CM 109 Integrated Basic Sciences II Pharmacology PDF

CM 109: INTEGRATED BASIC SCIENCES II (PHARMACOLOGY) BASIC PRINCIPLES OF PHARMACY DR. MICHELE BUELA | 23 AUGUST 2024 TABLE OF CONTENTS Excretion...

CM 109: INTEGRATED BASIC SCIENCES II (PHARMACOLOGY) BASIC PRINCIPLES OF PHARMACY DR. MICHELE BUELA | 23 AUGUST 2024 TABLE OF CONTENTS Excretion → The drug and its metabolites are eliminated from the body in urine, bile, or feces I. INTRODUCTION TO PHARMACOLOGY 1 C. PHARMACODYNAMICS A. PHARMACOLOGY 1 What the DRUG does to the body B. PHARMACOKINETICS 1 Action of the drug to the body C. PHARMACODYNAMICS 1 D. TYPES OF DRUG-RECEPTOR INTERACTIONS 1 II. DRUG ABSORPTION 2 A. TYPES OF DRUG ABSORPTION 2 PC B. FACTORS INFLUENCING ABSORPTION 3 does to body C. DRUG SOLUBILITY 3 drugs C. VOLUME OF DISTRIBUTION 3 - dose con2 III. BIOAVAILABILITY 3 A. FACTORS THAT INFLUENCE BIOAVAILABILITY 3 IV. DRUG ADMINISTRATION 4 A. ROUTES OF DRUG ADMINISTRATION 4 CE - B. BIOEQUIVALENCE VS. THERAPEUTIC EQUIVALENCE 4 -drug J lost V. DRUG CLEARANCE THROUGH METABOLISM 4 body A. CYTOCHROME P450 CYP ISOFORMS 4 - come. effect B. HALF-LIFE = HALF THE DRUG 5 Figure 2. The relationship between dose and effect Pharmacokinetic (dose-concentration) and pharmacodynamic V. DRUG DEVELOPMENT PROCESS 5 (concentration-effect). The three primary processes of pharmacokinetics are VI. FUTURE OF PHARMACOLOGY 5 input, distribution, and elimination IV. REFERENCES 5 Retrieved from Doc Buela’s PPT (2024). Starts with the administration of the drug up to the availability of the drug to the tissues I. INTRODUCTION TO PHARMACOLOGY Then, it will exhibit pharmacologic effect → either toxicity or A. PHARMACOLOGY effectiveness Study of substances that interact with living systems through D. TYPES OF DRUG-RECEPTOR INTERACTIONS chemical processes Drugs binds to regulatory molecules and either activates or inhibits Agonist and Antagonist normal body processes Medical Pharmacology Science of substances used to prevent, diagnose, and treat diseases Toxicology Deals with the undesirable effects of chemicals on living systems B. PHARMACOKINETICS Refers to what the BODY does to a drug 4 principles of ADME: Administration → Distribution → Metabolism → Excretion Figure 3. Agonist and Antagonist Retrieved from Doc Buela’s PPT (2024). Agonist drugs attach to the receptor → Attachment is like a lock and key mechanism which is highly specific → Bind and activate the receptor in some fashion which directly or indirectly brings about the effect Antagonist drugs bind to the same receptor, has the same shape as an agonist, turns off the mechanism so there would be no biological response → Act by binding to a receptor, compete with and prevent binding by other molecules Figure 1. Pharmacokinetics Retrieved from Doc Buela’s PPT (2024). Four pharmacokinetic properties determine the onset, intensity, and duration of drug action (Dto) - ADM Absorption → Absorption from the site of administration permits entry of the drug (either directly or indirectly) into plasma. Distribution → The drug may reversibly leave the bloodstream and distribute into the interstitial and intracellular fluids Metabolism → The drug may be biotransformed through metabolism by the liver or other tissues Figure 4. Drug-Receptor Interaction → It makes the drug more polar so that t would be excreted Retrieved from Katzung's Basic & Clinical Pharmacology, 16th Edition. Trans 1 SGD B1: Espeña, Llorando, Magsaysay, Mendoza, Mirandilla, R., Mirandilla, T., Pedarios, Peña, Ramos, Siao, Villanueva TH: Poche 1 of 7  Drugs that alter the agonist (A) response may activate the agonist A. TYPES OF DRUG ABSORPTION binding site, compete with the agonist (competitive inhibitors, B), or Passive Diffusion act at separate (allosteric) sites, increasing (C) or decreasing (D) the response to the agonist Driving force for passive diffusion of a drug include: Allosteric activators (C) may increase the efficacy of the agonist or → Concentration gradient across a membrane separating two body its binding affinity compartments → Movement of drug from an area of higher to lower PRECEPTOR NOTES concentration Allosteric activator Does not involve a carrier → Means different shape Not saturable → Enhances the clinical response when bound to a receptor Shows low structural specificity Allosteric Inhibitor Vast majority of drugs are absorbed by this mechanism → Decreases the action of agonists → Water-soluble drugs penetrate the cell membrane through → Taken into account when giving multiple drugs aqueous channels or pores → Lipid-soluble drugs readily move across most biologic membranes due to solubility in the membrane lipid bilayers In passive diffusion, molecules move from an area of higher concentration to an area of lower concentration directly through the cell membrane, without the need for energy or the involvement of carrier proteins. Because this process relies solely on the concentration gradient, it continues as long as there is a difference in concentration on either side of the membrane. Figure 5. Dose-response curves Reflects an increase in efficacy; an increase in affinity would result in a leftward shift of the curve Retrieved from Doc Buela’s PPT (2024). Figure 6. Passive Diffusion Agonist Retrieved from Doc Buela’s PPT (2024). → When administered with an allosteric activator, there will be Facilitated Diffusion higher biological response (green line in graph) Requires drug transporter → Action of agonist alone will produce normal response (black line Involves carrier proteins that facilitate the