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 : E_max (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 E_max)
- A Noncompetitive antagonist shifts to the right and no parallel ( lower E_max)

- 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 TD_0.1 to ED_99.9


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.