W9 - Anxiolytics & Sedative-Hypnotics Flashcards
What do anxiolytics and sedatives do?
Used to reduce anxiety, sedate, aid sleep, anticonvulsants & anesthetics
What are the three classes of drugs used to achieve these effects?
Benzodiazepines (BDZ), barbiturates, and other) - nave similar neural mechanisms
What is the administraton of BBTs and BDZs
• May be administered: orally, parenterally (including i.v. or i.m.), but absorption from digestive system better than i.m. absorption bc of biochemical properties
When are BBTs and BDZs readily absorbed?
After oral and parenteral routes
Are they acids or bases?
Weak acids
What is the absorption of barbiturates?
- All barbiturates have pKa near 8.0 → almost entirely non ionized at pH of digestive system (∴ readily absorbed)
- Variability in lipid solubility
What is the absorption of Bezodiazepines?
- pKa of about 3.5 to 5.0 ∴ readily absorbed from digestive system
- Range of lipid solubility
- Absorption may be á by alcohol
- Compete for same enzyme between benzos and alcohol
What is the distribution?
- Determined by lipid solubility
* Cross placental barrier & present in breast milk
What happens with highly lipid soluble BBTs and BDZs
Cross BBB
• Different – more highly lipid soluble reach brain quickly but then redistributed very quickly to areas high in fat and then slowly released into bloodstream
→ effects may be seen quickly, but also dissipate quickly
• Drug released slowly from fat deposits → metabolized by liver
What is the excretion curve of BDZs?
- 2-phase excretion curve (similar to cannabis):
- Phase 1: rapid drop in blood level due to redistribution in fat deposits
- Half-life ~ 2-10 hours
- Phase 2: metabolism (liver, CYP450 enzyme)
- Half-life ~ 27-48 hours (stay in system for long time)
- Cant often talk about half life and active effect because of active metabolites – ongoing effect in terms of metabolism
Are older BDZs metabolized?
- Fully metabolized, and the active metabolites of these drugs = duration of effect not determined by half-life
What effects the metabolism of BDZs?
Increased by repeated administration, slowed (for some BDZs) by alcohol (increased blood level of BDZs)
How are barbiturates excreted
Most fully metabolised by liver enzymes before excretion
Is there any cross tolerance of BBTs?
Yes - cross tolerance for people with alcohol dependence - if chronic alcohol user and is sober then is metabolised much more efficiently
What is metabolism increased by
- Repeated administration
- Anti-psychotics
- chronic alcohol use
- Antihistamines
- nicotines
What do BBZs stimulate physiologically and what other drugs does this effect?
- Stimulate enzymes and metabolizes drugs:
- Chlorpromazine
- Morphine
- Caffeine
- General and local anaesthetics
How can overdoses be treated?
- By making urine more alkaline (because barbiturates are acidic)
What receptors are affected?
GABAa receptors (ionotropic, mainly postsynaptic, quick response, coupled to Cl- channels)
What are the receptors similar to?
Alcohol but not as diffuse (more specific than alcohol)
How do they affect the receptor sites
Have their own receptor sites on GABA- Chloride Ionophore Complex
How do they affect the ion channels?
- Make GABA NT more effective at sites
- -> positive allosteric modulations, therefore increasing ability to open the channel
What is the effect of opening the ion channel
More Cl- ions in postsynaptic neuron - increased inhibition
What is barbiturates mode of action? How is this different from BDZs?
- Increases the time of the channel being open - larger increase of Cl- (compared to BDZ)
What is BDZs mode of action?
- Increase frequency of channel opening and increased affinity of GABA for receptor
What type of moderator is BDZs? How does this work?
Allosteric modulator - binds to a different site on the ion channel to increase it’s affinit for GABA - it is GABA that opens the channel
What is the difference between BDZs and BBTs in how they work on the ionotropic receptor?
BDZs always JUST an allosteric modulator - increases GABA affinity. BBTs can also act directly on the receptor to open the channel - this is what can cause respiratory repression and death
What is a negative GABA modulator
Decreased likelihood of channel opening
What is the effect of BDZs on adenosine?
BDZs may also affect adenosine (inhibitory neurotransmitter) by blocking reuptake - enhances’s it’s effect (opposite to alcohol )
What are the effects of BDZs and BBTs on dopamine
Decreased DA (dopamine) in nucleus accumbens - highly reinforcing (lots of GABA receptors in NA - may be a secondary inhibitory effect - inhibit some inhibitory processes
What are the effects of BDZs on the body?
- Mostly due to the effects on CNA
- Relatively mild decreased respiration
- Mild decreased BP
- Increased appetite and weight gain
- Increased muscle relaxation
- –> possibilities for disorders like parkinson’s which originate in CNS but effect muscles
- Anticonvulsant
What are BDZs widely used for to do with sleep?
- Widely used for S-H properties
What are BDZs useful for to do with sleep?
- short term intervention - but shouldn’t be prescribed for sedative purposes for more than 2 - 4 weeks
What are the effects of BDZ on skeep
Decreased awakenings, Increased total sleep time, decreased REM and stage 3&4 sleep - withdrawal rebound effect
Does tolerance to sleep effects develop?
No - the longer on the greater the rebound
BUT in order to eliminate rebound, re-adminster drug = dependence
What are the subjective effects of BDZs
- Sedation/fatigue/confusion
- Euphoria & “liking”
- Generally don’t report as pleasant unless they are dependent
- Anxiolytics (but not in individuals with normal anxiety levels) – only works for people with clinical anxiety (even in this population only works for approx. 60 % people)
What are the effects on vision?
Lowered visual and auditory acuity
What are the implications of BDZs impact on reaction time?
- Decreased simple RT (at high doses)
- -> Risky for tasks such as driving
What are BDZ’s effects on memory
Explicit memory effected even at low doses
- -> Anterograde amnesia (acquisition of new explicit information), but not implicit memory (skill acquisition)
- -> Deficits observable on wide variety of tests
Are there any situations in which BDZs would improve performance?
If the patient is clinically anxious
What are the hangover effects of BDZs
- Distribution of mood & performance 12 hourse after administration - Amplifies effects of alcohol
What are the effects of BDZs on driving?
- Increased collisions
- Increased risk with alcohol
- Increased risk in first-time users who usually report feeling fine
What are the effects of BBTs on the body
- Significant decrease in respiration
- Decreased HR
- Decreased BP
- Can be used as anticonvulsants
