1. CHAPTER 4 L. VanValkenburg, RVT, BAS Pharmacokinetics

2. DRUG MOVEMENT PHARMACOKINETICS is the physiological movement of drugs. 4 Steps:  Absorption  Distribution  Biotransformation (metabolism)  Excretion

3. DRUG MOVEMENT Pharmacokinetics includes the movement of substances across cell membranes. Basic mechanisms:  Passive diffusion  Facilitated diffusion  Active transport  Pinocytosis/phagocytosis

4. They don’t! Drugs molecules go “wherever”

5. Movement of Drug Molecules Drug molecules move randomly from one point to another This process is called passive diffusion No cellular effort is needed to transport the molecules (hence the process is passive)

6. Passive Diffusion High concentration in this area Movement is random from areas of higher to areas of lower concentration Eventually the drug molecules are equally distributed (equilibrium)

7. Cell MembraneCell Membrane Drug molecules may move from one side of a cell membrane to another by passive diffusion But drug molecules will only cross by passive diffusion if they can dissolve in the membrane Passive Diffusion

8. Facilitated Diffusion CellMembraneCellMembrane These molecules can’t pass through the membrane without help These drug molecules need a carrier to get across the membrane Cell MembraneCell Membrane

9. MembraneMembrane Here is the carrier protein molecule in the membrane When the drug molecule encounters the carrier protein, it “carries” it across CellCell Facilitated Diffusion

10. MembraneMembrane Here is the carrier protein molecule in the membrane When the drug molecule encounters the carrier protein, it “carries” it across CellCell Facilitated Diffusion

11. MembraneMembrane Here is the carrier protein molecule in the membrane The carrier molecule then resets itself No cellular energy is used to transport the molecule across Only the concentration gradient moves the molecules CellCell Facilitated Diffusion

12. MembraneMembrane Involves a carrier molecule again The drug molecule encounters the carrier molecule CellCell The cell expends energy to PUMP the molecule across the membrane to the other side Active Transport

13. MembraneMembrane Involves a carrier molecule again The drug molecule encounters the carrier molecule CellCell The cell expends energy to PUMP the molecule across the membrane to the other side

14. Active Transport MembraneMembrane Involves a carrier molecule again Unlike diffusion, active transport is not dependent upon concentration gradient CellCell All of the molecules can end up on this side

15. Phagocytosis and Pinocytosis Phagocytosis – the cell flows around large particles and engulfs it Pinocytosis – cell takes in molecules through invaginations in the membrane Cell Foreign particle

16. In summary….

17. Movement of particles from an area of high concentration to an area of low concentration  Good for small, lipophilic, nonionic particles  The drug must dissolve and pass through in the cell membrane Passive Diffusion

18. Facilitated Diffusion Passive diffusion that uses a special carrier molecule  Good for bigger molecules that are not lipid soluble  No energy is needed for a facilitated diffusion

19. Active Transport Molecules move against the concentration gradient from areas of low concentration of molecules to areas of high concentration of molecules Involves a carrier molecule and energy  Good for accumulation of drugs within a part of the body

20. Phagocytosis and Pinocytosis Molecules are physically taken in or engulfed. Pinocytosis is engulfing liquid; phagocytosis is engulfing solid particles  Good for bigger molecules or liquids

21. Getting In: DRUG ABSORPTION

22. Getting in: DRUG ABSORPTION

23. Moving Around: DRUG DISTRIBUTION Drug distribution is the physiological movement of drugs from systemic circulation into the tissues. Goal is for the drug to reach the target tissue or intended site of action Factors affecting drug distribution:  Membrane Permeability  Tissue Perfusion  Protein Binding  Volume of Distribution

24. Membrane Permeability Capillary fenestrations allow movement of small molecules in and out of them. Large molecules usually cannot pass through them blood-brain barrier Exception: Only lipophilic drugs can pass through the blood-brain barrier because it has no fenestrations and it has an extra layer of cells surrounding them (glial cells). However, fever/inflammation can make the membrane more permeable to some drugs. placenta Exception: The placenta has the ability to block SOME drugs from affecting the fetus with its barrier.

25. TISSUE PERFUSION Definition – the relative amount of blood supply to an area or body system. It affects how rapidly drugs will be distributed.  Drugs travel rapidly to well perfused tissues (brain, heart, liver, kidneys).  May initially have high levels of drug  Drugs travel slowly to poorly perfused tissues (fat).  May inititially have low levels of drug  Can also be affected by blood flow rates that are altered via vasoconstriction or vasodilation.  Decreased rates decrease the amount and rate of the drug that’s delivered to the tissues.

