Anxiolytic and Hypnotic Drugs. Anxiety Neurotransmitters implicated in Anxiety GABA Norepinephrine Serotonin.

Anxiolytic and Hypnotic Drugs

Anxiety

Neurotransmitters implicated in AnxietyGABANorepinephrine 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. cognitive2. somatic 3. emotional 4. behavioral

• These components combine to create an unpleasant feeling that is typically associated with uneasiness, fear, or worry.

1. Cognitive component: expectation of a diffuse and uncertain danger.

2. 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.

• 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 non-specific 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:

• 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

• BZD act selectively on GABA A receptor.

• BZD acts by binding at a site distinct from GABA binding site on the receptor.

• BZD increase the frequency of channel opening.

• BZD is GABA facilitatory in nature.

Molecular target of Benzodiazepines:

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.

1. Anti-anxiety 2. Hypnotic activity3. Anterograde amnesia: the individual is severely

impaired in learning new information (temporary)4. Muscle relaxation5. Anticonvulsant action

6. Respiration: suppression at high dose.7. GIT: decrease nocturnal gastric secretion.

CNS actions 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

Pharmacokinetics of BZD

Adverse effects, contraindications, and drug

interactions of BZD

1. Benzodiazepines commonly produce: 1.daytime drowsiness2.Sedation3.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:

• anxiety and insomnia • gastrointestinal

disturbances • headache • tremor

• Withdrawal occurs sooner and is more severe after abrupt discontinuation of shorter-acting benzodiazepines

• Withdrawal symptoms can be minimized by: 1. tapering the dose2. substituting longer-

acting benzodiazepines such as diazepam.

Therapeutic uses of Benzodiazepines

A. Short-term treatment of anxiety disorders:

1. Generalized anxiety disorders2. 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 onset2. sufficient duration3. minimal “hangover”

C. Seizures: – Benzodiazepines elevate the seizure threshold.1. Lorazepam (and diazepam), given by intravenous (IV) infusion, is

preferred for initial treatment of: – status epilepticus – drug- or toxin-induced seizures.

2. 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

• 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.

BENZODIAZEPINE ANTAGONIST Flumazenil:

B. Barbiturates

Duration of Action of Barbiturates

Drug and classification

1. Ultra-short acting• Thiopental [Pentothal]• Methohexital [Brevital]• Thiamylal [Surital]

2. Intermediate acting• Amobarbital [Amytal]• Pentobarbital [Nembutal]• Secobarbital [Seconal]

3. Long acting• Phenobarbital [Luminal]• Mephobarbital [Mebaral]

Indications

• Intravenous general anesthesia

• 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)

Classification and Indications of Barbiturates

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: – 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: – The ultrashort-acting barbiturates, such as thiopental, are used

intravenously to induce anesthesia

2. Anticonvulsant: • Phenobarbital is used in:

– long-term management of: • 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: • 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.

• 5-HT1A partial agonist.• other receptors involved: DA2 dopamine receptors and

5-HT2A serotonin receptors. • 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.

Buspirone : (Buspar)

Adverse effects of buspiron

• 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

– 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):

• 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):

• 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

• 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: – 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