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Antidepressant drugs
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Major depressive disorders characterized by pervasive mood altering illnesses affecting energy, sleep, appetite, libido and the ability to function.Depression is different from schizophrenia which produces disturbances in thought.
The symptoms of depression are:intense feelings of sadness;hopelessness;despair;the inability to experience pleasure in usual activities.
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The amine theory proposes that depression is due to a deficiency of monoamines such as NA and serotonin (5HT) at certain key sites in the brain.All antidepressant drugs (also called thymoleptics) potentiate, either directly or indirectly, the actions of NA, dopamine (DA) and/or serotonin (5HT) in the brain.
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Classification of Antidepressants
I) Monoamines re-uptake inhibitors:
Nonselective (Tricyclics (TCAs) and Tetracyclic)
Imipramine Doxepin
Maprotiline Amitriptyline
Selective Serotonin Reuptake Inhibitors (SSRIs)
Fluoxetine Sertraline Paroxetine
Serotonin and Norepinephrine Reuptake Inhibitor (SNRI)
Venlafaxine Duloxetine
Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)*
Bupropion
*Atypical antidepressant
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Classification of Antidepressants (Newer)
II) Monoamine Oxidase Inhibitors (MAOIs)
Moclobemide (selective type A)
Nialamide (non-selective – not used now)
III) Atypical antidepressants:
Serotonin-2 Antogonist and Reuptake Inhibitors (SARIs)
Nefazodone Trazodone
Noradrenergic and Specific Serotonergic Antidepressant (NaSSAs)
Mirtazapine
Noradrenaline Reuptake Inhibitor (NRI)
Reboxetine
Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)*
Bupropion
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Contraindications to Use
Use cautiously in schizophrenia, mixed mania and depression
Suicidal tendencies
In severe renal, hepatic or cardiovascular disease
In narrow-angle glaucoma
Seizure disorders
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TRICYCLIC ANTIDEPRESSANTS (TCAs)
Imipramine Desipramine
Clomipramine Amitriptyline
Nortriptyline Doxepin
Trimipramine
TETRACYCLIC ANTIDEPRESSANTS
Maprotiline
Amoxapine
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MECHANISM OF ACTION of TCAs:
• All tricyclics block reuptake pumps for both 5HT and NE in nerve terminals by competing for binding site of the transport protein
So ↑ concentration of NE and serotonin in the synaptic
cleft & at the receptor site
Facilitation of NE and serotonin transmission ----
improves symptoms of depression.
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Other MOA of TCAs
Blocking of receptors
TCAs also block :
Serotonergic receptors
Alpha adrenergic receptors
Histaminic receptors
Muscarinic receptors
Their role in therapeutic benefit is not known
These actions produce the adverse effects
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PHARMACOLOGICAL ACTIONS
1- Elevate mood
2- Improve mental alertness
3- Increase physical activity
4- In non-depressed patients They cause sedation,
confusion & motor incoordination
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Therapeutic uses of TCAs
Endogenous (Major) Depression -- moderate to severe.
Panic attack /acute episode of anxiety.
Imipramine is used for treatment of nocturnal enuresis in
children and geriatric patients as it constricts internal urethral
sphincter ( anti-muscarinic effect).
Generalized Anxiety Disorder .
Obsessive Compulsive Disorder
Attention Deficit Hyperkinetic Disorder .
Chronic neuropathic pains or Unexplained body pains.
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Side Effects of TCAs
TCAs block:
- α1 adrenergic receptors
- H1 histamines receptors
- M1 cholinergic receptors
- 5HT2 receptors
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Side Effects of TCAs
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Side Effects of TCAs
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ANTICHOLINERGIC EFFECTS
Sedation, Delirium, coma
Tachycardia
Mydriasis
Dry mucous membranes and skin
Dry mouth
Decreased or absent bowel sounds
Constipation
Urinary retention
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CARDIOVSCULAR EFFECTS
1- Inhibit neuronal catecholeamines reuptake
leading to Cardiac arrhythmias
2- Inhibit alpha-adrenergic receptors induces
vasodilatation and Postural Hypotension
3- Membrane Depressant (quinidine like) effects
cause myocardial depression and cardiac
conduction disturbance due to:
* Sodium channel blockade
* Potassium channel blockade
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SEIZURES
* Seizures occur as a result of inhibition of reuptake
of Norepinepherine and serotonin in the brain.
• TCAs lower the seizure threshold.
• The muscular hyperactivity from seizures combined
with decreased sweating can lead to severe
HYPERTHERMIA.
