Chapter12 今日のメモ☆
第三回目の項はStructural Features[構造特性] & Pharmacologic activity[薬理活性]。
Nonspecific drugs[構造非特異的薬物]
- nonspecific drugs : drug molecule's physical characteristics > chemical structure
physical characteristics : cell membrane's lipid nature & drug's lipid attraction
ex)anesthetics[麻酔薬]、 hyponotics[睡眠薬]、bactericidal agents[殺菌剤]
Structurally specific[構造特異的薬物]
- specific drugs : drug's ability to bind to a specific endogenous receptor.
* Receptor-site theory[受容体部位説]
The lock-and-key theory
: complementary relationshiop[補完関係]、Not conformational change[立体構造変化]
Induced-fit theory
: complementary relationship、mutual conformational changes ex) allosteric inhibitors
Ocupational theory of responce
: proportional[比例する] to the number of receptors occupied by the drug
* Receptor-site binding[受容体部位結合]
ability to bind to a specific receptor (its binding ability, exactness of its fit to the receptor)
critical portion[臨界量] of the drug moleculeが関与(Not entire drug molecure)
pharmacophore[活性基] : critical portionを作っているfunctional group[官能基]
similar critical regions have similar qualitative 薬理学的反応を示す
the better a drug fits to the receptor site, the higher the affinity and the geater response.
agonist[作動剤] & antagonist[阻害剤]
Stereochemistry[立体異性体]
- Optical isomer[光学異性体]
asymmetric or chiral carbon[不斉炭素]を１つ以上含む
* Enantiomers[鏡像異性体]
dextrorotatory[右旋性](D/+) : clockwise
levorotatory[左旋性](L/－) : counterclockwise
* racemic mixture[ラセミ混合物] : D:L=1:1, optically inactive
鏡像異性体は、potency, receptor fit, biological activity, transport, metabolismが異なる。
ex) lovorphanol : narcotic[麻薬性]、analgestic[鎮痛性]、antitussive[鎮咳]作用有
ex) dextorphanol : only antitussive作用
* Diastereomers[ジアステレオマー]
at least two chiral centers、光学異性体のうち鏡像異性体でないもの
それぞれのジアステレオマーは、solubility, colatility[揮発度], melting pointにおいて異なる
* Epimers[エピマー]
special type of diastereomers
one chiral centerのみの立体は一が異なる化合物のこと
ex) α-glucose & β-glucose
- Geometric isomers[幾何学異性体]
* Cis-trans isomers[シス－トランス異性体]
biological properties & pharmacologic activityが異なる
ex) cic-diethylstil-bestrol & trans-dietylstilbestrol
- Conformational isomers[配座異性体](rotamer[回転異性体])
ex) trans conformation of acetylcholine－musucarinic receptor
ex) gauche conformation of it－nicotinic receptor
*Bioisosteres[生物学的等価体]
spatially[空間的に] & electronically equivalentのため、interchangeable[互換性]がある
isosteric replacement : potency↑, side effect↓, duration of action↑
isosteric analogs[類似体] : act antagonistically[阻害作用]を表す
ex) procainamide(-O- ⇒ -NH-) : amide(longer duration than procaine)
ex) alloxanthine(isostere of xanthine) : inhibitor of xanthine oxidase
Today's question
- Stereochemistry(立体異性体)の問題
Q: All of the following statements about a structually specific agonist are true except which one?
(A) Activity is determined more by its chemical structure than by its physical properties.
(B) The entire molecule is involved in binding to a specific endogenous receptor.
(C) The drug cannot act unless it is first bound to a receptor.
(D) A minor structural change in a pharmacophore can produce a loss in activity.
(E) The higher the affinity between the drug and its receptor, the greater the biological response.
A: (B)
The binding of drug to its receptor usually involves only specific functional group. These groups make up what is known as the pharmacophore of the drug molecule. Although the entire drug molecule is present at the receptor site, only a portion of it, the pharmacophore, is required for a biological response.
