Anxiolytic, Sedative, and Hypnotic Drugs

Kaukab Azim, MBBS, PhD

Drug ListBenzodiazepines

Benzodiazepine antagonistsLong-acting Medium-acting Short-acting

Diazepam Temazepam Triazolam Flumazenil

Flunitrazepam Lorazepam Midazolam

Alprazolam Oxazepam

Clonazepam

BarbituratesOthers

Long-acting Medium-acting Short-acting

Phenobarbital Pentobarbital Thiopental Buspirone

Zolpidem

Eszopiclone

Zaleplon

Remelteon

Diphenhydramine

Ethanol

Learning Outcomes

By the end of the course the students should be able to

• Explain the mechanism of action of each drug in each group

• Describe the main pharmacological effects of each drug in each group

• Describe the main features of benzodiazepine pharmacokinetics

• Describe the main adverse effects of each drug in each group

• Describe benzodiazepine inverse agonists and antagonists

• Outline the main therapeutic uses of each drug in each group

Some Definitions

Term Definition

Anxiolytic A drug that reduces anxiety

Sedative A drug that reduces a person’s response to most external stimuli and causes drowsiness

Hypnotic A drug that induces sleep

General anesthetic A drug that causes loss of consciousness associated with absence of response to painful stimuli

Dose-response relationship

Increasing sedative-hypnotic dose

Sedation, disinhibition,anxiolysis

Possible selective anticonvulsant and

muscle-relaxing activity

Hypnosis

Anesthesia

Medullary depression

Coma

Cent

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us S

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sBarbiturates

Benzodiazepines

Fear and AnxietyFear

An alarm reaction to a perceived threat, that mobilizes an organism to action (i.e. stress response) [the adapting value of fear to threatening situations is obvious]

Anxiety

A diffuse, anticipatory response to an uncertain, potentially threatening situation. [anxiety disorders are characterized by an unrealistic or inappropriate expression of fear (i.e. a dysregulated stress response)]

Brain circuits of fear and anxiety

• The limbic system is the brain system controlling emotions and instinctual behavior.

• A neurocircuit arising from the output pathways of the central nucleus of amygdala is believed to mediate fear and anxiety responses.

• Therefore amygdala is the central processing unit for fear and anxiety.

The GABA-A Receptor Chloride Channel Complex

The GABA-A receptor has a pentameric structure assembled from subunits selected from multiple polypeptide classes (alpha, beta, gamma etc.)

Multiple subunits of these classes have been characterized (i.e alpha 1,2,3,4,5,6, beta 1,2,3,4, and gamma 1,2,3).

Receptors with an alpha-1 subunit are widely distributed through most brain areas and are the most abundant type. Their activation seems to induce sedative and amnestic effects

Receptors with an alpha-2 subunit are localized mainly in the limbic system, cerebral cortex and striatum. Their activation seems to induce anxiolytic effects

BenzodiazepinesMechanism of action

Benzodiazepines (BDZ) bind to receptors located at the interface between alpha and gamma subunits of the GABA-A receptor-chloride ion channel macromolecular complex.

The binding increases the affinity of the GABA-A receptor for GABA, which in turn causes an increased frequency of chloride channel opening (since BDZ need GABA for their activity, a ceiling effect occurs with high doses).

In this way BDZ potentiate GABAergic inhibition at all levels of CNS.

Their sedative, hypnotic and amnestic effects seem mediated at the alpha-1 subunit.

Their anxiolytic effect seems mediated at the alpha-2 subunit

Their muscle relaxant effect seems mediated at the alpha-3 subunit.

Benzodiazepines

Pharmacological effects

CNS effects:

• All BDZ produce a dose-dependent but limited depression of the CNS.

• This leads to the following four actions:

1. Anxiolytic: reduction of anxiety, fear, and apprehension.

2. Sedative-hypnotic: reduction of restlessness, induction of sleep, impairment of formation of new memory (which can lead to anterograde amnesia).[ high doses can cause general anesthesia , but BDZ are not fully effective when are given alone because of the ceiling effect].

