Transcript Antidepressant, Anti-anxiety Drugs

Antidepressant, Anti-anxiety Drugs
Dr. R. K. Dixit
Professor
Pharmacology and Therapeutics
C. S. M. Medical University Lucknow, 226003
Classification of Major Affective Disorders
Major Affective
Disorders
Episodal
Depression
Seasonal
Affective
Disorder
Atypical
Depression
Major/
Endogenous
Depression
Mania
Bipolar
depression
Episodal (reactive) Depression
Adverse
life events.
Physical illness.
Drugs.
Other psychiatric disorders.
Reactive (episodal) Depression
 More
than 60% of all depressions.
 Core depressive syndrome: feelings of misery,
apathy, inadequacy, pessimism, anxiety, tension,
guilt. Ugliness, Low self –esteem,
 Bodily complaints


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Withdrawn.
Loss of interest in pleasurable activities.
Indecisiveness, loss of motivation.
Retardation of thought and action.
Sleep disturbance
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In severe cases, it is accompanied by
hallucinations and delusions.
Recurrent suicidal ideation, a suicide attempt or
a specific suicide plan.
•significant weight change (without dieting )
•Psychomotor agitation or retardation.
1. Has a genetic component.
2. Depression can be drug-induced.
3. Depression can be drug-repressed.
4. Depression can be treated with drugs.
5. Depression can be treated with
Electroconvulsive Therapy (ECT).
Mania
Mania alone is rare (10%) and most frequently cycles with
Major/endogenous depression
(Manic-Depressive Disease, Bipolar Disorder).
Core Symptoms:
Characterized by an elevated “high” mood.
Talkative, go on-and-on about the things they will do.
Increased self-esteem.
Auditory hallucinations.
Decrease need to sleep. Expensiveness, unnecessary
buying.
Lack judgment, Supermen
 The
precise cause of affective disorders remains
elusive.
 Evidence implicates alterations in the firing
patterns of a subset of biogenic amines in the
CNS,
Norepinephrine (NE) and Serotonin (5-HT).
 Activity of NE and 5 -HT systems?.
Almost all NE pathways in the brain originate from the cell
bodies of neuronal cells in the locus coereleus in the
midbrain, which send their axons diffusely to the cortex,
cerebellum and limbic areas
(hippocampus, amygdala, hypothalamus, thalamus).
 Mood: -- higher functions performed by the cortex.
 Cognitive
function: -- function of cortex.
 Drive and motivation: -- function of brainstem
 Memory and emotion: -- function of the hippocampus and
amygdala.
 Endocrine
response: -- function of hypothalamus.
Serotonin System
As with the NE system, serotonin neurons located in
the pons and midbrain
(in groups known as raphe nuclei)
send their projections diffusely to the cortex,
hippocampus, amygdala, hypothalamus, thalamus,
etc. --same areas implicated in depression.
This system is also involved in:
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•
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Anxiety.
Sleep.
Sexual behavior.
Temperature regulation.
CSF production.
Blocked by
Blocked
antidepressants
by antidepressants
Serotonin receptors
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5–HT1
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subtypes
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5–HT1A, 5–HT1B, 5–HT1D, 5–HT1E,
5–HT1F
primarily responsible for the
therapeutic (antidepressant) effects
of increased intrasynaptic serotonin
5–HT2
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subtypes
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5–HT2A, 5–HT2B, 5–HT2C
primarily responsible for the toxic
effects of increased intrasynaptic
serotonin
Serotonin receptors
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Over all 14 types divided in to 1, 2, 3, and 4-7
family
All are G-protein coupled receptors except 3
1- decreases cAMP while 4-7 increase
3- ligand gated cation channel
Alternative Therapies
No way of a priori knowing which therapy will be
best for a patient.
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Light Therapy
Psychological Treatment
ECT (patients with suicidal tendency and for quick action)
St. John’s Wort (Plant)
Antidepressants
 TCAs
SSRIs
TCAs
MAOIs
MAOIs
TCAs
MAOIs
maprotiline
MAOIs
MAOIs SSRIs
Venflaxine
MAOIs
Reversible inhibitor of MAO-A (RIMAs)
•CM
Moclobemide ,Clorgyline
A
•RITA-Don't- Copy

