L15 - GABA R's and Anxiolytics Flashcards
What is glutamate?
- a dietary amino acid
- main neurotransmitter in the brain
- excitatory neurotransmitter
What is GABA?
- Gamma Butaric Acid
- main inhibitory neutrotransmitter in the brain
What is GAD?
- enzyme
- converts glutamate to GABA
What are examples of drugs that act on GABA receptors in the brain?
- 1,4-butandiol
- GHB (date rape drug)
- inhibit the brain = unconscious
What are local circuits in the CNS?
- involving neurons and interneurons
- interneurons receive input simultaneously to the main neuron
- have a feed-forward or feed-back effect on the neuron with some delay
- hyperpolarise to prevent firing of multiple AP after initial one
- multiple AP = seizure
What are the types of GABA receptor? What is their mechanism of action and physiological effect?
GABAa - fast acting - ligand gated ion channel - chloride movement = fast hyperpolarisation for short time - post-synaptic inhibition GABAb - slower acting - G-protein coupled receptors - increased K+ efflux - delayed onset but longer duration effect - pre- and post-synaptic inhibition
Features of the GABAa receptor?
- pentameric ligand gated ion channel
- consists of many subunits coded for by different genes
- different neurons express different subunits which come together in a variety of combinations
- 70% GABAa receptors have the configuration of B A and Y units (alpha + beta = GABA binding site, alpha + gamma = benzodiazapine binding site)
What is the effect of benzodiazapine (and barbiturates)?
positive allosteric modulator (PAM)
- act to increase the efficiency of GABA to decrease the excitability of neurons = enhances GABAa chloride conductance
What are the uses of benzodiazapines and barbiturates?
- PAM (positive allosteric modulators) are important in the emergence treatment of seizures in hospitals
- large dose of benzodiazapines (or barbiturates but less common)
What are some benzodiazapine drugs? Their effect and use?
- clonazepam + diazepam + alprazolam
- allosterically enhance the GABAa receptor
- highly sedative
- for emergency treatment of seizures
What are some barbiturates? Their effect and use?
- phenobarbitone
- allosterically enhances GABAa receptor
- highly sedative
- for emergency treatment of seizures
What is the most common type of anxiety and how is it characterised?
GAD - general anxiety disorder
- characterised by excessive anxiety and worry occurring more days than not for at least 6 months
- at least 3 of:
restlessness, easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance
What are the dose dependent effects of GABAa receptor activation?
lowest level:
- sedation, decreased anxiety, decreased seizure activity, muscle relaxation
- sleep, amnesia, anaesthesia
- coma (drug-induced for burn victims etc.) respiratory depression
- death at highest level
What are the low and high dose effects of barbiturates? what are the disadvantages of them?
GABAa receptor activators:
- low dose = PAM
- high dose = direct agonist
replaced by benzodiapines because:
- there is a high risk of overdose, particularly in combination with CNS depressants e.g. alcohol
- causes death due to respiratory depression and - there is no antidote
- now only used for epilepsy or anaesthesia
What are the benefits of using benzodiazapine?
- fast acting = no therapeutic delay so useful in emergency situations
- large therapeutic window = safe
- has an antagonist (Flumazenil) to displace diazepam from its binding place
What is the antidote for benzodiazapines (diazepam?)?
flumazenil
What are the uses for benzodiazapines?
- anxiolytic
- hypnotic
- amnestic/sedative
- muscle relaxant
- anticonvulsant
What are the side effects and problems associated with benzodiazepines?
- drowsiness
- confusion
- amnesia
- impaired coordination
- can produce substantial impairment in every day life
- problems in elderly
- problems with tolerance and dependence
Why is benzodiazepine a problem in the elderly?
- increased half-life due to accumulation (takes longer to clear from the body)
- motor impairment also increases risks of falls/injuries
- can cause significant cognitive impairment
What are tolerance problems with benzodiazepine?
- GABAa receptors become less sensitive over time
- more drug is required to have the same effect
What are the problems with benzodiazepine dependence?
- withdrawal symptoms if stopped suddenly
- opposite effects: increased anxiety, insomnia, tremor, seizure in severe cases
- now only recommended for acute treatment <4 weeks
What is buspirone?
- only clinically approved drug for generalised anxiety disorder
- partial agonist for serotonin 5HT1a receptors (more serotonin released = relieve anxiety + feel good)
- also low affinity D2 receptor antagonist
What is the serotonin 5HT1a receptor?
- presynaptic autoreceptor
- detects how much neurotransmitter is released and turns down its release
What are the side effects of buspirone?
side effects in ~10% of patients: - dizziness - headache - nervousness - light headedness - nausea side effects generally subside over time or with decreased dosage
What are the benefits of buspirone?
- safer for long-term use than benzodiazepines
- no withdrawal symptoms
- no evidence for tolerance or dependence
(^^ above two points worth knowing) - non-sedating so safer in overdose
How do antidepressants work?
block reuptake enzymes to increase neurotransmitter in the synapse
first line treatment for anxiety disorders:
- SSRI’s - selective serotonin reuptake inhibitors
- SNRI’s - selective noradrenaline reuptake inhibitors
(both classes have effects on both 5HT (serotonin) + NA reuptake)
- TCA’s - tricyclic antidepressants also effective but avoided in first instance due to side effects
What are the side effects of antidepressants? Problems associated with their use?
side effects for SSRI’s (up to 15% people):
- anxiety
- insomnia
- fatigue
- nausea
- dizziness
- palpitations
more common with higher doses and subside after 1-2 weeks
- withdrawal syndrome with sudden discontinuation but milder than with benzodiazepines
What are the benefits of antidepressants?
- therapeutic lag and some side effects can be overcome with adjunctive benzodiazepine treatment in the first 1-2 weeks
- antidepressants have wide range of effectiveness
- slower onset than BZD so treatment often started with BZD then decreased while increasing anti-depressants
What are are the first line treatments for anxiety (acute and chronic)?
What is the second line treatment for when antidepressants don’t work?
first line treatment
- acute: benzodiazepine (short term)
- chronic: SSRIs or SNRIs
second-line treatment:
- buspirone but only for GAD
What is the definition of insomnia?
- difficulty in falling or staying asleep leading to impairment of daytime function
- causes daytime sleepiness, irritability, lack of energy
- chronic insomnia can lead to psychiatric problems, alcohol or drug abuse, and cognitive impairment in elderly
common for patients to have other underlying health conditions or medications interfering with sleep
What are the treatment options for insomnia?
- benzodiazepine: triazolam
- anti-histamines: diphenhydramine
Why is triazolam effective in insomnia treatment?
- rapid onset + short half-life
- reduces latency falling asleep
- wears off during the night = rebound effect in the morning
What are the problems associated with triazolam?
all the same problems as BZDs:
- tolerance, dependence, withdrawal and abuse liability
- only recommended for treatment of severe short-term insomnia
- lowest effective dose for shortest possible time
Why is diphenhydramine effective in insomnia treatment?
- first generation anti-histamine because BBB permeable = block histamine receptors in the brain = drowsiness
- central histamine pathways are involved in sleep/wake cycles