3. Anticonvulsant: inhibition of the development and spread of epileptic activity in the CNS.

4. Muscle relaxant: inhibitory effects on polysynaptic reflexes in the spinal cord (a central action)

Benzodiazepines

Pharmacokinetics and Administration Very good oral bioavailability. Distribution in all tissues. Redistribution contributes to the termination of CNS

effects. Extensive biotransformation in the liver. Many metabolites are active (so increasing the duration

of drug action). Half-lives vary widely (4 – 100 hours) Administered PO or IV.

Benzodiazepines: Half Lives and Metabolites

Drug Half life (t½ in hours) Metabolites

Diazepam 43 ± 13 Active metabolites

Flurazepam 2 ± 1 Active metabolites (with t½ 74 ± 24)

Clonazepam 23 ± 5 Active metabolites

Flunitrazepam 22 ± 4 Active metabolites

Lorazepam 14 ± 5 No active metabolites

Alprazolam 12 ± 2 Active metabolites

Temazepam 11 ± 6 No active metabolites

Oxezepam 8 ± 3 No active metabolites

Triazolam 3 ± 1 Active metabolites

Midazolam 2 ± 1 Active metabolites

Benzodiazepines: Adverse EffectsCNS

• Drowsiness, dizziness, sedation (common, dose related)

• Impaired motor skills (can be insidious because underestimated)

• Impaired concentration and judgment

• Paradoxical effects, i.e. symptoms of CNS stimulation (2-5%)

• Confusional states, anterograde amnesia (with high doses)

• Lethargy, medullary depression (with very high doses)

• Rebound effects (insomnia, restlessness, etc.) after abrupt discontinuation of 2-3 weeks of treatment.

• Increased risk of falls and fractures in the elderly (mainly with long half-life drugs)

(All the above mentioned effects are more common in the elderly)

Tolerance and dependence develop after long-term use of high doses. (These effects are discussed in detail under ‘Drugs of Abuse’)

Benzodiazepines: Adverse Effects

Respiratory system

• No effect on respiration at low/intermediate doses in healthy subjects. .

• Respiration can be depressed by high doses, or when BDZ are used together with other CNS depressants, or in persons with pulmonary diseases.

Cardiovascular system

• Hypotension (mainly in the elderly).

Overdosage

• Massive doses of BDZ are rarely fatal when used alone (the therapeutic index is more than 200).

Pregnancy

• BDZ are included in pregnancy category D by FDA because exposure has been associated with malformations (mainly cleft lip/palate).

BenzodiazepinesContraindications and Precautions

Contraindications / Precautions ExplanationsWhen the CNS is already depressed (e.g. due to drugs, coma, shock, etc.) CNS depression can worsen

Major depressive illness Depression can worsen if these drugs are used

Bipolar disorder Mania and hypomania can ensue

Parkinson’s disease Impaired cognition and psychosis can worsen

Myasthenia Gravis, muscular dystrophies These condition can be exacerbatedStates of respiratory depression (COPD, asthma, sleep apnea, etc.) Ventilatory failure can ensue

History of substance abuse Benzodiazepine can cause dependence

Closed-angle glaucoma An acute attack of glaucoma can start (mechanism unknown)

Elderly CNS effects are more pronounced

Pregnancy Benzodiazepines are classified as FDA category D

Benzodiazepines: Therapeutic Uses

Situational stress (short term use)

Anxiety disorders (second choice drugs)

Sleep disorders

Seizure disorders

Muscle spasms and spasticity

Induction of ‘conscious sedation” and amnesia

Induction of general anesthesia

Ethanol (or barbiturate) detoxification

BenzodiazepinesUses of Specific agents

Drug Specific Clinical Use

DiazepamAnxiety disordersEthanol detoxificationSevere muscle spasmsStatus epilepticus

Flunitrazepam Mainly abused e.g. criminal date rape

Lorazepam*Anxiety disordersAcute tonic-clonic seizuresNocturnal insomniaAnesthetic premedication

* Since these drugs are directly biotransformed into inactive glucuronide conjugates, they may be preferable in the elderly (glucuronidation does not decline significantly with aging)

Drug Specific Clinical Use

Temazepam*Anxiety disordersNocturnal insomniaAnesthetic premedication

Clonazepam Myoclonic and absence seizuresAcute panic attack

Alprazolam Anxiety disordersPanic disorder

TriazolamSleep onset insomniaSedation and amnesia before medical and surgical procedures

* Since these drugs are directly biotransformed into inactive glucuronide conjugates, they may be preferable in the elderly (glucuronidation does not decline significantly with aging)

BenzodiazepinesUses of Specific agents

Benzodiazepines: Inverse agonists and antagonists

Inverse agonists

• Beta-carboline derivatives act as inverse agonists at BDZ receptors (an inverse agonist is a drug that decreases the response of an effector system below its basal level).

