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  1. 1. 11/18/2015 1 Dr. Hiwa K. Saaed, PhD, Pharmacology & Toxicology School of Pharmacy, University of Sulaimani Ref: Lippincott’s Illustrated Review Pharmacology, 6th edition 2015-2016 ANTIDEPRESSANTS SEROTONIN REUPTAKE INHIBITORS (SSRIs) Citalopram Escitalopram Fluoxetine PROZAC Fluvoxamine Paroxetine Sertraline ZOLOFT SEROTONIN/NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIs) Desvenlafaxine Duloxetine Venlafaxine ATYPICAL ANTIDEPRESSANTS Bupropion WELLBUTRIN, ZYBAN Mirtazapine REMERON Nefazodone Trazodone TRICYCLIC ANTIDEPRESSANTS (TCAs) Amitriptyline Amoxapine Clomipramine ANAFRANIL Desipramine Doxepin Imipramine TOFRANIL Maprotiline LUDIOMIL Nortriptyline Protriptyline Trimipramine MONOAMINE OXIDASE INHIBITORS (MAOIs) Isocarboxazid Phenelzine Selegiline Tranylcypromine DRUGS USED TO TREAT MANIA and BIPOLAR DISORDER Carbamazepine Lithium Valprioc acid
  2. 2. DEPRESSION Depression: is the most common of affective disorders; disorder of mood rather than disturbances of thought or cognition. it may range from a very mild condition, bordering on normality, to severe (psychotic) depression accompanied by hallucinations and delusions. 11/18/2015 2
  3. 3. DEPRESSION The symptom of depression include emotional & biological: # Emotional symptoms:  intense feeling of sadness, hopelessness and despair  inability to experience pleasure in usual activities,  Low self-esteem: feelings of guilt, inadequacy and ugliness  Indecisiveness, loss of energy and motivation, and suicidal thoughts. # Biological symptoms: Retardation of thought and action Loss of libido changes in sleep patterns and appetite, 11/18/2015 3
  4. 4. MANIA Mania is characterized by the opposite behavior that is enthusiasm rapid thought and speech patterns extreme self-confidence impaired judgment. 11/18/2015 4
  5. 5. 11/18/2015 5
  6. 6. MAJOR TYPES OF DEPRESSION The three major types of depression are: 1. Reactive depression, a response to external event: adverse life events, grief, physical illness, and drugs (reserpine). 2. Bipolar affective (manic-depressive) disorder: expansive mood, grandiosity, inflated self-esteem, pressured speech, flight of ideas, and poverty of sleep. 3. Major depressive disorder (unipolar 75%, endogenous depression 25%): a depression of mood without any obvious medical or situational causes, 11/18/2015 6
  7. 7. 3. MAJOR DEPRESSIVE DISORDER (MDD) manifested by • inability to cope with ordinary events or experience pleasure, • anorexia, with significant weight loss, • insomnia, • fatigue, • and inability to concentrate. 11/18/2015 7
  8. 8. BIOLOGIC AMINE HYPOTHESIS Depression is due to deficiency in neuronal and synaptic catecholamine concentration, such as NE and 5-HT at certain key sites in the brain Mania: excess amines 11/18/2015 8
  9. 9. BIOLOGIC AMINE HYPOTHESIS This theory was based on observations that:  Most clinically useful antidepressant drugs potentiate, either directly or indirectly, the actions of norepinephrine (NE) and/or serotonin (5-HT) in the brain.  Reserpine (which was used to Rx schizophrenia and HTN) caused sever depression in ~15% of patients. This drug depletes neuronal stores of monoamines.  Iproniazide (MAOI) used to treat TB sometimes induced euphoria. 11/18/2015 9
  10. 10. MECHANISM OF ANTIDEPRESSANT DRUGS ACTION Q. What is happen in depression? The monoamine in the limbic system are depleted → → upregulation of • postsynaptic β receptor • & presynaptic α2, 5-HT2A, 5-HT2C. 11/18/2015 10 Although antidepressant drugs may cause changes in brain amine activity within hours, weeks may be required for them to achieve clinical effects!!!!
