The document provides an overview of pharmacokinetics (PK) and pharmacodynamics (PD), focusing on key concepts such as absorption, distribution, metabolism, excretion (ADME), clearance, volume of distribution, and half-life. It discusses the factors that modify PK, the differences between first-order and zero-order elimination, and the importance of bioavailability and target dosing in achieving therapeutic goals. Additionally, it covers the impact of variables like protein binding and patient-specific factors on drug pharmacokinetics and dynamics.
The document provides an overview of pharmacokinetics (PK) and pharmacodynamics (PD), focusing on key concepts such as absorption, distribution, metabolism, excretion (ADME), clearance, volume of distribution, and half-life. It discusses the factors that modify PK, the differences between first-order and zero-order elimination, and the importance of bioavailability and target dosing in achieving therapeutic goals. Additionally, it covers the impact of variables like protein binding and patient-specific factors on drug pharmacokinetics and dynamics.
The document provides an overview of pharmacokinetics (PK) and pharmacodynamics (PD), focusing on key concepts such as absorption, distribution, metabolism, excretion (ADME), clearance, volume of distribution, and half-life. It discusses the factors that modify PK, the differences between first-order and zero-order elimination, and the importance of bioavailability and target dosing in achieving therapeutic goals. Additionally, it covers the impact of variables like protein binding and patient-specific factors on drug pharmacokinetics and dynamics.
The document provides an overview of pharmacokinetics (PK) and pharmacodynamics (PD), focusing on key concepts such as absorption, distribution, metabolism, excretion (ADME), clearance, volume of distribution, and half-life. It discusses the factors that modify PK, the differences between first-order and zero-order elimination, and the importance of bioavailability and target dosing in achieving therapeutic goals. Additionally, it covers the impact of variables like protein binding and patient-specific factors on drug pharmacokinetics and dynamics.
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Overview of Pharmacokinetics (PK) and Pharmacodynamics (PD) RACHEL BASINGER, PHARMD, BCACP, CTTS, DIPACLM HPPA5306 2 Readings and Lecture Objectives
Required Reading: Basic & Clinical Pharmacology; (16th edition) Chapter 3 Lecture Objectives Define pharmacokinetic and dynamic terminology Explain how the various pharmacokinetic and dynamic are related such as but not limited to clearance, volume of distribution, elimination, half-life, accumulation, bioavailability, concentration, and effect Given the equation, complete pharmacokinetic calculations Therapeutic goal 3 Maximize efficacy, minimize toxicity Pharmacokinetic Body does to the drug (ADME) Pharmacodynamic What the drug does to the body
Age, body size, maturation of organ “Healthy” patient function Doses may vary based on effects of Pathologic processes PK Heart failure, renal failure, liver failure Drug interactions Anything that effects ADME 5 Clearance (CL) & Volume of Distribution (V)
Clearance: measurement of the body’s ability to eliminate the
drug Volume of Distribution: where in the body the drug goes
None CL only V only CL & V
6 CL & V
Volume of distribution (V) Clearance
Total amount of drug in the body versus Rate of elimination/concentration concentration in the blood/plasma (C) CL = rate of elimination/C V = total/C Sites of elimination “Apparent volume” = true volume Kidney (urine) and liver Human body ~ 5 L of blood (biotransformation or bile) >>> V of Drugs contained in vascular <<< lungs, sweat, bile, blood, muscle, etc. V of drugs with extravascular distribution Furosemide 7.7 <<< Fluoxetine 2,500 7 Rate of Elimination (First Order)
Rate of elimination = CL X C First order elimination No saturation Elimination ∞ concentration (more drug, quicker elimination) CL (estimated) = dose/AUC
AUC: area under the curve
8 Rate of Elimination (Zero Order)
Also known as: capacity-limited, mixed-order, saturable, nonlinear,
Michaelis-Menten elimination Eliminated at a constant rate, regardless of the plasma concentration. Elimination is dependent on time, NOT the amount ingested. Examples: Phenytoin, alcohol, aspirin Vmax = maximum elimination capacity Km = drug concentration at which the rate of elimination is 50% of V max 9 Comprehension Check
Zero Order First Order
