CHAPTER 3 Pharmacokinetics （ body a cts on drug ）

1. PHARMACOLOGIC PRINCIPLES CHAPTER 3Pharmacokinetics （ body acts on drug ）

2. Undergoing of drugs in body pharmacokinetics (sites of action) binding free (accumulation) free binding distribution (plasma) Free drugs binding drugs metabolites (renal)excretion absorption distribution drugs po sc im peroral subcutaneous intramuscular out of body distribution Metabolism (liver) transport transformation

3. permeation across membranes pharmacokinetics Ⅰ.Drug permeation across membranes 1. membrane The membranes with pore are composed of lipids and proteins in a ratio of 70:1. The liquid-form double-deck of membranes is formed from lipid molecules; The special proteins inserted into the double-deck are receptors, enzymes, ion channels, carriers…… Facilitated transport Active transport lipid diffusion filtration High concentration ecto- ATP membrane Intra- pore carrier Low oncentration fenestrated membrane

4. permeation across membranes pharmacokinetics 2. Passive transport across membranes (down hill) low high A drug molecule moves from a side of membrane relatively high concentration to another side of low concentration without requiring energy, until an equilibrium has been achieved on both sides of the membrane. ….. ….. ….. ….. ….. .. ….. ….. ….. ….. ….. ….. ….. ….. ….. .. ….. ….. ….. ….. equilibrium Lipid diffusion; Filtration; Facilitated transport

5. k1 k2 permeation across membranes pharmacokinetics 1) Lipid diffusion ( Simple diffusion) The most important mechanism of drug transport Drug movement across membranes is driven by a concentration gradient after solution in the lipids of membranes. Nonionized form Ionized form pKa is pH when Ionized rate is 50% pH (pKa) ┐ more lipid soluble less lipid soluble easy permeation hard permeation less polar molecules polar molecules ion trapping

6. Lipid diffusion pharmacokinetics HA (weak acids)B (weak bases) k1 k1 HAH+＋A-B＋H+ BH+ k2k2 k1 [H+][A-]k1[H+][B] Ka＝──＝─────Ka＝──＝ ──── k2 [HA]k2 [BH+] [A][B] pKa＝pH－log ───pKa＝pH－log ─── [HA][BH+] [A-][B] pH－pKa＝log ───pH－pKa＝log ─── [HA][BH+]  [A-][B] ───＝10pH－pKa───＝10pH－pKa [HA][BH+]

7. Lipid diffusion pharmacokinetics [A-][B] ───＝10pH-pKa───＝10pH-pKa [HA][BH+] weak acidsweak bases ★ pH↑↓→[A-]↑↓★ pH↑↓→[BH+]↓↑ →ionization↑↓→ionization↓↑ →lipid solution↓↑→lipid solution↑↓ →permeation↓↑→permeation↑↓ Conclusion: Neither weak acids or weak bases are dissolved in same acid-base solution, the lipid solution↑, permeation↑; They are dissolved in opposite acid-basesolution, the lipid solution↓, permeation↓. More polar (molecules), less permeation; Less polar, Morepermeation

8. Lipid diffusion pharmacokinetics For example, Bicarbonate (NaHCO3) is very effective for treatment of acute toxication from weak acid drugs (like barbiturates). why？

9. Lipid diffusion pharmacokinetics ① Alkalization of gastric juice →ionization↑ → permeation↓ →absorption ↓ ②Alkalization of blood plasma → permeation↓→across blood-brain barrier↓ pH ↑ > pH [A-]↑> [A-] blood gastric juice drug drug Gastrolavage of NaHCO3 pH↑> pH [A-]↑> [A-] Cerebrospinal fluid blood drug drug Intravenous drop of NaHCO3

10. urinepH ↑ drug[A-]↑ Lipid diffusion pharmacokinetics ③ Alkalization of humor (extra-cellular fluid) →ionization↑ →permeation↓ ④Alkalization of urine→ionization↑ →permeation↓→ drugtubular reabsorption↓ → excretion↑ cell pH < pH↑ [A-] < [A-] ↑ drug drug blood

11. filtration pharmacokinetics 2) Filtration (Aqueous diffusion) The aqueous (hydrophilia) drugs with low molecular weight (<100-200 daltons) can diffuse through aqueous pores in membrane without requiring energy, the diffusion is driven by concentration gradient. Daltons: the unit of atomic weight The almost free drugs can be filtrated across biggish pores of capillaries from or to plasma. (drug distribution, glomerular filtration and absorption following im or sc injection).

