药理重点总结课件

1、首关效应(first-pass effect)：又称首过消除(first-pass elimination)。指某些药物在通过肠粘膜和肝脏时，部分可被代谢灭活而使进入全身循环的药量减少，药效降低。First-pass Effect, following absorption from the gastrointestinal tract, drugs pass initially through the hepatic circulation. Some drugs are metabolized so extensively in the gut wall or liver before t

2、hey reach the systemic circulation.肝肠循环(hepato-enteral circulation)the drug is excreted into intestine by bile and is reabsorbed from intestine into blood.全身清除率（CLs）： 指单位时间内多少毫升血浆中的药物被清除。Clearance of a drug is defined as the volume of plasma which contained drug will be removed per unit time.反映药物在体内

3、消除快慢。为全身清除率的总和。判断药物在消除器官的清除方式。消除速率常数（elimination rate constant ,Ke）：单位时间内药物消除的分数。Ke大小反映药物在体内消除的快慢。It refers the speed of drug elimination.Ke是一常数，与剂型无关。It is a constant, and be independent of preparation.Ke代表体内各种消除途径的总和。It sums for all the routes of drug elimination.Ke在消除器官障碍时发生改变。 The dysfunction of

4、 eliminational organs can affects it.半衰期（t1/2）:多指血浆药物浓度下降一半所需时间。 Half-life: The time which is taken for the concentration of drug to fall to half of the initial value .代表药物在体内消除的快慢。确定给药间隔(the dosing interval)，一般情况下是间隔一个t1/2给药一次。估算药物消除百分比。估算重复给药(repeated dosage)达稳态(steady state)的百分比。表观分布容积（Vd）:指理论上药物

5、均匀分布所需容积。Apparent distribution volume: A hypothetical volume of body fluid that would be required to dissolve the total amount of drug at the same concentration as that found in the blood.表示药物进入体内的深度和范围。越大，预示药物排泄越慢。年龄、体重、体态不同可有变化。水肿、脱水、低蛋白时可有变化。曲线下面积（AUC）： 指由横坐标轴和曲线围成的区域，代表一段时间内药物吸收的相对累积量。Means the

6、area under the plasma concentration versus time curve, it represent the relative accumulation of absorption for a time interval.是计算生物利用度(bioavailability) 的重要依据。生物利用度（F）： 指药物实际被利用的程度。即进入血液的药量与给药量之比。It is defined as the fraction of unchanged drug reaching the systemic circulation to dose.是评价生物等效性(bioe

7、quivalence)的重要依据之一。稳态浓度（Css）： 指多次给药后血药浓度达到一定高度后保持在基本稳定水平。又称坪水平（plateau level）。Concentration at steady state may be defined as plasma concentration reach a stable level or input rate equals output rate after repeat dosing.波动度（DF）: 指峰谷浓度之差占二者平均值的百分比。即Degree of fluctuation: the percentage of the differ

8、ence between C(ss)mas and C(ss)min to their average concentration.药物代谢酶(Drug Metabolizing Enzymes)：肝药酶主要包括有：细胞色素P450酶系（cytochrome P450，简称P450 or CYP）含黄素单氧化酶系（flavin-containing monooxygenases，简称FMO）环氧化物水解酶系（epoxide hydrolases，简称EH）结合酶系（conjugating enzymes，简称CE）。表. 常见的肝药酶诱导剂和抑制剂及相互作用 P-450 底物 诱导药 抑制药C

9、YP1A2咖啡因 奥美拉唑 非那西丁 CYP2A6香豆素 地塞米松 香豆素CYP2C9S-华法令 巴比妥类 异烟肼 CYP2C19地西泮 苯妥英钠 S-美芬妥英 CYP2D6异喹胍 奎尼丁CYP2E1PAS 异烟肼 西咪替丁 CYP3A红霉素 利福平 酮康唑药物的量效关系（Dose-Effect Relationship of Drug）在一定范围内，随着药物剂量增加，药物效应也相应增加，这种关系称为量效关系(dose-effect relationship)。At a certain range , the drug effect will increase accompanied by t

10、he augment of the drug dose. This relationship can be called dose-effect relationship.效价强度(potency)：引起同等效应(50%最大效应)的剂量或浓度，其数值越小，强度越大，又称等效剂量(equivalent dose)。Potency means the same level of effects are produced by different doses of two drugs. The lower dose, the higher potency. It is also called equ