Elimination is dependent on Elimination is dependent on TIME CONCENTRATION 10 Flow Dependent Elimination & Large Molecules
Flow Dependent Elimination
Rate dependent on the delivery of the drug to the organ of elimination Examples: blood flow to kidney urine; blood flow to liver first pass effect Factors Blood flow, protein binding, blood cell binding Large Molecules (often proteins) Low elimination rate = long duration in body due to size (weeks) Binds to target = quicker elimination rate because the molecule gets cleared with the target Target-mediated drug disposition Example: monoclonal antibodies 11 Half-Life (t1/2) and Drug Accumulation
t1/2 time required to change the amount of drug in the body by one-half during elimination ; Dependent on V and CL Used to estimate time to reach steady state or elimination from body (~ 4 t1/2 ) Larger V = longer t1/2 Drug Accumulation with multiple dosing Inversely proportional to the fraction of the dose lost in each dosing interval 12 Bioavailability (F)
Fraction of unchanged drug reaching the
systemic circulation following administration by any route IV = 100%; Others < 100% Absorption Passive, transports, pumps Lipophilic or hydrophilic molecules First pass effect (liver) (ER): extraction ratio Clliver: hepatic blood clearance Q: hepatic blood flow f: extent of absorption 13 Bioavailability
Rate (how quickly) versus extent (how much) of absorption
Avoiding liver first pass effect Completely Topical Transdermal Sublingual Inhalations Lung have their own metabolism “first pass” effect
50% Rectal 14 Concentration and Effect
Does NOT always correlate
Immediate effects Enalapril (short t1/2, 24 hour effect = once daily) Delayed effects Warfarin (therapeutic effect ~5 days) Scheduled dependent effects Aminoglycoside (Intermediate dosing = saturates renal cortex absorption = less renal toxicity than steady infusion) Cumulation effects DNA binding cancer drugs = AUC dosing for individuals 15 Target Dosing
Some drugs are dosed based on
reaching [drug] found to be therapeutic Example: dixogin for Afib (2 ng/mL) versus HF (1 ng/mL); vancomycin (20 mg/L) Maintenance dose Keep [target] by the amount given with each dose replaces the drug eliminated since the preceding dose Relationship between frequency of dosing and maximum and minimum plasma concentrations when a steady-state TC: total concentration theophylline plasma concentration of 10 mg/L is desired. The : steady state smoothly rising black line shows the plasma concentration SS achieved with an intravenous infusion of 28 mg/h. The doses for 8-hour administration (orange line) are 224 mg; for 24-hour administration (blue line), 672 mg. In each of the three cases, the mean steady-state plasma concentration is 10 mg/L. 16 Example
IV theophylline Oral theophylline
[target] = 10 mg/L F = 0.96 CL = 2.8 L/h/70 kg ER tablets dosed Q 12 hours F=1 Dosing (oral) = dosing rate/F X dosing interval
= 28 mg/h/0.96X12 hours Dosing (infusion) Rate = CL X TC = 29.167 mg/h X 12 hours = 2.8 L/h/70 kg X 10 mg/L = 350 mg = 28 mg/h/70 kg ER: 300, 450, or 600 mg capsules Vials: 80 mg/15 mL Give 300 mg BID (twice daily) 5.25 mL 17 Loading Dose
Drugs with long t1/2, long time to reach Css
May wish to reach [target] quicker with loading dose Most drugs are first order kinetics, but for zero order kinetic drugs, like phenytoin, MUST factor in accumulation factor to avoid toxicity 18 Variables for Target Concentrations
Kinetics Input Clearance Volume of distribution Dynamics Emax : maximum effect Plateau: more drug ≠ more effect Sensitivity (C50): the amount of drug to reach 50% of E max Individual physiology, pathophysiology, or drug interaction Example: hyperkalemia = blunts response to digoxin 19 Variables in Protein Binding (Clearance)
Albumin plasma concentrations
Decreased in liver disease, kidney disease, malnutrition, infection, large body burns, etc. Most common; phenytoin, salicylates Alpha1-acid glycoprotein concentration Increased in acute inflammation disorders Quinidine, lidocaine, propranolol. Capacity-limited protein binding Steroids Binding to red blood cells Tacrolimus, cyclosporine 20 Predicting V and CL
V in references based on 70 kg patient
Can adjust based on patient height and weight FFM: fat free mass used for highly hydrophilic drugs Edema, ascites, or pleural effusions V increased for highly hydrophillic drugs Adjustments needed Renal elimination Creatinine Clearance (estimation) = [[140 - age(yr)]*weight(kg)]/[72*serum Cr(mg/dL)] (multiply by 0.85 for women) Weight used varies: actual, ideal, or adjusted 21
