anxiolytic new

PharmacologyPHARMA BOARD

AnxietyFear, apprehension and worryAccompanied by physical sensations such

as anxiety, nausea, chest pain and/or shortness of breath

NeurotransmittersExcitatory NTs

Key words: sodium, calcium, depolarization

Inhibitory NTs Key: chloride, GABA, hyperpolarization

Excitatory neurotransmitters

opens Na or Ca channels/ influx depolarization (more positive) nerve impulse

e.g. Norepinephrine, Dopamine, Acetylcholine, Glutamate, Aspartate

Inhibitory neurotransmitters

opens Cl channels hyperpolarization (more negative) no nerve impulse

e.g. glycine, gamma-aminobutyric acid (GABA)

1. Panic disorder- recurrent unexpected panic attacks that can occur with agoraphobia in which patients fear places in which escape might be difficult.

2. Specific phobia- intense fear of particular objects or situations (e.g. snakes, heights);most common psychiatric disorder

3. Social phobia-intense fear of being scrutinized in social or public situations (e.g., giving a speech, speaking in class).

4. Generalized anxiety disorder- intense pervasive worry over virtually every aspect of life

5. Post-traumatic stress disorder- persistent reexperience of a trauma, efforts to avoid recollecting the trauma, and hyperarousal

6. Obsessive-compulsive disorder- recurrent obsessions and compulsions that cause significant distress and occupy a significant portion of one’s life

Sedatives-Hypnotics Benzodiazepines

Increase the frequency of GABA-mediated chloride ion channel opening

Barbiturates Increase the duration of GABA-mediated

chloride ion channel opening

Classes of Anxiolytic and Hypnotic drug

Benzodiazepines 5-HT1A-receptor agonists β-adrenoceptor antagonists

Benzodiazepines Act by binding to a specific regulatory site

on the GABA A-receptor enhances the inhibitory effect of GABA. Subtypes of the GABA A-receptor exist in

different regions of the brain differ in their sensitivity to benzodiazepines.

Anxiolytic benzodiazepines are agonists at this regulatory site.

Receptor Empty

Intra cellular

GABA

GABA Receptor

- CL

+++++++

- - - - -

Na

Channel

Na

Channel

Intra cellular

GABA

GABA Receptor

- CL

+ + + +

- - - -

Na

Channel

Na

Channel

- - - -

Use of The DrugsClinical indications for the use of the

anxiolytics, sedatives and hypnotics 1. Prevention of anxiety 2. Formation of sedative state 3. Induction of sleep

ACTIONS Reduction of anxiety Sedative – hypnotics Anticonvulsant Muscle relaxant

The BENZODIAZEPINES

The benzodiazepines are the most frequently used anxiolytic drugs.

These agents prevent anxiety states without causing much sedation, with less physical dependence than other agents.

The BENZODIAZEPINES

Long Acting Intermediate Acting Short Acting

Long Acting (1-3 days) Charlie Chaplein Died From Q-fever

Long Acting (1-3 days) Charlie - Chlorazepate Chaplein - Chlordiazepoxide Died - Diazepam From - Flurazepam Q-fever - Quazepam

Intermediate L A T E

Intermediate L - Lorazepam A - Alprazolam T - Temazepam E - Estazolam

Short Acting O- Oxazepam T- Triamzolam

Uses: Anxiety- alprazolam, diazepam Seizures- diazepam, clonazepam,

lorazepam Insomnia- flurazepam, midazolam Pre-operative sedation- midazolam

The BENZODIAZEPINESSpecial uses

Diazepam(Valium)

Status epilepticus

Chlordiazepoxide (Librium)

Alcohol withdrawal

Alprazolam (Xanax)

Panic attack

The BENZODIAZEPINES

These agents are indicated for the treatment of

1. anxiety disorders2. alcohol withdrawal3. hyperexcitability, and agitation4. pre-operative relief of anxiety and tension

and in induction of balanced anesthesia.

The BENZODIAZEPINESPharmacodynamics: The adverse effects CNS effects= drowsiness,

depression, lethargy, blurred vision GIT= dry mouth, constipation, nausea,

vomiting

. sedation,

CVS= Hypotension or hypertension, arrhythmias, palpitations, and respiratory difficulties.