11、ivalent dose.半数有效量(median effective dose, ED50)，使半数群体产生药效或某一反应的剂量称之；Means the dose at which 50% of the individuals exhibit the specified quantal effect.半数致死量(median lethal dose, LD50)，使半数群体死亡的剂量。The dose at which 50% of the animals exhibit death.根据药物受体结合可逆性不同，将药物划分为：竞争性拮抗药 (competitive antagonist)：能

12、和受体产生可逆性结合，与激动药竞争同种受体，谁的浓度大谁占优势，量效关系曲线平行右移。如阿托品是乙酰胆碱的竞争性拮抗药。非竞争性拮抗药(noncompetitive antagonist)：能与受体产生相对不可逆结合，使激动药与受体的亲和力不变，而内在活性降低，使最大效应降低，量效曲线下移。如受体拮抗药酚苄明就属于此类药物。Introduction to Autonomic Pharmacology1. Cholinergic receptors (Cholinoceptors )M-R（muscarinic receptor，毒蕈碱型胆碱受体）: particularly responsiv

13、e to alkaloid muscarine. All effector cells innervated by postganglionic cholinergic fibersM1-R: ganglion (+), CNS (+), parietal cell of stomach M2-R: SA node, atrium, AV node, ventricle(-), presynaptic sites (negative feedback)M3-R: exocrine glands (+), smooth muscle(+), endothelium (release EDRF)M

14、4 R: exocrine glands, smooth muscle, CNSM5 -R: CNSN-R（nicotinic receptor）: particularly responsive to nicotine; N1-R (NN-R, Nicotinic neuronal type ): autonomic ganglia (+), adrenal medulla N2-R (NM-R, Nicotinic muscle type ): skeletal muscle neuromuscular end-plates (+)2. Adrenergic receptor (Adren

15、oceptor)-R: respond to norepinephrine and to such blocking agents as phentolamine. 1-R: 1A、1B、1D postsynaptic effector cells, smooth muscle (vascular, genitourinary, intestinal, puipllary dilator muscle)2-R: 2A、2B、2C presynaptic adrenergic terminals (negative feedback), platelet (aggregation), lipoc

16、ytes, smooth muscle-R1-R: heart (+), juxtaglomerular cell,2-R: presynaptic nerve terminals (positive feedback), smooth muscle (vascular, bronchial, genitourinary, intestinal, ciliary), skeletal muscle3-R: lipocytes (lipolysis)Parasympathomimetics拟副交感神经药Pilocarpine（毛果芸香碱，匹鲁卡品） 一、Uses:1.Glaucoma（青光眼）2

17、.Iritis虹膜炎3.Dry mouth(2)Glands : increases secretion Smooth muscle: Increase peristaltic activity of the GI tract, contract bronchial, bladder, gallbladder and uterus smooth muscle (3)Cardiovascular system:Transient decrease in BP Marked increase in BP(4)CNS: characteristic cortical arousal or activ

18、ation response in catsNeostigmine (新斯的明，Prostigmine)Anticholinesterase agentsIt is absorbed poorly after oral administration. cannot cross BBB一、Pharmacologic mechanism :1.form a neostigmine-AchE complex.2.inhibits the activity of AchE, 3.accumulates Ach concentration in the synaptic clefts. 4.expres

19、ses M-and N-effects.三、Clinical Uses1. Myasthenia gravis (重症肌无力): produce acummulation of excess of ACh , activating N2-receptor on skeletal muscle, Overdosage will produce sustain depolarzation, exacerbate加剧disturbance of neuromuscular transmision, increase the symptoms of myasthenia. It is called “

20、cholinergic crisis”. Treatment: atropine and cholinesterase activator, such as PAM. 2.Postoperative ileus (Paralytic Ileus ) and urinary retention:(1)excites GI tract smooth muscle and bladder detrusor (2)Neostigmine should not be used when the intestine or urinary bladder is obstructed.3.Paroxysmal

21、 supraventricular tachycardia（阵发性室上性心动过速）：Decrease heart rate 4.Overdosage of non-depolarizing muscle relaxants Tubocurarine(筒箭毒碱) intoxication5.Glaucoma Alzheimers disease 他克林，多奈哌齐、利凡斯的明四、Side EffectsLarge dosage: nausea, vomiting, abdominal pain, tachycardia, fibrillation of muscle fibers, “cholin

