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The Pharmacology of Antidepressants Tracy Womble, Ph.D Florida A&M University, College of Pharmacy and Pharmaceutical Sciences Dept. Of Neuroscience
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Objectives What is depression Pathophysiology of Depression History Classes Pharmacology Therapeutic use Mechanism of action pharmacokinetics Adverse effects toxicity
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Depression Depression is defined as intense feelings of sadness, mental slowing, hoplesness, despair, pessimistic worry, agitation, self-deprecation and inability to experience pleasure during usual activities
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Neurological disorder Prolonged depression of mood and impairment of function Causes include genetic predisposition, grief following the death of a loved one, abuse, major life changes, serious illness, personal disputes, and substance abuse Complex illness with many contributing factors Exact biological causes are not yet fully understood What is depression?
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Major Depressive Disorder Symptoms interfere with ability to function normally 10% of people in the US suffer at any one time 2x more women are diagnosed than men Chronic (Dysthymia) Less severe, but symptoms linger for longer Seasonal Affective Disorder (SAD) Psychotic Postpartum Types of Depression
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Manic Depression Mania is characterized by opposing behavior to depression; enthusiasim, rapid thought and speech patterns, extreme self-confidence and impaired judgement, and elevated “high” mood. Talkative, go on-and-on about the things they will do. Increased self-esteem. Auditory hallucinations. Decrease need to sleep. indiscrete SuperME
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Pathophysiology of Depression Biogenic amine Hypothesis Neurotrophic Hypothesis Neuroendocrine Factors
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Biogenic Amine Hypothesis Depression and mania are due to an alteration in neuronal and synaptic catecholamine concentration at adrenergic receptor sites in the brain Depression: deficiency of biogenic amines ( NE, 5-HT) Mania: excess amines (NE, 5-HT)
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Neurotrophic Hypothesis Loss of neurotrophic support or NGF’s BDNF (brain-derived neurotrophic factor) regulation of neural plasticity, resilience and neurogenesis. Effective therapies increase neurogenesis and synaptic connectivity in cortical areas (hypothalamus) Activation of tyrosine kinase receptor B in neurons and glia.
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Neuroendocrine Factors Abnormalities in HPA axis – hormonal abnormalities Elevated cortisol levels Clinical hypothyroidism Sex steroids Estrogen deficiency (postpartum and postmenopausal) Testosterone deficiency
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History of Antidepressants Introduction of Reserpine in 1950’s Used for hypertension and schizophrenia Induced depression in these pts. MOA – inhibit storage of NE and 5-HT Reasoned that depression is associated with decrease in amine dependent synaptic transmission
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Clinical Indications of Antidepressants Depression Anxiety Disorders Pain Disorders Premenstrual Dysmoric Disorder Smoking Cessation Eating Disorders Off label usage – urinary stress incontinence, sexual disorders (premature ejaculation)
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Antidepressant (Thymoleptic) Drugs Tricyclic antidepressants (TCA’s) Monoamine oxidase inhibitors (MAOIs) Newer-generation antidepressants Selective serotonin reuptake inhibitors (SSRIs) Selective norepinephrine reuptake inhibitors (SNRIs) 5-HT Antagonists
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Tricyclic Antidepressants First-Generation mostly replaced as first-line antidepressant drugs by SSRIs in 80’s and 90’s. Considered second-line patients who fail with SSRIs or other newer-generation antidepressants As adjunct therapy with newer antidepressants
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Common TCA’s Secondary Amine Amoxapine Nortiptyline Desipramine Protriptyline Tertiary Amine Imipramine * Amitriptyline * Clomipramine Doxepin Trimipramine * prototype
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Tricyclic Antidepressants TCA’s) Characteristic three-ring structure Block NE and 5-HT reuptake Can not be used with MAOI’s No food interactions Antagonize 5-HT, α-adrenergic, H 1 and muscarinic receptors
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Mechanism of Action of TCA’s Block reuptake of neurotransmitters, (NE, 5-HT) causing accumulation at the nerve endings increasing NE and 5-HT will correct the abnormally low levels that lead to depression
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Tricyclic Antidepressants Imipramine strong anticholinergic action strong NE and 5-HT reuptake inhibitor Most likely to cause orthostatic hypotension Desipramine Metabolite of imipramine Less anticholinergic, more potent, more selective for NET than imipramine Nortriptyline Least likely to cause orthostatic hypotension
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Indications for TCA’s Depression Childhood enuresis (imipramine) Obsessive-compulsive disorders (clomipramine) Adjunctive analgesics for chronic pain conditions, such as trigeminal neuralgia, neuropathy
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TCA’s (cont’) Mode of action – inhibit NE and 5HT reuptake into presynaptic nerve terminal Actions – elevate mood Therapeutic uses – severe depression, some panic disorders. Pharmacokinetics – well absorbed PO, lipophilic, penetrate CNS Fate – metab. By hepatic microsomal system
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Adverse affects of TCA’s Antimuscarinic Cardiovascular Orthostatic hypotension Sedation Precaution Toxicity Drugs used for toxicity
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Drug Effects Blockade of norepinephrine reuptake Antidepressant*, tremors, tachycardia Blockade of 5-HT reuptake Antidepressant*, nausea, headache, anxiety, sexual dysfunction *Desired therapeutic effects
