PHARMACOKINETICS

1. dr. Dian Nugrahenny, M.Biomed. Dr. drg. Nur Permatasari, MS. Laboratory of Pharmacology Faculty of Medicine Brawijaya University Email: diannugr2407@gmail.com PHARMACOKINETICS

2. PHARMACOKINETICS • Fate of drugs in the body • Absorption • Distribution • Metabolism/Biotransformation • Excretion

5. Interspecies Differences in PK Result from: • Anatomical, • Physiological, and/or • Behavioral differences: • Feeding behavior: goats vs sheep • Goats: chooses most nutritious food that also containing toxic alkaloids • Sheep: grazes non-selective grassgenerally low in alkaloid content •  differences in metabolism •  which one have more active metabolism?

6. Absorption

7. Preparations for:(1)parenteral, (2)inhalational, (3)rectal/vaginal, (4) percutaneous application

8. To reach their site of action, drugs have to pass through several membranes  transmembrane transport • Structure of the plasma membrane

9. Mechanisms of Transport • Passive diffusion: Passage of drugs through the lipid surface Major mechanism of drugabsorption • Lipid-soluble drugs • Small water-soluble drugs • Non-charged form of weak electrolytes

10. Weak electrolytes and membrane permeability Most drugs are small (MW < 1000) weak electrolytes (acids/bases). This influences passive diffusion since cell membranes are hydrophobic lipid bilayers that are much more permeable to the non-ionized forms of drugs.

11. Bases are increasingly ionized with decreasing pH (acidic environment), whereas… Acids are increasingly ionized with increasing pH (basic environment). Ionizedforms of drugs= water-soluble. Non-ionized forms of drugs = lipid-soluble.

12. Other transmembrane transport ……… • Filtration: bulk flow of water-soluble drugs through pores (glomerular, capillary) • Facilitated diffusion: carrier-mediated, ATP not required (e.g., glucose) • Active transport: carrier-mediated, ATP required (e.g., Na+, K+, Ca++) • Endocytosis and exocytosis: (e.g., for very large compounds)

13. From administration to distribution

14. Mode of application and time course of drug concentration Onset vs duration of action of drugs

15. ORAL INGESTION, governed by: • Surface area for absorption, blood flow, physical state of drug, concentration. • Occurs via passive process. • In theory: weak acids optimally absorbed in stomach, weak bases in intestine. • In reality: the overall rate of absorption of drugs is always greater in the intestine (surface area, organ function).

16. Unique characteristics of the oral route • Influences of gastric emptying (accelerates gastric emptying  increase the rate of absorption) • Small intestine usually most important because of large surface area (folds of Kerckring, villi, microvilli) • The motility of the small intestine • Drug inactivation important for oral route:stomach (acid), small intestine (ester/other enzyme), distal small intestine/colon (gut bacteria)

17. Ingestion of a solid dosage form with a glass of cold water, fasting, lying on the right side, hyperthyroidism accelerate gastric emptying. • Ingestion with a fatty meal, acidic drink, or with another drug with anticholinergic properties, lying on the left side, hypothyroidism, sympathetic output (as in stress) retard gastric emptying.

18. First-Pass Metabolism • Extent of metabolism occurring before drug enters systemic circulation • Main site: Liver • Decrease in drug efficacy (orally) can be overcome by using a greater dose • e.g. Propranolol (5 mg vs. 100 mg) • Extensive metabolism may render oral administration impossible • e.g.Lidocaine

19. Hepaticextraction ratio (ERH): The fraction of drug eliminated from portal blood during absorption. • Bioavailability (F): Thefraction of drug dose that reachesthe circulation in unchanged formand becomes available for systemic distribution. Presystemic elimination >> bioavailability <<. • T1/2(half-life): Timerequired to reduce the concentration by 50%.

20. Important Properties AffectingDrug Absorption • Physiologic variables • gastric motility • pH at the absorption site • area of absorbing surface • blood flow • pre absorptive hydrolysis • ingestion with/withoutfood • Chemical properties • acid or base • degree of ionization • polarity • molecular weight • lipid solubility or... • partition coefficient

21. ORAL INGESTION • Advantages • Painless (usually) • Safe • Most drugs can be given orally • Disadvantages • Some drugs donot withstand stomach/GI conditions • Drug absorption more variable • May cause GI distress • Not suitable for uncooperative, vomiting,unconscious • FIRST PASS through liver

22. Oral Ingestion in Species Assignment 1: • Explain the interspecies differences in the absorption of oral drugs between monogastric species vs ruminants. • Is it possible to give drug administered orally to ruminants?

