Anxiolytic and Hypnotic

Drugs
by: Muamar Shaheen
Benzodiazepines, Azaspiro-decanediones, Barbiturates,
Others (Antihistamines, chloral hydrate)
Overview of the anxiety
⚫ It is an unpleasant state of tension, *apprehension, or
uneasiness_ a fear that seems to arise from known or
unknown source.
⚫ The most common mental disturbance
⚫ Symptoms of severe anxiety are similar to those of fear;
tachycardia, sweating, trembling, & palpitations and
(involves sympathetic activation).
⚫ Mild anxiety is a daily experience & need no ttt.
* (Apprehension: fear of the unknown)
Overview….
⚫ Severe or chronic anxiety is treated by meds and/or
behavioral or psychotherapy
⚫ Anxiolytic agents have different properties:
- Minor tranquilizers/sedation/sedatives
- Inducing-sleep/hypnotics
- Anticonvulsants
⚫ SSRI are also used in anxiety disorders
Benzodiazepines

⚫ They produce their calming and hypnotic effects by

depressing the limbic system and reticular formation
through potentiation of the inhibitory NT GABA.
a. binding affinity to a macromolecular complex of GABA
a R and chloride channels
b. ↑ frequency of Cl- channel opening→ facilitate Cl-
conductance→ membrane hyperpolarization→ synaptic
inhibition
c. BNZ ↑the depressant effects of alcohol and other CNS
depressants
MOA of BNZ
⚫ BNZ modulate GABA effects by binding to a specific, high-affinity
site (distinct from the GABA-binding site) located at the interface of
the α subunit and the γ subunit on the GABA-a receptor.
⚫ sometimes labeled as BNZ receptors.”
⚫ Common BZ receptor subtypes in the CNS are designated as BZ1 or
BZ2 depending on whether the binding site includes an α1 or α2
subunit, respectively.
⚫ BNZ ↑the frequency of channel openings produced by GABA.
``Binding of a BNZ to its receptor site ↑ the affinity of GABA
for the GABA-binding site (and vice versa).``
⚫ The clinical effects of the various BNZs correlate well with the
binding affinity of each drug for the GABA receptor–chloride ion
channel complex
Reticular formation ?
⚫ Neurons of the reticular formation, particularly those of
the ascending reticular activating system, play a crucial
role in maintaining behavioral arousal and consciousness.
The functions of the reticular formation are modulatory
and premotor. The modulatory functions are primarily
found in the rostral sector of the reticular formation and
the premotor functions are localized in the neurons in
more caudal regions.
Function of RF!
⚫ Sleep and consciousness – The reticular formation has
projections to the thalamus and cerebral cortex that allow
it to exert some control over which sensory signals reach
the cerebrum and come to our conscious attention.
⚫ It plays a central role in states of consciousness like
alertness and sleep.
BNZ/cont.
⚫ Actions:
- Reduction of anxiety(α2 subunit in their GABA-A
receptors, thereby inhibiting neuronal circuits in
the limbic system of the brain.
- Sedative/hypnotic actions(α1-GABAA receptors)
- Anterograde amnesia/impairment of learning & formation
of new memory
- Anticonvulsant(α1-GABA-A receptors/partially
- Muscle relaxant
Muscle relax and amnesia
⚫ Anterograde amnesia: Temporary impairment of memory
with use of the BNZ is also mediated by the α1-GABAA
receptors.
⚫ The ability to learn and form new memories is also
impaired.
⚫ BNZs relax the spasticity of skeletal muscle, probably by
↑ presynaptic inhibition in the spinal cord/α2-GABA-A
are largely located.
⚫ Baclofen is a muscle relaxant that is believed to affect
GABA receptors at the level of the spinal cord.
BNZ are divided into:
1) Short-acting(3-8 hrs): oxazepam, triazolam
2) Intermediate-acting (10-20 hrs): - alprazolam
- estazolam, lorazepam, temazepam
3) Long-acting (1-3 days):
- Chlorazepate
- Chlodiazepoxide
- Diazepam
- Flurazepam, quazepam
BNZ
⚫ TU: Pharm.k properties specially duration of action and
differences in affinity to the receptor where binding of
BNZ or GABA to the receptor enhances each others`
affinity and binding abilities to the receptor plays a major
role in choosing one over another for different anxiety or
mental disorders.
1. Anxiety disorders: panic disorder, GAD, Social anxiety
Disorder, performance anxiety, PTSD,OCD,
BNZ
- phobias(social phobia, specific phobia, agoraphobia
without history of panic D.)
- Also for anxiety due to other medical condition as
depression or schizophrenia.
- Used for continued severe anxiety, use them for short
periods of time/addiction potential
- For prolonged period of time use; diaz, loraz, or
clonazepam.
BNZ