Hematologic= blood dyscrasias and anemia

GU= urinary retention, hesitancy, loss of libido and sexual functions changes.

The BENZODIAZEPINES

Instruct to avoid consuming ALCOHOL while taking the drug.

The BENZODIAZEPINES

Have available FLUMAZENIL as an antidote for benzodiazepine overdose.

5-HT1A Agonists as Anxiolytic Drugs Buspirone

potent (though non-selective) agonist at 5HT1A-receptors.

Lacks anti-seizure and muscle relaxant properties as benzodiazepines

Headache, minimal tolerance and withdrawal Anxiolytic effects take days or weeks to develop.

Ipsapirone and Gepirone are similar. Side effects include dizziness, nausea, headache, but

not sedation or loss of coordination

The BARBITURATES These are also anxiolytics and

hypnotics with a greater likelihood of producing sedation, with increase risk of addiction and dependence.

Barbiturates

Non-selective CNS depressants Sedation and unconsciousnessBind to the GABA receptor and enhances activity

potent inducers of hepatic drug-metabolising enzymes

Tolerance and dependence occur.

Barbiturates

Non-selective CNS depressants Sedation and unconsciousnessBind to the GABA receptor and enhances activity

potent inducers of hepatic drug-metabolising enzymes

Tolerance and dependence occur.

MODE OF ACTION Interferes with Na and K transport Potentiates GABA action on Cl

ACTIONS Depression of CNS Respiratory depression Enzyme induction

CLASSIFICATION ULTRA – SHORT Thiopental Thiamylal Methohexital Duration: 30min

SHORT ACTING Hexobarbital Pentobarbital Secobarbital Duration: 2hrs

INTERMEDIATE ACTING Amobarbital Butabarbital Duration: 3 – 5hra

LONG ACTING Barbital Phenobarbital Duration: > 6hrs

The BARBITURATES

Pharmacodynamics: The Adverse effects CNS= CNS depression, somnolence, vertigo,

lethargy, ataxia, paradoxical excitement, anxiety and hallucinations.

GIT= nausea, vomiting, constipation/diarrhea and epigastric pain

CVS= bradycardia, Hypotension and syncope.

Respi= serious hypoventilation, respiratory depression and laryngospasms

Others= hypersensitivity and Stevens-Johnson syndrome.

Other Notes Benzodiazepines have no analgesic

properties Fatality of alcohol and benzodiazepines Hypnotics does not induce REM so less

restful than normal sleep Longer acting drugs are easier to dose so

effective in alcohol withdrawal

Sedative-Hypnotics: BarbituratesDrug Interactions Additive effects:

ETOH, antihistamines, benzodiazepines, narcotics, tranquilizers

Inhibited metabolism: MAOIs will prolong effects of barbiturates

Increased metabolism: Reduces anticoagulant response, leading to

possible clot formation

Benzodiazepines vs. BarbituratesCriteria BZ Barb.

Relative Safety High Low

Maximal CNS depression Low High

Respiratory Depression Low High

Suicide Potential Low High

Abuse Potential Low High

Antagonist Available? Yes No

Ion channel that contains the GABA receptor:

A. sodiumB. calciumC. chloride D.potassium

Anxiolytic drug acting through serotonin receptors:

    A.diazepam (Valium)  B. buspirone (BuSpar)    C. triazolam (Halcion)    D. phenobarbital

A comatose patient is brought to the emergency department with severe respiratory depression caused by diazepam overdosage. Reasonable intervention at this point include:

  A.  administer naloxone (Narcan) to block the drug's effect at the receptor  B.   provide supportive therapy until the drug effect wears off.  C.   administer flumazenil D. B & C

Short-acting benzodiazepineA. diazepam (Valium) B.    flurazepam (Dalmane)C. triazolam (Halcion) D.    buspirone (BuSpar)

Most useful in reversing symptoms of benzodiazepine overdosage:

   A. amphetamine   B.  buspirone (BuSpar)   C.flumazenil (Romazicon)   D. naltrexone (ReVia)