Pharmacokinetics PDF

Pharmacology Pharmacokinetics Kyle R. Scully, PhD [email protected]  Learning Objectives Define the following: pharmacokinetics, absorption, distribution, metabolism, excretion, and bioavailability Compare and contrast the routes of drug administration...

Pharmacology Pharmacokinetics Kyle R. Scully, PhD [email protected]  Learning Objectives Define the following: pharmacokinetics, absorption, distribution, metabolism, excretion, and bioavailability Compare and contrast the routes of drug administration Apply the concept of bioavailability to a clinical scenario Describe how pH affects the diffusion of weak acids and weak bases; apply this concept to a clinical scenario Compare and contrast Phase I and Phase II reaction; describe the effects of each on drug properties Describe the role of cytochrome P450 enzymes in drug metabolism (biotransformation) Define prodrug; compare and contrast the metabolism of prodrugs and active compounds (consider pharmacogenetics, enzyme inhibitors, and enzyme inducers) Predict the effects of enzyme inducers and inhibitors; apply this concept to a clinical scenario Describe the role of metabolic enzymes in the progression of acetaminophen toxicity; apply the appropriate intervention Compare and contrast elimination and excretion Compare and contrast Zero-order and First-order elimination kinetics  Resources Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 4th ed., Lippincott Williams & Wilkins. 2017 Chapter 3 – Pharmacokinetics  A 58-year-old male patient presents to the emergency department complaining of dizziness, nausea/vomiting, and palpitations. Physical examination reveals hypotension and tachycardia. Medical Case history reveals that the patient is prescribed a medication to treat Scenario hypertension. Labs reveal elevated BUN and serum creatinine. Based on the findings; what is the most likely explanation for the patient’s current condition?  A 27-year-old female presents to their primary care physician complaining of abdominal pain, nausea, and vomiting. The patient’s vitals are within normal limits and the patient denies any other symptoms. Medical history reveals that the patient is prescribed Case oral contraceptives. During history taking, the patient discloses that Scenario they began taking St. John’s wort supplements after reading that they can improve mood and treat minor depression (patient has not been previously diagnosed). A urine dipstick for human chorionic gonadotropin (HCG) is positive. What is the best explanation for the patient’s urinalysis findings?  Outline Pharmacokinetics Introduction Absorption – Bioavailability – Routes of administration Distribution – Volume of distribution Excretion – Half-life and clearance Clinical applications – Therapeutic dosing Dynamics Vs Kinetics  Pharmacokinetics PK Describes the movement of a drug in the body (how the body acts on the drug) ØADME – A drug needs to reach its site of action for any of the pharmacodynamics to matter… – The body acts on endogenous and exogenous compounds to limit exposure and detoxify  Drug Characteristics Factors which affect absorption: Physical state of drug Water/lipid solubility Particle size Ionization of drug Disintegration time of drug Oral Dosage forms Dissolution time of drug  Modes of Movement jun A. Aqueous diffusion: passive diffusion through aqueous channels in the paracellular junctions (tight junctions); driven by concentration gradient B. Special carriers: selective, saturable, and inhibitable active transport or facilitated transport; only those with appropriate characteristics can utilize this mechanism 1 has maxate  Modes of Movement C. Endocytosis and exocytosis: process of binding to cell surface receptor, engulfment by cell membrane, and carried into the cell in vesicles; require specific receptors D. Lipid diffusion: most important limiting factor as lipid barriers separate aqueous compartments; determined by a drug’s lipid:aqueous partition coefficient, pH, pKa primary mode ofmovement primary Lipid Diffusion Fick’s Law  Weak Acids and Weak Bases The role of pH Only the non-ionized form of the drug can diffuse through the lipid membrane  Role of Transporters Uptake and Efflux Substrate specificity – Affinity and Competition Tissue distribution vClinically relevant drug-drug interactions Kdfor tran affinity transport  pret raspol Pharmacokinetics ADME Absorption: Process of a substance entering the blood circulation Distribution: Metabolism: Excretion:  Absorption Humans are made up of physiological barriers which prevent the movement of exogenous compounds and microorganisms into the body – Skin – Mucous membranes – Gastrointestinal tract – Blood brain barrier – Placenta had to get in A drug must move through these physiological barriers effectively to reach its site of action (be clinically effective)  Bioavailability bioavailable adulistened drug 1100 reaches bloodstream that Quantity of drug reaching systemic circulation Bioavailability = Quantity of drug administered  Routes of Administration Enteral Generalized Oral Oral Sublingual Injectable Rectal Mucous membrane Parenteral – Sublingual Injectable – Rectal Transdermal – Pulmonary Inhalation Transdermal  Routes of Administration