Lecture 5 Flashcards
What is the difference between sedatives and hypnotics?
Sedatives are calming drugs to help treat anxiety without drowsiness. Hypnotics are drugs that induce sleep to treat insomnia. Insomnia can cause anxiety and vice versa
What is anxiety?
Is a fear/stress response that activates the sympathetic NS. Animals have behavioural responses e.g. freezing or going to a dark place. Is a good survival reaction if not prolonged.
What are the types of anxiety?
1) General= most difficult to treat as there is no clcear cause- overwhelming anxiety which interferes with daily activities
2) Panic disorder= overwhelming fear marked with somatic response e.g. sympathetic nervous system- sweating, difficulty breathing- easy to relate to animal model due to symptoms
3) OCD= repetitive and unproductive behaviour- extreme cases can damage hands
4) PTSD= extreme fear caused by a memory of a threat that is no longer there
5) Phobias= an extreme fear of something
What are the treatments for anxiety?
1) Benzodiazepines e.g. valium= sedative effects but can cause drowsiness, not able to drive, increase in tolerance and can develop addiction
2) Anti-depressants e.g. SSRIs- depression and anxiety usually come hand in hand- take time to see effects so take benzos while waiting
3) Buspirone= is a 5HT agonist- shows anxiolytic effects without unwanted side effects e.g. drowsiness
4) beta blockers e.g. propanolol to inhibit sympathetic activity such as heart thumping and sweating
How can anxiolytics be tested?
1) Elevated cross= one with no walls and one with walls- mice prefer walls but when treated with benzo they show no preference
2) light dark box= rodents usually hide in the dark side, when treated they show no preference
What are the properties of GABAaRs and what drugs act on it?
Are ionotrophic nicotinic receptors that cause influx of Cl- at the post synapse for rapid hyperpolarisation. Made from 3 alpha, 2 beta and 1 gamma subunit which creates binding sites
1) Orthosteric site= Muscimol (agonist used to differentiate between type A and B), Bicuculine (competitive antagonist), Pictoxin= blocks channel directly and is competitive. Has 2 binding sites that need to be filled by the agonist in order to open.
2) Allosteric site- adjusts opening and activity of the receptor when the orthosteric site is occupied e.g. Flamazenil (antagonist used to treat diazepam overdose), beta carboline= inverse agonist that decreases duration of channel opening.
3) regulated by barbiturates (euthanasia), neurosteroids, general anaesthetics and alcohol
What are the properties of the GABAbR and what drugs act on it?
Is found on post and pre synapse= metabotropic R (Gprotein coupled receptor) that inhibits Ca2+ channels and stimulates K+ channels.
baclofen= agonist
phaclofen= antagonist
What isoforms of GABAaR can bind benzodiazepines?
Those with alpha 1, 2, 3, 5 subunits
How were the drug targets for benzos identified on GABAaRs?
KO mouse for each subunit and observe if they are responsive to benzos. KO of alpha 2 subunit= not responsive. Once identified they changed aa histidine to arginine= no longer respond to valium but were happy in light and dark box which highlights the receptors role in anxiety and that a single aa change is sufficient to change the fear/anxiety of that animal.
What are the effects of benzodiazepines?
1) anxiolytic= sedative effects that decrease the response to constant level of fear stimulation
2) hypnotic= as you increase the concentration you increase drowsiness- increase in stage 2 (non-REM) and decrease in non-rem, decrease in duration of slow wave, decrease in latency of sleep onset
3) Anterograde amnesia= rohypnol (flunotrazepam) used as a date rape drug but useful for surgery
4) reduction in muscle tone= useful for surgery
5) anti-convulsant= prevention in development and spread in epileptic activity
How are benzodiazepines thought to be mediated?
By binding to the alpha 5 subunit. When KO= increase in memory and learning therefore inverse agonists would be memory enhancing
How can you measure the effects of benzos?
Measure current between in presence of GABA and in presence of GABA and benzos. Increase in current. Use single channel patch clamp test to observe effects. Increase frequency in channel opening, increase duration in channel opening, decrease closing time and increase in single channel conductance (increases amount of Cl- ions go through the pore)
How is GABAaR regulated?
1) beta carboline= inverse agonist that decreases the duration of channel opening- some can increase memory
2) Flumazenal= competitive antagonist to prevent channel from opening- used as treatment for benzo overdose
What is Zoipidam?
Is used as a hypnotic to treat insomnia, is very lipophilic and metabolised quickly= has a half life of 4hrs- want it to be long enough induce enough sleep. Not strong enough to treat anxiety
What is diazepam?
Drug used to treat status epilepticus (intravenous route) and has a half life 20 times longer than the duration of zoipidam (1-2 days). Is metabolised into a second active drug to increase duration of action. Side effects= drowsiness, impaired mobility.
What are the effects of benzos and barbiturates on brain activity?
1) Benzos= allosteric agonist that increases activity and eventually plateaus as it only modifies the response to GABA. With alcohol its effects continue through the stages and are fatal
2) Barbiturates= used in euthanasia, is an allosteric agonist that eventually shuts down the whole brain.
What are the developed effects to benzos?
1) misuse and abuse can lead to gain of teolerance- possibly due to receptor subunit change over time or increase in metabolic enzymes. Can be overcome by increasing the dose concentration but that is bad long term
2) Misuse= patients don’t stick to the guidelines
3) Can develop dependence and withdrawal symptoms= exaggerated symptoms
What are other anxiolytics/hypnotics?
1) propanolol= Beta adrenoreceptor agonist- used to treat physical sympathetic responses
2) Partial benzo agonists= reduced efficacy- decrease in tolerance and prevents dependence without impacting motor coordination
3) Anti-histamines= hypnotic
4) non-benzo= buspirone- 5HT agonist= takes a while to be effective and doesn’t treat depression (usually come hand in hand)
