L17 - Sedatives and Hypnotics Flashcards
Compare the action of sedative and hypnotics?
Sedative = reduce anxiety + calming without motor or mental function effect
Hypnotics = Produce drowsiness, encourage onset and maintenance of a state of sleep close to natural sleep
Anxiety is only a psychiatric illness. T or F?
False
Can be both normal emotion (act as stimulant), or psychiatric illness when it becomes excessive and disproportional
Mental features of anxiety?
Unpleasant emotional state consisting of: Tension, Apprehension (sense of dread) Uneasiness, Feelings of danger
Without a real / logical cause
List some physical symptoms of anxiety
Increased muscle tension Shortness of breath / choking Rapid heartbeat (tachycardia) Dizziness / feel faint Restlessness Sweating Trembling / shaky / wobbly legs Difficulty concentrating Insomnia Nervousness
List the 4 Type of anxiety disorders?
Generalized anxiety disorder (GAD)
Obsessive-compulsive disorder (OCD)
Panic disorder (panic attacks)
Post-traumatic stress disorder (PTSD)
Define Generalized anxiety disorder (GAD)?
most common (50%)
Extreme feeling of anxiety about a wide variety of things
absence of any clear cause
on most days over a long period of time
Define OCD?
Obsessions: uncontrollable recurring anxiety-producing / intrusive thoughts
Compulsions: need to carry out certain rituals in order to feel less anxious
Define Panic disorder (panic attacks)?
Rapid-onset, frequent attacks of extreme fear
Feeling of heart palpitations, choking, shortness of breath
Encompass phobic anxiety:
i.e. social phobia
Define PTSD?
recurrent recollections of a traumatic event of unusual clarity
(e.g. traumatic delivery, sexual assault, violence, major disaster, car accidents)
which produce bursts of intense psychological distress
Criteria for insomnia?
>30 min to fall asleep
Waking up for >30 min at night
Sleep disturbed >3 nights a week (e.g. for a month)
Impairment of daytime functioning
List some causes of insomnia? Divide into Physical, Physiological, Psychological, Psychiatric and Pharmacological
Physical disorders: cardiovascular system, obstructive sleep apnea, asthma
Physiological disturbances: late heavy meals, noise, shift work
Psychological: stress, tension, grief (e.g. death of relative)
Psychiatric: anxiety, depression, mania, dementia
Pharmacological: caffeine (e.g. coffee / tea), alcohol, nicotine (e.g. cigarette smoke), medicines (side effect)
2 principal chemical classes of sedatives and hypnotics?
- Benzodiazepines
* Barbiturates
List other sedatives other than BDZ and barbiturate?
–Buspirone
–Antihistamines: e.g. hydroxyzine
–Antidepressants
List other hypnotics other than BDZ and barbiturate?
–Zolpidem/Zaleplon (Z-drugs)
–Ramelteon
–Chloral hydrate
–Antihistamines
List 2 short acting BDZ
t1/2: < 5 hr
Short lived or no active metabolites
–Midazolam
–Triazolam
List 3 intermediate acting BDZ
t1/2: 5-24 hr
Short lived or no active metabolites
–Alprazolam
–Lorazepam
–Temazepam
List 2 long acting BDZ
t1/2 > 24 hr
long-lived active metabolites
–Chlordiazepoxide
–Clonazepam *
–Diazepam * (Valium)
–Flurazepam
Describe the metabolism of BDZ?
All are lipid soluble, easily distributed, cross BBB
Short and intermediate acting»_space; α-hydroxy-alprazolam»_space; Glucuronidation
Long- acting»_space; Lots of intermediates (some transform into intermediate acting BDZ)»_space; Glucuronidation
List the BDZs that are Sedatives/ Anxiolytics?
–Diazepam * (Valium)
–Chlordiazepoxide * (Librium)
–Clonazepam *
–Alprazolam ^
–Lorazepam ^
^ = intermediate * = long
List the BDZs that are Hypnotics?
–Diazepam (Valium) (long)**
–Flurazepam (long)
–Temazepam (Inter)
–Triazolam (short)**
MoA of BDZ?
