Anxiolytics Flashcards
What is an anxiolytic drug?
A drug that is used to treat chronic anxiety (i.e. apprehension, restlessness, tension)
What is a sedative drug?
A drug that decreases activity, moderates excitement and calms the patient
What is a hypnotic drug?
A drug that produces drowsiness and facilitates the onset and maintenance of sleep
What determines the range of CNS depressant drugs? (if the drug is an anxiolytic, sedative, or hypnotic)
The dose; the higher the dose concentration, the more severe the drug becomes (i.e. anxiolytic–>sedative–>hypnotic)
What are the clinical uses of anxiolytics? (7)
(1) Reduce anxiety
(2) Induce sleep
(3) Sedation before surgery (may produce some anterograde amnesia)
(4) Epilepsy
(5) Balanced anesthesia for surgery
(6) Control of withdrawal symptoms
(7) Muscle relaxation (only if muscle tension is associated with anxiety- does not work on neuromuscular junction)
What are the two types of CNS drugs?
(1) Type A: Continuous CNS depressants- well defined therapeutic index
(2) Type B: Lower therpeutic index
What are the Type A drugs? (4+)
(1) Barbiturates
(2) Alcohol
(3) Chloral hydrate
(4) GHB (gamma hydroxybutyrate)
(5) other general anesthetics
What are the Type B drugs? (1)
(1) Benzodiazepines
What is the different between the therapeutic index of Barbiturates (i.e. Phenobarbital) and Benzodiazepines (i.e. Diazepam)?
Diazepam has a 10 fold increase in therapeutic index
If you want to depress activity of the CNS, what is the primary inhibitory neurotransmitter in the brain? How do these receptors work?
GABAa receptors; they permit Cl- ions to flow through the membrane, keeping the cell’s potential negative, which makes the action potential less likely.
T/F The Anxiolytics increase the synthesis of GABAa to make it work better.
FALSE; they don’t replace GABAa but make the natural GABAa work better
How do the Axiolytics work with the GABAa receptors? How do the Benzodiazepines differ from Barbiturates in the channel?
When benzodiazepines or barbiturates bind to the ligand gated channels (at a different site than where the GABAa goes), the channels are more likely to open or stay open when the drugs are bound to them; Benzodiazepines only open the channels when GABAa is also bound to them while Barbituates can open the channel in absence of GABAa
Benzodiazepines: Mechanism of Action
Potentiation of GABA-stimulation of GABA receptors:
(1) Does not stimulate the receptor itself. It is not an agonist.
(2) When it binds to the GABA receptor, the receptor bings to GABA with a higher affinity
(3) Therefore, they increase GABA transmission, but only through GABA that has already been released into the synapse
<p>
| Why are Benzodiazepines safer than Barbiturates?</p>
<p>
(1) With Benzodiazepines you get receptor saturation at a lower concentration but do not increase its efficacy (2) With Benzodiazepines, you increase the efficacy in the brain which is unsafe</p>
What are the classifications of Anxiolytics?
(1) Barbituates (less common in current practice)
(2) Principal type: Benzodiazepines
What determines the choice of Benzodiazepines? What is the exception to this?
- The pharmacokinetics (this will tell you how long it’s going to be acting; i.e. different drug for sleep aid vs. anxiety)
- Alprazolam for panic disorders and agoraphobia
Where are Benzodiazepines metabolized? What is special about where they are metabolized (what are the exceptions)?
- Liver
- There are ACTIVE metabolites with long half lives, over 24 hours; one drug that can turn to 3 drugs in a sequence (Lorazepam and Oxazepam are fast acting, rapidly metabolized)
What is important about the active metabolites of Benzodiazepines? What is an exception?
- The half life of the molecule is not important but the half life of the effect of the molecule is important because you have to add up all the different metabolites
- Triazolam does have an active metabolite but for some reason they are readily metabolized in the liver; they have one of the shortest duration of effects
T/F Benzodiazepines are bound up to 90% to plasma proteins therefore you have to make sure to give elderly lower dosages to combat their slowing metabolism.
TRUE
What are the 5 Benzodiazepines (including short-intermediate, fast acting, peak plasma concentration, and effect half life)?
