1. Renal 生理科 許明志 PhD, RPh hsumj@mail.cmu.edu.tw Office hours: 星期三早上 (8-12),

2. Contents Overviews of Renal function Assessment of renal function Regulation of Renal blood flow (RBF) & Glomerular filtration rate (GFR) Solutes and water homeostasis Acid-base balance

3. 1.Body fluid osmolality & volume 2.Maintain the normal cell volume is essential for cardiovascular system (through regulation of NaCl and H2O) 3.Electrolyte balance: Na +, K +, Cl -, HCO 3 -, H +, Ca ++, PO 4 3- （ intake = excretion ） Positive balance (intake > excretion) 、 Negative balance 4.Acid-balance balance: Lung & kidneys 5.Excreteion (metabolites, foreign substances): Urea （ aa ）,Uric acid (nucleic acid), Creatinine （ muscle creatine ）, end product of hemoglobin, drugs, pesticides, chemical ingested 6.Endocrine organ A.Renin(RAAS) 調整血壓, 以及 Na+, K+ 平衡,Renin(RAAS) B.calcitriol （ Vitamin D3 之代謝物 : 在 GI 幫助鈣的吸收 及 鈣骨骼之 deposition) C.Erythropoietin (when  erythrocyte production): 通常慢性 腎衰竭會產生 anemia

4. 腎功能之改變 -1 Decreased ability to excrete Na + → ↑ECF → hypertension （ occasionally, the patients have high plasma renin and angiotensin level → produce even further ↑↑ECF, and arteriolar vasoconstriction → HP ） Inability of kidney to produce NH 4 + →↓capacity to excrete H + in urine → metabolic acidosis

5. 腎功能之改變 -2 ↑K + （ become excessive ） → hyperkalemia （ acidosis ↑↑hyperkalemia ） 高鉀 –Acidosis in renal failure patients further ↑hyperkalemia –Patients with renal failure can produce membrane depolarization and cardiac failure

6. 腎功能之改變 -3 Renal failure causes ↓ECF ionic calcium concentration （ hypocalcemia ）低鈣 –↓ECF calcium （ hypocalcemia ） ↓excrete PO 4 -3 ↑ECF PO 4 -3 → ↓ECF Ca ++ （ Ca ++ x PO 4 -3 = 35-45 ） Reduce the ability of the kidney to active vitamin D →↓absorb calcium from GI Reduced [Ca +2 ] ECF promotes increased release of Parathyroid hormone （ PTH ）,

7. ☆ ※ 無法製造 NH 4 +

8. Diseases related with construction

9. Nephrotic syndrome Causes: Increased permeability of the glomerular capillaries to proteins Incidence: Proteinuria: protein excretion Indicting kidney disease (protein in urine) Develop edema and hypoalbuminemia

10. Nephrin A transmembrane protein, a major component of the slit diaphragm Gene mutation leads to the abnormal or absent slit diaphragms Develop massive proteinuria and renal failure So, Nephrin plays essential role in the formation of the normal glomerular filtration barrier

11. Alport’s syndrome Hematuria (blood in the urine) and progressive glomerulonephritis (inflammation of glomerular capillaries) 1-2% of cases of end-stage renal failure Cause: defects in type IV collagen, a major component of the glomerular basement membrane Result: basement membrane fails to serve as the barriers.

12. Nephrolithiasis (kidney stone) 80-90%: calcium salts Uric acid, magnesium-ammonium acetate Cysteine Formed by crystalization in a supersaturated urinary milieu. 如果 ureter is blocked with kidney stone, reflex constriction of the ureter around the stone elicits severe flank pain.

13. Micturition Process of emptying the urinary bladder –Progressive filling of the bladder Stretches the bladder wall and triggers a reflex initiated by stretch receptors –Micturition reflex

14. Assessment of renal function

15. Renal clearance Based on Fick principle

16. P x a ; P x v ： 表示 substance X in renal artery and renal vein plasma 之濃度 RPF a RPF v ： renal plasma flow rates In artery and vein U x ： [X] in urine V ： urine flow rate P x a (mg/ml) × C x = U x (mg/ml) × V (ml/min) C x = clearance of substance X Cx = （ Ux × V ） / P x a Fick Principle = Mass balance P x a ~ U x x V 正比關係

