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Year 2 - Pharm Lectures 11+ > Anxiolytics, Sedatives & Hypnotics > Flashcards

Anxiolytics, Sedatives & Hypnotics Flashcards

1
Q

Explain the process of GABA Neurotransmission

A
  1. Glutamate –> GABA via GAD (Glutamate Decarboxylase)
  2. GABA can bind to:
    • GABAaR on the postsynaptic cell = hyperpolarise cell

• GABAbR on pre-synaptic cell = -VE inhibition of release

  1. GABA can then be re-up-taken by:
    • Glial cells – GABA-Transaminase breaks down GABA into SSA (Sunninic Semialdehyde)

• Pre-synaptic cell – GABA-T breaks down GABA into SSA

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2
Q

Explain what GABA is metabolised into

A

GABA –> Succinic Semialdehyde (SSA)
• via. GABA-T

SSA –> Succinic Acid
• via. SSDH

GABA found in cytosol
GABA-T & SSDH found in mitochondrial membrane

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3
Q

What do Sodium Valproate & Vigabatrin do?

A

GABA metabolism inhibitiors
• leads to MORE GABA
• = MORE INHIBITION in the brain

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4
Q

Describe the GABAa receptor complex

A 
Made up of 4 main proteins:
 • GABA-R Protein
 • GABA modulin
 • Barbiturate receptor protein
 • BDZ (Benzodiazepine) receptor protein

BDZ & Barb need GABA to function to some degree

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5
Q

What do Bicuclline & Flumazenil do?

A

BOTH are COMPETITIVE ANTAGONISTS

Bicuclline
• GABA

Flumazenil
• BDZ

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6
Q

What are the 6 different pathways of GABAa-Receptor MoActivation

A

Pathway 1
– linkage of GABA-RP, GABA-M and BDZ-RP and opening of Cl—channel
• GABA

Pathway 2
– initiation of pathway 1
• BDZ

Pathway 3
– increased affinity of binding of GABA/BDZ (reversible)
• GABA, BDZ

Pathway 4
– linkage of Barb-RP and BDZ-RP and opening of Cl—channel
• Barb

Pathway 5
– increased affinity of binding of GABA (NOT-reversible)
• Barb

Pathway 6
– direct activation of Cl—channel
• GABA, Barb

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7
Q

What are some facts about BZs & BARBs?

A

(1) NO activity ALONE
• allosteric action

(2) DIFFERENT binding sites & mechanisms
• BZs increase the FREQUENCY of openings
• BARBs increase the DURATION of openings

(3) BARBs are LESS SELECTIVE than BZs so have:
• LESS excitatory transmission
• BARBs are MORE dangerous
(may explain induction of surgical anaethesia & small therapeutic window)

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8
Q

Clinical uses of BZs & BARBs?

A

o Anaesthetics
• BARBs ONLY (thiopentone)

o Anticonvulsants
• Diazepam, Clonazepam, Phenobarbital

o Anti-spastics
• Diazepam

o Anxiolytics
• BDZs ONLY

o Sedatives/Hypnotics
• BARBs & BDZ

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9
Q

Define anxiolytivs

A

Remove anxiety WITHOUT impairing mental or physical activity

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10
Q

Define Sedatives

A

Reduce mental AND physical activity without producing a loss of consciousness

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11
Q

Define Hypnotic

A

Induces SLEEP

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12
Q

What should these 3 types of drugs ideally be?

A 
o Have a large therapeutic window
o Not depress respiration
o Produce natural sleep
o Not interact with other drugs
o Not produce “handovers”
o Not produce “dependence”
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13
Q

What do Barbiturates nornally end in?

A
  • tone
  • tol
  • tal
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14
Q

Describes the structures of BARBs & the effect they normally have

A

Tend to have a single-ring structure
• with 2 R-groups

Have a SEDATIVE/HYPNOTIC effect
• cause severe intractable insomnia (as dependent)
• T1/2 = 20-25hrs

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15
Q

Example BARB drug?

