1.4 CNS Drugs - Sedatives and Hypnotics - Dr. Rani Qasem 2014-2015
1.4 CNS Drugs - Sedatives and Hypnotics - Dr. Rani Qasem 2014-2015
1.4 CNS Drugs - Sedatives and Hypnotics - Dr. Rani Qasem 2014-2015
Objectives
At the end of the lecture, the students should be able to:
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Introduction
• Sedatives-hypnotics produce sedation (with concomitant
relief of anxiety) and encourage sleep.
• Drugs have considerable variation in chemical structure.
– Drug classification is based on clinical uses rather than on similarities
in chemical structure.
• Anxiety states and sleep disorders are common problems
that are treated with sedative hypnotics.
BASIC PHARMACOLOGY OF
SEDATIVE-HYPNOTICS
• Sedative-hypnotics produce graded dose-dependent
depression of CNS function.
• Sedatives (anxiolytics): reduce anxiety and exert a calming
effect.
– The degree of central nervous system depression should be
the minimum consistent with therapeutic efficacy.
• Hypnotics: produce drowsiness and encourage the onset
and maintenance of sleep.
– Produce more pronounced depression of the CNS than
sedation, and this is achieved by increasing the dose.
• Individual drugs differ in the relationship between the
dose and the degree of CNS depression……. See next slide!
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Chemical Classification-
Benzodiazepines
• Benzodiazepines are widely used sedative-hypnotics.
• Core chemical structure is the fusion of a benzene ring and a 1,4 diazepine ring.
• Most contain a carboxamide group in the 7-membered heterocyclic ring.
• An electronegative substituent (halogen, nitro group) in position 7 is required
for sedative-hypnotic activity.
• Triazolam and alprazolam have a triazole ring at 1,2-position.
Carboxamide group
1,4-benzodiazepine
An
electronegative
substituent
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Chemical Classification-
Benzodiazepines
Triazole ring
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General Pharmacokinetic
Principles of Sedatives- Hypnotics
A. Absorption and Distribution
• Rate of oral absorption of sedatives hypnotics varies-
depends on a number of factors, including lipophilicity.
• Lipid solubility plays a major role in determining the rate at
which a particular sedative-hypnotic enters the CNS.
• All sedative-hypnotics cross the placenta during pregnancy.
• If sedative-hypnotics are given during the predelivery
period, they may depress neonatal vital functions.
• Sedative-hypnotics are detectable in breast milk and may
exert depressant effects in the nursing infant.
General Pharmacokinetic
Principles of Sedatives- Hypnotics
B. Biotransformation
• Metabolic transformation to water-soluble metabolites is
necessary for clearance of sedative-hypnotics from the body.
• Microsomal drug-metabolizing enzyme systems of the liver
are most important for metabolism.
• t1/2 depends on rate of metabolic transformation.
C. Excretion
• The water-soluble metabolites of sedative-hypnotics are
excreted mainly via the kidney.
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Anxiolytics-
Tranquilizers-
BENZODIAZEPINES
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Benzodiazepines potentiate
GABAergic inhibition!!!
• Binding of GABA to its receptor triggers an opening of a chloride channel,
which leads to an increase in chloride conductance.
• The influx of chloride ions causes a small hyperpolarization.
• Benzodiazepine binding to GABA receptor increases the affinity of GABA
for the GABA-binding site-
– Benzodiazepines do not substitute for GABA- they enhance GABA’s
effects allosterically and without directly activating GABA A
receptors or opening the associated chloride channels.
– The enhancement in Cl- conductance takes the form of an increase in
the frequency of channel-opening events.
• The clinical effects of benzodiazepines correlate with the binding affinity
for the GABA receptor.
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Benzodiazepines-
Pharmacological Effects
• Have neither antipsychotic activity nor analgesic action, and they do not
affect the autonomic nervous system.
• Individual benzodiazepines show small differences in their relative
anxiolytic, anticonvulsant, and sedative properties.
Benzodiazepines exhibit the following actions:
1. Reduction of anxiety: At low doses, benzodiazepines are anxiolytic at the
GABA-A receptors.
2. Sedative and hypnotic actions: Benzodiazepines have sedative properties
and some at high doses produce hypnosis (artificial sleep) by acting on α1-
GABA-A receptors.
3. Anterograde amnesia: Mediated through α1-GABA-A
4. Anticonvulsant: Several benzodiazepines have anticonvulsant activity and
some used to treat epilepsy. Partially mediated by α1-GABA-A receptors.
5. Muscle relaxant: At high doses, benzodiazepines relax spastic skeletal
muscles by increasing presynaptic inhibition through α2-GABAA receptors.
