Chapter 13 Medicinal Chemistry and pharmacology : Drug Affecting the Nervous System vol.2

Chapter13 今日のメモ☆

今回はAdrenergic Antagonistのお話。

antagonists has little resemblance structure to the agonist.
 - α-adrenargic antagonist :
    α₁ : vascular relaxation
    α₂ : free NAd⇒heart function↑
    α₂ : vascular contraction, smooth muscle contraction, myometrial contraction[子宮筋収縮]
 - β-adrenargic antagonist :
    catechol ring can be replaced.
    The length of the side chain is important
    β₁-selective agents may lose their selectivity at higher doses and thus block β₂-receptors as well.
    side chain hydroxyl, as well as propyl or other bulkyl substitution on the chain nitrogen
    β₁ : heart receptor block : myocardial constraction↓, heart beart↓, cardiac output↓
    β₁ : renal glomerulus[腎糸球体] block : renin secretion↓
    β₁ : fatty tissue block : lipase activation↓ ⇒ lipolysis↓
    β₂ : vascular smooth muscle block: vascular contraction
    β₂ : bronchial smooth muscle block : bronchial contraction
    β₂ : liver block : glicogenolysis↓ ⇒ blood sugar level ↓

 - Adrenergic antagonists inhibitor[アドレナリン作動性神経遮断薬]
    inhibit free NAd or depletion[枯渇] of NAd

Therapeutic indications
 - Ergotamine & Ergometrine : competitive α₁/α₂ antagonists
    α₂ : smooth muscle contraction & vascular contraction (migraine headache[片頭痛] : 脳血管収縮)
    α₂ : myometrial contraction[子宮筋収縮]
    ※Ergometrine : vascular<myometrial : atonic uterine bleeding[適応：弛緩性子宮出血]

 - Trazoline & phentolamine & Phenoxybenzamine : competitive α₁/α₂-antagonists
    α_1? : relieve vasospasm[血管痙攣] in Raynaud's syndrom[レイノー症候群]
    α₁ : acute hypertensive
    α₂ : heart function↑

 - Prazosin & related : α₁-selective antagonists
    α₁ : vasodilation[血管拡張] (antihypertensive agents)
    α_1D&A : treat urination disorder[排尿障害] (& 良性前立腺過形成)(e.g., tamsulosin, naftopidil)
    ※it doesnt affect α₂ (heart rate) so that less tachyrhythmia[頻脈]

 - Labetalol & Carvedilol : selective α₁-blocking & β-blocking
    α₁ : used for hypertension

 - Propranolol : β₁/β₂ -antagonist
    β₁ : used for prophylaxis of angina pectoris[狭心症]
    β₁ : supraventricular[上室性] & ventricular dysrhythmias[心室性リズム障害]
    β₁ : antihypertensive(heart rate↓, renin secretion↓)
    β₂ : 禁忌:bronchial asthma(bronchial contraction↑)
    ※negative inotropic agent[変力薬] in hypertropic obstructive cardiomyopathy[異常肥大閉塞性心筋症], negative chronotropic agent in anxiety & hyperthyroidism[甲状腺機能亢進症]

 - Pindolol : β₁/β₂ -antagonist
    ※simlar to Propranolol
    weak β-agonist activity
    heart β₁ : 心機能の過度の抑制が避けられ、高齢者に使いやすい
    vascularβ₁ : 血管収縮が起こらず、血管動態が悪化しにくい

 - β₁-selective antagonists (e.g., metoprolol, betaxolol, atenolol, acebutolol)
    β₁ : hypertension, tachyarrhythmias[頻脈性不整脈], angina pectoris[狭心症]

 - Betaxolol & Timolol
    decrease ciliary body[毛様体] production of aqueous humor[房水] (tropical treatment of glaucoma)

- Reserpine
    Depletion[枯渇] of NAd(&Adrenaline& dopamine& serotonin)  (取り込み阻害により、inactivate by MAO&COMT) : treat hypertension

 - Guanethidine
    inhibit free NAd by membrane stabilizing effect[膜安定化作用] : treat hypertension
    ※it doesnt affect central nervous function

 - α-methyldopa
    inhibit synthesis of NAd
    α₂ agonist : free NAd↓, vascular relaxation : treat hypertension

Adverse effects
 - Phenoxybenzamine : orthostatic hypotension, tachycardia[頻脈], & inhibision of ejaculation[射精], miosis[縮瞳], nasal congestion
 - Prazosin : sudden syncope[失神], orthostatic hypotension[起立性低血圧], diziness, headache, drowsiness, palpitations[動悸], fluid retention[体液貯留], priapism[持続性勃起]
 - Propranolol & Metoprolol: bradycardia[除脈](β₁) , congestive heart failure[うっ血性心不全](β₁), serum triglycerides↑(β₁), HLD lipoprotein cholesterol↓(β₁), blood sugar level↓(β₂)、blood dyscrasias[造血機能障害], proriasis[乾癬], depression,  hallucinations[幻覚], transient hearing loss[一時的難聴], withdrawal[離脱症状]
 - Reserpine : extrapyramidal disturbance[錐体外路障害], depression, nasal congestion, diarrhea, peptic ulcer, bradycardia[徐脈]


Today's question
- Adrenergic & Cholinergic agents(交感神経＆副交感神経薬)の問題
Q: Which of the following agents would not be appropriate in the treatment of glaucoma?
(A) atropine
(B) pilocarpine
(C) physostigmine
(D) timolol
(E) epinephrine




A: (A)
Both direct-acting(e.g., pilocarpine) and indirect-acting (e.g., physostigmine) cholinergics may be used in glaucoma to increase cholnergic activity and facilitate outflow of aqueous humor.  Similarly, both adrenergic β-agonist(e.g., epinephrine) and adrenergic antagonists (e.g., timolol) may be used respectively to increase outflow and decrease production of aqueous humor. Atropine is contraindicated in glaucoma because its anti-cholinergic effects can block the outflow of aqueous humor and, consequently, increase intraocular pressure.