Principle of Pharmacology Pharmacokinetics Dr. Guangyu Wu Department of Pharmacology

1. Principle of Pharmacology Pharmacokinetics Dr. Guangyu Wu Department of Pharmacology LSU Health Sciences Center New Orleans, LA

2. Pharmacodynamics Drug actions and their mechanisms DRUGS RECEPTORS RECEPTORS RECEPTORS PHARMACOLOGICAL RESPONSES

3. Pharmacokinetics The study of drug movement into, within and out of the body, which includes absorption, distribution and elimination. Absorption - Transfer of drug from site of administration to systemic circulation Distribution - Transfer of drug from systemic circulation to tissues Elimination - Removal of drug from the body Excretion Metabolism

4. Other storage tissues Site of action Pharmacological effects AT A + T AR A + R plasma Distribution Unchanged A Absorption Drug (A) Administration Free drug [A] Excretion Distribution Metabolism A’ Systemic circulation A + P AP Plasma protein-bound drug (AP) Protein-drug complex Drug metabolite (A’)

5. Drug 1 Physical Properties Structure Lipid solubility Ionization state [Drug] Drug 2 Time (h)

6. Mechanisms of drug transport • Drug administration • Drug absorption • Drug distribution • Drug elimination – excretion

7. DRUG DRUG DRUG DRUG PHARMACOLOGICAL EFFECTS

8. Mechanisms of Drug Transport • Passive diffusion • Passive diffusion of non-electrolytes • Passive diffusion of electrolytes • Filtration • Carrier-mediated transport • Active transport • Facilitated diffusion • Receptor-mediated endocytosis • Ion-pair transport Endogenous compounds and drugs

9. Mechanisms of Drug Transport • Passive diffusion – Low molecular weight drugs that are both water and lipid soluble dissolve in membrane and cross to the other side. • Primary means by which drugs cross membranes

10. A A A A A A A A A A A A A A A A A A A A A A A A Mechanisms of Drug Transport 1. Passive diffusion Compartment 1 Compartment 1 Membrane Membrane Compartment 2 Compartment 2 Driving force: the concentration gradient across the membrane

11. Mechanisms of Drug Transport • Passive diffusion • 1) Passive diffusion of non-electrolytes • 2) Passive diffusion of electrolytes

12. Mechanisms of Drug Transport • Passive diffusion • Passive diffusion of non-electrolytes • Lipid-water partition coefficient (Kp) -the ratio of the concentration of the drug in two immiscible phases: a nonpolar liquid (representing membrane) and an aqueous buffer (representing the plasma). • Kp can be measured. Kp = [drug] in lipid phase/[drug] in aqueous phase. • If the drug is more soluble in the lipid, Kp is higher. If the drug is more soluble in the aqueous phase, Kp will be lower. • The partition coefficient is a measure of the relative affinity of a drug for the lipid and aqueous phases. • One can control the Kp by modifying the side groups on the compound. The more C and H on the compound, the more lipid soluble, and thus the higher the Kp. The more O, S and the more water-soluble the compound, and the lower the Kp.

13. Mechanisms of Drug Transport • Passive diffusion • Passive diffusion of non-electrolytes • The higher the Kp, the more lipid soluble, the faster the rate of transfer across biological membranes

14. Mechanisms of Drug Transport • Passive diffusion • 2) Passive diffusion of electrolytes • Electrolytes: tend to ionize in physiological solutions. • Two main categories – weak acids and weak bases. • Weak acids: HA H+ + A- R-COOH, R-OH and R-SH • Weak bases: BH+ B + H+ R-NH2 • Most drugs are either weak acids or weak bases.

15. Mechanisms of Drug Transport • Passive diffusion • 2) Passive diffusion of electrolytes • pKa: the pH at which half of the molecules are in the ionized form and one half are in the unionized form. • pKa is a characteristic of a drug. • Henderson-Hasselbalch equations: • For acids: pH = pKa + log [A-]/[HA] • For bases: pH = pKa + log [B]/[BH+] • pH and drug concentration are log based scale - Every point difference in pH is 10-fold difference in drug concentration

16. Mechanisms of Drug Transport • Passive diffusion • 2) Passive diffusion of electrolytes HA H+ + A- BH+ H+ + B pH > pKa Predominate forms: A- and B pH = pKa HA = A- BH+ = B pH < pKa Predominate forms: HA and BH+ pH 3 4 5 6 7 8 9 10 11

17. Mechanisms of Drug Transport • Passive diffusion • 2) Passive diffusion of electrolytes • Only the unionized forms of the drug or the uncharged drug can pass through or across the membranes by passive diffusion. • By controlling the pH of the solution and/or the pKa of the drug, you can control the rate at which the drug is transferred

