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Antidepressant drugs
- 1. Prepared by ShaguftaFarooqui Department of Pharmacology Nanded Pharmacy College, Nanded
- 2. DEPRESSION It isa mental illnesses characterized by pathological changes in mood, loss of interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, low energy, and poor concentration . It can be severe and some times Fatal.
- 3. Symptoms A. Depressed moodmost of the day… B. Markedly diminished interest or pleasure C. Significant weight loss /gain D. Insomnia or hypersomnia E. Agitation F. Fatigue or loss of energy Change in appetite G. Lack of concentration H. Poor self esteem I. Thought of suicide or death.
- 4. Abuse. Physical, sexual,or emotional abuse can make you more vulnerable to depression later in life Death or a loss. long-term isolation or loneliness prolonged work stress long-term unemployment
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- 7. Blocking theaction of MAO leads to an increased availability of neurotransmitters. MAO-A oxidizes epinephrine, norepinephrine, serotonin - MAO-B oxidizes phenylethylamine -Both oxidize dopamine non-preferentially. This theory is based on the ability of the monoamine oxidase- A inhibiting drugs to facilitate NE/5-HT neurotransmission and to act as effective antidepressant drugs.
- 8. SERETONIN NORADRENALINE AND DOPAMINEHYPOTHESIS Depression is caused by a functional deficit of NE and /or 5-HT and Dopamine at Hippocampus in brain. Therefore, it was reasoned that depression must be associated with a decreased NE/5-HT neurotransmission.
- 12. ANTIDEPRESSANTS These are drugswhich can elevate mood in depressive illness. Practically all antidepressants affect monoaminergic transmission in the brain in one way or the other, and many of them have other associated properties. Depression occur due to decrease level of mood elevating neurotransmitters like serotonin,Noeadrenalin,Dopamine in Hippocampus, hence we are using agonist or drugs which increase level of noradrenalin and serotonin wither by inhibiting reuptake or metabolism.
- 13. CLASSIFICATION I. Reversible inhibitorsof MAO-A (RIMAs) Moclobemide, Clorgyline II. Tricyclic antidepressants (TCAs) A. NA + 5-HT reuptake inhibitors Imipramine, Amitriptyline, Trimipramine, Doxepin, Dothiepin, Clomipramine B. Predominantly NA reuptake inhibitors Desipramine, Nortriptyline, Amoxapine, Reboxetine
- 14. III. Selective serotoninreuptake inhibitors (SSRIs) Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Citalopram, Escitalopram, Dapoxetine IV. Serotonin and noradrenaline reuptake inhibitors (SNRIs) - Venlafaxine, Duloxetine V. Atypical antidepressants Trazodone, Mianserin, Mirtazapine, Bupropion, Tianeptine, Amineptine, Atomoxetine
- 15. MAO INHIBITORS MAO isa mitochondrial enzyme involved in the oxidative deamination of biogenic amines (Adr, NA, DA, 5-HT). Two isoenzyme forms of MAO have been identified. MAO-A: Preferentially deaminates 5-HT and NA, and is inhibited by clorgyline, moclobemide. MAO-B: Preferentially deaminates phenylethylamine and is inhibited by selegiline. Dopamine is degraded equally by both isoenzymes. Their distribution also differs. Peripheral adrenergic nerve endings, intestinal mucosa and human placenta contain predominantly MAO-A, while MAO-B predominates in certain areas (mainly serotonergic) of brain and in platelets. Liver contains both isoenzymes.
- 16. MAO inhibitors MAO inhibitors(relatedto amphetamine) like tranylcypromine were used as antidepressants in the 1960s. The selective MAO-A inhibitors possess antidepressant property. Selegiline selectively inhibits MAO-B at lower doses (5–10 mg/day).
