Chemical class Agent(examples)

Antidepressants
SSRI(1stline for panic dso, social anxiety dso, Paroxetine, sertraline, escitalopram
OCD,GAD,PTSD)
SNRI(line for GAD; 2 line for panic dso, social Venlafaxine
anxiety dso, OCD,PTSD)
TCA(2 line for panic dso, OCD,GAD,PTSD) Clomipramine
NaSSA(2 line for panic dso, GAD, PTSD) Mirtazapine
MAOI(3 line for panic dso, social anxiety Phenelzine
dso,PTSD)
Anticonvulsants
GABA analogs (2 line for social anxiety disorder, Gabapentin, pregabalin)
GAD)
Phenyltriazine (2 line for PTSD) Lamotrigine
Benzodiazepines (2 line for panic dso, social Gabapentin, pregabalin
anxiety disorder, GAD)
Phenyltriazine (2 line for PTSD) Lamotrigine
Benzodiazepines (2 line for panic dso, social Alprazolam, diazepam, lorazepam
anxiety disorder, GAD)
Azaspirone(2 line for GAD) Buspirone

Chemical class Trade name Dosage forms

Midazolam Versed Syrup, injection
Nitrazepam Mogadon Tabs
Oxazepam Serax Tabs, caps
Quazepam Doral Tabs
Temazepam Restoril Caps
Triazolam Halcion Tabs

Generic name Trade name Dosage forms

Alprazolam Xanor, Xanax, Niravam Tabs, oral concentrate,
triscored tabs, extended
release tabs, oral disintegrating
tabs
Bromazepam Lectopam Tabs
Chlordiazepoxide Librium Caps
Clonazepam Rivotril, Klonopin Tabs, Disintegrating tabs
Clorazepate Tranxene, Tranxene T-tab Tabs
Diazepam Valium, Diazepam Intensol, Tabs, caps, oral solution,
Diastat injection, oral concentrate,
rectal gel, injectable emulsion
Estazolam ProSom Tabs
Flurazepam Dalmane Caps
Lorazepam Ativan Tabs, SL tabs, oral solution,
injection
 Anxiety Panic Insomnia Perioperative Seizure Skeletal Alcohol
dso dso sedation dso muscle withdrawal
toxicity
Long- Chlordiazepoxide
acting
Clonazepam
Clorazepate
Diazepam
Flurazepam
Nitrazepam
Quazepam

OTHER INDICATIONS

Akathisia due to antipsychotic agents

Abnormal movements associated with tardive dyskinesia (clonazepam)
Sedation in severe agitation
Social phobia(alprazolam, clonazepam, diazepamlorazepam)
Catatonia(parenteral and sublingual lorazepam, diazepamand clonazepam)
Acute dystonia(SL or IM lorazepam)
Delirium (lorazepam)
Delirium Tremens(DT)(diazepam)
Neuralgia pain(clonazepam)
Premenstrual dysphoric disorder(alprazolam)
Control of violent outburst, assaultive behavior(clonazepam, lorazepam)

INDICATIONS

Anxiety Panic Insomnia Perioperative Seizure Skeletal Alcohol

dso dso sedation dso muscle withdrawal
toxicity
Short-acting Alprazolam
Midazolam
Triazolam
Intermediate Bromazepam
Estazolam
Lorazepam
Oxazepam
Temazepam

The potency of benzodiazepine is the affinity of the parent drug or its active metabolites.

Potency does not necessarily correlate with onset of action.

Relieve behavioral and somatic manifestations of anxiety, but have little effect on psychic or
cognitive symptoms like worry, anger, interpersonal sensitive and obsessions.

Most helpful during the beginning phase of treatment and not recommended long-term.

PHARMACOLOGY

Benzodiazepines are positive allosteric modulators of the GABA-chloride receptor complex

Benzodiazepine + GABA-chloride receptor binding increase in frequency of the opening of

the chloride channels Inhibition of neuronal firing at the level of the limbic system, brainstem
reticular formation and cortex

Intensity of action depends on a degree of receptor occupancy

Benzodiazepines bind nonselective to various subtypes of benzodiazepine-GABAA-receptor

complexes

GABAA-receptor subtypes containing an 1 subunit are associated with sedation, ataxia and
amnesia
Those containing 2 and/or 1 subunits generally have greater anxiolytic activity

Dose of benzodiazepine increases increased receptor occupancy

Anxiolytic effects are noticed first

Followed by anticonvulsant effects
Then a reduction in muscle tone
Finally sedation and hypnosis

DOSING

Majority are for short-term (<2months) treatment although many have extended treatment
Clinicians should discuss the risk of long-term treatment with patients
Can cause physical and psychological dependence, tolerance and withdrawal symptoms

IM use is discouraged with diazepam because absorption is slow, erratic and possibly
incomplete; local pain often occurs.

