Pharmacokinetics PDF

James E Beaulieu, PharmD Department Coordinator Lifespan Pharmacy [email protected] Objectives 1. Define 1. Pharmacokinetics 2. Pharmacodynamics 3. Absorption 4. Distribution 5. Metabolism 6. Excretion 2. Understand 1. Concepts of half life and...

James E Beaulieu, PharmD Department Coordinator Lifespan Pharmacy [email protected] Objectives 1. Define 1. Pharmacokinetics 2. Pharmacodynamics 3. Absorption 4. Distribution 5. Metabolism 6. Excretion 2. Understand 1. Concepts of half life and steady state 2. Role of protein binding on drug distribution and response 3. Recognize the role of CYP450 enzymes and drug metabolism 7/22/2024 Objectives 1. Differentiate between active and inactive metabolites 2. Understand the correlation between Creatinine Clearance and drug excretion 3. Identify enterohepatic circulation and the first pass effect. 4. Understand the factors affecting drug disposition. 7/22/2024 Definitions Therapeutic Index – (also called margin of safety), range between the concentration of drug needed to produce a therapeutic response and toxicity Half life (t ½) – time it takes for the plasma concentration to decrease to half the value it had at the start of the time interval (takes 5 half-lives to reach steady state or most of drug will be eliminated after dose is terminated 7/22/2024  Two Phases of Drug Action 1. Pharmacokinetics (plasma conc. relationship) Dose Cp 2. Pharmacodynamics (conc. at site of action) Csite Effect 7/22/2024 Lecture_one.ppt Pharmacokinetics Plasma Concentration (Cp)  Utilized to determine effectiveness or end point (not the observable or measurable effect)  Predict how plasma concentration (Cp) of drug changes over time  Helps establish  Dose and dosing schedule  Adjust an existing schedule  Increase effectiveness  Minimize adverse events or toxicity 7/22/2024 Lecture_one.ppt  Dose Response Influencing Factors (response): Pharmacokinetic Principals  Dose (bioavailability) (dictates amount available)  Age  Absorption  Weight (Obesity)  Distribution  Sensitivity  Metabolism  Renal/Hepatic Function  Elimination  Genetics  Responder/Nonresponder  Race  Gender  Interactions with other meds. 7/22/2024 Adverse Intra-luminal Events  Absorption to food or other substances  Degradation by stomach acid (pH = 1)  Drug is attacked by an enzyme  Drug is metabolized by enzymes in the GI lumen 7/22/2024  First Pass Effect  Liver is loaded with enzymes that metabolize drugs  Drugs with a high affinity for liver enzymes will have a reduced bioavailability after the first pass effect 7/22/2024 Other Influences on Bioavailability 1. Dosage form (tablet, capsule, liquid, IV etc) 2. Manufacturer 3. Excipients used (corn starch, talc) 4. Individual Lots (i.e., Lot #) 5. Generic vs. Brand Name 6. Dissolution (particle size) 7/22/2024 Absorption Basic principles: 1. Drugs administered (PO, IM, SQ, INH etc) must cross membranes to be absorbed and enter systemic circulation 2. Membranes are composed of a lipid (fat) bilayer which is hydrophobic (does not like water) 3. Drug must have some affinity for water (hydrophilicity) or they cannot dissolve and be transported by blood and other body fluids to site of action 7/22/2024 Factors which favor absorption 1. Uncharged – allows for lipid solubility 2. Nonpolar – lipid environment of membrane is nonpolar, polar compounds with a separation of positive and negative charges are not easily absorbed 3. Low molecular weight – the ordered structure of lipid membrane does not allow for aqueous pores large enough in diameter (> 0.4 nm) to allow for the passage of most drugs (> 1 nm) 4. High lipid solubility – especially true for the blood brain barrier 7/22/2024 Mechanism of absorption 1. Simple passive diffusion (most common) 2. Active transport – involves specific carrier molecules in membrane - primarily found in the GI tract, biliary tract, renal tubule, and the blood-brain-barrier - drugs may compete for same carrier - there are a finite number of carriers 3. Facilitated diffusion - 4. Pinocytosis – drug engulfed by the membrane 7/22/2024 Mechanism of absorption 7/22/2024 Lecture_one.ppt Mechanism of absorption 7/22/2024 Lecture_one.ppt Active Transport - Intestines 7/22/2024  Enterohepatic recycling  Occurs by biliary excretion and intestinal reabsorption of a solute  Often associated with multiple peaks and a longer apparent half-life of compound  Factors affecting biliary excretion  Drug characteristics (chemical structure, polarity and molecular size)  Transport across sinusoidal plasma membrane and canniculae membranes  Biotransformation  Possible reabsorption from intrahepatic bile ductules 7/22/2024  Enterohepatic recycling  Intestinal reabsorption to complete the enterohepatic cycle may depend on hydrolysis of a drug conjugate by gut bacteria.  