1) Selectively activate GABA- A receptors
» mediate fast inhibitory synaptic response produced by activity in GABAergic neurons
2) Bind allosterically to benzodiazepine receptor BZ1 and BZ2
» facilitate opening of GABA-activated chloride channels
» enhance response to GABA
> > Hyperpolrization, reduce neural excitability by increasing frequency of Cl channel opening
Describe the structure of the receptor that BDZ acts on?
GABA-A receptor-chloride ion channel complex
2α, 2β, γ subunits + BZ1 + BZ2
Indication of Alprazolam?
Panic disorders
Indication of Diazepam apart from anxiolytic/ sedative?
Skeletal muscle spasms
Spasticity from degenrative disorders: MS, Cerebral palsy
Indication of Midazolam apart from anxiolytic/ hypnotic?
Induction of anesthesia for unpleasant procedures i.e. bronchoscopy
BDZs used for seizures?
diazepam,clonazepam,lorazepam
BDZs used for sleep disorders?
triazolam
List some pharmacological effects of BDZ apart from hypnotic/ sedative? Side effects?
1) Temporarily impair memory»_space; ADR: Cognitive impairment and anterograde amnesia
2) Decrease hypoxic respiratory drive»_space; ADR: respiratory depression (lethal)
3) Decrease BP, Increase HR»_space; ADR: dizziness, light headedness
4) Motor ADR: Impaired motor coordination, Ataxia
5) Slurred speech, blur vision, mood swings
No Analgesic/ Antipsychotic effects
BDZ antagonist name, action, admin, indication?
flumazenil:
= competitive antagonist of benzodiazepines at the GABAA receptor
- IV only
- Reversal of BDZ overdose
Flumazenil ADR?
BDZ antagonist:
Dizziness, nausea, confusion
Withdrawal in dependent patients
Seizures, agitation
Compare the therapeutic index between BDZ and Barbituates.
BDZ = High therapeutic index: Increasing dose > sedation > hypnosis
- High doses do not produce anesthesia, coma
- patients can be aroused
Barbituate = Low therapeutic index / margin of safety:
- Effects of increasing dose > sedation >hypnosis > anesthesia > coma (loss of consciousness)
Compare physical dependence and tolerance between BDZ and Barbituate.
BDZ = Less physical dependence and withdrawal symptom
Barbituate = More physical dependence, severe withdrawal symptoms
Both induce tolerance, both induce some psychological dependence
Compare D/D interaction between BDZ and Barbituates?
BDZ = Do not induce hepatic microsomal enzyme (CYP450) = no drug-drug interaction
Barbituates = Induce hepatic drug-metabolizing enzymes (CYP450) = drug-drug interaction
Compare the change in sleeping pattern between BDZ and Barbituates?
BDZ = Do not alter normal sleeping pattern or morning hangover, used as daytime anxiolytics
Barbituates = esp. suppress REM sleep, cannot enter deep sleep, unacceptable drowsiness
Which has antagonist: BDZ or Barbituates?
BDZ
Flumazenil
Example of Ultra-short-acting (10-20 min) Barbituates?
–Thiopental
Example of Short-acting (2 to 8 hr) barbituate?
–Pentobarbital
–Amobarbital
–Secobarbital
Example of Long- acting (1-2 days) Barbituate?
Phenobarbital
Contraindication of barbiturates? Explain why.
1) Induce cytochrome P450 = drug-drug interaction
2) Increase heme synthesis = contraindicated in porphyrias (hereditary disorder of hemoglobin metabolism), cause:
Mental disturbance
Extreme sensitivity to light
Excretion of dark pigments in urine)
Triple MoA of Barbituates?
- Prolong duration (not frequency) of Cl- channel openings
» potentiate GABA action on Cl- entry into neuron - Block excitatory glutamate AMPA receptors
» decreased glutamate-induced excitation - Anaesthetic / high concentrations of pentobarbital: also block high-frequency Na+ channels
» decreased neuronal activity (= analgesic)
Difference between Barbituate and BDZ action on Cl channels?