⚫ Antianxiety effects of these agents are less subjected to
tolerance than sedative/hypnotic
⚫ Tolerance(↓responsiveness to drug after 1-2 wks of ttt) is
linked to ↓in GABA R density)
⚫ Panic D`s: alprazolam(xanax); effective for short- & long-
term ttt although withdrawal occurs in 30% of patients.
Cross-tolerance exists between BNZs and Alcohol.
2. Muscular disorders: diazepam
Diazepam in 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
BNZ
- 3. Amnesia: short acting agents are used for this purpose
for short unpleasant procedures such as endoscopic, MRI,
dental, angioplasty.
- They cause a sort of conscious sedation
- Midazolam injectable is used prior to anesthesia.
- 4. seizures: clonazepam for certain forms of epilepsy as
an adjunctive therapy, whereas,
- Diaz. & loraz. DOC in terminating status epilepticus.
- Alcohol withdrawal/ dia, chlorz, chlordia, oxaz, loraz.
Amnesia
⚫ In amnesia these agents allowing the person to be
receptive to instructions during these procedures without
feeling the pain or the pain experience as if he is under
hypnoses(awake hypnoses).
⚫ Midazolam: used to facilitate amnesia while causing
sedation prior to anesthesia
BNZ
- 5. Sleep disorders:
- BNZ tends to↓ the latency to sleep onset, ↑ stage II
of non-REM sleep &↓ slow-wave sleep.
In insomnia we should balance sedative effects at night with
the hangover in the morning.
- Long- acting; flurazepam; is rarely used due to its
extended half-life, result in excessive daytime sedation &
accumulation of the drug, especially in the elderly
- Intermediate -acting temazepam;
- Short -acting triazolam
1. Temazepam in sleep
⚫ useful in patients who experience frequent wakening.
⚫ Peak sedation in 1-3 hrs orally, so it should be given 1-2
hrs before bedtime.
⚫ So patient has no problem falling asleep but keep awaking
during the night.
⚫ In other words; temazepam is useful for insomnia caused
by the inability to stay asleep
2. Triazolam in sleep
⚫ It is effective in treating individuals who have difficulty in
going to sleep.
⚫ Tolerance/ within a few days
⚫ Withdrawal/results in rebound insomnia.
⚫ Therefore, this drug is not a preferred agent, and it is best
used intermittently.
⚫ In general, Hypnotics should be given for < 2 to 4 wks.
BNZ
⚫ “Zolpidem, zaleplon, eszopiclone (nonBNZ`s), at usual
doses, don`t alter sleep stages so they are preferred for
sleep induction and maintenance due to selectivity to
BZ1.’’
⚫ Flurazepam: ↓sleep-induction time and no. of awakenings,
↑duration of sleep, little rebound insomnia, up to 4-wks,
t1/2 85 hrs, day time sedation/accumulation
Absorption/distribution Duration of action
Kinetics of BNZs
lipophilic., rapidly longer-acting agents form
completely absorbed after active metabolites with
oral admin., distribute long half-lives,
throughout the body Clinical DOA does not
penetrate into the CNS correlate with the actual
half-life (otherwise,
a dose of diazepam could
conceivably be given only
every other day, given its
active metabolites), may be
due to receptor dissociation
rates in the CNS and
subsequent redistribution
to fatty tissues and other
areas.
Fate
Metab. by hepatic
microsomal system to
Cpds that are also active,
so the apparent half-life of
the drug represents the
combined actions of the
parent drug and its
metabolites. Drug effects
are terminated by
excretion &
redistribution. urine excr.
as glucuronides or
oxidized metabolites
All cross placenta and may
depress the new born CNS
before birth/cross to breast
milk too.
BNZ
⚫ Dependence: psychological and physical dependence on
BNZ can develop if high doses of the drug are given for
prolonged period.
⚫ Abrupt D/C of the drug leads to withdrawal
symptoms(confusion, anxiety, agitation, restlessness,
insomnia, tension, and rarely seizures.)BNZ with short
t1/2, triazolam, induce more abrupt & severe W/reactions.
BNZ
⚫ AE: drowsiness and confusion/most common
⚫ Ataxia/ at high doses/(preclude activities that require fine
motor coordination, driving)
⚫ Cognitive impairment(↓long-term recall and retention
⚫ of new knowledge.)
⚫ Triazolam: very potent/tolerance, early morn. insom,
day-time anxiety, amnesia, confusion
⚫ Precautions:- liver dz, NA-glaucoma, alcohol and other
CNS-depressants enhance BNZ sedative-hypnotic effects.
Antidote/antagonist
⚫ Flumazenil: a GABA receptor antagonist that can rapidly
reverse the effects of BNZs.
⚫ (IV) administration only, t1/2= 1 hour/ Frequent
administration may be necessary for long acting BNZ.
⚫ may ppt. withdrawal in dependent patients
⚫ SE: Dizziness, nausea, vomiting, and agitation