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Overdose of TCA’s Brief excitement and restlessness, myoclonus, tonic-clonic seizures, coma, depressed respiration, hypoxia, hypothermia, hypotension, mydriasis, urinary retention Cardiac toxicity, hypotension
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Overdose of TCA’s No specific antidote Decrease drug absorption with activated charcoal Speed elimination by alkalinizing urine Sodium Bicarbonate Manage seizures and dysrhythmias Lidocaine, propranolol, phenytoin Provide basic life support
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Overdose of TCA’s Lethal—70% to 80% die before reaching the hospital CNS and cardiovascular systems are mainly affected Death results from seizures or dysrhythmias
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Antidepressant (Thymoleptic) Drugs Tricyclic antidepressants (TCA’s) Monoamine oxidase inhibitors (MAOIs) Newer-generation antidepressants Selective serotonin reuptake inhibitors (SSRIs) Selective norepinephrine reuptake inhibitors (SNRIs) 5-HT Antagonists
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Monoamine Oxidase Inhibitors Phenelzine Isocarboxazid Tranylcypromine Selegeline Patch
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Monoamine Oxidase Inhibitors
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Mitochondrial enzyme, (MAO) regulates metabolic degradation Found in nerve terminal, intestinal mucosa (gut), liver, etc. MAOI irreversibly/reversibly inactivate MAO Allow NT to escape degradation
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Monoamine Oxidase Inhibitors Irreversible MAO inhibitors (Hydrazides) Phenelzine, Isocarboxazid Reversible MAO inhibitors (non-hydrazide) Tranylcypromine
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Monoamine Oxidase Inhibitors 2 forms of monoamine oxidase MAO-A - present in both DA and NE neurons and found mostly in brain, gut, placenta and liver. (NE, 5-HT) Mocolobemide, Clorgyline MAO-B - present mainly in serotonergic and histaminergic neurons, distributed in brain, liver and platelets. (tyramine, DA) Deprenyl, Seligiline
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MAOI classification Classified according to specificity for MAO-A or MAO-B and whether they are reversible or irreversible. Non-selective irreversible- phelnelzine, trancypromine Selective MAO-A reversible – moclobemide, displaced by tyramine MAO-B irreversible – selegiline (low dose) used in PD, high dose becomes non-selective
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Monoamine Oxidase Inhibitors (MAOI’s) Considered second-line treatment for depression not responsive to TCA’s Disadvantage: potential to cause hypertensive crisis when taken with tyramine Use is limited due to dietary restrictions Onset time and time to wear off – 2 wks
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Wine and Cheese reaction Fatal interaction w/ tyramine containing foods (fermented foods) MAO-A breakdown tyramine in body – MAOI’s cause circulating NE – induces hypertensive crisis – can lead to intracranial bleeding, organ damage
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Monoamine Oxidase Inhibitors Prolong action of drugs metabolized by MAO and hepatic metabolic P450 Contraindicated in pts. Using TCA’s Drug to drug interaction - use of SSRI’s cause life- threatening serotonin syndrome. Drug to food interaction - hypertensive crisis when taken with tyramine
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Monoamine Oxidase Inhibitors Mechanism of action inactivate MAO, result in increased stores of 5- HT, NE and DA. Brain and peripheral (high drug-drug, drug-food interaction) Therapeutic use Depression not responsive to TCA’s Used in phobic states Very effective in atypical depression
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Monoamine Oxidase Inhibitors Pharmacokinetics well absorbed p.o. antidepressant effect (2-4 weeks) wash out period(2 weeks) required when switching antidepressants metabolized, excreted rapidly in urine
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Monoamine Oxidase Inhibitors Adverse Effects drowsiness orthostatic hypotension blurred vision dry mouth dysuria constipation contraindicated w/ SSRI’s – serotonin syndrome
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MAOI Toxicity Toxic reactions may occur in hrs, despite therapeutic response delay Agitation, hallucinations, hyperreflexia, hyperpyrexa and convulsions Both hypertension and hypotension
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MAOI Toxicity Symptoms appear 12 hours after ingestion Tachycardia, circulatory collapse, seizures, coma Treatment: protect brain and heart, eliminate toxin Gastric lavage Urine acidification Hemodialysis
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Antidepressant (Thymoleptic) Drugs Tricyclic antidepressants (TCA’s) Monoamine oxidase inhibitors (MAOIs) Newer-generation antidepressants Selective serotonin reuptake inhibitors (SSRIs) Selective norepinephrine reuptake inhibitors (SNRIs) 5-HT Antagonists
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Selective Serotonin Reuptake Inhibitors (SSRI’s) Mainly replaced TCA’s and MAOIs as drug of choice for depression Do not affect reuptake of NE Decreased incidence of anticholinergic and adrenergic action of TCA’s. All admin. PO May interfere with P450 (CYP2Ds) metabolism of other drugs (enzymes responsible for metabolism of TCA’s)
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Selective Serotonin Reuptake Inhibitors Fluoxetine (Prozac) Citalopram (Celexa) Fluvoxamine (Luvox) Paroxetine (Paxil) Sertraline (Zoloft)
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Selective Serotonin Reuptake Inhibitors SSRIs Selectively inhibit serotonin reuptake Little or no effect on norepinephrine or dopamine reuptake Result in increased serotonin concentrations at nerve endings Advantage over TCA’s and MAOIs: little or no effect on cardiovascular system, and no CNS stimulation
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Selective Serotonin Reuptake Inhibitors (SSRI’s) Most widely prescribed drugs for depression, OCD,GAD, PDD, bulimia They have few side effects and seem to be rather safe. Adverse effects include: nausea, decreased libido,anorexia, anxiety, insomnia, tremors, sleepiness, sweating Low threat for overdose. Suicide may be considered in severe depression.