17. Assessment of renal function Renal Clearance (Cx) 的概念  A volume of plasma from which all the substance (substance x) has been removed and excreted into the urine per unit of time Cx = Mass of X excreted per unit of time Plasma concentration of X (Unit : volume/time) Ux * V Cx = Px

18. 病例 1234 Urea excretion  M/min 20040020020 Plasma Urea  M /min 36303 Ratio 67 77 3 and 4 are patients with kidney diseases Renal Clearance (Cx) 的概念 Ratio = Urea in Urine/Plasma Urea concentration Ratio is a reliable index as renal function (normal = 70)

19. Assessment of renal function 利用 Inulin Clearance (C in ) 求出 GFR Inulin: polymer of fructose: neither reabsorbed, secreted nor metabolized by the cells of nephron 所以每ㄧ分鐘之 Amt filtered = amt excreted P in x GFR = U in x V GFR = U in x V/P in Determine C in = determine GFR

20. Assessment of renal function Creatinine Clearance (C cr ) Creatinine:  By product of sketeal muscle creatine metabolism  Produced at a constant rate  Endogenous, not reabsorbed but small amount of secretion in urine

21. Glomerular Filtration Rate （ GFR ）  Index of kidney function  Essential in evaluating the severity and course of kidney diseases  GFR = the sum of filtration rate of all functioning nephrons  ↓GFR 最開始同時也是唯一之臨床表徵 疾病正在進行  ↑GFR （ recovery ）

22. 1. GFR 必須要降到很顯著才 會發現 P cr 下降 2. GFR: 120-100 ml/min P cr : 1.0-1.2 mg/dl

23. Glomerular filtration GFR = 90-140 ml/min, female (80-125); after 30 GFR declines with age The first step in the formation of urine is the production of an ultrafiltrate of the plasma at the glomerulus The ultrafiltrate is devoid of cellular components and protein free. Salt, organic molecules (glucose, aa), are similar as plasma

24. Ultrafiltration is driven by Starling forces across the glomerular capillaries, and changes in these factors alter the GFR. GFR and RPF are regulated by autoregulation The force responsible for the glomerular filtration of plasma are the same as those involved in fluid exchange across all capillariry beds

25. Hydrostatic and oncotic pressure

26. Hydrostatics of glomerular filtration Filtration coefficient （ K f ） : intrinsic permeability of the glomerular capillary and the glomerular surface area available for filtration

27. Determinants of glomerular filtration rate （ GFR ） Starling equation –GFR = K f × [ （ P GC - P BS ） - π GC ] Changes in K f : –Drugs, hormones could dilate the glomerular arterioles also increase K f –A reduction in P GC is caused by »Decline in renal arterial pressure »Increase in afferent arteriolar resistance »Decrease in efferent arteriolar resistance –Increased P BS reduces GFR. Acute obstruction (kidney stone) of the urinary tract increase P BS

28. Regulation of renal blood flow and GFR

29. Renal Blood Flow (RBF): 1.25 L/min 與 GFR 的速率有關 在近端腎小管之部位之調節電解質與水之再吸收 Participate in the concentration and dilution of the urine Deliver O 2, nutrients and hormones to renal cells and returning CO 2 and reabsorbed fluid and solutes to the general circulation Deliver substrates for excretion in the urine

30. Renal blood flow (RBF) Q (blood flow) = △ P (arterial pressure – venous pressure of ea organ) / R (resistance) RBF = aortic pressure – renal venous pressure/ renal vascular resistance

31. Autoregulation Regulate the tone of afferent arteriole –Change in arterial pressure Myogenic mechanism: 血壓上升, renal afferent arterioles is stretched, the smooth muscle contract, increase in the resistance of the arteriole offsets the increase in pressure, RBF and GFR remains constant –Change in NaCl concentration of tubular fluid Tubuloglomerular feedback: 增加 GFR, 增加 NaCl in the tubule fluid in the loop of Henle, increases resistance of afferent arteriole, 接下來 decrease GFR

32. Autoregulation - 不會因為血壓上升而影響 RBF 及 GFR -achieved by changes in vascular resistance Vascular R Precisely responds to changes of arterial pressure 90-180 mmHg Myogenic mechanism

33. NaCl 在 tubular fluid 會被 JGA 感受到, 然後 JGA 送訊號到 Afferent arteriole 產生 Resistance 所以 GFR 增加時, NaCl 於 Tubular fluid 增加, -------- Tubuloglomerular feedback

