ses_3_principles

ses_3_principles - 20.201 Mechanisms of Drug Action Session...

Info iconThis preview shows pages 1–8. Sign up to view the full content.

View Full Document Right Arrow Icon
20.201 Mechanisms of Drug Action Session #3: Principles, Uptake and Distribution
Background image of page 1

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full DocumentRight Arrow Icon
Metabolism Excretion Entry Distribution Exposure Who gets exposed to what and how much? Response • DNA processing and repair • Infection • Inflammation • Altered cell cycle •Disease •Mutation •Cancer •Necrosis •Apoptosis •Aging •Therapy Endpoint Targets Tissues and Cells •Extracellular Matrix º± Cell membrane º Signalling •Nucleus º Chromatin º DNA • Mitochondria DNA Toxicology/Pharmacology Paradigm
Background image of page 2
Definitio n of a dose-response relationship: correlative relationship between he degree of a response a biological system and the amount of drug or toxicant administered. • Why do we need to understand this relationship? ~ Society and government needs to know if a chemical is safe ~ Physicians need to know how much drug to give, how the patient will respond, if a drug is safe • Prerequisites for defining a dose-response relationship: ~ Certainty that the response is due to the chemical (otherwise it is an epidemiologic study and not a dose response) ~ Certainty that the level of response is due to the level of chemical ~ A quantifiable parameter for the response and a means to measure it • Types of dose-response relationships: ~ Individual or graded or continuous : study that demonstrates dose- related increase in the intensity of a response; e.g. , inhibition of an enzyme as function of dose ~ Quantal : single end-point ("quanta") dose-response study in which an organism either "responds" or doesn't. Focus on this type
Background image of page 3

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full DocumentRight Arrow Icon
• Degree of response to different doses of chemical often often follows a normal distribution (Gaussian distribution) • Bell-shaped probability distribution: ~ Left end - hypersusceptible ~ Right end - resistant • Recalculate response as cumulative response and replot versus logarithm of dose ~ Sigmoidal curve ~ More useful for comparisons 1 10 100 1000 10000 100000 0 3 6 9 12 15 18 21 Dose, mg/kg 0 1 2 3 4 5 0 10 20 30 40 50 60 70 80 90 100 log(Dose, mg/kg)
Background image of page 4
• Normally-distributed sigmoid cumulative distribution • In population with normal distribution: mean ± 1 SD…68.3% of population mean ± 2 SD…95.5% of population mean ± 3 SD…99.7% of population • Convert % response to units of deviation from the mean = NED (normal equivalent deviations): ~ 16% response (-1 SD) NED = -1 ~ 50% response (0 SD) NED = 0 ~ 84% response (+1 SD) NED = +1 0 1 2 3 4 5 0 10 20 30 40 50 60 70 80 90 100 log(Dose, mg/kg) Mean = 50% ±1 SD = 26% and 84% ±2 SD = 2% and 98% ±3 SD = 0.2% and 99.8% +2 SD +1 SD -1 SD 16%
Background image of page 5

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full DocumentRight Arrow Icon
• Avoid negative numbers: convert to Probit scale • Probit ( prob ability un it ) = NED + 5 16% response (-1SD) NED = -1 probit = 4 50% response (0 SD) NED = 0 probit = 5 84% response (+1 SD) NED = 1 probit = 6 • Probits plot as a straight line LD 50 obtained interpolation of linear regression line at probit = 5 0 1 2 3 4 5 2 3 4 5 6 7 8 log(Dose, mg/kg) Probit = 5 is EC50
Background image of page 6
15 10 5 2.5 15 10 5 2.5 15 10 5 2.5 a c
Background image of page 7

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full DocumentRight Arrow Icon
Image of page 8
This is the end of the preview. Sign up to access the rest of the document.

Page1 / 21

ses_3_principles - 20.201 Mechanisms of Drug Action Session...

This preview shows document pages 1 - 8. Sign up to view the full document.

View Full Document Right Arrow Icon
Ask a homework question - tutors are online