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Ken-Ichi Takemaru Assistant Professor BST 7-182, 4-7976 takemaru@pharm.stonybrook.edu

Pharmacokinetics vs. Pharmacodynamics

Fig. 3-1. The relationship between dose and effect can be separated into pharmacokinetic (dose-concentration) and pharmacodynamic (concentration-effect) component (Basics & Clinical Pharmacology, Katzung, 2007)

**Lithium vs. Activase (Alteplase)
**

Li+ MW = 7 Mood-stabilizing drug (bipolar disorder) Oral administration

Activase (Recombinant tissue plasminogen activator) MW = 59,050 (527 amino acids) Blood clot-dissolving enzyme Administered into the vascular compartment by IV injection

which determines the concentration of a drug at its sites of action (‘what the body does to the drug’). . 2004). Lehne. • Pharmacokinetics is the study of drug movement throughout the body. The four basic pharmacokinetic processes (Pharmacology for Nursing Care.Pharmacokinetic Processes Figure 4-1.

Routes of drug administration (Principles of Pharmacology.. Golan et al.Routes of Drug Administration Table 3-1. 2005) First-pass metabolism .

. Routes of parenteral drug administration (Principles of Pharmacology. 2005) . Golan et al.Routes of Parenteral Drug Administration Table 3-2.

Membrane diffusion: most drugs diffuse through the membrane. Structure of the cell membrane (Pharmacology for Nursing Care. and polar molecules can not penetrate membranes. Transport systems: important for certain drugs and also utilized for renal excretion. 2. Fick’s law of diffusion states the net drug flux across the membrane: Rate of diffusion = Partition coefficient x Surface Area x (C2-C1) Thicknessmembrane C1: intracellular concentration of drug C2: extracellular concentration of drug This equation applies to an ideal situation where there is an absence of complicating factors such as pH and charge gradients across the membrane.Passage of Drugs across Membranes 1. 2004) In the absence of any other factors. Lehne. a drug will enter a cell until the intracellular and extracellular concentrations of the drug are equivalent. Figure 4-2. . Channels and pores: very few drugs with low molecular weights cross membrane via channels or pores. 3. A drug must be lipid soluble.

Effect of pH on Drug Absorption Weak acid HA H+ + AWeak base BH+ B + H+ 100 Dissociation Curve: Aspirin Percent HA 75 50 25 0 1 2 3 4 5 6 pK 3.5 pH Stomach Plasma Henderson-Hasselbach equation [A-] pH = pKa + log [HA] ____ ____ [B] pH = pKb + log ________ + [BH ] .

99. 2005) [HA] 4 = 1 + log ________[A ] [HA] 3 = log ________ [A ] [HA] 1. plasma and urine (pH = 4.000 times the concentration of charged from. 3-2.9% of the drug is charged. Golan et al. plasma. . pH trapping across lipid bilayers (Principles of Pharmacology. In contrast.pH Trapping across Lipid Bilayers Henderson-Hasselbach equation [HA] pKa = pH + log ________ [A ] In case of a weakly acidic drug with a pKa of 4 (stomach pH=1): Fig.6 to 8) vs. 99. in plasma.9% of the drug is in the uncharged form.000 = ________ [A ] In stomach. the uncharged form of the drug exists 1. pH trapping is also applied to other situations such as breast milk (pH = 6 to 7) vs..

Morphine is a weak base with pK = 8.8 [Btotalbm ]/[B] = 16.98 [Btotalp ] = 4.8 [B] The ratio [Btotalbm ]/[Btotalp ] = 16.8 [BH+bm ]/[B] + 1 = 15.98 + 1 [BH+p] + [B]/[B] = 4.0631 [BH+bm ]/[B] = 1/0.98 [BH+p]/[B] + 1 = 3. breast milk. From rearranging the Henderson-Hasselbach equation: [B]/[BH+] = 10 (pH-8.0) Plasma pH = 7.98 = 3.251 Breast milk pH = 6.6 = 0.8 + 1 [BH+bm ] + [B]/[B] = 16. calculate the distribution of morphine in plasma vs.0631 = 15.8 [Btotalbm ] = 16.4 [Bp]/[BH+p] = 10 -0.0.0631 Neutral form equilibrates across the plasma membrane [Bp] = [Bbm ] [B]/[BH+p] = 0.8 and that of plasma is 7.8 [Bbm ]/[BH+bm ] = 10 -1.98 [Btotalp ]/[B] = 4.4. If the pH of breast milk is 6.37 times more concentrated in breast milk than in plasma.251 = 3.37 Morphine is 3.8/4. .2 = 0.251 [BH+p]/[B] = 1/0.98 [B] Let’s simplify this as [B] [B]/[BH+bm ] = 0.