A

Amobarbital

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16
Q

Explain the Unwanted SEs of BARBs

A

o Small therapeutic windows
– depress respiration

o Reduce REM sleep –> “hangovers”

o Induce enzymes

o Potentiate effects of other CNS depressants
– alcohol

o Tolerance and dependence become issues
– insomnia, anxiety, tremor, convulsion, death

17
Q

What do Benzodiazepines normally end in?

A
  • epam

- epate

18
Q

Explain the structure of BDZs and what they act on

A

Usually a triple-ring structure

ALL act on GABAa receptors
• NOT GABAb
• have similar potencies BUT the pharmacokinetics differentiate use (T1/2 vary greatly)

19
Q

Explain the pharmacokinetics of BDZs

A

The pharmacokinetics that differentiate use:
• the durations of action vary greatly

o Administration
– orally or IV, peak plasma at ~1h

o Binds plasma proteins strongly
o High lipid solubility
o Extensive liver metabolism

o Excretion
– urine (glucuronide conjugates)

o Duration of action – VARIES GREATLY
 Short-acting.
 Long-acting – slow metabolism and/or active metabolites

20
Q

Explain the Metabolism of BDZs

A

Long-acting (t1/2 = 32hrs):
• e.g. Diazepam

Short-acting (t1/2 = 8hrs):
• e.g. Temazepam, Oxazepam

The FINAL excreted products are GLUCURONIDE CONJUGATES

(onenote!!!)

21
Q

Advantages of BDZs?

A

Wide margin of safety (therapeutic window)
•OD = prolonged sleep
• Flumazenil is a BDZ antagonist and can reverse effect

Mild effect on REM sleep

Does NOT induce liver enzymes

22
Q

Unwantd effects of BDZs?

A

o Sedation, confusion, amnesia, ataxia
– all impaired manual skills

o Potentiates other CNS depressants
– alcohol, BARBs

o Tolerance (less than barbs and includes “tissues only”) & dependence (less intense than barbs)

o Free plasma concentration increases when co-administered with aspirin, heparin

23
Q

What can be used as anxiolytics (long-acting)?

A

• Diazepam(BDZ)(Valium)
• Chlordiazepoxide (Librium)
• Nitrazepam
Oxazepam can also be used if the patient has hepatic impairment
(as the liver will take longer to metabolise the Oxazepam so the half-life will be longer)

BDZs ONLY!

24
Q

What can be used as sedatives/hypnotics (short-acting)?

A

• Temazepam (BDZ)
• Oxazepam (BDZ)
• Amobarbital (Barb)
Nitrazepam can also be used for a hypnotic effect at night
followed by an anxiolytic effect during the day

Barbiturates, BDZ!!

25
Q

Example of another Sedative/Hypnotic and facts?

A

Zopiclone

  • Short-acting (t1/2=5hrs)
  • Acts of BDZ receptors (but are NOT BDZ, they are cyclopyrrolones)

Minimal hangover effects BUT dependency is still a problem

26
Q

Other Anxiolytics examples?

A

 Antidepressants:
o SSRIs – effective but have a delayed response (a week) but are very popular

 Antiepileptic’s:
o Valproate, Tiagabine

 Antipsychotic’s:
o Olanzapine, Quetiapine – have marked SEs

 Propranolol – improves the physical symptoms of anxiety

 Buspirone – 5HT1A-Receptor agonist with fewer side effects (less sedation) but has a slow onset of action.

27
Q

Benzodiazepines are used to treat ‘panic attacks’ and other anxiety states. By what mechanism do they produce their anti-anxiety effects?

A: Inhibition of GABA breakdown
B: Activation of 5HT1A receptors
C: Enhancement of the action of GABA at GABA-A receptors
D: Inhibition of GABA reuptake
E: Enhancement of the action of GABA at GABA-B receptors

A

C

28
Q

Which of the following drugs is commonly used in the treatment of insomnia?

A: Thiopental
B: Phenytoin
C: Baclofen
D: Sodium valproate
E: Temazepam
A

E

Year 2 - Pharm Lectures 11+ (23 decks)

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