(Isocarboxacid, phenelzine, tranylcypromine.)
N
T
•Exams-For-PCS
•MAD-Boy-turned-violent I
Tricyclic antideprssants
D
(TCAs)
E
 NA + 5 HT reuptake inhibitor Predominantly NA reuptake inhibitor
P
Imipramine, Amitriptyline
Desipramine, Nortriptyline
R
Amoxapine, Reboxetine
Trimipramine, Doxepin
E
S
Dothiepin, Clomipramine
S
A
N
T
Selective serotonin reuptake
Atypical antidepressants
S
inhibitors (SSRIs)
Trazodone, Mianserine
Fluoxetine, Fluvoxamine
Mirtazapine, Venlafaxine
Duloxetine,Tianeptine
Paroxetine, Sertraline
Amineptine, Bupropion
Citalopram, Escitalopram
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Mechanism of Action
1. Inhibition
of MAO enzymes.
(MAOIs).
2. Inhibition of NE and 5-HT reuptake.
(TCAs, SSRIs, Newer TCAs).
A
T
Y
P
I
C
A
L
3. Prominent alpha blocking and weak 5-HT antagonists.
(Nefazodone, trazodone,)
4. Serotonin and noradrenalin reuptake inhibitor (SNRIs)
(venlafaxine, duloxetine)
5. Noradrenergic and specific serotonergic antidepressants (NaSSA)
(Mirtazapine)
6. Inhibitor of Dopamine and Noradrenalin
(Bupropion)
7. Blockade of pre-synaptic alpha 2 receptors
(Mianserin)
8. Increases rather than inhibiting 5-HT uptake
(Tianeptine, Amineptine)
MAO ( monoamine oxidase) an enzyme
Two types
 MAO
–A
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-Peripheral adrenergic nerve
endings
-Intestinal mucosa
-Human placenta
-Liver
-Serotonin , Noradrenalin
and dopamine
-Inhibited by
MAO-B
A-B
moclobemide
and clorgyline
-brain ( basal ganglia)
-Platelets
-Liver
-Deaminates dopamine
-Inhibeted by selegiline
(deprenyl)
C-D
Isoniazide, iproniazide, phenelzine, isocarboxazide,tranylcypromine were non selective and
irreversible inhibitors (Hit and run drugs) used previously but not used now due to drug
drug and drug food interactions. Linezolide (new drug against MRSA) Cheese and
serotonin syndrome
Nonselective MAOIs not favorable Cheese Reaction
Cheese, beer, wine,
meat, fish, yeast,
(contain large amount of
tyrammine and other
indirectly acting amines)

Hypertensive crises,
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CVA
Medical Emergency
Due to irreversible block of
MAO These escape
degradation in intestinal wall
and liver
Reach to circulation Displace
large amount of noradrenalin
from loaded nerves
Tt. I.V. Phentolamine, Prazosin
Nonselective MAOIs not favorable
 Cold
and Cough medicines contain
Ephedrine
(Same result as cheese reaction)
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Levodopa- excitement and hypertension
Tricyclic antidepressants- excitement, rise in BP,
temperature
Reversible inhibitor of MAO-A
(RIMAs)
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Moclobemide Reversible and selective MAO-A inhibitor
 Short duration of action
 Competitive enzyme inhibition
 Tyramine is able to displace it
 Cheese reaction is less likely
 Devoid of anticholenergic, sedative,
cognitive, cardiovascular effects
 Good for elderly with heart diseases
Tricyclic Antidepressants (TCAs)
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Imipramine represents the class (Prototype)
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Inhibit monoamine reuptake
(serotonin and noradrenalin)
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Increase the concentration of
synapse and potentiate the action (therapeutic effects)
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Other receptors acted (Adverse effects)
 Muscarinic- Anticholinergic side effects
(dryness etc.) #
 Alpha- alpha blocking actions (postural
hypotension etc.) #
 Histamine-Antihistaminic (sedation) #
Serotonin and NA at
 Dopamine-
antipsychotic (amoxapine,
maprotiline)
TCAs actions (CNS)
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In Normal person
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Tiredness
Light-headedness
Sleepiness
Difficulty in thinking
Difficulty in concentration,
Gait disturbances
Provoke anxiety
Unpleasant
-Sedation immediately
-Elevation of mood (2-4Weeks)
-Suppresses REM prolongs total
sleep duration
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In Depressed
Lower seizure threshold and produce convulsions in overdose
Don’t carry abuse potential, Development of dependence is less
TCAs uptake blockade
is not directly responsible for antidepressant action?
 Uptake blockade occurs quickly but antidepressant
action occurs after months
 Initially
Pre synaptic alpha 2 and 5-HT1 auto receptors are
activated by increased amount of NA and Serotonin in
synaptic cleft resulting in decreased firing

