Normal sleep cyclic and repetitive , consists of distinct stages,based on three physiologic measures: the electroencephalogram, the electromyogram, and the electronystagmogram.
Non-rapid eye movement(NREM) sleep : 70%-75%
Stage 3,4:slow wave sleep, SWS
Rapid eye movement(REM) sleep
SEDATIVE - HYPNOTIC
Drugs that have an inhibitory effect on the CNS to the degree that they reduce:
Irritability without causing sleep
(McKenry et al., 2003)
An effective sedative (anxiolytic) agent should reduce anxiety and exert a calming effect with little or no effect on motor or mental functions.
(Katzung et al., ed 11)
Calm or soothe the CNS to the point that they cause sleep
A hypnotic drug should produce drowsiness and encourage the onset and maintenance of a state of sleep that as far as possible resembles the natural sleep state.
A sedative can become a hypnotic if it is given in large enough doses dose dependent
(Katzung; Goodman & Gilman)
Anxiolytics: reduce anxiety Sedatives: decrease activity, calming effect Hypnotics: induce sleep Some drugs have anxiolytic and sedative/hypnotic effects.
Benzodiazepines Barbiturates Miscellaneous agents
Intermediate Short Buspirone
action action Chloral hydrate
Long Long Zaleplon
action action Zolpidem
is the major inhibitory neurotransmitter in the brain.
It has specific receptors in chloride channels present on the membrane of post synaptic neurons.
regulates the entrance of chloride into the postsynaptic cells.
Binding of GABA to its receptor (GABA A receptor)
results in opening of the chloride channel and increased conductance of cl¯ ions to inside the post-synaptic neuron. hyperpolarization of the postsynaptic neuron and decreased synaptic neurotransmission.
Site and Structure of Action
Site of action is the GABA A receptor
Structure of GABA A receptor
Comprised of 5 subunits
2 α subunits (to which GABA binds)
2 β subunits (to which barbiturates bind)
1 γ subunit (to which benzodiazepines bind)
Characteristics of an “Ideal” Hypnotic
No active metabolites
Adapted from Bartholini G. In: Sauvanet JP, Langer SZ, Morselli PL, eds. Imidazopyridines in Sleep Disorders . 1988:1-9.
Rapid sleep induction
Physiological sleep pattern
Mechanism other than general CNS depression
Improved Daytime Function
No residual sedation
No respiratory depression
No ethanol interaction
No physical dependence
No rebound insomnia
No effect on memory
Ideal Hypnotic Pharmacokinetic Properties Pharmacokinetic Effect Side Effect
Sedative/hypnotics death surgical anesthesia coma unconsciousness sleep sedation Drug dose Most non-benzodiazepine sedative/hypnotics Benzodiazepines, Zolpidem, Zaleplon
BENZODIAZEPINES : Pharmacodynamic
act selectively on gamma-aminobutyric acid A (GABA A ) receptors , which mediate fast inhibitory synaptic transmission through the CNS.
bind to the gamma sub-unit of the GABA-A receptor.
causes an allosteric (structural) modification of the receptor that results in an increase in GABA A receptor activity.
not substitute for GABA, which bind at the alpha sub-unit, but increase the frequency of channel opening events which leads to an increase in chloride ion conductance and inhibition of the action potential
The antagonist – f l u m a z e n i l
BENZODIAZEPINES : Pharmacodynamic
well absorbed if given orally , Cma x reached in about 1 h
strongly bound to plasma proteins
large Vd: accumulation in body fat (high lipid solubility)
M etabolism :
conjugation with glucuronic acid
short-, medium- and long-acting BZ
the role of N-desmethyldiazepam
BENZODIAZEPINES : Biotransformation
BENZODIAZEPINES: Short Acting and the Elderly
Short-lasting benzo’s are not converted to active intermediates; they are metabolized directly into inactive products
The elderly have a reduced ability to metabolize long-acting benzo’s (and their active metabolites)
Pharmacokinetics are not drastically altered with the short-acting benzo’s
Benzodiazepine Binding Site Ligands
Three types of ligand-benzodiazepine receptor interactions have been reported:
facilitate GABA actions occurs at multiple BZ binding sites
nonbenzodiazepines zolpidem, zaleplon, and eszopiclone are selective agonists at the BZ sites that contain an 1 subunit.
are typified by the synthetic benzodiazepine derivative flumazenil, which blocks the actions of benzodiazepines, eszopiclone, zaleplon, and zolpidem
(3) Inverse agonists
act as negative allosteric modulators of GABA-receptor function.
Their interaction with BZ sites on the GABAA receptor can produce anxiety and seizures, an action that has been demonstrated for several compounds, especially the -carbolines, eg, n-butyl- -carboline-3-carboxylate ( -CCB ). In addition to their direct actions, these molecules can block the effects of benzodiazepines.
