sedative hypnotic drugs arf

SEDATIVE HYPNOTIC DRUGSAditia Retno FitriAditia Retno Fitri

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OUTLINES

Sleep

Hypnotic vs Sedative

Hypnotic Sedative Drugs

Benzodiazepine

Barbiturates

Miscellaneous Agents

Summary

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SLEEP

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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 1,2

Stage 3,4:slow wave sleep, SWS

Rapid eye movement(REM) sleep

Normal sleep

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SEDATIVE - HYPNOTIC

SEDATIVE

Drugs that have an inhibitory effect on the CNS to the degree that they reduce:

Nervousness

Excitability

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)

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HYPNOTICS

Calm or soothe the CNS to the point that they cause sleepA 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)

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CNS DepressionCNS Depression

Sedation

Hypnosis

General Anesthesia

Poisoning

Death

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Anxiolytics: reduce anxiety

Sedatives: decrease activity, calming effect

Hypnotics: induce sleep

Some drugs have anxiolytic and sedative/hypnotic effects.

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SEDATIVE-HYPNOTIC DRUGS

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SEDATIVE-HYPNOTIC DRUGSSEDATIVE-HYPNOTIC DRUGS

SEDATIVE-HYPNOTICS

Benzodiazepines Barbiturates Miscellaneous agents

Short Ultra

action action

Intermediate Short Buspirone

action action Chloral hydrate

Long Long Zaleplon

action action Zolpidem

Ramelteon

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GABA System

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.

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Site and Structure of Action

Site of action is the GABAA receptor

Structure of GABAA 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)

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Characteristics of an “Ideal” Hypnotic

Rapid absorption

No active metabolites

Optimal half-life

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

• Sleep maintenance

• Improved Daytime Function

• No residual sedation

• No respiratory depression

• No ethanol interaction

• No tolerance

• No physical dependence

• No rebound insomnia

• No effect on memory

Ideal Hypnotic

PharmacokineticProperties

PharmacokineticEffect

SideEffect

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Sedative/hypnoticsdeath

surgical anesthesia

coma

unconsciousness

sleep

sedation

Drug dose

Mostnon-benzodiazepine sedative/hypnotics

Benzodiazepines,Zolpidem, Zaleplon

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BENZODIAZEPINES

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BENZODIAZEPINES : PharmacodynamicBENZODIAZEPINES : Pharmacodynamic

• act selectively on gamma-aminobutyric acid A (GABAA) 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

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BENZODIAZEPINES : PharmacodynamicBENZODIAZEPINES : Pharmacodynamic

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BENZODIAZEPINES: PharmacokineticsBENZODIAZEPINES: Pharmacokinetics

Absorption: well absorbed if given orally , Cmax reached in

about 1 h Binding:

strongly bound to plasma proteins Distribution:

large Vd: accumulation in body fat (high lipid solubility)

Metabolism: Hydroxylation conjugation with glucuronic acid short-, medium- and long-acting BZshort-, medium- and long-acting BZ the role of N-desmethyldiazepam

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BENZODIAZEPINES : BiotransformationBENZODIAZEPINES : Biotransformation

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BENZODIAZEPINES: Short Acting and the Elderly

Short-lasting benzo’s are not converted to active intermediates; they are metabolized directly into inactive productsThe 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

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Benzodiazepine Binding Site Ligands

Three types of ligand-benzodiazepine receptor interactions have been reported:

(1)Agonists •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.

(2) Antagonists •are typified by the synthetic benzodiazepine derivative flumazenil, which blocks the actions of benzodiazepines, eszopiclone, zaleplon, and zolpidem

(3) Inverse agonists

(1)act as negative allosteric modulators of GABA-receptor function.

(2)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.

Benzodiazepine Binding Site Ligands

Three types of ligand-benzodiazepine receptor interactions have been reported:

(1)Agonists •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.

(2) Antagonists •are typified by the synthetic benzodiazepine derivative flumazenil, which blocks the actions of benzodiazepines, eszopiclone, zaleplon, and zolpidem

(3) Inverse agonists

(1)act as negative allosteric modulators of GABA-receptor function.

(2)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. 31

Pharmacological effects

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

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Receptor Ligands

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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

anticonvulsant effect

anterograde amnesia.

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Benzodiazepines: Unwanted Effects

Unwanted effects• acute overdosage• 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

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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.

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Benzodiazepine Therapy

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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 abnormalitiesAdministration 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 

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BARBITURATES

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Barbiturates: PharmacodynamicBarbiturates: Pharmacodynamic

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.

Pharmacodynamics:•increase the duration of the GABA-gated chloride channel openings. •At high concentrations, the barbiturates may also be GABA-mimetic, directly activating chloride channels. •β subunits binding site in GABA receptor•more pronounced central depressant effects

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Absorptionsmall intestine

Distributionlipid solubilityrapidly cross placenta

Eliminationliver microsomal enzymesrenal tubular reabsorption

BarbituratesBarbiturates : Pharmacokinetics : Pharmacokinetics

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CNS depression

Respiratory depression

CV depressiondecreased myocardial contractility, vasodilation, hypotension

GI motility inhibition

Poor safety， easy to cause dependence • The application has been declining and is mainly used for

anticonvulsant , antiepilepsia and anaesthesia .

