Pharmokinetics

1. Pharmokinetics CHAPTER 3 - 2 Dr. DipaBrahmbhatt VMD MpH dbrahmbhatt@vettechinstitute.edu

3. Drug Movement • Pharmacokinetics includes the movement of substances across cell membranes. • Basic mechanisms: • Passive diffusion • Facilitated diffusion • Active transport • Pinocytosis/phagocytosis

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

5. Passive Diffusion Movement is random from areas of higher to areas of lower concentration Eventually the drug molecules are equally distributed (equilibrium) Once equilibrium reached, molecules still moving around but no net direction of movement High concentration in this area

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

7. Passive Diffusion • Movement of particles (atom, ion, molecules) from an area of high concentration to an area of low concentration • Rapid for small, lipophilic, nonionic particles • The drug must dissolve and pass through in the cell membrane • No energy / carrier • Temperature depended • Oxygen, carbondioxide

8. Passive Diffusion • Rate of diffusion is dependent on • Drug molecule size: smaller > faster • Lipophilic: dissolve in PL bilayer • Temperature: Low: slower rate • Thickness of membrane

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

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

11. Facilitated Diffusion Cell When the drug molecule encounters the carrier protein, it “carries” it across Membrane Here is the carrier protein molecule in the membrane

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

13. Facilitated Diffusion • Passive diffusion that uses a special carrier molecule • Usually transport protein in PL bilayer • Good for bigger molecules that are not lipid soluble • No energy is needed for a facilitated diffusion • Glucose and insulin Revolving door analogy

14. Facilitated Diffusion Passive Diffusion

15. Active Transport Cell The drug molecule encounters the carrier molecule Membrane The cell expends energy to PUMP the molecule across the membrane to the other side Involves a carrier molecule again

16. Active Transport Cell The drug molecule encounters the carrier molecule The cell expends energy to PUMP the molecule across the membrane to the other side Membrane Involves a carrier molecule again

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

18. Active Transport • Molecules move against the concentration gradient • Carrier molecule • Energy – ATP • Good for accumulation of drugs within a part of the body • Electrolytes: Na, K proton pump • Creates pH gradient • Move acidic/alkaline substance into urine

19. Active Transport

20. Carrier molecules • Saturated: carrier molecules are full • Can’t move any faster • Transportation maximum: t-max • Drugs arrive at rate that exceeds t-max, drug jam

21. Pinocytosis/Phagocytosis • Molecules are physically taken in or engulfed by a cell • Pinocytosis (cell drinking) is engulfing liquid particles (insulin) • Phagocytosis (cell eating) is engulfing solid particles (nutrients) • Good for bigger molecules (proteins) or liquids Active transport

22. Mechanisms of Drug Movement

23. Terminology • Lipophilic drugs: Fat loving (cell membrane: phospholipids e.g. intestinal mucosa) • Hydrophilic drugs: Water loving, chemicals dissolved in water: IM hydrophilic: faster absorption; • Ionized: +/- charge depended on pH. Mostly hydrophilic form • Non-ionized: No charge, neutral. Mostly lipophilic form • Polarized: charges at the end of the molecule

24. Phospholipid Bilayer • Lipophilic in nature • Nonpolarized/ nonionized molecules

25. DRUG MOVEMENT • PHARMACOKINETICS is the physiological movement of drugs. • 4 Steps: therapeutic range • Absorption • Distribution • Biotransformation (metabolism) • Excretion

26. Drug Absorption • Drug absorptionis the movement of a drug from the site of administration into the fluids of the body that will carry it to its site(s) of action (IV is directly in blood) • Drug factors include bioavailability, route of administration, lipophilic/ hydrophilic, pH of the environment, ion trapping, dissolution, first pass effect, perfusion • Patient factors include the animal’s age, health, metabolic rate, genetic factors, sex, and species

27. Bioavailability • Bioavailability:% of drug administered that actually enters the systemic circulation • IV/IA: 100% available, bioavailability F = 1 • < 1: Drugs that are partially absorbed • LOWER the bioavailability > the LESS drug in circulation > LESS drug in the tissue • Exceptions where you don’t want high bioavailability: local drugs, enteral drugs

28. Route of Administration • IV (F=1): “stat” > IM > SC > PO • Plasma (serum concentration) of drugs: pg. 57 figure 3-6 • IV: rapid high peak conc. for short period of time. If toxic: CRI e.g. digoxin bolus > toxic: vomiting, arrhythmias

29. Lipophilic/ Hydrophilic • SQ/ IM: hydrophilic > extracellular fluid (ECF) > capillaries • In GI lumen (outer): Deworming agents or antibiotics for GI tract • PO: lipophilic > lumen GI tract • SQ/IM slow release drug

30. References • Romich, J.A. Pharmacology for Veterinary Technicians, 2nd edition. 2010. • Bill, R.L. Clinical Pharmacology and Therapeutics for the Veterinary Technician, 3rd edition. 2006. • Ahearn Gregory, Life on Earth, 5th edition, 2008.