34. RBF= △ P/R R= k/r 4 P GC : hydrostatic pressure in the glomerular capillary AP  N 1 2 3 4

35. 荷爾蒙及神經調控 RBF and GFR Sympathetic nerve: binds to  1 receptor, which are located mainly on the afferent arterioles Angiotensin II : 收縮入球及出球小動脈, 所以降低 RBF 以及 GFR ( 出球對於 AgII 較敏感, 低濃度時作 用於出球, 濃度高時作用於入球及出球 )Angiotensin II Angiotensin-converting enzyme (ACE) ACE inhibitors increase RBF and GFR Prostaglandins NO Endothelin bradykinin

36. Regulation of GFR and RBF Extrinsic （神經、內分泌） –Renal sympathetic nerves （交感神經興奮 → NE → 血管 收縮 → ↓GFR ） –α 1 receptor （主要是位於入球小動脈 afferent artreioles ） ↓Effective circulating volume （ ECV ） : hemorrhage Fear, pain → ↓ RBF GFR –Angiotensin II （ ↓GFR ）Angiotensin II –Prostaglandins PGE 2 ， PGI 2 → 擴張 → ↑GFR NSAID ？NSAID Intrinsic –Autoregulation

37. Regulation of renal blood flow and GFR Prostaglandins – 正常人不會有影響 May not regulate RBF and GFR in normal healthy person –PGI 2 PGE 2 are produced locally within the kidney, and ↑RBF w/o changes of GFR--- 病態生理 –Prevent severe and harmful vasoconstriction and renal ischemia –Prostaglandin synthesis is stimulated by decreased ECV and stress, angiotensin II, and sympathetic nerves NO （ endothelium-derived relaxing factor ） –Counteracts vasoconstriction produced by angiotensin II and catecholamines –An increase in shear force acting on endothelial cells in arterioles –Acetylcholine, histamine, bradykinin, ATP → increase production of NO Abnormal production of NO: 1.Diabetes Mellitus, HP: Excess of NO production → glomerulat hyperfiltration and damage of the glomerulus 2.Salt intake triggers NO production

38. Regulation of renal blood flow and GFR Endothelin A potent vasoconstrictor Secreted by –Endothelial cell of renal vessels, –Mesangial cells –Distal tubular cells in response to angiotensin II, bradykinin, epinephrine, and shear stress –Elevated in number of disease states （ renal diseases with DM ） Bradykinin Kallikrein is a proteolytic enzyme produced in the kidney Kallikrein cleaves circulating kininogen to bradykinin, a vaodilator Bradykinin is a vasodilator that acts by stimulating the release of NO and prostaglandins

39. Adenosine Produced in the kidney Cause vasoconstriction of the afferent arterioles Reduce RBF and GFR Atrial Natriuretic peptide （ ANP ） Secreted by the heart rises with HP and expansion of extracellular fluid volume Cause vasodilation of afferent arteriole and vasoconstriction of efferent arterioles The net effect of ANP is therefore to produce a modest increase in GFR with little change in RBF Regulation of renal blood flow and GFR

40. Hemorrhage Hemorrhage → ↓arterial pressure → baroreceptor reflex → ↑sympathetic nerve to the kidney → Intensive constriction of afferent and efferent arterioles →↓RBF and GFR → ↑ Sympathetic → ↑release of epinephrine and angiotensin II → further vasoconstriction and ↓RBF GFR Rise of vascular resistance of the kidney →↑TPR ↑BP offset the fall in MAP caused by hemorrhage

41. Regulation of renal blood flow and GFR

43. Solutes and water homeostasis

44. Types of cellular transport pathway Na + = 145 mEq/L Na + = 12 mEq/L 感受到 Na + 進來時 會增加 Na + 進入 blood

45. Collecting duct: Principal cell

46. Solute and H 2 O reabsorption along the nephron 1. Proximal tubule: early segment 鈉與 HCO 3 - 或 glucose, amino acids, P i, lactate ㄧ齊被吸 收 Acetazolamide Diamox Key

47. Solute and H 2 O reabsorption along the nephron 2. Proximal tubule: late segment 鈉與 Cl - ㄧ齊被吸收 為何此處之 Cl - 會較高 因為 : Na + 在 early proximal tubule 較多 再吸收的關係

