This document discusses anxiety disorders and methods for screening anxiolytic drugs. It defines anxiety and lists some common clinically recognized anxiety disorders. The causes of anxiety are described including neural circuits in the brain, genetics, medical conditions, substance use, and poor coping skills. Methods for screening potential anxiolytic drugs are outlined, including binding assays, tests based on unconditioned and conditioned responses in animals, and the elevated plus maze test in rats. The elevated plus maze test procedure and parameters measured are detailed.

1. JAYANT KUMAR PATWA
PHARMACOLOGY AND TOXICOLOGY
2nd SEMESTER
15PCM2167
NIPER MOHALI

2. CONTENT
1. TERMINOLOGY
2. ANXIETY DISORDERS AS
RECOGNIZED CLINICALLY
INCLUDE
3. CAUSE OF ANXIETY
4. CLASSIFICATION OF
ANXIOLYTIC DRUGS
5. NEWER DRUG
6. DISCRIPTION OF
PARTICULAR DRUG
7. SCREENING METHOD FOR
ANXIOLYTICS

3. DEFINITION
A 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

4. ANXIETY DISORDERS AS RECOGNIZED CLINICALLY
INCLUDE
GENERALISED ANXIETY DISORDER:- An ongoing state of
excessive 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 of
contamination

5. CAUSE
Neural circuitry Amygdala (which regulates emotions like anxiety and fear, stimulating
the HPAAxis 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

6. 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 problems
such 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......

7. 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 anxiety
whether 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

8. CLASSIFICATION OF ANXIOLYTIC DRUGS
1 •Benzodiazepines ( BDZ )
2 •5HT1A agonists
3
•5HT reuptake inhibitors
4 •Antidepressants
5 • Beta-adrenergic blockers
6 •MAO inhibitors

9. 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
Pharmaceuticals
Aloradine is a clear-cut favorite to get FDA approval simply because it is already in
Phase III clinical trials

10. 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.

11. 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

13. Examples
CNS depressants Alcohol & Antihistaminics
effect of benzodiazepines
Cytochrome P450
(CYT P450) inhibitors
Cimetidine & Erythromycin
t ½ of benzodiazepines
CYT P450 inducers Phenytoin & Rifampicin
t 1/2 of benzodiazepines

14.  Ataxia (loss of full control of body)
 Cognitive impairment
 Hangover: (drowsiness, confusion)
 Tolerance & dependence
 Risk of withdrawal symptoms
Rebound Insomnia, anorexia, anxiety, agitation, tremors and convulsion
Toxic effects: respiratory & cardiovascular depression in large doses
ADVERSE EFFECTS OF BZDS

15. 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.

17. 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

18. 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

19. 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

20.  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.

21. SCREENING
METHOD FOR
ANXIOLYTICS

22. 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)

23.  Methods based on unconditioned (spontaneous) response:
 Exploratory activity
elevated plus-maze
light-dark model (two compartment box)
 Social behaviour
social interaction
Isolation induced aggression

24.  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......

25.  Stress-induced anxiety
 Vogel lick conflict test
 Pathological anxiety
 Neurochemically - induced anxiety
 mCPP induced anxiety in rats
 [meta-Chlorophenylpiperazine]
Contd......

26. 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.

27. 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.

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

29. 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.
29

30.  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
30

31.  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.

32.  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.