Craig & Stitzel. 2004) • Each kidney contains about one million functional filtering units called nephrons. • The kidneys filter about 45 gal (180 L) of blood each day. .Renal Elimination of Drugs and Metabolites Glomerular filtration Passive tubular reabsorption Active tubular secretion Nephron Fig. 4-2. Renal excretion of drugs (Modern Pharmacology.

Drug accumulation with repeated administration (Pharmacology for Nursing Care. Single-dose time course (oral) (Pharmacology for Nursing Care. Lithium’s toxic conc. Lehne. Lehne. is only 3 times greater than the MEC. 2004) A drug with a half-life of 1 day. What happens if you take 1 gm of the drug every 12 hours instead? Acetaminophen’s toxic conc. 2 gm given once a day on days 1 through 9. 2004) Figure 4-14.Time Course of Drug Responses Peak conc. How do you predict time course of drug action? . " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " " Trough conc. (MEC) Figure 4-15. is 30 times greater than the MEC.

. Schematic model of drug distribution and elimination (Principles of Pharmacology. 2003) First-order kinetics Fig.. 8-6. Rang et al. Single-compartment pharmacokinetic model (Pharmacology. B. Golan et al. 3-7. 2005) .Single Compartment Model A highly simplified model of a human being. Fig. which consists of a single well-stirred compartment (Vd) into which a quantity of drug Q introduced. and from which it can escape either by being metabolized or being excreted.

hepatic metabolism when enzymes are not saturated 2.First-Order Kinetics • First-Order Kinetics: a constant fraction of drug is handled per unit of time. (Pharmacology. • The rate of elimination is directly proportional to drug concentration. glomerular filtration 3.. radioactive decay • The majority of drugs are eliminated by first-order kinetics. 2003) . Rang et al. Predicted behavior of single-compartment model following intravenous drug administration at time 0. 8-7. Examples: 1. Fig.

First-Order Drug Elimination The decrease in the plasma concentration of drug X over time can be written as: -d[X]/dt = k[X] (k is the elimination rate constant) Rearrange: d[X]/[X] = -kdt Integrate: ln[X] = -kt + C Evaluate the value of C (the constant of integration): when t = 0. Slope = -k/2.kt or log [X] = log [X]0 . elimination constant).kt/2. [X] = [X]0. k. initial plasma drug concentration.3 time ln([X]/[X]0) = -kt [X] = [X]0 e-kt [X] is the plasma drug concentration at any time t after administration ([X]0 . thus C = ln[X]0 Substitute: ln[X] = -kt + ln[X]0 ln[X] = ln [X]0 .3 Log10 [X] .

(Pharmacology. Rang et al. Kinetics of diazepam elimination in humans following a single oral dose. 8-6. (Pharmacology. The peripheral compartment represents the tissues while the central compartment represents the plasma. Rang et al. 2003) Fig.. representing the process of transfer between plasma and tissues (fast phase) and elimination from the plasma (slow phase).Two-Compartment Model Fig. 3-7.. Two-compartment pharmacokinetic model. 2003) The kinetics are biexponential.. . 8-6. 2005) Fig. Schematic model of drug distribution and elimination (Principles of Pharmacology. C. Therefore. Golan et al. it still follows the first-order kinetics.

