2. Pharmacology: Studying the principles of Drug Action Pharmacokinetics Pharmacodynamics: Drug action Two ways to measure drug effects: Psychopharmacology and Neuropharmacology

3. Pharmacokinetics I. Administration II. Absorption & distribution III. Binding and bioavailability IV. Inactivation/Biotransformation (metabolization) V. Elimination/excretion

4. I. Administration A. Dose or dosage Calculation: Take the desired or prescribed dose (typically in mg/kg) and multiply by the persons mass (in kg). Thus, for example, 0.10mg/kg x 60kg = 6 mg dose Dosage may also be measured in mg/dl of blood plasma, but that is after administration and absorption.

5. B. Administration methods 1. Oral Advantages and disadvantages Formulations: Elixirs and syrups Tablets, capsules, and pills Historic formulations: Powder (Take a powder) Cachets Lozenges and pastilles

6. B. More administration methods 2. Parenteral (Injection) a. Intravenous b. Intramuscular c. Subcutaneous d. Intracranial e. Epidural f. Intraperitoneal

7. B. Administration methods, continued 3. Respiratory a. Inhalation v. intranasal (snorting) b. Smoke (Solids in air suspension) c. Volatile gases 4. Transcutaneous or transdermal 5. Orifice membranes a. Sublingual b. Rectal: Suppositories or enemas c. Vaginal: pessaries or douches (1860) d. Other orifices: bougies 6. Topical

8. Pharmacokinetics I. Administration II. Absorption & distribution Bioavailability III. Binding IV. Inactivation/biotransformation (metabolization) V. Elimination/excretion

9. II. A. Absorption 1. Absorption Principles 2. Absorption Barriers 3. Absorption mechanics

10. 1. Absorption Principles a. General principle: Diffusion, which depends on i. Solubility (fat and/or water) ii. Molecular diameter iii. Volatility (air) iv. Affinity (Proteins, water [hydrophilic], oil b. Absorption is influenced by amount of blood flow at the site of administration

11. 2. Absorption Barriers Barriers to absorption include Mucous layers Membrane pores Cell walls First-pass metabolism Placenta Blood proteins Fat isolation Blood-brain barrier Exceptions: Area postrema, median eminence of hypothalamus

12. The blood-brain barrier Glial feet Basement membrane (Pia mater)

13. Absorption Barriers To review, barriers to absorption include Mucous layers Membrane pores Cell walls First pass metabolism Placenta Blood proteins Fat isolation Blood-brain barrier

14. 3. Absorption Mechanics For each drug, water and fat solubility vary. Relative solubilities depend on i. pH of the drug ii. pH of the solution iii. pKa of the drug Solubility percentages depend on ionization ratios

15. Determining the pKa of a drug 10243567 891011 12 13 14 Solution pH:

16. Determining the pKa of a drug 28162638506274 10243567 891011 12 13 14 Solution pH: % Ionized % Ionized 84 92 98 99 99 99 99

17. % Ionization for Darnital

18. Relative solubilities

19. Computing Ionization Ratios According to the Henderson-Hasselbalch equation, the difference between the pH of the solution and the pKa of the drug is the common logarithm of the ratio of ionized to unionized forms of the drug. For acid drugs log(ionized/unionized) = pH - pKa, or ratio of ionized to unionized is 10 X / 1, where X = pH – pKa

20. Computing ionization ratios, 2 For basic drugs, everything is the same except that the ratio reverses: Log(unionized/ionized) = pH – pKa, or Ratio of unionized to ionized is 10 X / 1, where X = pH – pKa

21. Examples Darnital, a weak acid, has a pKa of 5.5. Taken orally, it is in a stomach solution of pH 3.5. pH – pKa = 3.5 – 5.5 = -2 Since Darnital is an acid drug, we use the alphabetical formula ionized/unionized. ionized/unionized = 10 -2 /1= 1/100 For every 1 molecule of Darnital that is ionized, 100 are unionized. Darnital in the stomach is highly fat soluble.

22. But look what happens… The highly fat soluble Darnital readily crosses the stomach membranes and enters blood plasma, which has a pH of 7.5 pH – pKa = 7.5 – 5.5 = 2 ionized/unionized = 10 2 /1= 100/1 For every 100 molecules of Darnital that are ionized, only 1 is unionized. Darnital in the blood is not very fat soluble. Darnital will be subject to ion trapping.