• Therefore they decrease the affinity of GABA for its receptor, so decreasing chloride influx by the GABA-A ionophore.

• Their effects are opposite to those of BDZ.

Antagonists

• Flumazenil is a competitive BDZ receptor antagonist that can block both the effects of BDZ and those of beta-carboline derivatives.

• It also blocks the effects of zolpidem but does not antagonize those of other CNS depressants (barbiturates, buspirone, ethanol etc.).

• It is used clinically to counteract excessive effects of BDZ.

• Since it can cause several (and sometimes serious) unwanted effects is not used in case of BDZ poisoning.

Other Anxiolytic DrugsBuspironeMechanism of action

• The precise mechanism is still unknown. The drug acts as a partial agonist at 5-HT1A receptors in the limbic system, where they are mainly postsynaptic and facilitate serotonin transmission.

Pharmacological effects• Selective anxiolytic actions• Negligible sedative, hypnotic and amnesic effects• Negligible anticonvulsant and muscle relaxant effects.• Negligible abuse liability.• No cross tolerance with benzodiazepines.• Delayed onset of action (initial effects are observed within the first 7-10 days, but 3-4

weeks may be needed for optimal results).

Adverse effects• Most common (up to 10%): dizziness, drowsiness.

Therapeutic uses• To treat anxiety disorders that have not responded to SSRis/SNRIs. (The drug is

ineffective in severe anxiety, panic disorders and acute anxiety attack)

BarbituratesMechanism of action

• Barbiturates(BRB) bind to receptors located on the alpha and beta subunits of the GABAA receptor-chloride ion channel

macromolecular complex.

• The binding increases the affinity of the GABAA receptor for GABA,

which in turn causes an increased duration of chloride channel opening

• High doses of BRB may also:

a. can directly increase chloride channel opening in the absence of GABA (it is mainly for this reason that they do not exhibit a ceiling effect).

b. can block AMPA glutamate receptors.

BarbituratesPharmacological effects

• All BRB produce a dose-dependent depression of the CNS, but the dose-effect curve is much steeper than that of BDZ. Therefore:

1. After low doses: reduction of anxiety with pronounced sedation and sleep induction (the duration of REM sleep during the night is decreased).

2. After intermediate doses: euphoria disinhibition, impaired judgment, emotional instability, loss of self-control.

3. After high doses: induction of general anesthesia.

• Inhibition of the development and spread of epileptic activity in the

CNS (anticonvulsant action).

• Dose-dependent depressant effects on respiration (neurogenic drive is affected first, followed by the chemoreceptor drive, and finally by the hypoxic drive).

• Induce cytochrome P450 in the liver. Therefore BRB can hasten their own metabolism as well as that of other drugs.

BarbituratesPharmacokinetics and administration.

• Good oral bioavailability.

• Redistribution is the main factor for the termination of CNS effects of lipid-soluble compounds.

• Variable biotransformation in the liver.

• Half-lives vary widely (lipid solubility and rate of metabolic inactivation determine the duration of action).

• Administered PO, IM or IV.

Barbiturates: Adverse EffectsCNS• Dose-dependent CNS depression• Euphoria and behavioral disinhibition• Hangover effects• Confusional states (these effects are more common in the elderly)• Paradoxical effects (1-5% of patients)• Increased pain perception• Lethargy, medullary depression (with high doses)• Tolerance and dependence (not with phenobarbital)(These effects are discussed in detail under ‘Drugs of Abuse’)

Respiratory system• Dose-dependent depression of respiration.• Coughing, sneezing, laryngospasm (respiratory reflexes are only slightly

affected).

Cardiovascular system• Hypotension.• Cardiovascular collapse (when given IV).

Barbiturates: Adverse EffectsHypersensitivity reactions

• Minor allergic reactions are common• Serious allergic reactions can occur (exfoliative dermatitis, lupoid

syndrome, Stevens-Johnson syndrome).