drug is removed at a constant rate that is independent of plasma concentration).Zero-Order Kinetics (Saturation Kinetics) • In a few cases. the time course of disappearance of drug from the plasma does not follow the exponential patterns but initially linear (i. 2003) • Zero-Order Kinetics: a constant amount of drug is handled per unit time. The rate of disappearance of ethanol from the plasma is constant at about 4 mmol/l per hour irrespective of its plasma concentration because the rate of oxidation by the alcohol dehydrogenase reaches a maximum at low ethanol concentrations..e. Saturating kinetics of alcohol elimination in humans. drug given by an infusion pump 3. Rang et al. absorption from a sustained release preparation 2. Fig. Examples: 1. hepatic metabolism of drug when enzymes are saturated . 8-12. (Pharmacology.

However. 90L/h/70kg) F = extent of absorption (f) x (1-ER) Morphine is almost completely absorbed (f=1). 3-3. bioavailability is less than 100% for two main reasons. Fig. so (1-ER) is 0. Golan et al. Bioavailability following administration of a single dose of drug (Principles of Pharmacology.67.33. the hepatic extraction ratio for morphine is 0. so that loss in the gut is negligible. first-pass elimination) = CLliver (L/h/70kg) Q (hepatic blood flow. 2005) . Hepatic extraction ratio (ER.Bioavailability (F) Bioavailability (F)= fraction of a drug reaching the systemic circulation (quantity of drug reaching systemic circulation/quantity of drug administered) For a drug administered orally.. incomplete extent of absorption and first-pass elimination. The bioavailability of morphine is therefore expected to be about 33%.

7 ng/ml would be observed. Vd = 500.Volume of Distribution (Vd) Represents the fluid volume required to contain the total amount of absorbed drug in the body at a uniform concentration equivalent to that in the plasma at a steady state. digoxin distributes widely throughout the body.8 L. • Vd can be altered by liver or kidney disease. • Drugs (digoxin) that are highly distributed to extravascular compartments (fat and muscle) have a high Vd. a plasma concentration of approximately 0. Vd = (Cp) Amount of drug in the body (Dose) Concentration of drug in blood or plasma If 500 ug of digoxin were in the body of a 70-kg subject. Ibuprofen typically exhibits a Vd of 10.000/0. this drug does not distribute widely to into tissues.7 = 714 L. Thus. . Hence. • Drugs (ibuprofen) that are primarily retained within the vascular compartment have a relatively low Vd.

2005) . • Because a highly protein-bound drug tends to remain within the vasculature. each of which is highly bound to plasma protein. Golan et al. Fig.. leaving 10% of the concentration in the blood as free drug and available for pharmacological action and metabolism. • Co-administration of two or more drugs. 3-5. such a drug often has a relatively low Vd. could results in higher-than-expected plasma concentration of the free form of either or both drugs. Protein Binding and Drug Trapping (Principles of Pharmacology. • Phenytoin is approximately 90% bound to plasma proteins.Plasma Protein Binding • Albumin is the most abundant plasma protein and is responsible for drug binding.

g. 100 mL/min). CL is defined as the volume of plasma that was completely cleared of the drug per unit of time (e.Clearance (CL) CL is the efficiency of irreversible elimination of drug from the body. CL = Rate of elimination / Concentration of drug in plasma (Cp) CLSystemic = CLKidney + CLLiver + CLOther . and involves both metabolism and elimination of drug..

69/k log scale t1/2 = 4 h MEC (minimum effective concentration) . Doubling the dose increases duration of action by one half-life.69 = kt1/2 t1/2 = 0.Half-Life (t1/2 ) (1) t1/2 = the time required to change the amount of drug in the body by one-half during elimination. Need logarithmic increase in dose to get linear increase in duration of action. [X] = [X]0 e-kt [X]0/2 = [X]0 e-kt 1/2 1/2 = e-kt 1/2 2 = ekt 1/2 ln 2 = kt1/2 0.

2005) . Golan et al.Half-Life (t1/2 ) (2) Table 3-5. Factors affecting drug half-life (Principles of Pharmacology..