48. Proximal Tubule Na + transport –Early PT Glucose and amino acid Hydrogen ion ： driving the reabsorption of HCO 3 - ， In the early PT, HCO 3 - is the major anion reabsorbed with Na +, and luminal HCO 3 - falls 影響鈉吸收的藥物 –Phlorhizin （ block Na + - glucose cotransporter ） –Digoxin （ ↓ Na + K - - ATPase ） –Acetazolamide （ ↓H + - Na + counter transporter → H + 排出減少 → 身體偏 酸）。 CAI block bicarbonate reabsorption ：

49. Protein in the urine Nephrotic syndrome Fanconi’s syndrome: 無法吸收 aa, glucose, low-molecular-weight proteins. 因為其他地 方無法吸收, so….. Synthesis by thick ascending limb of Henle’s loop (Tamm-Horsfall glycoprotein: 由正常孕婦尿液轉化而來的 Tamm- Horsfall 糖蛋白會促進多型核白血球 PMN 的吞噬機能 )

50. Renal excretion of anions 因為 organic anions 競爭相同之 transporter, 因此增加 PAH 可以 降低 penicillin 之 secretion Glutamate 代謝

51. Renal excretion of cations (OC + ) Cimetidine-H 2 blocker, 經由 organic cation pathway 路徑 secretion. 會降低 procainamide (antiarrhythmic) 之 secretion.

52. Renal excretion of cytotoxic drugs blood Tubular fluid Mrp2 Mrp1 P-glycoprotein Multidrug resistance (MDR)-associated protein

53. Thick ascending limb Na + Cl - transport （ mainly of the reabsorption in Loop of Henle ） Basolateral membrane: –Key element in solute reabsorption by the thick ascending limb is the Na + /K + ATPase in the Lumen positive potential –Electrogenic: 2 Cl - for each Na + that exit lumen （ K + diffuse back out via channel ） –Positive lumen potential difference is an important force for driving Na + K + Ca ++ Mg ++ reabsorption Inhibited by Furosemide ®Furosemide ® – 若只阻斷 PT 則尿液還是會被濃縮 – 只有當 HL 被阻斷，才會使大量 Na + 水排出

54. Thick ascending limb Na + Cl - transport Loop diuretics: Furosemide 抑制 NaCl 再 吸收 抑制 K, Ca 再 吸收, 增加 K, Ca, excretion 增加水之 excretion Symporter

55. Bartter’s syndrome Autosomal recessive genetic disease: mutations in the gene coding for the 1Na+- 2K+-2Cl - symporter, apical K + channel, or baslateral Cl - channel in tick ascending limb 降低 NaCl, K + 再吸收 引起 hypokalemia, decrease in effcetive circulating volume (ECV), 刺激 aldosterone 之 分泌 A.Metabolic alkalosis B.hyperaldosteronism

56. Distal tubule

57. Early distal tubule Na + Cl - transport Reabsorbs ~5% of filtered NaCl –Na + enters cell via a Na + /Cl - cotransporter Inhibited by thiazide diureticsthiazide diuretics Relatively little water reabsorption, not responsive to ADH

58. Early distal tubule Na + Cl - transport Thiazide Diuretics

59. Late distal tubule Principal cells –Na + reabsorption, K + secretion Aldosterone –↑number of open Na + - channels at the apical membranes –↑Na + /K + ATPase and open apical K + channels Intercalated cells

60. Solute and H 2 O reabsorption along the nephron Distal tubule-last segments Amiloride: 間接抑制 Cl - 再吸收 所以抑制 K + 分泌, 造成 保鉀利尿劑

61. Liddle’s syndrome Genetic disorder characterized by an increase in extracellular fluid volume (ECFV) 會引發高血壓 病因 : Na + channel 之  或是  -subunit 產生 mutation 之後會增加在 apical cell membrane 之 Na + -channel 的活性 (overactive), 所以, Na + 再吸收也增加了, 同時 ECFV 也增加

62. Pseudohypoaldosteronism type I (PAH1) Increase in Na excretion A reduction in ECFV Hypotension

63. Hormones regulate NaCl reabsorption Angiotensin- II renin  PT  Na, H 2 O aldosterone Ag-II  TAL, DT/CT  Na, H 2 O ANP ECFV  CD  Na, H 2 O Urodilatin ECFV  CD  Na, H 2 O 交感神經 ECFV  PT  Na, H 2 O Dopamine ECFV  PT  Na, H 2 O ADH ECFV  CT/DT  H 2 O