2013年1月23日水曜日
Chapter12 Principles of Pharmacodynamics and Medical Chemistry vol.2
Chapter 12 今日のメモ☆
第二回目はMedical Chemistryの項。
Natural Product
- Alkaloids (N containing compounds)
ex) morphine(opium poppyケシの果実), atropine(belladonnnaplant), colchicine(autumn crocus)
- Peptides / polypeptides (Polymers of amino acids)
ex) somatostatin, glucagon
- Steroids (derivatives 誘導体 of cyclopentanoperhydrophenanthrene)
ex) estradiol, testosterone, hydrocortisone
- Hormones
ex) insulin, thyroid hormones, conjugated estrogens
- Glycosides（配糖体）
ex) digotoxin, streptomycin, doxorubicin
- Vitamins
ex) water-soluble vitamines : B1, B2, B3, B6, B12, C, H lipid-soluble vitamines : A, D, E, K
- Polysaccharides
ex) heparin, tinzaparin, enoxaparin, sucralfate
- Antibiotics
ex) penicillin, tetracycline, doxorubicin
Synthetic Product
- chemical structures closely resembling
ex) hydroxymorphine, ampicillin
- similar spacing of functional groups
ex) losartan (peptidomimeticsペプチド模倣薬)
- completely new products
Physicochemical Properties（物理化学的特性）
- Drug Polarity（薬物の極性） ≒ drug's lipid and water solubility
* Partition Coefficient分配係数 (P) = [Drug]lipid ／[Drug]aqueous
※log係数で表される
* water solubility ( or hydrophilicity)
depends on two factors ; ionic character & hydroge-bounding capabilities(O-, N- )
* lipid solubility (or lipophilicity)
nonionizable hydrocarbon chains(-CH2-CH2-…) & ring systems (C6H6)
- Ionization of acids & bases
* ionization constant (Ka)
※ acidの場合 1×10[-3] ＞1× 10[-7], baseの場合はその逆
* negative log of ionization constant (pKa)
※ acidの場合 pKa = 3 (Ka = 1×10[-3] ) ＞ pKa=5 (Ka = 1×10[-5]), baseの場合はその逆
* Strong acid
ex) HCl, H2SO4, HNO3, HBr, HlO3, HClO4
ex) -COOH, Ar-OH, -SO3H, SO2NH-R, -CO-NH-CO-, -CO-CHR-CO-, CHN4
* Strong bases
ex) NaOH, KOH, Mg(OH)2, Ca(OH)2, Ba(OH)2,
ex) primary, secondary, or tertiary aliphatic or alicyclic amino group (-NH2, -NHR, -NR2)
ex) aromatic or unsaturated heterocyclic N (weakly basic)
ex) imine N (-N=C-), hydrazine N (-NH-NH2), amidine N (-NH-C=N-), guanidine N (CH4N3)
* Weak acids
ex) CH3COOHacetic acid(pKa: 4.76)
in an acid medium : the equilibrium shifts to the left. ionized < salt
in an alkaline (basic) medium : ionized > salt
* Weak bases is opposit to weak acid.
※percent ionization
[pH－pKa] = 1 then a 90:10 ratio, [pH－pKa]=2 then a 99:1 ratio
- Salt (combination of cid and base)
salts are strong electrolytes（電解質） （例外； Hg, Cd, lead acetate)
* Inorganic Salts
ex) HCl, H2SO4, KOH, NaOH
water solubility : aqueous dissolution↑
* Organic Salts
ex) succinic acid（コハク酸）, citric acid（クエン酸） ： hydrophilic
ex) procaine（プロカイン） ： lipophilic
* Amphoteric compounds（両性物質）
- neutralization reaction（中和反応）
強酸ｖｓ弱塩基、弱酸vs強塩基の組み合わせの際
non-ionized organic acidとnon-ionized organic baseがprecipitate（沈殿・凝集する）
：Drug Incompatibilities（適合性/配合性）に関与
ex) strong acid : nitrate(NO3), sulfate(SO4), hydrochloride(塩酸塩)
ex) strong base : Na, K, Mg
ex) "-onium" / "-inium"
Today's question
- Acid & Base(酸と塩基)の問題
Q: Which of the following salts will most likely yield an aqueous solution with a pH<7?