are the most common side effects.
Antidepressants
⚫ For chronic anxiety disorders/should be considered 1st line
agents, esp. in patients with concerns for addiction or
dependence
⚫ SSRIs (escitalopram, or paroxetine) or SNRIs( venlafaxine
or duloxetine) may be used alone or in combo. c low dose
of BNZ during 1st wks.
⚫ After 4-6 wks, when begins to produce an anxiolytic
effect, the BNZ dose can be tapered.
Advantage
⚫ SSRIs and SNRIs have a lower potential for physical
dependence than the BNZ and have become first-line
treatment for GAD.
⚫ Long-term use of antidepressants & BNZs for anxiety
disorders is often required to maintain
ongoing benefit and prevent relapse.
Non-BNZ/Buspirone
⚫ Acts 5-HT-1a(serotonin R), on DA2 R & 5-HT-2a
too.
⚫ Comparable to BNZ & anxiolytic agent for GAD.
⚫ Lacks anticonv. & muscle relax activity/ causes
minimal sedation/CYP 3A4 substrate
⚫ SE: headache, dizziness, nervous, light headedness
⚫ Minimal Sedation, psychomotor and cogn. Dysf.
⚫ Disad: Slow Onset of action, so not effective for
short-term or “as-needed” ttt of acute anxiety states.
/dependence is unlikely
Barbiturates
⚫ MOA: sedative-hypnotic action/GABAa R, enhance
GABA-ergic transmission.
⚫ Actions: classified as per onset of A & DOA.
⚫ Thiopental: acts within seconds and lasts 30 min, used iv
for induction of anesthesia
⚫ Phenobarbital: DOA> one day, seizures
⚫ Phen., seco.,& amo. are short acting, sedative/hypnotic but
not anxiolytic.
MOA:
⚫ The sedative–hypnotic action of barbies is due to their
intxn. with GABAa receptors at a site distinct from that of
BNZs.
⚫ They potentiate GABA action on Cl entry into the neuron
by prolonging the duration of the Cl-channel openings.
⚫ They can block excitatory glutamate receptors.
⚫ At Anesthetic conc., pentobarbital also blocks
high-frequency Na channels.
Barbi/cont.
⚫ ….Actions: - depression of CNS: at low doses produce
sedation(calming effect, reducing excitement)
⚫ At higher doses: hypnosis, followed by anesthesia (loss of
feelings or sensation), & finally coma and death.
⚫ They do not raise the pain threshold and have no analgesic
properties. They may even exacerbate pain. Chronic use
leads to tolerance.
- respiratory depression
- enzyme induction
Therapeutic uses
⚫ Anesthesia: The ultra–short-acting barbies, such as
thiopental, have been used IV to induce anesthesia but
have largely been replaced by other agents.
⚫ Anticonvulsant/phenobarbital: has specific anticonvulsant
activity that is distinguished from the nonspecific CNS
depression.
⚫ It is used in long-term management of tonic–clonic
seizures.
However….
⚫ Phenobarbital can depress cognitive development in
children and decrease cognitive performance in adults, and
it should be used only if other therapies have failed.
⚫ May be used for the treatment of refractory status
epilepticus.
TU…
⚫ Sedative/hypnotic: Barbies have been used as mild sedatives to
relieve anxiety, nervous tension, and insomnia.
⚫ As hypnotics; they suppress REM sleep more than other stages.
⚫ However, the use of barbiturates for insomnia is no longer
generally accepted, given their adverse effects and potential for
tolerance.
⚫ Butalbital is commonly used in combination products (with
acetaminophen and caffeine or aspirin and caffeine) as a
sedative to assist in the management of tension-type or
migraine headaches.
AE; C/I; overdose
⚫ Drug hangover: hours after waking/ impaired ability to
function/nausea, dizziness
⚫ Precautions: inducers of P450. C/I in patients with acute
intermittent porphyria.
⚫ Physical dependence/withdrawal symptoms if withdrawn
abruptly.
⚫ Poisoning; breathing depression/artificial breathing and
stomach purging/hemodialysis if large amount/alkalin. of
urine for phenobarb.
AE
⚫ Drowsiness,
⚫ Impaired concentration,
⚫ Mental and physical sluggishness.
⚫ These effects synergize with those of ethanol.
Barbies toxicity
⚫ Abrupt withdrawal may cause tremors, anxiety, weakness,
restlessness, N/V, seizures, delirium, and cardiac arrest.
⚫ Withdrawal is much more severe than that assoc. c opiates
and can result in death.
⚫ Death may also result from overdose.
⚫ Severe depression of respiration is coupled with central
CV depression and results in a shock-like condition with
shallow, infrequent breathing.
⚫ Treatment includes supportive care and gastric
decontamination for recent ingestions.
Kinetics
⚫ well absorbed orally/distribute to all body tissues.
⚫ All barbies redistribute from the brain to the splanchnic areas,
to skeletal muscle, and, finally, to adipose tissue.