Relating CL to t1/2 and Vd From the first order elimination. and if elimination is occurring only by the kidney then kX = uv/t. X = c Vd.69 Vd/clearance CL = Vdk or t1/2 = 0. and since X = total amount of drug in body. c = drug concentration in plasma = gm/ml u = drug concentration in urine = gm/ml v = volume of urine = ml then uv/t = gm/time = the rate of drug excretion into urine Divide this by c uv/tc = ml/time = clearance = the volume of plasma that was completely cleared of the drug in the time interval.69 Vd/CL .Relationship between Clearance. k c Vd = uv/t or k Vd = uv/tc = clearance or t1/2 = 0. the rate of drug excretion is -dX/dt = kX. and t1/2 Renal clearance describes the efficiency with which a drug or metabolite is excreted by the kidney. Vd. Consequently.

3-11. and toxic drug dosing (Principles of Pharmacology. each influences the design of an optimal dosing regimen for a drug. 2005) .Dosage Regimen • A rational dosage regimen is based on a target concentration that will produce the desired therapeutic effect.. and excretion. distribution. Golan et al. • Therapeutic window is the safe opening between the minimum therapeutic concentration and the minimum toxic concentration of a drug Fig. • Absorption. Therapeutic subtherapeutic. metabolism.

Dosing rate = Rate of elimination = CL x Target Concentration (TC) If the drug is given by a route that has a bioavailability less than 100%.Maintenance Dosage At steady state. the dosing rate (rate in) must equal the rate of elimination (rate out). Dosing rate = CL x Target Concentration (TC) Bioavailability (F) If intermittent doses are given. Maintenance dose = Dosing rate x Dosing interval .

Maintenance dose = Dosing rate x Dosing interval = 28 mg/h x 12 hours = 350 mg F 0. Katzung.96 If an 8-hour dosing interval was used.8 L/h/70 kg.Maintenance Dosage: Example A target plasma theophylline concentration of 10 mg/L is desired to relive acute bronchial asthma in a patient. the dose would be 700 mg. Since the drug will be given via IV. which is given every 12 hours. 3-6. Relationship between frequency of dosing and maximum plasma concentrations when a steady state theophylline plasma level of 10 mg/L is desired. Fig. If the patient is a nonsmoker and otherwise normal except for asthma. 2004) . Dosing rate = CL x TC = 2. Foral = 0. the clinician might want to maintain this plasma level using oral theophylline. the ideal dose would be 233 mg. clearance is 2. F = 1.8 L/h/70 kg x 10 mg/L = 28 mg/h/70 kg If the asthma attack is relieved. and if the drug was given once a day. (Basics & Clinical Pharmacology.96.

8 L x 1. . Sensitive patients may be exposed to a toxic concentration of a drug. if the drug has a long half-life.8 L (70 kg).90 mg • A loading dose may be desirable if the time required to attain steady state by the administration of drug at a constant rate (four elimination half-lives) is long relative to the temporal demands of the condition being treated such as arrhythmia.01 mg/L = 9. when a TC is 1.01 mg/L. • The use of a loading dose has significant disadvantages. warfarin has a Vd of 9. it will take a long time for the concentration to fall. In addition.Loading Dose Initial (loading) dose to rapidly achieve a therapeutic concentration when the Vd is large Loading dose = Vd x Target Concentration (TC) For example. loading dose is calculated as Loading dose = 9.

Corrected dose = Average dose x Patient’s creatinine clearance (measure for glomerular filtration rate) .Adjustment of Dosage with Compromised Clearance Drugs cleared by the renal route require adjustment of clearance in proportion to renal function (renal disease or reduced cardiac output).

Table 3-1. Katzung. Pharmacokinetic and pharmacodynamic parameters for selected drugs (Basic & Clinical Pharmacology. and eliminate the drug. . distribute. 2004) The standard dose of a drug is based on trials in healthy volunteers with average ability to absorb.

Problem 1 When 0.3 g of drug X is given by IV to a subject. Vd = Amount of drug in the body (Dose) Concentration of drug in plasma (Cp) = 300 mg/15 mg/L = 20 L . the resulting drug concentration is 15 mg/L. Calculate the volume of distribution.