(A) Sodium salicylate
(B) Potassium chlorideMagnesium sulfate
(C) Magnesium sulfate
(D) Potassium penicillin
(E) Atropine sulfate
A: (E) Atropine sulfate
The solution must contain an acidic substance to have a pH <7. Atropine sulfate is a salt of a weak base and a strong acid; therefore, its aqueous solution is acidic. Sodium salicylate and potassium penivillin are both salts of strong bases and weak acids; therefore; their aqueous solutions are alkaline. Magnesium sulfate and potassium chloride are salts of strong bases and strong acids; therefore, their aqueous solutions are neutral.
第二回目はMedical Chemistryの項。
Natural Product
- Alkaloids (N containing compounds)
ex) morphine(opium poppyケシの果実), atropine(belladonnnaplant), colchicine(autumn crocus)
- Peptides / polypeptides (Polymers of amino acids)
ex) somatostatin, glucagon
- Steroids (derivatives 誘導体 of cyclopentanoperhydrophenanthrene)
ex) estradiol, testosterone, hydrocortisone
- Hormones
ex) insulin, thyroid hormones, conjugated estrogens
- Glycosides（配糖体）
ex) digotoxin, streptomycin, doxorubicin
- Vitamins
ex) water-soluble vitamines : B1, B2, B3, B6, B12, C, H lipid-soluble vitamines : A, D, E, K
- Polysaccharides
ex) heparin, tinzaparin, enoxaparin, sucralfate
- Antibiotics
ex) penicillin, tetracycline, doxorubicin
Synthetic Product
- chemical structures closely resembling
ex) hydroxymorphine, ampicillin
- similar spacing of functional groups
ex) losartan (peptidomimeticsペプチド模倣薬)
- completely new products
Physicochemical Properties（物理化学的特性）
- Drug Polarity（薬物の極性） ≒ drug's lipid and water solubility
* Partition Coefficient分配係数 (P) = [Drug]lipid ／[Drug]aqueous
※log係数で表される
* water solubility ( or hydrophilicity)
depends on two factors ; ionic character & hydroge-bounding capabilities(O-, N- )
* lipid solubility (or lipophilicity)
nonionizable hydrocarbon chains(-CH2-CH2-…) & ring systems (C6H6)
- Ionization of acids & bases
* ionization constant (Ka)
※ acidの場合 1×10[-3] ＞1× 10[-7], baseの場合はその逆
* negative log of ionization constant (pKa)
※ acidの場合 pKa = 3 (Ka = 1×10[-3] ) ＞ pKa=5 (Ka = 1×10[-5]), baseの場合はその逆
* Strong acid
ex) HCl, H2SO4, HNO3, HBr, HlO3, HClO4
ex) -COOH, Ar-OH, -SO3H, SO2NH-R, -CO-NH-CO-, -CO-CHR-CO-, CHN4
* Strong bases
ex) NaOH, KOH, Mg(OH)2, Ca(OH)2, Ba(OH)2,
ex) primary, secondary, or tertiary aliphatic or alicyclic amino group (-NH2, -NHR, -NR2)
ex) aromatic or unsaturated heterocyclic N (weakly basic)
ex) imine N (-N=C-), hydrazine N (-NH-NH2), amidine N (-NH-C=N-), guanidine N (CH4N3)
* Weak acids
ex) CH3COOHacetic acid(pKa: 4.76)
in an acid medium : the equilibrium shifts to the left. ionized < salt
in an alkaline (basic) medium : ionized > salt
* Weak bases is opposit to weak acid.
※percent ionization
[pH－pKa] = 1 then a 90:10 ratio, [pH－pKa]=2 then a 99:1 ratio
- Salt (combination of cid and base)
salts are strong electrolytes（電解質） （例外； Hg, Cd, lead acetate)
* Inorganic Salts
ex) HCl, H2SO4, KOH, NaOH
water solubility : aqueous dissolution↑
* Organic Salts
ex) succinic acid（コハク酸）, citric acid（クエン酸） ： hydrophilic
ex) procaine（プロカイン） ： lipophilic
* Amphoteric compounds（両性物質）
- neutralization reaction（中和反応）
強酸ｖｓ弱塩基、弱酸vs強塩基の組み合わせの際
non-ionized organic acidとnon-ionized organic baseがprecipitate（沈殿・凝集する）
：Drug Incompatibilities（適合性/配合性）に関与
ex) strong acid : nitrate(NO3), sulfate(SO4), hydrochloride(塩酸塩)
ex) strong base : Na, K, Mg
ex) "-onium" / "-inium"
Today's question
- Acid & Base(酸と塩基)の問題
Q: Which of the following salts will most likely yield an aqueous solution with a pH<7?
