Chapter 13 Medicinal Chemistry and pharmacology : Drug Affectin the Nervous System vol.1

Chapter13 今日のメモ☆
Nervous System[神経系]の話です。新しい単語も頻出です。

Nervous systemに影響を与える医薬品は、CNS(Central Nervous System)[中枢神経]（brainとspinal cord[脊髄]で構成）やPNS(Peripheral Nervous System)[末梢神経]のneurotransmission[神経伝達]を調整している。
PNAはANS(Automatic Nervous System)[自律神経]とSomatic system[体性神経]で構成されており、ANSはsympathetic(adrenargic)[交感]及びparasympathetic(cholinergic)[副交感] branches神経で構成されている。
Nercous systemに影響を与えるdrugは、synaptic concentration[シナプス（間隙）の濃度]やreceptor actions of neurotransmitters[神経伝達物質]の調整によって効果を発揮する。

Adrenergic Agonists[交感神経刺激薬]

β-phenylethylamine

 - Direct-acting adrenergic agonists
    ex) epinephrine & norepinephrine : occur catecholamines (biosynthesized from tyrosine)
    * ethylamine chain (naturally adrenergic agonist)
    * N-substitution[置換] : small substituents[置換基]=α-receptor activity, larger substituents=β-receptor activity
    * removal of para(4) hydroxyl group(-OH)=α-receptor activity
    * meta(3) hydroxyl group(-OH) is α&β-activity
    * amino group ⇒ tertial amin : No α & β activity
    * catecholamines are inactivated by methylation(catechol-O-methyltransferase=COMT) & oxidative deamination(monoamine oxidase=MAO)

 - Indirect-acting adrenergic agonists
    * chemically related to the catecholamines but NOT direct-acting.
    (called as sympathomimetic amines[交感神経様作用のアミン])
    * effect by release of the endogenous neurotransmitters
    * only 1 or 2 or NO hydroxy group(-OH) : lipophilicity↑
    * Alkyl substitution at α-carbon : lipophilicity↑
    * N-substitution with large group : β-receptor activity↑

Pharmacology
Adrenergic peripheral responses[交感神経節後繊維における反応]
 - α-receptor
    * Postjunctional(postsynaptic)[神経節後] α₁-adrenergic receptor
        in radial smooth muscle[平滑筋] of iris[虹彩], arteries[動脈], veins[静脈], heart, sphincters[括約筋] of GI tract
        cause excitatory[興奮性] response (e.g., vasconstriction[血管収縮])
    * Prejunctional(presynaptic)[神経節前] α₂-adrenergic receptor
        inhibition of neurotransmitter release
        inhibit lipolysis[脂肪分解]↓,  platelet aggregation[血小板凝集]↑

 - β-receptors
    * Postjunctional β₁-adrenergic receptor
        in the myocardium[心筋]
    * Postjunctional β₂-adrenergic receptor
        relaxation of smooth muscle of the vasculature[血管系], bronchioles[気管支], and uterus[子宮]
        liver(glicogenolysis[グリコーゲン分解]↑⇒blood sugar level↑)
    * Postjunctional β₃-adrenergic receptor
        in fat cells, causes lipolysis[脂肪分解](potential treatment for obesity)

Therapeutic indications[治療指標]
 - Epinephrine : α & β-adrenergic agonist
    α₁ : hypotensive[低血圧]
    α₁ : prolong anesthetic[麻酔薬] solution(※)
    α₁,β₁,β₂ : hypersensitivity reaction, anaphylactic reaction
    α₁,β₂ : urinary frequency[頻尿](urinary bladder sphincters[括約筋]収縮(α₁)+smooth muscls 弛緩(β₂)
    α₁ : topically use : glaucoma[緑内障]
    α₁ : local use : arrest blood flow in epistaxis[鼻血], gingival[歯肉] surgery
    β₁ : restore cardiac arrest[心不全]
    β₂ : treat bronchospasm[気管支痙攣], bronchial asthma[気管支ぜんそく]
    β₂ : hypoglycemia？[低血糖](glicogenolysis[グリコーゲン分解]↑⇒blood sugar level↑)
    ※血管収縮⇒血流↓⇒局所麻酔の吸収↓⇒麻酔作用時間↑
    ※血圧反転が起こる(α receptor inhibitorによりα<β₂なりblood pressure↓)

 - Phenylephrine :  α₁-selective agonist
    α₁ : provide pressor[昇圧の] activity in hypotensive
    α₁ : prolong local anesthetic solution
    α₁ : relieve paroxysmal atrial tachycardia[発作性心房(上室)頻拍症](冠動脈血流量↑)
    α₁ : for nasal decongestion (e.g., naphazoline)

 - Chronidine & related :  α₂-selective agonist
    α₂ : used as antihypertensives (inhibit central sympathetic[交感神経] outflow)
    α₂ : topically in the eye to decrease intraocular pressure

 - Isoproterenol : β-adrenergic agonist
    β₁ : cardiac stimulant[強心薬]
    β₂ : used as bronchodilator[気管支拡張剤]
    ※N-methyl group=isopropyl (bulky group) : β-receptor activity↑

 - Dobutamine : relatively β₁-selective agonist (4 times stronger than Dopamine)
    β₁ : used to myocardial function↑

 - Terbutaline(2nd generation), salbutamol & tulobuterol(3rd generation) : β₂-selective agonist
    β₂ : used as systemic[全身] or local bronchodilators in the treatment of asthma
    β₂ : relax uterine smooth muscle in the treatment of premature labor[早産]　(ex ritodrine)

In-direct acting drugs
 - Amphetamine & Metamphetamine
 - Tyramine
    free NAd[ノルアドレナリン] ↑& inhibit MAO : sympathomimetic effect[交感神経興奮作用]

mix(direct and indirect) acting drugs
 - Ephedrine, Metylephedrine
    Central nerve excitatory effect (pass through blood-brain barrier)
    α : vascular contraction (indirect acting)
    β₂ : bronchial dilatation (direct acting)
    ※they are not inactivated by COMT & MAO
    ※β₂-activity : Metylephedrine>Ephedrine, α-activity : Ephedrine>Metylephedrine

 - Dopamine
    small amount=D₁ : vascular dilatation[血管拡張]
    medium amouont=β₁ : myocardial contraction[心筋収縮](血圧&心拍数は変わらない:D₁作用のため)
    large amount=α₁ : vascular contraction

Adverse effects - cardiac dysrhythmias[不整脈]
 - cerebral hemorrhage[脳出血]
 - pulmonary hypertension[肺高血圧]、edema
 - anxiety, headache, rebound nasal congestion
 - psychic dependence[精神的依存](e.g., amphetamine)
 - schizophrenic disorder[統合失調症], extrapyramidal symptom[錐体外路症状](e.g., dopamine)

Today's question
- Adrenergic agents(交感神経薬)の問題
Q: Which of the following drug is considered to be the agent of choice for anaphylactic reactions?
(A) clonidine
(B) isoproterenol
(C) epinephrine
(D) phenylephrine
(E) terbutaline




A: (C) epinephrine
Of the adrenergic agonists listed in the quesion, only epinephrine, because of its broad, nonselective α- and β-activity, is an agent of choice for anaphylactic reactions.  Epinephrine improves circulatory α- and respiratory function and counteracts the vascular effects of histamine-related anaphylaxis.