12. facilitated transport pharmacokinetics The passive movement of a drug across the membrane is facilitated by its special carrier. 3) Facilitated transport (Carrier-mediated transport) a. saturable process; b. special binding to the carrier; c. transport driven by concentration gradient without consuming energy. The drug is released to another side of the membrane, and the carrier then returns to original side and state.

13. Active transport pharmacokinetics 2. Active transport (up hill) A drug molecule moves from a side of membrane relatively low to one of high concentration with requiring energy and special carrier. a. saturable process b. special binding to the carrier c.transport against concentration gradient with consuming energy.

14. Active transport pharmacokinetics For example: penicillin and probenecid blood→tubule (low →high) blood→tubule (high → low) After glomerular filtration, penicillin undergoes tubular secretion (an active transport), having a very short half-life (t1/2=20~30 min). Probenecid having the same active mechanism can competitively inhibit the tubular secretion of penicillin. The t1/2 & effects of penicillin are prolonged. H2O absorption glomerular filtration (passive) tubular secretion (active) penicillin Tubule high osmosis competitive inhibition probenecid excretion of penicillin (-)

15. The transport of drugs from administration locale to bloodstream. Absorption pharmacokinetics Ⅱ.Absorption

16. Absorption pharmacokinetics 1. The routes of absorption 1) im or sc Absorption of drugs in solution through filtration from subcutaneous or intramuscular injection sites to blood is limited mainly by blood perfusion rate. why? Adrenalin: im > sc a. blood perfusion rate (im > sc) b. adrenalin ┌ α↑→vesseel↑(subcutaneous) → perfusion↓ └β↑→vesseel↓(skeletal muscle) →perfusion ↑

17. gastric mucosa small intestinemucosa Absorption pharmacokinetics 2) po (per oral) What about weak acids? Drugs are absorbed in gastrointestinal tract through lipid diffusion. The absorption takes place mainly in the upper small intestine. First-pass elimination: The extensive gastrointestinal and hepatic metabolism may occur before the drugs are absorbed into systemic circulation when oral administration of drugs.

18. Nitroglycerin given sublingually bypasses liver and enters the superior vena cava and, in turn, perfuses the coronary and systemic blood vessel, therefore it is immediately effective to relive patients with angina pectoris. Absorption pharmacokinetics 3) Sublingual or rectal administration Absorption properties of the administration a. incomplete and irregular absorption; b. without or less First-pass elimination. For example

19. C Cmax AUC T Tmax Absorption pharmacokinetics 2. Bioavailability (F) F is the paramete judging the extent and rate of drug absorption following extravascular administration (like orally). A (drug amounts in body) F＝───────────── ×100% D (administered dose) F could be the absolute value between of extravascular and intravascular administration, or relative value between ofstandard preparationandtest preparation (pharmaceutical products). AUC: area under C-T curve

20. C C iv standard im test po T T Absorption pharmacokinetics AUC (extravascular administration) ＝───────────────── ×100% AUC (intravenous administration) F (absolute) judging availability of different routes or administrations  AUC (test preparation) ＝──────────────×100% AUC (standard preparation) F (relative) judging qualification of availability of different products in the same administration (same route and dose).

21. Distribution pharmacokinetics pharmacokinetics Ⅲ.Distribution The transport of drugs from bloodstream to various organs and tissues, or to different physical compartments of body.

22. Distribution pharmacokinetics 1. Compartments According to perfusion rate of drugs to various organs and tissues, body could abstractly be divided into one, two or more parts (one compartment model, two compartments model, three…).