BDZ = increase frequency of Cl channel opening
Barbituate = increase duration of chloride channel opening + block excitatory glutamata AMPA receptors
List some ADR of Barbituate at normal dose?
Drowsiness
Decreased motor control
Induce hepatic cytochrome P450 system
(drug-drug interaction can decrease the effect of other drugs metabolized by these enzymes)
List some ADR of Barbituate at high dose?
High degree of tolerance, dependence
In high doses: respiratory depression, coma = death
MoA of Buspirone (BuSpar)?
multi-receptor:
1) partial agonist at 5-HT1A receptors: inhibits presynaptic serotonin release
2) Some affinity for (+)5-HT2A serotonin, (-)D2 dopamine receptors
Indication of Buspirone?
No anticonvulsant, muscle relaxant, hypnotic, sedative effects
> > just treat anxiety, not hypnotic
Indication: generalized anxiety disorder (GAD) (takes 1-2 weeks to exert anxiolytic effects)
D/D interactions of Buspirone?
Metabolism by CYP3A4
1) Shorter half-life if taken with rifampin (= inducer of the enzyme)
2) Longer half-life if taken with erythromycin (= inhibitor of the enzyme; macrolide)
ADR of Buspirone?
–Headaches –Dizziness –Nervousness –Hypothermia –Increase prolactin –Gastrointestinal distress
Indication of Hydroxyzine as anxiolytic/ hypnotic? ADR?
Antihistamine with antiemetic (H1) activity
Indications:
1) Patients with anxiety + history of drug abuse
2) Sedation before dental procedures / surgery
ADR:
Drowsiness
Indication and 3 examples of antidepressants for anxiolytic?
managing long-term symptoms of chronic anxiety disorders:
Selective serotonin reuptake inhibitors (SSRIs)
Tricyclic antidepressants (TCAs)
Monoamine oxidase inhibitors (MAOIs)
MoA and indication of Propranolol to treat anxiety?
MoA:
- Antagonizes B-adrenoceptors
> > excessive catecholamine release does not produce sympathetic responses
> > alleviate somatic manifestations of anxiety (e.g. tachycardia, palpitations, tremor, sweating)
MoA of Zolpidem/ Zaleplon?
Binds selectively to BZ1 (= subtype of BZ receptor family)
Facilitates GABA-mediated neuronal inhibition (opens Cl- channel)
> > No muscle-relaxing, anticonvulsant effects (pure sleeping pill)
Advantages of Zolpidem/Zaleplon as a hypnotic?
Little effect on stages of sleep (like BDZ)
Less risk of developing tolerance, dependence with extended use
Short duration of action, rapid onset
Metabolism of Zolpidem?
hepatic oxidation by cytochrome P450 ( unlike BDZ which doesnt induce P450 )
> > D/D interaction!!
CAN BE ANTAGONIZED BY FLUMAZENIL (like BDZ)
List possible ADR of Zolpidem?
Daytime drowsiness (cf. benzodiazepines) Ataxia (loss of full control of bodily movements) Confusion Nightmares Agitation Headache Dizziness Gastrointestinal upset
MoA, indication and ADR of Eszopiclone?
Z-drug
Acts on BDZ receptor
For Insomnia
ADR:
Anxiety, dry mouth, headache, peripheral edema, drowsiness, bad taste
MoA, indication and ADR of Ramelteon?
Selective agonist at MT1, MT2 subtypes of MELATONIN receptors in hypothalamus
> > induce, promote sleep (act like endogenous hormone)
Treat mild insomnia
ADR: Dizziness Fatigue Drowsiness Increased production of prolactin levels
Metabloism, Indication, ADR of Chloral hydrate?
= trichlorinated derivative of acetaldehyde: converted to trichloroethanol (= active metabolite) in the body
effective sedative, hypnotic:
Induces sleep in ~30 minutes
Duration of sleep ~6 hr
Adverse effects:
Gastrointestinal distress
Unpleasant taste
List 3 OTC antihistamines? ADR?
–Diphenhydramine (Unisom SleepGels)
–Doxylamine
–Promethazine
ADR:
Dry mouth
Blurred vision
Drowsiness