But on long term
desensitize and down regulation of these receptors and
induce adaptive changes in the number and sensitivity of
receptors and amine turnover leading to enhanced NA and
Serotonin transmission required for antidepressant action.
TCAs on other systems
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ANS
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CVS
Potent anticholinergic
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(dry mouth, blurring of
vision,, constipation,
urinary hesitancy)
 Weak alpha 1 blocking
(postural hypotension,
impairment of ejaculation,)
 H1 antihistaminic
(sedation)
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Tachycardia
Postural hypotension
Cardiac arrhythmias
(T wave suppression or
inversion) due to intra
ventricular conduction
interference due to NA
and Anti cholinergic
actions
Tolerance to Anticholinergic and
hypotensive actions develop latter on
TCAs (Pharmacokinetics)
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Good oral absorption
Highly bound to Proteins (plasma and tissue)
Metabolized in liver (oxidation, glucuronide
conjugation and CYP2D6, CYP3A4, CYP1A2
Many active metabolites may be produced
Mostly can be given once a day (at bed)
Have Therapeutic Window phenomenon
(50-200ng/ml of imipramin)
TCAs Adverse effects
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Anticholinergic- dry moth, bad taste, constipation,
epigastric fullness, urinary retention (more common in
elderly male), blurred vision, palpitation
Sedation, mental confusion, weakness
Increased appetite and weight
Sweating, fine tremors
Precipitation of seizures
Postural hypotension
Cardiac arrhythmias
Rashes and jaundice
TCAs (Acute Poisoning)


Usually suicidal attempt
Presents as
Excitement
 delirium,
 Anticholinergic
symptoms like
atropine poisoning
 Muscle spasm
 Convulsions
 Respiratory
depression
 Coma
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Treatment
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Gastric lavage
I.V. line
Oxygen
Maintenance of BP and
Temperature
Diazepam iv
Propranolol / lignocain
TCAs (Interactions)
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Potentiation of sympathomimetics (direct acting)
Reduce action of sympathomimetics (indirect acting)
Reduce antihypertensive action of guanethidine and
clonidine ( by preventing their transport in to neurons)
Potentiate other CNS sedatives
SSRIs inhibit metabolism of TCAs
With MAO inhibitors dangerous hypertensive crisis with
excitement and hallucinations
Retard the absorption of other drugs
Phenytoin, phenylbutazone, chlorpromazine, aspirin, displace
TCAs and produce toxicity
Phenobarbitone induce metabolism and inhibit the effect of
the drug
Miscellaneous
 Amoxapine
Tetra cyclic
compound
 Blocks D2 reuptake
also
 Has mixed
antidepressant and
neuroleptic effects
 Good for psychotic
depression

 Reboxetine
 Selective
NA
reuptake blocker
 Weak action on 5HT mechanism
 Anticholinergic
effects are
minimal
Selective Serotonin Reuptake Inhibitors
(SSRIs)