23. Another example Endital, a weak base with a pKa of 7.5 is dissolved in the stomach, pH 3.5 pH – pKa = 3.5 – 7.5 = -4 Since Endital is a base drug, we use the ratio backwards: unionized/ionized. unionized/ionized = 10 -4 /1= 1/10,000 In the stomach, Endital will be mostly ionized, and not very fat soluble.

24. But… If we inject Endital intravenously into the blood, with a pH of 7.5, pH – pKa = 7.5 – 7.5 = 0 unionized/ionized = 10 0 = 1/1 In the blood, Endital will be equally ionized and unionized. Half of the molecules of Endital will be fat soluble, and will readily leave the blood and enter the brain. A dynamic equilibrium follows.

25. An oddity Caffeine is a base drug, but it has a pKa of 0.5 pH – pKa = 3.5 – 0.5 = 3 Since caffeine is a base drug, we use the ratio backwards: unionized/ionized. unionized/ionized = 10 3 /1= 1000/1 In the stomach, caffeine will be mostly unionized, and fat soluble! In the blood, caffeine will be even more unionized and fat soluble: pH – pKa = 7.5 – 0.5 = 7, ratio = 10 7 /1= 10,000,000/1. Caffeine is a 600 pound gorilla.

26. 2b. Distribution The generalized distribution of a drug throughout the body controls the movement of a drug by its effect on ionization ratios Distribution also controls how long a drug acts and how intense are its effects Generalized distribution of a drug accounts for most of the side effects produced Is there a magic bullet?

27. Mechanisms of distribution Blood circulation: The crucial minute But blood flow is greater to crucial organs than to muscle, skin, or bone. Blood circulation is the main factor affecting bioavailability. Lymphatic circulation Depot binding CSF circulation: The ventricular system

28. Distribution half-life and therapeutic levels Distribution half-life: the amount of time it takes for half of the drug to be distributed throughout the body Therapeutic level: the minimum amount of the distributed drug necessary for the main effect.

29. Half-life curves Time in hours Blood level Elimination Distribution 2 4 6 8 10 12 14 Resultant

30. Pharmacokinetics 1. Administration 2. Absorption and distribution 3. Binding and bioavailability 4. Inactivation/biotransformation 5. Elimination/excretion

31. Pharmacokinetics 1. Administration 2. Absorption 3. Distribution and bioavailability 4. Biotransformation and elimination

32. 4. Elimination Routes of elimination: All body secretions Air Perspiration, saliva, milk Bile Urine Regurgitation Kidney action Liver enzyme activity: Generalized

33. Enzyme activity Enzymes in gi tract cells Buspirone and grapefruit juice Enzymes in hepatocytes Cytochrome P-450 families: CYP1-3 Cross-tolerance Biotransformation Type I and type II Metabolites are larger, less fat soluble, more water soluble Metabolite activity is usually lowered

34. Elimination phenomena Elimination half-life and side effects Tolerance and Mithradatism Metabolic tolerance or enzyme- induction tolerance Cross-tolerance: Carbamazepine and fluoxetine (Tegretol and Prozac) Cellular-adaptive tolerance Behavioral conditioning and state- dependent tolerance

35. Tolerance More tolerance phenomena Tachyphylaxis Acute tolerance: The BAC curve Mixed tolerance Reverse tolerance or sensitization and potentiation: Fluvoxamine and clozapine; Zantac or Tagamet and alcohol

36. Balancing distribution and elimination Elimination half-life and hangovers Accumulation dosing: The 6 half-life rule and regular dosing Steady-state dosing Therapeutic drug monitoring (TDM)

37. Accumulation dosing A 1 B 2 C 3 D 4 E 5 F 6 G 7 Letters = doses; numbers = half-lives Plasma level, mg/dl 50 100 150 200 250 300 350

38. Dependence and Addiction Physiological dependence: The abstinence syndrome Cross-dependence Habituation and conditioning Addiction and behavioral reinforcement Positive reinforcement Negative reinforcement

39. Automatic enemas

40. Nineteenth century inhaler