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Death
Sudden Death Occurs from:
1- Ventricular fibrillation
2- Status Epilepticus
3- Hyperthermia
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Interaction of TCA with other drugs
TCA (inhibitors of monoamine reuptake) should not be given with MAOIs (inhibitors of monoamine degradation) "hypertensive crisis".
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Monoamine Oxidase Inhibitors
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Monoamine Oxidase Inhibitors (MAOIs)
1- Irreversible and nonselective MAOIs (Classic MAOI)
Nialamide
- Can not distinguish between the two isoenzymes
- MAO-A and B enzyme activity can not be restored
unless new enzyme is synthesized, therefore the
effect of MAOIs persists for a period of 2-3 weeks
after stopping treatment, where a new (fresh)
enzyme has to be synthesized
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2-Reversible and selective inhibitors of MAO-A:
- Moclobemide
(antidepressant action, Short acting)
3- Selective inhibitor of MAO-B:
- Deprenyl (neurodegenerative disorder)
- Selegiline (used in the treatment of
Parkinsonism)
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MAO Enzyme
MAO-A: Metabolizes norepinephrine, serotonin and tyramine.
Inhibition of MAO-A produces Antidepressant effect .
MAO-B: specific for dopamine.
Inhibition of MAO-B produces Anti-parkinsonian effect.
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Therapeutic uses of MAOIs
Considered to be the last –line agents due to
Drug / Food interactions
1. In endogenous depression, specially patients
non responsive / allergic to TCAs
2. Atypical depression
3. Phobic states
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Side Effects of MAOIs
1- Hypotension: After MAO inhibition, other amines such as dopamine are able to accumulate in peripheral sympathetic nerve terminals and displace vesicular NA, thus reducing NA release and sympathetic activity (sympathetic block).
2- Antimuscarinic effects (atropine-like side-effects):
Dry mouth
blurred vision
Urinary retention
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Side Effects of MAOIs
3- CNS stimulation:
Insomnia
Tremors
Excitement
Convulsions
4- Weight gain: associated with increased appetite
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Drug interactions of MAOIs
1- MAOIs and SSRIs - Serotonin syndrome.
2- Levodopa:
precursor of dopamine can interact with
MAOIs leading to hypertensive crisis.
3- Amphetamine and Ephedrine:
Indirectly acting sympathomimetics can interact with MAOIs
causing the liberation of accumulated monoamines in
neuronal terminals leading to hypertensive crisis.
4-TCAs (inhibitors of monoamine reuptake) can interact
with MAOIs (inhibitors of monoamine degradation)
leading to hypertensive crisis.
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This occurs when Tyramine rich foods are taken with
MAOIs.
Tyramine rich foods include Old cheese , Concentrated
yeast products, Pickled or smoked fish, Red beans, Red
Wine, Chicken liver, Sausages.
Tyramine in food is normally degraded in the gut by
MAO-A.
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Since the enzyme is inhibited by MAOIs, tyramine from
ingested food is absorbed, and then taken up into
adrenergic neurons where it is converted into
octopamine - a false transmitter which causes massive
release of NE and may result in hypertensive crisis ;
severe hypertension, severe headache and fatal
intracranial haemorrhage.
The special advantage claimed for Moclobemide. is
that, No cheese reaction occurs with its use.
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Selective 5-HT reuptake inhibitors
(SSRIs)
- Fluoxetine
- Paroxetine
- Sertraline
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Selective Serotonin Reuptake Inhibitors
The SSRIs are currently the most widely utilized class of antidepressants in clinical practice.
They act within the brain to increase the amount of the neurotransmitter, serotonin (5-hydroxytryptamine or 5-HT), in the synaptic gap by inhibiting its re-uptake.
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Therapeutic Uses of SSRIs
Same as for TCAs, in addition effective in the following conditions
Depression.
Anxiety Disorder.
Eating disorders- bulimia nervosa (fluoxetine).
Post traumatic stress disorder.
Premenstrual dysphoric disorder.
Attention Deficit Hyperkinetic Disorder.
Treatment of premature ejaculation.
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Adverse effects of SSRIs:
GIT symptoms: Nausea, vomiting & diarrhea.
Changes in appetite - weight loss/ gain.
Anxiety & Tremors.
Sexual dysfunction: Loss of libido , delayed ejaculation.
Discontinuation syndrome:
Symptoms are headache ,malaise & flu like symptoms, agitation , irritability & nervousness
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Drug interactions of SSRIs
SSRIs are potent inhibitors of liver microsomal enzymes.
Therefore they should not be used in combination with TCAs
because they can inhibit their metabolism increasing their
toxicity.