- 17. Clorgyline/Selegline MAO inhibitor NA,DA.5-HT escape metabolism Increaseneuronal level of NA,DA,5-HT Antidepressant effect
- 19. Interactions These drugs inhibita number of other enzymes as well, and interact with many food constituents and drugs. (i) Cheese reaction Certain varieties of cheese, beer, wines, pickled meat and fish, yeast extract contain large quantities of tyramine etc. (i) In MAO inhibited patients these indirectly acting sympathomimetic amines escape degradation in the intestinal wall and liver → reaching into systemic circulation they displace and release large amounts of NA from transmitter loaded adrenergic nerve endings → hypertensive crisis, cerebrovascular accidents. (ii) When such a reaction occurs, it can be treated by i.v. injection of a rapidly acting α blocker, e.g. phentolamine. Prazosin or chlorpromazine are alternatives.
- 21. (ii) Cold andcough remedies They contain ephedrine or other sympathomimetics—hypertensive reaction can occur. (iii) Reserpine, guanethidine, tricyclic antidepressants Excitement, rise in BP and body temperature can occur when these drugs are given to a patient on MAO inhibitors. This is due to their initial NA releasing or uptake blocking action.
- 22. TRICYCLIC ANTIDEPRESSANTS (TCAs) Imipramine,an analogue of CPZ was found during clinical trials (1958) to selectively benefit depressed but not agitated psychotics. In contrast to CPZ, it inhibited NA and 5-HT reuptake into neurones. A large number of congeners were soon added and are called tricyclic antidepressants (TCAs).
- 24. These older compounds,in addition to uptake blockade have direct effects on adrenergic, cholinergic and histaminergic receptors, and are referred to as ‘first generation antidepressants,’ a group which also includes MAOIs. The subsequently produced second generation antidepressants have more selective action on amine uptake; are either Selective serotonin reuptake inhibitors (SSRIs), or Serotonin and noradrenaline reuptake inhibitors (SNRIs), with no direct action on cholinergic/adrenergic/ histaminergic receptors, or have some atypical features. They have a limited spectrum of action resulting in fewer side effects
- 26. ADVERSE EFFECTS Side effectsare common with TCAs because of which SSRIs, SNRIs and atypical antidepressants have become the first line drugs. 1. Anticholinergic: dry mouth, bad taste, constipation, epigastric distress, urinary retention (especially in males with enlarged prostate), blurred vision, palpitation. 2. Sedation, mental confusion and weakness, especially with amitriptyline and more sedative congeners. 3. Increased appetite and weight gain is noted with most TCAs and trazodone, but not with SSRIs, SNRIs and bupropion.
- 27. 7. Sweating (despiteantimuscarinic action) and fine tremors are relatively common. 5. Seizure threshold is lowered—fits may be precipitated, especially in children. Bupropion, clomipramine, amoxapine have greater propensity, while desipramine, SSRIs and SNRIs are safer in this regard. 6. Postural hypotension, especially in older patients. It is less severe with desipramine like drugs and insignificant with SSRIs/ SNRIs.
- 29. SELECTIVE SEROTONIN REUPTAKEINHIBITORS (SSRIs) The major limitations of TCAs (first generation antidepressants) are: Frequent anticholinergic, cardiovascular and neurological side effects. Relatively low safety margin. They are hazardous in overdose; fatalities are common Lag time of 2–4 weeks before antidepressant action manifests. Significant number of patients respond incompletely and some do not respond. To overcome these shortcomings, a large number of newer (second generation) antidepressants have been developed since 1980s.
- 31. A. SSRI have300-3000 fold greater selectivity = serotonin transporter(SERT) B. Show less side effects than TCAs C. Safe even at over dose that’s why it replaced MAOI D. Block serotonin reuptake and increase serotonin level thereby improve antidepressant activity Takes 2 weeks to give significant improvement Other uses of SSRIs The SSRIs are now 1st choice drugs for OCD, panic disorder, social phobia, eating disorders
- 32. USES Endogenous (major) depression: Obsessive- compulsive and phobic states Anxiety disorders Neuropathic pain: Attentiondeficit- hyperactivity disorder (ADHD) in children: Enuresis Migraine: Pruritus: