Pharmacokinetics Lecture Notes PDF

PHARMACOKINETIC S   Review the presentation Pharmacokinetics on Brightspace.  Read Chapter 5 (pp 71-81) and Chapter 6 (pp 90- 105). You should be able to answer the following chapter questions:  Chapter 5:...

PHARMACOKINETIC S   Review the presentation Pharmacokinetics on Brightspace.  Read Chapter 5 (pp 71-81) and Chapter 6 (pp 90- 105). You should be able to answer the following chapter questions:  Chapter 5: 3, 5, 6, 7, 8, 9, 14, 15.  Chapter 6: 1, 2, 3, 4, 5, 7, 13, 14, 15. REQUIREMENT  Complete the Nearpod exercise Pharmacokinetics Practice Questions. You will find the link on S Brightspace under Week 2.  Optional: You may choose to watch the following Handwritten Tutorials videos on pharmacokinetics:  Pharmacokinetics 1 – Introduction (5:49)  Pharmacokinetics 2 – Absorption (6:35)  Pharmacokinetics 3 – Distribution (5:35)  Pharmacokinetics 4 – Metabolism (5:20)  Pharmacokinetics 5 – Excretion (7:04)   Define: pharmacokinetics, absorption, distribution, metabolism, elimination, enteral and all its forms, parenteral and all its forms, zero-order, first-order, half- life, total body clearance, loading dose, onset of effect, peak effect, therapeutic window, sub-therapeutic, desired response, adverse response.  Compare the routes of drug administration and how drugs may be administered.  Describe the various drug formulations.  Define and explain: OBJECTIVES  Absorption: the ways drugs enter systemic circulation, factors affecting absorption, bioavailability and its factors.  Distribution: factors affecting distribution, half-life  Metabolism: sites of metabolism, factors affecting metabolism, first-order and zero-order kinetics, Phase I and II of metabolism, the cytochrome oxidase system.  Elimination: sites of elimination, factors affecting elimination, forms of renal clearance  Drug dosing: forms of oral and IV administration, considerations for dosing and dosing intervals, therapeutic dosing goals and considerations. PHARMACOKINETICS Absorption Distribution Metabolism Elimination The process by The movement of The chemical The sum of the which a drug leaves a drug to and from alteration of processes of its site of the blood and a drug by the body. removing an administration and various tissues of The substances that administered drug fr travels to its site of the body and the result from om the body. action. relative proportions metabolism may be They may be Formulated to be of drug in the inactive, or they eliminated after given by various tissues. may be similar to, or being chemically routes: oral, buccal, Distribution is different from, the altered or they may sublingual, rectal, generally uneven original drug in be eliminated intact. parenteral, topical, because of therapeutic activity inhalational differences in blood or toxicity. perfusion, tissue binding, regional pH, and permeability of cell membranes. NEARPOD QUESTION 1 NEARPOD QUESTION 1 Mary has broken her ankle and would like some pain relief. What factors about Mary, her injury, and the drugs you have available are you considering when deciding on your course of action? ABSORPTION  FORMULATIONS  Liquids  Usually a solid medication (solute) dissolved in a liquid (solvent). The combination of solute and solvent is called a solution.  Liquid formulations: solutions, tinctures, suspensions, spirits, emulsions, elixirs, syrups.  Stored in syringes, ampules, or vials.  Solids  A dry form of medication  Solid formulations: powder, capsule, tablet  Suppositories  Medication is carried in a solid base compound that melts at body temperature allowing the drug to dissolve and be absorbed.  Inhalants  Powdered or liquid form of medication that is intended to be inhaled and absorbed across the lining of the lung.  May be administered by nebulizer, metered dose inhaler, turbo inhaler, aerosol generator, or vaporizer. ROUTES OF ADMINISTRATION DOSING Continuous infusion Most fluids and some medications are given continuously until the condition being treated has resolved. Continuous infusions are administered intravenously and are charted as dose per time or volume per time. For example, saline may be administered at 75 mL/h IV and norepinephrine may be administered at 0.1 mcg/kg/min IV. Intermittent Infusion Some fluids and medications are given at regular intervals over a defined time. These infusions may be intravenous, subcutaneous, intrathecal, nebulized, transdermal, or enteral. Intermittent infusions are charted as dose per specific time or volume per specific time. For example, tranexamic acid is administered 2 g IV over 10 minutes and salbutamol is administered 5 mg nebulized over 5-10 minutes. Slow Bolus Dose Some fluids and medications are given as a single dose but are administered over several minutes to limit side effects (“slow push”). Slow bolus doses may be administered via any route of administration. For example, calcium gluconate is administered 1 g IV over 2-3 minutes. Rapid Bolus Dose Some medications are administered as a single dose very rapidly (“rapid push”). Rapid bolus doses may be administered via any route. For example, epinephrine is administered 0.5 mcg IM. DRUG DOSING Oral dosing IV dosing  Multiple oral administrations  Multiple IV injections  Continuous infusion  Single administration  Loading dose THERAPEUTIC DOSING NEARPOD QUESTION 2 NEARPOD QUESTION 2 "Beer before liquor, never sicker". Using your understanding of therapeutic dosing, suggest a pharmacological explanation for the saying. Hint: beer has a lower alcohol concentration than other liquor. ENTERAL ROUTE  Drug is absorbed through oral mucosa, gastric mucosa, or intestinal mucosa.  Easily self-administered.  Complicated absorption route, highly affected by gastric pH.  Enteric-coated pills have a coating that protects the drug from gastric acid, delaying absorption until the drug reaches the small intestine.  Extended-release pills are specially formulated to allow a slow release with an extended duration of action. ENTERAL ROUTES OF ABSORPTION Passive diffusion Drug follows its concentration gradient across a membrane separating two body compartments Water-soluble drugs move through protein channels. Lipid- soluble drugs diffuse directly through the lipid membrane Facilitated diffusion Large drug molecules may enter the cell via transmembrane carrier proteins It does not require energy, can be saturated, and may be inhibited by compounds that compete for the carrier. Active transport Transmembrane carrier protein that uses energy to move drug molecules across the membrane, often against concentration gradients These carriers are selective and subject to competitive binding and, site saturation. Endocytosis Very large drugs may be engulfed by the cell membrane and transported into the cell by pinching off the drug-filled vesicle FACTORS INFLUENCING ABSORPTION  Non-ionized drug passes through membranes with greater ease than pH ionized forms.  Increased blood flow increases absorption rate. P-  A greater surface area for absorption glycoprot Blood flow ein increases the rate of absorption.  A longer contact time with absorptive surfaces increases absorption rate.  P-glycoprotein is a transport protein that Contact transports drugs out of cells. An increase Surface time area in P-glycoprotein decreases the absorption of a drug. BIOAVAILABILITY  Bioavailability: The rate and extent to which an administered drug reaches systemic circulation.1  Factors affecting bioavailability:  First-pass hepatic metabolism  Drug solubility  Drug chemical instability  Drug formulation  First-pass metabolism: Drugs absorbed through the GI tract enter portal circulation and undergo metabolism in the liver prior to systemic circulation.  Bioequivalence: Two drug formulations are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentrations.1 PARENTERAL ROUTE  Drug is administered by a route that does not involve the GI system.  More rapid onset of action with a more predictable distribution to tissues.  Requires special training to administer.  Other routes: While technically still parenteral, some references classify parenteral routes not requiring injection as “other”. This includes intranasal, inhalational, transdermal, vaginal, and topical routes of administration. DISTRIBUTION  DRUG DISTRIBUTION  Distribution: The process by which a drug reversibly leaves the bloodstream and enters the extracellular fluid and tissues.1  Half-life: An estimate of the time that it takes for the concentration or amount of drug in the body to be reduced by 50%.  