Lecture 11 - Anxiolytics & Hypnotics Flashcards
1
Q
BZDs with long half-lives
A
chlordiazepoxide diazepam pazepam clorazepate flurazepam
2
Q
BZDs with short half-lives
A
lorazepam and oxazepam (without active metabolites)
alprazolam and triazolam ( with active metabolites)
3
Q
Flumazenil is a ?
A
BZD antagonist
4
Q
Thiopental is a ?
A
barbiturate
5
Q
Buspirone is a ?
A
other anxiolytic
6
Q
Zopiclone is a ?
A
other hypnotic
7
Q
Anxiolytics provide ?
A
- calming effects
- relief of anxiety
8
Q
Hypnotics provide ?
A
- promote drowsiness
- promote onset and maintenance of sleep
9
Q
Describe the chemical classification:
A
A
BZDs
10
Q
Describe the chemical classification:
B
A
barbiturates
11
Q
Describe the chemical classification:
C
A
others
12
Q
What drugs are included in classification A: BZDs?
A
alprazolam oxazepam chlordiazepoxide diazepam lorazepam triazolam
13
Q
Describe the BZD basic foundation
A
benzene ring fused with a diazepine ring
14
Q
What drugs are included in classification B: Barbiturates?
A
thiopental
pentobarbital
15
Q
Describe the basic structure of barbiturates
A
all of the barbiturates are related to the structure of barbituric acid
16
Q
What drugs are included in classification C: others
A
busprione zopiclone ethanol chloral hydrate antihistamines ramelteon
17
Q
What is the action site of pharmacological mechanisms of BZDs?
A
GABA-A receptor
18
Q
Describe GABA-A receptor
A
-GABA is the primary inhibitory neurotransmitter in the brain
19
Q
Describe GABA-A subunits
A
- 2 alpha subunits
- 2 beta subunits
- 1 gamma subunit
20
Q
Alpha subunit has 5 isoforms with alpha 1-5:
Describe them
A
alpha 1 = hypnotic
alpha 2-5 = sedation, psychomotor effect
21
Q
GABA-A receptor = _____ channel
A
chloride
22
Q
Describe the activation of GABA-A receptor
A
activation - chloride influx, hyperpolarizes neurons and decreases neuronal activity
23
Q
How do BZDs work to interact with GABA-A receptors?
A
- BZDs bind to GABA-A receptors - enhance GABA actions and reduce excitability of neurons
- increases frequency of channel-opening events
- act as CNS depressants
24
Q
Describe affinity of BZDs for GABA-B receptors
A
low affinity
25
How do barbiturates work to interact with GABA-A receptors?
- barbiturates bind to GABA-A receptors
- increases duration of channel-opening events
- GABA-mimetic at high concentration
- inhibit glutamate AMPA receptor
26
Describe general concept of pharmacokinetics
(what the body does to the drug)
absorption
distribution
metabolism
excretion
see slide 11
27
Define: onset
the time required for drug to be effective after administration
28
What does lipophilicity of drugs affect?
onset of action
29
More lipophilic = ?
more rapid onset of action
30
Define: duration
the amount of time that a measurable drug effect persists
31
Define: biotransformation (affects duration of action)
- microsomal oxidation (cytochrome P450 isozymes: phase 1 rxns)
- conjugation (phase 2 rxns)
- metabolic conversion to more water-soluble metabolites is required for clearance for CNS drugs from the body
32
What affects onset?
lipophilicity
33
What affects duration?
biotransformation
34
Describe lipophilicity of BZDs
triazolam > diazepam > lorazepam, oxazepam
35
Describe onset of BZDs
triazolam > diazepam > lorazepam, oxazepam
36
The main differences between BZDs are ?
rate of onset and duration of actions
37
BZDs: therapeutic uses relate to half life:
| short acting is preferable for ______
hypnotic (to treat insomnia)
38
BZDs: therapeutic uses relate to half life:
| long acting is preferable for ______
anxiolytic (to treat anxiety)
39
BZDs with long half life = ?
cause cumulative effects with multiple doses
| there is overlap of drug in your system
40
BZDs are excreted from the _____.
kidney
41
Can BZDs cross placenta?
yes
*may inhibit CNS development of fetus
42
Can BZDs be detected in breast milk?
yes - therefore a risk to breastfeeding infants
43
Other than pregnant and breastfeeding patients, what other types of patients do BZDs pose a risk to?
