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Chapter 56 Renal Failure vol.1

Chapter 56 今日のメモ☆

Acute Renal Failure

acute renal failure[急性腎不全：ARF] is sudden, potentially reversible interruption of kidney function, resulting in retention[滞留] of nitrogenous waste products in body fuluids.

 - Prerenal ARF[腎前性腎不全]
  腎臓の前にある血管（流れる血液が減るなど）、心臓が原因で起こるものもある
    * arterial blood volume↓
    * urinary losses
    * cardiac output↓
    * renal vascular obstruction
    * severe hypotension

 - Intrarenal ARF[腎性腎不全]
 急性腎不全の場合はこれをさす。薬剤によって起こるものがある。（アミノグリコシド系抗生物質　代謝性アシドーシス　（Na上昇による高血圧）
    * Acute tubular necrosis[急性腎尿細管壊死：ATN]（leading cause of ARF）
      ･ aminoglycosides, anethetics, pesticides, organic metal, radiopaque contrast materials[放射線造影剤]
      ･ ischemic injury[虚血性障害]
      ･ heme pigment[ヘム色素]－hemolysis[溶血], myoglobinuria[ミオグロビン尿]
    * Acute glomerulonephritis[急性糸球体腎炎]
    * Tubular obstruction[尿細管閉塞]
    * Acute inflammation
    * renal vasculitis
    * malignant hypertension[悪性高血圧]
    * radiation nephritis

 - Postrenal ARF[腎後性腎不全]
 腎臓のあとの尿管等が原因で起こり尿量が低下するもの。尿路の閉塞等。尿管の圧迫。尿道の閉塞。GFRの低下。
    * ureteral obstruction[尿管閉塞]
    * bladder obstruction[膀胱閉塞]
    * urethral obstruction[尿道閉塞]
    * extrinsic obstruction[外因性閉塞]

Pathophysiology
 -1. Intiating phase
  may not be well-defined clinically
    * Urine output↓ － >400mL/day : oliguria[欠尿症], >100mL/day : anuria[無尿症]
    ※ 40-50% of ARF patients are not oliguric or anuric.
    * Nitrogen waste products ↑
    － azotemia[尿毒症] : glomerular filtration↓& concentrating capacity↓
    － creatinine concentration↑, sulfate↑, phosphate↑, organic acid level↑
    * Na concentration↓ : due to dilution[希釈]
    * Hyperkalemia[高K血漿] : due to organic acids↑(metabolic acidosis)
    ※ without treatment, neuromuscular paralysis, respiratory muscle paralysis, cardiac arrest, arrhythmias and ultimately death.

 -2. Maintenance phase
  when urine output >500mL/day
  urinary output↑ does NOT signal recovery of renal function
    * Urine out put↑ － >300~500mL/day then double day by day
    * Azotemia may persist until urine output >1000~2000mL/day
    * carries risk of electrolyte abnormalities, GI bleeding, infection, respiratory failure

 -3. Recovery phase
  recovery of renal function may continue for a year.
  residual[後遺症] may persist indefinitely[永久的に]

Clinical Evaluation

Order of physical finindings
 1. Azotemia
 2. oliguria (50-60%)
 3. electrolyte abnormalities
 4. other severe systemic effects

 - Urine output : low (200~500mL/day), complete anuria is rare
 - hyperkalemia[高K血症](metabolilc acidosis)
    * neuromuscular depression (paralysis)
    * diarrhea and abdominal distention[腹部膨満]
    * slow / irregular pulse
    * electrocardiographic[心電図] change
 - uremia[尿毒症]
    * excessive nitrogen waste product retention
    * vomiting, diarrhea, edema, fatigue[疲労], coma
 - metabolic acidosis
    * mental status ↓, lethargy[倦怠感], coma
    * hypotension, pulmonary edema, ventricular fibrillation[心室細動]
    * nausea
    * respiratory abnormalities
 - hyperphosphatemia[高ホスファターゼ血症] : phosphate[リン酸塩] ↑
    * cause hypocalcemia[低Ca血症] : P-Ca（リン酸カルシウム複合体）形成のため
        * neuromuscular irritability, spasm, tetany[手足のけいれん]
        * hypotension
        * soft-tissue calcification[石灰化]
        * mental status change
 - hyponatremia[低Na血症] in the diuretic phase[利尿期（維持期）]
    * lethargy, weakness, unconsciousness
    * seizures[発作]
    * cognitive impairment[認知低下]
 - intravascular volume depletion[血管内容量低下] : prerenal failure[前腎性不全]
    * flat jugular venous[頸静脈] pulses
    * dry mucus membranes