(A) Sodium salicylate
(B) Potassium chlorideMagnesium sulfate
(C) Magnesium sulfate
(D) Potassium penicillin
(E) Atropine sulfate
A: (E) Atropine sulfate
The solution must contain an acidic substance to have a pH <7. Atropine sulfate is a salt of a weak base and a strong acid; therefore, its aqueous solution is acidic. Sodium salicylate and potassium penivillin are both salts of strong bases and weak acids; therefore; their aqueous solutions are alkaline. Magnesium sulfate and potassium chloride are salts of strong bases and strong acids; therefore, their aqueous solutions are neutral.
2013年1月2日水曜日
Chapter12 Principles of Pharmacodynamics and Medical Chemistry vol.1
Chapter 12 今日のメモ☆
Pharmacodynamics(薬理学)とMedical Chemistry(医科学)の分野
この項では、基本に関しておさらい
Antagonist & Agonist（受容体作動薬と拮抗薬）
- Antagonist : lack intrinsic activity（内活性)
* competitive antagonist : reversible manner
* non competitive antagonist : irreversible manner. ex) MAO(mono amine oxidase)
Down-regulation and desensitization （抑制と脱感作)
- Down regulation : caused by continuous prolonged exposure. Degradation or inactivation of the receptor
- Desensitization : result of down-regulation. same concentration of the drug is reduced.
* homologous desensitization : desensitization to only ligands.
* heterologous desensitization : desensitization to several ligands.
- Hyperactivity / super sensitivity : long term exposure to receptor antagonist followed by abrupt cessation（突然の中止）
Not mediated by receptor
- Volatile（揮発性）anesthetic agent（麻酔薬）: lipophilic （膜浸透性↑）
- Cathartics（下剤）ex) Mg, Sorbitol : osmolarity↑= Change H2O distribution
- Antimetabolites（代謝拮抗薬） ex) Methotrexate, Cytarabin, 5-fluorouracil : structural analog（構造類似体）= incorporate into cellular componentに影響
- Antacid ex) Mg, Al, Ca : neutralize gastric acid
Response curve（反応曲線)
- Dose response relationship : up to maximum effect
- A quintal dose-response curve : Gaussian distribution（ガウス分布=正規分布）
- A grades dose-response curve（段階的投与）
* efficacy（有効性） : Emax(maximum effect)
* potency（効力）: relative measure
- A log dose-response curve
* efficacy : Emax (hight of its curve : the higher the curve, the greater the efficacy)
* potency : compared ED50 (50% of Emax) the smaller the ED50, the greater the potency
- A competitive antagonist shifts to the right and parallel (same Emax)
- A Noncompetitive antagonist shifts to the right and no parallel ( lower Emax)
- Addition（相加作用）: = sum of the individual effect
- Synergism（共同作用）: > sum of the individual effect
- Potentiation（相乗効果）: 独立して効果のないものが、一緒に使うことで効果を発揮して通常以上の効果を表すもの
- therapeutic index（治療指数）
: relative measure of the safety and effectiveness,
: ratio of the TD50 to ED50
: the greater the TD50 / the smaller the ED50, the greater the therapeutic index thus safer
- margin of safety（安全域）
: more practical term. Ratio of TD0.1 to ED99.9
Today's question
- Receptor(受容体)の問題
Q: A 72-year-old NAND with Hypertension and high dose propranolol for 20 years. He left home for a week and forgot to bring his medication with him. One day, he was found collapsed on the floor and was brought to emergency room. His blood pressure was 300/180, heart rate was 180 beat per minutes, and retinal hemorrhage was observed. Which of the following this explains this situation?
(A) The β-adrenergic receptors in the cardiac muscles underwent spontaneous mutation and became hyperactive.
(B) Reduction in the chronic antagonism of the β-adrenergic receptor led to down-regulation of the β-adrenergic receptor.
(C) The Propranolol that he had previously ingested remained in his body acted as a receptor agonist.
(D) Long-term administration of Propranolol results in desensitization of cardiac muscles to endogenous β-adrenergic stimulation.
