L5 - Drug Action in the CNS - Anxiolytics Flashcards
What are the 5 types of anxiety?
Generalised anxiety Panic disorder Phobias Posttraumatic stress disorder Obsessive compulsive disorder
What is generalised anxiety?
No clear reason or focus
Symptoms interfere with normal behaviour
What is panic disorder?
Overwhelming fear to a particular situation
Marked somatic symptoms – activation of sympathetic nervous system
What is PTSD?
Fear associated with a memory
What is OCD?
Reproductive behaviour - not normally a productive behaviour
Physical demonstration of a stress response
What are benzodiazepines?
Anxiolytics E.g. diazepam Have a quick calming/sedative effect Often used to treat panic disorders Long term use has some negatives - Addictive - Tolerance develops - Sedative
What are anti-depressants?
E.g. SSRIs
If you can manage the depression the management of the anxiety comes within
Take several weeks to become effective
- Often prescribe benzodiazepines while you are waiting
What are buspirones?
5HTIA agonist
Takes several weeks to become effective
Shows its anti-anxiety effects without any negative side effects
Has no hypnotic activity – does not make you drowsy
What are beta blockers?
E.g. propranolol
Blocks sympathetic physical displays of anxiety
What are animal models of anxiety based on?
Based on fear or conflict within the animals
What is the elevated cross animal model?
At one side of the cross you have walls, on the other side you don’t
Rodent tends to go on the side of the cross that has the walls
- Has less fear of falling off
If rodent treated with anxiolytics it spent equal time on each side of the cross
What is the light/dark box animal model?
Rodent tends to go on the dark side of the box
If rodent treated with anxiolytics they will spend equal time on each side of the box
What did animal models of anxiety show?
Studies using these behavioural tests which rely on rodents innate fear responses showed GABA plays a major role
What are some examples of excitatory amino acids?
Glutamate
Aspartate
What are some examples of inhibitory amino acids?
GABA
Glycine
GABAa receptor overview
GABAb receptors not affected in anxiety Ionotropic receptors - ligand gated Chloride Selective Nicotinic 5 subunits - 2α : 2β : 1γ
What do GABAa receptors mediate?
Mediate fast inhibitory transmission between neurons – postsynaptic
Can hyperpolarise neuron to stop it reaching threshold
Can cause input resistance to hyperpolarise neuron
What are the agonists at the orthosteric sit of GABAa receptors?
Muscimol
- Used to distinguish between GABAA and GABAB
- When agonist binds the channel opens
What are the antagonists at the orthosteric sit of GABAa receptors?
Bicuculline
Picrotoxin
What are the inverse agonists at the orthosteric sit of GABAa receptors?
Beta-Carboline
- Decreases the responsiveness of the receptor to its natural agonist
What are the agonists at the allosteric sit of GABAa receptors?
Diazepam
What are the antagonists at the allosteric sit of GABAa receptors?
Flumazenil
- Useful for the treatment of an overdose
What are GABAa receptors regulated by?
Barbiturates – used in euthanasia
Neurosteriods
General anaesthetics
What GABAa receptors targets for?
Sedatives Anxiolytics Hypnotics Anti-convulsants General anaesthetics
What is the effect of alcohol at the GABAa receptor?
Mixing benzodiazepines and alcohol has negative impact
How can you model animal aggressive behaviour?
Aggressive behaviour induced by isolation followed by introduction of new animal
What amino acid change leads to reduction in the affinity of benzodiazepines?
His→Arg mutation
When was knock in experiments used in mice?
Creation of mice containing His→Arg mutation in α subunit
- Show a loss in affinity for benzodiazepines at GABAA receptors containing mutated subunit
- When in light/dark box no longer showed a preference
- No other effect on the receptor
What are the physiological effects of Benzodiazepine agonist?
Sedation/anxiolytic Hypnosis Anterograde amnesia Anti-convulsant Reduction of muscle tone
What is sedation/anxiolytic?
Decreased responsiveness to constant level of stimulation
What is hypnosis?
Latency of sleep onset is decreased
Duration non-rem sleep increased
Duration of rem sleep decreased
Duration of slow-wave (associated with sleep walking and night terrors) sleep decreased
What is anterograde amnesia?
Prevents memory of events experienced while under the influence of the drug
o Eg. Flunitrazepam – date rape drug
What is anti-convulsant?
Inhibit development and spread of epileptiform activity
What is the reduction in muscle tone?
Due to effects of GABA transmission in the CNS
What are the possible ways benzodiazepines can increase the activity of GABAa receptors?
Increases Cl current
Increases frequency of channel openings
Increases channel open time and decreases channel close time
Increases channel conductance
How did they work out which method benzodiazepines used to increase the activity of GABAa receptors?
Carried out single channel studies and patch clamping with and without Benzodiazepines
What is the difference between the modulation of GABAa receptors by Benzodiazepines vs. Barbiturates?
Benzodiazepines increase probability/frequency of opening
- Increase the affinity of the receptor for GABA
Barbiturate and steroids increase mean open time
Both result in more current flow and bigger response
What is beta carboline?
Inverse agonist
In the presence of GABA – cause the channel to open less
What is Flumazenil?
Competitive antagonist
Prevents or reverses the action of an agonist
Useful for treatment of overdoses of benzodiazepines
What pharmacokinetic properties of Benzodiazepines determine their therapeutic use?
Lipid solubility Redistribution and accumulation Onset of action Drug half life Presence of active metabolites Plasma protein binding
What is drug half life dependent on?
Dependent on renal function – age and microsomal enzyme induction
Diazepam metabolism
Metabolized to produce active intermediates with very long-half life – prolongs its activity
Intravenous diazepam - treat status epilepticus
Long 1-2 days duration of action
Zolpidem metabolism
Short 2-hour half life
Short 4-hour duration of action
What are the adverse effects of Benzodiazepine Agonists
Sleepiness, impaired psychomotor function, amnesia Additive effects Tolerance Misuse Physical dependence
Why are Benzodiazepines not useful for generalised anxiety?
Not useful for long term issues due to sleepiness effects
What are the different types of tolerance of Benzodiazepines?
Decreased responsiveness to a drug following continuous exposure
May be overcome by increasing dose
Changed responsiveness of CNS - with benzodiazepines
Metabolic tolerance - with barbiturates
Physical dependence of Benzodiazepines
Characterized by withdrawal
Increased anxiety, insomnia, CNS excitability, convulsions
More problematic with drugs with short half lives - E.g. triazolam may cause daytime anxiety
Withdrawal may be alleviated by using slower acting drug
At what stage does benzodiazepine decrease its effects?
Decreases its effects at the level of hypnosis
Only increases activity of GABA in area of brain where is ongoing GABA activity
At what stage do barbiturate decrease their effects?
Does not decrease its level of activity and can lead to anaesthesia and comas
May be rescued by addition of Flumazenil
What are some examples of other anxiolytics and hypnotics?
Benzodiazepine partial agonists
- Will lead to less tolerance and physical dependence
Receptor selective benzodiazepine agonists
Non-benzodiazepines
- Buspirone 5HT 1 agonist - non-sedative
β-Adrenoceptor antagonists
- Propranolol
- Used to block physical symptoms associated with activation of sympathetic nervous system
Over the counter sleep aids – anti-histamines
- Promethazine
