Drug Abuse – 2약물남용 -2

Pharmacodynamic (PD) aspect of drugs약물 작용학 & 제형

Chungnam Natl. Univ.Dept. of Forensic Sciences

충남대 과학수사학과

Aug. – Dec., 2013

최성운 Sungwoon Choi

1

Class Objective – ‘Deep’ Understanding of Illicit Drugs & Psychoactive Materials

전체소개

Basics of Drug (Controlled Substances 조절약물 , 마약류 ) ---- What are they?약물 기초 무엇인가 ?

Drug Actions (Controlled Substances) ---- How they work?약물 작용 General concepts 일반 개념

Drug Action Mechanisms (Controlled Substances) Exact Mechanism – Receptor interactions – PD (drug to body) 작용학약물 작용기전

약용량 –정상작용 ( 효과 ), 과대용량 - 독작용

2

Class Objective – ‘Deep’ Understanding of Illicit Drugs & Psychoactive Materials

전체소개 … .. 계속

Pharmacokinetics(PK) – Body to drug 동역학 , 왜 ? 중요한가 약물의 체내에서의 움직임 마약류에 대한 신체의 작용

Types of Drugs (Controlled Substances) 약물의 타입 Name & Classify commonly abused drugs

약물의 종류Analysis of Drugs (Controlled Substances) 약물 분석 - 정성 , 정량 Lab Tests for Drug I.D. Analysis (Lab work is not ready) TLC, Common Chromatography, HPLC, LC-MS, GC-MS etc. 증거물로서의 약물목적 - 일반인 마약류 교육Can Teach about Drugs (Controlled Substances) to general public

3

Drug 광범위의 약물을 정의 하시오

Broad Def. : “any substance, all chemicals (natural, synthetic), - 천연 , 합성

광범위 약물 when absorbed( 흡수 시 ) into the body (skin also), changes

(alter)

정의 ( 변화 / 변경 ) normal body(mind) function - affect living

processes”

coffee, wine, beer, psychoactive mushroom – food ? Or drug ?

Medicine vs. Poison (dose 용량 ) – Music or Noise?

No drug produces single effect 단일효과를 내는 약물은 없다

기준이 정확치 않다

4

Drug

Pharmacological Def: “a chemical substance (medicinal agents) 의약품

치료약 정의 to treat, prevent, cure, diagnose disease, or 치료 ,

예방 , 진단

used to enhance( 증대 ) physical, mental well-being”

insulin – introduced from outside – a drug

외부투여 인슐린 - 약물

용도 :

Medication 치료용 / 의료용

Spiritual & Religious use - hallucinogens etc. 종교적 / 정신적 사용

Self-improvement – steroids 자가 증진 – 스테로이드 종류

Recreational Use – alcohol, tobacco, caffeine, etc. (psychoactive drugs)

기분 전환으로 사용

약물을 치료약 / 약물학적으로 정의

하시오

5

Drugs & Medicine

“Integral part of everyday life for many people” 다수인 에게 일상의 필수 / 필요 부분 Drug by regulation (government) 정부의 약물 규제

OTC (Over-the-Counter) No specific regulation 특정규제 없음 ex.) Cough(Cold) Medicine 감기약

BTC (Behind-the-Counter) By pharmacist, 약사에 의해 No Doc’s prescription needed 의사 처방 불필요

POM (Prescription( 처방 ) only Medicine) Oxycodone (OxyContin®) - Opioid Analgesic

6

Drug overdose (OD), Misuse & Illicit drug --- Def. 약물 과용 , 오용 , 남용을 구분해서 자세히 설명하시오

Drug overdose, overdose (OD) 과용 약용량에 대비해서 Ingestion( 섭취 ) or application( 적용 ) of a drug/other chemical substance in larger (greater) quantities than recommendation ( 권장량 ) 보다 과량 사용 --- toxic state or death (not applied to poisons) 독에 중독 / 사망 --- accidental, intentional, unintentional (suicide) 사고 , 의도적 , 비의도적

Drug Misuse 오용 for Prescription medications, linked to improper use 부적절한 사용 --- uses without prescription, route of administration, 처방없이 , 다른 투여경로 co-ingestion with alcohol etc. 예 ) 술과 복용

Illicit( 금제 , 불법 , 위법 ) drug – Not necessarily illegal (Schedule I & II), Taken outside its regulated or medically prescribed use, Unexpected purity Cocaine – narrow window – pleasurable sensation vs. overdose 예측할 수 없는 순도 – 좁은 안전 역 – 과용과 즐길 수 있는 용량 차이 일반적으로 마약만이 남용되는가 ?