Limitations of TCAs
 Anticholinergic effects
 Alpha blocking action
 Cardio toxicity
 Sedation, seizures ppt
 Low safety margin
 Weight gain
 Therapeutic window
 Overdose poisoning
common
 Lag of 1 month period
 Incomplete response to
Tt
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Answers may be given by SSRIs
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Selectively inhibit membrane associated
SERT (serotonin transporter)
More tolerability and better acceptability
Used in depression as well as in OCD,
phobias
No sedation, No seizure ppt
No alpha blocking action
Less chances of arrhythmia
No weight gain
Now 1st choice for OCD, Panic disorders,
Social Phobia, Eating disorders,
Premenstrual syndrome, Post traumatic
stress
Important points
TCAs have slightly more efficacy
Some patients not responding to TCAs
may respond to SSRIs,
SSRIs preferred in prophylaxis of recurrent
depression
In severe depression TCAs appear to be
more efficacious
Individual compounds
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Fluoxetine
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Prototype of SSRIs
Longest acting
Paroxetine
Short acting
 More GI side effects
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Fluvoxamine
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Short acting
Commonly used in
indoor patients
Sertraline

Less chances of drug
interactions due to low
potency to cause
cytochrome enzyme
depression
Citalopram
Escitalopram
•Similar to sertraline but should be
avoided in patients attempting
suicide
•Active enantiomer of
citalopram side effects are less
SSRIs

Side effects
Gastric upset
 Nausea
 Interfere with
ejaculation
 Nervousness
 Restlessness
 Insomnia
 Anorexia
 Headache
 Diarrhea
 Epistaxis
 Ecchymosis
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Others
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Inhibit cytochrome
enzymes and elevate the
plasma level of other drugs
Other serotonergic drug
( MAOIs) is taken may
precipitate Serotonin
Syndrome manifesting as
agitation, restlessness,
sweating, twitching,
convulsions
Atypical Antidepressants
 Trazodone
Blocks 5-HT uptake
 Has prominenent alpha
blocking
 Weak 5-HT2 antagonistic
 No anticholinergic effect
 Bradycardia
 Has anxiolytic action also
 Prolonged and painful
penile erection
(priaprism)

 Mianserin
 Unique not inhibit NA
and 5-HT uptake
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Blocks pre-synaptic alpha
2 receptors increases
release and turnover of
NA
Antagonist at serotonin 2,
1c, and H1 receptors
Has sedative effect
Damages liver and bone
marrow (Reserve drug)
Atypical Antidepressants

Tianeptine / and
Amineptine
 Increases rather
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
inhibiting 5-HT uptake
Neither sedative nor stimulant
Effective in anxiodepressive
states

Venlafaxine / Duloxetine
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Mirtazapine (NaSSA)
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Noradrenergic and specific
serotonergic antidepressant
Blocks alpha 2 auto receptor
(on NA neuron) and hetero(on 5-HT neuron) receptors
increasing both NA and
serotonin release.

SNRI selective in action
Faster onset of action
Increases BP
Duloxetine increases
uretheral tone used in urinary
incontinence ( over active
bladder)
Bupropion
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Inhibits DA and NA
uptake has excitant effect
Used to reduce smoking
Antidepressant uses
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Depression (ECT may be needed in severely
depressed and patients having suicidal tendency)
Bipolar affective disorders TCAs and lithium or
SSRIs with lithium or valporate/ lamotrigine
SSRIs with atypical antipsychotic in psychotic
depression
Obsessive compulsive disorders (SSRI and
Clomipramine)
Eating disorders
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Anxiety disorders
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Neuropathic pain
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Attention deficit hyperactivity disorder in
children
Enuresis- (Imipramine 25mg at night)
Overactive bladder (stress incontinence)
Migraine prophylaxis
Pruritus (Topical doxepin)
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Antianxiety Drugs
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Anxiety -
emotional state
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Unpleasant
Associated with uneasiness
Discomfort
Fear
Undefined threat
Fear about future
Some amount of anxiety is must for progress
When it becomes excessive, disproportionate, hampers performance
then only
needs treatment
Antianxiety Drugs
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Drugs producing restful state of mind without
interfering with normal mental or physical functions.
Have no effect on thought control
Don’t produce extra pyramidal side effects
Can Produce physical dependence
May Have abuse potential
Don’t selectively block conditioned avoidance response
in animals
 Have
anticonvulsant activity
Antianxiety Drugs
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Benzodiazepine
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Diazepam
Chlordiazepoxide
Oxazepam
Lorazepam
Alprazolam
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Azapirones
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Others
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PHO/BIG/DOCLA
Buspirone
Gepirone
Ispapirone
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Beta blocker- Propranolol
AntihistaminicsHydroxyzine
SSRIs and other
antidepressant drugs
Benzodiazepines
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Relieve anxiety at low dose ( higher dose induce sleep
and impair performance )
Selective taming effect
More selective to limbic system
Have low side effects in Antianxiety dose
Lorazapam and clonazepam IM for psychotic and
manic patients
Act by
facilitating GABAergic transmission
Benzodiazepine MOA
Cl
α subunit
Diazepam +
DMCM –
Flumazenil- 0
Extra-tracellular
Others
δεθπ
γ subunit
Barbiturates
Intracellular
GABA β subunit
GABA- A
Receptor
Cl
More Clintracellular
more polarized
more refractory
Benzodiazepines

