Principles of Pharmacology I PDF - 2 Sep 2024

PHARMACOLOGY AND TOXICOLOGY PRINCIPLES OF PHARMACOLOGY I WO N G C H U N K E U N G 2 SEP 2024 1 PHARMACOLOGY Pharmacology - Scientific study of the effects of drugs and chemicals on living organisms Drug - Natural or synthetic chemical substance that affect a biolo...

PHARMACOLOGY AND TOXICOLOGY PRINCIPLES OF PHARMACOLOGY I WO N G C H U N K E U N G 2 SEP 2024 1 PHARMACOLOGY Pharmacology - Scientific study of the effects of drugs and chemicals on living organisms Drug - Natural or synthetic chemical substance that affect a biological system https://www.sharinginhealth.ca/sih/modules/pharmacology.html 2 IMPORTANCE OF PHARMACOLOGY Understand the biochemical and physiologic aspects of drug effects Determine the effectiveness and safety of drugs Help in the diagnosis, prevention and treatment of diseases. https://elifesciences.org/articles/70148 3 TOXICOLOGY Toxicology - The field of science that studies the harmful and adverse effects of chemicals, substances, physical agents or situations, that have on living organisms, and the environment https://www.slideserve.com/chance/toxicology 4 CONCEPT OF RECEPTORS IN PHARMACOLOGY Receptor is a macromolecule present in the membrane or inside the cell that specifically (chemically) bind a ligand (drug) Binding of a drug to receptor depends on the types of chemical establishing between drug and receptor 5 DRUG–RECEPTOR INTERACTIONS Concern with the ability of a drug to affect a given receptor Probability or strength of the drug to occupy a receptor at any given time - Drug's affinity Degree to which a drug or ligand activates the receptors and resulting in the cellular response - Intrinsic efficacy https://www.youtube.com/watch?v=X9TkD8DbomY 6 WHAT IS THE LIGAND Ligands can be anions, cations, or neutral molecules that bond to a central metal atom or ion It is a chemical messenger that binds to a protein, for producing a chemical signal Ligand can be organic or inorganic molecules Ligand can also be natural or synthetically made in the https://chem.libretexts.org/Bookshelves/Inorganic_Chemistry/Supplemental_Modul laboratory es_and_Websites_(Inorganic_Chemistry)/Coordination_Chemistry/Structure_and _Nomenclature_of_Coordination_Compounds/Ligands 7 RELATIONSHIP BETWEEN LIGAND AND PHARMACOLOGY Cellular receptors are proteins located on the surface of inside a cell for receiving the signal Molecules such as neurotransmitters, hormones and drugs binding to the receptor are ligands Such binding can be reversible or irreversible Receptor can be activated or inactivated by the ligand Such activation results either an increase or decrease in a certain cell function 8 LIGAND-GATED CHANNELS The neurotransmitter acetylcholine, the ligand, binds to the specific location on extracellular surface of the channel protein The pore opens for allowing select ions to go through The ions, in this case, are cations of sodium, calcium, and potassium 9 https://philschatz.com/anatomy-book/contents/m46526.html EFFECT OF A DRUG DEPENDS ON: Disease states: – Chronic kidney diseases affects dramatically the drug pharmacology – Pharmacokinetics studies how body does to the drug Number of Receptors: – Differentially expressing of receptors mediate biological responses of different levels Drug dosage: – Increase in drug amount increase drug effect until saturation of receptor Drug potency/affinity: – More potent drug – Faster binding to receptor and slower releasing from receptor Drug efficacy – Ability of drug to block or activate the receptor 10 DRUG–RECEPTOR INTERACTIONS Binding of the drug to the receptor Agonist drug – Close fits with the receptor site – Able to initiate a response Antagonist drug – Only partially fits the receptor site – Depresses or blocks the normal response for that receptor – Not produce a response https://wtcs.pressbooks.pub/pharmacology/chapter/1-2-pharmacokinetics/ 11 TWO AREAS OF PHARMACOLOGY Pharmacodynamics – effects of a particular drug on the body are studied Pharmacokinetics – effects of biological systems of our body on a drug are studied 12 WHAT IS PHARMACODYNAMICS? Pharmacodynamics (PD) is the branch of