Transcript Anxiolytics and Hypnotics

Anxiolytic and Hypnotic Drugs
Anxiety
Neurotransmitters implicated in Anxiety
GABA
Norepinephrine
Serotonin
Anxiety
Anxiety disorders includes • Generalized Anxiety Disorder (GAD)
• Phobia / Panic Disorder
• Obsessive Compulsive Disorder (OCD)
• Post traumatic Stress Disorder (PTSD)
Anxiety
• A psychological and physiological state characterized by the
following components:
1. cognitive
2. somatic
3. emotional
4. behavioral
• These components combine to create an unpleasant feeling
that is typically associated with uneasiness, fear, or worry.
1.
2.
Cognitive component: expectation of a diffuse and
uncertain danger.
Somatically the body prepares the organism to deal with
threat (fight or flight reaction):
– blood pressure and heart rate are increased
– sweating is increased
– Blood flow to the major muscle groups is increased
– immune and digestive system functions are inhibited.
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Externally, somatic signs of anxiety may include:
• pale skin
• sweating
• trembling
• pupillary dilation
3.
Emotionally, anxiety causes a sense of dread or panic and
physically causes nausea, and chills.
4.
Behaviorally, both voluntary and involuntary behaviors may
arise directed at escaping or avoiding the source of anxiety.
•
These behaviors are frequent and often maladaptive, being
most extreme in anxiety disorders.
Generalized anxiety disorder (GAD)
• a chronic disorder characterized by:
– long-lasting anxiety
– not focused on any one object or situation.
• Those suffering from generalized anxiety experience nonspecific persistent fear and worry and become overly
concerned with everyday matters
Panic disorder
• A person suffers from brief
attacks of intense terror and
apprehension, often marked by:
– trembling
– shaking
– confusion
– dizziness
– nausea
– difficulty breathing
– Chest pain or discomfort
– Dizziness or faintness
– Fear of dying
• Acute panic attacks:
– defined by fear or
discomfort that abruptly
arises and peaks in less
than ten minutes
– can last for several hours
– can be triggered by
stress, fear, or even
exercise
Phobias
• The largest category of anxiety disorders
• Fear and anxiety is triggered by a specific stimulus or
situation.
• Sufferers typically anticipate terrifying consequences from
encountering the object of their fear, which can be anything
from an animals to a location to a body fluid.
Agoraphobia
• Agoraphobia is the specific anxiety about being in a place or
situation where escape is difficult or embarrassing.
• A common manifestation involves needing to be in constant
view of a door or other escape route.
Social anxiety disorder
(Social phobia)
• An intense fear of negative public scrutiny or of public
embarrassment or humiliation.
• This fear can be specific to particular social situations (such as
public speaking) or, more typically, is experienced in most (or
all) social interactions.
• Social anxiety often manifests specific physical symptoms
– blushing
– sweating
– difficulty speaking
Obsessive-compulsive disorder (OCD)
• Characterized by :
– repetitive obsessions (distressing, persistent, and intrusive
thoughts or images)
– compulsions (urges to perform specific acts or rituals).
• The OCD thought pattern may be likened to superstitions in so
far as it involves a belief in a causative relationship where, in
reality, one does not exist.
Post-traumatic stress disorder
• An anxiety disorder which results from a traumatic
experience.
• Can result from an extreme situation, such as combat, rape,
hostage situations, or even serious accident.
• Common symptoms include
– flashbacks
– avoidant behaviors
– depression
Anxiolytics and Hypnotics
Anxiolytics and Hypnotics
A. Benzodiazepines:
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High therapeutic index
Cannot induce a state of surgical anesthesia
Dependence liability low
Specific antidote – Flumazenil
Does not induce cytochrome P450
Duration of Action of Benzodiazepines
Molecular target of Benzodiazepines:
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BZD act selectively on GABA A receptor.
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BZD acts by binding at a site distinct from GABA binding
site on the receptor.
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BZD increase the frequency of channel opening.
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BZD is GABA facilitatory in nature.
Bzs  facilitation of GABA action on GABA receptors
 chloride channels opening 
 chloride influx to the cell  cell membrane
hyperpolarization  inhibition of propagation of
action potential  inhibitory effect on different
sites of the brain especially motor cortex, and limbic
system.
CNS actions of BZD
1. Anti-anxiety
2. Hypnotic activity
3. Anterograde amnesia: the individual is severely impaired in
learning new information (temporary)
4. Muscle relaxation
5. Anticonvulsant action
6. Respiration: suppression at high dose.
7. GIT: decrease nocturnal gastric secretion.
Pharmacokinetics of BZD
• BZD are lipophilic and cross placental barrier and
secreted in the milk.
• Most of them are metabolized by CYP450 enzyme
system to active compounds.
