pharmacotherapy of anxiety
TRANSCRIPT
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.
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