Anxiolytics, Sedatives & Hypnotics Flashcards
Explain the process of GABA Neurotransmission
- Glutamate –> GABA via GAD (Glutamate Decarboxylase)
- GABA can bind to:
• GABAaR on the postsynaptic cell = hyperpolarise cell
• GABAbR on pre-synaptic cell = -VE inhibition of release
- 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
Explain what GABA is metabolised into
GABA –> Succinic Semialdehyde (SSA)
• via. GABA-T
SSA –> Succinic Acid
• via. SSDH
GABA found in cytosol
GABA-T & SSDH found in mitochondrial membrane
What do Sodium Valproate & Vigabatrin do?
GABA metabolism inhibitiors
• leads to MORE GABA
• = MORE INHIBITION in the brain
Describe the GABAa receptor complex
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
What do Bicuclline & Flumazenil do?
BOTH are COMPETITIVE ANTAGONISTS
Bicuclline
• GABA
Flumazenil
• BDZ
What are the 6 different pathways of GABAa-Receptor MoActivation
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
What are some facts about BZs & BARBs?
(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)
Clinical uses of BZs & BARBs?
o Anaesthetics
• BARBs ONLY (thiopentone)
o Anticonvulsants
• Diazepam, Clonazepam, Phenobarbital
o Anti-spastics
• Diazepam
o Anxiolytics
• BDZs ONLY
o Sedatives/Hypnotics
• BARBs & BDZ
Define anxiolytivs
Remove anxiety WITHOUT impairing mental or physical activity
Define Sedatives
Reduce mental AND physical activity without producing a loss of consciousness
Define Hypnotic
Induces SLEEP
What should these 3 types of drugs ideally be?
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”
What do Barbiturates nornally end in?
- tone
- tol
- tal
Describes the structures of BARBs & the effect they normally have
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
Example BARB drug?
Amobarbital
Explain the Unwanted SEs of BARBs
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
What do Benzodiazepines normally end in?
- epam
- epate
Explain the structure of BDZs and what they act on
Usually a triple-ring structure
ALL act on GABAa receptors
• NOT GABAb
• have similar potencies BUT the pharmacokinetics differentiate use (T1/2 vary greatly)
Explain the pharmacokinetics of BDZs
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
Explain the Metabolism of BDZs
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!!!)
Advantages of BDZs?
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
Unwantd effects of BDZs?
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
What can be used as anxiolytics (long-acting)?
• 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!
What can be used as sedatives/hypnotics (short-acting)?
• 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!!
Example of another Sedative/Hypnotic and facts?
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
Other Anxiolytics examples?
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.
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
C
Which of the following drugs is commonly used in the treatment of insomnia?
A: Thiopental B: Phenytoin C: Baclofen D: Sodium valproate E: Temazepam
E
