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2013 fall 6th class 약물남용 physicochemical
2013 fall 6th class 약물남용 physicochemical
2013 fall 6th class 약물남용 physicochemical
2013 fall 6th class 약물남용 physicochemical
2013 fall 6th class 약물남용 physicochemical
2013 fall 6th class 약물남용 physicochemical
2013 fall 6th class 약물남용 physicochemical
2013 fall 6th class 약물남용 physicochemical
2013 fall 6th class 약물남용 physicochemical
2013 fall 6th class 약물남용 physicochemical
2013 fall 6th class 약물남용 physicochemical
2013 fall 6th class 약물남용 physicochemical
2013 fall 6th class 약물남용 physicochemical
2013 fall 6th class 약물남용 physicochemical
2013 fall 6th class 약물남용 physicochemical
2013 fall 6th class 약물남용 physicochemical
2013 fall 6th class 약물남용 physicochemical
2013 fall 6th class 약물남용 physicochemical
2013 fall 6th class 약물남용 physicochemical
2013 fall 6th class 약물남용 physicochemical
2013 fall 6th class 약물남용 physicochemical
2013 fall 6th class 약물남용 physicochemical
2013 fall 6th class 약물남용 physicochemical
2013 fall 6th class 약물남용 physicochemical
2013 fall 6th class 약물남용 physicochemical
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2013 fall 6th class 약물남용 physicochemical

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  • 1. Abused Drugs– 6 약물 남용 -6 Physicochemical properties of toxic agents(illicit drugs) ( 마 ) 약 . 독물의 물리화학 Chungnam Natl. Univ. Dept. of Forensic Sciences 충남대 과학수사학과 Aug. – Dec., 2013 최성운 Sungwoon Choi 1
  • 2. Physical-Chemical Properties - general What Physical-Chemical Properties of the compound (drug) need to be considered? 마약류의 어떠한 물리 / 화학적 성질을 고 려 해야 하나 Physical – Chemical Properties 약독물의 물리 - 화학적 성질 - 투과도 ( 세포막 ) - 지용성 - 용해도 - 염 , 수소결합 등 - 대사 안정도 - 지용성 , 구조 - 혈액내 안정도 - 대사효소 억제 - 뇌혈액관문 - 지용성 - 지용도 Discoveryadme.com 흡수 , 분포 , 대사 , 배설과 밀접한 관계 흡수된 용량관계 - 마약의 효과 / 부작용에 관련 2
  • 3. Physical-Chemical Properties - general 기름층 물층 비극성 극성 -COO- + Na+ 비극성 기름층 극성 비극성 물층 극성 3
  • 4. Physical-Chemical Properties – general 마약류 염의 형태와 흡수에 대해 논 하시오 마약류의 극성도와 산염기 성질 에 대해 논하시오 Two of the most important physicochemical properties of a drug (toxicant) molecule are its POLARITY & its ACID-BASE nature 마약류의 2 가지 가장 ( 극성도 ) ( 산 - 염기 성질 ) 중요한 물리화학적 성 Drug polarity: relative measure of a drug’s lipid & water solubility 수용 / 지용 ( 약물극성도 ) usually expressed in terms of a partition coefficient (P) 분배계수 지질 or 물에 대한 상대적 용해도 - 분배계수 (P) 로 표현 P = [drug]lipid / [drug]aqueous 4
  • 5. Physical-Chemical Properties - general ater solubility (Hydrophilicity): depends on two factors 수용성도 – 두 가지 요소 ionic character 이온화 성질 에 의거 hydrogen bonding capability 수소결합 형성 가능도 the presence of oxygen- & nitrogen-containing functional groups 산소 , 질소 usually enhances water solubility 수용성 증강 포함 기능기들 --- dissolution in GI tract 위장관내 용해 용이 비 이온화 탄화수소 pid solubility (Lipophilicity): nonionizable hydrocarbon chains & ring system --- penetration through the lipid bilayer, BBB, 지질이중층 - 뇌혈액관문 통과용이 enhanced plasma protein binding etc. 혈장단백질 결합 지용도 ( 지방용해도 )- 비 이온화 경향 – 뇌로 침투 용이 5
