Module 1 - Pharmacokinetics Principles PDF

Module 1: Pharmacokinetic Principles  Copyright ©2024 by The Michener Institute of Education at UHN 222 St. Patrick Street Toronto, Ontario, Canada M5T 1V4 This material...

Module 1: Pharmacokinetic Principles  Copyright ©2024 by The Michener Institute of Education at UHN 222 St. Patrick Street Toronto, Ontario, Canada M5T 1V4 This material has been prepared and developed by The Michener Institute of Education at UHN. Reproduction of any part of this material, written, audio, visual or electronic, in any form, without the written consent of The Michener Institute is forbidden. Pharmacology  Pharmacokinetics Pharmacokinetics: The study of how the body absorbs, distributes, metabolizes and excretes drugs I.e. What the body does to the drug Watch: https://www.youtube.com/watch?v=1MnyBRNhutM  Pharmacokinetics Drug Administration Distribution: Excretion: Absorption: Metabolism: Drug leaves Elimination of a Movement of a Biotransformation of a bloodstream and drug or its drug into the drug to one or more goes into the metabolites from bloodstream metabolites (primarily in organs and the body (primarily the liver) tissues by the kidneys)  Drug Administration The route of administration (ROA) that is chosen for the delivery of a drug has a profound effect upon the speed and efficiency with which the drug acts The possible routes of drug entry into the body may be divided into two classes: 1. Enteral 2. Parenteral  Enteral Routes Enteral Routes: Drug placed directly in the GI tract Oral Rectal  Enteral Routes: Oral Some drugs are swallowed and absorbed from the GI tract Advantages Disadvantages 1. Convenient in that drug can be 1. Destruction of drugs by gastric easily/painlessly self- acid and digestive juices administered 2. Irritation to gastric mucosa may 2. Absorption may take place along cause nausea, vomiting, and/or the whole length of the GI tract GI damage 3. Cheap as compared to most 3. Variable and inefficient other parenteral routes absorption  Enteral Routes: Oral Some drugs are swallowed and absorbed from the GI tract Advantages Disadvantages (Cont’d) 1. Convenient in that drug can be 4. Effect too slow for emergencies easily/painlessly self- 5. Unpleasant taste of some drugs administered 6. Unable to use in unconscious 2. Absorption may take place along patient the whole length of the GI tract 7. First-pass effect through the liver 3. Cheap as compared to most other parenteral routes..and yet this is the most common ROA  Enteral Routes: Oral Variable factors influencing PO absorption: 1. Blood flow to absorption site Absorption from the intestine more efficient than from stomach 2. Total surface area available for absorption Absorption from intestine more efficient than from stomach 3. Contact time at absorption surface Conditions that move contents through GI tract very quickly such as presence of food or diarrhea decrease the efficiency of absorption  First-Pass Effect Hepatic metabolism of a pharmacological agent when it is absorbed from GI and delivered to liver via portal circulation Liver often inactivates drugs on their way from the GI tract to the body The greater the first-pass effect the less the agent will reach systemic circulation First-Pass Effect  Enteral Routes: Rectal Unconscious patients and children If patient is nauseous or vomiting Easy to terminate exposure Absorption may be variable Good for drugs affecting the bowel such as laxatives  Parenteral Routes Intravascular: (IV, IA) Placing a drug directly into the blood stream Intramuscular: (IM) Drug injected into skeletal muscle Intraosseous Drug injected into bone Subcutaneous: Absorption of drug from the subcutaneous tissues Inhalation: Absorption of drug through lungs Intra or transdermal Sublingual  Parenteral Routes: Sublingual Held in mouth or under tongue where they dissolve and absorbed by capillaries Administered for direct absorption component Otherwise would be simply administered PO Advantages Disadvantages Rapid absorption Inconvenient Drug stability Small doses Avoid first-pass effect Unpleasant taste of some drugs  Parenteral Routes: Intravascular Absorption phase is bypassed therefore 100% bioavailability Precise, accurate, and almost immediate onset of action Large quantities can be given fairly pain free Greater risk of adverse effects high concentration attained rapidly risk of infection, vessel damage, embolism Watch: little room for error http://www.youtube.com/watch?v=4G6Rem38aks&feature=player_embedded  Parenteral Routes: Intramuscular Very rapid absorption of drugs in aqueous solution Repository and slow-release preparations Pain at injection sites for certain drugs Watch: https://www.youtube.com/watch?v=6XiuWrgvhyY&ab_channel=GABAYMEDICALlibrary  Parenteral Routes: Subcutaneous Repository and slow-release preparations Slow and constant absorption Absorption is limited by blood flow, therefore affected if circulatory problems exist Concurrent