  11. 11. Q. WHAT IS ANTIDEPRESSANT DO? Antidepressant drug decrease the presynaptic inhibitory receptor densities in the brain over a two-to four-week period upregulation → downregulation → greater synthesis and release of neurotransmitters into the synaptic cleft → enhanced signalling in the postsynaptic neurons, presumably leading to therapeutic response. 11/18/2015 11
  12. 12. DRUG CATEGORIES 11/18/2015 12 Class drugs TCA Imipramine, Amitriptyline, Cloimpramine, Doxepin, Trimpramine Heterocyclic Desipramine, Nortriptyline, Amoxapine, Maprotiline, Portriptyline 5-HT/NERIs Venlafaxine, Duloxetine Atypical Bupropion, Mirtazapine Nefazodone, Trazodone SSRIs Fluoxetine, Citalopram, Escitalopram, Fluvoxamine, Paroxetine, Sertraline MAOIs Phenelzine, Moclobemide, Isocarboxazid, Tranylcypromine
  13. 13. 11/18/2015 13
  14. 14. SSRIs • a group of chemically unique drugs • They specifically inhibit serotonin reuptake, • They have 300 to 3000 fold greater selectivity for the serotonin transporter as compared to the NE transporter. • They typically take 2 to 12 weeks to produce improvement in mood • SSRI have little ability to block the dopamine transporter. • SSRI have little blocking activity at muscarinic, α-adrenergic, and histaminic H1 receptors (fewer side effects). Thus, they are well tolerated by patients with heart disease, the elderly, who are especially sensitive to the anticholinergic and orthostatic effects of the TCA. 11/18/2015 14
  15. 15. THERAPEUTIC USES OF SSRIS: 1. Depression. 2. Obsessive compulsive disorder (the only indication for fluvoxamine ). 3. Panic disorder . 4. Generalized anxiety . 5. Premenstrual dysphoric disorder . 6. Bulimia nervosa (only fluoxetine is approved for this last indication). 11/18/2015 15
  16. 16. PHARMACOKINETICS • All the SSRIs are well absorbed after oral administration, • Only sertraline undergoes significant first-pass metabolism. • Fluoxetine and Sertraline are given in the morning because of its potential for being activating and causing insomnia. • The majority of SSRIs have plasma half-lives that range between 16 and 36 hours. • Metabolism by P450-dependent enzymes and glucuronide or sulphate conjugation occur extensively. • Excretion of SSRIs is primarily through the kidneys, except for paroxetine and sertraline, which also undergo faecal excretion. 11/18/2015 16
  17. 17. Fluoxetine differs from the other members of the class in two respects : 1. It has a much longer half-life (50hrs). 2. The metabolite is as potent as the parent compound . the half-life of the metabolite is quite long, ~10 days. Fluoxetine and paroxetine are potent inhibitors of a hepatic CYP P450 isoenzyme (CYP2D6) CYP2D6 responsible for the elimination of TCA drugs, neuroleptic drugs, and some antiarrhythmic and β-adrenergic antagonist drugs. • Note; about 7% of the white population lack (CYP2D6) and, therefore matabolize fluoxetine very slowly. 11/18/2015 17 PHARMACOKINETICS
  18. 18. • With initiation of therapy with an SSRI, some patients describe anxiety or agitation. Insomnia • Paroxetine and fluvoxamine are sedating, and may be useful in patients who have difficulty sleeping. • Conversely, patients who are fatigued may benefit from one of the more activating antidepressants, such as fluoxetine. • Sexual dysfunction: loss of libido, delayed ejaculation, and anorgasmia. Replace with a drug having fewer sexual side effects, such as Bupropion or mirtazapine. • The SSRIs tend to be weight neutral with the exception of paroxetine (Paxil), which is associated with weight gain. • Use in children and teenagers: 1/50 children become more suicidal as a result of SSRIs treatment. 11/18/2015 18 Adverse effects