  • 6. Physical-Chemical Properties – general 강산과 유기산 - 약산 Strong acid – hydrochloric acid (HCl), sulfuric acid (H2SO4), nitric acid 강산 (HNO3), hydrobromic acid (HBr), HF etc. are completely ionized Organic acid – weak acid, contain functional group(s) as below 완전 이온화 유기산 약산 녹아있는 매질의 pH( 산 / 알칼리도 ) 에 의거 1) carboxylic acid group (-COOH) 카르복실산 2) phenolic group (Ar-OH) 3) sulfonic acid group (-SO3H) 4) sulfonamide group (-SO2NH-R) 5) Imide group (-CONHCO-) 6) beta-carbonyl group (-CO-CHR-CO-) 7) tetrazole ring (five-member CHN4 ring) 마약류에는 많지 않음 – 대마의 대사물에 존재 Naproxen-Aleve 진통제 Naproxen-Na 염 6
  • 7. Physical-Chemical Properties - general Strong base –NaOH, KOH, Mg(OH)2, Ca(OH)2, Ba(OH)2 are completely ionized Organic bases – weak base, contain functional group(s) as below 수산이온 유기 알칼리 H+ 을 받아들임 1) a primary amine (-NH2) 일차아민 암페타민 2) a secondary amine (-NH-R) 이차아민 필로폰 3) a tertiary aliphatic, alicyclic amine (-NR2) 삼차아민 코카인 / 몰핀 4) most aromatic amines (very weak base, do not form salt with acid) 5) unsaturated heterocyclic nitrogens – also weak base 6) saturated heterocyclic nitrogens – similar to alphatic amines(1-3) 7) imine nitrogen(-N=C-), hydrazine nitrogens(-NH-NH2), amidine nitrogens(-NH-C=N-), guanidine nitrogens 대부분의 마약류는 아민을 함유한 유기 알칼리 이다 - 염의 형 염산 코케인 Morphine-free base Morphine-HCl 7
  • 8. Physical-Chemical Properties - general H N O O N O NH O HN N Cl O COOH NH O O Phenobarbital Acidic Diazepam Basic N O Aspirin Acidic Phenytoin Acidic N N O OH OH Codeine Basic Morphine H2N O S O O O Cl O OH O O O Heroin N O NH S O O Chlorthiazide Acidic 8
  • 9. Physical-Chemical Properties - general pH = pKa + log([A-]/[HA]) Cl NH2 N AM H N Cl H N MAM NH2 NH Guanabenz antihypertensive COOH Cl N NH N Chlorpheniramine antihistamine Mefenamic acid NSAIDs pH = pKa + log([conjugate base]/[undissociated acid]) 농도 해리안된 산의 농도 The actual meaning of pKa: the negative log of the dissociation constant, which is a measure of strength of an acid/base 산과 알칼리의 강도를 의 미 when pKa = pH, there is equal concentration of acid and its conjugate base. pKa helps to understand the nature of acid and base like pH: 산 , 알칼리 이해에 도움 pKa <2 --strong acid pKa >2 but <7 -- weak acid pKa >7 but < 10 -- weak base pKa >10 --strong base 9
  • 10. Physical-Chemical Properties - general Weak acid: ionization of weak acid 약산의 이온화 acetic acid (pKa=4.76) CH3COOH CH3COO- + H+ d in an acid medium – equilibrium shifts to the left ess ionization 산성용액 중 약산 – 이온화 억제 , 좌측으로 평형상태 이동 d in an alkaline medium – equilibrium shifts to the right 우측으로 평형이동 tion increases – ions from the acid & OH- from the alkaline 이온화 증가 medium combine to form water 물 형성 cidic drugs – less ionized in acid media than in alkaline media 성 약물 – 산성 용액 중 이온화 감소 / 알칼리성 용액에 비교해서 pKa of an acidic drug is greater than the pH of the medium – pKa 가 매질 be > 50% in its nonionized form – more likely to cross 의 pH 보다 lipid cellular membrane 클 경우 비이온화 – 세포막통과용이 , 흡수용이 Weak base : opposite of that for a weak acid 약 알칼리성 약물은 반대 50% 10
  • 11. Physical-Chemical Properties – charged states What Physical-Chemical Properties of the compound (drug) need to be considered? Charged states - quick review of pH and pKa (acid dissociation constant) 산해리상수 HA 평형상태 pKa = H+ pH - log + A- [ A- ] [ HA ] 농도 농도 Henderson-Hasselbalch Equation 11