Diagnostic test result
 - Urinalysis[検尿]
    * urinary sediment[沈殿物] examination
        ATN : renal tubular epithelial cells[尿細管上皮細胞]
        inflammatory dissease : red blood cell & white blood cell casts
        chronic renal failure : large number of white cell casts
    * hematuria[血尿] / proteinuria[タンパク尿] : （renal dysfunction[腎不全]）
    * urine-specific gravity[比重] : ranges 1.010~1.016
    * urine osmolality[浸透圧] ↑ （prerenal ARF）
 - urine Na & creatinine levels
    prerenal ARF : creatinne ↑↑ / Na ↓↓
    intrarenal ARF, ATN : creatinine ↓↓ / Na ↑↑
 - creatinine clearance : index of the glomerular filtration rate(GFR)
    renal dysfunction : cratinin clearance ↓↓
 - Blood chemistry[血液化学] : index of renal excretory function
    * blood ure nitrogen(BUN) ↑
    * creatinin concentration ↑
    * hemoglobin & hematocrit values ↑ : due to dehydration
    * abnormal serum elctrolyte values
      K > 5mEq/L, P > 2.6mEq/L(4.8mEq/L), Ca < 4mEq/L (8.5mg/dL), Na < 135mEq/L
      ※ Ca level must be correlated[相関がある] with the serum albumin level
    * abnormal arterial blood gas value (pH < 7.35) : metabolic acidosis
 - Renal failure index (RFI) : ratio of Na/creatinine
    prerenal ARF > 1, intrarenal ARF < 2
 - electrocardiography (ECG)[心電図] : evidence of hyperkalemia
    テント状T波、P波の消失、QRS幅延長
 - radiographic findings[放射線（X線写真）]
    * ultrasound[超音波] : upper urinary tract obstruction
    * radiography
      urinary tract calculi[尿管結石]
      enlarged kidney[腎臓肥大] : ATNによるものの疑い
      asymmetrical kidneys : renal artery disease, ureteral abstruction, chronic pyelonephritis[腎毒腎炎]
    * radionuclide scan[放射性核種スキャン]
      ATN : diffuse, slow, dense uptake
      acute glomerulonephritis : patchy or absent uptake
      ※正常な腎臓ほど吸収率が良い
    * Computed tomography(CT) scan
      better visualization of an obstruction
 - Renal biopsy[生検] : when otehr test results are inconclusive.

Chapter 13 Medicinal Chemistry and pharmacology : Drug Affecting the Nervous System vol.4

Chapter 13 今日のメモ☆
神経系第四回目はAnesthetics[麻酔]に関する項です。

Kinds of Anesthetics
＊Ideal general anesthetics
 induce anesthesia[感覚消失] rapidly and smoothly and permit rapid recovery of the patient once administration of the agent ceases.

- Volatile[揮発性] or inhalation anesthetics (gas or vapor[蒸気])
    * Nitrous oxide(N₂O)
    * nonflammable[不燃性] halogenated hydrocarbon & ether ; e.g., halothane, methoxyflurane

 - Nonvolatile or intravenous(i.v.), intramuscular(i.m.) anesthetics (aqueous solution)
    * water-soluble(short acting) ; barbiturates, cyclohexylamine, benzo-diazepines, butyrophenone, opioid
    * aqueous propylene glycol solution(compatible) ; imidazole, etomidate
    * emulsion(not mixed with others) ; dialkylphenol, propofol

Pharmacology
 - General anesthetics
    depress the CNS ; reversible loss of consciousness & loss of sensation

 - Inhalational anesthetics
    absorbed and excreted through the lungs.  these drugs are supplemented with below,
    * Analgesics[鎮痛薬] : concentration of anesthetics↓
    * Skeletal muscle relaxants : muscle relaxation during surgery
    * Antimuscarinic agents : buccal & bronchiolar secretions↓

Therapeutic indications
 - Inhalational anesthetics : general surgical anesthesia
 - Nonvolatile anesthetics : induce dowsiness and procide relaxation before the inhalational anesthetics
※ use of previous popular volatile anesthetics was discontinued due to their toxicity, flammable[引火性] and explosive[爆発性] properties.
    e.g., chloroform, cyclopropane, diethylether

Adverse effects
 - depress respiration, circulation and the CNS
 - hepatic & kidney function↓
 - cardiac dysrhythmia[不整脈] (e.g., halothane)


Today's question
- Anesthetics(麻酔剤)の問題
Q: The brief duration of action of an ultra-short-acting barbiturate is the result of a
(A) slow rate of metabolism in the liver.
(B) low lipid solubility, resulting in a minimal
(C) high degree of binding to plasma proteins.
(D) rapid rate of redistribution from the brain owing to its high liposolubility.
(E) slow rate of excretion by the kidneys.





