hapter12 Principles of Pharmacodynamics and Medical Chemistry vol.4

Chapter12 今日のメモ☆

第四項はDrug actionのメカニズムに関するお話。
薬物は、receptor[受容体]（protein、enzyme、cell lipids、DNA/RAN)で様々な反応を起こすことで薬物作用を示す。

Agonist とAntagonist
 - Agonist[刺激薬]
    * Partial agonists
        full agonistと同じreceptorに結合するが、
        unable to elicit the same maximum response.
        lower/same intrinsic activity[内活性]

 - Antagonist[拮抗薬]
    * Pharmacological antagonist
        bind to either same site or at an allosteric site
        lack intrinsic activity
        subdivided into reversible, irreversibe, competitive, noncompetitive categories
    * Chemical antagonist
        ex) heparin (acid polysaccharide) & protamine (basic protein) : acid-base interaction
        ex) Chelating agents[キレート剤] : antidotes[解毒剤] for metal posoning
          = EDTA : Ca, lead[鉛]　= penicillamine : copper[銅] = dimercaprol : Hg, Au, antimony, arsenic[ヒ素]
    * Functional (or physical) antagonist
        bind at separate receptors.
         ex) Acetylcholine constricts[収縮する] the pupil[瞳孔] / Norepinephrine dilates[拡張する]the pupil

Interaction with Enzymes
 - Activation / increased enzyme activity
    induction of enzyme protein syntheesis
    by barbiturates, phenytoin, other antiepileptics[抗てんかん薬], rifampin,
    antihistamines, griseofulvin, oral contraceptives[避妊薬]
    * Allosteric binding
    * Coenzymes
        activate enzyme by complexation[錯体形成]
        ex) vitamin B complex, cofactors(metalic ions Na, K, Mg, Ca, Zn, Fe)

 - Inhibition / decreased enzyme activity
    interact with the apoenzyme, the coenzyme, enzyme complex (destroy protein conformation, bind)
    * reversible inhibition : noncovalent interaction (enzyme & drug)
    * irreversible inhibition : covalent interaction
    * Competitive inhibition
        mutually exclusive[独占的な] binding (substrate[基質] & inhibitor)
        can be overcome by increasing the concentration of the substrate
    * Noncompetitive inhibition
        binds to an allosteric site on the enzyme and change conformation of enzyme
        can NOT be overcome by the concentraion of the substrate

Interaction with DNA/RNA formation and function
 - Inhibition of nucleotide biosynthesis
    * Folic acid[葉酸] analogs (e.g., methotrexate, trimetrexate)
        inhibit purine & thymidylate synsesis by inhibiting dihydrofolate reductase[還元酵素]
    * Purine analogs (e.g., 6-mercaptopurine, thioguanine)
        antagonists in the synthesis of purine bases.
    * Pyrimidine analogs (e.g., 5-fluorouracil)
        inhibit thymidine synthetase

Inhibition of DNA / RNA biosynthesis
  drugs interfere with nucleic acid synthesis (antineoplastic agents[抗腫瘍薬])
 - interfere with DNA replication[複製]
    ex) intercalating agents[挿入剤] (e.g., anthracyclines, dactinomycin)
    ex) alkylating agents[アルキル化剤] (e.g., nitrogen mustards, nitrosoureas)
    ex) antimetabolites[代謝拮抗剤]
  - damage and destroy DNA
    ex) produce free radicals (e.g., bleomycin, anthracyclines)
    ex) inhibit topoisomerases (e.g., epipodophyllotoxins, mitoxantrone, irinotecan, topotecan)
 - interefere with microtubule assembly in the metaphase of cell mitosis[有糸分裂]
    e.g.,) vinca alkaloids & paclitaxel

Inhibition of protein synthesis
 -Tetracyclines : inhibit tRNA binding to the ribosome and block release of peptides from ribosome
 -Chloramphenicol & Erythromycin : bind to ribosome and inhibit peptidyl transferase and block peptid bound
 -Aminoglycosides : bind to ribosome and inhibit transcription[転写] and cause misreading of mRNA template
 -Quinupristin & Dalfopristin : constrict[抑える] the exit channel on rRNA that prevents synthesize polypeptide.

Interaction with cell membranes
 - Digitalis glycosides : inhibit the cell membrane's Na-K pump.
 - Quinidine : prolong both the polarized[分極] and depolarized[脱分極] state.
 - Local anesthetics[局所麻酔薬] : interfere with membrane permeability[浸透性] to Na & K.
 - Polyene antifungal drugs (e.g., amphotericin B, Nystatin) : cause leakage[漏出] of cellular constituents
 - Antibiotics (e.g., polymyxin B, colistin) : affect cell membrane permeability
 - Acetylcholine : membran permeability to cations↑
 - Omeprazole & lansoprazole : inhibit H/K pump and H↓ to stomach
 - antineoplastic