Oral Oral administration is the most convenient self- administered route of administration Advantages 1st pass 1stmetabolism – Increased patient compliance importesailability – Painless – Safety Disadvantages – Exposure to the gastrointestinal tract (Nausea and vomiting) – First pass effect – Harsh conditions (drug stability) – Slow onset of action  First Pass Metabolism Drug must first be absorbed in the stomach or intestine Drug passes through the liver where it is metabolized (inactivated) and/or excreted into the bile  Prodrug Takes advantage of first pass effect to activate the drug. Rational drug design uses this principle – Ex. Tamoxifen  Routes of Administration Injectable Advantages – Bypass limitations of oral administration GI absorption First pass effect Disadvantages – Increased risk of toxicity – Often administered in medical setting – Risk of infection  Routes of Administration Injectable Subcutaneous Intramuscular Poorly vascularized Well vascularized Slow onset Rapid onset Small volume Larger volumes possible  Routes of Administration Injectable Intravenous Intrathecal Immediate onset Direct introduction into 100 % bioavailable cerebrospinal fluid High drug concentration may be attained rapidly There is no turning back  Routes of Administration Mucous Membranes Highly vascular – Rapid absorption – Avoidance of 1st pass effect – Absorption can be inconsistent Examples: – Sublingual (buccal) – Ocular – Pulmonary – Nasal – Rectal – Urinary – Reproductive tract  Routes of Administration Transdermal Drugs are absorbed from skin and subcutaneous tissues into bloodstream No risk of infection Simple and convenient administration Ideal for slow and continuous administration Routes of Administration think picture by  Pharmacokinetics ADME Absorption: Process of a substance entering the blood circulation Distribution: Dispersion or dissemination of substances throughout the fluids and tissues of the body (to the site of action) Metabolism: Excretion: Distribution  Distribution To produce a characteristic effect, a drug must present at appropriate concentration at its intended site of action Primarily distributed by the circulatory system Plasma concentration is used to monitor therapeutic drug concentration – Drug concentration in target tissue is not practical  Distribution Total body water Bone & teeth Extracellular Blood water plasma Adipose tissue Golan Fig. 3.5 Distribution Kinetics vessel rich groups vascularized on depends dinvention andmode of Golan Fig. 3.8  Distribution Kinetics Most drug distribute rapidly in to other compartments After the drug reaches equilibrium between compartments the drug is eliminated from circulation Equilibrium between the compartments allows this process to be slower than distribution Golan Fig. 3.6  Pharmacokinetics ADME Absorption: Process of a substance entering the blood circulation Distribution: Dispersion or dissemination of substances throughout the fluids and tissues of the body (to the site of action) Metabolism: Biotransformation, may change the substance to a more active form or inactive form Excretion:  Biotransformation (Metabolism) Foreign The process by which the Cotaron Compound body prepares a foreign compound for elimination from the body – Environmental chemicals – Toxins – Therapeutic drugs – Recreational drugs  Biotransformation (Metabolism) Biotransformation serves two purposes; functional Phase I – RedOx reactions addspoor groupfor – Render the drug less toxic (while preparing it for conjugation) Phase II – Conjugation or hydrolysis reactions – Conjugate the drug, making the drug more readily excreted vSee Golan Chapter 4 – Table 4.1 and 4.2 for examples not an order  Biotransformation (Metabolism) Biotransformation is NOT a linear process  Biotransformation Phase I Enzymes add a polar functional group Includes: oxidation and reduction Majority of the enzymes are heme protein mono- oxygenases of the cytochrome P450 (CYP) gene family vBut not all…  Biotransformation Phase I Non-CYP Not all Phase I biotransformation is mediated by CYP enzymes – Alcohol dehydrogenase Metabolizes both methanol and ethanol – Monoamine oxidase (MAO) Inactivates monoamines – Dopamine, norepinephrine, epinephrine do redox still  Cytochrome P450 Heme-containing membrane proteins that localize to the endoplasmic reticulum Closely associated with NADPH-cytochrome P450 reductase Reductase donates electrons to Redox reaction  Cytochrome P450 Classification is based on sequence Families homology – CYP1, CYP2, CYP3, CYP4 – >40% homology – family – Each family is subdivided by letter (>55% homology) Important CYP Enzymes CYP3A4 III – Responsible for metabolism of >50% of all therapeutic drugs metabolized by the liver CYP2D6, 2C, 1A2, 2E1  Induction and Inhibition Induction: Transcriptional Inhibition – physical activation of gene interaction with the enzyme expressing an enzyme (often at the heme) Increased amount of the resulting in decreased enzyme enzyme activity – Induction is CYP specific Suicide inhibitor – a Accelerated drug substrate which irreversibly prodrughboa binds to the CYP enzyme metabolism – Changes to bioavailability – Require synthesis of new and efficacy enzyme to restore function w actvedug bioav no