(E) Reduction in the chronic level of receptor blockade results in super sensitivity to stimulation with endogenous catecholamins.
A: (E)
A chronic level of blocking the β-adrenergic receptor by propranolol results in up-regulation of the receptor level. When the patient ceased taking the drug, the cardiac muscles became super sensitive to stimulation with endogenous catecholamins. This resulted in the hypertensive crisis that caused cerebral hemorrhage and loss of consciousness.
Pharmacodynamics(薬理学)とMedical Chemistry(医科学)の分野
この項では、基本に関しておさらい
Antagonist & Agonist（受容体作動薬と拮抗薬）
- Antagonist : lack intrinsic activity（内活性)
* competitive antagonist : reversible manner
* non competitive antagonist : irreversible manner. ex) MAO(mono amine oxidase)
Down-regulation and desensitization （抑制と脱感作)
- Down regulation : caused by continuous prolonged exposure. Degradation or inactivation of the receptor
- Desensitization : result of down-regulation. same concentration of the drug is reduced.
* homologous desensitization : desensitization to only ligands.
* heterologous desensitization : desensitization to several ligands.
- Hyperactivity / super sensitivity : long term exposure to receptor antagonist followed by abrupt cessation（突然の中止）
Not mediated by receptor
- Volatile（揮発性）anesthetic agent（麻酔薬）: lipophilic （膜浸透性↑）
- Cathartics（下剤）ex) Mg, Sorbitol : osmolarity↑= Change H2O distribution
- Antimetabolites（代謝拮抗薬） ex) Methotrexate, Cytarabin, 5-fluorouracil : structural analog（構造類似体）= incorporate into cellular componentに影響
- Antacid ex) Mg, Al, Ca : neutralize gastric acid
Response curve（反応曲線)
- Dose response relationship : up to maximum effect
- A quintal dose-response curve : Gaussian distribution（ガウス分布=正規分布）
- A grades dose-response curve（段階的投与）
* efficacy（有効性） : Emax(maximum effect)
* potency（効力）: relative measure
- A log dose-response curve
* efficacy : Emax (hight of its curve : the higher the curve, the greater the efficacy)
* potency : compared ED50 (50% of Emax) the smaller the ED50, the greater the potency
- A competitive antagonist shifts to the right and parallel (same Emax)
- A Noncompetitive antagonist shifts to the right and no parallel ( lower Emax)
- Addition（相加作用）: = sum of the individual effect
- Synergism（共同作用）: > sum of the individual effect
- Potentiation（相乗効果）: 独立して効果のないものが、一緒に使うことで効果を発揮して通常以上の効果を表すもの
- therapeutic index（治療指数）
: relative measure of the safety and effectiveness,
: ratio of the TD50 to ED50
: the greater the TD50 / the smaller the ED50, the greater the therapeutic index thus safer
- margin of safety（安全域）
: more practical term. Ratio of TD0.1 to ED99.9
Today's question
- Receptor(受容体)の問題
Q: A 72-year-old NAND with Hypertension and high dose propranolol for 20 years. He left home for a week and forgot to bring his medication with him. One day, he was found collapsed on the floor and was brought to emergency room. His blood pressure was 300/180, heart rate was 180 beat per minutes, and retinal hemorrhage was observed. Which of the following this explains this situation?
(A) The β-adrenergic receptors in the cardiac muscles underwent spontaneous mutation and became hyperactive.
(B) Reduction in the chronic antagonism of the β-adrenergic receptor led to down-regulation of the β-adrenergic receptor.
(C) The Propranolol that he had previously ingested remained in his body acted as a receptor agonist.
(D) Long-term administration of Propranolol results in desensitization of cardiac muscles to endogenous β-adrenergic stimulation.
(E) Reduction in the chronic level of receptor blockade results in super sensitivity to stimulation with endogenous catecholamins.
A: (E)
A chronic level of blocking the β-adrenergic receptor by propranolol results in up-regulation of the receptor level. When the patient ceased taking the drug, the cardiac muscles became super sensitive to stimulation with endogenous catecholamins. This resulted in the hypertensive crisis that caused cerebral hemorrhage and loss of consciousness.
登録:
投稿 (Atom)