Chapter 3. Pharmacokinetics & Pharmacodynamics

Transcription

1 Chapter 3 Pharmacokinetics & Pharmacodynamics

2 Pharmacokinetics & Pharmacodynamics Pharmacodynamics governs the concentration-effect part of the interaction, whereas pharmacokinetics deals with the dose-concentration part The pk processes of ADE determine how rapidly and for how long the drug will appear at the target organ

3 Distribution via circulation to sites of action sites of elimination

4 Pharmacokinetics Locus of action receptors Bound Free Tissue reservoirs Bound Free Systemic circulation Absorption Free drug Excretion Bound drug Metabolites Biotransformation

5 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.

6 Pharmacokinetics Locus of action receptors Bound Free Tissue reservoirs Bound Free Systemic circulation Absorption Free drug Excretion Bound drug Metabolites Biotransformation

7 Drug Reservoirs Body compartments where a drug can accumulate are reservoirs. They have dynamic effects on drug availability. plasma proteins as reservoirs (bind drug) cellular reservoirs Adipose (lipophilic drugs) Bone (crystal lattice) Transcellular (ion trapping)

8 Adipose Reservoir Many lipid-soluble drugs are stored in fat. In obesity, fat content may be as high as 50%, and in starvation it may still be only as low as 10% of body weight. 70% of a thiopental dose may be found in fat 3 hr after administration.

9 Bone Reservoir Tetracycline antibiotics (and other divalent metal ion-chelating agents) and heavy metals may accumulate in bone. They are adsorbed onto the bone-crystal surface and eventually become incorporated into the crystal lattice. Bone then can become a reservoir for slow release of toxic agents (e.g., lead, radium) into the blood.

10 GI Tract as Reservoir Weak bases are passively concentrated in the stomach from the blood because of the large ph differential. Some drugs are excreted in the bile in active form or as a conjugate that can be hydrolyzed in the intestine and reabsorbed. In these cases, and when orally administered drugs are slowly absorbed, the GI tract serves as a reservoir.

11 Factors Affecting Distribution Rate of blood flow greater amounts delivered to organs and tissues with greater blood flow

12 High vs. Low Blood Flow Heart.... High Adipose... Low Lungs.... High Bone.... Low Liver.... High Muscle.... Low Teeth.... Low Brain.... High Kidney.. High

13 Factors Affecting Distribution solubility of drug Lipid: readily moves into tissues Nonlipid: limited ability to cross cell membranes

14 Factors Affecting Distribution Protein binding unbound drug = active

15 Factors Affecting Distribution effect of protein binding limit action prolong action Crtitical Thinking Question: what implication does protein binding have for drug dosing?

16 Effect of Diseases on Plasma Protein Levels albumin: most common protein to bind drugs

17 Redistribution Termination of drug action is normally by biotransformation/excretion, but may also occur as a result of redistribution between various compartments. Particularly true for lipid-soluble drugs that affect brain and heart.

18 Barriers to Distribution specialized capillaries in selected tissues

19 Placental Membranes layer of epithelial cells not as much a barrier as once thought fetus exposed to same drug levels as mother

20 Barriers to Distribution blood brain barrier endothelial layers of capillaries in brain plus glial sheath

21 Blood Brain Barrier limit passage esp. ionized and protein-bound drugs what are the implications for drugs intended to reach brain?

22 Elimination & clinical PK

23 Drug elimination movement from tissues to blood to site of removal from body

24 Elimination Of Drugs Metabolism: Excretion: Liver Kidney Liver (bile) Lungs

25 Renal Excretion of Drugs Filtration (Glomerulus) Reabsorption - Passive Transport (Tubule) Secretion - Active Transport (Tubule) Transporter for Organic Acids Transporter for Organic Bases

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27 Glomerular Filtration Only unbound drug is filtered. Plasma Protein Binding of drug prevents filtration: Thyroxine is 99% bound. Molecular Size: Albumin (70,000) is not filtered. Inulin (5,500) is freely filtered; can be used to estimate GFR.

28 Tubular Reabsorption Passive Transport: ph, concentration, size, lipid solubility, ionization. acid urine favors reabsorption of weak acid. basic urine favors reabsorption of weak base. Active Transport: Uric acid, glucose, amino acids...

29 Secretion Vs. Active Reabsorption The acid and base transport systems can operate bidirectionally, and at least some drugs are both secreted and actively reabsorbed. However, active transport of most exogenous ions is predominantly secretory.

