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Pharmacology: Sedative-Hypnotic Drugs (Kapatos)
INTRODUCTIVE TO SEDATIVE-HYPNOTICS:

Definitions:
o Sedatives: produce calming or drowsiness
o Hypnotics: facilitate onset and maintenance of sleep

Classification (Sedative or Hypnotic):
Assignment indicates therapeutic use for sedation (relief of anxiety) or to encourage sleep (hypnosis)
Classification based on clinical use rather than structure due to chemical heterogeneity
Can also be classified based on duration of action
o Benzodiazepines can be short, intermediate or long acting
o Barbiturates can be ultra-short, short or long acting

Effects: dose-dependent CNS depressant effects

Subgroups:
Benzodiazepines: most important subgroup
Barbiturates
Miscellaneous Agents:
o Meprobamate (carbamate)
o Chloral hydrate (alcohol)
o Buspirone
o Zolpidem
o Zaleplon
o Eszopiclone
o Ramelteon

Non-Prescription Hypnotics:
Antihistamines:
o Diphenyhydramine
o Doxylamine
Serotonin Precursor: L-tryptophan
Product of Serotonin Biosynthetic Pathway: melatonin (synthesized and secreted by pineal gland in a circadian
rhythm controlled by SS nervous system)
PHARMACOLOGY:

Pharmacokinetics:
Absorption and Distribution:
o Highly Lipid Soluble:

Cross BBB after absorption from the GI tract

Lipophilic nature causes some benzos to be unreliable after IM injection
 For example, chlordiazepam and diazepam

Thiopental (barbiturate) has the highest lipid solubility and enters the CNS rapidly (used for
induction of anesthesia)
 CNS effects rapidly terminated by redistribution of the drug to other tissues
o Important Point:

Due to high lipid solubility, all sedative-hypnotics cross the placenta (depress normal
neonatal vital functions)

Also detected in breast milk (depressive effects in nursing infants)
Metabolism and Excretion:
o Benzodiazepine Metabolism:

Phase I Reactions: many (but not all) undergo hepatic microsomal oxidation by P450
enzymes (CYP3A4/2C19)

Phase II Reactions: all are eventually conjugated to form glucuronides that are excreted in
the urine

CYP3A4 Interactions:
 Inhibition: increases blood levels of benzodiazepines
o Erythromycin and clarithromycin (macrolides)
o Itraconazole and ketoconazole (antifungals)
o Nefazodone
o Grapefruit juice
o Cimetidine
o

Active Metabolites: many metabolites of benzodiazepines are biologically active (long half-lives)

Accumulate after continuous dosing: occurs with some drugs, leading to excessive sedation
 Diazepam and flurazepam
o Continuous Dosing:

Accumulation may occur in drugs with long half-lives (see above)

Less of an issue with benzodiazepines with shorter half lives (no active metabolites)
 Oxazepam and lorazepam (do not undergo hepatic microsomal activation and are
conjugated directly)
o Zolpidem/Zaleplon/Eszopiclone:

Short Duration of Action: due to rapid metabolism by liver enzymes
o Overall Duration of Action:

Can be only a few hours
 Eszopiclone
 Zaleplon
 Zolpidem
 Triazolam
 Chloral hydrate

Can be as long as >30 hours
 Chlordiazepoxide
 Clorazepate
 Diazepam
 Phenobarbital
Mechanism of Action:
General: no single MOA has been identified, and different subgroups may have different actions
Benzodiazepines:
o Receptors:

Located in many areas of the brain (thalamus, limbic structures, cerebral cortex)

Form part of the GABAA receptor-chloride ion channel macromolecule complex
o Receptor Binding:

Facilitates the inhibitory actions of GABA by increasing the chloride ion conductance and
hyperpolarizing the membrane (therefore, you need to have GABA present for these to work)

Increase the FREQUENCY of GABA-mediated chloride channel opening
o Receptor Antagonist: Flumazenil (reverses CNS effects of benzos)
Barbiturates:
o Receptor: do not compete for BZ or GABA binding; appear to interact with other sites on GABAA
receptor chloride ion channel
o Receptor Binding:

Depresses neuronal activity by PROLONGING the effects of the inhibitory effects of GABA and
glycine (therefore, also need GABA to be present for these drugs to work)

Increase the DURATION of GABA-mediated chloride channel opening
Other Drugs:
o Buspirone: partial agonist at 5HT1A receptors AND agonist/antagonist at DA D2 receptor

Precise mechanism of anxiolytic effects unknown

No hypnotic, euphoric, muscle relaxant or anticonvulsant effects

No cross-tolerance with benzos

Does not potentiate effects of other sedative hypnotics (including alcohol)
 Therefore, substitution of buspirone will NOT lessen/prevent benzo withdrawal
 If you want to switch to buspirone, need to first withdraw from benzo gradually
 Drug free interval between the 2 permits the physician to distinguish between
withdrawal effects of benzos and failure of buspirone once employed
o Eszopiclone/Zolpidem/Zaleplon: hypnotics that modulate GABAA receptor via interaction with BZ
binding site (but these are NOT benzos)

Because of MOA, also antagonized by flumazenil
o Ramelteon: melatonin receptor agonist

Approved for sleep-onset insomnia (not for sleep maintenance)

No abuse potential and is not a controlled substance

Increased serum prolactin and decreased serum testosterone are possible side effects

Pharmacodynamics:
General:
o CNS effects of these drugs are highly dose-dependent (effects can range from sedation to coma,
depending on the dose)
o Depressant effects often ADDITIVE when two or more drugs given together
o Steepness of dose-response curve correlated with safety

