全英文临床药理学问题答案完整版.doc

临床药理学问题答案鸣谢：沈剑波、王海林、孙俊龙、张玉鑫、汤晨雪、吴慧、郑雅、戴璐、方淼、孔亚男、张舒文、徐阳、蔡水灵、刘珊等同学的无私奉献整理：临床小胖子一、please illusrate how to develop a new drug(p4)Most new drugs or drug products are discovered or developed through the following approaches:(1) identification or elucidation of a new drug target;(2) Rational design of a new molecule based on an understanding of biologic mechanisms and drug receptor structure;(3) Screening for biologic activity of large numbers of natural products,banks of previously discovered chemical entities,or large libraries of peptides,nucleic acids,and other organic molecules;(4) Chemical modification of a known active molecule,resulting in a me-too analog.Steps(1) and (2) are often carried out in academic research laboratories ,but the costs of steps(3) and (4) usually ensure that industry carries them out.二、Please tell the meaning of loading dose and maintenance dose?(p17)Loading dose is one or a sevies of doses that may be given at the onset of therapy with the aim of achieving the target arcentration vapidly .a loading dose may be desirable if the time required to attain steady state by the administration of drug at a anstant rate is long relative to the temporal demands of the condition being treaded.Maintenance dose : Maintenance dose is the dose that continues to keep the drug in the dosing therapeatic range. In most clinical situations, drugs are administered in a sevies of repetitive doses or as a wntinuous infusion to maintain a steady state concentration of drug associated with the therapeatic window. Calculation of the appropriate maintain dosage is a primary goal. To maintain the chosen steady state or target concentration, the rate of drug administration is adjusted such that the rate of input equals the rate of loss.三、Please tell the classification of ADR?(p24) ADR can be divided into three groups according to onset acute:within 60 minutessub-acute:1 to 24 hourslatent:2 days. It can also be divided into another three groups because of severity mild:bothersome but requires no change in therapy moderate:require change in therapy,addition treatment, hospitalization severe:disabling or life-threatening四，How to access ADR(p33) ADR can be evaluated by causality assessment .You can access the ADR from the following aspects: 1.If the reaction had prior reports? 2.temporal relationship 3.de-challenge4. re-challenge5. Close-response relationship6. Alternative etiologies7. Objective confirmation8. If the patient had past history of reaction to same or similar medication . According to the results,the ADR can have four outcomes:highly probable,probable,possible and doubtful.五，whats the sympoms of schizophrenia.(p39) Postitive symptoms:1. Delusions2. Hallucinations3. Thought disorder4. Abnormal.disorganized behaviour5. Catatonia Negative symptoms:1. withdrawal from social contacts2. Flatten of emotional response3. Anhedonia(en inability to experience pleasure)4. Reluctance to perform everyday tasks. In addition,deficits in cognitive function are often present together with anxiety,guilt,depression and self punishment.A characteristic feature of schizophrenia is a defect in “selective attention”.Whereas a normal individual quickly accommodates to stimuli of a familiar or inconsequential nature,and responds only to stimuli that are unexpected or significant,the ability of schizophrenic patients to discriminate between significant and insignificant stimuli seems to be impaired6 what kinds of antidepressant drugs are used in clinic?(p53)Antidepressant drugs fall into the following categories：1. Inhibitors of monoamine uptake Selective serotonin (5-HT) reuptake inhibitors (SSRJs): fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopramClassical tricyclic antidepressants (TCAs): imipramine, desipramine, amitriptyline, nortriptyline, clomipramine; varying in their ability to inhibit noradrenaline and 5-HT reuptakeNoradrenaline reuptake inhibitors: bupropion, reboxetine, atomoxetineNewer, mixed 5-HT and noradrenaline reuptake inhabitors: bupropion, desvenlafaxine, duloxetine, milnacipran2. Monoamine receptor antagonistsDrugs such as mirtazapine, trazodone, mianserin are non-selective and inhibit a range of amine receptors including a2 adrenoceptors and 5-HT2 receptors. They may also have weak effects on monoamine uptake 3. Monoamine oxidase inhibitors(MAOIs)Irreversible, non-competitive inhibitors: phenelzine, tranylcypromine,which are non-selective with respect to the MAO-A and -B subtypesReversible, MAO-A-selective inhibitors: moclobemide个人觉得只需答第1点即可。7 what is the criteria for drug dependence？