30 Tubular Secretion Active Transport Organic Acids (inhibited by probenecid) Organic Bases No effect of protein binding on this process

31 Renal System lipid soluble drugs are passively reabsorbed changing ph of urine acidic urine = alkaline drugs eliminated acid drugs reabsorbed

32 Renal System changing ph of urine alkaline urine = acid drugs eliminated alkaline drugs absorbed

33 Renal System renal disease/ decreased clearance affects drug dosage

34 Hepatic or Biliary Excretion Some organic acids and bases are actively secreted into the bile. Some drugs are secreted into the bile. Glucuronides of steroids and morphine are actively secreted.

35 The Enterohepatic Cycle Prolongs drug half-life

36 Enterohepatic Cycle 2 Liver 3 Portal vein Common bile duct 1 4 Small intestine

37 Pulmonary Excretion Factors: Plasma solubility of drug Cardiac output Respiration

38 Gaseous Anesthetics *Rate of pulmonary excretion is proportional to alveolar tension of the gaseous drug and inversely proportional to its plasma solubility.

39 DRUG ELIMINATION KINETICS First-order kinetics Zero-order kinetics Michaelis-Menten Menten kinetics

40 First-order Kinetics A A fixed percent/fraction of the drug is eliminated per unit time. The rate of drug elimination is directly proportionate to plasma concentration C t =C 0 e -ket Vast majority of drugs

41 Exponential decay

42 Zero-order order Kinetics A A fixed amount of the drug is eliminated per unit time. The rate of drug elimination is independent of plasma concentration. C t = -k 0 t+c 0

43 Explaining First-order elimination is also know as constant fraction elimination. Its time-concentration curve presents a curve in a route plot as well as a beeline in a semilogarithmic plot Zero-order elimination is also know as constant quantity elimination. Its time-concentration curve presents a beeline in a route plot as well as a curve in a semilogarithmic plot

44 Figure 100 Routine plot 100 Semilogarithmic plot Drug concentration in blood Time Drug concentration in blood Time Zero-order elimination First-order elimination

45 Michaelis-Menten Menten Kinetics Most drug elimination pathways will become saturated if the dose is high enough. It is also known as saturable, dose- or concentration-dependent, nonlinear elimination. The relation between elimination rate and concentration is expressed mathematically in Michaelis-Menten equation

46 Michaelis-Menten Menten equation dc V max C = dt K m +C K m represents the concentration at which half of the maximal rate of elimination is reached V max is equal to the maximal rate of elimination When K m >>C, the drug elimination capacity is more and more than the amount of drug in body, so the C can be ignored. It can be considered as first-order kinetics When C> > K m, the amount of drug exceed the drug elimination capacity, so K m can be ignored. It can be considered as zero-order kinetics

47 Figure Drug concentration in blood A:high dosage B:low dosage Time

48 COMPARTMENTAL MODEL Considering the whole body as a system, and the system is divided into several compartments according to different dynamic characteristics. Compartmental Model is used to quantitatively describe the regularity of the dynamic change of drugs in the body with mathematical formula. Vd = amount of drug in body/c

49 One-compartment Model The central compartment Is sufficient to apply to most clinical situations for most drugs

50 One-compartment Model The c-t curve of one-compartment model demonstrates the feature of single exponent function in mathematics, i.e., semilogarithmic c-t curve demonstrates linear relationship. C t =C 0 e -kt

51 Two-compartment Model central compartment final compartment

52 Two-compartment Model CA4P / nmol.ml 实测值 -- 拟合曲线 时间 (h) The c-t curve of the drug according to two-compartment model after administered intravenously

53 The kinetics of compartmental model Whether the drugs adapted to onecompartment model or two-compartment model, they all obeys first-order kinetics elimination.

54 Clinical Pharmacokinetics The four most important parameters are Volume of distribution, a measure of the apparent space in the body available to contain the drug Clearance, a measure of the body s efficiency in eliminating drug Eliminiation half-life, a measure of the rate of removal of drug from the body Bioavailability, the fraction of drug absorbed as such into the systemic circulation

55 Volume of Distribution It is the volume necessary to contain the amount of drug as the same concentration as in the blood **The apparent volume of distribution is a calculated space and does not always conform to any actual anatomic space.** note: V d is the fluid volume the drug would have to be distributed in if C p were representative of the drug concentration throughout the body.

56 plasma interstitial volume Total body water extracellular 15 liters plasma volume 3 liters interstitial volume intracellular volume 42 liters intracellular 12 liters 27 liters

57 At steady-state: total drug in body (mg) V d = plasma conc. (mg/ml)

58 Example of V d The plasma volume of a 70-kg man ~ 3L, blood volume ~ 5.5L, extracellular fluid volume ~ 12L, and total body water ~ 42L. If 500 g of digoxin were in his body, C plasma would be ~ 0.7 ng/ml. Dividing 500 g by 0.7 ng/ml yields a V d of 700L, a value 10 times total body volume! Huh? Digoxin is hydrophobic and distributes preferentially to muscle and fat, leaving very little drug in plasma. The digoxin dose required therapeutically depends on body composition.