Lorazepam IM is adequately absorbed (although sometimes erratic)

Following IV administration of diazepam, local pain and thrombophelbitis may occur due to
precipitation of the drug or due to irritant effect of propylene glycol. A saline flush following IV
admin.

PHARMACOKINETICS; Marked inter-individual variation

Age, liver, disease, physical disorders as well as concurrent use of other drugs may influence
parameters by changing the volume of distribution , metabolism and elimination half-life

Generally well-absorbed from GIT after oral administration

 Food can delay rate BUT not extent of absorption
Onset of action is determined by rate of absorption and lipid solubility

Lipid solubility is positively correlated with enhancing the following properties of benzodiazepines:

Affinity for peripheral adipose tissue, resulting in redistribution from the vascular
compartment, causing increase in volume of distribution
Passage across BBB, facilitating its CNS activity

Duration of action is dependent on dose, rate of absorption, arte and extent of drug distribution,
and rate of elimination

Major pathway of metabolism is hepatic microsomal oxidation and demethylation

Renal impairment may increase free unbound plasma concentration of benzo and reduce its
clearance

Benzodiazepine with long half-life (diazepam) may have short duration of action if dose is
small or if it undergoes rapid and extensive distribution
Short half-life benzodiazepine(lorazepam) may have long duration of action if dose is large
or if it has limited peripheral distribution

Generally, short-acting drugs can be used as hypnotics and for acute problems relating to anxiety

Long-acting ones can be used for chronic conditions where a continuous drug effect is needed

The longer the half-life, the greater the likelihood it will have an adverse effect on daytime
functioning
The short half-life ones are often associated with interdose withdrawal, rebound anxiety
between doses and anterograde amnesia

ADVERSE EFFECTS

CNS

Most common are extensions of the generalized sedative effect like fatigue and drowsiness
Impaired mental speed, central cognitive processing ability, memory and performance
Chronic use: impaired visuospatial and visuomotor abilities, such as decreased motor
coordination, psychomotor speed and response time, concentration , speed of processing
info processing and verbal learning
Paradoxical irritability, impulsivity and agitation
Confusion and disorientation primarily in the elderly
Excessive doses can result in respiratory depression and apnea
Dysarthria, muscle weakness, incoordination, ataxia, nystagmus
Headache
Sexual dysfunction such as decreased libido, erectile dysfunction, anorganism, ejaculatory,
disturbance and gynecomastia
 Dizziness with higher doses of clonazepam
Increased salivation in clonazepam
Few reports of allergies

DISCONTINUATION SYNDROME

Withdrawal: Occur 1-2 days with short-acting agents, up to 5-10 days with long-acting agents after
discontinuation

Common symptoms include insomnia, agitation, anxiety, perceptual disturbances,

dysphoria, headache, muscle aches, twitches, tremors, loss of appetite, diaphoresis,
tachycardia and GI distress
Severe reactions such as seizures, delirium, depersonalization, psychotic states and coma

Relapse: occurs hours to days after discontinuation

Symptoms of anxiety that are more intense than the original

PRECAUTION

DO NOT give to patients with sleep apnea

Caution in the elderly or debilitated, those with liver disease, and those who perform
hazardous tasks requiring mental alertness and physical coordination
Produces lower tolerance to alcohol
High dose may produce mental confusion similar to alcohol intoxication
Abrupt withdrawal after prolonged use of high doses may produce grand mal seizures,
especially with alprazolam

At risk of being abused by susceptible individuals; they prefer those with rapid peak effects such as
diazepam, lorazepam and alprazolam

TOXICITY

Rarely if ever fatal when taken alone

Maybe lethal in combination with other drugs, such as alcohol and barbiturates
symptom of overdose include hypotension, respiratory depression and coma
Flumanzil injection (a benzodiazepine antagonist) reverse the hypnotic-sedative effects