pharmacology concerned with the effects of drugs and the mechanism of their action 13 PHARMACODYNAMICS Mechanisms and Effects of Drug Action Drug-Receptor Interactions – Involves the binding of drugs to receptors – Not all drug-receptor interactions cause tissue response and activation – Agonists: binding causes the receptor generating a cellular reaction – Antagonists: binding without causing their activation https://www.jove.com/science-education/14379/drug-receptor-interactions https://open.lib.umn.edu/pharmacology/chapter/characteristics-of-drug-receptor-interactions/ 14 PHARMACODYNAMICS Mechanisms and Effects of Drug Action Drug-Receptor Interactions (Continue) – Effect of drug on the tissue determined by the drug’s affinity and efficacy – High-potency drugs: High affinity drugs – Agonists: High affinity and efficacy – Partial agonists: Intermediate efficacy and produce submaximal responses – Antagonists: Negligible efficacy https://www.jove.com/science-education/14379/drug-receptor-interactions https://open.lib.umn.edu/pharmacology/chapter/characteristics-of-drug-receptor-interactions/ 15 DOSE-RESPONSE RELATIONSHIP The most important concept in pharmacodynamics is the dose-response relationship which describes the dependence of the effect of a drug from its concentration at its receptor Pharmacodynamics describes the course of action of drugs leading to the physiological effect at a specific site in the body 16 PHARMACODYNAMICS Mechanisms and Effects of Drug Action Dose-Response Relationships Dose-response data graphically represented as: – X-axis: Dose or dose function (such as log10 dose) – Y-axis: Measured response (effect) – There is a peak of measured response showing the maximal efficacy – Represented as the Hypothetical Dose- Response Curve https://www.msdmanuals.com/professional/clinical-pharmacology/pharmacodynamics/dose-response-relationships 17  PHARMACODYNAMICS Mechanisms and Effects of Drug Action Dose-Response Relationships (Continue) – Hypothetical Dose-Response Curve (Continue) – Potency: Represented along the dose axis – Maximal efficacy or ceiling effect: Represented as the greatest measured response – Slope: Represented as the change in measured response per unit dose https://www.msdmanuals.com/professional/clinical-pharmacology/pharmacodynamics/dose-response-relationships 18 PHARMACODYNAMICS Mechanisms and Effects of Drug Action Dose-Response Relationships – Comparison of Dose-Response Curves for Drugs X,Y, and Z Drug X – Greater response per dosing and more potent than drug Y or Z Drugs X and Z – Equal efficacy as shown by their maximal attainable response (ceiling effect). Drug Y – More potent than drug Z, but with maximal efficacy lower https://www.msdmanuals.com/professional/clinical-pharmacology/pharmacodynamics/dose-response-relationships 19 WHAT IS PHARMACOKINETICS? Pharmacokinetics studies how the body interacts with administered substances, such as the drugs, for the entire duration of exposure Closely related to pharmacodynamics, which examines the drug's effect on the body 20 FOUR MAIN PHARMACOKINETIC PROCESSES Four main components of pharmacokinetics include: Absorption, distribution, metabolism and excretion (ADME) They are used for explaining the various characteristics of different drugs in the body The pharmacokinetic processes may be influenced by: – Patient factors such as the sex, age, genetics, and diseases – The properties of drugs such as protein binding, molecule size, and chemical characteristics 21 PHARMACOKINETICS AND PHARMACODYNAMICS  Pharmacokinetics – refers to the absorption, distribution, metabolism, and excretion of drugs  Pharmacodynamics – refers to the molecular, biochemical and physiological effects of drugs, including drug mechanism of action 22  DIFFERENCE BETWEEN PHARMACODYNAMICS AND PHARMACOKINETICS Pharmacokinetics - What the body does to the drug Pharmacodynamics - What the drug does to the body https://basicmedicalkey.com/introduction-to-pharmacology/ 23 PHARMACOKINETICS – AN OVERVIEW Pharmacokinetics means what the body does to a drug Doctors apply knowledge of drug pharmacokinetic for reviewing: –Route of administration of drug –Frequency, dose and duration of treatment https://www.osmosis.org/learn/Pharmacokinetics:_Drug_absorption_and_distribution Whalen, K. (2023). Lippincott Illustrated Reviews: Pharmacology (Lippincott Illustrated Reviews Series) (8th ed.). LWW. 24 PHARMACOKINETICS – AN OVERVIEW Four pharmacokinetic properties of drug action: Absorption: Absorption of drug from the site of administration into plasma Distribution: Drug reversibly leave the bloodstream distribute to intracellular and interstitial fluids Metabolism: Drug metabolized and biotransformed by the liver or other tissues Elimination: Elimination of drug and its https://i.ytimg.com/vi/gP4xO-i41Is/maxresdefault.jpg Whalen, K. (2023). Lippincott Illustrated Reviews: Pharmacology (Lippincott metabolites in urine, bile or faeces Illustrated Reviews Series) (8th ed.). LWW. 25 ROUTES OF DRUG ADMINISTRATION 1. Oral administration of medication 2. Sublingual or buccal route 3. Rectal route 4. Intravenous injection 5. Intramuscular injection 6. Subcutaneous injection 7. Intraarterial route 8. Transnasal drug route 9. Inhaled medication route https://www.pharmacyteach.com/2022/09/different-routes-of-drug- 10. Vaginal route administration.html https://www.ncbi.nlm.nih.gov/books/NBK568677/ 11. Transdermal route 12. Intraosseous route 26 ABSORPTION OF DRUGS It is the transfer of the drug from site of administration to the bloodstream Extent and rate of absorption depend on: – Route of drug administration – Chemical characteristics of the drug – Environment of drug absorption Routes of administration other than intravenous: – May result in partial absorption and https://www.nonstopneuron.com/post/factors-affecting-drug-absorption-route- specific-factors lower bioavailability of drug Whalen, K. (2023). Lippincott Illustrated Reviews: Pharmacology (Lippincott Illustrated Reviews Series) (8th ed.). LWW. 27 ABSORPTION OF DRUGS Bioavailability of drug – The extent and rate at which the active moiety of drug or metabolite entering into the systemic circulation for accessing the site of drug action Bioavailability of drug largely determined by: – Properties of the dosage form – Affected by the routes of drug administration https://www.nonstopneuron.com/post/factors-affecting-drug-absorption-route- specific-factors Whalen, K. (2023). Lippincott Illustrated Reviews: Pharmacology (Lippincott Illustrated Reviews Series) (8th ed.). LWW. 28 MECHANISMS OF ABSORPTION OF DRUGS FROM THE GASTROINTESTINAL (GI) TRACT Drugs absorbed from the Gastrointestinal (GI) Tract by: Passive diffusion Facilitated diffusion Active transport Endocytosis and exocytosis Whalen, K. (2023). Lippincott Illustrated Reviews: Pharmacology (Lippincott Illustrated Reviews Series) (8th ed.). LWW. 29 MECHANISMS OF ABSORPTION OF DRUGS FROM THE GASTROINTESTINAL (GI) TRACT Passive diffusion: Vast majority of drugs absorbed by this mechanism Driving force: Concentration gradient across a membrane separating two body compartments Moving of drug: From an area of high concentration to one of lower concentration Passive diffusion does not involve a carrier https://www.nonstopneuron.com/post/factors-affecting-drug-absorption-route- specific-factors Whalen, K. (2023). Lippincott Illustrated Reviews: Pharmacology (Lippincott Illustrated Reviews Series) (8th ed.). LWW. 30 MECHANISMS OF ABSORPTION OF DRUGS FROM THE GASTROINTESTINAL (GI) TRACT Facilitated diffusion Specialized transmembrane carrier proteins allowing passage of drugs into interior of cells Does not require energy It facilitates the passage of large molecules Can be inhibited by compounds competing for the carriers https://nayturr.com/types-of-diffusion/ Whalen, K. (2023). Lippincott Illustrated Reviews: Pharmacology (Lippincott Illustrated Reviews Series) (8th ed.). LWW. 31 MECHANISMS OF ABSORPTION OF DRUGS FROM THE GASTROINTESTINAL (GI) TRACT Active transport Involves specific carrier proteins of the membrane for drug entry Adenosine triphosphate (ATP) is required Involving energy dependent active transport of drugs against a concentration gradient From a region of low drug concentration to those of higher concentration The process can be competitively