Pharmacodynamics-精品医学课件
合集下载
相关主题
- 1、下载文档前请自行甄别文档内容的完整性，平台不提供额外的编辑、内容补充、找答案等附加服务。
- 2、"仅部分预览"的文档,不可在线预览部分如存在完整性等问题,可反馈申请退款(可完整预览的文档不适用该条件!)。
- 3、如文档侵犯您的权益，请联系客服反馈,我们会尽快为您处理(人工客服工作时间：9:00-18:30)。
“Receptive substance”:explain the action of nicotine and curare on skeletal muscle.(in 1905)
2, A.V.Hill (a student working in J.N Langley’s lab)
Publication in 1909: emergence of “receptor theory” , time-course of the contraction of the frog rectus abdominis muscle produced by nicotine.
Pharmacodynamics
Pharmacodynamics
Dose response curve…...
Dose Response Curve
Morphine
Aspirin
From Nierenberg W and Melmon KL. Introduction to Clinical Pharmacology in Clinical Pharmacology: Basic Principles in Therapeutics, Third edition, 1992, Melmon KL et al., editors, p 1-51, McGraw Hill.
Figure 1 A.J. Clark’s early contributions to the receptor concept. (a) Concentration–effect curves for acetylcholine on (A) frog heart, (B) frog rectus abdominis muscle. Continuous curves fitted to the Hill–Langmuir equation (from Clark, 1926a, 1933). (b) Antagonism of acetylcholine by atropine on frog heart. Ordinate: % inhibition of contraction (y), plotted as log10[y/(100y)]. Abscissa: Acetylcholine concentration (log10M). Successive lines (I–VII) represent atropine concentrations from zero to 103M (from Clark, 1926b).
pharmacologists from that day to this.
Stephenson (in 1950s)
Concept of “efficacy” :a characteristic of the Drug that describes its ability to activate receptors, distinguishable from its affinity for the receptors.
(antagonist), or even action opposite to normal (inverse agonist).
G-protein coupled recector
The receptor concept: pharmacology’s big idea
British Journal of pharmacology 75th Anniversary Supplement
• Antacids and chelating agents combine chemically in the body.
• Enzyme-substrate binding is a way to alter the production or metabolism of key endogenous chemicals, for example aspirin irreversibly inhibits the enzyme prostaglandin synthetase (cyclooxygenase) thereby preventing inflammatory response.
➢GADDUM, J.H. (1926). The action of adrenaline and ergotamine on the uterus of the rabbit. J. Physiol., 61, 141–150.
➢GADDUM, J.H. (1937). The quantitative effects of antagonistic drugs. J. Physiol., 89, 6–7P.
different degrees of conformational change in the receptor, and thus different levels of response
• Colchicine(秋水仙碱), a drug for gout, interferes with the function of the structural protein tubulin。
• Digitalis, a drug still used in heart failure, inhibits the activity of the carrier molecule, Na-K-ATPase pump.
estimated,expressed as an equilibrium dissociation constant.
Since agonists and antagonists bind to the same site, the question clearly arises:
Why do agonists produce a response but antagonists do not ? –a question that has exercised
➢CLARK, A.J. (1926a). The reaction between acetyl choline and muscle cells. J. Physiol., 61, 530–546.
➢CLARK, A.J. (1926b). The antagonism of acetyl choline by atropine.J. Physiol., 61, 547–556.
Y:the response height; N: nicotine concentration; M: threshold; K and K’:constants
Langmuir (sical chemist)
Derived the equation in 1918 as one possible description of the absorption of gases as monolayers on metal surfaces: Hill-Langmuir equation.
Hormone receptors Neuromodulator receptors Neurotransmitter receptors
• General anesthetics were once thought to work by disordering the neural membranes, thereby altering the Na+ influx.
• The widest class of drugs act as ligands which bind to receptors which determine cellular effects. Upon drug binding, receptors can elicit their normal action (agonist), blocked action
Hill: lost interest in the area after student project, but became famous later for his work on haemoglobin and skeletal muscle.
After these early beginning, nothing happended untill 1926, when A.J Clark and JH Gaddum published:
The idea takes shape
1, J.N Langley (Cambridge physiologist)
Salivary secretion in the dog: the existence of a physiological substance or substances with which pilocarpine and atropine form “compound”.(in 1878)
Mechanisms of the desired activity of a drug:
• Cellular membrane disruption • Chemical reaction • Interaction with enzyme proteins • Interaction with structural proteins • Interaction with carrier proteins • Interaction with ion channels • Ligand binding to receptors:
binding and activation are independent processes, reflecting affinity and efficacy.
What is efficacy?
Graded activation:agonists (A1, A2, A3, etc) can induce
The theory evolves
Neither Hill nor Clark explain drug antagonism in terms of competition between agonist and antagonist molecules for the same receptors, though both had thought about this possibility.
Two more breakthrough needed: 1. The analysis of competitive antagonism; 2. The direct measurement of drug binding,
which led on to the isolation and cloning of receptors.
Schild (in 1947)
SCHILD, H.O. (1947). pA, a new scale for the measurement of drug antagonism. Br. J. Pharmacol., 2, 189–206.