administration of vasoconstrictor will slow absorption  Parenteral Routes: Inhalation Gas and volatile agents and aerosols Particles larger than 20 micron and the particle impact/precipitate in the mouth and throat Rapid onset of action due to rapid access to circulation as a result of: a) Large surface area b) Thin membranes separate alveoli and circulation c) High blood flow  Parenteral Routes: Topical Mucosal membranes: eye drops, nasal, etc. Topical administration a) Dermal – Applied to skin for local action b) Transdermal – Applied to skin for absorption through skin (systemic action): i. Stable blood levels ii. No first pass metabolism iii. Drug must be potent or patch becomes too large  Parenteral Routes: Intraosseous A process of injecting directly into the marrow of a bone to provide a non-collapsible entry point into the systemic venous system Used to provide fluids and drugs when IV access not available and is needed quickly  Route of Administration: Time Until Effect Intravenous: 30-60 seconds Subcutaneous: 15-30 minutes Intraosseous: 30-60 seconds Rectal: 5-30 minutes Inhalation: 2-3 minutes Ingestion: 30-90 minutes Sublingual: 3-5 minutes Transdermal: Variable Minutes to hours Intramuscular: 10-20 minutes  Route of Administration: Time-Release Preparations Oral controlled-release, oral timed-release, oral sustained-release Designed to produce slow, uniform absorption for 8 hours or longer Better compliance, maintain effect over night, eliminate extreme peaks and troughs  Route of Administration: Time-Release Preparations Depot or reservoir preparations: Parental administration (except IV) may be prolonged by using insoluble salts or suspensions in non-aqueous vehicles  Route of Administration The ROA is determined by: The physical characteristics of the drug The speed which the drug is absorbed and/or released The need to bypass hepatic metabolism and achieve high concentrations at particular sites No single method of drug administration is ideal for all drugs in all circumstances  Pharmacokinetics Drug Administration Distribution: Excretion: Absorption: Metabolism: Drug leaves Elimination of a Movement of a Biotransformation of a bloodstream and drug or its drug into the drug to one or more goes into the metabolites from bloodstream metabolites (primarily in organs and the body (primarily the liver) tissues by the kidneys)  Absorption Regardless of the ROA most drugs will need to cross a biologic membrane and/or plasma membrane to reach their site of action Factors which affect the crossing of drugs across these biologic and/or plasma membranes include; ionization state, molecular weight, and solubility (lipophilicity) Small, non-ionized, lipid-soluble drugs permeate across biologic and/or plasma membranes most readily Watch: https://www.youtube.com/watch?v=YlCulYOjKk0&ab_channel=CritIC  Drug Transport Across Membranes Passive Diffusion Facilitated Diffusion Aqueous Channels Active Transport  Passive Diffusion Requires no energy Requires no carrier Requires a concentration gradient across the membrane Most drugs reach their sites of action by this method Watch: https://www.youtube.com/watch?v=s0p1ztrbXPY&ab_channel=ppornelubio  Passive Diffusion Rapid for lipophilic, non-ionic, and small molecules (true for all transport types) Slow for hydrophilic, ionic, or large molecules (true for all transport types) Lipid soluble drugs simple move through the plasma membrane Watch: https://www.youtube.com/watch?v=s0p1ztrbXPY&ab_channel=ppornelubio  Facilitated Diffusion Requires no energy Requires a carrier Requires a concentration gradient across the membrane Drugs bind to a carrier to cross membrane Chemically similar drugs may compete for the carrier Watch: https://www.youtube.com/watch?v=38Ha7TIfWZI  Active Transport Requires energy Requires a carrier Drugs bind to a carrier to cross membrane Chemically similar drugs may compete for the carrier Identical to facilitated diffusion except that ATP powers drug transport against concentration gradient Watch: http://www.youtube.com/watch?v=STzOiRqzzL4  Influence of Size on Drug Absorption and Distribution Large molecules cannot easily pass through membranes and generally require active transport mechanisms Even with active transport mechanisms most high molecular peptides and proteins cannot pass membranes (cannot be given orally) Most drugs are weak acids or bases and will be ionized, charged, or polarized based on the pH of their surroundings  Influence of pH on Drug Absorption and Distribution Weak acids (HA) donate a proton (H+) to form anions (A-) Weak bases (B) accept a proton (H+) to form cations (HB+)  Influence of pH on Drug Absorption and Distribution Only the non-ionized form of a drug can readily cross cell membranes  Influence of pH on Drug Absorption and Distribution The unionized/uncharged/non-polar drug form is lipid soluble (lipophilic/hydrophobic) and crosses membranes easily I.e. Dissolve poorly in water/blood and other body