(1) Alprazolam (S-I), 1-2hr, 12-15hr
(2) Lorazepam (S-I) 1-6hr, 10-18hr
(3) Midazolam (S-I) IV only, 2-5hr
(4) Trizolam (S-I) 1-2hr, 1.5-5.0hr
(5) Diazepam (L) 0.5-2.0hr, 20-50hr
T/F you do not want to treat Benzodiazepines chronically.
TRUE
Benzodiazepines: Therapeutic Effects (4)
(1) Antianxiety: at low doses, associated with little CNS depression
(2) Sedation: suppression of responsiveness to a constant level of stimulation seen at low doses, but tolerance usually develops within days.
(3) Hypnosis: fast acting are the best, usually short acting if antianxiety action not wanted.
- latency of onset reduced, REM duration decreased, duration of slow wave reduced
- tolerance to hypnotic action observed over days/weeks; rebound increase in REM seen on withdrawal
(4) Anticonvulsants: Diazepam is used for status epilepticus and alcohol withdrawal
Benzodiazepines: Side Effects (4)
(1) Respiration- depression at the medullary respiratory center is observed at higher than sedating doses (not as toxic as barbituates)
(2) Euphoria- makes fast acting, short-lived benzodiapepines particularly likely to be abused; psychological dependence common with long term use
(3) Paradoxical excitement- may be associated with “CNS disinhibition”
(4) Anterograde amnesia- inability to remember events occurring while under effects of the drug
Benzodiazepines: Drug Interactions (4)
(1) Additive or even synergistic CNS depression with other sedative hypnotics and alcohol
(2) Functional cross tolerance with EtOH and other sedative hypnotics observed
(3) Oral contraceptives reduce Diazepam-elimination
(4) Asymmetric metabolic cross tolerance with EtOH and barbituates
- Benzodiazepines do not induce the liver P450 enzymes
- EtOH and Barbituates do induce the liver P450 enzymes
What is the concept of “Asymmetric Metabolic Cross Tolerance” with Barbiturates and Benzodiazepines? (4)
(1) Barbituates can induce the liver enzymes that metabolize BOTH Barbiturates and Benzodiazepines
(2) If a person takes Barbiturates, over a period of time the half life of the Barbituates in that individual becomes shorter
(3) On the reverse side: Benzodiazpeines are relatively ineffective at inducing the liver enzymes
(4) If a person takes Benzodiazepines, over a period of time the half-life of those drugs in that individuals will remain the same
What is the Benzodiazepine antagonist? What is its half life? How is it taken?
Flumazenil; Short half-life; I-V only
T/F Flumazenil attaches to a different site on the GABAa receptor than Barbiturates to enable its response.
FALSE; it goes to the same site but it keeps the Benzodiazepines from having the effect of increasing the effects of GABAa
What is Flumazenil used for?
If someone that overdoses and present with a coma, this takes away the effect of the Benzodiazepines and can help them to get out of a coma (make sure to monitor them because of the short half-life). Only takes away the Benzodiazepine component (it will not do alcohol)
What are the actions of Barbiturates? (1)
(1) Sedative- Hypnotic
(2) Anticonvulsant properties
(3) Induction liver microsomal enzymes
What are the 3 Barbiturates we need to know? What are their therapeutic uses? Which one is still used?
(1) Thiopental- IV anesthetic (ultra short acting)
(2) Pentobarbital- Sedatives
(3) Phenobarbital- Epilepsy
- Thiopental is still used-
Barbiturates- Mechanism of Action
Potentiation of inhibitory neurotransmission, GABAa receptor
- more efficacious than Benzodiazepines
What are other drugs that are used to treat anxiety? What do they do? (4)
(1) Busipirone- very slow acting, novel structure
(2) Beta-adrenergic blockers- decrease sympathetic tone
(3) Alpha-2 agonist- Clonidine
(4) Tricyclic antidepressants- panic attacks
What are other sedatives/hypnotics? What do they do? (3)
(1) Zolipidem, Zaleplon- act as benzodiazepine binding site, but have unique structures
(2) Chloral hydrate- largely restricted to institutional use, inexpensive but may have significant toxicity
(3) Antihistamines: Hydroxzine, Diphenhydramine- OTC sedatives/hypnotics