SSRIs should not be used in combination with MAOIs because of
the risk of life-threatening "serotonin syndrome" (tremors,
hyperthermia, cardiovascular collapse and death). Both drugs
require a "washout" period of 6 weeks before the administration
of the other.
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Atypical antidepressants: bupropion, mirtazapine, nefazodone, trazodone
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BupropionBupropion is a weak dopamine and norepinephrine reuptake inhibitor that is used to alleviate the symptoms of depression. Bupropion is also useful for decreasing cravings and attenuating withdrawal symptoms of nicotine in patients trying to quit smoking.Side effects may include dry mouth, sweating, nervousness, tremor, and a dose dependent increased risk for seizures. It has a very low incidence ofsexual dysfunction.
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MirtazapineMirtazapine enhances serotonin and norepinephrine neurotransmission by serving as an antagonist at presynaptic α2 receptors. Additionally, some of the antidepressant activity may be related to antagonism at 5-HT2 receptors. It is sedating because of its potent antihistaminic activity, but it does not cause the antimuscarinic side effects of the TCAs, or interfere with sexual function like the SSRIs. Increased appetite and weight gain frequently occur. Mirtazapine is markedly sedating, which may be an advantage in depressed patients having difficulty sleeping.
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Nefazodone and trazodoneThese drugs are weak inhibitors of serotonin reuptake. Their therapeutic benefit appears to be related to their ability to block postsynaptic 5-HT2a receptors. Both agents are sedating, probably because of their potent histamine H1-blocking activity. Trazodone is commonly used off-label for the management of insomnia. Trazodone has been associated with priapism, and nefazodone has been associated with a risk for hepatotoxicity. Both agents also have mild to moderate α1 receptor antagonism, contributing to orthostasis and dizziness.
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Mood Stabilizers
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In bipolar affective disorder patients suffer episodes
of mania, hypomania and depression, classically
with periods of normal mood in between.
Manic episodes involve greatly elevated mood, often
interspersed with periods of irritability or undue
excitement, accompanied by biological symptoms
(increased energy, restlessness, decreased need for
sleep, increased sex drive), loss of social inhibitions,
irresponsible behaviour and grandiosity. Psychotic
features may be present, particularly disordered
thinking, manifested by grandiose delusions and
“flight of ideas” with rapid speech.
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Hypomania is a less dramatic and dangerous
presentation but retains the features of elation or
irritability and the biological symptoms, abnormalities
in speech and in social conduct to overfamiliarity
and mild recklessness.
Depressive episodes include depressive symptoms
described before and may include psychotic features.
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Mood stabilizers
Indications: Bipolar, cyclothymia, schizoaffective, impulse control and intermittent explosive disorders.
Classes: Lithium, anticonvulsants, antipsychotics
Which you select depends on what you are treating and again the side effect profile.
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Lithium
Only medication to reduce suicide rate.
Effective in long-term prophylaxis of both mania and depressive episodes in 70+% of BAD I pts
Factors predicting positive response to lithium
Prior long-term response or family member with good
response
Classic pure mania
Mania is followed by depression
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Lithium
Mechanism of action
Not fully understood
- The main effect of lithium is probably to inhibit hydrolysis of
inositol phosphate, so reducing the recycling of free inositol for
synthesis of phosphatidylinositides.
- Mood-stabilizing effect has been postulated to reduction of
catecholamine neurotransmitter concentration
- Possibly related to Na-K-ATPase to improve membrane transport
of Na ion
- Alternative postulate that Li may decrease cyclic AMP
concentrations, which would decrease sensitivity of hormonal-
sensitive adenylcyclase receptors
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Lithium side effects
Most common are GI distress including reduced appetite, nausea/vomiting, diarrhea
Thyroid abnormalities
Nonsignificant leukocytosis
Polyuria/polydypsia secondary to ADH antagonism. In a small number of patients can cause interstitial renal fibrosis.
Hair loss, acne
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Lithium side effects
CNS: ataxia, dysarthria, choreoathetoid disturbances,
extrapyrimidal symptoms, confusion, tremor, epileptic
seizures, spasms, stupor, sedation, lethargy.
CVS: arrhythmia, hypertension, circulatory collapse.
Other effects: weight increase, muscular hypotonia,
thirst, rash etc.
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Lithium toxicity
Mild- levels 1.5-2.0 see vomiting, diarrhea, ataxia, dizziness, slurred speech, nystagmus.
Moderate-2.0-2.5 nausea, vomiting, anorexia, blurred vision, clonic limb movements, convulsions, delirium, syncope
Severe- >2.5 generalized convulsions, oliguria and renal failure
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Thanks!