PHARMACOTHERAPY OF ANXIETY

JAYANT KUMAR PATWA PHARMACOLOGY AND TOXICOLOGY

2nd SEMESTER15PCM2167

NIPER MOHALI

CONTENT1. TERMINOLOGY2. ANXIETY DISORDERS AS

RECOGNIZED CLINICALLY INCLUDE

3. CAUSE OF ANXIETY4. CLASSIFICATION OF

ANXIOLYTIC DRUGS5. NEWER DRUG 6. DISCRIPTION OF

PARTICULAR DRUG7. SCREENING METHOD FOR

ANXIOLYTICS

TERMINOLOGY

DEFINITIONA feeling of worry, nervousness, or

unease about something with an uncertain

outcome.

Anxiety can be either a short term "state" or a long

term "trait". Whereas trait

anxiety is a worry about future

events,

ANXIOLYTIC DRUG:- Drug

used for treatment of anxiety

ANXIETY DISORDERS AS RECOGNIZED CLINICALLY INCLUDE

GENERALISED ANXIETY DISORDER:- An ongoing state ofexcessive anxiety lacking any clear reason or focus

PANIC DISODER:-Sudden attacks of overwhelming fear occur in association with marked somatic symptoms, such as sweating, tachycardia, chest pains, trembling and choking

PHOBIAS:-Strong fears of specific objects or situations,e.g. snakes, open spaces, flying

POST-TRAUMATIC STRESS DISORDER (PTSD):-anxiety triggered by recall of past stressful experiences

OBSESSIVE-COMPULSIVE DISORDER (OCD):-compulsive ritualistic behaviour driven by irrational anxiety, e.g. fear ofcontamination

CAUSE

Neural circuitry Amygdala (which regulates emotions like anxiety and fear, stimulating the HPA Axis and sympathetic nervous system)

Hippocampus(which is implicated in emotional memory along with the amygdala) is thought to underlie anxiety

Genetics and family history (e.g., parental anxiety) may predispose an individual for an increased risk of an anxiety disorder, but generally external stimuli will trigger its onset

Biological vulnerabilities

Genetics/Neurochemistry/Endocrinology

Genetics accounts for about 43% variance in panic disorder and 28% in generalized anxiety disorder

Anxiety GENES : PLXNA2, SERT, CRH, COMT and BDNF. Genes influence neurotransmitters (such as serotonin and norepinephrine)Hormones (such as cortisol) which are implicated in anxiety. The epigenetic signature of at least one of these genes BDNF has also been associated with anxiety and specific patterns of neural activity

Anxiety can be a symptom of underlying health problemssuch as asthma or chronic obstructive pulmonary disease (COPD), heart disease (heart attack, heart failure or arrhythmia), sleep apnea, chronic pain, parkinson's disease, multiple sclerosis, cancer, diabetes, and stroke

Due to Medical Conditions

Contd......

Poor coping skills (e.g., rigidity/inflexible problem solving, denial, avoidance, impulsivity, extreme self-expectation, affective instability, and inability to focus on problems) are associated with anxiety

PSYCHOLOGY

Contd......

Substance induce anxiety

Several drugs of abuse can cause or exacerbate anxietywhether in intoxication, withdrawal, and from chronic use. These include alcohol, tobacco, cannabis, sedatives (including prescription benzodiazepines), opioids (including prescription pain killers and illicit drugs like heroin), stimulants (such as caffeine, cocaine and amphetamines), hallucinogens, and inhalants

CLASSIFICATION OF ANXIOLYTIC DRUGS

1 •Benzodiazepines ( BDZ )

2 •5HT1A agonists

3 •5HT reuptake inhibitors

4 •Antidepressants

5 • Beta-adrenergic blockers

6 •MAO inhibitors

Drug Clinical t. MOA

Aloradine (PH94B)

 B-GOS

 IW-2143 (BNC210)

S32212

SL-651,498

Phase III

Phase I

 Phase I 

under investigation

preliminary human trials

“nasal chemosensory

neurons”

waking cortisol levels

no information

i.a. 5-HT2C and alpha2 adr antagonist

Similar with bzds

New Anxiety Medications In Development (2015)

COMPANY

Pherins

Clasado Biosciences

Ironwood Pharmaceutical

s

  Aloradine is a clear-cut favorite to get FDA approval simply because it is already in Phase III clinical trials

Aloradine (PH94B)

Phase III clinical trials since 2013 Aloradine is administered via nasal spray  directly target peripheral receptors from “nasal

chemosensory neurons”  linked to the hypothalamus/limbic system of the

brain treatment of social anxiety disorder in women  still not sure why the product is tailored specifically

for women with anxiety thus far it has been found to be both safe and very

tolerable.