26. Protein Binding Protein bound drugs in the blood become trapped in circulation because they cannot leave capillaries. Free or unbound drugs are able to leave the capillaries.  INCREASED PROTEIN BINDING = less free drug available to the tissues  DECREASED PROTEIN BINDING = more free drug available to the tissues. Equilibrium is typically established between bound and unbound drugs. When given concurrently, protein bound drugs compete for binding sites.

27. Hypoalbuminemia Albumin is the #1 transport protein in circulation and is made in the LIVER. Animals with liver disease will have less protein in their body, thus more drug will be UNBOUND and available to the tissues. DECREASED dosages or different medications should be chosen for patients with liver disease.  Also important because most drugs will be metabolized by the liver.

28. Volume of Distribution

29. Volume of distribution is how well a drug is distributed throughout the body based on concentration of drug in the blood.  Assumes that the drug concentration in the blood is equal to the drug concentration throughout the rest of the body NOTE: THE LARGER THE Volume of Distribution, THE LOWER THE DRUG CONCENTRATION IN THE BLOOD AND OTHER TISSUES AFTER DISTRIBUTION. Lower concentrations may keep a drug out of therapeutic range and decrease its effectiveness. Dose may need to be increased in cases of larger volumes of distribution.

30. Changing: PHARMACOKINETICS Biotransformation is also called drug metabolism, drug inactivation, and drug detoxification Biotransformation is the chemical alteration of drug molecules by the body cells into a metabolite that is in an activated form, an inactivated form, and/or a toxic form. Primary site of biotransformation is the liver.  Inhibition or induction of Cytochrome P450

31. Drug Interactions Affecting Drug Metabolism: Altered absorption: one drug may alter the absorption of other drugs  Antacids alter pH of stomach. Competition for plasma proteins: drug A and drug B may both bind to plasma proteins; one may have a higher affinity than the other Altered excretion: some drugs may act directly on the kidney and decrease the excretion of other drugs  Diuretics increase production of urine and may affect drugs excreted via the kidneys. Altered metabolism: the same enzymes may be needed for biotransformation of two drugs that are prescribed at the same time for an animal  Enzyme = saturated; rate of metabolism decreased for both drugs

32. Other ways in which drug interactions affect drug metabolism: Some drugs induce the enzyme system, altering metabolism by causing liver enzymes to become more efficient.  Ex: Phenobarbital (may need to increase dose to maintain adequate therapeutic levels) Liver damage or immaturity decreases enzyme production and ability to metabolize drugs  Doses may need to be decreased to avoid toxicity. Tolerance is decreased response to a drug resulting from repeated use.  Metabolic – drug metabolized more rapidly  Cellular – “down regulation” = decreased receptor response  Doses need to be increased.

33. Getting out: PHARMACOKINETICS Drug elimination (drug excretion) is removal of a drug from the body. Most important routes = kidneys and liver Renal elimination of drugs involves  Glomerular filtration  Tubular secretion  Tubular reabsorption  Urine pH can also affect rate of drug excretion.  Weak acids better excreted in basic urine  Weak bases better excreted in acidic urine Other elimination routes include the intestine and through milk. Minor routes of elimination: sweat, saliva, and pulmonary route.

34. Drug Elimination Terminology Drug residue: amount of drug that can be detected in tissues after administration ceases. Withdrawal time: period of time after drug administration during which the animal cannot be sent to market for slaughter and the eggs or milk must be discarded because of the potential for drug residues Half-life: time required for the amount of drug in the body to be reduced by half of its original level Steady state: point at which drug accumulation and elimination are balanced

35. MEASURING DRUG ACTION Graphic depiction of the plasma concentration of the drug vs. time  X axis represents time  Y axis represents drug concentration in plasma Onset of action occurs when the drug enters the plasma The peak plasma level of the drug is when the elimination rate of the drug is equivalent to its rate of absorption

36. The time elapsed from the time of administration to the time that the peak plasma level is reached is known as the time to peak  Important in making clinical judgments about the use of a drug From the peak plasma level the concentration declines since the amount of drug being eliminated exceeds the amount being absorbed MEASURING DRUG ACTION

37. Drugs work in a variety of ways:  Drugs alter existing cellular functions  Drugs alter the chemical composition of body fluids  Drugs can form a chemical bond with specific cell components on target cells within the animal’s body HOW DO DRUGS WORK?

38. RECEPTORS Receptors are three-dimensional proteins or glycoproteins  Located on the surface, in the cytoplasm, or within the nucleus of cells Affinity is the strength of binding between a drug and its receptor  High-affinity drugs bind more tightly to a receptor than do low-affinity drugs

39. RECEPTORS

40. AGONISTS VS ANTAGONISTS Agonist: drug that binds to a cell receptor and causes action Antagonist: drug that inhibits or blocks the response of a cell when the drug is bound to the receptors

41. AGONISTS VS ANTAGONISTS