Pharmacokinetics

1. Pharmacokinetics Andrew Healey, Instructor Matthew Miller, Lab Assistant

2. Review • Pharmacokinetics • The life of a drug in the body • ?Route of Administration • Absorption – taken into the body • Distribution – moved into tissues • Metabolized – changed so can be excreted • Excreted – removed from the body

3. What We Will Cover (Quickly) • Routes of Administration • Absorption • Distribution • Metabolism • Excretion • Onset, Peak, and Duration • Pages 6 – 12 in CPMIE

4. Routes of Administration • Enteral • Uses the gastrointestinal tract for ingestion • Parenteral • Avoids or circumvents GI tract • All forms of injections: IM, SQ, IV, etc. • Inhalation, • Topical (also parenteral) • Applied to skin or mucous membranes

5. Local vs. Systemic Effects • Local • Drug exerts effect at site of administration • Systemic • Drug absorbed, distributed throughout the body systems • They are not mutually exclusive • Think about side effects!!!

6. Enteral Routes • Absorbed from stomach / intestine • To the liver = FIRST PASS EFFECT • IMPORTANT FACT • Drugs administered as rectal suppositories undergo relatively little first pass effect. • Then distributed to the rest of the body • Most drugs are fat-soluble – WHY?

7. FIRST-PASS EFFECT • EXTREMELY IMPORTANT!!! • PRINCIPLE: • Most blood supplying the GI tract travels to the liver before it goes to the rest of the body • THIS IS CALLED A “PORTAL” SYSTEM. • Liver = metabolic (change) machine • Often inactivates drugs

8. First Pass Effect – V/imp!

9. ADVANTAGES Convenient Relatively safe Economical Most common DISADVANTAGES Absorption can be variable Food-drug interactions!!!! Absorption – variable Irritation– N&V First pass effect Some drugs inactivated by gut (eg insulin) Effect too slow for emerg Some have unpleasant taste Enteral Route – A/D

10. Sublingual (under the tongue) Spray or pill Rapid absorption of certain drugs AVOIDS first-pass drug metabolism in liver Unpleasant taste Rectal (in anus) “suppository” Local (eg. Hemorrhoids) Systemic (eg. Abs) Useful when N&V RELATIVELY LITTLE first-pass metabolism Irritating, inconvenient Enteral Route – Special Points

11. Parenteral Routes • Intravenous injection • Intramuscular injection • Subcutaneous injection • Intrathecal injection (eg. “epidural”) • Intra-articular injection (eg. for arthritis) • Inhalation • Topical

12. ADVANTAGES Prompt response No first-pass effect More accurate dose Useful if N&V and/or change in LOC DISADVANTAGES Rapid onset therefore no recall > adverse effects quick too! Sterile preparations Painful Expensive Cannot usually self-administer Parenteral Injections – A/D

13. ADVANTAGES Rapid onset - emerg Continuous titration Accurate dose Larger vol over longer period of time Ability to administer irritating substances because of dilution in a large volume of fluid DISADVANTAGES Dangerous – rapid onset of pharmacological action Overdose – no recall / stopping absorption Safe doses given too rapidly may be toxic Embolism – oil! Sterile preparations and aseptic techniques required Intravenous Route – A/D

14. INTRAMUSCULAR Rapid absorption (solutions) Slow absorption (suspensions/oil) Painful Bleeding if on anticoag Absorption dependent on blood flow SUBCUTANEOUS Absorption slower than IM, dependent on flow Can’t be used with irritants or lg vols Less painful Special Points – IM, SQ

15. Topical Administration • BRIEF • “the patch” • Dose is proportional to the area of the patch • Distribution depends on blood flow • Nasal Mucosa (nose) • Potent drugs for systemic effects • Absorption irregular • very useful for local effects – vasoconstrictors

16. Inhalation – A/D ADVANTAGES • Extensive absorbing surface • Extensive blood supply • Particles < 2 um penetrate deep into lungs • Rapid, local effects DISADVANTAGES • Administration requires GOOD TECHNIQUE and special equipment • Amount reaching alveoli is variable • Many physiologic variables affect absorption – cilia, mucus, size of particle • Possible systemic side effects • Thrush

17. Case – Ms. Georgia Govans Georgia Govans, 79 years old, is admitted with osteomyelitis of the hip, a severe infection, after a recent repair of a hip fracture. Temp = 102.4°F and hx of severe peripheral vascular disease. Ms. Govans is admitted under your supervision. Your resident comments that he is worried about her because she is so severely ill.

18. Ms. Georgia Govans • What key factors/points must we consider in choosing the route of administration? • What drug do we give for bacterial infections?

19. Ms. Georgia Govans • State what route of administration you choose for this patient and justify your answer. • If she had a temperature of 100°F and it was a throat infection, would your route of administration differ? Explain.

20. THE LIFE OF A DRUG –Drug Absorption Pharmacokinetics

21. Absorption • Getting from outside the body to inside the body • In what routes of administration is this “skipped”?? • All drugs have to cross membranes at either this step or at the “distribution” step!