fluids The ionized/charged/polar drug form is not lipid soluble (lipophobic/hydrophilic) and has difficulty crossing membranes I.e. Dissolve easily in water/blood and other body fluids  Influence of pH on Drug Absorption and Distribution The pKa is a measure of the strength of the interaction of a drug with a proton The lower the pKa of a drug, the stronger the acid The higher the pKa of a drug, the stronger the base  Influence of pH on Drug Absorption and Distribution The pKa of a weak acid or weak base is the pH at which there are equal amounts of the protonated form and the non-protonated form *Consider if a drug is acid or base based on pKa *Consider what happens to drug form with varying pH levels (in which direction does equation move with)  Influence of pH on Drug Absorption and Distribution Henderson-Hasselbach Equation: Used to quantify the ratio of protonated and non-protonated forms of a drug  Influence of pH on Drug Absorption and Distribution For a weak acid, when the pH is less than the pKa, the protonated (non-ionized) form predominates For a weak acid, when the pH is greater than the pKa, the unprotonated (ionized) form predominates  Influence of pH on Drug Absorption and Distribution For a weak acid if we decrease the pH (add H+) we will drive HA B the equilibrium to the; non- ionized, protonated, uncharged form and vice versa HB+ increases A- increases and and non- non-ionized HA ionized B decreases decreases  Influence of pH on Drug Absorption and Distribution For a weak base, when the pH is less than the pKa, the protonated (ionized) form predominates For a weak base, when the pH is greater than the pKa, the unprotonated (non-ionized) form predominates  Influence of pH on Drug Absorption and Distribution For a weak base if we HA B decrease the pH (add H+) we will drive the equilibrium to the; ionized, protonated, charged form and vice versa HB+ increases A- increases and and non-ionized non-ionized HA B decreases decreases  pH of Selected Body Fluids pH 1-3 Stomach pH 5-6 Small Intestine (Duodenum) pH 8 Small Intestine (Ileum) pH 8 Large Intestine pH 7.4 Plasma pH 7.3 Cerebrospinal Fluid pH 4-8 Urine  Influence of pH on Drug Absorption and Distribution pKa=4 Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 2nd Edition, Golan  Influence of pH on Drug Absorption and Distribution In the stomach (pH 1-3) weak acids are uncharged and will be absorbed into the bloodstream In the stomach (pH 1-3) weak bases are charged and will remain in the GI tract  Bioavailability The fraction of administered drug that gains access to the systemic circulation in a chemically unchanged form The amount of drug that is absorbed after administration by route X compared with the amount of drug that is absorbed after IV administration  Bioavailability AUC=area under curve  Bioavailability Factors that influence bioavailability: First-pass effect (Hepatic metabolism) Solubility of the drug Chemical instability Nature of the drug formulation  Bioequivalence When two drugs show comparable bioavailability and similar time to achieve peak blood concentrations these two drugs would be referred to as bioequivalent Two related drugs with a significant difference in bioavailability or in the time needed to achieve peak blood concentrations are said to be bioinequivalent  Therapeutic Equivalence If two drugs have comparable efficacy and safety they are said to be therapeutically equivalent  Drug Distribution After a drug enters the bloodstream it is distributed to different parts of the body and to different tissues Watch: https://www.youtube.com/watch?v=vDRPNrFtgmQ  Drug Distribution Factors influencing drug distribution: Lipid solubility (capillary permeability) Organ blood flow Plasma protein binding Depot storage Molecular size  Drug Distribution: Lipid Solubility Lipid solubility is a major factor affecting the extent of drug distribution In order for a drug to reach an organ it must permeate all membranes that separate the organ from the site of drug administration Polar/ionized molecules have a difficult time crossing membranes  Drug Distribution: Lipid solubility Some areas have specialized barriers and membranes which give them unique selectivity to drug passage (liver, blood brain barrier, blood placenta barrier) Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 2nd Edition, Golan  Drug Distribution: Organ Blood Flow The rate at which drug is distributed to an organ is dependent on the proportion of cardiac output received by that organ Drug Distribution: Organ Blood Flow  Drug Distribution: Organ Blood Flow Brain, heart, liver, and kidneys are highly perfused tissues and this enables a rapid onset of action of action of drugs affecting these tissues Skeletal muscle has moderate perfusion Skin, bone, and adipose tissues have the lowest perfusion  Drug Distribution: Plasma Protein Binding Almost all drugs are reversible bound to plasma proteins (primarily albumin) Protein binding ranges from