Chapter 6 항우울약물 Antidepressants

Depression and Mania Decreasing of Biogenic monoamine Biogenic amines NE or Serotonin Increasing of Biogenic monoamine

Episode of MAOI as antidepressant

Biogenic amine and Function Serotonin and NE affect depressive mood Serotonin NE

Biosynthesis of serotonin(5-HT) and NE

Criteria for Depression 5 symptoms of left items depressed mood or loss of interest

Disease and Drugs associated with Depression

Antidepressants Tricyclic antidepressant MAO Inhibitor Serotonin Uptake Inhibitor

The site of action of Antidepressant at NE

The site of action of antidepressant at Serotonin

Structures of Antidepressants Structure of Antidepressant - Dihydordibenzazepines(imipramine, clomipramine) - Dihydrodibenzocycloheptenes(amitriptyline, nortriptyline) - Dibenzoxepins & Dibenzothiepins(doxepin, dothiepin) - Arylpiperazines - Non Tricyclics (mianserin, mirtazapine, bupropion, fluoxetine, trazodone)

Therapeutic Application The mechanism of TCA Therapeutic Application -Severe depression Phobiasis Enuresis: Control the bed-wetting by contraction of internal sphincter of the bradder

Drug interaction of TCA

The mechanism of MAOI

Metabolism of Biogenic amine MAOI Increase the Conc. of biogenic amine

Monoamine Oxidase MAOI

The Mechanism of MAOI

MAO-A,-B and Cheese Effect MAO-A preferentially deaminate Serotonin, Epinephrine and Norephinephrine MAO-A Inhibitor: Antidepressant MAO-A MAO-B MAO-B: MAO-B preferentially deaminates phenylethylamine and trace amines. Dopamine is equally deaminated by both types. MAO-B Inhibitor: Antiparkinson activity Cheese Effect Cheese Effect: MAOIs inhibit the catabolism of dietary amines. When foods containing tyramine are consumed (so-called "cheese effect"), the individual may suffer from hypertensive crisis. If foods containing tryptophan are consumed, hyperserotonemia may result

Tyramine

Cheese Effect Of MAOI Sublingual Nipedipine or Captopril(ACEI) Hypertensive Crisis Release of NE Tyramine Sublingual Nipedipine or Captopril(ACEI) Food : Cheese, wine, beer, yeast product

Dietary & Medication Restriction for MAOI Food Drugs Cheese, Yogrut Asthma inhalant Beer, Wine amphetamine Fermented food Appetite supressant Soy Sauce, Bean Ephedrine Coffee Sumatrytan Etc. Containing Tyramine Monoamine drugs

The receptor specificty of SSRI Low adverse effect

The clinical application of SSRI Advantage Low side effect Most widely used in US Therapeutic use Bulima nervosa(신경성과식) Obssesive compulsive disorder(강박신경증) Side effect Nausea(구역) Anxiety Insomnia(불면) Sexual dysfunction Anorexia(식욕부진) Weigh loss

Therapeutic application of Antidepressants

Imipramine 5-(3-Dimethylaminopropyl)-10,11-dihydro-5H-dibenzo[b,f]azepine hydrochloride 10,11-Dihydro-N,N-dimethyl-5H-dibenzo[b,f]azepine-5-propanamine hydrochloride Tofranil® (Norvatis), 이미프라민정 (환인, 영풍), Antideprin® (Ciba-Geigy) Dihydrodibenzazepine계

Tricycles(6,6,6)

Tricycles(6,7,6)

Imipramine Retrosynthesis

Imipramine Synthesis A Synthesis of A

Clomipramine 3-chloro-5-(3-dimethylaminopropyl)-10,11-dihydro-5H-dibenzo[b,f]azepine hydrochloride Anafranil® (Tyco Hilthecare/Norvatis), 염산 클로미프라민 캅셀 (환인) Dihydrodibenzazepine계

Clomipramine Retrosynthesis

Clomipramine Synthesis

Amitriptyline 5‑(3-dimethylaminopropylidene)dibenzo[a,d][1,4]cycloheptadiene hydrochloride 5‑(γ-dimethylaminopropylidene)-5H-dibenzo[a,d]-10,11-dihydrocycloheptene hydrochloride Elavil® (Merck), 에나폰 정 (환인), 에트라빌 정 (동화), 염산아미프리프틸 정 (명인) Dihydrodibenzocycloheptene계

Amitriptyline Retrosynthesis I SN Rx Grignard Rx & Dehydration

Amitriptyline Synthesis I A Synthesis of A

Amitriptyline Retrosynthesis II

Amitriptyline Synthesis II

Clinical application to Nocturnal enuresis(bed wetting)

Nortriptyline Not Dimethyl Monomethyl 3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine hydrochloride 5-(γ-Methylaminopropylidene)dibenzo[a,d]cyclohepta-1,4-diene hydrochloride Aventyl® (Lanbaxy), 센시발 정 (일성) Dihydrodibenzocycloheptene계

Nortriptyline Retrosynthesis

Nortriptyline Synthesis

Doxepin (E,Z)-3-(Dibenzo[b,e]oxepin-11(6H)-ylidene)-N,N-dimethylpropan-1-amine Sinequan® (Pfizer), 루시펜 크림 (삼천당), 세피드린 크림 (이알엔) Dibenzoxepin 계

Retrosynthesis Doxepin

Synthesis Doxepin

Dothiepin (E,Z)-3-(Dibenzo[b,e]thiepin-11H(6H)-ylidene)-N,N-dimethylpropan-1-amine 푸로치아덴 캡슐 (삼일) Dibenzothiepin계

Retrosynthesis Dothiepin

Synthesis Dothiepin

Mianserin 1,2,3,4,10,14b-Hexahydro-2-methyldibenzo[c,f]pyrazino[1,2-a]azepine 볼비돈 정(오가논) 비삼환계

Retrosynthesis Mianserin

Synthesis Mianserin

Mirtazapine 1,2,3,4,10,14b-Hexahydro-2-methylpyrazino[2,1-a]pyrido[2,3-c][2]benzazepine Remeron® (Organon), 레믹실 오디티 정 (명인), 미르락스 정/오디티 정 (산도즈), 레메론 정/솔탭 정 (쉐링-푸라우) 비삼환계

Retrosynthesis Mirtazapine

Synthesis Mirtazapine

Bupropion (+,+)-1-(3-Chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride Wellbutrin® (GSK), 웰부트린 서방정 (글락소스미스클라인) 비삼환계

Bupropion Retrosynthesis

Bupropion Synthesis

Fluoxetine (+)-N-Methyl-3-[4-(trifluoromethyl)phenoxy]benzenepropan-1-amine Prozac® (Lilly), 프로작 캡슐 (릴리), 폭세틴 캡슐 (환인, 신풍), 푸로핀 캡슐 (드림파마), 푸록틴 캡슐 (명인) 비삼환계

Drug Interaction and side effects of prozac

Fluoxetine Retrosynthesis

Synthesis Fluoxetine

Trazodone HCl 2-[3-[4-(3-Chlorophenyl)piperazin-1-yl]propyl]-[1,2,4]triazolo[4.5-a]pyridin-3-one 2-(3-[4-(3-Chlorophenyl)piperazin-1-yl]propyl)-[1.2.4]triazolo[4,3-a]pyridin-3(2H)-one 티리티코 정/ 국제, 트라조돈 캄셀(명인) 비삼환계

Retrosynthesis Trazodone HCl

Synthesis Trazodone HCl