Those compounds that bind and enhance the inhibitory actions of GABA are complete agonists
(Ex) Lorazepam, midazolam, etc.
Those compounds that bind with “less than complete agonist action” are termed partial agonists
(Ex) Ambien (zolpidem)
Those compounds that bind and decrease the inhibitory actions of GABA are inverse agonists
Benzodiazepines: Main Effects
The main effects of benzodiazepines are:
reduction of anxiety and aggression
sedation and induction of sleep
reduction of muscle tone and coordination
Benzodiazepines: Unwanted Effects
effects occuring during normal therapeutic use
tolerance and dependence
acute overdosage (BZs are relatively safe in overdose)
BZs produce prolonged sleep, without serious depression of respiration or cardiovascular function
Severe even life-threatening respiratory depression may appear in BZ combination with other CNS depressants, particularly alcohol .
Acute overdosage can be counteracted with flumazenil
Benzodiazepines: Unwanted Effects
unwanted effects occuring during therapeutic use
Influence of manual skills (such as driving performance) due to drowsiness, confusion, amnesia and impaired coordination
enhance of depressant action of other drugs (in a more than additive way )
tolerance , dependence
Tolerance (gradual escalation of dose needed to produce the required effect) occurs with all BZs. T.appears to represent a change at the receptor level.
Dependence – In human subjects and patients, stopping BZ treatment after weeks and months causes an increase in symptoms of anxiety, together with tremor and dizziness.
The withdrawal syndrome : short acting BZs cause more abrupt withdrawal effects
Addiction (-craving -severe psychological dependence) is not a major problem.
Effects on Pregnancy
Benzodiazepines (and their metabolites) can freely cross the placental barrier and accumulate in fetal circulation
Administration during the first trimester can result in fetal abnormalities
Administration in third trimester (close to the time of birth) can result in fetal dependence, or “floppy-infant syndrome”
Benzodiazepines are also excreted in the breast milk
BA: the sleep-inducing properties were discovered early
in the 20th century . Until the 1960s, they formed the largest
group of hypnotics and sedatives in clinical use.
increase the duration of the GABA-gated chloride channel openings.
At high concentrations, the barbiturates may also be GABA-mimetic, directly activating chloride channels.
The elimination half-life of buspirone is 2–4 hours, and liver dysfunction may slow its clearance.
Rifampin, an inducer of cytochrome P450, decreases the half-life of buspirone; inhibitors of CYP3A4 (eg, erythromycin, ketoconazole, grapefruit juice, nefazodone) can markedly increase its plasma levels.
A dverse effect:
causes less psychomotor impairment than benzodiazepines
does not potentiate effects of conventional sedative-hypnotic drugs, and elderly patients do not appear to be more sensitive to its actions.
Nonspecific chest pain, tachycardia, palpitations, dizziness, nervousness, tinnitus, gastrointestinal distress, and paresthesias and a dose-dependent pupillary constriction
FDA category B drug in terms of its use in pregnancy.
Differences between buspirone and benzodiazepines:
1- The full anxiolytic effect of buspirone takes several weeks to develop , whereas the anxiolytic effect of the benzodiazepines is maximal after a few days of therapy.
2- In therapeutic doses, buspirone has little or no sedative effect and lacks the muscle relaxant and anticonvulsant properties of the benzodiazepines.
3- Buspirone does not potentiate the central nervous system depression caused by sedative–hypnotic drug or by alcohol
4- Buspirone does not prevent the symptoms associated with benzodiazepine withdrawal.
binds selectively to the BZ 1 subtype of BZ receptors and facilitates GABA-mediated neuronal inhibition
Useful for the short-term treatment of insomnia
Primarily a sedative (rather than an anxiolytic)
are antagonised by f l u m a z e n i l
risk of tolerance and dependence < BZ
Rapidly absorbed in the GI tract following oral administration (75% reaches plasma)
Metabolized in the liver and excreted by the kidney’s
Dosage reduction in hepatic dysfuction, elderly
Zaleplon & Zopiclone
Short half-life resembles zolpidem, t 1/2 = 1h
Rapid onset and short duration of action are favorable properties for those patients who have difficulty falling asleep.
Only approx. 30% of an orally administered dose reaches the plasma, and most of that undergoes first-pass elimination
Half as potent as zolpidem
Improves sleep quality w/o rebound insomnia, and little chance of developing dependency
Sedative-Hypnotic: Misuse and Abuse
The search for sleep
Coping with stress
Appetitive drug use-motivated by desire for pleasurable responses and sensations
Escape-avoidance drug use-motivated by desire for relief from an unpleasant sensation, tension, fear, or anxiety