chiral effecton dug  g pro Induction and Inhibition Inducers Inhibitors Tobacco smoke, Charcoal grilling – 1A Competition Ethanol (chronic) – 2E1 Grapefruit juice – 3A4 Steroids – 3A4 Cimetidine and ketoconazole bind Fibrates – 4A tightly to heme and reduce metabolism of endogenous Barbiturates – Many substrates St. John’s wort – 3A4 Macrolide antibiotics are metabolized to reactive species, bind bold heme iron and render it catalytically in inactive throw  Biotransformation Phase II Parent drug or Drugs which have undergone Phase I biotransformation contain polar functional groups which allow for conjugation reactions to occur – Hydroxyl (-OH), amino (-NH2), carboxyl (-COOH) Conjugates are highly polar, often inactive, and are easily excreted Can run out ofreactant Biotransformation Phase II  Acetaminophen CYP2E1  Acetaminophen Toxicity Therapeutic: 10-25 μg/mL Toxic: >200 μg/mL  Acetaminophen Seves inplace of Toxicity – Intervention NAP QI N-acetyl cysteine (NAC) Dosage forms IV – 3 step in-patient (20 hours) Oral – 72 hours 4 times daily – Repeat if vomiting occurs – Rotten eggs smell  Biotransformation Factors which affect drug metabolism and elimination Genetics – Polymorphisms: 2D6, 2C19, 2C9, and Phase II (slow acetylators) Age and Sex hormones – Newborns lack Glucuronosyltransferase – Chloramphenicol à Gray baby syndrome – Androgenic hormone levels have been associated with differences in drug metabolism Diet and Environment – Grapefruit, BBQ, lead, supplements Drug Interactions – Induction, inhibition, competition Disease – Liver, cardiac, thyroid, kidney  Pharmacokinetics ADME Absorption: Process of a substance entering the blood circulation Distribution: Dispersion or dissemination of substances throughout the fluids and tissues of the body (to the site of action) Metabolism: Biotransformation, may change the substance to a more active form or inactive form Excretion: Removal from the body  Excretion Hydrophilic drugs and their metabolites are able to be cleared from the blood and eliminated from the body by Renal and Biliary excretion – Renal – major route – Biliary – minor route vMany orally dosed drugs are incompletely absorbed and will be eliminated in feces – Other: Respiration Breast milk  Excretion Kidney and Nephron 25% of total systemic blood flow  Excretion Renal Drugs may be: 1. Filtered at the glomerulus 2. Secreted by the proximal tubules 3. Reabsorbed from tubules back into the blood 4. Excreted in the urine Golan Fig. 3.9  Excretion Renal Reabsorption Urinary excretion of a drug may fall as the drug is reabsorbed in the proximal and distal tubules Reabsorption is limited primarily by pH trapping – Renal tubular fluid is acidic beyond the proximal tubule, which favors trapping of ionic form of weak bases – Modify urine pH to increase ionized form of the drug so it cannot be reabsorbed by the renal tubules (ionized drug is trapped in the lumen and excreted into the urine)  Excretion Biliary Route Transporters present in hepatocytes that secrete drugs from liver into bile – Bile duct enters small intestine 0 – Some drugs may be reabsorbed in small intestine Enterohepatic recycling – Drugs reenter blood stream from intestines and are carried to liver again  Excretion Other Routes Respiration – Volatile materials, regardless of administration Nitrous oxide Breast milk – Milk is more acidic than plasma – Basic compounds may concentrate in milk Ethanol and urea readily enter breast milk Sweat, saliva, and tears Rifampin  Elimination Kinetics Elimination is the sum of the pharmacokinetics which contribute to the removal of an administered drug – Often considered the sum of metabolism and excretion Constant Constant Amount Percentage  Why does all of this matter? Drug-drug interactions Clinical Pharmacokinetics – t½ = (0.693 x Vd)/Clearance – [Csteady state] = (Bioavailability x Dose)/(Dosing interval x clearance) – Doseloading = Vd x [Csteady state] – Dosemaintenance = Clearance x [Csteady state] – Clearance = (0.693 x Vd)/t½ – Vd = (t½ x Clearance)/0.693 – Vd = Dose/[Plasma] vDO NOT STRESS ABOUT CALCULATIONS NOW  A 58-year-old patient presents to the emergency department complaining of dizziness, nausea/vomiting, and palpitations. Physical examination reveals hypotension and tachycardia. Medical Case history reveals that the patient is prescribed a medication to treat Scenario hypertension. Labs reveal elevated BUN and serum creatinine. Based on the findings; what is the most likely explanation examination for the patient’s current condition? AKI excretion Blood of  A 27-year-old female presents to their primary care physician complaining of abdominal pain, nausea, and vomiting. The patient’s vitals are within normal limits and the patient denies any other symptoms. Medical history reveals that the patient is prescribed Case oral contraceptives. During history taking, the patient discloses that Scenario they began taking St. John’s wort supplements after reading that they can improve mood and treat minor depression (patient has not been previously diagnosed). A urine dipstick for human chorionic gonadotropin (HCG) is positive. st.Johwswofisaninduf.net What is the best explanation for the patient’s urinalysis findings? abolisn OCP'sCFP3A