  • 12. Physical-Chemical Properties - general Percent Ionization: rule of nine pH – pKa = 1, pH – pKa = 2, pH – pKa = 3, 90:10 99:1 99.9:0.1 이온화도 관련 -지용성관련 -세포막투과 관련 -흡수관련 - 용량관련 12
  • 13. Physical-Chemical Properties – charged states Salt – the combination of an acid & a base 염 – 산과 염기의 결합 ( 이온결합 ) with some exceptions, all salts are strong electrolytes 전해질 대부분의 염은 강한 전해질 이다 vast majority of drugs – organic molecules, drug salts 대부분의 약물 - 유기물 inorganic salt – HCl, H2SO4, NaOH, KOH 무기염 약물 염 - increased water solubility 수용성 증가 organic salt – with small, hydrophilic organic compds. (succcinic acid citric acid etc.) or lipophilic acid organic compds. (e.g., procaine) 유기염 - increased dissolution & bioavailability 용해도 증가 , 경구 유용도 증가 , 안정성 증가 Thyroid Hormone hypothyroidism Sildenafil citrate, 비아그라 13
  • 14. Physical-Chemical Properties – charged states Amphoteric compounds 양쪽성의 contain both acidic & basic functional groups 산 , 알칼리 기능 동시보 capable of forming internal salts, or zwitterions 자체 염 형성 often have dissolution problem 종종 용해도 문제 – 아미노산 Dissolution of Salt – alter the pH of an aqueous medium 물 매개체의 산도 변경 염의 용해 A neutralization reaction: when a acidic solution of an organic salt is 중화 반응 mixed with a basic solution, the unionized organic acid or base is likely to precipitate 침전 중화 후 비 이온화 되어 침전 된다 수용성이 낮아지므로 H N ClN O O Base O O O O O Salt form of Cocaine O Free base form of Cocaine 14
  • 15. Physical-Chemical Properties - general What Physical-Chemical Properties of the compound (drug) need to be considered? Physical – Chemical Properties      Charged states 전하를 가진 상태 Partitioning 분배 , 분할 Polar surface area (PAS) 극성표면면적 Solubility 용해도 Reactivity 반응성도 15
  • 16. Physical-Chemical Properties – charged states What Physical-Chemical Properties of the compound (drug) need to be considered? Charged states   The Charged State of a molecule is going to effect: Solubility 용해도 분자의 전하상태 Permeability 투과도 Interaction with proteins 단백질결합 The Charged State of a molecule is dependent on: 1) Functional group(s) present (pKa) 산해리상수 2) pH 산도 16
  • 17. Physical-Chemical Properties – charged states 마약류 염의 형태와 체내 흡수에 대해 논하시 오 What Physical-Chemical Properties of the compound (drug) need to be considered? Charged states 도변화 Formulation ( 위장관내 pH 의 변화 ) – 흡수 Digestive system or Blood Stream Stomach 위 pH 1.7 Duodenum pH 4.6 Jejunum 공장 pH 6.5 Sigmoid colon pH 8.0 s 자 결장 pH 5 ~ 8 pH 1.7 ~ 8 세포내 산 Inside a Cell compartment ~pH Mitochondria 8 Cytosol 7.3 ER 7.1 Golgi 6.0 Endosomes 5.7 Lysosomes 4.8 pH 4.8 ~ 8 17
  • 18. Physical-Chemical Properties – charged states What Physical-Chemical Properties of the compound (drugs) need to be considered? Charged states - quick review of pH and pKa pKa values of some important functional groups encountered by Forensic Tox. Chemist at pH = 7.4 중성 - 약알칼리성 alcohols protonated amines R2 H N R1 Protonated R3 O R H carboxylic acid O pKa ~ 4.5 de-Protonated NH2+ R N R N R R pKa ~ 13 +HN NH Partially Protonated pKa ~ 7 protonated pyridine guanidium O R Protonated R = alkyl pKa ~ 16 R = Ph (phenol) pKa ~ 10 pKa ~ 10.5 H protonated imidazole Protonated NH+ de-Protonated pKa ~ 5 18