18. Mechanisms of Drug Transport Acidic drug - pKa = 5 1 0.01 1.01 molecules HA H+ + A- pH = 3 Body compartment 1 Membrane Body compartment 2 HA H+ + A- pH = 7 101 molecules 1 100 Drug accumulation

19. Mechanisms of Drug Transport Acidic drug - pKa = 5 1 0.01 1.01 molecules HA H+ + A- pH = 3 Body compartment 1 Membrane Body compartment 2 HA H+ + A- pH = 7 101 molecules 1 100 Lipid solubility: Higher Kp – faster Lower Kp - slower

20. Mechanisms of Drug Transport Drug accumulation Basic drug - pKa = 5 100 1 101 molecules HB+ H+ + B pH = 3 Body compartment 1 Membrane Body compartment 2 HB+ H+ + B pH = 7 1.01 molecules 0.01 1

21. Mechanisms of Drug Transport • 2. Filtration • - Passage of molecules through pores or porous structures. • The rate of filtration • Driving force: The pressure gradient in both sides. • The size of the compound relative to the size of the pore. • Smaller compound – transfer rapidly • Larger compound – retained • Intermediate compound – barrier Lipid soluble – passive diffusion Water soluble – filtration

22. Mechanisms of Drug Transport • 2. Filtration • The rate of filtration: • In biological systems:Filtration is the transfer of drug across membrane through the pores or through the spaces between cells • Capillary endothelial membranes • Renal glomerulus

23. Mechanisms of Drug Transport 2. Filtration Interstitial fluid Capillary endothelium cells Blood Interstitial fluid • Most substances (lipid-soluble or not) – cross the capillary wall – very fast • Lipid soluble and unionized – filtration and passive diffusion – at the same time

25. Mechanisms of Drug Transport 3. Carrier-mediated transport • Active transport • Facilitated diffusion

26. Mechanisms of Drug Transport 3. Carrier-mediated transport 1) Active transport • Carrier or receptor-mediated • Reversible binding • Resemble with endogenous substances that are normal substances for that particular transport system (sugars, amino acids) • Selectivity - not for all the drugs • Energy-dependent - ATP hydrolysis • One-way process – against drug concentration gradient - drug accumulation • It can be saturated – Drug/receptor ration – enzyme-catalyzed reactions • Can be inhibited – ATP inhibitors, structural analogous compounds Drug Carrier Receptor Membrane

27. Mechanisms of Drug Transport 3. Carrier-mediated transport 2) Facilitated diffusion • Carrier or receptor-mediated • Selectivity • It can be saturated • Does not require ATP – concentration gradient • Bi-directional – no drug accumulation Drug Carrier Receptor Membrane

28. Mechanisms of Drug Transport • 4. Receptor-mediated endocytosis • -more specific uptake process • Drugs (peptide hormones, growth factors, antibodies, et al) bind to their receptors on the cell surface in coated pits, and then the ligand and receptors are internalized, forming endosomes. • Receptor-ligand complex may take four different pathways: • Receptor recycles, ligand degraded • Receptor and ligand recycle • Receptor and ligand degraded • Receptor and ligand transported

30. pH 7.4 Plasma, High affinity – Fe Low affinity - receptor High affinity - receptor Fe3+ Transferrin Transferrin receptor Endocytosis Recycling Low affinity – Fe High affinity - receptor Endosome, pH = 5

31. Mechanisms of Drug Transport 5. Ion-pair transport Highly ionized Passive diffusion + + _ _ + + _ _ Carrier

32. Routes of Drug Administration • The properties of the drug (such as water soluble or lipid soluble) and the therapeutic objectives (effective rapidly or slowly; long-term, restricted to a local site). • Major routes: • 1. Enteral administration: • Oral • Sublingual • Rectal • 2. Parenteral administration: • Intravenous (IV) • Intramuscular (IM) • Subcutaneous (SC)

33. Routes of Drug Administration • 1. Enteral administration: • Advantages: the most common route • Safe • Convenient • Economical • Disadvantages • Limited absorption - Some drugs can be destroyed by digestive enzyme and low gastric pH in GI tract • Irregularities in absorption in the presence of food or other drugs • Emesis as result of gastric irritation Requires patient cooperation • May be metabolized by first-pass effect

34. First Pass Effect Drugs administrated orally are first exposed to the liver and may be extensively metabolized before reaching the rest of body. IV Liver Rest of body Oral Example: Nitroglycerin – 90% cleared

35. Routes of Drug Administration 1. Enteral administration: 1) Oral: most common route most variable most complicate pathway to the tissues first-pass metabolism/effect

36. Routes of Drug Administration 1. Enteral administration: 2) Sublingual: Placement under the tongue and diffuse into the capillary network Bypass first pass effect For potent drug Nitroglycerin – nonionic, lipid soluble, potent

37. Routes of Drug Administration 1. Enteral administration: 3) Rectal: used when it is unable to use oral ingestion such as unconscious patients or children. About 50% of the drug absorbed from the rectum will bypass the liver – less first-pass effect