• Lorazepam, Oxazepam, Temazepam do not have active
metabolites
Adverse effects, contraindications, and drug
interactions of BZD
1. Benzodiazepines commonly produce:
1.daytime drowsiness
2.Sedation
3.Ataxia (Loss of the ability to coordinate muscular movement.)
Adverse effects……..
2.
rebound insomnia on discontinuation.
3.
In the elderly, benzodiazepines infrequently cause
reversible confusion and amnesia as well as blurred vision,
hypotension, tremor, and constipation.
4.
May depress respiration at higher than hypnotic doses
Adverse effects……..
5.
When given intravenously, may decrease blood pressure
and decrease heart rate in patients with impaired
cardiovascular function.
6.
These drugs cause rare paradoxical excitement.
7.
They enhance CNS depression when taken in combination
with other drugs that depress the CNS, most notably
alcohol.
8.
Drugs and grapefruit juice that inhibit CYP3A4 can extend
the duration of benzodiazepine action.
Tolerance, abuse, and dependence
A. With long-term administration, tolerance develops to:
– the sedative–hypnotic and anti-convulsant actions of
benzodiazepines
– but not to their anxiolytic action.
– patients exhibit cross-tolerance with other sedative–
hypnotic agents, including alcohol and barbiturates.
B. The abuse potential of benzodiazepines is low compared
with that of other classes of sedative–hypnotic drugs except
when there is already a history of substance abuse.
C. Withdrawal:
• Abrupt discontinuation
after long-term
benzodiazepine use (3–4
months)
• Signs of withdrawal may
include:
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anxiety and insomnia
gastrointestinal
disturbances
headache
tremor
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Withdrawal occurs sooner
and is more severe after
abrupt discontinuation of
shorter-acting
benzodiazepines
• Withdrawal symptoms can
be minimized by:
1. tapering the dose
2. substituting longeracting benzodiazepines
such as diazepam.
Therapeutic uses of Benzodiazepines
A. Short-term treatment of anxiety disorders:
1. Generalized anxiety disorders
2. Situational anxiety disorders (SADs; e.g., frightening
medical or dental procedures)
3. Panic disorders. Because of its apparent greater specificity,
alprazolam is widely used for urgent care.
4. Social anxiety disorder
B. Insomnia:
• Widely used benzodiazepines: (e.g., triazolam, triazepam,
flurazepam).
– agents with
1. a rapid onset
2. sufficient duration
3. minimal “hangover”
C.
Seizures:
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2.
Benzodiazepines elevate the seizure threshold.
Lorazepam (and diazepam), given by intravenous (IV) infusion, is
preferred for initial treatment of:
– status epilepticus
– drug- or toxin-induced seizures.
Clonazepam and clorazepate are used as adjuncts for:
– Absence
– Myoclonic
– atonic seizures.
Cannot be used for long-term treatment of seizures: due to tolerance
D. Preanesthetic and short medical/surgical procedures.
– Shorter-acting benzodiazepines (e.g., midazolam) are
preferred for their anxiolytic, sedative, and amnestic
actions prior to and during surgery, endoscopy, or
bronchoscopy.
– These drugs do not produce full surgical anesthesia.
E. Muscle relaxation.
– Diazepam is used to treat spontaneous muscle spasms,
spasms associated with endoscopy, and the spasticity of
cerebral palsy.
F. Treatment of agitation (physical and psychological
restlessness) in acute mania of bipolar disorder
G. Physical dependence.
– Long-acting benzodiazepines, such as diazepam and
chlordiazepoxide, are used to reduce the withdrawal
symptoms of physical dependence associated with the:
• long-term use of shorter-acting benzodiazepines
• other sedative–hypnotic drugs, including alcohol and
the barbiturates
BENZODIAZEPINE ANTAGONIST
Flumazenil:
• Competitive antagonist of BZD.
• Not given orally because of high first pass
metabolism in liver (only IV).
• Half life ~1 hr.
• It precipitates withdrawal symptoms in BZD
dependent patients.
• Used in BZD and zolpidem intoxication.
B. Barbiturates
Duration of Action of Barbiturates
Classification and Indications of Barbiturates
Drug and classification
Indications
1. Ultra-short acting
• Thiopental [Pentothal]
• Methohexital [Brevital]
• Thiamylal [Surital]
• Intravenous general anesthesia
2. Intermediate acting
• Amobarbital [Amytal]
• Pentobarbital [Nembutal]
• Secobarbital [Seconal]
3. Long acting
• Phenobarbital [Luminal]
• Mephobarbital [Mebaral]
• Preanesthetic medication and regional
anesthesia; sedation and hypnosis
(largely replaced by benzodiazepines)
• Seizure disorders; withdrawal syndrome
from sedative–hypnotics; congenital
hyperbilirubinemia, and neonatal
jaundice (enhance bilirubin metabolism
by induction of microsomal enzymes)
Barbiturates : Mechanism of action
• Can act on GABA A receptor even without GABA –
GABA mimetic.