Flatter curves (i.e., benzos) safer

Steeper curves (i.e., barbiturates) less safe
Sedation:
o Both sedation and relief from anxiety occurs with ALL drugs in this class
o Usually accompanied by:

Impaired psychomotor functions

Behavioral disinhibition
Hypnosis:
o Promote sleep onset and increase duration of sleep

High doses of benzodiazepines can lead to decreased REM sleep

Withdrawal from chronic drug use can lead to rebound increase in REM sleep
Anesthesia:
o Loss of consciousness may occur at high doses (with amnesia and suppression of reflexes)

Anterograde amnesia more common with benzos

Anesthesia can be produced by most barbiturates and certain benzos (midazolam)
Anticonvulsant Actions:
o Suppression of seizures occurs at high doses of most barbiturates and some benzos

However, marked sedation is a problematic side effect
o Selective anticonvulsant actions (i.e., do not cause severe sedation) occurs only with a few drugs

Phenobarbital

Clonazepam
o Treatment of status epilepticus

High doses of IV diazepam, lorazepam or Phenobarbital (induce heavy sedation)
Muscle Relaxation:
o Skeletal muscle relaxation occurs at LOW DOSES
o Use in specific spasticity states (i.e., cerebral palsy)

Diazepam is effective at SEDATIVE DOSES
o Meprobamate has some SELECTIVITY as a muscle relaxant
Medullary Depression:
o High doses can cause depression of medullary neurons

Respiratory arrest

Hypotension

CV collapse
o These effects are the cause of death in OD
Tolerance and Dependence:
o Tolerance: decrease in responsiveness to the drug over time

Occurs when sedative-hypnotics used CHRONICALLY or in HIGH DOSES

Cross tolerance may occur across subgroups

Tolerance to Benzodiazepines:
 Associated with downregulation of BZ receptors (GABAA receptors)
 Rapid rebound in these receptors occurs upon termination of benzo treatment
o Psychologic Dependence:

Occurs frequently with most sedative-hypnotics

Manifested by compulsive use to reduce anxiety
o Physiological Dependence:

Constitutes an altered state that leads to an abstinence syndrome (withdrawal state) when
drug is discontinued

Due to downregulation of BZ receptors, benzodiazepine withdrawal produces neuronal
hyperexctiability (anxiety, tremors, hyperrflexia, seizures)
 Occurs more commonly with shorter-acting drugs (i.e., pentobarbital or triazolam)
 Does not occur with longer acting drugs (i.e., diazepam) because they self-taper
 Less of an issue with zopidem/zalepon/eszopiclone than benzos


Clinical Use:
Anxiety States:
o Preferred Agents: benzodiazepines with intermediate or long durations of action (i.e., diazepam)
o Panic and Phobic Disorders:

Alprazolam (Xanax)

Clonazepam
o Buspirone: anxiolytic effects WITHOUT sedation of cognitive impairment; however, effects take a week
or more to develop

General Rule:
 Put on a benzo first to immediately treat anxiety
 Then taper and use buspirone

Use: generalized anxiety disorder (GAD) in patients with a past history of substance abuse
Sleep Disorders:
o Benzodiazepines: widely used for primary insomnia and other sleep disorders

Flurazepam

Triazolam
o Zolpidem/Eszopiclone/Zaleplon:

Cause less daytime impairment than most benzodiazepines

Minimal effects on sleep patterns (no rebound increase in REM sleep)
Other Uses:
o Anesthesia:

Induction: thiopental

Components of Protocol: diazepam and midazolam
o Seizure Disorders:

Clonazepam

Phenobarbital
o Spasticity:

Diazepam
o Management of Withdrawal: in people physiologically dependent on EtOH or other sedative-hypnotics

Longer acting agents: chlordiazpoxide, diazepam
Toxicity:
Psychomotor Dysfunction:
o Includes: cognitive impairment, decreased psychomotor skills, unwanted daytime sedation

More common with benzodiazepines that have long-lived active metabolites
 Diazepam and flurazepam

Short acting hypnotics (esp. triazolam) may cause daytime anxiety and amnesia

Anterograde amnesia may also occur with high doses of benzos
 Basis for use in cases of “date rape”
o Caution: dosage in elderly patients should be decreased by at least 50% to avoid daytime sedation

Increases risks of falls and fractures

Sedation in elderly due to CHANGE IN BRAIN FUNCTION, not change in liver metabolism
Additive CNS Depression:
o DDIs:

Alcoholic beverages

Antihistamines

Antipsychotics

Opioid analgesics

TCAs
o Inhibition of Benzodiazepine Metabolism (CYP3A4 interactions): see previous notes
o Buspirone: additive CNS depression uncommon
Overdose:
o Respiratory and CV Depression:

More likely with alcohols, barbiturates and carbamates than with benzos

More pronounced in people with respiratory depression, sleep apnea or CV disease
o Management:

Requires maintenance of patent airway and ventilatory support

Flumazenil can reverse CNS effects of benzos, zolpidem, zaleplon and eszopiclone ONLY
 Needs to be administered repeatedly due to short half-life
-
 Also important to take care with use in patients that have a history of seizures
Other Adverse Effects:
o Induction of the formation of liver microsomal enzymes that increase drug metabolism:

Barbiturates and carbamates only
o Precipitation of acute intermittent porphyria: barbiturates (in susceptible patients)
o Displacement of coumarins from plasma protein binding sites: chloral hydrate (increase anticoagulant
effects)