inhibited by other cotransported substances https://www.sciencefacts.net/wp-content/uploads/2020/03/Active-Transport.jpg Whalen, K. (2023). Lippincott Illustrated Reviews: Pharmacology (Lippincott Illustrated Reviews Series) (8th ed.). LWW. 32 MECHANISMS OF ABSORPTION OF DRUGS FROM THE GASTROINTESTINAL (GI) TRACT Endocytosis and exocytosis Transport drugs of exceptionally large size across the cell membrane Endocytosis – Drug engulfed by cell membrane, transported into the cell with pinching off of the drug-filled vesicle. Exocytosis – Substances secreted out of cell by vesicle formation (reverse of endocytosis) Certain neurotransmitters – Released by exocytosis Vitamin B12 – Transported across gut wall https://humanbiology.pressbooks.tru.ca/wp- through endocytosis content/uploads/sites/6/2019/06/Endocytosis-and-Exocytosis.png Whalen, K. (2023). Lippincott Illustrated Reviews: Pharmacology (Lippincott Illustrated Reviews Series) (8th ed.). LWW. 33 FACTORS INFLUENCING ABSORPTION Effect of pH on drug absorption Gastrointestinal pH – An important factor markedly affecting oral drug absorption – Have significant influence on drug dissolution, solubility, release, stability as well as intestinal permeability Different regions of Gastrointestinal tract – Different drug absorptive properties Whalen, K. (2023). Lippincott Illustrated Reviews: Pharmacology (Lippincott Illustrated Reviews Series) (8th ed.). LWW. 34 FACTORS INFLUENCING ABSORPTION Blood flow to the absorption site Comparing intestine and stomach – Intestines receive much more blood flow – Absorption from intestine is favored over stomach Total surface area available for absorption Comparing intestine and stomach – Intestinal surface rich in brush borders with microvilli – Intestinal surface area almost1000-fold that of stomach – Drug absorption across the intestine more efficient Whalen, K. (2023). Lippincott Illustrated Reviews: Pharmacology (Lippincott Illustrated Reviews Series) (8th ed.). LWW. 35 FACTORS INFLUENCING ABSORPTION Contact time at the absorption surface Drug moving through the Gl tract very quickly – For example: Diarrhea – Drug not well absorbed https://www.visiblebody.com/hubfs/Learn_Articles/Digestive_System/3B_Small_I ntestine_Villi.jpg Delays in drug transport Whalen, K. (2023). Lippincott Illustrated Reviews: Pharmacology (Lippincott Illustrated Reviews Series) (8th ed.). LWW. – Delays in rate of drug absorption 36 FACTORS INFLUENCING ABSORPTION Expression of P-glycoprotein: P-glycoprotein – Transmembrane transporter protein – Expressed in tissues such as intestines – Transport drugs from tissues to blood https://upload.wikimedia.org/wikipedia/commons/f/fe/MDR3_3g5u.png Whalen, K. (2023). Lippincott Illustrated Reviews: Pharmacology (Lippincott Illustrated Reviews Series) (8th ed.). LWW. – Pumps drugs out of cells If P-glycoprotein is highly expressed – Reduce in drug absorption 37  BIOAVAILABILITY It is the rate and extent that an administered drug reaches the systemic circulation Determining the bioavailability is important – Especially for calculating the drug dosages for the nonintravenous routes of administration Example: 100 mg of a given drug is administered orally by patient  60 mg is absorbed unchanged, What is the bioavailability? Whalen, K. (2023). Lippincott Illustrated Reviews: Pharmacology (Lippincott Illustrated Reviews Series) (8th ed.). LWW. 38  BIOAVAILABILITY Example: 100 mg of a given drug is administered orally by patient  60 mg is absorbed unchanged, What is the bioavailability? Answer: The bioavailability is 0.6 or 60% Whalen, K. (2023). Lippincott Illustrated Reviews: Pharmacology (Lippincott Illustrated Reviews Series) (8th ed.). LWW. 39 BIOAVAILABILITY Determination of bioavailability Determination of bioavailability By comparing plasma levels of a drug after a given route of administration (for example, oral administration) with levels achieved by the IV administration After IV administration: 100% of drug rapidly enters the circulation If drug is given orally: Only a proportion of the administered dose appears in the plasma Plot the plasma concentrations of the drug versus time, for both