Download Anxiolytic, Sedative, and Hypnotic Drugs

Anxiolytic, Sedative, and
Hypnotic Drugs
Kaukab Azim, MBBS, PhD
Drug List
Benzodiazepines
Long-acting
Medium-acting
Short-acting
Diazepam
Temazepam
Triazolam
Flunitrazepam
Lorazepam
Midazolam
Alprazolam
Oxazepam
Benzodiazepine
antagonists
Flumazenil
Clonazepam
Barbiturates
Long-acting
Medium-acting
Short-acting
Phenobarbital
Pentobarbital
Thiopental
Others
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
Barbiturates
Central Nervous System effects
Coma
Medullary depression
Benzodiazepines
Anesthesia
Hypnosis
Sedation, disinhibition,
anxiolysis
Possible selective
anticonvulsant and
muscle-relaxing activity
Increasing sedative-hypnotic dose
Fear and Anxiety
Fear
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
Benzodiazepines
Mechanism 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 alpha1 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 Effects
CNS
• 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).
Benzodiazepines
Contraindications and Precautions
Contraindications / Precautions
Explanations
When 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 exacerbated
States 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
Benzodiazepines
Uses of Specific agents
Drug
Specific Clinical Use
Diazepam
Anxiety disorders
Ethanol detoxification
Severe muscle spasms
Status epilepticus
Flunitrazepam
Mainly abused e.g. criminal date rape
Lorazepam*
Anxiety disorders
Acute tonic-clonic seizures
Nocturnal insomnia
Anesthetic 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)
Benzodiazepines
Uses of Specific agents
Drug
Specific Clinical Use
Temazepam*
Anxiety disorders
Nocturnal insomnia
Anesthetic premedication
Clonazepam
Myoclonic and absence seizures
Acute panic attack
Alprazolam
Anxiety disorders
Panic disorder
Triazolam
Sleep onset insomnia
Sedation 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)
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 Drugs
Buspirone
Mechanism of action
•
The precise mechanism is still unknown. The drug acts as a partial agonist at 5HT1A 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)
Barbiturates
Mechanism 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.
Barbiturates
Pharmacological effects
• All BRB produce a dose-dependent depression of the CNS, but the doseeffect 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.
Barbiturates
Pharmacokinetics 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 Effects
CNS
• 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 Effects
Hypersensitivity 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).
Barbiturates
Contraindications 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 Disorders
Dyssomnias
(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 Drugs
Drugs
•
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 Drugs
Drugs
Ramelteon
Mechanism 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 awakening
Difficulty to maintain sleep during early
hours of the morning
A benzodiazepine with intermediate /
long t ½ (11 - 14 hours)