(p57)A maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by three (or more) of the following, occurring at any time in the same 12 month period1. Tolerance2. Withdrawal3. Substance taken in larger amounts or over a longer period than intended4. Persistent desire or unsuccessful efforts to cut down or control substance use 5. Great deal of time spent in activities necessary to obtain substance, use substance(e,g., chain smoking), or recover from effects6. Important social,occupational, or recreational activities given up or reduced because of substance useSubstance use continued despite knowledge of persistent or recurrent physical or psychological problem likely to have been caused or exacerbated by substance 八、what is drug depends（p57）a maladaptive pattern of drug use leading to clinically-significant impairment or distress.associated with difficulty in controlling drug-taking behavior.withdraw and tolerancethe state of needing a drug to function withinnormal limits九、the characteristic of AMPA KA receptor(p67)AMPA,present on all neutrons are heterotetramers assembled from four subunits（GluA1-4） the majority of it contain the GluA2 and are permeable to Na+and K+not to Ca2+ some AMPA receptor.typically present on inhibitory interneurons.lack the GluA2 and are also permeable to Ca2+KA not as uniformly distributed as AMPA receptor .being expressed at high levels in the hippocampus.cerebellum and spinal cord formed from a number of subunits.including GluK1-5 GluK4 and 5 are unnable to form channel on their own.but they change its affinity and kineticssimilar to AMPA receptors. it is permeable to Na+ and k+. and in some subunit combinations can also be permeable to Ca2+十.why do we use levodopa but not dopamine to treat PD?(p72)Answer:Dopamine does not cross the blood-brain barrier and if given into the peripheral circulation,it will lose its therapeutic effect on PD.However,levodopa,the immediate metabolic precursor of dopamine,does enter the brain ,where it is decaiboxylated to dopamine.Although levodopa has convincing advantages in the therapy of PD,it also has a lot of uncomfortable side effects, such as:1. The gastrointestinal effects,including anorexia,nausea,vomit.Direct stimulation of the gastrointestinal tract as well as the activation of D2 receptors on chemoreceptors trigger zone in medulla.2.The cardiovascular effects,including orthostatic hypotension and arrthymia,The former effects can be included by activation of D2 receptors in the vascular vessels.3.Hyperkinesia:included by the over-activation of D2 receptors.4.On-off responses:occurrence in 40-80% patients.This symptom is included by the inability of the brain to store dopamine.5.Mental symptom:occurrence in 10-15% patients.十一.What are the mechanisms for the therapy of microcirculatory disorder of shock in different stages?(p91)Answer:Microcirculatory disorder theory1 stage: compensatory stage of shock(lschemic Hypoxic Stage)2 stage:decompensation(Progressive stage)3 stage:failure(refractory stage)十二、 Q:The classification of clinical shock?（p87）A:classification of shock by causes*hemorrhagic/dehydrated shock*traumatic shock*burn shock*infective shock*anaphylactic shock*neurogenic shock*cardiogenic shock classification of shock by initial changes*hypovolemic shock*cardiogenic shock*vasogenic shock 十三、Q:what are the pharmacological and adverse effects of ACEI?(p108)A: pharmacological effects:inhibite ACE,angiotens;bradykinin adverse effects:severe hypotension can occur after initial doses of any ACE inhibitor in patients who are hypovolemic as a result of diuretics,salt restriction,or gastrointestinalfluid loss.Other adverse effects common to all ACE inhibitors include acute renal failure,Hyperkalemia,dry cough sometimes accompanied by wheezing,and angioedema.HyperkalemiaIs more likely to occur in patients with renal insufficiency or diabetes.Bradykinin and substanceP seem to be responsible for the cough and angioedema seen with ACE inhibition.十四、What is the comparision of ACEI and ARB?(p109)(1) .AREs reduce activation of AT1 receptors more effectively than do ACE inhibitors.(2) .no effect on bradykinin metabolism.(3).cough and angioedema are less common than ACE inhibitors.十五、Please list the classification of antihypertensive agents.(p105)(1).Diuretics which lower blood pressure by depleting the body of sodium and reducing blood volume and perhaps by other mechanisms.(2).Sympathoplegic agents, which lower blood pressure by reducing peripheral vasculai resistance ,inhibiting cardiac function, and increasing venous pooling in capacitance vessels.These agents are further subdivided according to their putative sites of action in the sympathetic reflex arc. 1 Centrally acting sympathoplegic drugs2 Ganglion-blocking agents3 Adrenergic neuron-blocking agents4 Adrenoceptor antagonisis(3) .Agent that block production or action of angiotensin and thereby reduce peripheral vascular resistance and (potentially) blood volume.