7

Pharmaceutical Principles & Dosage Forms ( 독성물질 - 약물 의 제형 )

As Drug Evidence, 위 내용물검사 등 – 법 독성 관련 , 약물 ( 마약 ) 증거

Drug Product -- 마약은 ? Dosage form – solid, capsule, solution etc. 제형 – 고체 , 캡슐 , 액상 Active drug ingredient + excipients (inert, vehicle or formulation matrix) 활성약물 부분 비활성부분 대부분의 약은 활성부분 +비활성부분Tablet – oral route 정제 - 내복 tablet excipients 정제 중 비활성부분 diluent – fillers, make up the required bulk of the tablet 희석제 kaolin, lactose, mannitol, starch, powdered sugar etc. binders & adhesives 결합제 disintegrants 붕해제 lubricants, antiadherents, glidants colors & dyes 색소등 flavoring agents 미감제 artificial sweeteners 인공감미 adsorbents

8

Tablet types & classes 정제 종류 Compressed tablets 압축정 - 대부분 Multiple compressed tablets 다층 압축정 Repeat-action tablets Delayed-action & enteric-coated tablets 서방정 Sugar-coated & chocolate-coated tablet Film-coated tablet 필름정 Chewable tablets 씹어서 복용 Buccal & sublingual tablets 구강정

Capsules – oral 경구 캡슐제 Hard gelatin capsules – gelatin obtained from partial hydrolysis of collagen collagen from skin, white connective tissue, bones of animals Soft gelatin capsulesPowders 가루

Solutions – oral( 구강의 , 경구 ), injection( 주사 ) Syrup – P.O., high conc. of sucrose or other sugars Elixirs – P.O., 5-40% alcohol Spirits, Essences – high conc. of alcohol, 50-90% Tinctures

9

Solutions …contd. fluid extracts 액상 추출제 – ( 쌍화탕 ?) nasal( 비강 ), ophthalmic( 눈 ), otic, solution mouthwashes 구강세척제 astringents( 수렴제 ) – can be used as antiperspirants( 발한억제 ) – skin related (locally applied( 국소적용 ), precipitate protein, reduce cell permeability, ( 세포 투과도 변화 ) cause constriction( 수축 ), reduce secretion 분비억제 ) antibacterial solution 항생 액

Suspension – 화장품 등 또한 지문 등의 증거에 유류 lotions, magmasEmulsion – oil (drug) + waterOintments – semisolid preparations intended for external use 연고제Suppositories 식물의 잎 , 뿌리 , 꽃 , 등등한약

10

Drug Name 다양한 약물 이름 어떻게 약의 이름이 결정되나

1) Chemical Name : IUPAC, Assigned according to the rules of 화학명 nomenclature( 명명법 ) of chemical compounds N-acetyl-para-aminophenol(APAP, Tyrenol)2) Generic Name (Common Name) : A common established name 공정명 , 일반명 irrespective of its manufacturer acetaminophen, paracetamol3) Trade Name (Brand Name) : Always capitalized( 대문자 ) , selected 상품명 by the manufactured Tylenol

4) Street Name : 거리명

International Union of Pure and Applied Chemistry (IUPAC)

Acetyl group

11

Drug Name

1) Chemical Name : N-methyl-1-phenylpropan-2-amine methyl alpha-methylphenylethylamine.

2) Generic Name (Common Name) : Methamphetamine

3) Trade Name (Brand Name) : Desoxyn®

4) Street Name : “Crystal meth”, “Meth”, “Ice”, “Philopon”, “ 히로뽕” , etc.

Chemical Structure

Sites of action

VMAT: Vesicular Monoamine TransporterDAT: Dopamine Transporter

12

약물 - 마약류와 인체와의 상호작용 – 2 가지 작용 : 상호 밀접한 관계

Pharmacodynamics(PD) what drugs do to the body( 작용학 )약물이 인체에 행하는일

Pharmacokinetics(PD) What body does to the drug ( 약물 동력학 ) 인체가 약물에 행하는일

13

Pharmacodynamics(PD) what drugs do to the body( 작용학 ) “a branch of pharmacology that focuses on the study of the biochemical & physiological effects of drugs & the mechanisms by which they produce such effects” 약물학의 일부 분야로 생화학 , 생리학적 효과 , 기전을 연구