64. 使用 angiotensin-converting enzyme (ACEI) 降低 angiotensin II – 在 PT 之 NaCl and water reabsorption –Aldosterone 分泌降低, 所以降低 NaCl 再吸收 –Systemic arteriole 會 dilation, 所以降低血壓 (TPR 下降 )

65. Collecting tubule Water reabsorption –Relatively impermeable to water in the basal state, and is responsive to ADH, with the insertion of water channels

66. Collecting tubule Intercalated cells –Hydrogen ion secretion –Bicarbonate reabsorption Hydrogen and bicarbonate formed from water and CO 2 in the cell in the presence of carbonic anhydrase. Bicarbonate returns to the circulation by Cl - /HCO 3 - exchanger at basolateral membrane, and H + secreted into the lumen by a H + /ATPase. Process is stimulated by acidemia –K + reabsorption Although cortical collecting tubule normally secretes K + under circumstances of K + depletion, net reabsorption occurs by the K + - ATPase of the intercalated cells

67. Control of body fluid osmolality and volume 腎臟藉著水分及 NaCl 的調整 可以有效維持 osmolality 及體 液恆定

68. Plasma osmolality 鈉離子是在 extracellular fluid (ECF) 中之主要離 子, 其它還有 Cl -, HCO 3 - –So, Na + is the major determinant of the osmolality of the ECF Rough estimate –2 × (plasma [Na + ]) = 285-295 mOsm/kg H 2 O In clinical set –2 × (plasma [Na + ]) + [glucose]/18 + [urea]/2.8 特別對於糖尿病人以及慢性腎衰竭病人有用

70. Control of body fluid osmolality: urine concentration & dilution Renal excretion of water is regulated to maintain water balance

71. Water reabsorption along the nephron –PT 65-70% filtered water reabsorbed isoosmotically Na + concentration and osmolality remains constant along PT. remember that although 65-70% of the filtered Na + is rebasorbed in PT, water follows readily （ because of the high water permeability of PT ）, and therefore the concentration of Na + is essentially unchanged along PT –HL Descending limb is always water permeable （ ~20% of filtered water reabsorbed ） Ascending limb is always water impermeable –Late distal and collecting tubule Water reabsorption only in the presence of ADH

72. Water reabsorption along the nephron

73. Antidiuretic Hormone （ ADH ） ADH determines –The concentration of urine –The amount of water reabsorbed –The volume of urine produced ADH binds to receptor on basolateral surfaces of principal cells –Activate guanulate cyclase –Lead to produce of water channels, and insert them into the luminal membranes of principal cells –Water is reabsorbed passively down its concentration gradient into the interstitium of both cortex and medulla

74. Antidiuretic Hormone （ ADH ） A 9 amino acid peptide Synthesized in supraotic and paraventricular hypothalamic nuclei ADH release is regulated by –More sensitive to changes in osmotic pressure Osmotic regulation –Osmoreceptor in anterior hypothalamus in the regions of the supraoptic nuclei Hemodynamic regulation –volume （ stretch-sensitive neurons in the cardiac atria and great veins ） –Arterial pressure （ stretch-sensitive neurons in the carotid sinuses and aortic arch ）

76. PKA

77. ADH action on kidney ADH Blood Collecting duct lumen Activate GicAMP *PKA H 2 O channel H2O 磷酸化 UT-A1 urea UT-4 Aquaporin 2 gene Aquaporin 2/H 2 O channel H2O

79. Inadequate secretion of ADH Central diabetes insipidus –Inherited 鮮少發生 –Head trauma, brain neoplasm, brain infection –Corrected by administration of exogenous ADH Nephrogenic diabetes insipidus –Collecting duct do not respond to ADH ( 原因 如下 ) Defects in ADH receptors Failure to insert water channel to apical membrane 大多是因為 hypercalcemia, Lithium,

80. 鋰鹽（ lithium ） 治療雙極性情感疾病 (bipolar disorder) 的第一 線用藥。 由於該藥物的治療濃度範圍狹窄 (0.6-1.2 meq/L) 及毒性副作用, 使得我們必須小心地監 測它的血中濃度 長期服用鋰鹽也會造成許多副作用, 腎原性尿崩 症 (nephrogenic diabetes insipidus ), 主要就是 因為長期服用鋰鹽所造成的結果

