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.

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.

Chapter 13 Medicinal Chemistry and pharmacology : Drug Affecting the Nervous System vol.3

Chapter13 今日のメモ☆

第三項はCholinergic receptor[副交感神経受容体]に関連する医薬品のお話。

Cholinergic receptor はmuscarinic[ムスカリン受容体](M₁,M₂,M₃) & nicotinic receptors[ニコチン受容体](N_N,N_M)の二種類。(作用の強さ : musucarin>nicotin)

<ニコチンN_N受容体刺激反応>
 - 瞳孔 : 縮瞳(瞳孔括約筋 : 収縮)
 - 眼内圧 : 下降(毛様体筋 : 収縮⇒シュレム管 : 開口)
 - 心機能 : 抑制
 - 気管支 : 収縮
 - 胃腸運動 : 促進
 - 腸管平滑筋 : 収縮
 - 尿 : 出やすい(排尿筋 : 収縮)
 - 腺分泌 : 促進
※ 交感神経節：血管(収縮)、汗(分泌増加)

Acetylcholine is natural and most potent[強力な] cholinergic agonist[コリン作動薬].
    * quantenary amino alchol
    * unstable in the blood (hydrolysis[加水分解] by acetylcholinesterase : acetic acid + choline)
    * choline is reused in nerve termination[神経終末]

Acetylcholine

 - Direct-acting agonists
    acetyl group⇒carbamonyl group (more resisitant to acetylecholinesterase)
 - Indirect-acting agonists
    * reversible (short-acting) agents
    * irreversible (long-acting) agents : inhibit or block the activity of cholinesterase enzyme

Therapeutic indications
 - Direct-acting agonists
    M₃: micturition[頻尿] in acute nonobstructive urinary retention[非閉塞性尿閉] (e.g., bethanechol)
    M₃: miosis[縮瞳] in the treatment of glaucoma[緑内障] (e.g., pilocarpine)

 - Inrdirect-acting agonists (cholineesterase inhibitor)
    ex) reversible : physostigmine, neostigmine, distigmine, ambenonium
    ex) irreversible : echothiophate, sarin, parathion, organophosphate[有機リン酸化合物]
    M₁: congnitive function[認知能力]↑ in Alzheimer's disease (e.g., tacrine, donepezil, galantamine)
    M₂: treat paralytic ileus[麻痺性イレウス]、 tarchyarrythmias[不整脈] (e.g., edrophonium)
    M₃: miosis[縮瞳] in the treatment of glaucoma[緑内障] (e.g., pilocarpine)
    N_M: treat myathenia gravis[重症筋無力症](caused by nicotinic receptor hypofunction) (e.g., neostigmine, distigmine, ambenonium)

Adverse effects
 - topical S.E. : congested conunctivae[結膜]、myopic accommodation[近視調節麻痺]、transient lenticular opacity[一時的なレンズ混濁]
 - systemic S.E. : headache, syncope[失神], nausea, vomiting, bradycardia[除脈], hypotension, bronchospasm, abdominal cramps[腹痛], diarrhea, salvation[唾液分泌], sweating, lacrimation[流涙], flushing, tremor[震戦]

Cholinergic Antagonists
 competitively inhibit the activity of endogenous acetylcholine
 - 1. antimuscarinic agetns : inhibit muscarinic rceptor
 - 2. ganglionic-blocking agents : inhibit nicotinic receptor at the ganglia
 - 3. neuromuscular-blocking agents : inhibit nicotinic receptor at the neuromuscular

1. Antimuscarinic agents
 ex)Atropine (belladonna alkaloid) : its bulky shape prevents acetylcholine
  quanternary nitrogen or a tertiary nitrogen

Atropine

    * M₁：control Parkinson's disease symptoms (e.g., trihexyphenidy, biperiden)
    * M₁：control neurleptic-induced extrapyramidal reaction[錐体外路系反応] (e.g., benztropine, trihexyphenidyl)
    * M₁：induce sedation[鎮静]　(e.g., scopolamine)
    * M₁：motion sickness[乗り物酔い]↓ (e.g., scopolamine)
    * M₁：treat intoxication[中毒] by acute mushroom poisoning (e.g., atropine)
    * M₁: treatment of peptic ulcer[消化性潰瘍] (e.g., pirenzepine)
    * M₁：prophylaxis of miscarriage[流産] & premature labor (e.g., piperidolate)
    * M₃：mydriasis[散瞳] & cycloplegia[毛様体筋麻痺/弛緩] (e.g., homatropine, tropicamide)
    * M₃：GI smooth-muscle spasm↓ (e.g., propantheline)
    * M₃：treat bronchospasm bronchodilation[気管支拡張](e.g., ipratropium)
    * M₃：glandular[(分泌)腺] & bronchiolar[気管支] secretions↓ before anesthesia[麻酔] (e.g., atropine, glycopyrolate)
    * M₃：treat urinary frequency[頻尿] (e.g., propiverine, oxybutynine)

2. Ganglionic-blocking agents
    * N_N：hypertensive crisis (e.g., trimethaphan, mecamylamine, hexamethonium) by sympathetic activity↓

3. Neuromuscular-blocking agents : skeletal muscle relaxation
    * Endotracheal intubation[気管支内挿管], adjunct to surgical anesthesia[麻酔]
    * Bone placement & manipulation[関節を動かす手法]
    * electro convulsive shock therapy[電気痙攣ショック療法] : limit the trauma[外傷] by excessive
skeletal muscle contraction

 - competitive nondepolarizing[非脱分極] agents
    end-plate potential[終末電位]↓⇒depolarization threshold[閾値] is not reached
    ex) tubocurarine (curare[クラーレ] alkaloid) & metocurine : bulky molecules
           important structural feature : tertiary-quantenary amine
    ex) atracurium, doxacurium, mivacurium (potent synthetic analogues with isoquinolines[イソキノリン]
    ex) pancuronium, vecuronium, pipecuronium (steroid derivatives[誘導体])

 - noncompetitive depolarizing agents
     desensitize the nicotinic receptor
     slender aliphatic molecules, (Not bulky molecules like competitive agents)
     ex) succinylcholine (& gallamine)
           : short duration of action due to hydrolysis by pseudocholinesterase

Adverse effects
 - Topical adverse effects
    * hyperopic accommodation[遠視調節麻痺] & intraocular[眼内] pressure↑
 - Systemic adverse effects
    * headache, nervousness, drowsiness, diziness, palpitation[動悸], tachycardia[頻脈]
    * dry mouth, mydriasis[散瞳], blurred vision[視力障害], nausea, vomiting, constipation, urinary retention
    * respiratory paralysis[麻痺], histamine↑, bronchospasm, hypotention & hypertension,


Today's question
- Cholinergic agents(副交感神経薬)の問題
Q: Adverse reactions to atropine include all of the following except
(A) photophobia
(B) dry mouth
(C) sedation
(D) diarrhea
(E) tachycardia




A: (D) diarrhea
Classic sign and symptoms of muscarinic blockade, as with atropine, include mydriasis, which may cause light sensitivity (photophobia); dry mouth and constipation by decreasing secretory activity and motility in the GI tract; and tachycardia by inhibiting the normal inhibitory cholinergic control of the cardiac system.  Diarrhea is one of the common signs of cholinergic agonists (such as salivatio, lacrimation or tearing, urination and diarrhea).

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