the IV and oral administration https://www.abdn.ac.uk/medical/elf/courses/view/144053/pharmacokinetics-v/1/page15 Measure the area under the curve (AUC) and Whalen, K. (2023). Lippincott Illustrated Reviews: Pharmacology (Lippincott Illustrated Reviews Series) (8th ed.). LWW. thus determinate the bioavailability (Refer to the diagram on right) 40 BIOAVAILABILITY Factors Influencing Bioavailability: First-pass hepatic metabolism Orally administered drugs usually undergo first-pass metabolism Drug absorbed from the Gl tract enters the portal circulation before enters the systemic circulation If the drug is rapidly metabolized in the liver or gut wall, amount of unchanged drug entering the systemic circulation shall be decreased First-pass metabolism by the intestine or liver shall limits the efficacy of many oral medications Should be of sufficient doses for ensuring enough active drug reaches the desired site Whalen, K. (2023). Lippincott Illustrated Reviews: Pharmacology (Lippincott Illustrated Reviews Series) (8th ed.). LWW. 41 BIOAVAILABILITY Factors Influencing Bioavailability: Chemical instability Some drugs are unstable in the pH of gastric contents: – For example: Penicillin G Some drugs are destroyed by degradative enzymes in the gastrointestinal tract – For example: Insulin Nature of the drug formulation https://i.ytimg.com/vi/lm_0g7bgW8k/maxresdefault.jpg Drug absorption may be altered by factors such as – Particle size, salt form, enteric coating, etc Whalen, K. (2023). Lippincott Illustrated Reviews: Pharmacology (Lippincott Illustrated Reviews Series) (8th ed.). LWW. 42  DRUG DISTRIBUTION Process by which a drug reversibly leaves the bloodstream and enters the extracellular fluid and tissues Distribution of a drug from the plasma to the interstitium depends on: – Blood flow – Capillary permeability – Binding of drugs to plasma proteins and tissues https://sp- uploads.s3.amazonaws.com/uploads/services/5979043/20221225234846_6 3a8e15e65b81_drug_distributionpage0.jpg – Lipophilicity – Volume of distribution Whalen, K. (2023). Lippincott Illustrated Reviews: Pharmacology (Lippincott Illustrated Reviews Series) (8th ed.). LWW. 43  DRUG DISTRIBUTION Blood flow Rate of blood flow to the tissue capillaries varies widely Blood flow to vessel-rich organs such as liver, kidney and brain is greater than that to the skeletal muscles Adipose tissue, skin, and viscera have still https://media.istockphoto.com/vectors/normal-blood-flow-in-the-vein- lower rates of blood flow blood-cells-circulate-inside-the-vein-vector- id1172667424?k=6&m=1172667424&s=170667a&w=0&h=S1L3pWjemxt0 rdVmLO42jmB01vnq8bGdf1GRRL9kwLg= Whalen, K. (2023). Lippincott Illustrated Reviews: Pharmacology (Lippincott Illustrated Reviews Series) (8th ed.). LWW. 44  DRUG DISTRIBUTION Capillary permeability Determined by capillary structure and by chemical nature of the drug Capillary structure varies in terms of fraction of the basement membrane exposed by slit junctions between endothelial cells Liver and spleen: Significant portion of basement membrane is exposed due to large, discontinuous capillaries. Large plasma proteins can pass Brain: Capillary structure is continuous with no slit junctions. Drugs must pass through endothelial cells of CNS capillaries or undergo active transport Whalen, K. (2023). Lippincott Illustrated Reviews: Pharmacology (Lippincott Illustrated Reviews Series) (8th ed.). LWW. https://image.slideserve.com/313389/capillary-permeability39-l.jpg 45  DRUG DISTRIBUTION Binding of drugs to plasma proteins and tissues Binding to plasma proteins Isolates drugs in a nondiffusible form and slows transfer out of the vascular compartment Albumin is the major drug-binding protein and acts as a drug reservoir As concentration of free drug decreases in plasma the bound drug dissociates from albumin Binding to tissue proteins May lead to higher concentrations in tissues than in https://image2.slideserve.com/3857866/plasma-protein-binding-l.jpg interstitial fluid and blood. Tissue reservoirs may serve as major source of the drug and prolong its actions or cause local drug toxicity Whalen, K. (2023). Lippincott Illustrated