Genetic abnormalities, disease states, orally administered adsorbents and certain coadministered drugs all affect enterohepatic recycling. 7/22/2024  Enterohepatic recycling 7/22/2024 Drug Distribution  The actual volume in which a drug distributes within a patient’s body can not be measured  Apparent volume of distribution (Vd) – relates the concentration of drug in the blood or plasma to the total amount of drug in the body  Vd can serve as a guide to determine if a drug is bound primarily to plasma or tissue sites  Vd is measured in liters (sometimes may see L/kg) 7/22/2024 Drug Distribution (con’t)  Understanding the degree of protein binding (albumin, α1-acid glycoprotein or lipoprotein) helps interpret Vd and clearance (i.e., only unbound drug can distribute to site of action then be metabolized and cleared)  Large Vd – extensive distribution from plasma into tissues (less protein binding), plasma concentration will be small  Small Vd – extensive protein binding (less available to distribute to tissues), plasma concentration will be large 7/22/2024 Drug Distribution (con’t)  Serum albumin is the most abundant protein in human plasma  Albumin is synthesized in the liver and is greatly affected by disease states, age, and nutritional status  Binding of drugs to proteins may be affected by disease (e.g., uremia) 7/22/2024  Drug Distribution (con’t) 7/22/2024 Lecture_one.ppt Drug Distribution (con’t) 7/22/2024 Clearance (metabolism & excretion) Definitions:  Drug clearance (Cl) – volume of plasma cleared of drug per unit time (mL/min)  Describes efficiency of irreversible elimination of drug from body  Metabolism – conversion of drug to another chemical species (mainly liver)  Excretion – loss of chemically unchanged form of the drug (mainly kidney)  Disease states, age, ethnicity, and gender can affect metabolism and excretion 7/22/2024 Renal Clearance Mechanisms: 1. Glomerular filtration (GFR) 2. Tubular secretion 3. Tubular reabsorption 7/22/2024 Renal Clearance 7/22/2024  Glomerular Filtration  Normal GFR for healthy adult is 125 mL/min  Can be assessed by measuring CrCl  very little binding to plasma proteins  does not undergo appreciable tubular secretion or reabsorption) 7/22/2024 Calculating CrCl - Adults 1. Measure serum creatinine  Plasma concentration  24 hour urine collection 2. Patient’s age (years) 3. Patient’s weight (kg) CrL = (140 – age)* wt 72 * SrCr Multiply by 0.8 for women 7/22/2024 Calculating CrCl - Pediatrics 7/22/2024 Creatinine Clearance (Con’t) Considerations:  Age (best renal function when infant)  Weight (creatinine derived from muscle mass)  Gender 7/22/2024 Tubular Secretion & Reabsorption  Secretion  Active process which occurs in the proximal tubule – drug “extracted from blood” into renal tubule  Reabsorption  Filtered or secreted drug from the tubules is reabsorbed back into the venous blood surrounding the nephrons 7/22/2024  Liver Metabolism  Generally involves the conversion of a non-polar, lipid soluble, compound in the liver to a more polar form that is more water soluble, to facilitate urine excretion  Drug metabolizing enzymes can also be found in the lung, kidney, GI tract, placenta, and GI tract bacteria 7/22/2024  Liver Metabolism (con’t) In general the metabolic capability of the liver is dependent upon two variables 1. Delivery of the drug to the liver (Q = liver blood flow) 2. Intrinsic clearance – ability of the liver to metabolize drug in the absence of restrictions by blood flow and blood (protein) binding 7/22/2024  Liver Metabolism (con’t) Generally