Idiosyncratic reactions

• Exacerbation of acute intermittent porphyria (due to increase porphyrin biosynthesis).

Overdosage

• Poisoning is a significant medical problem (the therapeutic index of BRB is about 10-15).

Pregnancy

• BRB are included in pregnancy category D by FDA (the risk of malformations increases 2-3 fold if BRB are given during pregnancy).

BarbituratesContraindications and Precautions

• Absence, myoclonic and atonic seizures• Porphyria (acute intermittent, variegata)• Previous history of serious allergic reactions to BRB.• Major depression.• Serious respiratory, liver or kidney diseases• Patients with severe pain (BRB may cause excitement and even delirium in

patients with pain).• Elderly• Pregnancy

Therapeutic Uses

• Induction of general anesthesia (thiopental).• Seizure disorders (phenobarbital).• Sleep disorders (very rarely used).• Psychiatric procedures • Neonatal jaundice (phenobarbital, rarely used today).

Classification of Sleep DisordersDyssomnias

(Abnormality in the amount, time, and quality of sleep)

Parasonmias(Abnormal behaviour or physiologic events

associated with sleep)Primary insominia Night mare disorder

Primary hypersominia Sleep terror disorder

Narcolepsy

Breathing-related sleep disorder

Circadian rhythym sleep disorder

Neurotransmitters and Sleep-Wake cycle

Promoting wakefulness Promoting sleep

Catecholamines GABA

Acetylcholine Serotonin

Histamine Adenosine

Glutamate Endorphins

Substance P Interleukin-1 beta

Thyroxin releasing hormone

Corticotrophin releasing hormone

Newer Hypnotic DrugsDrugs

• Zolpidem, zaleplon, eszopiclone (so called Z-hypnotics) are pyridine derivatives.

Mechanism of action

• They bind selectively to alpha1 subunit of the GABA receptor chloride channel complex. The selective binding may account for their relative lack of effect on sleep architecture and stages.

Pharmacological effects

• Selective hypnotic actions

• Decreased sleep latency

• Negligible effects on sleep architecture and stages.

• Short duration of action (zolpidem, zaleplon: see t1/2)

• No effect on next day psychomotor performance.

• Negligible anxiolytic, anticonvulsant and muscle relaxant properties.

• Abuse liability seems low but abuse does occur (the fast acting nature and the short half-life of these compounds encourages the recreational use).

Newer Hypnotic Drugs

Pharmacokinetics

• Zolpidem: oral bioavailability 70%; t1/2 2-3 hs

• Zaleplon: oral bioavailability 30%; t1/2 1-2 hs

• Eszopiclone: oral bioavailability 80%; t1/2 4-7 hs

Adverse effects

• Most common (>5%): dizziness, drowsiness.• Sleep-eating disorder, brief psychotic reactions (rare)

Therapeutic uses

• Sleep-onset insomnia (zolpidem, zaleplon)• Nocturnal insomnia (eszopiclone)

Newer Hypnotic DrugsDrugs

RamelteonMechanism of action

• Melatonin receptors seem to be involved in maintaining circadian rhythms underlying the sleep-wake cycle

• The drug activates melatonin receptors located in the suprachiasmatic nuclei of CNS. It has no direct effects on GABAergic transmission.

Pharmacological effects

• Decreased latency to sleep onset.• Negligible rebound insomnia and withdrawal symptoms.• Abuse liability is absent.Pharmacokinetic

• Extensive first pass effect (increased plasma levels occur even with mild liver disease)• Half life: 1-2 hours.Adverse effects

• Dizziness, fatigue, endocrine changes (decrease testosterone, increased prolactin).Therapeutic uses• Approved by FDA for sleep onset insomnia.

The Pharmacological Treatment of Insomnia

Types of Insomnia Pharmacological Treatment

Sleep-onset insomnia(Difficulty falling asleep)

A z-hypnotic or benzodiazepine with short t ½ (1-2 hours)

Nocturnal insomnia(difficulty to maintain sleep during night)

A z-hypnotic or a benzodiazepine with intermediate t ½ (4 - 11 hours)

Early awakeningDifficulty to maintain sleep during early hours of the morning

A benzodiazepine with intermediate / long t ½ (11 - 14 hours)