(4) Calcium channel blocker(5) Direct vasodilators ,which reduce pressure by relaxing vascular smooth muscle, thus dilating resistance vessels andto varying degreesincreasing capacitance as well.16、 what are the mechanisms toxicity of Nicotinic acid?(p116) Rare adverse effects of fibrates include rashes,gastrointestinal symptoms,myopathy,arrhythmias,hypokalemia,and high bolld levels of aminotransferases or alkaline phosphatase.A few patients show decreases in white blood count or hematocrit.Both agents potentiate the action of coumarin and indanedione anticoagulants,and doses of these agents should be adjusted.Rhabdomyloysis has occurred rarely.Risk of myopathy increases when fibrates are given with reductase inhibitors.Fenofibrate is the fibrate of choice for use in combination with a statin.Fibrates should be avoided in patients with hepatic or renal dysfunction.There appears to be a modest increase in the risk of cholesterol gallstones,reflecting an increase in the cholesterol content of bile.Therefore,fibrates should be used with caution in patients with biliary tract disease or in those at high risk such as women,obese patients,and Native Americans.十七、 Whats the drug combination in the treatment of hyperlipidemia when Nicotinic acid is inefficiency?(p116)When Nicotinic acid is inefficiency, the drug combination in the treatment of hyperlipidemia are resins and gemfibrozil. Hyperlipidemia can lead to elevated VLDL and TG, a large increase in LDL and TG. The resins can cause the decrease of TC and LDL, and the TG is increase. However, gemfibrozil can make TG and VLDL lower. Elevation of TG induced by Resins complies with TG lowering caused by gemfibrozil , leading to a decrease in TG. After combined therapy of resins and gemfibrozil, TG decreases and HDL-C increases. When the two drugs combined treatment , we should decrease resins dosage. Its shortage is promoting cholelithiasis.图见P118十八、Please describe the clinical uses and adverse reaction of insulin.(p125)clinical uses of insulin: 1.Diabetes mellitus The only effective drug for type1 diabetes The following situations of type 2 diabetes（1）Not effectively controlled by food limitation & oral antidiabetic drug（2）Accompanies DKA & nonketotic hyperglycemia coma （3）Accompanies serious infection，hyperpyrexia，injury，gestation and consumptive diseases.2.OthersHyperkalemiaA component of GIK solution which is for limiting myocardial infarction & arrhythmiasAdverse reactions:1.Insulin allergy: itching，redness，swelling，anaphylaxis shock2.Insulin resistance 3.Hypoglycemia: nausea ，hungry，tachycardia，sweating and tremulousness .4.Lipodystrophy at injection sites: atrophy5.Obesity十九、Please describe twodrug combination therapy .(p131) Twodrug combination therapy is a kind of combination drug therapy ，which is an increasing trend in type2 diabetes that is not controlled by diet ，exercise，and singledrug therapy .They include the following:a. Insulin plus a sulfonylureaAdvantages inculde lower fasting blood glucose levels，decreased glycosylated hemoglobin levels ，increased secretion of endougenous insulin，smaller daily dosese of insulin，and no significant change in body weight.b. Insulin plus a glitazoneGlitazones increase the effectiveness of insulin ，whether endogenous or exogenous.c.Sulfonylurea plus acarbose or miglitol This combination is Food and Drug Administration（FDA） approved for clients who do not achieve adequate glycemic control with one of the drugs alone .d.Sulfonylurea plus a glitazone The sulfonylurea increases insulin and the glitazone increase insulin effectiveness.f.Metformin plus meglitinide If one of the drugs alone does not produce adequate glycemic control，the other one may be added. Dosage of each drug should be titrated to the minimal dose required to achieve the desired effects.二十.Please describe clinical uses or aspirin?