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Antidepressant pharmacology

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 2011 · 40 page(s)  (644 KB)    English    4    December 29 2018  
    
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Source: http://www.doksinet Antidepressant pharmacology Phychoenergetics, Timoanaleptics Source: http://www.doksinet Types of depression  Unipolar – bipolar  Unipolar: 1. Major 2 Minor (dysthimic disorder) Source: http://www.doksinet Antidepressants are used  MDD (Major Depressive Disorder)  Panic disorder  GAD (Generalized Anxiety Disorder  PTSD (PostTraumatic Stress Disorder)  OCD (Obsessive-Compulsive Disorder)  Neuropathic pain  Fibromyalgia Source: http://www.doksinet Theories of depression  Neurotrophic hypothesis (BDNF, trkB)  Monoamine theory  MHPG (3-methoxy-4-hydroxyphenylglycol)  5-HIAA (5-hydroxy-indol-acetic acid) Dexamethasone suppression test negative! Source: http://www.doksinet Animal models  Learned Helplessness: Delivery of repeated inescapeable painful stimuli)  Mother-infant separation  Reserpine Source: http://www.doksinet Symptoms of depression •Anhedonia- loss of interest in everyday activity

•Despondent mood •Altered sleep patterns •Changes in weight/appetite •Persistent feelings of guilt •Morbid thoughts •Agitation •Inability to concentrate •Loss of executive memory •Indecisiveness Physiological effects •Depleted monoamine neurotransmitters: serotonin, norepinepherine, dopamine •Degeneration of neurons and synaptic connectivity •Decreased GABA levels •Imbalanced HPT (hypothalamic-pituitarythyroid) axis •Increased cytokine levels Source: http://www.doksinet Systems of diagnosis DSM-IV  Major depressive disorder: 2 weeks depressed mood or loss of interest accompanied by 4 additional symptoms  Dysthymic disorder: 2 yrs depressed mood for more days than not ICD-10  Mild to moderate depression: common symptoms + functional impairment  Severe depression: physical symptoms Source: http://www.doksinet Treatments available  Antidepressant drugs (SSRIs, TCAs, MAOIs)  Counseling (Cognitive therapy, interpersonal psychotherapy,

non-directive counseling, befriending, exercise, problem solving therapy)  Natural supplements (St Johns Wort)  Electroconvulsive therapy (ECT) Source: http://www.doksinet Traditional Antidepressants  Tricyclic antidepressants  amitriptylline (Endep, Tryptanol)  clomipramine (Anafranil, Chem mart Clomipramine, GenRx Clomipramine, Placil, Terry White Chemists Clomipramine)  doxepin (Deptran, Sinequan)  dothiepin (Dothep, Prothiaden)  imipramine (Tofranil)  nortriptylline (Allegron)  trimipramine (Surmontil)  Tetracyclic antidepressants  Mianserin (Lumin, Tolvon)  MAOIs (monoamine oxidase inhibitors) (non-selectives, irreversible)  Phenelzine (Nardil)  Tranylcypromine (Parnate): fast onset, short duration  Iproniazid: (several weeks) Source: http://www.doksinet Source: http://www.doksinet Source: http://www.doksinet Bupropion •blocks reuptake of norepinepherine and dopamine •less risk of side effects •used as an aide to

quit smoking •85 % protein bound •3 active metabolite •Biphasic elimination (1h, 14h) Source: http://www.doksinet Newer antidepressants  SSRIs (specific serotonin reuptake inhibitors)  citalopram (Celapram, Chem mart Citalopram, Ciazil, Cipramil, GenRx Citalopram, Talam, Talohexal, Terry White Chemists Citalopram)  escitalopram (Lexapro)  fluoxetine (Auscap 20 mg Capsules, Chem mart Fluoxetine, Fluohexal, Fluoxebell, Fluoxetine-DP, GenRx Fluoxetine, Lovan, Prozac, Terry White Chemists Fluoxetine, Zactin)  fluvoxamine (Faverin, Luvox, Movox, Voxam)  paroxetine (Aropax, Chem mart Paroxetine, GenRx Paroxetine, Oxetine, Paxtine, Terry White Chemists Paroxetine)  sertraline (Chem mart Sertraline, Concorz, Eleva, GenRx Sertraline, Sertraline-DP, Terry White Chemists Sertraline, Xydep, Zoloft)  RIMA (reversible inhibitor of monoamine oxidase A)  moclobemide (Arima, Aurorix, Chem mart Moclobemide, Clobemix, GenRx Moclobemide, Maosig, Mohexal 150 mg, Terry