A: (D)
Ultra-short-acting barbiturates are characterized by having branched or unsaturated 5,5-side chains and by having a sulfur atom in place of oxygen in the 2 position of the barbituric acid molecule.  These modifications of barbituric acid result in an extremely liposoluble molecule that is very soluble in lipid tissues.  After administration, an ultra-short-acting barbiturate readily crosses the blood-brain barrier but then is quickly redistributed into extracerebral tissue, resulting in a rapid loss of activity.  While these agents do remain in the body for a long time and seem to have slow rates of metablism and excretion, their long retention time is due more to their slow rate of leaching out of lipid tissue.

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

hapter12 Principles of Pharmacodynamics and Medical Chemistry vol.3

Chapter12 今日のメモ☆

第三回目の項はStructural Features[構造特性] & Pharmacologic activity[薬理活性]。

Nonspecific drugs[構造非特異的薬物]
 - nonspecific drugs : drug molecule's physical characteristics > chemical structure
    physical characteristics : cell membrane's lipid nature & drug's lipid attraction
    ex)anesthetics[麻酔薬]、 hyponotics[睡眠薬]、bactericidal agents[殺菌剤]

Structurally specific[構造特異的薬物]
 - specific drugs : drug's ability to bind to a specific endogenous receptor.
    * Receptor-site theory[受容体部位説]
        The lock-and-key theory
          : complementary relationshiop[補完関係]、Not conformational change[立体構造変化]
        Induced-fit theory
          : complementary relationship、mutual conformational changes ex) allosteric inhibitors
        Ocupational theory of responce
          : proportional[比例する] to the number of receptors occupied by the drug

    * Receptor-site binding[受容体部位結合]
        ability to bind to a specific receptor (its binding ability, exactness of its fit to the receptor)
        critical portion[臨界量] of the drug moleculeが関与(Not entire drug molecure)
        pharmacophore[活性基] : critical portionを作っているfunctional group[官能基]
        similar critical regions have similar qualitative 薬理学的反応を示す
        the better a drug fits to the receptor site, the higher the affinity and the geater response.
        agonist[作動剤] & antagonist[阻害剤]

Stereochemistry[立体異性体]
 - Optical isomer[光学異性体]
    asymmetric or chiral carbon[不斉炭素]を１つ以上含む
    * Enantiomers[鏡像異性体]
        dextrorotatory[右旋性](D/+) : clockwise
        levorotatory[左旋性](L/－) : counterclockwise
    * racemic mixture[ラセミ混合物] : D:L=1:1, optically inactive
        鏡像異性体は、potency, receptor fit, biological activity, transport, metabolismが異なる。
        ex) lovorphanol : narcotic[麻薬性]、analgestic[鎮痛性]、antitussive[鎮咳]作用有
        ex) dextorphanol : only antitussive作用
    * Diastereomers[ジアステレオマー]
        at least two chiral centers、光学異性体のうち鏡像異性体でないもの
        それぞれのジアステレオマーは、solubility, colatility[揮発度], melting pointにおいて異なる
    * Epimers[エピマー]
        special type of diastereomers
        one chiral centerのみの立体は一が異なる化合物のこと
        ex) α-glucose & β-glucose

 - Geometric isomers[幾何学異性体]
    * Cis-trans isomers[シス－トランス異性体]
        biological properties & pharmacologic activityが異なる
        ex) cic-diethylstil-bestrol & trans-dietylstilbestrol

 - Conformational isomers[配座異性体](rotamer[回転異性体])
        ex) trans conformation of acetylcholine－musucarinic receptor
        ex) gauche conformation of it－nicotinic receptor      
    *Bioisosteres[生物学的等価体]
       spatially[空間的に] & electronically equivalentのため、interchangeable[互換性]がある
       isosteric replacement : potency↑, side effect↓, duration of action↑
       isosteric analogs[類似体] : act antagonistically[阻害作用]を表す
       ex) procainamide(-O- ⇒ -NH-) : amide(longer duration than procaine)
       ex) alloxanthine(isostere of xanthine) : inhibitor of xanthine oxidase


Today's question
- Stereochemistry(立体異性体)の問題
Q: All of the following statements about a structually specific agonist are true except which one?
(A) Activity is determined more by its chemical structure than by its physical properties.
(B) The entire molecule is involved in binding to a specific endogenous receptor.
(C) The drug cannot act unless it is first bound to a receptor.
(D) A minor structural change in a pharmacophore can produce a loss in activity.
(E) The higher the affinity between the drug and its receptor, the greater the biological response.





A: (B)
The binding of drug to its receptor usually involves only specific functional group.  These groups make up what is known as the pharmacophore of the drug molecule.  Although the entire drug molecule is present at the receptor site, only a portion of it, the pharmacophore, is required for a biological response. 