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SSRI’s indications Fluoxetine (Prozac) - mental depression, OCD, Bulemia Citalopram (Celexa) – mental depression Fluvoxamine (Luvox) - OCD Paroxetine (Paxil) – mental depression, panic disorder, OCD Sertraline (Zoloft) - mental depression
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Antidepressant (Thymoleptic) Drugs Tricyclic antidepressants (TCA’s) Monoamine oxidase inhibitors (MAOIs) Newer-generation antidepressants Selective serotonin reuptake inhibitors (SSRIs) Selective norepinephrine reuptake inhibitors (SNRIs) 5-HT Antagonists
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Serotonin-Norepinephrine Reuptake Inhibitors (SNRI’s) 2 classes of antidepressants act as combined NE and 5-HT reuptake inhibitors SNRI’s and TCA’s SNRI’s Venlafaxine - weak inhibitor of NET Duloxetine – inhibit both NET and SERT
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Serotonin-Norepinephrine Reuptake Inhibitors (SNRI’s) Additional indications Major depression, pain disorders, generalized anxiety, urinary incontinence and vasomotor symptoms of menopause Bind SERT and NET transporters Differ from TCA’s - no α-adrenergic blocking, and anticholinergic effects
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Pharmacokinetics of SNRI’s Venlafaxine extensively metabolized in the liver to Desvenlafaxine Both have the lowest protein binding of all antidepressants Desvenlafaxine conjugated, does not undergo extensive oxidative metabolism about 45% is excreted unchanged in the urine Duloxetine tightly bound to protein (97%) Undergoes extensive oxidative metabolism hepatic impairment alters levels, unlike Desvenlafaxine
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Antidepressant (Thymoleptic) Drugs Tricyclic antidepressants (TCA’s) Monoamine oxidase inhibitors (MAOIs) Newer-generation antidepressants Selective serotonin reuptake inhibitors (SSRIs) Selective norepinephrine reuptake inhibitors (SNRIs) Tetracyclic and Unicyclic 5-HT 1 and 2 Antagonists
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5-HT 1 Antagonists Trazodone and Nefazodone Mechanism of action Therapeutic effect related to ability to block 5-HT 1 Weak but selective inhibitors of 5-HT reuptake Little or no effect on NE or DA reuptake Increased 5-HT concentrations Both are sedating (antihistimine effect) Trazodone associated with causing priapism
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5-HT 2 Antagonists Mirtazapine Mechanism of action Antagonist of 5-HT 2/3 – inc. release 5-HT Antagonist of α 2 receptors-inc. release NE, 5-HT Side effects sedative due to antihistamine activity effective in depressed having difficulty sleeping no antimuscarinic (TCA) does not interfere w/ sexual function (SSRIs) increased appetite, weight gain
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Tetracyclic, Unicyclic Bupropion Mechanism of action – poorly understood Release of catocholamines – NE, DA No effect on 5-HT Decreases cravings for nicotine in tobacco users Side effects – dry mouth, sweating, tremor, seizure at high dose Lower seizure threshold
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Tetracyclic, Unicyclic (cont) Amoxapne and maprotiline Mechanism of action – potent NET inhibitors and less potent SERT inhibitors Side effects – both possess anticholinergic properties inhibits D2 receptor Possess antipsychotic properties Lower seizure threshold
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Conclusion Main similarities and differences, which explain why SSRIs are more commonly prescribed than TCAs in the treatment for depression: SSRIs and TCAs have similar efficacy for the treatment of depression SSRIs have fewer anticholinergic and cardiovascular side effects TCA have fewer sexual and gastrointestinal side effects SSRIs are better tolerated by patients SSRIs are safer in overdose than TCAs
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