⚫ This movement is important in causing the short DOA of

thiopental and similar short-acting derivatives.
⚫ Barbies readily cross the placenta/ depress the fetus.

⚫ Metabolized in the liver, and inactive metabolites are excreted

in urine.
Other hypnotics
Zolpidem: non-BNZ, act on BZ1-R, has no anticonvulsant or
muscle-relaxing actions./structure not related to BNZ
⚫ Few withdrawal effects, min. rebound insomnia/ little tolerance
on prolonged use.
⚫ Rapidly absorbed from GI/, rapid OOA, short elim. t1/2 of 2-3
hrs, [O] by P450 hepatic enzymes to inactive products. DOA =
5 hrs
AE: - nightmare, agitation, headache, anterograde
amnesia
- GI upset, dizziness, daytime drowsiness
- Oral spray/SL tab. for nighttime awakening
Zaleplon
⚫ Very similar to zolpidem in it`s hypnotic actions.
⚫ It causes fewer residual effects on psychomotor and
cognitive functions compared to zolpedim and BNZ.
⚫ Rapid elimination/t1/2 ~ 1 hr
⚫ It is metabolized by CYP3A4
Eszopiclone
⚫ Non-BNZ hypnotic/BZ1R similar to zop.& zalep.
⚫ Used also for insomnia, could be used for up to 6 months,
rapidly absorbed, peak in 1hr
⚫ Extensively metabolized by CYP 450 enzymes and
excreted mainly in the urine
⚫ t1/2 elimination 6 hrs
⚫ AE: anxiety, dry mouth, headache, peripheral edema,
somnolence & unpleasant metallic taste
Melatonin receptor agonists
Ramelteon & Tasimelteon
⚫ They are selective agonists at the MT1 and MT2 subtypes
of melatonin receptors.
⚫ Melatonin is a hormone secreted by the pineal gland that
helps to maintain the circadian rhythm of normal
sleep–wake cycle.
⚫ Stimulation of MT1/MT2 Rs by ramelteon is thought to
induce and promote sleep.
⚫ Indicated for insomnia charac. by difficulty falling asleep
(increased sleep latency.)
Ramelton…
⚫ has minimal potential for abuse/ no evidence of
dependence or withdrawal effects so,
⚫ Both Ramelteon and Tasimelteon, therefore, can be
administered long term.
AE: - dizziness
- fatigue
- somnolence
Ramelteon may also increase prolactin levels.
Tasimelteon
⚫ Indicated for non–24-hour sleep–wake disorder ( in blind
people).
⚫ AE: headache, abnormal dreams, increase in liver function
tests, & possible URT infections.

⚫ CYP450 1A2 and 3A4 are the principle isoenzymes

required for metabolism of both drugs drug–drug
interactions are possible with inducers or inhibitors of
these enzymes.
Ethanol
⚫ Has anxiolytic sedative effects but it has toxic effects
that overweighs it`s benefits.
⚫ Alcoholism is a serious medical & social problem
⚫ It is a CNS depressant, sedation, hypnosis at higher
doses, absorbed readily and Vd in total body water
⚫ Metabo/liver to acetate fig 9.9/excre in urine/lungs
⚫ It synergizes with other CNS depressants
⚫ Chronic consumption can lead to sever liver dz,
gastritis, nutritional deficiency
Ethanol
⚫ ttt of choice for alc. withdrawal are the BNZs.
⚫ Carbamazepine used for convulsions episodes during
withdrawal
⚫ Disulfiram/(antabuse) inhibit aldehyde dehydrogenase →
acetaldehyde accum→ flushing, tachycardia,
hyperventilation, nausea
⚫ Used to stop alcohol ingestion where it produces a
conditioned avoidance response.
Other agents used as hypnotics
⚫ Antihistamines: with sedating properties, such as
diphenhydramine, hydroxyzine, and doxylamine, are
effective in treating mild types of situational insomnia.
⚫ Their undesired anticholinergic effects (dry mouth, urine
retention, constipation) make them drop from use
comparing to BNS and non- BNZ.
Other agents…..
⚫ Tricyclic Antidepressants: with strong antihistamine
profiles such as Doxepin with SNRI mechanisms of
antidepressant and anxiolytic action, was recently
approved at low doses for insomnia.
⚫ Trazodone & mirtazapine are also used off-label for the
treatment of insomnia as TCA.