  19. 19. Adverse effects • SSRI+MAOIs cause Serotonin syndrome: characterized by: hyperthermia, muscle rigidity, myoclonus and changes in mental status and vital signs. • Discontinuation syndrome: include headache, malaise, and flu-like symptoms, agitation and irritability, nervousness, and changes in sleep pattern. • All of the SSRIs, particularly the agents with shorter half- lives and inactive metabolites cause discontinuation syndrome. Q. Fluoxetine has the lowest risk of causing an SSRI discontinuation syndrome? Answer: due to its longer half-life and active metabolite. 11/18/2015 19
  20. 20. SEROTONIN/NE REUPTAKE INHIBITOR:  Venlafaxine, desvenlafaxine, levomilnacipran and duloxetine, selectively inhibit the reuptake of both serotonin and NE.  effective in treating depression and neuropathic pain (such as backache and muscle aches) in patients in which SSRIs are ineffective.  SNRIs, unlike the TCAs, have no activity at adrenergic, muscarinic, or histamine receptors and thus have fewer side effects than the TCAs. 11/18/2015 20
  21. 21. VENLAFAXINE VS DULOXETINE Venlafaxine: • Is a potent inhibitor of serotonin reuptake and, at higher doses, is an inhibitor of NE reuptake. It is also a mild inhibitor of dopamine reuptake. • It has minimal inhibition of the CYP P450 isoenzymes. The t1/2 of the parent compounds plus its active metabolite is approximately 11 hours. • SE: nausea, dizziness, insomnia, sedation, and constipation. At high doses, there may be an increase in blood pressure.. Duloxetine:  inhibits serotonin and NE reuptake at all doses.  It is extensively metabolized in the liver to numerous metabolites, should not be administered to patients with hepatic insufficiency. Metabolites are excreted in the urine.  Food delays the absorption of the drug. t1/2 is ~12 hours.  SE: nausea, dry mouth, and constipation are common, Insomnia, dizziness, somnolence, sweating, Sexual dysfunction also occurs. 11/18/2015 21
  22. 22. ATYPICAL ANTIDEPRESSANTS They are a mixed group of agents that have actions at several different sites. Bupropion: (smoking cessation) • Acts at unidentified site. It has minimal effects on NE or 5-HT systems, but blocks DA reuptake. • Its short half-life may require more than once-a-day dosing or the administration of an extended release formulation, it decreases the craving of nicotine in tobacco abusers. • Side effects include: dry mouth ,sweating ,tremor and seizures at high doses. Mirtazapine: • block 5-HT2 and α2 receptors. • It is a sedative because of its potent antihistaminic activity, which may be used to advantage in depressed patients having difficulty sleeping, • but it does not cause the antimuscarinic SEs of TCAs, • Does not interfere with sexual functioning, as do the SSRIs. • Increased appetite and weight gain frequently occur. 11/18/2015 22
  23. 23. NEFAZODONE AND TRAZODONE: • Nefazodone (P450 inhibitor) blocks both NE and 5-HT reuptake, and is a 5-HT2 antagonist, • trazodone weak inhibitor of serotonin reuptake by blocking 5-HT1 presynaptic autoreceptors and thereby, increase serotonin release, and is a 5-HT2 antagonist. • Both are sedating because of potent H1 blocking activity. • Trazodone has been associated with causing priapism. • Vilazodone • vortioxetine 11/18/2015 23
  24. 24. 11/18/2015 24
  25. 25. TCAs • Tertiary amines; imipramine (prototype), amitriptyline, clomipramine, doxepin and trimipramine • Secondary amines; desipramine, and nortryptyline (N-demethylated metabolites of imipramine and amitriptyline respectively), amoxapine, maprotiline, and protriptyline. Mechanism of Action: Inhibition of neurotransmitter (serotonin and NE) uptake: ↑adrenergic and serotonergic neurotransmission. Blocking of four receptors: serotonergic, α-adrenergic, histaminic, and muscarinic receptors. actions at these receptors are probably responsible for many of the untoward effects of TCAs. 11/18/2015 25
  26. 26. MECHANISM OF ACTION: 11/18/2015 26
