Transcript Antidepressant Drugs

Antidepressant Drugs
Serotonin
(5-HT)
MOOD
NA
DA
Depression
•  Activity of NE and 5 -HT systems
Classification of Major Affective
Disorders
Major Affective
Disorders
Episodal
Depression
Seasonal
Affective
Disorder
Atypical
Depression
Major/
Endogenous
Depression
Mania
Bipolar
depression
Depression
 feelings
of misery
apathy
 inadequacy
 pessimism
 anxiety
 tension
 Guilt
 Ugliness


Low self –esteem
 Bodily
complaints
 Indecisiveness
 Ioss of motivation
 Retardation of
thought and
action
 Sleep disturbance
• 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.
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, Superman, spiderman.
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:
•
•
•
•
Anxiety.
Sleep.
Sexual behavior.
Temperature regulation.
Blocked by
antidepressant
s
Serotonin receptors

5–HT1

subtypes



5–HT1A, 5–HT1B, 5–HT1D, 5–
HT1E, 5–HT1F
primarily responsible for the
therapeutic (antidepressant)
effects of increased
intrasynaptic serotonin
5–HT2

subtypes


5–HT2A, 5–HT2B, 5–HT2C
primarily responsible for the
toxic effects of increased
intrasynaptic serotonin
Serotonin receptors
• 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
• 2- generation of IP3/DAG
• 3- ligand gated cation channel
Reversible inhibitor of MAO-A (RIMAs)
Moclobemide ,Clorgyline
A
• (Isocarboxacid, phenelzine, tranylcypromine.)
N
T
I
Tricyclic antidepressants (TCAs)
D
E
 NA + 5 HT reuptake inhibitor
Predominantly NA reuptake inhibitor P
Imipramine, Amitriptyline
Desipramine, Nortriptyline
R
Amoxapine, Reboxetine
Trimipramine, Doxepin, Dothiepin,
E
S
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