Chapter12 Principles of Pharmacodynamics and Medical Chemistry vol.2

Chapter 12 今日のメモ☆

第二回目はMedical Chemistryの項。

Natural Product
 - Alkaloids (N containing compounds)
    ex) morphine(opium poppyケシの果実), atropine(belladonnnaplant), colchicine(autumn crocus)
 - Peptides / polypeptides (Polymers of amino acids)
    ex) somatostatin, glucagon
 - Steroids (derivatives 誘導体 of cyclopentanoperhydrophenanthrene)
    ex) estradiol, testosterone, hydrocortisone
 - Hormones
    ex) insulin, thyroid hormones, conjugated estrogens
 - Glycosides（配糖体）
    ex) digotoxin, streptomycin, doxorubicin
 - Vitamins
    ex) water-soluble vitamines : B₁, B₂, B₃, B₆, B₁₂, C, H     lipid-soluble vitamines : A, D, E, K
 - Polysaccharides
    ex) heparin, tinzaparin, enoxaparin, sucralfate
 - Antibiotics
    ex) penicillin, tetracycline, doxorubicin

Synthetic Product
 - chemical structures closely resembling
    ex) hydroxymorphine, ampicillin
 - similar spacing of functional groups
    ex) losartan (peptidomimeticsペプチド模倣薬)
 - completely new products

Physicochemical Properties（物理化学的特性）
 - Drug Polarity（薬物の極性）　≒　drug's lipid and water solubility
    * Partition Coefficient分配係数 (P) = [Drug]_lipid ／[Drug]_aqueous
    ※log係数で表される

    * water solubility ( or hydrophilicity)
      depends on two factors ; ionic character & hydroge-bounding capabilities(O-, N- )
    * lipid solubility (or lipophilicity)
      nonionizable hydrocarbon chains(-CH₂-CH₂-…) & ring systems (C₆H₆)

 - Ionization of acids & bases
    * ionization constant (Ka)
     ※ acidの場合　1×10[-3] ＞1× 10[-7], 　baseの場合はその逆
    * negative log of ionization constant (pKa)
     ※ acidの場合 pKa = 3 (Ka = 1×10[-3] ) ＞ pKa=5 (Ka = 1×10[-5]), 　baseの場合はその逆

    * Strong acid
      ex) HCl, H₂SO₄, HNO₃, HBr, HlO₃, HClO₄
      ex) -COOH, Ar-OH, -SO₃H, SO₂NH-R, -CO-NH-CO-, -CO-CHR-CO-, CHN₄

    * Strong bases
      ex) NaOH, KOH, Mg(OH)₂, Ca(OH)₂, Ba(OH)₂,
      ex) primary, secondary, or tertiary aliphatic or alicyclic amino group (-NH₂, -NHR, -NR₂)
      ex) aromatic or unsaturated heterocyclic N (weakly basic)
      ex) imine N (-N=C-), hydrazine N (-NH-NH₂), amidine N (-NH-C=N-), guanidine N (CH₄N₃)

    * Weak acids
      ex) CH₃COOHacetic acid(pKa: 4.76)
     in an acid medium : the equilibrium shifts to the left.  ionized < salt
     in an alkaline (basic) medium : ionized > salt

    * Weak bases is opposit to weak acid.
    
    ※percent ionization
      [pH－pKa] = 1 then a 90:10 ratio, [pH－pKa]=2 then a 99:1 ratio

 - Salt (combination of cid and base)
    salts are strong electrolytes（電解質）　（例外； Hg, Cd, lead acetate)

    * Inorganic Salts
      ex) HCl, H₂SO₄, KOH, NaOH
     water solubility : aqueous dissolution↑

    * Organic Salts
     ex) succinic acid（コハク酸）, citric acid（クエン酸） ： hydrophilic
     ex) procaine（プロカイン） ： lipophilic

    * Amphoteric compounds（両性物質）

 - neutralization reaction（中和反応）
    強酸ｖｓ弱塩基、弱酸vs強塩基の組み合わせの際
    non-ionized organic acidとnon-ionized organic baseがprecipitate（沈殿・凝集する）
     ：Drug Incompatibilities（適合性/配合性）に関与
     ex) strong acid : nitrate(NO₃), sulfate(SO₄), hydrochloride(塩酸塩)
     ex) strong base : Na, K, Mg
     ex) "-onium" / "-inium"


Today's question
- Acid & Base(酸と塩基)の問題
Q: Which of the following salts will most likely yield an aqueous solution with a pH<7?
(A) Sodium salicylate
(B) Potassium chlorideMagnesium sulfate
(C) Magnesium sulfate
(D) Potassium penicillin
(E) Atropine sulfate






A: (E) Atropine sulfate
The solution must contain an acidic substance to have a pH <7.  Atropine sulfate is a salt of a weak base and a strong acid; therefore, its aqueous solution is acidic.  Sodium salicylate and potassium penivillin are both salts of strong bases and weak acids; therefore; their aqueous solutions are alkaline.  Magnesium sulfate and potassium chloride are salts of strong bases and strong acids; therefore, their aqueous solutions are neutral.

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.