81. 經由腎絲球濾過的鋰有 60% 在近端小管被 再吸收， 20% 在亨利氏環及收集管間被再 吸收。鋰在腎小管會和鈉及鉀競爭，因 此鈉和體液的平衡不但會影響血中鋰濃 度也會影響其毒性。 在體內鋰會與鈉、鉀、鎂以及鈣離子競 爭而將它們從細胞內及骨頭中移出

82. 鋰離子可經由下列機轉來影響神經傳 遞物質的傳送 它可以經由減少 CAMP 的合成來抑制 Arginine vasopressin 的水合滲透 (hydro- osmotic effect) 效應。（這個機轉可能 可以解釋某些病人會產生腎原性尿崩 症以及甲狀腺功能的改變）

83. Syndrome of inappropriate ADH secretion (SIADH) 引起原因 –Infection and neoplasms of brain –Drugs (antitumor agents) –Pulmonary disease Plasma ADH is elevated Retain water Urine is more concentrated

84. Renin-angiotensin-aldosterone Captopril

85. Efferent is more sensitive to A-II than afferent Low concentration of A-II, constriction of efferent arteriole predominates High concentration of A-II, constriction of both afferent and efferent arterioles occurs

86. Phosphatidyl choline Arachidonic acid Prostaglandin Thromboxanes Leukotrienes CyclooxygenaseLipooxygenase Vasodilation Neutrophil function Phagocytosis Bacterial killing NSAID PAF NO Permeability Leukocyte trapping

87. Potassium homeostasis

88. K + homeostasis K + distribution K + balance 98% in cell 2% in ECF Normal [K] = 4mEq/L 增加上述物質 會增加 K + 進入細胞 而降低 plasma K + 體內之 K + 是由腎臟來 決定的

89. 調控 K + distribution Insulin: after K + ingestion; increase K + uptake into cell Epinephrine: Exercise  K + out of cell: increase by 2-4 mEq/L ( 如果再併用  -adrenergic blockers, 會導致致命性 hyperkalemia) Stress  K + uptake into cell Aldosterone: 留鈉排鉀 Plasma K + is increased  increase K + uptake into cell and excreted by kidney  decrease plasma K +

90. Factors 影響 K distribution Acid-base balance Plasma osmolality Cell lysis Exercise Drug-induced hyperkalemia

91. Two processes of cellular K + secretion

92. Factors regulate renal K secretion Plasma K Aldosterone Glucocorticoids: Antidiuretic hormone(ADH) GFR Tubular flowK excretion

93. [K + ] and aldosterone regulate renal K + secretion Hyperkalemia Na + /K + -ATPase Flow rate of tubular fluid Permeability of apical m. to K + Aldosterone K + secretion 增加 Driving force for K + across apical m.

94. Control of aldosterone and its effect on Na reabsorption and K secretion

95. ADH maintain constant K balance Even when H2O excretion is fluctuated Na uptake from apical m.  electrochemical driving force for K

96. Hyperkalemia Low aldosterone GFR below 20% of the normal 缺乏 –Insulin –Epinephrine –Aldosterone Burns Tumor lysis syndrome Rhabdomyolysis 橫紋 基溶解症 Gastric ulcer: blood cells are digested, and the K + released from the cells

97. 高血鉀 若出現血液中鉀質過高，便需限制進食高鉀質 食物，因高血鉀會引起嚴重的心臟傳導和收縮 異常而引致心跳減慢，甚至於死亡。由於鉀質 可從尿液中排走，當每日排尿量少於 1000 毫升， 便更應注意血液中鉀質是否過高。 高鉀食物有蔬菜、水果，如：胡蘿蔔、芹菜、 茼蒿、空心菜、菠菜、莧菜、香菇、馬鈴薯、 硬柿、蕃石榴、香瓜、香蕉、龍眼、葡萄、柳 橙 … 等。 易造成高血鉀的藥物有： ACEIs 、 Cyclosporine 、 Digitalis overdose 、 Heparin 、 Lithium 、 NSAIDs 、 Spironolactone 、 Succinylcholine 、 Trimethoprim 。