  27. 27. • Sever major depression, • phobic and panic anxiety disorders, • Neuropathic pain, • obsessive compulsive disorder (OCD), • nocturnal enuresis; Imipramine has been used to control bed-wetting in children (older than six years) by causing contraction of the internal sphincter of the bladder. THERAPEUTIC USES 11/18/2015 27
  28. 28. Adverse effects  Muscarinic blockade leads to blurred vision, xerostomia, urinary retention, constipation, and aggravation of glaucoma and epilepsy.  Sympathomimetic: in tremor, and cardiac overstimulation, arrhythmia.  α-adrenergic receptors blockade, causing orthostatic hypotension and reflex tachycardia.  Imipramine is most likely and nortriptyline is least likely to cause orthostatic hypotension.  H1 receptors blockade; Sedation  Metabolic: Weight gain is a common adverse effect of the TCAs.  Endocrine: Sexual dysfunction, as evidenced by erectile dysfunction in men and anorgasmia in women.  Drug interactions:  Hyperthermia, seizures, coma, and death with MAOIs, serotonin syndrome with SSRIs, 11/18/2015 28
  29. 29. 11/18/2015 29
  30. 30. MAO INHIBITORS  Mechanism of action: They increase stores of norepinephrine ,serotonin and dopamine within the neuron and subsequent diffusion of excess neurotransmitter into the synaptic space.  Therapeutic uses: 1. Indicated for depressed patients who are unresponsive or allergic to TCAs. 2. Patient with low psychomotor activity. 3. Treatment of phobic states . These drugs inhibit not only MAO in the brain but also peripheral oxidase, therefore MAOIs show a high incidence of drug-drug and drug-food interactions. • Cheese reaction: Individuals receiving MAOIs are unable to degrade tyramine obtained from the diet, tyramine causes the release of large amounts of stored catecholamine from nerve terminals, resulting in headache, tachycardia, nausea, hypertension ,cardiac arrhythmias and stroke . • Other side effects include: drowsiness, orthostatic hypotension ,blurred vision, dry mouth, dysuria and constipation . 11/18/2015 30
  31. 31. TREATMENT OF MANIA AND BIPOLAR DISORDER • For more than 40 years, Lithium (Li+) has been used to treat mania. • lithium carbonate is effective in 60 to 80% of all acute manic episodes within 5 to 21 days of beginning treatment. • Because of its delayed onset of action in the manic patient, Li+ is often used in conjunction with low doses of high-potency anxiolytics (e.g., lorazepam) and antipsychotics (e.g., haloperidol) to stabilize the behaviour of the patient.. Mechanism of Action: Lithium interferes with the resynthesis (recycling) of PIP2, by inhibition of the dephosphorylation of both IP2 to IP, and IP to Inositol, necessary steps in the recycling of inositol→↓ PIP2 in neuronal membranes of the CNS. 11/18/2015 31
  33. 33. LITHIUM • Lithium is given orally, and the ion is excreted by the kidney like Na+; • low Na+ diet or chronic diuretic treatment enhances toxicity, medical conditions (diarrhoea), or physical activities (those that induce sweating) that deplete the body of Na+. • Lithium salts are very toxic. Their safety factor and therapeutic index are extremely low-comparable to those of digitalis. Adverse Effects: • ataxia, tremors, confusion, convulsions, acne, edema, visual dysfunction, • goiter, hypothyroidism; nephrogenic diabetes insipidus (treat with amiloride, not thiazides), teratogenicity (cardiac malformations, neonatal cyanosis, and hepatomegaly); 11/18/2015 33
  34. 34. OTHER MOOD-STABILIZING AGENTS • Several anticonvulsant; Valproic acid and carbamazepine are the best studied to date. • In 1995, valproic acid was approved by the FDA for treatment of acute mania and is now considered a first-line agent. • In pregnancy clonazepam or gabapentin are preferred. • Other anticonvulsants under investigation include lamotrigine and topiramate. • The atypical antipsychotics (risperidone, olanzapine, ziprasidone, aripiprazole, asenapine, and quetiapine) have also received FDA approval for use in acute mania and mixed episodes associated with bipolar disorder. 11/18/2015 34