What should be the daily dose for an 80-year-old patient? t1/2 = 0. Dose/3 = Cp x CL/3 x time interval Dose for older patients = 12 mg/kg per day / 3 = 4 mg/kg per day . in patients 70 to 90 years old. its elimination half-life is increased to 270 minutes. Assume that the volume of distribution per body weight is not changed by the patient’s age. Dose = Cp x CL x time interval In older patients.Problem 2 An aminoglycoside has a normal elimination half-life of 90 minutes in young adults.693 x Vd / CL CL for older patients must be 3 times lower than that for young patients. The normal dose of the aminoglycoside is 12 mg/kg per day. However.

1. Warfarin has a volume of distribution of 9.01 mg/L = 9. Calculate the steady-state plasma concentrations of warfarin. and its clearance is 0.01 mg/L 24 h x 0. Calculate the loading dose. Walsh is taking 5 mg of warfarin every 24 hours for his chronic atrial fibrillation. 1.93 x 5 mg = 1. The steady state is reached only when the amount of drug entering the system is equivalent to the amount being removed from it.192 L/h 2.90 mg .Problem 3 Mr.8 L x 1. Loading dose = 9.192 L/h.8 L. 2. The bioavailability of warfarin is 0. Bioavailability x Dose = Css x Clearance Dosing interval Css = = Bioavailability x Dose Dosing interval x Clearance 0.93.

Problem 4 A known abuser of narcotic analgesics is brought to the emergency department in a deep coma.2 L/hr. k = CL/Vd [X] = [X]0 • e-kt [X] = D/Vd • e-CL/Vdt 0 3 Time (hr) 6 0. His friends state that he took a large dose of IV morphine 6 hours earlier. is given by the following equation: [X] = [X]0 • e-kt ([X]0 . Assuming that the pharmacokinetics of morphine in this patient are similar to the population pharmacokinetics (volume of distribution 200 L.5 mg/L The plasma drug concentration at any time t after administration.25 mg/L. approximately how much morphine did the patient inject? Plasma morphine conc. [X]. elimination constant). k. (log scale) 1 mg/L 0. clearance 46. half-life 3 hrs). A blood sample shows a morphine level of 0. initial plasma drug concentration.25 mg/L D = 200 mg .

(log scale) Therapeutic window 40 mg/L 0 Time The plasma drug concentration at any time t after administration.1 hour -1 . k. [X] = [X]0 • e-kt 40 mg/L = 1000 mg / 8 L x e-0. Vd = 8 L 125 mg/L Plasma drug conc. elimination constant). calculate how long the clinical effect will last following a one-gram dose. Given the relevant characteristics of this compound below and assuming a one-compartment model.4 hours . is given by the following equation: [X] = [X]0 • e-kt ([X]0 .1t t = 11. [X].Problem 5 A compound is given as an intravenous bolus to a patient requiring a minimum plasma concentration of 40 mg/L for a therapeutic effect. initial plasma drug concentration. k = 0.

1325 mg / Bioavailability = 334.Ctrough ) x Vd x body weight (kg) = (80 ug/mL . Considering the relevant characteristics of the drug given below.A. t1/2 = 30 hours.3 mg .63 ug/mL The amount of drug being eliminated during the dosing interval of 12 h = (Cpeak . an 8-year-old.. is taking ethosuximide for treatment of absence seizures.1325 mg / 0. Vd = 0. (log scale) Peak conc. 80 ug/mL Trough conc. calculate the maintenance dose required with a dosing interval of 12 hours.69 L/kg.693/30h)x12h = 60. k = 0. Peak target plasma concentration at steady state = 80 ug/mL.60. 25-kg boy.5 ug = 334.93 = 359. Bioavailability = 93% Plasma ethosuximide conc.693 / t1/2 Ctrough = [X]0 • e-kt = 80 ug/mL x e -(0.Problem 6 C.63 ug/mL) x 690 mL/kg x 25 kg = 334132. 12 h Days [X] = [X]0 • e-kt .1325 mg Maintenance dose = 334.

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