Effects of Drugs 약물의 효과

A. Perturbation of normal physiological processes

drug molecules – cellular components (receptors)

정상신체의 생리과정을 흐트린다 ( 변화시킴 )

B. Agonist & Antagonists 효능약 과 길항약

drug receptors – any macromolecular components 거대분자 , 수용체

ex.) chromosomal DNA – cisplatin (cross-linked, anticancer)

physiological receptors – for endogenous ligands 항암제중 – DNA 수용체

adrenergic receptors – adrenaline rush 아드레날린 러쉬

catecholamines

epinephrine

14

길항약 :자체는 약의작용이 없다 .체내 효력물질을차단하여 효과 냄

Pharmacodynamics(PD) what drugs do to the body( 작용학 )

Effects of Drugs 약물의 효과 효능 약 vs. 길항 약

agonist – drugs whose responses resemble the effects of

the endogenous molecules 체내물질과 유사한 작용 , 효능약

antagonist – lack intrinsic( 고유 , 본래 ) activity and produce effects by

competitively( 경쟁 ) or noncompetitively( 비경쟁적 ) inhibiting

the action of the endogenous( 내인성 ) molecules at the receptor

자신은 스스로 효과 없으나 내인성 물질을 차단하여 효과를 나타냄

ex.) Morphine – opioid receptor (CNS) – naloxone

rapid reversal of opioid-induced respiratory depression

호흡기 억제를 반전 / 파기 시킴

epinephrine15

길항약 :자체는 약의작용이 없다 .체내 효력물질을차단하여 효과 냄

Cell (Biological) Membrane 세포막 ( 구조 ) ---- 최초 접촉 후 흡수 시 , 피부 / 뇌 / 비강

Wikipedia.org

지질 이중층

극성비극성비극성극성

Details on molecular targets – Receptors - Basics

Types & Locations

Peripheral Membrane Proteins

Relatively Rare 외부 , 주변 - 드물다 Transmembrane Proteins

Most Common, GPCR 가로지르는 – 가장 흔하다 Intracellular Proteins 내부 Nuclear Receptors, Steroid Hormone Receptor 세포내부 , 핵의 내부

images from Google

More on Targets of Toxicant & Drugs

17

R (Receptor) + D (Drug, Ligand) - Agonist

R-D Responses 반응

(Free Drug)

Receptor & Ligands( 약물 ), Interaction

18

( 결합체 )

예로 인슐린 - 인슐린 수용체 - 작용기전

Molecular Targets are mostly …

수용체 , 효소 , 이온채널 , 트랜스포터

Receptors - Morphine, Cannabis etc.

“Receptor concept” 수용체 개념 Mediators of Cell Signaling 신호중재 Enzymes - Alcohol metabolism 대사 Catalyze Biochemical Reactions

Ion Channels - Benzodiazepine

GABA-A R: Mediators of Cell Signaling

Transporters - Cocaine

Mediators of Small Molecule Transport

Across Cell Membrane

Let’s look at Drugs’ Targets

receptor

Ion channels

enzyme

19

Theories on Receptor-Drug Interaction – Basics (법독성 - drug screening, immunoassay 에관련) --- 코카인과 트랜스포터의 상호작용

Rate Theory 결합체 - 결합/분리 율 Effect by rate of Associ. & Dissoci. of Drug-Receptor complex

Occupation(점유) Theory 점유 수용체 수 Effect by number of Receptor occupied by ligand Induced Fit Theory 수용체 구조 변경력 Receptor conformation change by ligand 수용체 구조변경

Ariens Theory Affinity – Ability to form Drug-Receptor complex Efficacy – Drug-Receptor complex’s Ability to response** Then what are the currently accepted theories?