White Chemists Moclobemide)  brofaramine  befloxatone  toloxatone Source: http://www.doksinet Source: http://www.doksinet Selective Serotonin Reuptake Inhibitors •Similar efficacy with Tricyclic’s, but lower side effects •Introduced in the 1980s-90s •Block serotonin uptake @ presynaptic 5-HT transporter •Act on 4-TM ion channel receptors and 7-TM GCPRs •Mode of action remains largely inconclusive •Direct-to-consumer marketing •Sales exceed $17 billion worldwide in 2003 •Interference with MDMA, cocaine, TCAs •May intitially increase suicide risk Source: http://www.doksinet Newest antidepressants SNRI (serotonin noradrenergic reuptake inhibitors)  venlafaxine (Efexor-XR)  duloxetine (Cymbalta) NaSSA (noradrenergic and specific serotonergic antidepressant)  mirtazapine (Avanza, Avanza SolTab, Axit, Mirtazon, Remeron) NaRI (selective noradrenaline reuptake inhibitor )  reboxetine (Edronax) most effective at improving social

functioning, Side effects: blurred vision, hypotension tremors, headache, urinary hesitancy Source: http://www.doksinet Source: http://www.doksinet Selectivity of antidepressants 1000 Nisoxetine Nomifensine Maprotiline (approx) Nonselective 5-HTselective Ratio NA: 5-HT uptake inhibition 100 NAselective 10 1 0.1 Desipramine Imipramine Nortriptyline Amitriptyline Clomipramine Trazodone Zimelidine 0.01 Fluoxetine 0.001 Citalopram (approx) Source: http://www.doksinet After Dosing Antidepressants (days) Synaptic effects (hours to days) Side effects (hours to days) Therapeutic effect (1 to 6 weeks) 0 1 2 3 4 5 6 7 Source: http://www.doksinet Theories for 2-3 week delay in effectiveness Quickly increase serotonin concentraion, which inhibits 5-HT firing, autorecptors become desensitized after prolonged SSRI exposure Feedback regulation at 5-HT receptors requiring chronic administration to sustain therapeutic serotonin levels Need for alterations in

genetic alpha and betaadrenergic receptor expression Changes in nerve connectivity and neurotrophic factors Source: http://www.doksinet Pharmacokinetics of TCA  Absorption is rapid  Peak: 2-3 h  Metabolism: extensive 1st pass  Oxidation, hydroxylation, demethylation  5% = “slow acetylators”  Protein bound: 90 – 95%  Renally cleared Source: http://www.doksinet Pharmacokinetics of SSRI  Fluoxetine--- Norfluoxetine (3xt1/2 than fluoxetine)  Should be discontinued before change to MAOI  Fluoxetine, Paroxetine CYP2D6 inhibitor!!! Inhibits of desipramine metabolism Source: http://www.doksinet Phamacokinetics of SNRIs  Venlafaxine ---- desvenlafaxine (CYP2D6)  T1/2=11 h ---11 h  4-8 % unchanged (U) ---45 % unchanged (U)  Lowest protein bounding: 27-30 %  Duloxetine – 97 % prot bound  Metab: CYP2D6 and 1A2 (hepatic impairment prolongs) Source: http://www.doksinet Pharmacokinetics of 5-HT2 antagonists  Trazodone