Reviews: Pharmacology (Lippincott Illustrated Reviews Series) (8th ed.). LWW. 46  DRUG DISTRIBUTION - LIPOPHILICITY Chemical nature of a drug influences its ability to cross cell membranes Lipophilic drugs Move readily across most biologic membranes Dissolve in the lipid membranes Penetrate the entire cell surface Hydrophilic drugs https://nativesciencereport.org/wp-content/uploads/2020/11/figure_1- 2048x1106.jpg Do not penetrate cell membranes readily Must pass through slit junctions Whalen, K. (2023). Lippincott Illustrated Reviews: Pharmacology (Lippincott Illustrated Reviews Series) (8th ed.). LWW. 47 DRUG DISTRIBUTION - VOLUME OF DISTRIBUTION The volume of distribution (Vd) is a pharmacokinetic parameter representing an individual drug's propensity to either remain in the plasma or redistribute to other tissue compartments Vd is a proportionality constant that relates the total amount of drug in the body to the plasma concentration of the drug at a given time The following equation can represent Vd: Volume of Distribution (L) = Amount of drug in the body (mg) / Plasma concentration of drug (mg/L) A drug with a high Vd has a propensity to leave the plasma and enter the extravascular compartments of the body, meaning that a higher dose of a drug is required to achieve a given plasma concentration A drug with a low Vd has a propensity to remain in the plasma meaning a lower dose of a drug is required to achieve a given plasma concentration 48 DRUG DISTRIBUTION - VOLUME OF DISTRIBUTION Features of Drugs affecting the Volume of Distribution Acid-Base Characteristics Drugs may have a propensity to bind proteins throughout the body Reach a point of equilibrium between a bound & unbound phase Basic (alkaline) molecules Strong interactions with negatively charged phospholipid head groups located on phospholipid membranes Will leave the systemic circulation leading to higher Vd as compared to acidic molecules Acidic molecules Higher affinity for albumin molecules at lower lipophilicity than neutral or basic molecules More likely to bind albumin and remain in the plasma Leading to lower Vd as compared to more basic molecules 49 DRUG DISTRIBUTION - VOLUME OF DISTRIBUTION Features of Drugs affecting the Volume of Distribution Lipophilicity Lipophilic molecules More likely to pass through lipid bilayers More likely to leave the bloodstream and distribute to areas with high lipid density such as adipose tissue Have a higher Vd Hydrophilic molecules Less likely to pass through lipid bilayers More likely to remain in the bloodstream Have a lower Vd 50 DRUG DISTRIBUTION - DRUG CLEARANCE BY THE KIDNEY A drug passes through several processes in the kidney before elimination; such as glomerular filtration, active tubular secretion, and passive tubular reabsorption Glomerular filtration Drugs enter the kidney through renal arteries, which divide to form a glomerular capillary plexus The glomerular filtration rate (GFR) is normally about 120 ml/min/1.73m2 GFR may diminish significantly in renal disease Variations in GFR and protein binding influence the passage of drugs 51 DRUG DISTRIBUTION - DRUG CLEARANCE BY THE KIDNEY Proximal tubular secretion Drugs not transferred into the glomerular filtrate leave the glomeruli through efferent arterioles It divide to form a capillary plexus surrounding the nephric lumen in the proximal tubule Secretion occurs in the proximal tubules by two energy-requiring active transport systems: – One for anions (for example, deprotonated forms of weak acids) – One for cations (for example, protonated forms of weak bases) 52 DRUG DISTRIBUTION - DRUG CLEARANCE BY THE KIDNEY Distal tubular reabsorption Drug moves toward the distal convoluted tubule Concentration of drug increases and exceeds that of the perivascular space Drug, if uncharged, may diffuse out of the nephric lumen, back into the systemic circulation 53 TUTORIAL Introduction to Pharmacology https://www.youtube.com/watch?v=r95HUvHa4VM Bioavailability and First Pass Metabolism https://www.youtube.com/watch?v=BQQns7RAUzA Introduction to Pharmacokinetics https://www.youtube.com/watch?v=E1a-MIbAGdU 54 PRINCIPLES OF PHARMACOLOGY I 55