Adverse effects
Sedation
 Light headedness
 Psychomotor impairment
 Cognitive impairment
 Vertigo
 Confusional state
 Increased weight
 Impaired sexual functions
 Potential to produce dependence
 All are almost similar selection is empirical
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Benzodiazepines (Individual drugs)
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Chlordiazepoxide
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First BZD
Long lasting effect
Chronic anxiety
Oxazepam
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Diazepam
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Has two phase of metabolism
Broken in to active metabolites
Long duration of action
Lorazepam
Polar compound
 Less lipid soluble
Penetration In brain is slow
 Slow entry in brain
No active metabolite
 No active metabolite
Used in short lasting anxiety
 IM
state
Alprazolam-
high potency, mood elevating in depressed pt. less drowsiness
Buspirone
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Does not produce sedation, cognitive
impairment,
Does not interact with BZD receptor or modify
GABAergic transmission
No tolerance
No physical dependence
No muscle relaxant
No anticonvulsant property
Buspirone
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Relieves mild to moderate generalized anxiety
Effects develop slowly (not used for acute)

Partial agonist on 5HT1A (pre-synaptic) and
antagonist on 5HT postsynaptic receptors

Presynaptic auto-receptors stimulated leading to
reduced activity of dorsal raphe serotonergic
neurones
Also has weak D2 blocking effect
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Hydroxazine
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H1 antihistaminic
Sedative, anti -emetic and
spasmolytic
Anti - Pruritus

Propranolol
Reduces sympathetic
symptoms like rise in BP,
Tremors, sweating etc.
 Performance or
situational anxiety
(like examination fear, social
phobia, public lecture)

Questions
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Classify antipsychotic drugs
Classify antidepressant drugs
Pharmacological actions of chlorpromazine
Pharmacological actions of amitriptyline
Drug indued parkinsonism
MOA of antipsychotic
MOA of antidepressants
Lithium
Questions
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Drug of choice of cheese reaction-Phentolamine
Moclobemide is reversible and selective MAO-A inhibitor
All antidepressants don’t inhibit DA uptake except amoxapine, maprotiline, Bupropion
Antidepressants don’t carry abuse potential
SSRIs are inhibitor of CYP enzymes
Serotonin syndrome
Trazodone – may produce priaprism due to high α1 blocking property
Mianserin unique not inhibiting NA or 5HT but blocks Pre-synaptic α2 receptors
Tianeptine, Amineptine - unique increase 5-HT uptake
Venlafaxine, Duloxetine – SNRI
Mirtazapine- NaSSA- blocks α2 auto and hetro receptors and enhance NA and 5HT
release
Nocturnal enuresis- Imipramine
Benzodiazepines- GABA facilitatory
Buspirone- partial agonist at 5HT1A autoreceptors,antagonist at 5HT1A postsynaptic
DOC of performance or situational anxiety- B-blockers
Thanks