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Pharmacokinetics of
Benzodiazepines
• The duration of action varies widely among this group, and
pharmacokinetic considerations are important in favoring one
benzodiazepine over another.
Intermediate acting
Long acting
Long acting
Long acting
Long acting
Intermediate acting
Short-intermediate-acting
Intermediate acting
Short acting
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Categorization of Benzodiazepines
According to Duration of Action
• Short-acting compounds:
– Half-life of 1–12 hours- Have few residual effects if taken before bedtime,
– Upon discontinuation- Rebound insomnia and daytime withdrawal
symptoms- next day rebound anxiety.
– Brotizolam, midazolam, and triazolam.
• Intermediate-acting compounds:
– Half-life of 12–40 hours- Have some residual effects in the first half of the
day if used as a hypnotic.
– Upon discontinuation- Rebound insomnia is more common than longer-
acting benzodiazepines.
– Alprazolam, estazolam, flunitrazepam, clonazepam, lormetazepam,
lorazepam, nitrazepam, and temazepam.
• Long-acting compounds:
– Half-life of 40–250 hours- may accumulate in the elderly and patients with
severely impaired liver function.
– Reduced severity of rebound and withdrawal effects.
– Diazepam, clorazepate, chlordiazepoxide , and flurazepam.
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Pharmacokinetics of
Benzodiazepines
• Benzodiazepines are lipophilic- are rapidly and completely absorbed orally.
• All benzodiazepines subject to hepatic metabolism.
– Most undergo microsomal oxidation (phase I reactions)- catalyzed by
cytochrome P450 - especially CYP3A4.
– Metabolites are then conjugated (phase II reactions) to form glucuronides
that are excreted in the urine.
• Many phase I metabolites are pharmacologically active with long half-lives.
– Example: Desmethyldiazepam has an elimination half-life > 40 hours is the
active metabolite of chlordiazepoxide, diazepam, prazepam, and
clorazepate.
• Alprazolam and triazolam undergo hydroxylation and the resulting
metabolites exert short-lived pharmacologic effects because they are rapidly
conjugated to inactive glucuronides.
• The short elimination half-life of triazolam (2–3 hours) favors its use as a
hypnotic rather than as a sedative drug.
• Metabolism is affected by inhibitors and inducers of hepatic P450 isozyme.
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Biotransformation of Benzodiazepines
-Active metabolites labelled with an asterisk-
Prodrug
“Half-life of
36–200 hours”
“Half-life of
40–250 hours”
Microsomal oxidation – • Glucuronide conjugation –
1. Slow and metabolic 1. Rapid and metabolic
products may be active. products are inactive.
2. Significant changes with 2. Little change with aging.
aging. 3. Lorazepam, oxazepam
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Therapeutic Uses
1. Anxiety disorders: Treatment of anxiety symptoms that accompany:
– Panic disorder
– Generalized anxiety disorder (GAD)
– Social anxiety disorder
– Performance anxiety
– Posttraumatic stress disorder
– Obsessive-compulsive disorder
– Extreme anxiety encountered with specific phobias such as fear of flying.
– Anxiety that accompanies some forms of depression and schizophrenia.
• Drugs should not be used to alleviate normal stress of everyday life and
should be reserved for continued severe anxiety- only used for short periods
of time because of their addiction potential.
• Clonazepam, lorazepam and diazepam are preferred for anxiety that may
require treatment for prolonged periods of time.
• Anti-anxiety effects are less subject to tolerance than sedative & hypnotic
effects – Tolerance is decreased responsiveness to repeated drug doses.
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Adverse effects
1. Drowsiness and confusion- very common.
2. Ataxia occurs at high doses- interferes with fine motor activities.
3. Cognitive impairment (decreased long-term recall and retention of new
knowledge- especially problematic in the elderly- may worsen
dementia)
– Triazolam shows rapid development of tolerance, early morning
insomnia, and daytime anxiety, amnesia and confusion.
4. Precautions: liver disease- acute narrow-angle glaucoma-alcohol and
other CNS depressants.
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Contraindications
1. Pregnancy- Benzodiazepines are pregnancy category D or X.
– If used, benzodiazepines with longer safety record
like diazepam or chlordiazepoxide are recommended over potentially
harmful temazepam or triazolam.
– Use lowest effective dose for shortest period to minimizes risks to the
unborn child.
2. Elderly - benzodiazepine benefits are least and risks are greatest in elderly.
– Have increased risk of dependence and more sensitive to adverse effects.