38. Routes of Drug Administration • 2. Parenteral administration: • Drugs - poorly absorbed or not stable in the GI tract • Advantages: • Better regulated and more predictable absorption • Can more accurately select effective dose • Avoids first pass effect • Disadvantages: • Risk of infection – asepsis must be maintained • Pain associated with injection • Difficulties in self medication

39. Routes of Drug Administration • 2. Parenteral: • Intravenous administration (IV): • The most common parenteral route • Advantages: • Can attain desired drug concentration immediately • Dosage can be readily adjusted • Bypass first pass effect • Can give certain irritating (GI tract) solutions (blood vessel –insensitive; drug dilution by blood) • Disadvantages: • Cannot be reversed – overdose • May introduce bacteria through contamination – hemolysis • Unfavorable reaction – the rate of infusion • Must maintain patent vein – repeated IV • Drugs in oily vehicles, extremely lipid soluble drugs that precipitate in blood, or drugs that may cause hemolysis, cannot be given.

40. Routes of Drug Administration • 2. Parenteral: • 2) Intramuscular administration: Injected into the muscle - aqueous solution or nonaqueous suspension (in oil vehicles) • Absorption by filtration or bulk flow • Bypass first-pass effect of the liver • Constant and slow absorption • Absorption dependent on blood flow • Absorption rate can be intentionally altered by mixing with oil - slow down, or by jagging, local heating or exercise – facilitate

41. Routes of Drug Administration • 2. Parenteral: • 3) Subcutaneous administration - drugs are injected underneath the skin. It can be used only for drugs that are not irritating to tissues. Otherwise, severe pain, necrosis may occur. • Absorption by filtration or bulk flow. • Bypass first-pass effect of the liver. • Slow and constant absorption – generally slower than IM. • Absorption rate can be intentionally altered. • Aqueous solution – fast absorption • Suspension in oil – slow absorption • Implanted solid drug under the skin – slow absorption

42. Absorption of Drugs • Transfer of drug from the site of administration to the systemic circulation • Sites of absorption through the GI tract • Factors that modify absorption in the GI tract • Bioavailability • Other sites of drug administration/absorption

43. Absorption of Drugs • Sites of absorption through the GI tract • Mouth • Stomach • Small intestine • Large intestine

44. Absorption of Drugs • 1. Sites of absorption through the GI tract • 1) Mouth: • Small amount of surface area but good blood flow – best for potent drugs. • Transfer by passive diffusion – good for lipid soluble drugs. • pH = 6. Weak base drugs have better absorption. • Nicotine pKa 8.5 Mouth GI tract • pH 6 1-5 • Ionization more less • Absorption 4 times faster • d. Can bypass first pass effect.

45. Absorption of Drugs • 1. Sites of absorption through the GI tract • 2) Stomach: • Moderate surface area – more than mouth, less than small intestine. • Good blood supply. • Drugs absorbed in the stomach will experience first pass effect. • Transfer by passive diffusion. • Low pH (1-2) – ionization - Drugs that are weak acids will be absorbed better than weak base drugs. • Ion trapping: Accumulation of weak base drugs in the stomach.

46. Absorption of Drugs • 1. Sites of absorption through the GI tract • 3) Small intestine • The primary site for most drugs. • Large surface area - Folds, villi and microvilli and high blood perfusion rate. • pH = 5-8. • Passive diffusion. • Absorption can also take place by active transport, facilitated diffusion, endocytosis and filtration.

47. Absorption of Drugs • 1. Sites of absorption through the GI tract • 4) Large intestine • Not important for drug absorption, if the drug is absorbed effectively in small intestine. • Can be a site of absorption for incompletely absorbed drugs. • Less absorption then small intestine – less area and solid nature of contents. • Rectum can be used for drug administration. • For drugs that cause irritation to the stomach • After GI surgery • Children • Partially avoids liver first pass effect: The half of blood flow goes into liver, the half of blood flow enters the systemic circulation directly.

48. Absorption of Drugs • 2. Factors that modify absorption in the GI tract • Drug solubilization • Formulation factors • Concentration of drug at the absorption site • Blood flow at the absorption site • Surface area of absorption • Route of administration • Gastric emptying • Food • Intestinal motility • Metabolism of drug by GI tract

49. Absorption of Drugs 2. Factors that modify absorption in the GI tract Hydrophilic drugs - poorly absorbed - inability to cross the lipid-rich cell membrane. Hydrophobic drugs - poorly absorbed - insoluble in the aqueous body fluids - cannot gain access to the surface of cells. - largely hydrophobic yet have some solubility in aqueous solutions

50. Absorption of Drugs 2. Factors that modify absorption in the GI tract 1) Drug solubilization – breaking drugs into smaller, more absorbable particles Solid Granules fine particles: disintergration deaggregation Solution