates
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11
Q

Explain the MAO of Barbiturates

A
  1. Bind to the Barbiturate Receptor protein of the GABA receptor unit causing
    • enhanced normal action of GABA (unidirectional)
    • at high doses: direct stimmulaiton and opening of Cl- channels causing
      • increased duration of Cl- channel opening
    • Also: decrease Glutamate mediated exitation (less selective than Bz)
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12
Q

Explain why Barbiturates have a lower margin of safety but can also be used to induce anesthesia?

A

They are less selective than Benzodiazepines

  • reduce exitory transmission (Glutamate mediated)
    • have also more membrane effects
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13
Q

What are the clinical uses of Barbituates?

A
  • Induction of Anesthetic e.g. Thiopentone
  • Anticonvulsants
  • Sedative/Hypnotic effects (e.g. Amobarbital in severe insomnia (with t1/2 20-25 h)
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14
Q

What are the clinical uses of Benzodiazepines?

A
  • Anticonvulsants (e.g. Diazepam, Clonazepam)
  • Anti-spastics
  • Anxiolytic (long acting)
  • Sedative/Hypnotics (short acting)
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15
Q

What is an anxiolytic?

A

Remove Anxiety wihout impairing mental or physical activity

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16
Q

What is an sedative?

What is an Hypnotic?

What is their difference?

A
  1. Sedative= reduce mental and pyhsical activity without producing loss of consciousness
  2. Hypnotics= induce sleep
    • Difference: often only the dose is different not the drug
17
Q

What are the side effects of the use of Barbiturates?

A

Many side effects: not first choice of treatment

  1. Respiratory depressive
    • low safety margin
    • overdose it lethal
  2. Alter natural sleep pattern (reduction in REM) –> Hangovers
  3. Enzyme inducer
  4. Potentiate effects of other CNS depressants (e.g. Alcohol)
  5. Tolerance development (tissue and pharmacokinetic)
  6. Dependance with severe withdrawl symptoms
    • insomnia
    • anxiety
    • tremor
    • convulsants
    • death
18
Q

What are the differences between the different benzodiazepines available?

A

Normally: all same/similar structure but different pharmakokinetic properties (all same target+ similar potencies)

19
Q

Summarise the pharmacokinetics of Benzodiazepines

A
  1. Administration
    • PO (after 1h effects)
    • IV as anti-convulsant treatment in status epilepticus
  2. Distibution
    • heavily Plasma Protien bound
    • soluble –> wide distribution
  3. Metabolism (extensive in the liver) –> forms glucuronite conjugates
  4. Excretion in urine
20
Q

Name an example of a long acting Benzodiazepine

What is its use?

How is it metabolised?

A

E.g. Diazepam (t1/2 32h)

  • normally used as anxiolytic
  • metabolised via forming active metabolies (of short acting Benzodiazepines)
    • Exception: Oxacepam in liver impairment –> bcomes long-acting due to slow metabolism
21
Q

Which Benzodiazepines can be used as an Anxiolytic?

A

Long Acting (e.g. Diazpam)

  • exeption: Oxazepam in liver damage might get metabolised slower –> made long acting
22
Q

Name short acting benzodiazepines and summarist their use and metabolism

A

Metabolised and form Glucuronide conjugates

  • E.g. Temazepam, Oxazepam (t1/2 8h)
    • used as sedatives/hypnotics
  • Exeption: NITRAZEPAM long acting but can be used to treat insomia + have daytime anyiolytic effects
23
Q

What are the advantages of the use of Benzodiazepine over Barbiturates?

A
  • wide margin of safety
    • overdose caues prolonged but rousable sleep
    • Antagonist Available (Flumazenill)
  • only mild effect on REM sleep
  • no enzyme inducers
24
Q

What are the side-effects of Benzodiazepines?

A
  1. Sedation, Confusion, amnesia, ataxia (–> should not drive)
  2. Potentiation of other neurodepressants
  3. Tolerance (but less than Barbs –> only tissue)
  4. Dependance (similar to Barbs but less intense)
    • slow withdraw aimed
  5. Can be displaced from PP by other PP binding drugs
25
Q

Other than Bz and Barbs, which drug can be used in the treatment of Anxiety?

A
  • Zopiclone
    • same MOA of Benzodiazepine
    • similar effect but less severe side effects
  • Some anti-depressants (SSRI)

Year 2 LCRS Pharmacology (38 decks)

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