23. INJECTION • Advantages • Fast • Bypasses first pass • Bypasses digestion • More accurate dose • Can be done byperson with training • Disadvantages • Painful • Too fast to respond if bad reaction or overdose • Potential for infection • No recall of drug

24. Route of Drug’s Administration Intravenous injection  avoids absorption Oral Gavage

25. Route of Drug’s Administration Intraperitoneal injection into stomach cavity (between organs) Subcutaneous injection Absorbedby diffusion and affected by blood flow

26. Route of Drug’s Administration Intradermal/intracutaneous injection Absorbedby diffusion and affected by blood flow

27. Route of Drug’s Administration Intramuscular injection Absorbedby diffusion and affected by blood flow

28. Intramuscular Injection • Popularmodality of drug administration inveterinary medicine: Intramuscular administration. • No major differences in interspecies skeletal muscular systemsno major differences for the bioavailability of intramuscularly injected drugs. Assignment 2: • Explain best site of intramuscular injection for species, example for poultry, reptiles, horses, and others. Explain the reason.

29. LUNG Inhalation: passive diffusion, rapid absorption, dependent on particle size (6 µm cutoff) • Advantages • Painless and quick • Very rapid • 5 - 8 sec to brain • Intense effects • Smoke, examples:methamphetamine • Vapor, examples:anesthetics • Disadvantages • Potential harm to lungs • – Short term = pneumonia • – Long term = cancer • Only viable for volatileforms of drugs or that canbe in very tiny particles • Drug is sometimes destroyedin process

30. MUCOUS MEMBRANE • Sublingual, buccal, nasal, vaginal or rectal mucosa: passive diffusion • Advantages • Quick absorption • Little chance ofinfection or tissueharm (except withvasoconstrictors) • Disadvantages • Can taste bad orirritate membranes • Not all drugsabsorbed readily • Ease and speed

31. SKINTransdermal drug delivery systems are pasted to the epidermis.They contain a reservoir from whichdrugs may diffuse and be absorbedthrough the skin. • Advantages • Easy • Not painful • Slow, sustained release • Bypasses GI tract & first pass • Only have to changeevery few days/weeks • Disadvantages • Can fall off • Potential toxicity tochildren and pets • Very few drugs absorbed sufficiently, low permeabilityof skin • Local irritation possible • Toxicity if additional drug consumed

33. Distribution

34. Distribution • The actual pattern of drug distribution reflects various physiological factors and physicochemical properties of the drug.

35. Phases of Distribution • First phase • Reflects cardiac output and regional blood flow. • Thus, heart, liver, kidney & brain receive most of the drug during the first few minutes after absorption. • Next phase • Delivery to muscle, most viscera, skin and adipose is slower, and involves a far larger fraction of the body mass.

36. Protein Binding Only that fraction of drug which is non-protein-bound can bind to cellular receptors and pass across tissue membranes, thus being distributed to other body tissues, metabolized, and excreted.

37. Plasma protein • albumin- binds many acidic drugs • a1-acid glycoprotein for basic drugs

38. Drug Reservoirs Reservoirs: Body compartments where a drug can accumulate. They have dynamic effects on drug availability. • GIT • Plasma proteins • Cellular reservoirs • Adipose • Bone • Transcellular Assignment 3: Explain and give examples about each of drug reservoirs.

39. Penetrating into the Brain • Drugs that are small molecules • Lipid-soluble • Active transport systems (require energy: mitochondria) • Carrier-mediated transport systems (don’t need energy) • Pinocytotic vesicles • Other factors that affect absorption into the CNS – Drugs that are highly bound to plasma proteins are less likely to penetrate the BBB – Drugs that are weak acids (are highly ionized at the pH of blood, 7.4) are less likely to penetrate (have low lipid-solubility)

41. Termination of Drug Action Drug Elimination

42. Termination of Drug Action • Metabolism (Biotransformation) • Excretion • Redistribution Clearance (Cl): the measurement of blood cleared of the drug by elimination per unit time (as in units of mL/sec).

43. Metabolism/Biotransformation

44. Drug Metabolism • Usually inactivates the drug. • Can generate active metabolite (PRODRUG) • Can generate toxic metabolite (isoniazid). • Often generates polar, highly ionized metabolites. • Conversion rate influences pharmacological activity. • Some drugs are eliminated unchanged (digoxin).

46. Phase I “functionalization” reactions (oxidation, reduction, hydrolysis) expose a functional group on the parent compound  result in loss of pharmacological activity • Phase II conjugation reactions lead to covalent linkage of a functional group on the parent drug or phase I metabolite with endogenously derived glucuronic acid, sulfate, methyl, glutathione, amino acids, acetate, etc result in highly polar conjugates

47. Phase I Reactions Dominated by oxidation by cytochrome P450 enzymes

48. Phase I and Phase II Metabolic Reactions Absorption Metabolism Excretion Phase I Phase II Metabolite with modified activity Conjugate Drug Inactive metabolite Conjugate Lipophilic Hydrophilic

49. Inter-species differences in metabolism There are inter-species differences in: • Hepaticblood flow. • Phase I (quantitatively) and phase II (qualitatively). • CYP enzymes.

50. Inter-species differences in metabolism • Cats:deficiency for glucuronidations (BEWARE the use of acetaminophen), • Dogs:deficiency for acetylation reactions (BEWARE the use of sulfonamide, e.g.trimethoprim/sulfa), • Pigs: low level of sulphateconjugation (Baggot, 1977). • Drugs have lower clearance in carnivores than in herbivores with omnivores having an intermediary position. (Duration of drugs’ action?)