Drug’s Target More on Targets … 약물 - 수용체 상호작용

Details on molecular targets – Receptors - Basics

Agonists 효능약 Full-, maximal response Partial- < maximal response

Antagonists 길항약 basal response

Inverse Agonist < basal response

More on Targets …

pharmacologycorner.com

21

Mechanisms of Drug (Toxicant) Action – some background review

1. Cell surface receptor 세포표면 수용체

a. Protein or glycoprotein 단백질 , 당 단백질

b. Highly specific, a variety of interactions-hydrophobic, van der Waals, ionic

Hydrogen, covalent bonds 특징적 , 많은 상호작용 – 결합

c. Chemical modification of the structure – change PK & PD properties of Drug

화학적 구조변경 – 물리화학적 성질 변경 – PK/PD 변경

2. Signal transduction by cell-surface receptors 표면에서 내부로 신호전달

Second messengers or effectors 2 차 전달 메신저 , 효과기 사용

22

Mechanisms of Drug (Toxicant) Action – some background review 계속 ----

3. Signaling mediated by intracellular receptors 세포내부 수용체

Steroid hormons-receptors, DNA binding proteins, alter transcription

스테로이드 호르몬 – 수용체 ( 핵내부 )- 전사 변경 – ( 약물 ) 효과

4. Target cell desensitization and hypersensitization 타겟세포 - 둔감 / 민감화

protective( 방어 ) mechanism, maintain homeostatic control to ( 항상성유지 )

prevent over-stimulation & under-stimulation

down-regulation; continued, prolonged exposure to drugs

desensitization-the result of down-regulation

hyper-reactivity or super-sensitivity 과대 / 과민 반응

after long-exposure( 장시노출 ), abrupt cessation( 급작스런 중지 )

– receptor up-regulation 수용체 증가

23

5. Pharmacological effects not mediated by receptors 비수용체매개 작용

a. Colligative drugs; volatile general anesthetic – lipophilic, interact with ( 마취약 ) lipid bilayer of cell membranes – depressed excitability

b. Cathartics( 하제 , 배변약 ); magnesium sulfate, sorbitol – increase osmolarity

c. Antimetabolites; methotrexate, cytarabine, 5-fluorouracil etc. 항대사제 – 주로 항암제 , 주로 효소관련 d. Antacids; aluminum hydroxide, calcium carbonate, 제산제 magnesium hydroxide etc. – neutralizing gastric acid

24

Efficacy ( 효능 ) & Potency ( 효력 ) from Dose-Response Curve

Potency: Morphine > Codeine dose 용량 관련

Efficacy: A=B=D > Aspirin from intrinsic activity 자체 활성

Potency is the relationship between the the dose of a drug and the therapeutic effect. It refers to the drug's strength. A drug is considered potent when a small amount of the drug achieves the intended effect. ED50

Efficacy is the ability of a drug to produce the desired therapeutic effect. Efficacy means that the drug is effective. When comparing two drugs that work equally, the one with the lower dose has a higher potency. They have equal efficacy. Emax

Emax A,B,D

Emax C

25효능과 효력을 비교 , 설명하시오

진통

용량

Neurotransmission 신경전달

26

Major Neurotransmitters (NTs) 주 신경전달 물질

27

Acetylcholine (Ach)

Acetylcholinesterase Nerve gases – 효소 억제 muscles-uncontrollably stimulated by Ach respiratory failure Curare(tubocurarine) 경쟁적 neuromuscular blocking Ach 접합부위 – cause paralysis

효소 Ach 접합부위

Esters

28

29

…. 계속

Dopamine 도파민

Catechol 카테콜

Major mediator of reward-reinforcing 주 매개체 mechanism 보상 - 강화Dopaminergic neurons in ventral tegmental area VTA

코카인 , 암페타민 작용부위All habit forming drugs

일차아민

도파민 관련 주요질병 – 범죄의 희생 Schizophrenia 정신분열 Parkinson’s 파킨슨씨 병

30

…. 계속

Dopamine Transporter 도파민 수송체 ( 재흡수 단백질 )

31

…. 계속

Norepinephrine (NE)

Adrenaline - adrenal gland( 부신 )Under stress -

대부분 교감신경계 + CNS (inactivation) by NE transporter, Monoamine oxidase(MAO) 대사암페타민 – 도파민 + 노르에피네프린 에 간접적 영향

32

…. 계속

r(gamma)-Aminobutyric acid (GABA) major inhibitory NT in the CNS, restored by active uptake barbiturates, benzodiazepines(eg. Valium), and alcohol

Glycine, Glutamic acid, Aspartic acid amino-acid NT in CNS

33

…. 계속

r(gamma)-Aminobutyric acid (GABA) major inhibitory NT in the CNS, restored by active uptake barbiturates, benzodiazepines(eg. Valium), and alcohol

Glycine, Glutamic acid, Aspartic acid amino-acid NT in CNS

34

…. 계속

Serotonin(5-HT), 5-hydroxytryptamine

5

5

5

43

2

1

35

…. 계속

Endorphines – β-endorphin: polypeptides, 31 amino acids Enkephalins interact with opioid receptor 내인성 물질 --- opium, heroin

Q & A others ?

36