L32 Drugs Used in Anxiety and Insomnia→↑↓

Question 1

Classes of Anxiolytic and Hypnotic Drugs

Answer 1

Two principal chemical classes
→ Benzodiazepines
→ Barbiturates

Other anxiolytic drugs
→ Buspirone
→ Hydroxyzine (an antihistamine)
→ Antidepressants (e.g. SSRIs or SNRIs)
→ Propranolol (a b-blocker)

Other hypnotic drugs
→Zolpidem/Zaleplon (“Z” drugs)
→ Ramelteon
→ Chloral hydrate
→ Antihistamines

Question 2

Types of Benzodiazepines

Answer 2

Short-acting (1-8 hrs)
→ Midazolam *
→ Triazolam *

Intermediate-acting (8-40 hrs)
→ Alprazolam
→ Chlordiazepoxide (Librium)
→ Lorazepam
→ Temazepam

Long-acting (40-200 hrs)
→ Clonazepam *
→ Diazepam * (Valium)
→ Flurazepam

Question 3

Advantages over Barbiturates

Answer 3

Much safer – high therapeutic index
As hypnotics
→→ don’t alter normal sleeping pattern
→→ don’t produce morning hangover
→ Not cause drug-drug interaction (NO induction of hepatic
microsomal enzyme CYP450)
→ Produce tolerance and psychological dependence but physical dependence and withdrawal symptom are less
marked
→ Benzodiazepine antagonist is available

Question 4

Actions of Benzodiazepines

Answer 4

Anxiolytic:
→ Alprazolam
→ Chlordiazepoxide
→ Clonazepam *
→ Diazepam *
→ Lorazepam

Sedative / Hypnotic:
→ Diazepam *
→ Flurazepam
→ Lorazepam
→ Midazolam *
→ Temazepam
→ Triazolam

Short-acting compounds
→ better hypnotics
Long-acting compounds
→ better anxiolytics

Question 5

Therapeutic Uses of Benzodiazepines

Answer 5

Treatment of anxiety symptoms

Panic attacks: alprazolam is effective

Muscular disorders:
→ Diazepam is useful in the treatment of skeletal muscle spasms, such
as occur in muscle strain, and in treating spasticity from degenerative
disorders, such as multiple sclerosis and cerebral palsy

Amnesia:
→ Midazolam is used for induction of anesthesia as premedication for
anxiety-provoking and unpleasant procedures, such as endoscopy /
bronchoscopy

→ Seizures: diazepam, clonazepam, lorazepam

→ Sleep disorders: triazolam is used for insomnia, especially in
the elderly

Question 6

Mechanism of action for BDZs

Answer 6

→ BDZs do NOT activate GABAA receptors but rather enhance the binding of GABA to its receptors

→ By enhancing the response to GABA, BDZs facilitate the
opening of GABA-activated chloride channels after binding to
the benzodiazepine receptors (BZ1 and BZ
2) which is part of the GABAA receptor-chloride ion channel complex

→ The influx of chloride causes hyperpolarization, that moves the
postsynaptic potential away from its firing threshold inhibiting formation of action potentials

Question 7

Benzodiazepines and Sleep Disorders

Answer 7

Commonly prescribed benzodiazepines for sleep disorders:

→ Flurazepam: long-acting, reduces sleep-induction time and the
number of awakenings, increases the duration of sleep and causes
little rebound insomnia

→ Temazepam: intermediate-acting, useful in patients with frequent
awakening

→ Triazolam: short-acting and rapid onset, used to induce sleep in
elderly patients with recurring insomnia (i.e. difficulty in falling sleep)

Question 8

Side Effects of Benzodiazepines

Answer 8

Drowsiness and confusion (the most common)

Ataxia – a neurological sign consisting of lack of voluntary
coordination of muscle movements

Cognitive impairment

Anterograde amnesia – temporary impairment of memory

Respiratory depression and death, especially if taken with ethanol

Question 9

Drug-drug Interaction (Benzodiazepines)

Answer 9

↓Absorption :Antacids

↑CNS depression :
Antihistamines Ethanol Barbiturates

↑BDZ
cimetidine estrogens fluoxetine erythromycin

↓BDZ level : carbamazepine

Question 10

Benzodiazepine Antagonist

Answer 10

Flumazenil
→ A competitive antagonist of benzodiazepines at the GABAA
receptor

Adverse effects
→ Dizziness, nausea, vomiting, and agitation
→ Withdrawal in dependent patients
→ Seizures

Question 11

Barbiturates

Answer 11

Low therapeutic index
⎼ Induce tolerance, physical dependence, very severe
withdrawal symptoms
⎼ Induce hepatic microsomal drug-metabolizing CYP P450
enzymes
⎼ Ability to cause coma in toxic doses
⎼ When used as hypnotics, they suppress REM sleep more than other stages

Question 12

Mechanism of action for Barbiturates

Answer 12

Potentiate GABA action on chloride entry into the neuron by
prolonging the duration of the chloride channel openings

→ Can block excitatory glutamate AMPA receptors leading to decreased glutamate-induced excitation

→Anesthetic (high) concentrations of pentobarbital also block
high-frequency Na+ channels
→→Decreased neuronal activity

Question 13

Types of Barbiturates

Answer 13

Ultra-short-acting (10-20 min)
→ Thiopental (high lipid solubility with rapid tissue distribution)