22、ergic crisis” (large amount of ACh keep prolonged depolarization). 五、ContraindicationsMechanical intestinal obstruction (ileus)urinary obstructionbronchial asthma. chapter 8 Cholinoceptor-Blocking Drugs Atropine一、Mechanism of Action1.Atropine causes reversible blockade of the actions of cholinomimet

23、ics at muscarine receptors. Antagonism by atropine is competitive 2.Atropine is highly selective for muscarinic receprors. It does not distinguish among the M1 , M2 , M3 subgroups of muscarinic receptors. 3.Large dosage also blocks Nn-receptor of ganglia.二、Pharmacological Effects1. Glands : (1)Inhib

24、it the secretion of salivary gland, sweat, lacrimal gland and bronchial secretory glands, dry mouth, dryness of the skin, elevated body temperature (atropine fever), dry eyes. (2)Large dosage may inhibit the secretory function of the stomach2. Eye : blocks all cholinergic activity on the eye (1)mydr

25、iasis (dilated pupil )(2)Cycloplegia调节麻痹: paralysis of ciliary muscle, loss of the ability to accommodate; the fully atropinized eye cannot focus for near vision, the lens is fixed for far vision, near objects are blurred.(3)increase of ocular pressure3. Smooth muscle: Relaxation of visceral smooth

26、muscle，Relax bronchial muscle，Relax detrusor（压出器） of bladder and urinary tract, slow voiding，antispasmotic action on the gallbladder and bile ducts，very weak effect on Uterus（子宫）4. Heart(1)Small dosage: decreases heart rate (2)Larger dosage: tachycardia (3)Atropine facilitate AV conduction and short

27、ens the functional refractory period of the AV node, increase ventricular rate and lessen the degree of AV block.5. Dilate blood vessels and improve microcirculation(1)therapeutic dosage : not striking (2)Large dosage : dilates cutaneous blood vessels(3)Pathological condition, relieve vasospasm, imp

28、rove microcirculation, recover the blood supply to the important organs, relieve anoxia of the tissues.6. CNS stimulating effecttherapeutic doses : only mild弱的vagal excitation toxic doses : central excitation becomes more prominentstill larger doses : stimulation is followed by depression三、Clinical

29、Uses1. Relaxation of smooth muscle spasm: gastric and intestinal colic painbladder irritating symptomschildrens bed-wetting（遗尿症）. Gallbladder colic pain and renal colic pain: less effective (atropine should be used with Pethidine ).2. Inhibition of the secretory gland secretion(1)preanaesthetic medi

30、cation前驱麻醉药 (2)As an adjuvant used for peptic ulcer, relaxation of the stomach smooth muscle. (3)salivation induced by heavy metal intoxication(4)Parkinsons disease3. Ophthalmologic disorders(1)Accurate measurement of refractive error屈光不正in uncooperative patients.(2)Ophthalmoscopic examination of re

31、tina视网膜 and optic disc is greatly facilitated by mydriasis扩瞳(3)Prevent adhesion formation in uveitis葡萄膜炎 and iritis 4.Cardiovascular disorder :(1)bradycardia, SA block, A-V block. AV block Sinus bradycardia (2)Restore heart rate to a level sufficient to maintain adequate hemodynamic status.5. Antish

32、ock : mainly used in infectious intoxicated (1)Dilates the spasm of arteriol, improves microcirculation, increases the blood supply of important organs, increases the blood return to the heart, increases BP. (2)Atropine is not used to the shock patient accompany with fever and tachycardia.6. Organop

33、hosphate intoxication(1)reverse the muscarinic effects, nicotinic effects, central nervous system effects and peripheral effects(2)It does not interfere with the effects at the skeletal neuromuscular junction.(3)also block the effects of excess acetylcholine that results from inhibition of CHE胆碱酯酶 b

34、y physostigmine毒扁豆碱.四、Side EffectsDry mouth, blurred vision, tachycardia, dryness of skin and dizziness头晕, difficulty in urination, constipation便秘. Toxic effects: hyperthermia过热, tachypnea(气促) , restlessness坐立不安, delirium谵妄, hallucination幻觉, convulsion, then coma, respiratory paralysis.五、Treatment:P