• Increase the duration of opening of the chloride
channel.
• AMPA (Glutamate) receptor are blocked at high dose.
• High dose can block Na channel.
Actions of Barbiturates :
1. Conc. Dependent CNS Depression:
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At low doses, the barbiturates produce sedation (have a calming
effect and reduce excitement).
At higher doses, the drugs cause hypnosis
followed by anesthesia (loss of feeling or sensation)
finally, coma and death.
Chronic use leads to tolerance.
2. Respiratory depression:
• Barbiturates suppress the hypoxic and chemoreceptor
response to CO2, and overdosage is followed by respiratory
depression and death.
3. Enzyme induction: Barbiturates induce
cytochrome P450 (CYP450) microsomal
enzymes in the liver.
Therapeutic uses of Barbiturates
1. Anesthesia:
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The ultrashort-acting barbiturates, such as thiopental, are used
intravenously to induce anesthesia
2. Anticonvulsant:
• Phenobarbital is used in:
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long-term management of:
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tonic-clonic seizures
status epilepticus
eclampsia.
the drug of choice for treatment of young children with recurrent
febrile seizures.
should be used cautiously in children, because phenobarbital can depress
cognitive performance
3. Anxiety:
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Barbiturates have been used as mild sedatives to
relieve anxiety, nervous tension, and insomnia.
When used as hypnotics, they suppress REM sleep
more than other stages.
Most have been replaced by the benzodiazepines.
Pharmacokinetics of barbiturates
• Absorbed orally
• Distributed widely throughout the body.
• Barbiturates readily cross the placenta and can depress the
fetus.
• These agents are metabolized in the liver
• Inactive metabolites are excreted in urine.
Barbiturates : Adverse effects:
• Hangover: may lead to impaired ability to function
normally for many hours after waking.
• Drowsiness and impairment of fine motor skills.
• Distortion of mood and judgments.
• Behavioral disturbances after long term
treatment.
• Tolerance and dependence – severe.
C. OTHER ANXIOLYTIC AGENTS
A. Antidepressants
• Used in managing the long-term symptoms of chronic anxiety
disorders especially in patients with concerns for addiction or
dependence or a history of addiction or dependence to other
substances.
a. Selective serotonin reuptake inhibitors (SSRIs, such a
escitalopram), or
b. Selective serotonin and norepinephrine reuptake
inhibitors (SNRIs, such as venlafaxine) may be used alone,
or prescribed in combination with a low dose of a
benzodiazepine during the first weeks of treatment.
– After four to six weeks, when the antidepressant begins to
produce an anxiolytic effect, the benzodiazepine dose can
be tapered.
Buspirone : (Buspar)
• 5-HT1A partial agonist.
• other receptors involved: DA2 dopamine receptors and 5-HT2A
serotonin receptors.
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Anxiolytic effects appear after a week. (slow onset)
Non-addictive and non-sedative.
No muscle relaxation and anti-seizure activity.
Preferred in elderly and may improve sexual dysfunction
secondary to SSRI.
• Used for generalized anxiety disorder.
Adverse effects of buspiron
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Causes hypothermia
Can increase prolactin and growth hormone.
The frequency of adverse effects is low
The most common effects:
– Headaches
– Dizziness
– Nervousness
– light-headedness.
II. HYPNOTICS
• Hypnotics may be indicated in insomnia
• Major symptoms of insomnia include inability to
initiate asleep or stay asleep once initiated (i.e.,
frequent/premature awakenings).
• Causes of insomnia include organic and psychological
disorders, life style, environmental factors)
Physiology of sleep:
• The awake state: maintained largely by the arousal system
(reticular formation) of the brain stem.
• Induction and maintenance of sleep: involves
(i) active inhibition of pathways involved in wakefulness
and arousal (e.g., serotonergic, muscarinic, adrenergic,
histaminic and dopaminergic systems), and
(ii) specific brain nuclei (e.g., median raphe nucleus of the
lower brain stem).
Stages of sleep:
• Non-rapid eye movement (NREM) sleep:
accounts for 70-75% total sleep duration and progresses through 4
stages: -
• Stage I (~5-10 min duration),
• Stage II (~15 min duration),
• Stages III and IV (Slow wave sleep; ~ 70 min)
• Rapid eye movement (REM; paradoxical) sleep: a sleep phase
during which most dreams occur
Sleep
• In healthy young adults, the four stages of NREM sleep
(averaging about 90min) is followed by a REM stage (lasting about
20-30 min).