Mechanism of Action
1. Inhibition of MAO enzymes.
(MAOIs).
A
T
Y
P
I
C
A
L
2. Inhibition of NE and 5-HT reuptake.
(TCAs, SSRIs, Newer TCAs).
3. Prominent alpha blocking and weak 5-HT2 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 uptake
(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
-Peripheral adrenergic
nerve endings
-Intestinal mucosa
-Human placenta
-Liver
-Serotonin , Noradrenalin
and dopamine
-Inhibited by
• MAO-B
-brain ( basal ganglia)
-Platelets
-Liver
-Deaminates dopamine
-Inhibeted by selegiline
(deprenyl)
moclobemide
and clorgyline
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
tyramine and other
indirectly acting amines)
Due to irreversible block of
MAO These escape
degradation in intestinal
wall and liver
• Hypertensive crises,
Reach to circulation Displace
large amount of
noradrenalin from loaded
nerves
CVA
• Medical Emergency
Tt. I.V. Phentolamine, Prazosin
Nonselective MAOIs not favorable
–Cold and Cough medicines contain
Ephedrine
(Same result as cheese reaction)
Reversible inhibitor of MAO-A
(RIMAs)
• 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)
• Imipramine represents the class (Prototype)
• Inhibit monoamine reuptake
(serotonin and noradrenaline)
Serotonin and NA at
• Increase the concentration of
synapse and potentiate the action (therapeutic effects)
• Other receptors acted (Adverse effects)
»Muscarinic- Anticholinergic side effects
(dryness etc.)
»Alpha receptor blocking actions (postural
hypotension etc.)
»Histamine-Antihistaminic (sedation)
»Dopamine- antipsychotic (amoxapine,
maprotiline)
TCAs actions (CNS)
• In Normal person
• In Depressed
-
-Sedation immediately
-Elevation of mood (24Weeks)
-Suppresses REM
-prolongs total sleep
duration
Tiredness
Light-headedness
Sleepiness
Difficulty in thinking
Difficulty in
concentration,
- Gait disturbances
- Provoke anxiety
- Unpleasant
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.
• Signaling via NE or 5-HT increases the
expression of
brain-derived neurotrophic factor (BDNF)
• BDNF- related to the ultimate mechanism of
action of antidepressant drugs
• Increase in BDNF levels
increased neurogenesis in the hippocampus
TCAs Adverse effects
• Anticholinergic- dry mouth, 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 (mianserin)
TCAs (Acute Poisoning)
• Usually suicidal attempt
• Presents as
– Excitement
– delirium
– Anticholinergic
symptoms like
atropine poisoning
– Muscle spasm
– Convulsions
– arrhythmias
– Respiratory
depression
– Coma
• Treatment
–
–
–
–
Gastric lavage
I.V. line
Oxygen
Maintenance of BP
and Temperature
– Diazepam iv
– Propranolol /
lignocaine
Miscellaneous
• Amoxapine
– Blocks D2 +
inhibition of NA
reuptake
– Has mixed
antidepressant
and neuroleptic
effects
– Good for
psychotic
depression
• Reboxetine
• Selective NA
reuptake
blocker
• Weak action on
5-HT
mechanism
• Anticholinergic
effects are
minimal
Selective Serotonin Reuptake Inhibitors (SSRIs)
• Limitations of TCAs
–
–
–
–
–
–
–
–
–
–
• Answers may be given by SSRIs
Anticholinergic effects
• Selectively inhibit SERT (serotonin
transporter)
Alpha blocking action
• More tolerability and better
Cardio toxicity
acceptability
Sedation, seizures ppt
• Used in depression as well as in OCD,
phobias
Low safety margin
• No sedation, No seizure ppt
Weight gain
• No alpha blocking action
Therapeutic window
• Less chances of arrhythmia
Overdose poisoning
• No weight gain
common
• Now 1st choice for OCD, Panic disorders,
Social Phobia, Eating disorders,
Lag of 1 month period
Premenstrual syndrome, Post traumatic
Incomplete response to
stress
Tt
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
• Fluoxetine
– Prototype of SSRIs
– Longest acting
• Paroxetine
• Short acting
• More GI side effects
Citalopram
•Similar to sertraline but should be avoided
in patients attempting suicide
• Fluvoxamine
– Short acting
– Commonly used in
indoor patients
• Sertraline
• Less chances of drug
interactions due to
low potency to cause
cytochrome enzyme
depression
SSRIs
• Side effects
• Gastric upset
• Nausea
• Interfere with
ejaculation
• Nervousness
• Restlessness
• Insomnia
• Anorexia
• Headache
• Diarrhea
• Epistaxis
• Ecchymosis
• Others
• 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
• Mianserin
– Blocks 5-HT uptake
– Has prominenent alpha
blocking
– potent 5-HT2 antagonist
– No anticholinergic effect
– Bradycardia
– Has anxiolytic action also
– Prolonged and painful
penile erection (priapism)
– Unique not inhibit NA and 5-HT
uptake
– 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
inhibiting 5-HT uptake
– Neither sedative nor
stimulant
– Effective in anxiodepressive
states
• Mirtazapine (NaSSA)
– 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.
• Duloxetine
– Duloxetine increases
uretheral tone, used in
urinary incontinence ( over
active bladder)
– Used in panic attacks,
diabetic neuropathic pain
• Bupropion
– Inhibits DA and NA
uptake has excitant
effect
– Used to reduce smoking
Antidepressant uses
• 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
• Anxiety disorders
• Neuropathic pain
• Attention deficit hyperactivity disorder in
children
• Enuresis- (Imipramine 25mg at night)
• Overactive bladder (stress incontinence)Duloxetine
• Migraine prophylaxis (Amitriptyline)
• Pruritus (Topical doxepin)
Mania and MDI
Treatment
• Lithium
• Carbamazepine
• Sodium Valproate
• Lamotrigine
• Topiramate
• Gabapentin
• Olanzapine, aripiprazole, quetiapine
Lithium
inhibition of
inositol
monophosphatase
decreased
cerebral inositol
concentrations
suppresses
inositol signaling
inhibits glycogen
synthase kinase-3
(GSK-3), a
multifunctional
protein kinase.
GSK-3 is a
component of
diverse intracellular
signaling pathways.
Dec NA and DA, Without affecting 5-HT release
S/E of Lithium
•
•
•
•
•
Tremors
seizures
Diabetes incipidus
Goiter, Hypothyroidism
C/I during pregnancy- may cause congenital abnormalities
(cardiac)
• TDM is required
(maintained level 0.5 - 0.8mEq/L)
Toxicity appears when serum level exceeds 1.5 mEq/L
MCQs
Q1. Monitoring of serum lithium concentration
is done because of:
A. Low therapeutic efficacy
B. Adverse effects
C. Long half-life
D. Very low therapeutic index
Ans- D. Very low therapeutic index
Q2. Long term use of lithium causes:
A. Peripheral neuropathy
B. Hypothyroidism
C. Anemia
D. Jaundice
Ans- B
Q3. Most common congenital anomaly
associated with lithium is:
A. Cardiac malformations
B. Neural tube defects
C. Renal anomaly
D. Fetal hydantoin syndrome
Ans- A
Q4. Antidepressant, which is also useful in the
treatment of neuropathic pain and migraine
is
A. Amitriptyline
B. Amoxapine
C. Reboxetine
D. Sertraline
Ans- A
Q5. Which of the following antidepressant drug
can also be used for treatment of anxiety,
panic disorder, obsessive compulsive disorder
and posttraumatic stress disorder?
A. Bupropion
B. sertraline
C. reboxetine
D. Moclobemide
Ans- B
Q6. Antidepressants are not recommended as
monotherapy for bipolar illness because of
A. ineffectiveness
B. electroconvulsive therapy is the modality of
choice in such patients
C. weight gain
D. the "switch" from a depressed episode to a
manic or hypomanic episode
Ans- D
Q7. Electroconvulsive therapy (ECT) is treatment of
choice for agitated, depressed patients with a
high risk of suicide because
A. ADRs are common due to antidepressant drugs
B. antidepressant drugs are not effective
C. antidepressant drugs takes 3-4 weeks before a
measurable therapeutic response becomes
evident
D. antidepressant drugs are not palatable
Ans- C
Bibliography
• Essentials of Medical Pharmacology -7th edition by KD Tripathi
• Goodman & Gilman's the Pharmacological Basis of Therapeutics 12th
edition by Laurence Brunton (Editor)
• Lippincott's Illustrated Reviews: Pharmacology - 6th edition by Richard A.
Harvey
• Basic and Clinical pharmacology 11th edition by Bertram G Katzung
• Rang & Dale's Pharmacology -7th edition
by Humphrey P. Rang
• Clinical Pharmacology 11th edition By Bennett and Brown, Churchill
Livingstone
• Principles of Pharmacology 2nd edition by HL Sharma and KK Sharma
• Review of Pharmacology by Gobind Sparsh
Thanks