categorized into four groups: 1. Conjugation 2. Oxidation (cytochrome P450 system) 3. Reduction 4. Hydrolysis 7/22/2024  Liver Metabolism (con’t) 7/22/2024  Conjugation  Involves coupling a drug molecule to an endogenous group to allow for greater water solubility  Leads to enhanced renal or biliary elimination  Main coupling group is glucuronic acid 7/22/2024  Oxidation (cytochrome P450)  Associated with the endoplamic reticulum of the cell  More than 30 isoforms exist (allows for body to metabolize a large number of drugs and environmental chemicals)  Common feature of P450 substrates is lipid solubility  Most abundant subfamily – CYP3A 7/22/2024 Oxidation (cytochrome P450)  Has a role in biosynthesis & catabolism of steroid hormones, bile acids and fatty acids, and fat soluble vitamins  Clinical importance  identify substrates, inhibitors, and inducers of P450  assist in predicting drug interactions  http://medicine.iupui.edu/flockhart/ 7/22/2024 Lecture_one.ppt P-glycoprotein  Membrane transporter (protein)  Pumps lipophillic drugs out of cells  Acts as a defense mechanism  Recognized for contribution to multi- drug resistance during chemotherapy 7/22/2024 P-glycoprotein  Located in:  Liver  Kidney  Pumps drugs back into urine  Blood-brain barrier  Blood-testis barrier  Lymphoctes  Placenta 7/22/2024 P-glycoprotein  Enterocytes of small and large intestines  Carry lipophyllic molecules from enterocyte back into intestinal lumen for elimination  Many lipophyllic drugs maybe metabolized by CYP3A4 or pumped back into lumen by P-glycoprotein  Work in tandem  Similar substrates, inhibitors, and inducers 7/22/2024 Pharmacokinetic Variability  Age  Concomitant drugs, endogenous substances, or environmental substances  Genetic polymorphism  Testing before administer drug therapy  Nutrition  Hepatic disease and other diseases  Hormones (gender)  Foods 7/22/2024 44 Lecture_one.ppt  Diseases  Liver failure and cirrhosis (difficult to adjust medications, no handy equation)  CHF (decreases) - perfusion to one or more tissues - decrease or erratic absorption - rate of distribution (except heart and CNS - extent of distribution - hepatic blood flow 7/22/2024 45 Gender  Little studied – hormonal changes  Probably an estrogen effect  Clearance of some medications decreases in women on oral contraceptives  FDA now requires medications to be tested in women  Still underrepresented  Gender specific analysis usually not included in evaluation of clinical trials  Limited recommendations for dosage adjustments of medications 7/22/2024 Gender  Differences have been found in all four PK phases  Metabolism accounts for major cause of differences in PK between genders 7/22/2024 Gender Differences - PK  Absorption  Slower gastric motility in women  Longer wait between food consumption and medication if drug is to be taken on an empty stomach  P-glycoprotein  Lower expression in women resulting in greater absorption of drugs that use this transporter protein  Lower gastric acid secretion  Drugs that require gastric acid to be absorbed 7/22/2024  Gender Differences - PK  Distribution  Higher percentage of adipose mass  Effects volume of distribution of medications  Lower body water content  Excretion  Renal blood flow and glomerular filtration lower in women  Slower clearance of drugs actively eliminated by the kidney  Other factors  Lower body weight  Smaller organ size (cardiac output)  Plasma volume  Regional blood flow 7/22/2024  Gender Differences - PK  Pregnancy  Changes in drug distribution  Increased plasma volume  Increased total body water  Changes in absorption  Prolonged gastric emptying  Increased metabolism of medications  Excretion  Increased GFR 7/22/2024  Gender Differences - PK  Women often exhibit a higher hepatic clearance for CYP2D6 and CYP3A4  Differences in drug disposition (summary)  lower body weight  smaller organ size  higher proportion of body fat  lower glomerular filtration rate  lower gastric acid secretion 7/22/2024 51  Gender Differences - PD  Lengthening of the QT interval  Women at greater risk than men to develop torsade de pointes from drugs that prolong cardiac repolarization  Effect of sex hormones 7/22/2024 52