Pharmacology: Studying the principles of Drug Action

1. Pharmacology: Studying the principles of Drug Action • Pharmacokinetics • Pharmacodynamics: Drug action • Two ways to measure drug effects: • Psychopharmacology—look at changes in mood, cognition, and action after taking a drug • Neuropharmacology—examine changes in the way cells function after exposure to a drug

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

3. I. Administration • A. Dose or dosage • Calculation: Take the desired or prescribed dose (typically in mg/kg) and multiply by the person’s 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.

4. 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

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

6. 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

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

8. II. A. Absorption • 1. Absorption Principles • 2. Absorption Barriers • 3. Absorption Mechanics

9. 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

10. 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

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

12. 2. 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 • a. For each drug, water and fat solubility vary. Some of the molecules of a given drug are fat soluble while other molecules of the same drug are water soluble. • b. Relative solubilities (fat soluble % and water soluble %) depend on • i. pH of the drug • ii. pH of the solution • iii. pKa of the drug • c. Solubility percentages depend on ionization ratios

15. Determining the pKa of a drug Solution pH: 0 1 2 3 4 5 6 7 Solution pH: 8 9 10 11 12 13 14

16. Determining the pKa of a drug % Ionized 2 8 16 26 38 50 62 74 Solution pH: 0 1 2 3 4 5 6 7 % Ionized 84 92 98 99 99 99 99 Solution pH: 8 9 10 11 12 13 14

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 10X / 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 10X / 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 = 102/1= 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.

24. 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.

25. But… If we inject Endital intravenously into the blood, with a pH of 7.5, pH – pKa = 7.5 – 7.5 = 0 unionized/ionized = 100 = 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.

26. 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 = 103/1= 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 = 107/1= 10,000,000/1. Caffeine is a 600 pound gorilla.

27. 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?

28. 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

29. 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.

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

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

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

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

34. 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

35. 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

36. Tolerance More tolerance phenomena • Tachyphylaxis • Acute tolerance: The BAC curve • Mixed tolerance • Reverse tolerance or sensitization and potentiation: Fluvoxamine (Luvox®) and clozapine (Clozaril®); Zantac® or Tagamet® and alcohol

37. 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)

38. Accumulation dosing Plasma level, mg/dl 50 100 150 200250 300 350 A 1 B 2 C 3 D 4 E 5 F 6 G 7 Letters = doses; numbers = half-lives

39. An example: Clozapine pharmacokinetics • Pharmacokinetics and metabolismAfter oral administration the drug is rapidly absorbed. There is extensive first pass metabolism and only 27-50%of the dose reaches the systemic circulation unchanged.Clozapine's plasma concentration has been observed to vary from patient to patient. Various individual factors may vary response such as smoking, hepatic metabolism, gastric absorption, age, and possibly gender.Clozapine is rapidly distributed; it crosses the blood-brain barrier and is distributed in breast milk. It is 95% bound to plasma proteins. Steady state plasma concentration is reached after 7-10 days. The onset of anti-psychotic effect can take several weeks, but maximum effect may require several months. In treatment resistant schizophrenia, patients have been reported to continue to improve for at least two years after the start of clozapine treatment. Clozapine metabolizes into various metabolites, out of which only norclozapine (desmethyl metabolite) is pharmacologically active. The other metabolites do not appear to have clinically significant activity.Its plasma concentration declines in the biphasic manner, typical of oral anti-psychotics and its mean elimination half-life ranges from 6-33 hours. About 50% of a dose is excreted in urine and 30% in the faeces.

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

41. Automatic enemas

42. Nineteenth century inhaler