Factors affecting distribution:  Blood flow  Capillary permeability  Drug binding to plasma proteins and tissue proteins  Degree of lipophilicity  Volume of distribution NEARPOD QUESTION 3  If 100 mg of a drug with a half-life of 60 NEARPOD minutes is taken, QUESTION 3 how much drug is remaining after 2 hours? FACTORS AFFECTING DRUG DISTRIBUTION Blood flow Cardiac output and local circulation affect drug distribution to organs and tissues Capillary Organs and tissues with high capillary permeability have a greater distribution of drug. permeabil ity Drug Reversible binding to plasma or tissue proteins sequesters drug in a non-active form. As free-drug levels drop, the bound drug binding to is freed and enters circulation. proteins Lipophilici Lipophilic drugs easily cross biological membranes making the drug freely available to target tissues. ty Volume of Once in the bloodstream, drugs have the potential to be sequestered in 3 main body compartments: large or protein- distributio bound drugs stay in the plasma; small but hydrophilic drugs n may leave plasma but stay in the extracellular fluid; small and lipophilic drugs easily leave plasma and are globally distributed. METABOLISM METABOLISM Improved  Metabolism: The drug is chemically altered by the renal body. The goal of metabolism is to make the drug clearanc e easier to excrete. The drug is usually rendered inactive through metabolism, but some metabolites have Drug biological activity of their own. Metabolism is Decrease inactivati d toxicity catalyzed by enzymes. on  Sites of metabolism: The primary site of metabolism is Results the liver. Drugs may also be metabolized by the of intestinal lining, lungs, blood vessel lining, and metaboli kidneys. sm Increase  Factors affecting metabolism: Increase d d toxicity therapeu  Individual genetics tic action  Co-morbidities (especially hepatic, renal, and cardiac Activatio diseases) n of pro- drugs  Co-ingestion and chronic ingestion KINETICS OF METABOLISM  First-order kinetics: The amount of drug is less than the availability of the enzyme, so the rate of metabolism is proportional to the amount of free drug.  Zero-order kinetics: The amount of drug exceeds enzyme availability, so the rate of metabolism is independent of the amount of free drug and is, instead, proportional to the rate of enzyme function. FIRST-ORDER KINETICS THE NUMBER OF BOATS INCREASES IN RESPONSE TO THE NUMBER OF PEOPLE THAT NEED SAVING. THE SAME PROPORTION OF PEOPLE CAN BE SAVED, REGARDLESS OF HOW MANY PEOPLE THERE ARE. ZERO-ORDER KINETICS  THERE IS ONLY ONE BOAT NO MATTER HOW MANY PEOPLE NEED SAVING.  THE BOAT CAN ONLY TRANSPORT A CERTAIN NUMBER OF PEOPLE, REGARDLESS OF HOW MANY PEOPLE NEED SAVING.  PHASES OF METABOLISM  The kidneys are not effective at excreting lipophilic drugs so lipophilic drugs must first be converted into a more hydrophilic (polar) form. These transformation reactions are referred to as Phase I and Phase II reactions.  Phase 1: Phase I reactions usually involve reduction, oxidation, or hydrolysis and may increase, decrease, or have no effect on pharmacologic activity. Phase I reactions are most often catalyzed by the cytochrome P450 (CYP) system. CYP is a superfamily of heme-containing isozymes located in most cells, but primarily in the liver and GI tract.1  Phase II: If the Phase I metabolite is still too lipophilic for excretion, it may be conjugated with a highly polar molecule in a Phase II reaction. NEARPOD QUESTION 4 NEARPOD QUESTION 4 The goal of metabolism is to make render True or false? a drug biologically inactive. NEARPOD QUESTION 5 MATCH THE TERM TO ITS DEFINITION ELIMINATION ELIMINATION  Elimination: The removal of a drug or drug metabolite from the body. Excretion occurs primarily via the kidneys.  Total body clearance: The sum of all clearances by drug-metabolizing and drug-eliminating organs.  Cltotal = CLhepatic + CLrenal + CLpulmonary + Clother Renal clearance Glomerular filtration Active diffusion Passive diffusion Free drug or drug metabolite is Free drug that is not filtered at the Drug concentration increases filtered by the glomerulus glomerulus may be secreted from relative to the peri-tubular space efferent capillaries into the tubules as it progresses from the proximal via two active transport systems, tubules to the distal tubules. one for anions and one for cations Uncharged drug molecules may passively diffuse back into systemic circulation FACTORS AFFECTING ELIMINATION Factors affecting drug Sites of drug elimination elimination Renal Rate of and drug hepatic metaboli blood sm flow Kidney function QUESTIONS ? lavergn@algonquincollege. com