BarbituratesBarbiturates : Clinical Effect : Clinical Effect

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Table 12-3 Barbiturates: Onset and Duration

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Barbiturates: Disadvantage of useBarbiturates: Disadvantage of use

• if given in a large dose• death from respiratory and cardiovascular depression

(flumazenil not effective)• a high degree of tolerance:

• BA strongly induce the synthesis and activity of hepatic CYP450 and conjugating enzymes thus increasing the rate of metabolic degradation of many other drugs

• drug-drug interactions• dependence BA are now little used as anxiolytic and hypnotic drugs

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CNS systemconsciousness changerespiratory depressionareflexia

CV systemlow cardiac output

• GI system– ileus

Barbiturate PoisoningBarbiturate Poisoning

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MISCELLANEOUS AGENTS

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Ramelteon : Melatonin receptors

Pharmacodynamic:

Melatonin receptors circadian rhythms

an agonist at MT1 and MT2 melatonin receptors located in the suprachiasmatic nuclei of the brain.

no direct effects on GABAergic neurotransmission

Indication

reduced the latency of persistent sleep with no effects on sleep architecture and no rebound insomnia or significant withdrawal symptoms.

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Ramelteon: Melatonin Receptors ....cont’d

Pharmacokinetic

rapidly absorbed per oral administration

first-pass metabolism!!!!forming an active metabolite with longer half-life (2–5 hours)

The CYP1A2 isoform and CYP2C9of cytochrome P450 are involved.

Drug Interaction

should not be used in combination with :inhibitors of CYP1A2 (eg, ciprofloxacin, fluvoxamine, tacrine, zileuton) or CYP2C9 (eg, fluconazole)

The CYP inducer rifampin markedly reduces the plasma levels of both ramelteon and its active metabolite.

caution in patients with liver dysfunction.

Adverse effects

dizziness, somnolence, fatigue, and endocrine changes as well as decreases in testosterone and increases in prolactin.

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Buspirone: 5 -HT1A -receptor agonists

Pharmacodynamic: selective anxiolytic effects relieves anxiety without causing marked sedative, hypnotic, no anticonvulsant or muscle relaxant properties. \

does not interact directly with GABAergic systems.

a partial agonist at brain 5-HT1A receptors, but it also has affinity for brain dopamine D2 receptors.

no rebound anxiety or withdrawal signs on abrupt discontinuance.

not effective in blocking the acute withdrawal syndrome from abrupt cessation of use of benzodiazepines

minimal abuse liability.

anxiolytic effects of buspirone may take >1week to become established less effective in panic disorders

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Buspirone: 5 -HT1A -receptor agonists

Pharmacokinetic:

rapidly absorbed orally extensive first-pass metabolism

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.

Adverse 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. 54

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.

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Zolpidem

Effect: • binds selectively to the BZ1 subtype of BZ receptors

and facilitates GABA-mediated neuronal inhibitionUseful for the short-term treatment of insomniaPrimarily 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

Pharmacokinetics:Rapidly absorbed in the GI tract following oral administration (75% reaches plasma)Metabolized in the liver and excreted by the kidney’sDosage reduction in hepatic dysfuction, elderly

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Zaleplon & Zopiclone

Short half-life resembles zolpidem, t1/2 = 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

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Sedative-Hypnotic: Misuse and Abuse

Motivational FactorsThe search for sleepCoping with stressAppetitive drug use-motivated by desire for pleasurable responses and sensationsEscape-avoidance drug use-motivated by desire for relief from an unpleasant sensation, tension, fear, or anxietyPotentiating (synergistic)- exaggerated depressant effectOffset effects of stimulant drugs

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Sedative-Hypnotic: Withdrawal SyndromeFirst 12-15 hours, patient appears to improve

16+ hours Restless, anxious, tremulous, weak, abdominal crampingVomiting, orthostatic hypotension, tremors, increased deep tendon flexion, convulsions

Days 2-3Delirium, hallucinations (persecutory) disorientation to time & placeOnce delirium starts can’t be reduced by administration of other sedative hypnotics-has to run its courseIncludes hyperthermia (increased body temp), exhaustion, cardiovascular collapse & sometimes death

Depending upon type of drug, withdrawal symptoms reach peak severity at days 2-3 & last upwards of a week ( & in some cases, some of the symptoms may last several weeks)

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Sedative-Hypnotics: Clinical Uses

For relief of anxietyFor insomniaFor sedation and amnesia before and during medical and surgical proceduresFor treatment of epilepsy and seizure statesAs a component of balanced anesthesia (intravenous administration)For control of ethanol or other sedative-hypnotic withdrawal statesFor muscle relaxation in specific neuromuscular disordersAs diagnostic aids or for treatment in psychiatry

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SLEEP TIME

0 20 40 60 80 100 120 140

HOURS after first dose ( taken each bedtime )

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100

150

200

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300

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400R

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HALF LIVES OF HYPNOTICS~ 8 HOURS ~ 2 HOURS ~ 48 HOURS +

TRIAZOLAMZOLPIDEMZALEPLON

TEMAZEPAMLORAZEPAMOXAZEPAM

DIAZEPAMFLURAZEPAMQUAZEPAM

HALF-LIFE EFFECTS ON PLASMA LEVELS

EXAMPLES:

HIGH EARLYLOW BEFOREWAKE

HIGH AFTERWAKE

ACCUMULATESNIGHT & DAY

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TIME IN BED HOURS AFTER BEDTIME

DRUG METABOLISM: TOO SHORT: EARLY AWAKENING. TOO LONG: HANGOVER.SOMETIME BOTH!

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SUMMARY

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Summary

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THANK YOU

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