Anxiolytics and hypnotics Flashcards
Describe GABA neurotransmission
- glutamate -> GABA via glutamate decarboxylase
- GABA can bind to:
a. GABA A receptors on post synaptic cell that hyperpolarise cell
b. GABA B receptors on pre synaptic cell that have -ve inhibition of release - GABA can then be re up taken by:
a. glial cells - GABA transaminase breaks down GABA into SSA (sunninic semialdehyde)
b. pre synaptic cell - GABA-T breaks down GABA into SSA
How is GABA broken down?
GABA broken down into Succinic Semialdehyde (SSA) via GABA-T
which is broken down into Succinic Acid via SSDH
Where is glutamate decarboxylase found
In the cytosol
Where are GABA T and SSDH found
In the mitochondrial membrane
What are the main proteins found in the GABA A receptor
- GABA R protein
- GABA modulin
- barbiturate receptor protein
- BDZ (benzodiazepine) receptor protein
What is bicucullin
A GABA competitive antagonist
What is flumazenil
A BDZ competitive antagonists
What are the 6 pathways of GABA A receptor activation
o Pathway 1 – linkage of GABA-RP, GABA-M and BDZ-RP and opening of Cl—channel.
o Pathway 2 – initiation of pathway 1.
o Pathway 3 – increased affinity of binding of GABA/BDZ (reversible).
o Pathway 4 – linkage of Barb-RP and BDZ-RP and opening of Cl—channel.
o Pathway 5 – increased affinity of binding of GABA (NOT-reversible).
o Pathway 6 – direct activation of Cl—channel.
What effect do barbs have on opening of binding sites
Increase frequency
What effect do BZDs have on opening of binding
Increase duration
Compare the GABA A receptor binding of barbs and BDZs
Less excitatory transmission
Barbs are MORE dangerous - more dangerous than SEs; induction of surgical anaesthesia and small therapeutic window
What are clinical uses of BDZs and Barbs
Anaesthetics Anticonvulsants Anti-spastics Anxiolytics (BDZs only) Sedatives/Hypnotics (barbituates, BDZ)
What are examples of drugs used as anxiolytics
Diazepam (valium), Chlordiazepoxide, Nitrazepam. (Oxazepam can be used if the patient has a hepatic impairment as liver will take longer to metabolise it)
what are examples of drugs that are used as sedatives/hypnotics
Temazepam (BDZ), Oxazepam (BDZ), Amobarbital (barb) and Nitrazepam can also be used for a hypnotic effect at night followed by an anxiolytic effect during the day
Define anxiolytics
remove anxiety without impairing mental or physical activity
Define sedative
reduce mental and physical activity without producing a loss of consciousness
Define hypnotic
Induce sleep
What characteristics should an anxiolytic, sedative or hypnotic have?
Large therapautic window, not depress respiration, produce natural sleep, not interact with other drugs, not produce ‘handovers’, not produce ‘dependance’.
What is the structure of barbiturates
tend to have a single ring structure with two R groups that are ethyl groups and phenyl/1-methylbutyl
What effect do barbiturates have, give an example
Sedative/hypnotic effects
eg amobarbital that causes severe intractable insomnia with half life 20/25hr
What are unwanted effects of barbiturates
Small therapeutic windows - depress respiration
Reduce REM sleep -> hangovers
Induce enzymes
Potentiate effects of other CNS depressants - alcohol
Tolerance and dependence becomes issues
What is the chemical structure of benzodiazepines
Triple ring structure
What do benzodiazepines act on
GABA A receptors (not GABA B) and there are similar potencies in different benzodiazepines but its the pharmacokinetics that differentiate use
Pharmacokinetics of benzodiazepines
- Administration – orally or IV, peak plasma at ~1h.
- Binds plasma proteins strongly, high lipid solubility.
- Extensive liver metabolism.
- Excretion – urine (glucuronide conjugates).
- Duration of action – VARIES GREATLY.
Short-acting or long-acting – slow metabolism and/or active metabolites.
What are advantages of BDZs?
- wide therapeutic window - overdose just leads to a prolonged sleep
- mild effect on REM sleep
- does not induce liver enzymes
What are unwanted effects of BDZs
- sedation, confusion, amnesia, ataxia -> impair manual skills
- potentiate other CNS depressants
- tolerance (less than barbs and include ‘tissues only’) and dependence (less intense than barbs)
- free plasma concentration increases when co administered with aspirin, heparin
What is flumazenil
A BDZ antagonist that can reverse effect of BDZs (prolonged sleep)
What is zopiclone
A ‘z drug’ that is short acting and acts on BDZ receptors (but they are not BDZs, they are cyclopyrrolones) - minimal hangover effects but dependency is a problem
What are examples of other anxiolytics
Antidepressants Antiepileptics eg tigabines Antipsychotics eg olanzapine Propanolol Buspirone - 5HT1A Receptor agonist