• This NREM-REM cycle is repeated 4-5 times as follows for a total
sleep duration of about 8 hr:
Management of sleep disorders
1. Nonpharmacological approaches:
include good “sleep hygiene” (e.g., constant bedtime,
avoidance of stimulants immediately prior to bedtime, etc)
2. Pharmacological approaches:
• The “ideal” hypnotic drug should have
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a rapid onset of action
minimal effect on normal sleep pattern/stages
the ability to sustain sleep of normal duration
no hangover, daytime sedative effects, or memory
impairment potential
– minimal addiction or tolerance potential and rebound
insomnia
– a high therapeutic index
• Effects of most hypnotics on sleep pattern:
1.↓ onset latency (time to fall asleep)
2.↑ NREM duration
3.↓ REM duration
DRUGS USED IN THE MANAGEMENT OF INSOMNIA
1. Benzodiazepines
a. Mechanism of action:
decrease neuronal excitability via agonist effect
at the GABAA receptor.
b. Classification: by duration of action as
• short-acting (e.g., triazolam)
• intermediate-acting (e.g., temazepam)
• long-acting (flurazepam)
2. Non-benzodiazepine that act at benzodiazepine receptor
All three drugs are selective for α1-containing GABA A receptors.
Zolpidem (Ambien):
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Acts on subset of GABA A – BZD-1.
Orally effective, half life – 3hrs.
No muscle relaxation and anti-convulsant action.
No dependence and less distortion of sleep
architecture.
• Can be used in pregnancy.
• Adverse effects of zolpidem:
– nightmares, agitation, headache, GI upset,
dizziness, and daytime drowsiness.
Zaleplon (Sonata):
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Non benzodiazepines
Acts on subset of BZD receptor – BZD-1.
Orally effective, half life – 1hr.
Causes fewer residual effects on psychomotor and
cognitive functions
• One of the best choice for inducing sleep.
Eszopiclone
• an oral nonbenzodiazepine hypnotic
• Eszopiclone been shown to be effective for up to 6 months
compared to a placebo.
• Eszopiclone is rapidly absorbed (time to peak, 1 hour),
extensively metabolized by oxidation and demethylation via
the CYP450 system, and mainly excreted in urine.
• Elimination half-life is approximately 6 hours.
• Adverse events: anxiety, dry mouth, headache, peripheral
edema, somnolence, and unpleasant taste.
Antihistamines
• Some antihistamines with sedating properties, such as
diphenhydramine, hydroxyzine and doxylamine, are effective
in treating mild types of insomnia.
• these drugs are usually effective for milder forms of
situational insomnia.
• Numerous undesirable side effects (such as anticholinergic
effects)
Ethanol
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Has anxiolytic and sedative effects.
• CNS depressant, producing sedation and, ultimately, hypnosis
with increasing dosage.
• Because ethanol has a shallow dose–response curve, sedation
occurs over a wide dosage range.
• It is readily absorbed orally and has a volume of distribution
close to that of total body water.
Aldehyde
dehydrogenase
• Elimination:
– through the kidney, but a fraction is excreted through the lungs.
• Ethanol synergizes with many other sedative
• Chronic consumption can lead to:
– severe liver disease
– Gastritis
– nutritional deficiencies.
• Heavy drinking can lead to cardiomyopathy
• The treatment of choice for alcohol withdrawal is the
benzodiazepines.
• Carbamazepine is effective in treating convulsive episodes
during withdrawal.
Drugs to treat alcohol dependence
1. Disulfiram:
• blocks the oxidation of acetaldehyde to acetic acid by
inhibiting aldehyde dehydrogenase.
• This results in the accumulation of acetaldehyde in the blood,
causing flushing, tachycardia, hyperventilation, and nausea.
• A conditioned avoidance response is induced so that the
patient abstains from alcohol to prevent the unpleasant
effects of disulfiram-induced acetaldehyde accumulation.
2. Naltrexone:
– long-acting opiate antagonist that should be
used in conjunction with supportive
psychotherapy.
– Naltrexone is better tolerated than disulfiram
and does not produce the aversive reaction that
disulfiram does.
3. Acamprosate:
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an agent used in alcohol dependence treatment
programs with an as yet poorly understood mechanism
of action.
This agent should also be used in conjunction with
supportive psychotherapy.
Ramelteon
• A selective agonist at the MT1 and MT2 subtypes of
melatonin receptors.
• Normally, light inhibits the release of melatonin from the
pineal gland.
• Darkness stimulates melatonin release from the pineal gland.
• Stimulation of MT1 and MT2 receptors by melatonin in the
induces and promotes sleep
• It is thought to maintain the circadian rhythm underlying the
normal sleep–wake cycle.
• Ramelteon is indicated for the treatment of insomnia in which
falling asleep (increased sleep latency) is the primary
complaint.
• Ramelteon can be administered long term because
– Minimal potential for abuse
– No evidence of dependence or withdrawal
• Adverse effects
– dizziness, fatigue, and drowziness.
– Hyperprolactinemia