22. How do things get across the membrane? • Passive Transport (LAZY!) • Diffusion of lipid soluble substances • Protein channels • Facilitated transport • Active Transport (HARD WORK!) • Transport against gradients • Active, co-transport, counter transport

23. PASSIVE Diffusion • Movement from an area of high concentration to low concentration

24. PASSIVE Protein Channel T • Protein channels in the membrane allow certain drugs to pass through

25. PASSIVE Facilitated Transport • “conformational help” from a protein • Binding site exposed • Rock • Spit inside cell

26. Molecules move uphill (towards higher concentration) Rocking the protein using energy!!! <ATP!!!> ACTIVE transport

27. One molecule goes downhill The other (the one that needs to be transported) goes uphill Hence “CO” transport CO-transport

28. Similar to co-transport One moves downhill (in one direction) The other moves uphill (in the OTHER direction) COUNTER-transport

29. Taking a bite… pinocytosis • A cell engulfs a drug particle • Often occurs with Vitamins (A, D, E, K) • Big fat-soluble molecules!

30. Watch speed limit… • Ask yourself how many cells lie between the site of administration and the bloodstream = more layers, slower • Slower rates in the oral, IM, SQ routes • Complex membrane systems – GI, muscle, skin

31. SAMPLE Question Which of the following routes of administration will result in the quickest absorption? • Sublingually • Intravenous injection • Intramuscular injection • Rectal suppository

32. Other factors affect speed… • Most oral administered drugs absorbed in small intestine • Surface area • The bigger the basket, the more likely you are to score • The bigger the surface, the more drug gets across

33. Other factors affect speed… • Blood Flow • Especially IM, SQ injections • EXAMPLE Question: • A nurse calls you to see a patient who is feeling unwell and has been vomiting for the past three hours. You both agree this patient requires an injection of Gravol. The nurse draws up the Gravol and asks, “Doctor, does it matter where I do the injection – in the deltoid or the gluteal? • HOW DO YOU RESPOND?

34. Other factors affect speed… ANSWER • In theory, yes, it does matter. • More blood, more absorption • Blood flows faster through the deltoid muscle than through the gluteal muscle. • However, gluteal muscle can accommodate a large volume of drug. • In practice, it really doesn’t matter.

35. Other factors affect speed… • Pain + Stress = decreased absorption • Drug-Food Interactions • Fatty meals slow rate of moving from stomach to small intestine • Delays absorption • Dosage form • Drug-Drug interactions

36. THE LIFE OF A DRUG –Drug Distribution Pharmacokinetics

37. Drug Distribution • How drug, once absorbed, gets to tissues and fluids of the body • We must talk about: • Water Compartments in the body • Volume of Distribution • Depends on several factors • Blood flow • Solubility • Protein Binding

38. Water Compartments Total Body H20 = Inside cells + Outside cells Inside cells = 28 L Outside cells = 14 L Outside cells = Between cells + Water in blood Water in blood is “plasma” = 4 L Between cells = 10 L

39. Volume of Distribution • Vol of Distribution (VD) is equal to the dose (mg (bits)) divided by the plasma concentration (mg/mL (bits in vol)) • VD = Dose (mg) Plasma concentration (mg/mL)

40. Sample Problem • 500 mg of Newdrug was administered to a 70 kg 25 year old medical student. The plasma concentration, shortly after its administration, was 0.01 mg/mL. What is the volume of distribution? Let’s do the calculation!

41. Sample Problem • How do we explain this? EITHER He is a very large water balloon OR The drug is hiding somewhere. BUT WHERE?????

42. Drugs “Hidden” From Measurement • Drugs can “hide” if they: • Dissolve well in fat and are stored there • Bound to PROTEINS in the blood • Volume of distribution is a THEORETICAL volume not an actual volume. • Why do we use it? • Gives us estimate of where drug is in body!

43. Drug Distribution… depends on blood flow!! • Blood flow is large to: • Heart • Liver • Kidneys • Brain • But…. Let’s think for a minute about this…

44. This is your brain on drugs… • Brain • Very special place • Has a very, very, tight blood-brain barrier • Guarded by tightly bound cells in the capillary walls • Have to be special to get in • Small, lipid soluble • Not bound to protein • Or actively pumped

45. I’ve been working on the railroad … not just at the end! • As drug travels, may encounter • Site of action = can work there • Plasma protein (albumin) • Can bind there or remain free • IF IT IS BOUND, CANNOT EXERT AN EFFECT • Only free, unbound drug can act

46. SAMPLE Question • A drug, Coumadin (makes people bleed on purpose), is highly bound to plasma proteins. Only 0.2% is free in the blood. • Your friend administers a drug that displaces 0.2% of the bound drug from the protein because it too binds there. • What happens to the concentration of drug in the plasma?

47. Sample Question – ANSWER • Go from 0.2% free to 0.4% free! • YOUR FRIEND HAS DOUBLED THE DRUG AVAILABLE TO EXERT A THERAPEUTIC EFFECT… oops! • Be aware of drug-drug interactions!

48. Drug Distribution - REVIEW • How drug gets to tissues and fluids of the body – and what tissues and fluids it gets to! • We talked about: • Water Compartments in the body • Volume of Distribution • Depends on several factors • Blood flow • Solubility • Protein Binding

49. THE LIFE OF A DRUG –Drug Metabolism Pharmacokinetics

50. Drug METABOLISM • Metabolism = Biotransformation • Metabolism = Change • Changes from the form in which it was administered to a more WATER-SOLUBLE (hydrophilic) form! • WHY? Cause you can pee it out better!