23. Ka drug Ke C elimination phase T Distribution 1) One compartment model Drugs within the model are assumed to be distributed only to the organs with high blood flow and rapid uniform (brain, heart, liver, kidneys, lungs, active muscle, …). The C-T curve have one phase: elimination phase. The distribution is too rapid to be found in the C-T curve.. C elimination phase T Intravenous injection extravascular injection 。 。

24. C Co 1/2 1/4 T t1/2t1/2 Ke 。 。 Distribution drug buret Ke differential equation exponential curve exponential equation logC logC0 Y = a + b x straight equation T

25. Distribution pharmacokinetics 2) Two compartments model Drugs are not only distributed to the organs or tissues with rich blood perfusion (central compartment), but also to that with low blood flow (peripheral compartment: fat, skin, bone, resting muscle). The C-T curve have two phases or rates: a. The distribution rate (alpha half-life, t1/2α). b. The elimination rate (beta half-life, t1/2β).

26. C buret α α β β 。 。 T Distribution pharmacokinetics central peripheral K1 K2 Ka Ke distribution Ct＝CAe-kαt＋CBe-kβt elimination diphasic exponential equation

27. Distribution pharmacokinetics 2. Apparent volume of distribution (Vd) Vd relates the amount of drug in the body (A) to the drug plasma concentration (C), used for judging drug'sdistribution range (L). total amount of drug in body, A(mg) F.D Vd(L)＝──────────────────── ＝── concentration of drug in plasma, C(mg/L) C According to the drug plasma concentration,the amount of drug in the bodyshould be solved in apparent volume of body fluid.

28. free drug＋plasma binding drug (active form) (inactive storage form) small particle large particle→rapid filtration → no filtration →rapid distribution → → no distribution →┌ action ┌no action└elimination└noelimination (metabolism & excretion) Distribution pharmacokinetics 3. Factors influencing distribution 1) drug-plasma protein binding moving balance

29. Characters of binding to plasma a. saturability 5mg…15mg…20mg…22.5mg→toxication Dose↑↑→binding rate↓→free drug↑ malnutrition liver dysfunction renal dysfunction free drug↑ Plasma- albumin↓ binding rate↓ b. nonselective binding binding rate↓ free drug↑ Warfarin (anticoagulant) A 98% (2%) ┅ ┅ ┅ ┅ ┅→94% (6%) →effect (toxicity)↑↑→bleeding 4%↓ B 92% (8%) ┅ ┅ ┅ ┅ ┅→88% (12%) → Phenylbutazone (anti-inflammatory drug)

30. Distribution pharmacokinetics 2) Barrier: blood-brain barrier, placental barriera. less ionized drug & small particle→permeableb. inflammation→permeable 3) active transport→tissues concentration↑ active transport iodium thyroid 4) regional blood flow central compartment > peripheral compartment

31. Biotransformation pharmacokinetics Ⅳ.Biotransformation mainly in the liver hepatic microsomal mixed function oxidase system 1. two phases Phase 1 Prodrugs activation oxidation reduction hydrolysis drug activity↓ inactivation (effects↓toxicity↓) toxicity↓ binding to plasma↓ more polar Phase 2 conjugation excretion↑ with glycuronic acid and acetyl…..

32. Biotransformation pharmacokinetics 2. Factors affecting drug metabolism 1) drugs enzyme inducer activity of enzyme↑ chlorpromazine phenobarbital tolerance (dosage↑) activity of enzyme↓ enzyme inhibiter phenylbutazone chloromycetin hypersensitivity (dosage↓)

33. Biotransformation pharmacokinetics 2) Pharmacogenetics hereditary variation in handling of drugs For example: *Deficiency in activity of acetylase results peripheral neuritis from isoniazid; *Absence of glucose-6-phosphate dehydrogenase (G-6-PD) results hemolytic anemia from some drugs sulfonamides vitamin K (antihemorrhagic) primaquine (antimalarial agent) phenacetin (antipyretic analgesic) broad beans. Hemolytic anemia & jaundice absence of G-6-PD

34. Biotransformation pharmacokinetics age sex weight sport… 3) Physiological factors newborn Infant elder liver function↓ renal function↓ deficiency of drug elimination effects ↑ drug toxicity↑ For example: newborn ↓ gray syndrome chloromycetin prohibition Circulatory failure elder ↓ toxicity↑ many drugs dosage↓

35. Biotransformation pharmacokinetics 4) pathological condition drug metabolism↓ enzyme production↓ hepatic disease plasma production↓ plasma binding↓ →free drug↑ plasma loss↑ renal dysfunction hypersensitivity

36. pharmacokinetics Ⅴ.Excretion of drugs Drugs and their metabolites in circulation are excreted by kidneys, bile, milk, sweat and lungs.