35、hysostigmine（毒扁豆碱）. symptomatic management: temperature control (cooling blanket); seizure control (diazepam)六、Contraindications: glaucoma, prostatic hypertrophy.Anisodamine (山莨菪碱)Peripheral anticholinergic effect, high selectivity (smooth muscle and vessel)Uses: 1.colic pain (gastriointestinal)2.in

36、fectious intoxicated shock3.various circulatory disorders, migraine（偏头痛）Scopolamine （东莨菪碱）Uses：1.Preanaesthetic medication2.Traditional Chinese herb anaesthesia3.Motion sickness晕动病4.Parkinsons diseasePirenzepine（哌仑西平）M1 cholinergic antagonistUses: gastric ulcers and duodenal ulcers, acute gastric mu

37、cosa bleeding and gastrinoma（胃泌素瘤）. Depolarizing Muscle Relaxants: Succinylcholine (scoline) 琥珀胆碱, act by depolarizing the plasma membrane of the skeletal muscle fiber. This persistent depolarization makes the muscle fiber resistant to further stimulation by ACh. Nondepolarizing Muscular Relaxants:

38、d-tubocurarine筒箭毒碱, act by blocking the binding of ACh to its receptors, Nm -cholinergic Blocking Drugs Adrenoceptor AgonistsEpinephrine, Adrenaline, ADClinical uses:1.Cardiac arrest(心脏骤停) 2.Anaphylactic shock（过敏性休克）3.Acute attack of bronchial asthma and immediate (type I) lgE-mediated allergic reac

39、tions (angioedema(血管神经性水肿), serum sickness(血清病)4.Local application : Use with local anesthetics to constrict the regional blood vessels, prolong the action.used topically to reduce bleeding (epistaxis鼻衄), gingival bleeding(牙龈出血) )5.open-angle glaucoma.Adrenaline reversal(肾上腺素作用的翻转): a1-receptor anta

40、gonist may convert a pressor response of epinephrine to a depressor response.Isoprenaline (Isoproterenol, 异丙肾上腺素)Uses：1.Cardiac arrest2.Atrial ventricular block3.Shock: now seldom used. It is effective to shock with high central venous pressure and low cardiac output, but it does not improve microci

41、rculation in tissue markedly 4.acute episode of asthma Phentolamine(酚妥拉明): reversible nonselective -antagonist Clinical Uses：1.Peripheral vascular diseases2.Dermal necrosis after extravasation外渗 of NA 3.Shock: It is better to combine phentolamine with NA. 4.Myocardial infarction and stubborn难治性 cong

42、estive heart failure5.Pheochromocytoma (嗜铬细胞瘤)6.Impotence (阳痿)Prazosin (哌唑嗪)1 Receptor BlockerUsage：hypertension stubborn难治性congestive heart failure. Benignprostatic hyperplasia induced urinary obstruction良性前列腺增生 -Receptor Blocking Drugs nonselective blockers: Antagonist without ISA: propranolol(普萘洛

43、尔), timolol(噻吗洛尔) Antagonist with ISA: pindolol(吲哚洛尔) selective b1 blockers: Antagonist without ISA: atenolol(阿替洛尔), metoprolol(美托洛尔)Antagonist with ISA: acebutolol(醋丁洛尔)a, b blocker: labetalol(拉贝洛尔), carvedilol(卡维地洛)一、Pharmacological Effects1.-blocking effectsA. Heart: negative chronotropic: decrea

44、se heart rate,negative inotropic: decrease cardiac contractility, cardiac output, myocardial oxygen consumption. negative dromotropic: Slow atrioventricular conduction; increase PR interval.B. Blood vessel and BP: decrease blood pressure in patients with hypertension, no effects on normal men. witho

45、ut prominent postural体位性 hypotension (1)reduction in cardiac output (2)reduction of renin release from the juxtaglomerular cells of the kidney (3)a central action, reducing sympathetic activity.(4)Inhibition of peripheral presynaptic receptors to reduce sympathetic vasoconstrictor nerve activity.C.