➢Competitive antagonism: “Parallel shift” ➢KD: the affinity of antagonist for the receptors to be
The idea could not be pursued that the competitive antagonism by deriving the very simple equations for the binding of two mutually exclusive compounds at the same population of sites.
2, A.V.Hill (a student working in J.N Langley’s lab)
Publication in 1909: emergence of “receptor theory” , time-course of the contraction of the frog rectus abdominis muscle produced by nicotine.
Pharmacodynamics
Pharmacodynamics
Dose response curve…...
Dose Response Curve
Morphine
Aspirin
From Nierenberg W and Melmon KL. Introduction to Clinical Pharmacology in Clinical Pharmacology: Basic Principles in Therapeutics, Third edition, 1992, Melmon KL et al., editors, p 1-51, McGraw Hill.
Figure 1 A.J. Clark’s early contributions to the receptor concept. (a) Concentration–effect curves for acetylcholine on (A) frog heart, (B) frog rectus abdominis muscle. Continuous curves fitted to the Hill–Langmuir equation (from Clark, 1926a, 1933). (b) Antagonism of acetylcholine by atropine on frog heart. Ordinate: % inhibition of contraction (y), plotted as log10[y/(100y)]. Abscissa: Acetylcholine concentration (log10M). Successive lines (I–VII) represent atropine concentrations from zero to 103M (from Clark, 1926b).
pharmacologists from that day to this.
Stephenson (in 1950s)
Concept of “efficacy” :a characteristic of the Drug that describes its ability to activate receptors, distinguishable from its affinity for the receptors.
(antagonist), or even action opposite to normal (inverse agonist).
G-protein coupled recector
The receptor concept: pharmacology’s big idea
British Journal of pharmacology 75th Anniversary Supplement
• Antacids and chelating agents combine chemically in the body.
• Enzyme-substrate binding is a way to alter the production or metabolism of key endogenous chemicals, for example aspirin irreversibly inhibits the enzyme prostaglandin synthetase (cyclooxygenase) thereby preventing inflammatory response.
➢GADDUM, J.H. (1926). The action of adrenaline and ergotamine on the uterus of the rabbit. J. Physiol., 61, 141–150.
➢GADDUM, J.H. (1937). The quantitative effects of antagonistic drugs. J. Physiol., 89, 6–7P.
different degrees of conformational change in the receptor, and thus different levels of response
• Colchicine(秋水仙碱), a drug for gout, interferes with the function of the structural protein tubulin。
• Digitalis, a drug still used in heart failure, inhibits the activity of the carrier molecule, Na-K-ATPase pump.
estimated,expressed as an equilibrium dissociation constant.
Since agonists and antagonists bind to the same site, the question clearly arises:
Why do agonists produce a response but antagonists do not ? –a question that has exercised
➢CLARK, A.J. (1926a). The reaction between acetyl choline and muscle cells. J. Physiol., 61, 530–546.
➢CLARK, A.J. (1926b). The antagonism of acetyl choline by atropine.J. Physiol., 61, 547–556.
Y:the response height; N: nicotine concentration; M: threshold; K and K’:constants
Langmuir (sical chemist)
Derived the equation in 1918 as one possible description of the absorption of gases as monolayers on metal surfaces: Hill-Langmuir equation.
Hormone receptors Neuromodulator receptors Neurotransmitter receptors
• General anesthetics were once thought to work by disordering the neural membranes, thereby altering the Na+ influx.
• The widest class of drugs act as ligands which bind to receptors which determine cellular effects. Upon drug binding, receptors can elicit their normal action (agonist), blocked action
Hill: lost interest in the area after student project, but became famous later for his work on haemoglobin and skeletal muscle.
After these early beginning, nothing happended untill 1926, when A.J Clark and JH Gaddum published:
The idea takes shape
1, J.N Langley (Cambridge physiologist)
Salivary secretion in the dog: the existence of a physiological substance or substances with which pilocarpine and atropine form “compound”.(in 1878)
Mechanisms of the desired activity of a drug:
• Cellular membrane disruption • Chemical reaction • Interaction with enzyme proteins • Interaction with structural proteins • Interaction with carrier proteins • Interaction with ion channels • Ligand binding to receptors:
binding and activation are independent processes, reflecting affinity and efficacy.
What is efficacy?
Graded activation:agonists (A1, A2, A3, etc) can induce
The theory evolves
Neither Hill nor Clark explain drug antagonism in terms of competition between agonist and antagonist molecules for the same receptors, though both had thought about this possibility.
Two more breakthrough needed: 1. The analysis of competitive antagonism; 2. The direct measurement of drug binding,
which led on to the isolation and cloning of receptors.
Schild (in 1947)
SCHILD, H.O. (1947). pA, a new scale for the measurement of drug antagonism. Br. J. Pharmacol., 2, 189–206.
➢Competitive antagonism: “Parallel shift” ➢KD: the affinity of antagonist for the receptors to be
The idea could not be pursued that the competitive antagonism by deriving the very simple equations for the binding of two mutually exclusive compounds at the same population of sites.