泌尿系统教学课件：Drugs and the Kidney.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,Drugs and the Kidney,Introduction,Renal dysfunction may affect clearance and distribution of drugs.,eg.phenobarbital,Drugs may directly influence renal,function.,eg.,dopamine,Eeffect of renal impairment,on drug excretion,The Processes of Drug in the Body,free,circulation,Bound drug,Free drug,metabolites,receptor,B,F,tissue,bound,excretion,absorption,metabolism,The Drug Processes in the Body,The Classifications,Absorption,吸收,Distribution,分布,Metabolism,代谢,Excretion,排泄,Disposition,处置,:,transportation,and,transformation,Elimination,消除,:,metabolism and excretion,First-order Elimination Kinetics,一级消除动力学,The character of first-order kinetics is that the,rate of elimination is directly proportional to,the drug dose(linear relationship),here the,half-life time keeps constant and has nothing,to do with the amount of drug in the body.,Most drug are eliminated with this kind of,kinetics in their metabolism capacity.,Zero-order Elimination Kinetics,零级消除动力学,The character of zero-order kinetics is that,the rate of elimination is constant,i.e.,independent of drug doses,and that the half-,life time is positively relates to the drug doses.,When the concentration of drug exceeds the,capacity of the metabolism of the body,the,drug is eliminated with zero-order kinetics.,And then turn to the first-order kinetics,elimination.,Minimum effective concentration(MEC),The concentration inducing the minimal effect.,Minimum toxic concentration(MTC),Elimination half-life time(t,1/2,):,The time,required for any given drug concentration in plasma to decrease by half.,TimeConcentration(effect)Curve,时,量（效）曲线,Transportation of Drug Molecules,Modes of transportation,转运方式,(1)Filtration,滤过,(2)Simple diffusion,简单扩散,(down hill),Passive transport,被动转运,No need for energy,carrier.,No saturation limited.,No competitive inhibition.,Passive Transport,by Factors,Affected by properties,areas of membrane,concentration between memb.,and properties of drug:molecular size,lipid solubility,polarity.,Ion trapping(,离子障,):,non-ionic,drug is free to penetrate while ionic drug is limited to one side of the biomembrane.,Transports of weak acidic and weak basic drug by Handerson-Hasselbalch Equation,Weak acidic drug,weak basic drug,HA H,+,+A,-,BH,+,H,+,+B,Ka=,H,+,A,-,/,HA,Ka=,H,+,B,/,BH,+,pKa=,A,-,/,HA,pKa=,H,+,B,/,BH,+,pKa=pH-log,A,-,/,HA,pKa=pH-log,B,/,BH,+,pHpKa=log,A,-,/,HA,pK pH=log,BH,+,/,B,when pH=pKa,A,-,=,HA,B,=,BH,+,Transports of weak acidic and weak basic drug by Handerson-Hasselbalch Equation,pH,pKa=log,A,-,/,HA,pK,pH=log,BH,+,/,B,HA/A,-,=10,pka-pH,BH,+,/,B,=,10,pka-pH,A,-,/HA=10,pH-pka,question,Aspirin PKa=3.5,，,PH(Stomach,）,=1.5,，,PH,（,blood,）,=7.5,，,PH,（,urine,）,=6.5,The extent of dissociation in stomach?,The extent of dissociation in blood?,(Drug in blood)/(drug in stomach)?,(Drug in blood)/(drug in urine)?,Absorption,The movement of a drug from its site of,administration into the blood circulation.,The pathways of absorption,Gastroentestinal pathway,Steps,：,gastric stasis,，,gastric acidity,，,concurrent treatment drugs,Distribution,Conception,The process by which a drug leaves the blood circulation to enter the extracellular fluids and the tissues of the body.,Parameters of kinetics,Apparent volume of distribution,(,表观分布容积,V,d,),V,d,means that the ratio of in vivo drug quantity verses concentration in plasma when the drug reaches the dynamic equilibrium in the body.,V,d,=A/C,0,=A/AUC x K,e,(L),Apparent volume of distribution,For instance,if the V,d,of a drug is about 3-5L,this drug may mainly distribute in the blood.,If the V,d,of a drug is about 10-20L,the drug,chiefly distributing in plasma and extacellular,fluid.And if a drug has the V,d,of 40L,the,drug could distribute in extra-cellular and,intracellular fluids,indicating its widespread,distribution in whole body.,Importances of Vd,V,d,:5L(plasma),1020L(systemic fluid),40L(tissue and organs),100L(concentrate in some organ or large area of tissue),a 70kg,male,blood volume is 5.5L,plasma 3L,extracellular fluid is 12L,total