- older patients, patients with liver diseases
| - obese patients, redistributed to adipose tissue
44
Barbiturates are ______
lipophilic
*therefore they are absorbed and distributed rapidly
45
Barbiturates are metabolized in the ____
liver
46
______ are hepatic Cyt-P450 system inducers
Barbiturates
47
Duration of action for ultra short acting barbiturates
30 mins
48
Example of an ultra short acting barbiturate
thiopental - used for induction of anesthesia
49
Duration of action for short acting barbiturates
18-48 hours
50
Example of a short-acting barbiturate
secobarbital and pentobarbital - for hypnotic and sedative
51
Duration of action for long acting barbiturate
4-5 days
52
Example of long -acting barbiturate
phenobarbital - for seizures
53
List 6 therapeutic uses of BZDs
1-treats anxiety
2-treats insomnia
3-sedation and amnesia before and during surgical procedures
4-treats epilepsy and seizure states
5-muscle relaxation in specific neuromuscular disorders
6-control of ethanol withdrawal symptoms or other sedative-hypnotic withdrawal states
54
For relief of anxiety, BZDs act as a ______
sedative
55
List some anxiety disorders
- generalized anxiety disorder (GAD)
- panic disorder
- social phobia
- post-traumatic stress disorder (PTSD)
- obsessive-compulsive disorder (OCD)
56
List some general symptoms of anxiety disorders
- feelings of panic, fear and uneasiness
- uncontrollable, obsessive thoughts
- nightmares
- insomnia
- cold or sweaty hands/feet
- shortness of breath
- palpitations
- dry mouth
- numbness or tingling in hands or feet
- nausea
- muscle tension
- dizziness
57
How are BZDs used in anxiety?
used for the management of acute anxiety states and for rapid control of panic attacks
58
What is the first choice treatment for long-term management of GAD (generalized anxiety disorder) and panic disorders?
SSRIs
59
______ for panic disorders and agoraphobia
Alprazolam
60
For treatment of insomnia, BZDs act as a _____
hypnotic
61
symptoms of insomnia
- trouble falling or staying asleep-leads to sleep deprivation
- lying awake for a long time before falling asleep
- sleeping for only short periods
- being awake for much of the night
- waking up too early
62
Describe the physiology of sleep
NREM (non-rapid eye movement) (Stage 1-4)
and
REM (rapid eye movement)
63
Stage 1 of NREM sleep
light sleep during which the muscles begin to relax
64
Stage 2 of NREM sleep
brain activity slows down and eye movement stops
65
Stages 3/4 of NREM sleep
deep sleep during which all eye and muscle movement ceases
66
REM sleep
paradoxical sleep, rapid eye movement where most muscles are paralyzed
67
Do you just go from NREM to REM as you sleep?
No - you bounce back and forth between NREM and REM over your sleep period
68
How do BZDs work as hypnotics?
- decrease the latency to sleep onset and increase Stage 2 of NREM
- decrease both REM and slow sleep
69
For falling asleep, use _______ drug
fast acting, but shorter duration
ex. triazolam
70
For frequent awakenings, what type of drug would you use?
since falling asleep is not the problem, you would use a drug of medium duration
ex. lorazepam
71
Do you start benzos with high or low doses?
low doses obvs (eye roll like kelsey)
72
What are first choice of benzos for before and after surgery?
midazolam
| lorazepam
73
How do BZDs work for before and after surgical procedures
- produce sedative effects
| - cause anterograde anmesia (loss of ability to create new memories) - so you don't remember the surgery
74
Are BZDs anesthetics?
nope - but used in conjunction with anesthetics
75
Which 2 BZDs are used for epilepsy and seizure states?
lorazepam and diazepam
76
Can BZDs help with management of seizures such as generalized tonic-clonic status epileptics, absence seizures, partial seizures, etc. ?
Yes
77
BZDs can also be used as a ____ relaxant - for muscle relaxation in skeletal muscle spasms caused by CNS disorder
muscle
ex. diazepam as a muscle relaxant
78
How can BZDs be used for withdrawl symptoms?
- can substitute for alcohol or other sedative-hypnotics during withdrawal states
- reducing the risk of withdrawl-related seizures
79
What is more powerful for CNS depression:
| barbiturates or BZDs?
barbiturates
80
Therapeutic uses for barbiturates?
- Rarely used as a sedative and hypnotic. These drugs have largely been replaced by SAFER agents such as BZDs for the treatment of anxiety and insomnia.