46、Respiratory tract: Blockade of the b2 receptors may lead to bronchoconstriction and an increase in airway resistance, so asthma is contraindicated. D. Eyes: reduce intraocular pressure in glaucomatous eyes. decrease aqueous humor production. E. Metabolic effects : inhibit lipolysis and glycogenolysi

47、s分解.F. Other effects : -blockers inhibit the release of renin, block presynaptic b2 receptor of nerve ending, inhibit the positive feedback, decrease NA secretion.2.Intrinsic sympathomimetic activity (ISA, 内在拟交感活性): Some antagonists, after combining with and blocking -receptors, may have partial ago

48、nistic action. weak effect. characteristics: Weak heart inhibition and bronchoconstriction; increase the dosage or on low levels of intrinsic catecholamines may increase heart rate and cardiac output.eg: Pindolol吲哚洛尔, alprenolol阿普洛尔, oxprenolol氧烯洛尔3.Membrane stabilizing action (膜稳定作用): They decrease

49、 the membrane ion channel permeability. 4.Other effects : Propranolol has prominent antiplatelet aggregating effect. 二、Clinical Uses1.Cardiac arrhythmias: reduce ventricular rates, effective in the treatment of both in supraventricular and ventricular arrhythmias.2.Hypertension: Use -blocker alone o

50、r combine with diuretics or vasodilators. 3.Angina pectoris: blockade of cardiac beta-receptors, resulting in decreased cardiac work and reduction in oxygen demand.4.Congestive heart failure: dilated cardiomyopathy 5.Others: Timolol噻吗洛尔is used to treat glaucoma. Propranolol used to treat hyperthyroi

51、dism.三、Side Effects and Contraindications1.Induction or exacerbation of asthma. 2.Inhibition of cardiac function: Severe cardiac insufficiency, pulmonary edema, complete A-V block or cardiac arrest . 3.Peripheral blood vessel constriction and spasm, block of the 2 of blood smooth muscle. 4.Rebound:

52、Abrupt discontinuation of blockers after long-term treatment, increase BP, severe arrhythmias, angina pectoris, acute cardiac infarction, sudden death. (1)Up regulation of the number of -receptors;(2)increase the sensitivity to catecholamine.Others: Depression, insomnia. In insulin treated diabetes

53、patient, the incidence of hypoglycemic episodes may occur.Chapter 12 Sedative-Hypnotics镇静催眠药. Benzodiazepines （BDZ）1.BDZs act by binding to a specific regulatory site on the GABAA-receptor in neuronal membranes in the central nervous system, thus enhancing the inhibitory effect of Gamma-aminobutyric

54、 acid (GABA, -氨基丁酸 )2.BDZs do not activate GABAA receptors directly; rather, act allosterically别构调节by modulating调节the effects of GABA. 3.BDZs combine with GABA-receptor-chloride ion channel complex. It can promote the binding of GABA and GABAA receptor. Then, increase the opening frequency of Cl- ch

55、annel. but does not directly initiate Cl- current. Diazepam一、Pharmacological effects:1.Antianxiety: high selectivity(1)With smaller dose than sedative dose, Diazepam shows anxiolytic effects and also exerts taming effect, allowing animals to be handled much more easily(2)Diazepam may relieve the pat

56、ient from tension, agitation烦乱, fear, anxiety, restlessness，gastrointestinal tract disturbances or insomnia induced by anxiety.(3)inhibiting neuronal circuits回路in the limbic边缘system of the brain.2. Sedation hypnosis:If high enough doses are given, all the BDZs will induce sleep, decrease the latency

57、 of sleep onset. The characteristics of sedation hypnosis of BDZs:(1)Increase the duration of stage2 NREM.(2)Decrease the duration of SWS(decrease the probability of somnambulism梦游症and night terrors夜惊). (3)No marked effect on REM.3. Anticonvulsant effects, antiepileptic effects :(1)Can not inhibit t

58、he onset of abnormal discharge放电. (2)But can inhibit the spread of epileptiform activity in CNS.(3)It can exert anticonvulsant effects without marked central nervous system depression, so that mental activity and physiologic activity are relatively unaffected.4. Central / peripheral muscle relaxatio

59、n(1)Relieve muscle spasm due to brain/spinal cord injury, relieve acute local muscle spasm(2)Especially when the drug is given intravenously. (3)No effect on normal activity.5. Inhibition respiration:(1)Hypnotic doses: no effect (2)Higher doses: slightly depress alveolar ventilation and cause respir

60、atory acidosis; 6. Cardiovascular SystemPreanesthetic doses: decrease BP and increase HR.Advantages of diazepam:(1) Therapeutic index is high, large dosage does not induce anesthesia.(2) no hepatic enzyme induction effect (3) mild side effects, less danger of overdosage toxicity.(4) after withdrawal