PEDIATRIC

Probable indications include seizure disorders, insomnia, night terrors and somnambulism
Metabolizes faster in children than in adults so may require small divided doses to maintain
blood levels

GERIATRIC

Caution when using it with those drugs that can cause CNS effects; excessive sedation can
cause confusion and disorientation
Increases incoordination and risks of falls three-fold
USE IN PREGNANCY

Benzodiazepines and metabolites freely cross the placenta and accumulate in fetal
circulation
Excreted into breast milk in levels sufficient to produce effects in the newborn
Associated with increased risk of congenital anomalies in the first trimester esp. and
neonatal withdrawal with chronic doses
If used in last week of pregnancy, may produce neonatal CNS, depression, poor feeding,
hypothermia, flaccidity and respiratory depression
Metabolism in infants is slower esp. during first six weeks
Long-acting drugs may accumulate

EXCESSIVE DOSES OF CAFFEINATED DRINKS CAN COUNTERACT THE EFFECTSOF ANXIOLYTICS

Use of grapefruit and pomegranate juice while taking benzodiazepines can result in
increased blood levels and result in more pronounced effect of the benzodiazepines
Antacids delay absorption of benzodiazepines in the intestines
Separate their administration

BUSPIRONE

Chemical class Generic name Trade name Dosage form&strength

Azaspirone Buspirone Buspar Tabs5,7.5,10,15,30mg

INDICATIONS

GAD
Alternative to benzodiazpines when sedation and psychomotor impairment may be
dangerous
In patients with history of alcohol or substance abuse
OCD: for relief of anxiety
Depression: augment effects of antidepressants
Agitation: aggression, antisocial behaviors

Some positive reports for use in:

Social phobia
Premenstrual syndrome
Bruxism caused by antidepressants

PHARMACOLOGY - not fully understood, it has affinity for central D2 receptors and 5-HT1A receptor
as partial agonist

Its major metabolite (1-(2-pyramidinyl)-piperazine) is an 2 -adrenergic receptor antagonist, thus

enhancing norepinephrine release
DOSING

Usual therapeutic dose 20-30 mg/day (10-15 mg bid)

NOT effective on PRN basis
Slow onset of action, may take as long as 2 weeks for anxiolytic effect to occur

PHARMACOKINETIC

Absorption virtually complete

Food may reduce rate of absorption, decrease the extent of the first-pass effect and thus
increase the oral bioavailibility
Highly bound to plasma proteins(95%)
Parent drug metabolized by CYP3A4; metabolite is active and metabolized by 2D6
Clearance reduce in renal and hepatic impairment.

BUSPIRONE is a SELECTIVE anxiolytic, unlike the benzodiazepines

Has no anticonvulsant effect or muscle relaxant properties

Has low potential for abuse
Lack of effect on respiration, making it useful for those with pulmonary disease or sleep
apnea
Minimal effect on cognition, memory or driving
May have preferential effect for symptoms of anxiety, irritability and aggression, but with
little effect on behavioral symptoms

ADVERSE EFFECTS

Headache, dizziness, lightheadedness, nervousness, excitement, fatigue, paresthesia, numbness, GIT

upset

Because of its binding to central dopamine receptors, it potentially increases risk of dystonia,
pseudoparkinsonism

Has been reported to precipitate mania and hypomania primarily in the elderly; high doses may
worsen psychosis

Effect of Buspirone is gradual

Improvement seen in 7-10 days but may take as long as 2-4 weeks
To switch to buspirone, taper benzodiazepines first
Should be taken consistently and not PRN

DISCONTINUATION SYNDROME - withdrawal effects have not been reported

TOXICITY- No death reported

Excessive dose may just produce extension of pharmacologic effects such as dizziness,
nausea, vomiting
 Monitor vital signs and give supportive therapy

PRECAUTIONS

Has no cross-tolerance with benzodiazepines and will not alleviate benzodiazepine

withdrawal
Does not have anticonvulsant activity and not really recommended for those with seizures

PEDIATRIC

Indicated for ADHA, aggressive, autism and to augment SSRIs in OCD

Dizziness, euphoria, increased aggression and psychosis have been reported

Geriatric

Indicated for behavior disturbance of dementia

Dosage should be decreased in those with hepatic or renal problem

PREGNANCY - no adequate data