body fluids about 42L,V,d,of aspirin is 11L,diazepam 80L,morphine 230L.,Factors Affecting Drug Distribution,a.Plasma protein binding,血浆蛋白结合,Acidic drug-albumin,basic drug-albumin,lipoptrotein,and,1,acidic glycoprotein.,D,D,+P DP,Free drug bound drug,Plasma Protein Binding Rate(PPBR),The fraction of,drug binding to plasma protein to,amount of drug in the body:,The extent of combination of drugs with plasma protein differs,which is usually expressed by the ratio of the concentration of bound drug over total drug in the body,i.e.,PPBR.,Plasma Protein Binding,Reversibility,Inactivation,Molecule bigger,Unmetabolized,No transmembrane,Capacity-limited protein binding,Replacement,Drug A:1000 molecules,99.9%bound,1 molecules free,100-fold increase in free pharmacologically active concentration at site of action.,Effective,TOXIC,+,Drug B with 94%bound,90.0%bound,100 molecules free,Drug interaction of plasma protein binding,Plasma Protein Binding,Replacement,Anticoagulant warfarin with PPBR of,99%,an anti-inflammatory agent,phenylbutazone with PPBR of 98%,when the two drugs are used at the,same time,the replacement may occur,and eventually bleeding tendency due,to the high free warfarin.,Organ blood flow,The more blood flow of tissue and organ,the more drugs go to these tissues or,organs.Such as liver,brain,kidney,and lung.,Organ blood flow,Some higher lipid-solubility drug first go to,the abundant blood flow tissue or organ and,then go to the much poor blood flow tissue or,organ,such as thiopental first go to brain,and then go to muscle or other lipid tissue to,form new equilibrium called,redistribution.,The properties of drug and physical pH,The pH of body fluid may influence the,extent of dissociation of drugs and thus,affect the distribution and transport of,drugs in the body.,The properties of drug and physical pH,The pH of cellular fluid is 7.0 and that,of extracellular fluid is 7.4 under,physiological circumstances,so the,concentration of weak acidic drugs in,extracellular fluid is higher than that in,cellular fluid.,The properties of drug and physical pH,Reducing the pH of the blood can transfer,weak acidic drugs into cells,while decreasing,the pH of the blood can cause right-about,transfer of acidic drugs.The situation for,weak basic drugs is opposite.,The properties of drug and physical pH,Pentobarbital is a weak acidic drug,when it is used overdose and,intoxication,the sodium bicarbonate,may used to base the blood and urine to,increase the excretion of pentobarbital,and to anti-toxicant.,Metabolism (Biotransformation),The process in which drugs result in chemical,changes,that may lead to the termination or,alternation of biological activity.it is also,called biotransformation of drug in the body.,The metabolism and excretion of drugs are,generally called elimination.,Cytochrome P,450,(P,450,),Enzyme induction,Enzyme inhibition,Enzyme inducer:phenobarbital,rifampin,carbamazepine,phenytoin sodium,dexamethasone,Enzyme inhibitor:chloramphenicol,ketoconazole,cimetidine,Excretion of Drug,The process in which of their prototype,and their metabolites transferred from,the internal to the external environment,of body.,The pathways of excretion includes:,renal,peptic,respiratory and milk excretion.,The pathways of excretion,Kidney,肾脏,Glomerular filtration:accumulation,Active tubular secretion:,Probenecid,丙磺舒,penicillin,Passive tubular reabsorption,phenobarbital sodium bicarbonate,MTC,MEC,稳态,约经,5,个半衰期达,到,STEADY STATE,时间（半衰期）,血药浓度,稳态浓度,与给药间隔和剂量相关,与生物利用度和清除率相关,靶浓度,（,target concentration,）,有效而不产生毒性反应的稳态血浆药物浓度（,C,ss,）,Css-max MEC,Characteristics of drugs that predict that a dosage adjustment should be made in renal disease,Primary urinary excretion of the parent drug or active metabolites 50%,Low therapeutic index,Therapeutic index,(,TI),LD,50,/ED,50,High protein binding,Small volume of distribution of the drug,Renal impairment induced by drugs,Antipyretic-analgesic and anti-,inflammatory drugs,non-steroidal anti-inflammatory drugs(NSAIDs),Aspirin-like drugs,Membrane phospholipids,Arachidonic,acid,PGG,2,PGH,2,PGI,2,PGF,2,PGE,2,TXA,2,(vascular (bronchial,(vascular dilation;(vascular,dilation;constriction)GI protection;constriction;,platelet pain,fever,)thrombosis),disaggregate;,pain),PLA,2,LTs,LTC,4,/,D,4,/E,4,LTB,4,chemotaxis,Bronchial,constriction;,Alteration of,vascular,permeability,COX,lipoxygenase,glucocorticoid,NSAIDs,COX-1 COX-2,Production Constitutive Inducible,Function,Physiological function,Pathological function,gastric protection facilitate inflammation,platelet aggregation cause fever and pain,peripheral vessel regulation,renal blood distribution,NASIDs effects unwanted side effects therapeutic effects,Nephrotoxicity,worsening of renal function,，,hypertension,，,fluid retention,，,hyperkalaemia,necrosis of renal papillae,interstitial nephritis,renal failure,etc.,-caused by the inhibition of renal cox-1 by,NSAIDs(eg.,fenoprofen,),Treatment aim,Drug,Mechanism,Acute gout,relieve the acute,gouty arthritis,attack,control the,hyperuricemia,colchicine,(-),inflammation,NSAIDs,Indomethacin,(-),inflammation,chronic gout,reduce,the serum level of uric acid,allopurinol,uric acid,synthesis,probenecid,uric acid,excretion,Appendix:,purine,uric,acid,excretion,xanthine,oxidase,hyperuricemia,joints,kidney,Other,tissues,arthritis,Kidney,damage,Other tissue,damages,probenecid,allopurinol,NSAIDs,I,ndomethacin,colchicine,Appendix:,Drugs-induced interstitial nephritis,Drugs-induced glomerular pathology,A relatively uncommon condition which is characterised by inflammation of the renal tubules,glomeruli and surrounding tissue.Interstitial nephritis is usually be temporary and often associated with the use of a particular medication.Chronic and progressive forms do exist.,Drugs that have been associated with interstitial nephritis include penicillins,ampicillin,cephalosporins,sulpha drugs,non-steroidal anti-inflammatory agents,furosemide and thiazide diuretics.May result in mild kidney dysfunction or acute renal failure.Treatment may be with corticosteroids.,Glomerular pathology is less common than tubulointerstitial injury in drug-induced nephrotoxicity.Prognosis.,eg.,NSAIDs,Important causes of nephrotoxicity,Gentamicin,Aminoglycosides,Pharmacokinetics,Absorption:po poorly,im,iv,Distribution:,low concentration in most tissue except,renal cortex,Can pass placental barrier,BBB,Excretion:in unchanged form by glomerular filtration,Adverse reactions,Dangerous factors:,Using continuously more than 5 days,High dose,Eldly and children,Renal insufficiency,Concurrent use with loop diuretics or other nephrotoxic drugs,cyclosporin,Cyclic undecapeptide isolated from Tolypocladium inflatum,that has potent immunosuppressant activity on both humoral and cellular systems.The use of cyclosporin has made transplant surgery(eg.,renal,transplantation)much easier,although the long term consequences of suppressing immune function are not yet clear.,Used widely as an an antirejection drug in transplant surgery and to prevent and treat rejection and graft-versus-host disease in bone marrow transplant patients by suppressing their normal immune system,.,How cyclosporin nephrotoxicity is manifested,Long term usage of Cyclosporin generally may results in Cyclosporin Nephrotoxicity,Short term usage at high dosages can also cause Cyclosporin Nephrotoxicity,Characterised by:,Renal dysfunction,Reduced GFR,Reduced renal blood flow,Rise in serum creatinine,Decrease in renal clearance,Rise in RAS,arteriolopathy of afferent arteriole vascular dysfunction and elevated BUN,Non-prescription medicines,eg.NSAIDs compound preparation,Contrast agents,eg.iodinated radiological contrast agents,Nephrotoxicity,Principle for treatment of renal damage,early discovery,early diagnosis,timely withdrawal,timely treatment,prevention first,Diuretics,Diuretics are a family of drugs that act on,kidney,and promote the,excretion of urine,(including water and electrolyte).(mainly used in edema),Classification of Diuretics,.Loop(high efficacy diuretics)diuretics,.Thiazide(moderate efficacy)diuretics,.Potassium-sparing(low efficacy,),diuretics,.Carbonic anhydrase inhibitors,.Osmotic diuretics(dehydrants),Thank you,