Benzodiazepines act by binding to BZ receptors In the brain

Chloride channels opening

Enhance GABA action on brain

Chloride influx to the cell

Hyper- polarization

MECHANISM OF ACTION

DRUG INTERACTIONS

Examples

CNS depressants Alcohol & Antihistaminics effect of benzodiazepines

Cytochrome P450 (CYT P450) inhibitors

Cimetidine & Erythromycint ½ of benzodiazepines

CYT P450 inducers Phenytoin & Rifampicint 1/2 of benzodiazepines

Ataxia (loss of full control of body) Cognitive impairment Hangover: (drowsiness, confusion) Tolerance & dependence Risk of withdrawal symptomsRebound Insomnia, anorexia, anxiety, agitation, tremors and convulsion Toxic effects: respiratory & cardiovascular depression in large doses

ADVERSE EFFECTS OF BZDS

5HT1A AGONISTS

BUSPIRONE

Acts as agonist at brain 5ht1a receptors

Rapidly absorbed orally.

Slow onset of action (delayed effect)

T½ : (2 – 4 h).

Liver dysfunction its clearance.

Drug interactions with cyt p450 inducers and inhibitors.

5HT1A AGONISTS

BETA BLOCKERS

Drug – Propranolol, Atenolol

Act by blocking peripheral sympathetic system.

Reduce somatic symptoms of anxiety

Decrease BP & slow HR

Used in social phobia

Are less effective for other forms of anxiety

TRICYCLIC ANTIDEPRESSANTS

DRUG- Doxepin - Imipramine

Act by reducing uptake of 5HT & NA.

Used for anxiety especially associated with depression

Effective for panic attacks

Delayed onset of action (weeks)

Dry mouth, postural hypotension, sexual dysfunction, weight gain

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIS)

DRUG- Fluoxetine

Acts by blocking uptake of 5HT

Orally

Delayed onset of action (weeks).

Used for panic disorder – ocd depression-Generalized anxiety

disorders - phobia.

Side effects : Weight gain, sexual dysfunction, dry mouth

MONOAMINE OXIDASE INHIBITORS

DRUG -:Phenelzine Acts by blocking the action of MAO enzymes. Used for panic attacks and phobia. Require dietary restriction Avoid wine, beer, fermented foods as old cheese that contain

tyramine. Side effects Dry mouth, constipation, diarrhea, restlessness,

Dizziness.

SCREENING METHOD FOR ANXIOLYTICS

IN VITRO METHODS

GABAA receptor binding

GABAB receptor binding

Benzodiazepine receptor: [3H]-flunitrazepam binding

assay

Serotonin (5-HTIA) receptor: binding of [ 3H]-8-hydroxy-2-

(di-n-propylamino)-tetralin ([3H]-DPAT)

Serotonin (5-HTIB) receptors in brain: binding of [3H]5-

hydroxytryptamine (3[H]5-HT)

Methods based on unconditioned (spontaneous) response:

Exploratory activity

elevated plus-maze

light-dark model (two compartment box)

Social behaviour

social interaction

Isolation induced aggression

IN VIVO METHODS

Methods based on conditioned (learned) response: Conflict models

Vogel punished drinking/ Vogel’s lick conflict model

Normal (adaptive) anxiety Elevated plus-maze test Social interaction Light-dark model Marble burying test

Contd......

Stress-induced anxiety Vogel lick conflict test

Pathological anxiety Neurochemically - induced anxiety

mCPP induced anxiety in rats [meta-Chlorophenylpiperazine]

Contd......

ELEVATED PLUS MAZE TEST

o Most widely used method; male mice used.

o For selective identification of anxiolytic and anxiogenic drugs

o Anxiolytics –decrease anxiety – increase open arm exploration time

o Anxiogenics – decrease open arm exploration time.

ELEVATED PLUS MAZE

o 2 open arms and 2 closed arms of 50 ˣ 10 ˣ 40cm dimensions

o Open roof arrangement

o Two open arms are opposite to each other.

o Maze elevated at 50cm height.

EXPERIMENTAL DESIGN

Group I : control Group II : standard Group III : test treated with dose x Group IV : test treated with dose 2x ….

The rats weighing around 200g - housed in pairs for 10 days prior to testing; 6animals selected for each group

Test drug administered 30min prior to experimentation by i.p route.

The rat is then placed in the centre of the maze facing one of the enclosed arms.

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Parameters Measured During Next 5 minutes:

time spent in the open arms

entries into the open arms

time spent in the closed arms

entries into the closed arms

total arm entries

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Anxiolytic effect indicated by:

o increase in the proportion of time spent in open arms i.e.,

time in open arms/total time in open or closed arms

o increase in the proportion of entries into open arms i.e.,

entries into open arms/total entries into open or closed arms.

Evaluation of results:

o Motor activity and open arm exploratory activity determined.

o Values of treated groups expressed as % of control values.

o Benzodiazepines and valproate – decrease motor activity and increase exploratory time.

thank you