37. excretion Penicillin? Probenecid? pharmacokinetics tubular secretion tubular reabsorption 1. Renal excretion Plasma (Drugs & metabolites) glomerular filtration tubular water reabsorption hyperosmosis in renal tubules Bicarbonate? tubular reabsorption (lipid-solubility) tubular secretion (active diffusion) Drug excretion↓ (tubule→blood) Drug excretion↑ (blood→tubule)

38. excretion pharmacokinetics 2. Excretion in bile bile active transport Plasma (drug) liver Hepato-enteric circulation intestine portal vein PO • prolongation of half-life • high concentration in bile Excretion Beneficial for antiinflammatory of cholecystitis Exclusion （erythrocin）

39. excretion pharmacokinetics If the mother was the addict, what would be resulted? 3. Excretion in milk lactiferous Ducts milk (low pH) nursing mother weak alkaline drugs (morphine, atropine) concentrations in breast milk↑ effects↑ reabsorption  reactions in infant dissolved in milk↑ High-lipide soluble drugs (sodium pentothal)

40. 2 compartment 1 compartment K12 K 21 drug drug K K Kinetics pharmacokinetics Ⅵ.Kinetics and rate process Kinetics model Differental equation

41. C α C β T logC logC α T A B β T T Kinetics pharmacokinetics 1 compartment 2 compartments Exponent equation Linear equation Semi-logarithmic equation

42. C T Elimination pharmacokinetics 1.Elimination of drugs Drugs and their metabolites are eliminated from the body by excretion and metabolism with decrease of drug blood concentration. Michaelis-Menten kinetics high dose: 0-order low dose: 1st-order non-linear kinetics Michaelis-Menten kinetics

43. C one compartment T t1/2 Elimination pharmacokinetics 1) First-order kinetic All most drugs Blood concentration of drug is reduced in equal rate or in constant half-life (t1/2). The eliminated rate is direct ratio with blood concentration of a drug. Exponent=1

44. C T 2) Zero-order kinetic Blood concentration of drug is reduced in equal amount or eliminated in continuant shorten half-life (t1/2). Exponent=0

45. C first T 3) non-linear kinetics Michaelis-Menten kinetics Low dose→ 1st order Overdose→ zero order salicylic acid, phenytoin, alcohol Low dose 1st order kinetics t1/2=2-3 h aspirin Large dose Urine pH↓→reabsorption↑ zero order kinetics t1/2=15-30 h C zero T

46. The half-life (t1/2) is the time taked to decrease the drug plasma concentration by one-half (50%) during elimination. It is considered that drugs are almost (97%) eliminated after 5 t1/2. Elimination pharmacokinetics 4) Half-life of drug (t1/2)

47. C C iv T T1/2 T T1/2 T1/2 Elimination pharmacokinetics 1st-order po lipid-solubility, size of particle, molecular structure drug interaction Relation to drug character constant of a drug t1/2 Individual variation Relation to body condition Kidneys Liver …… concentration of drug (therapeuticdose) way of administration No relation to

48. Steady state pharmacokinetics 2. Steady state concentration (Css) When given at a regular interval, a drug plasma concentration approximately could reach a plateau after 5 t1/2.

49. Steady state pharmacokinetics 1) Level of Css relates to: *dose ↑→Css↑ *interval shorten → wave of Css ↓ intravenous drip→smooth concentration curves. （the most effective and safe administration) 2) Time to reach Css relates to: *When a drug is given at a regular interval, its Css could reached after 5 t1/2; * loading dose (first dose↑)→reaching Css rapidly When the regular interval is t1/2 and loading dose is double，Css can be reached immediately in intravenous injection.

50. T1/2 0 1 2 3 4 5… n first -orderA. dose 100 100 100 100 100 100 amount 50 75 87.5 93.5 96.9… 100B. dose 200 200 200 200 200 200 amount 100 150 175 187.5 193.8… 200C. dose 200 100 100 100 100 100 amount 100 100 100 100 100zero -order dose 100 100 100 100 100 100… amount 50 100 150 200 250… Steady state pharmacokinetics Steady state concentration