(p136)1.Commonly used for management of mild to moderate pain(300-600mg)2.Combination agents(cold)3.Used for for reducing fever(300-600mg)4.useful in treatment of: (high doses 3-6g)T1/212 hours Rheumatic fever Rheumatoid arthritis Other inflammatory joint diseases5.Antiplatelet(low doses)40-100mg Reduce incidence of transient ischemic attacks Reduce incidence of unstable angina May reduce incidents of coronary artery thrombosis6.Hypertension in pregnancy: (low does)60-100mg7.local indication:GI inflammation:5-amido-salicylic acid二十一.Please describe clinical uses or glucoconicoids(p141)1.immune diseases a.autoimmune disorders:reumatic fever, rheumatic carditis, rheumatic arthritis, rheumatoid arthritis,osteoarthritis,systemic lupus erythematosus,polyarthritis nodosa,nephritic syndrome,etc. b.rejection of organ transplantation c.allergic diseases:urticaria,serum sickness,contact dermatitis,drug allergic reactions,chronic severe asthma,status asthmaticus,angioneurotic edema,etc.2.severe infection and inflammationa.acute severe infections:merely suppressing inflammatory manifestations but at times lifesavingb.prevention of sequelae of some types of inflammation,such as in brain,heart,eye,joint,etc3.septic shock4.hemological diseases:acute lymphocytic leukemia,lymphomas,aplastic anemia,hemolytic anemia,leukocytopenia,thrombocytopenia,etc,5.topical applications:skin,eye,respiratory tract,joint6.some types of tumors:breast and prostatic cancers,acute lymphocytic leukemia,etc.二十二、What questions should be asked before antimcrobial therapy is warranted for a gived patient?(p144)1、 Is an antimicrobial agent indicated on the basis of clinical findings?Or is it prudent to wait until such clinical findings become apparent?2、 Have appropriate clinical specimens been obtained to establish a microbiologic diagnosis?3、 What are the likely etiologic agents for the patients illness?4、 What measures should be taken to protect individuals exposed to the index case to prevent secondary cases,and what measures should be implemented t prevent future exposure?5、 Is there clinical evidence(eg,from well-executed clinical trials) that antimicrobial therapy will confer clinical benefit for the patient?二十三、General principles of antibacterial surgical prophylaxis?(p152)1、 the antibiotic should be active against common surgical wound pathogens;unnecessarily broad coverage should be avoided.2、 The antibiotic should have proved efficacy in clinical trials.3、 The antibiotic must achieve concentrations greater than the MIC of suspected pathogens ,and these concentrations must be present at the time of incision.4、 The shortest possible course ideally a single dose of the most effective and least toxic antibiotic should be used.5、 The newer broad-spectrum antibacterial agents should be reserved for therapy of resistant infections. If all other factors are equal,the least expensive agent should be used.二十四.Case study (Page153)What is this patients prognosis? Should he receive adjuvant chemotherapy?The 5-year survival rate for patients with high-risk stage CRC is on the order of 25-30%.Because the patient has no symptoms after surgery and has no comorbid illness, he would be an appropriate candidate to receive adjuvant chemotherapy. Adjuvant chemotherapy is usually begun 4-6 weeks after surgery to allow sufficient time for surgical wound to heat.The usual recommendation would be to administer 6 months of oxaliplatin-based chemotherapy using either infusional 5-FU or oral capecitabine as the fluoropyrimidine base in combination with oxaliplatin.二十五.General principles of drug combinations(Page156)The Role of Drug CombinationsEfficacy: Only drugs known to be somewhat effective when used alone against a given tumor should be selected for use in combinations. If available, drugs that produce complete remission in some fraction of patients are preferred to those that produce only partial responses.Toxicity: When several drugs of a given class are available and are equally effective, a drug should be selected on the basis of toxicity that does not overlap with the toxicity of other drugs in the combination. Although such selection leads to a wide range of adverse effects, it minimizes the risk of a lethal effect caused by multiple insults to the same organ system by different drugs and allows dose intensity to be maximized.Optimum scheduling: Drugs should be used in their optimal dose and schedule, and drug combinations should be given at consistent intervals. Because long intervals between cycles negatively affect dose intensity, the treatment-free interval between cycles should be the shortest time necessary for recovery of the most sensitive normal target tissue, which is usually the bone marrow.Mechanism of interaction: There should be a clear understanding of the biochemical, molecular, and pharmacokinetic mechanisms of interaction between the individual drugs in a given combination, to allow for maximal effect. Omission of a drug from a combination may allow overgrowth by a tumor clone sensitive to that drug alone and resistant to other drugs in the combination.Avoidance of arbitrary dose changes: An arbitrary reduction in the dose of an effective drug in order to add other less effective drugs may reduce the dose of the most effective agent below the threshold of effectiveness and destroy the ability of the combination to cure disease in a given patient.