59 CLEARANCE CONCEPTS systemic clearance and organ clearance In general, clearance means the systemic clearance, that is the sum of renal clearance, hepatic clearance and others Clearance is usually further defined as blood clearance, plasma clearance or others depending on the concentration measured. In general, it is defaulted as plasma clearance

60 Clearance Clearance does not indicate how much drug is removed but, rather, the volume of blood that would have to be completely freed of drug to account for the elimination rate. CL is expressed as volume per unit time.

61 Sum of all process contributing to disappearance of drug from plasma Drug in plasma at concentration of 2 mg/ml Drug concentration in plasma is less after each pass through elimination/metabolism process Drug molecules disappearing from plasma at rate of 400 mg/min CL = 400 mg/min 2 mg/ml = 200 ml/min

62 Example: propranolol, CL p = 12 ml/min/kg or 840 ml/min in a 70-kg man. The drug is cleared almost exclusively by the liver. Every minute, the liver is able to remove the amount of drug contained in 840 ml of plasma.

63 Clearance of most drugs is constant over a range of concentrations. This means that elimination is not saturated and its rate is directly proportional to the drug concentration: this is a description of 1st-order elimination.

64 CL in a given organ may be defined in terms of blood flow and [drug]. Q = blood flow to organ (volume/min) C A = arterial drug conc. (mass/volume) C V = venous drug conc. rate of elimination = (Q x C A ) - (Q x C V ) = Q (C A - C V )

65 Extraction Ratio Division of the previous equation by the concentration of drug that enters the given organ of elimination yields an expression for clearance of the drug by the organ: CL organ = Q(C A -C V /C A ) = Q x E E is referred to as the extraction ratio

66 Half-Life (t 1/2 ) amount of time required for plasma concentration to decrease by half

67 Half Life (t 1/2 ) Is the time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50% Indicate the rate of drug elimination in vivo

68 Half-Life each half-life: the concentration decreases by half of remaining concentration 5 half-lives = 97% of drug eliminated useful in determining drug dosage frequency

69 Give 100 mg of a drug 1 half-life half-lives 25 3 half-lives half-lives half-lives half-lives. 1.56

70 Meanings of t 1/2 Confirm the interval of administration, generally the interval of administration is one t 1/2 Predict the elimination or accumulation of drug in vivo As to a single administration, drugs can be eliminated from body after 5 t 1/2 As to continuous administration, drugs concentration can reach steady state concentration after 5 t 1/2

71 The elimination & accumulation of drug t 1/2 After dosing Before next After termination dosing of dosing Accumulation Elimination 1 100% 50% 50% 2 150% 75% 25% 3 175% 87.5% 12.5% % 93.75% 6.25% % % 3.125% % % 1.26%

72 Steady-state concentration The steady state will be achieved when the rate of drug elimination equals the rate of drug administration To the majority of drug eliminated by firstorder kinetics, the time achieved to steady state is only determined by the half life

73 The alteration of the amount of drug in vivo with different dose and same frequency D=100% D=200% t 1/2 After Before next After Before next dosing dosing dosing dosing 1 100% 50% 200% 100% 2 150% 75% 300% 150% 3 175% 87.5% 350% 175% % 93.75% 375% 187.5% % % 387.5% % % % % 196.9%

74 The alteration of the amount of drug in vivo with same dose and different frequency After dosing =2 t 1/2 =1/2 t 1/2 Before next dosing After dosing Before next dosing 1 100% 25% 100% 70.88% 2 125% 31.25% % % % 32.8% % % % 33.2% % % % 33.3% % % % % % % % %

75 Bioavailability (F)( The fraction of unchanged drug reaching the systemic circulation following administration by any route The area under the blood concentrationtime curve (AUC) is a common measure of the extent of bioavailability for a drug. For an intravenous dose of the drug, bioavailability is assumed to be equal to unity.

76 AUC (area under the curve) C To multiply concentration by time t

77 AUC (area under the curve) Indicates the area under the concentration-time curve Is an important index to appraise the extent of drugs entering systemic circulation Unit: (mg/ml) min, (mg/l) h, (ng/l) min, (ng/ml) h, etc

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79 Bioavailability (F)( Bioavailability is used to calculate the PK parameters When drugs are extravascular administered, the equations that contain the term dose must include the bioavailability term F,, such that the available dose is used. For a drug administered orally, bioavailability may be less than 100% for two main reasons Incomplete extent of absorption First-pass elimination