–nefazodone  Rapid absorption  Extensive hepatic metabolization  Highly protein bound  CYP3A4 inhibitor (nefazodone) Source: http://www.doksinet Antidepressant half-lives (hrs) 3 3,5 3,6 8 nefazodone trazodone venlafaxine amoxapine 13 15 17 19 21 21 21 23 26 28 trimipramine bupropion doxepin fluvoxamine desipramine amitriptyline paroxetine 36 clomipram sertraline 43 imipramine nortriptyline 78 87 0 20 40 60 80 100 maprotiline protriptyline fluoxetine Source: http://www.doksinet Norepinephrine uptake blockade Possible clinical consequences  Tremors  Tachycardia Source: http://www.doksinet Norepinephrine uptake blockade (potency) amitriptyline imipramine doxepin clomipramine trimipramine desipramine nortriptyline protriptyline amoxapine potency maprotiline trazodone buproprion venlafaxine nefazodone fluoxetine sertraline paroxetine fluvoxamine 0 20 40 60 80 100 120 Source: http://www.doksinet Serotonin reuptake blockade Possible

clinical consequences  Gastrointestinal disturbances  Anxiety (dose – dependent)  Sexual dysfunction Serotonin uptake blockade Source: http://www.doksinet (potency) amitriptyline imipramine doxepin clomipramine trimipramine desipramine nortriptyline protriptyline amoxapine potency maprotiline trazadone buproprion venlafaxine nefazodone fluoxetine sertraline paroxetine fluvoxamine 0 20 40 60 80 100 120 140 Blocking selectivity Source: http://www.doksinet 5-HT vs. NE amitriptyline imipramine doxepin clomipramine trimipramine desipramine nortriptyline protriptyline amoxapine potency maprotiline trazodone buproprion venlafaxine nefazodone fluoxetine sertraline paroxetine fluvoxamine 0 10 20 30 40 50 60 70 80 Source: http://www.doksinet Dopaminergic uptake blockade Possible clinical consequences  Psychomotor activation  Antiparkinsonian effects  Psychoses  Increased attention/concentration Dopamine uptake blockade Source:

http://www.doksinet (potency) amitriptyline imipramine doxepin clomipramine trimipramine desipramine nortriptyline protriptyline amoxapine Series 1 maprotiline trazodone buproprion venlafaxine nefazodone fluoxetine sertraline paroxetine fluvoxamine amphetamine 0 0,2 0,4 0,6 0,8 1 1,2 Source: http://www.doksinet Histamine H1 blockade Possible clinical consequences  Sedation, drowsiness  Weight gain  hypotension Histamine H1 receptor blockade Source: http://www.doksinet (affinity) amitriptyline imipramine doxepin clomipramine trimipramine desipramine nortriptyline protriptyline amoxapine Series 1 maprotiline trazodone buproprion venlafaxine nefazodone fluoxetine sertraline paroxetine fluvoxamine diphenhydramine 0 50 100 150 200 250 300 350 400 450 Source: http://www.doksinet Muscarinic receptor blockade possible clinical consequences  Blurred vision  Dry mouth  Sinus tachycardia  Constipation  Urinary retention  Memory

dysfunction Muscarinic receptor blockade Source: http://www.doksinet (affinity) amitriptyline imipramine doxepin clomipramine trimipramine desipramine nortriptyline protriptyline amoxapine Series 1 maprotiline trazodone buproprion venlafaxine nefazodone fluoxetine sertraline paroxetine fluvoxamine 0 1 2 3 4 5 6 Source: http://www.doksinet alpha – 1 receptor blockade possible clinical consequences  Postural hypotension  Reflex tachycardia  Dizziness Source: http://www.doksinet alpha-1 receptor blockade (affinity) amitriptyline imipramine doxepin clomipramine trimipramine desipramine nortriptyline protriptyline amoxapine maprotiline trazodone buproprion venlafaxine nefazodone Series 1 fluoxetine sertraline paroxetine fluvoxamine 0 0,5 1 1,5 2 2,5 3 3,5 4 4,5 Source: http://www.doksinet Cardiac Side-effects of tricyclic antidepressants  Cardiac conduction delay  Anti-arrhythmic at therapeutic doses  Arrhythmigenic at toxic doses 

Minimal effects on cardiac output Source: http://www.doksinet Antidepressant Dis-continuation Syndrome  Occurs within 3 days of  Flu-like symptoms, cessation, only occurs after taking antidepressants for at lease 6 weeks  Also occurs when switching antidepressants or switching to generic “equivalent” (may be up to 20% different) insomnia, nausea, imbalance, sensory disturbances, hyperarousal  Generally resolves itself after 2 weeks  Misleadingly termed “withdraw,” since antidepressant are not habit-forming