- They are however, used as an anticonvulsant in epilepsy and seizure
* Barbituates (phenobarbital) are used as treatment of generalized tonic-clonic seizures but they are not the drug of first choice
81
Barbituates can also act as a component of ??
balanced anesthesia
- barbiturates such as thiopental can produce anesthesia (loss of feeling or sensation)
- enhance inhibitory neurotransmission
- inhibit excitatory neurotransmission
82
Describe thiopental
- used to induce anesthesia, often followed by inhalation agent
- rapid induction of anesthesia (30-40 sec rapid clearance)
- rapid redistribution from brain (short duration)
- anesthetic, but not analgesic
83
Describe the adverse effects of BZDs
CNS depression: drowsiness, confusion, anterograde amnesia, dizziness, lethargy, ataxia (these effects may persist and cause "hangover" or residual daytime effects)
84
When are benzo's not safe?
when used in combination with other CNS depressants (ex. alcohol, opiates)
85
Define: tolerance
decreased responsiveness to a drug following repeated treatment
86
BZD tolerance is ______ tolerance
pharmacodynamic (has been associated with down-regulation of brain BZD receptors
87
Define: dependence
an altered physiologic state that requires continuous drug administration to prevent withdrawal symptoms
88
BZD withdrawal symptoms
relapse or rebound anxiety, insomnia, restlessness
89
Severity of BZD withdrawal symptoms is related in part to _______
half-life
* withdrawal symptoms are more common and more severe in patients on BZDs with short half lives vs. long half lives
ex. triazolam vs diazepam
90
Causes and risk factors of abuse potential of BZDs
- women
- elderly
- environmental factors (low socioeconomic status, unemployment, stress, over adherence...)
91
Contraindications
```
myasthenia gravis
narrow-angle glaucoma
alcoholism
severe sleep apnea
pregnant or nursing mothers
```
92
What is Flumazenil used for?
used to reverse the CNS depressant effects of BZD overdose
93
Flumazenil is a ??
BZD competitive antagonist
94
Does Flumazenil inhibit the effects of other sedative-hypnotics?
no - just benzos
95
How is Flumazenil given?
IV - acts rapidly and has a short half-life (0.7-1.3 hours)
96
When is Flumazenil a caution?
if BZDs given for seizures
97
Adverse effects of barbiturates?
- CNS depression
- can cause cardiac and vascular depression
- therapeutic index is low
- not safe
- barbiturates are less safe than BZDs
- metabolic and pharmacodynamic tolerance
- physical dependence with more severe withdrawal symptoms
98
What is a common reason to abuse barbiturates?
is to counteract the symptoms of other drugs
99
Barbiturate withdrawal symptoms
```
restlessness
insomnia
weakness
dizziness
nausea
sweating
anxiety
(similar to BZD withdrawal symptoms)
```
100
see slides 36-39: good review slides
yayayayaya
101
Action site of Buspirone (anxiolytic)
- acts as a partial agonist at serotonin 5-HT1A receptor
- acts as a presynaptic antagonist at the presynaptic dopamine D2 receptor
- does not bind GABA receptors
102
Pharmacokinetics of Buspirone
- is rapidly absorbed orally
- undergoes extensive first-pass metabolism to form several active metabolites.
- elimination half-life of buspirone is 2-4 hours
- takes more than one week to produce therapeutic effects
103
Therapeutic use of Buspirone
anxiolytic
-effects take more than 1 week to develop: unsuitable for management of acute anxiety states
-good for management of anxiety disorders but not good for panic disorders (due to the long onset)
- no hypnotic effect
- causes less psychomotor impairment than BZDs and does not affect driving skills
- has no anticonvulsant properties
- has no muscle relaxant properties
104
Adverse effects of Buspirone
-tachycardia, palpitations, dizziness, and others may occur
105
Is there a risk of tolerance and dependence with Buspirone?
no
- minimal abuse potential
- no withdrawal effects
- no potentiation of CNS depression caused by other sedative-hypnotics and ethanol
106
Consideration with Buspirone?
do not use with monoamine oxidase (MAO) inhibitors
107
What are the Z drugs?
zopiclone (Imovane)
| zolpidem (Sublinox)
108
Action site for Zopicole?
- zopiclone targets GABA-A receptor and is specific for alpha 1
- enhances GABA-mediated neuronal inhibition
109
Zopiclone is ______
lipophilic - rapidly absorbed and peak plasma concentrations occur within 1-2 hours.
110
Zopiclone is rapidly _____
metabolized - by cytochrome P450s
111
half life of zopiclone ?
3-5 hours
112
Therapeutic use of zopiclone
Not for anxiety
Used for insomnia
-short term treatment of insomnia
-increases total sleep time, mainly via increases in stage 2 NREM sleep
-more effective than BZDs because tends to increase stage 3 and 4 sleep
Causes less amnesia
Minimal muscle relaxing effects
Minimal anticonvulsant effects
113
Adverse effects of Zopiclone
- drowsiness
- memory impairments
- dizziness and fatigue
114
Is there a low or high risk for tolerance and dependence of zopiclone?
low risk (over a 6 month period)
115
What is zopiclone antagonized by?
flumazenil