– Long-term effects resemble dementia, depression, or anxiety syndromes, and
progressively worsen over time- adverse effects on cognition can be mistaken
for the effects of old age.
– Benzodiazepines should be prescribed with caution and for a short period at
low doses in the elderly.
– Short to intermediate-acting benzodiazepines are preferred such
as oxazepam and temazepam.
– Nonbenzodiazepines such as zaleplon and zolpidem and low doses of sedating
antidepressants are preferred alternatives.
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Benzodiazepine antagonist-
Flumazenil
• Flumazenil has high affinity for the benzodiazepine binding site on GABA-A
receptor and acts as a competitive antagonist.
• Flumazenil blocks the actions of benzodiazepines and Z-drugs but does NOT
antagonize ethanol, barbiturates, meprobamate, opioids, or general anesthetics.
• Clinical uses: Reversal of CNS depressant effects of benzodiazepine overdose
and to speed recovery in anesthetic and diagnostic procedures using BZDs.
• For intravenous (IV) use only.
• Onset is rapid, but duration is short- t1/2≈1 hour- rapid hepatic clearance.
• Frequent administration may be needed to revere long-acting benzodiazepines.
Adverse effects:
• Dizziness, nausea, vomiting, and agitation are the most common side effects.
• Reversal of the benzodiazepine may precipitate withdrawal in dependent
patients or cause seizures if used to control seizures.
• Seizures and cardiac arrhythmias may result if the patient ingests tricyclic
antidepressants (TCAs).
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Barbiturates
• Largely replaced by benzodiazepines because of the following negative
properties of barbiturates:
1. Induce tolerance
2. Induce Drug-metabolizing enzymes
3. Induce physical dependence,
4. Cause very severe withdrawal symptoms and coma in toxic doses.
Mechanism of action of Barbiturates
1. Barbiturates interact with GABA-A receptors enhancing GABAergic
inhibitory transmission- produces sedation and hypnosis!
• The binding site is distinct from that of the benzodiazepines.
• Barbiturates prolong the duration of the chloride channel openings.
2. At high doses, may act as a GABA-mimetic, directly activating chloride
channels.
3. Barbiturates block excitatory glutamate AMPA receptors.
4. Anesthetic concentrations block high-frequency sodium channels.
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Drugs EMMS Program Dr. Rani Qasem
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Classification of Barbiturates
Classified according to their duration of
action:
• Thiopental – Ultra-short acting – Given IV
for induction of anesthesia.
• Pentobarbital, Secobarbital, Amobarbital
– Short-acting barbiturates that are
effective as sedatives and hypnotics (but
not antianxiety).
• Phenobarbital –Long-acting – duration of
action > 1 day- used to treat seizures.
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Z-drugs
• Zolpidem, Zaleplon, Eszopiclone
Pharmacological properties:
• Act on a subset of the benzodiazepine receptor family, BZ1.
• Have no muscle-relaxing properties and no anticonvulsant effects.
• Few withdrawal effects, minimal rebound insomnia, little or no tolerance.
• General adverse effects of the group: CNS effects like nightmares, agitation,
headache, dizziness, daytime drowsiness and somnolence. Gastrointestinal
upset.
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Ramelteon
• Selective agonist at melatonin receptors MT1 & MT2.
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Chloral Hydrate
• A trichlorinated derivative of acetaldehyde
• Converted to an active metabolite- Trichloroethanol.
• Used for the short-term treatment of insomnia and as a sedative before
minor medical or dental treatment.
• Induces sleep in 30 minutes and lasts for 6 hours.
• Has a very narrow therapeutic window. High doses depress respiration & BP.
• Has unpleasant taste & is irritating to GI tract and causes epigastric distress.
Inactive
Active
Inactive Inactive
“Trichloroacetic acid” “Dichloroacetic acid” 41
Antihistamines
• 1st generation antihistamines have sedating properties.
• Diphenhydramine, hydroxyzine and doxylamine, are
effective in treating mild types of situational
insomnia.
• Have numerous undesirable side effects (such as
anticholinergic effects) that make them less useful
than the benzodiazepines.
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• Disulfiram:
– Inhibits aldehyde dehydrogenase & blocks the oxidation of
acetaldehyde to acetic acid.
– Causes the accumulation of acetaldehyde in the blood that in
unpleasant reactions- flushing, tachycardia, hyperventilation, and
nausea.
– This is considered a “conditioned avoidance response” to quit drinking.
• Naltrexone:
– Long-acting opiate antagonist used in conjunction with supportive
psychotherapy.
• Acamprosate:
– Used in alcohol dependence treatment programs- unknown
mechanism of action.
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