Principles of Pharmacology: Part 2

1. Principles of Pharmacology: Part 2 Lecture 9

3. Capillaries Exchange of materials b/n blood and cells Capillary walls one cell thick Pores materials can move in/out

4. Movement Across Membrane Passive diffusion Carrier assisted transport diffuse thru gated channels Active transport requires energy

5. Active Transport Metabolic pumps require energy Membrane proteins Pump materials across membrane

6. Barrier b/n circulatory system & brain Capillaries cells in wall tightly packed astrocytes wrap around capillaries tight seal Blood-Brain Barrier (BBB)

7. *BBB: Development Incomplete at birth up to 2 yrs old vulnerable during pregnancy Weakening of BBB trauma infection ~

8. Chemical Trigger Zone (CTZ) Also called Area Postrema BBB weaker Substances can enter brain safety mechanism neurons monitor blood fast increase in blood concentration ----> vomiting dopaminergic neurons

9. Placental Membrane Exchange nutrients & wastes w/ mother Less selective than BBB all lipid soluble substances Fetus is vulnerable incomplete BBB lack enzymes for metabolism ~

10. Placental Membrane Teratogens chemicals that cause birth defects alcohol, nicotine, cocaine, etc. Smoking ---> CO reduced O2 levels ---> brain damage ~

11. Solubility Ability to dissolve in a medium water-soluble lipid-soluble easily crosses membranes also BBB ~

12. Solubility: Size & Configuration Molecular size small absorbed easily Molecular configuration 3 dimensional structure isomers - mirror images l-amphetamine, d-amphetamine generally, l- isomer more active ~

13. Solubility: Ionization Ionization decreases solubility ion = charged particle Lipid-soluble ---> little ionization Water-soluble ---> ionizes easily requires active transport ~

14. Polarity positive & negative poles H2O Polar ---> hydrophylic tend to ionize will not cross membrane Nonpolar ---> hydrophobic crosses membrane easily ~ Solubility: Polarization

16. Solubility: pH pH scale: 0-14 Drugs in solution can ionize H2O ---> H+ and OH- # of H+ in solution relative to OH- Hi = acidic Low = basic (alkaline) ~

18. Ion Trapping Drug & pH important Ionization decreases solubility acidic drug in alkaline = ionize alkaline drug in acidic = ionize Per Os ? acidic drug best ~

19. Redistibution Dynamic equilibrium maintained Example: acidic drug in blood 40% ionized to 60% un-ionized drug is metabolized some ionized ---> un-ionized ratio ionized to un-ionized retained 4:6 ~

20. Best Absorption Lipid soluble Small Nonpolar Un-ionized pH ~

21. Depot Binding Drug disperses throughout system Accumulates in organs & tissues does not reach target silent receptors Fat, muscle, organs, bones, etc. ~

22. Depot Binding Unable to cross membranes Slow drug fx or prevent Prolong drug fx not metabolized redistribution Termination of drug fx ~

23. Protein Binding Large blood proteins albumin Nonselective binding multiple drugs ---> compete higher effective dose for 1 Valium 99% bound, 1% free Redistribution ~

24. Drug Fate Immediate & long-term drug disposal Determines duration of drug fx drug in system---> drug fx Terminates drug fx ~

25. Half-life After complete absorption Plasma half-life time blood levels drop by half distribution half-life elimination half-life metabolism & excretion ~

26. Biotransformation Metabolism structure altered ---> metabolite By enzymes site of action blood plasma liver Inactivation Active metabolites e.g., valium, codeine ~

27. Liver Main site of metabolism nutrients detoxification 1st pass metabolism GI tract ---> liver Cytochrome P-450 main enzyme enzyme induction contributes to tolerance ~

28. Excretion: Kidneys Active & inactive forms Filtration of blood Ionization required ion-trapping Excretion in urine Antidiuretic Hormone (ADH) regulation of water alcohol, caffeine inhibit dehydration ~

29. Excretion: Other routes Lungs alcohol breath Breast milk acidic ---> ion traps alkaloids alcohol: same concentration as blood antibiotics Also bile, skin, saliva ~~

30. Drug Effects & Dose Effect of drug depends on dose In general... as dose increases, fx increase to a maximum then fx decrease

32. Dose Response Drug Effects Variable Probability Statements Based On Dose response Information All or None Graded

33. All or None % of Subjects Affected Drug Dose Not magnitude

34. Drug Response Curve: All or None

35. ED50 = effective dose in 50% of population

37. Potency vs. Efficacy Potency relative term drug A has same effect as drug B... but at lower dose Maximum efficacy maximum response magnitude more drug ---> no effect increase but might increase side fx

38. Maximum Efficacy B has greater max efficacy than A

39. Potency A is more potent than B Lower probability of side fx with A

40. Predicting Drug Effects Dose Response Curve represents mean from groups Predict individual’s response to drug? variability standard error of the mean

41. Standard Error Gives idea of response range Prediction represents probability

43. To use or not to use? Need information Therapeutic Index (safety margin) LD50/ED50 LD = lethal dose TI: 10mg/10mg = 1 100mg/10mg = 10 1000mg/10mg = 100 Decision Making

45. ED50 side/ED50 desired Side Effects Benign Untoward Side Effects

46. Comparisons of variables sex, age, etc. or tolerance

47. Tolerance After repeated use Decreased response to the same dose Compensatory responses

48. Tachyphylaxis Drug Disposition Tolerance Metabolic Pharmacodynamic Tolerance NT synthesis & Down regulation Behavioral Tolerance Volitional vs. Associative Cross Tolerance Types of Tolerance

49. Cumulative Additive Synergistic Drug Interactions

53. Other Sources of Variability Nonspecific factors Organism Psychological Environmental Task

54. Organism Variables Weight Interspecies differences Intraspecies differences Sex & Hormonal states Age Disease Nutrition Biorhythms Physiological state

55. Nonspecific Variables (continued) Psychological Expectations set Placebo fx Environmental Setting Task Rate dependent fx

56. Rate Dependency Interaction of drug & baseline behavior ADHD & ritalin stimulant to treat hyperactivity?

57. Different Effects, Same Dose Why? initial activity of system Low activity in system increases fx Hi activity in system may decrease fx

60. Rational judgment process But often not Many factors involved Learning: Classical & Operant Conditioning Should you take a drug?