  • 19. Physical-Chemical Properties - partitioning What Physical-Chemical Properties of the compound need to be considered? Partitioning / Permeability 분배 / 투과 Cell Lipid bi-layer Solvent non-miscible water (octanol) aqueous Water aqueous Permeability Partitioning 19
  • 20. Physical-Chemical Properties – partitioning 분배 , 분할 What Physical-Chemical Properties of the compound need to be considered? Partitioning / Permeability Partition coefficient P = Solvent non-miscible water (octanol) Water log P = log [ Soct] [Swater] 분배상수 [ Soct] [Swater] In general, most drugs have logP -2 to 6 In general, drugs targeting CNS have logP 2 to 4 Partitioning Active transport or other assistance mechanisms of permeability are not counted Many exceptions are known 많은 예외 존재 20
  • 21. Physical-Chemical Properties - Partitioning What Physical-Chemical Properties of the compound need to be considered? Partitioning / Permeability * clog P is a calculated log P Solvent non-miscible water (octanol) 계산치 * Many times these values are quite accurate Water * Accessible clog P calculator: ChemDraw Partitioning 21
  • 22. Physical-Chemical Properties - solubility What Physical-Chemical Properties of the chemicals need to be considered? Solubility 용해도 Concerned with intrinsic solubility of a molecule, although formulation techniques can help assist with some solubility problems 분자고유의 성질 포뮬레이션으로 용해도 문제 약간 해결 ( 여러 보조용매사용 ) Governed by thermodynamics 열역학 Increase solubility by: Reducing crystal packing forces Increasing favorable interactions with the solvent 용매와 반응성 증가 22
  • 23. Physical-Chemical Properties - reactivity What Physical-Chemical Properties of the toxicant need to be considered? Reactivity 반응성 – 안정성관계 , 흡수후 Small Molecule + Protein 대사체도 포함 Small Molecule-Protein conjugate 공유결합 형성 Protein – serves as Nucleophile Primarily the amino group of Lys and the Thiol of Cys Small Molecule – serves as the Electrophile 23
  • 24. Physical-Chemical Properties - reactivity What Physical-Chemical Properties of the toxicant need to be considered? Reactivity 반응성 Electrophile (E) 친전자 - electron-lover - accepts electrons (Lewis acids) - carries a partial positive charge - alkyl halides, acyl halides, carbonyl compounds etc. Nucleophile (Nu) 친핵 - nucleus-lover - donate electrons (Lewis bases) - carries a free pair of electrons - electron-rich chemical reactants, thols, ammonia, amines etc. 24
  • 25. Physical-Chemical Properties - reactivity What Physical-Chemical Properties of the toxicant need to be considered? Kojic acid, 미백제 Reactivity Small Molecule electrophile Acid Chloride O O O R Cl R δ+ O H N N H + R Cl H N X R = alkyl X = Cl, Br, I R EWG O H O EWG = electron withdrawing group Many others R R o-quinone Michael Acceptor Toxic effects R = alkyl R R O R Michael Acceptor R HN O X X = Cl, Br, I N H Cl NH2 R O + O- + H N O N H SH O H N S N H R O 25

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