Short-acting (2 to 8 hr)
→ Pentobarbital
→ Amobarbital
→ Secobarbital

Long-acting (1 to 2 days)
→ Phenobarbital (as an anticonvulsant)

Question 14

Metabolism of Barbiturates

Answer 14

Because of increase in heme synthesis, they are contraindicated
in porphyrias

Porphyrias: a hereditary disorder of hemoglobin metabolism causing
→ Mental disturbance
→ Extreme sensitivity to light
→ Excretion of dark pigments in the urine

Question 15

Side Effects of Barbiturates

Answer 15

Drowsiness and decreased motor control

Induction of the hepatic CYP P450 enzymes, which can therefore decrease the effect of other drugs metabolized by these enzymes
High degree of tolerance and dependence

Cardiovascular system
→Fall in blood pressure
→ Elevation in heart rate

Respiratory system
→ Decreases ventilatory responses to hypercapnia and hypoxia
→ Tidal volume / respiratory rate – decreased
→ In high doses, respiratory depression and coma

Question 16

MoA and S/E of Other Anxiolytic Drugs Buspirone

Answer 16

(MOA):
→Acts as a full agonist at presynaptic 5-HT1A receptors to inhibit serotonin release
→ Displays some affinity for DA
2 dopamine receptors and 5-HT2A serotonin receptors

Undergoes metabolism by CYP P450 enzymes like CYP3A4
→ Its half-life is shortened if taken with rifampin (an inducer of the
enzyme)
→ Its half-life is lengthened if taken with erythromycin (an inhibitor
of the enzyme)

Adverse effects
→ Headaches
→ Dizziness
→ Nervousness
→ Hypothermia
→ Increase prolactin
→ Gastrointestinal distress

Question 17

Hydroxyzine

Answer 17

An antihistamine (H1 receptor antagonist) with antiemetic activity

Drowsiness is a possible adverse effect

Question 18

Antidepressants

Answer 18

Proven efficacy in managing the long-term symptoms of chronic anxiety disorders
→ Selective serotonin reuptake inhibitors (SSRIs), such as escitalopram, citalopram or paroxetine
→ Serotonin/norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine or duloxetine

→ SSRIs and SNRIs have a lower potential for physical dependence than benzodiazepines

Question 19

Propranolol (b-Blocker)

Answer 19

Very effective in alleviating the somatic manifestations of anxiety (e.g. social phobias, performance anxiety) caused by
marked sympathetic arousal, such as palpitations, tremor, sweating and diarrhea

→ Acts by antagonism at b-adrenoceptors so that excessive catecholamine release does not produce the sympathetic responses

Question 20

Clonidine (2-Adrenoceptor Agonist)

Answer 20

MOA: acts by stimulating the pre-synaptic a2 adrenoceptors, thereby decreasing noradrenaline release from both central
and peripheral sympathetic nerve terminals

→ Used for the treatment of panic disorder

→ Useful in suppressing anxiety during the management of
withdrawal from nicotine and opioid analgesics

Question 21

Other Hypnotic Agents “Z” Drug Zolpidem

Answer 21

Zolpidem
Structurally unrelated to benzodiazepines

→ Binds selectively to the BZ1 subtype of benzodiazepine
receptors

→ Facilitates GABA-mediated neuronal inhibition

→ Rapid onset and short duration of action

→Also antagonized by flumazenil

Adverse Effects of Zolpidem
→Ataxia: the loss of full control of bodily movements
→ Nightmare
→ Agitation
→ Headache
→ Gastrointestinal upset
→ Dizziness
→ Daytime drowsiness
→ Confusion

Question 22

Other Hypnotic Agents “Z” Drug Zaleplon

Answer 22

Zaleplon

→Similar to zolpidem

→ Rapid onset and short duration of action

→ Fewer residual effects on psychomotor and cognitive functions compared to zolpidem, due to its rapid elimination

Question 23

“Z” Drug – Eszopiclone

Answer 23

Interact with GABAA receptor complexes located close to or
allosterically coupled to benzodiazepine receptors
⎼ Effective for long-term treatment of insomnia
⎼ Adverse effects:
→ Dry mouth
→ Anxiety
→ Headache
→ Peripheral edema
→ Drowsiness
→ An unpleasant taste

Question 24

Drugs acting on GABAA receptors Ramelteon

Answer 24

A selective agonist at the MT1 and MT2 subtypes of melatonin receptors

Stimulation of MT1 and MT2 receptors by melatonin in the hypothalamus is able to induce and promote sleep

Treatment of insomnia characterized by difficulty falling asleep
(increased sleep latency)

NO effects on sleep architecture, NO rebound insomnia or
significant withdrawal symptoms

⎼ Minimal potential for abuse, and NO evidence of dependence
ow withdrawal effects

Adverse effects:
→ Dizziness (most common)
→ Fatigue
→ Drowsiness
→ Increased production of prolactin levels

Question 25

Chloral Hydrate

Answer 25

A trichlorinated derivative of acetaldehyde that is converted to
the active metabolite, trichoroethanol in the body

An effective sedative and hypnotic that induces sleep in about
30 minutes and the duration of sleep is about 6 hr

Adverse effects:
→ Gastrointestinal distress
→ Unpleasant taste

Question 26

Antihistamines

Answer 26

Over-the-counter (nonprescription) antihistamines with sedating properties:

→ Diphenhydramine (Benadryl)
→ Doxylamine
→ Promethazine

Adverse effects:
→ Dry mouth
→ Blurred vision
→ Drowsiness
→ Constipation and urinary retention