passage of large in graph) molecules → When given with a competitive inhibitor, there is slower → Carrier proteins undergo conformational changes, allowing the biological response (orange line in graph) passage of drugs or endogenous molecules into the interior of → When given with allosteric inhibitor, it produces decreased dose cells response (violet line in graph) Does not require energy II. DRUG ABSORPTION Saturable May be inhibited by compounds that compete for the carrier Unlike facilitated diffusion or active transport, which can become saturated when all available transport proteins are occupied, passive diffusion does not involve a finite number of carriers or channels and, therefore, cannot be saturated. Figure 6. Structure of Cell Membrane Figure 7. Facilitated Diffusion Retrieved from Doc Buela’s PPT (2024). Retrieved from Doc Buela’s PPT (2024). PRECEPTOR NOTES Active Transport Structure of cell membrane is composed of lipid bilayer and in Involves specific carrier proteins that span the membrane between are the integral proteins Energy dependent → Driven by the hydrolysis of adenosine triphosphate (ATP) Table 1. Types of Drugs Capable of moving drugs against a concentration gradient, from a Hydrophilic Drugs Hydrophobic Drugs region of low drug concentration to one of higher concentration Saturable Lipophobic Lipophilic Selective and may be competitively inhibited by other cotransported Aqueous diffusion Lipid diffusion substances Polar Non-polar Requires transporter or pores Can pass/cross thru barriers Usually don't cross the BBB Can cross the BBB Absorption → Transfer of a drug from the site of administration to the bloodstream → Rate and extent of absorption depends on the following: ▪ Environment where the drug is absorbed ▪ Chemical characteristics of the drug ▪ Route of administration (which influences bioavailability) → Routes of administration other than IV may result in partial Figure 8. Active Transport absorption and lower bioavailability Retrieved from Doc Buela’s PPT (2024). CM 109 B1: Espeña, Llorando, Magsaysay, Mendoza, Mirandilla, R., Mirandilla, T., Pedarios, Peña, Poche, Ramos, Siao, Villanueva 2 of 7  Endocytosis and Exocytosis Used to transport drugs of exceptionally large sizes across the cell REMEMBER: membrane BIPPS: Bases (are) lonized Polar Protonated Soluble Endocytosis PANNN: Protonated Acids (are) Nonionized Nonpolar Non-soluble → Involves engulfment of a drug by the cell membrane and transport C. VOLUME OF DISTRIBUTION into the cell by pinching off a drug-filled vesicle Volume of drug in the blood if concentration will remain constant and Exocytosis none of the drug will be bound to the tissues → Reverse of endocytosis → Used by many cells to transfer substances out of the cell through 𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑖𝑛 𝑡ℎ𝑒 𝑏𝑜𝑑𝑦 a similar process of vesicle formation Vd = 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑖𝑛 𝑡ℎ𝑒 𝑏𝑙𝑜𝑜𝑑 Example: 500 𝑚𝑔 Vd = 250 𝑚𝑔/𝐿 = 2L → You take in 500 mg of drug and the concentration in the blood is only 250 mg/L, so the volume of the drug is 2L Factors affecting distribution Blood flow Size of the organ Drug solubility Binding in the blood Binding in the blood: When a drug binds to proteins in the blood (like albumin), it remains in → Decreases the volume of distribution the bloodstream and is less likely to move into tissues. This decreases the volume of distribution (Vd) because the drug stays mainly in the blood and is not widely distributed throughout the body. Binding in the extravascular space Binding in the extravascular space: When a drug binds to components outside the blood, such as in tissues, it is more likely to move out of the bloodstream and into different parts of the body. This increases the volume of distribution (Vd) because the drug spreads more widely throughout the body, not just in the blood. → Increases the volume of distribution Figure 9. Endocytosis and Exocytosis Retrieved from Trans - Batch 2026. III. BIOAVAILABILITY Determined by comparing plasma levels of a drug after a particular route of administration Total AUC reflects the extent of absorption of the drug Figure 10. Mechanisms of Drug Permeation Retrieved from Doc Buela’s PPT (2024). A - Passive diffusion thru aqueous channel B - Diffusion thru lipid cell membranes C - Absorption with carrier proteins D - Endocytosis/Exocytosis B. FACTORS INFLUENCING ABSORPTION pH Most drugs are either weak acids or weak bases → A drug passes through membranes more readily if it is uncharged Relative concentration of charged and uncharged forms of a drug → Determines effective concentration of the permeable form of a drug at its absorption site The ratio between the two forms is determined by: → The pH at the site of absorption → The strength of the weak acid or base ▪ Represented by the ionization constant, pKa Blood Flow Absorption from the intestine is favored over the stomach Figure 11. Determination of the Bioavailability of a Drug; → Intestines receive much more blood flow than the stomach AUC = area under curve; IV = intravenous Retrieved from Doc Buela’s PPT (2024). Surface Area Absorption of the drug across the intestine is more efficient due to: PRECEPTOR NOTES → Surface rich in brush borders containing microvilli Fig.11 Compares Bioavailability IV drug and Oral medications → Surface area about 1000-fold that of the stomach IV direct in blood, the plasma conc high at start, then slowly Increased blood flow and surface area = increased absorption decreases as metabolized Contact time at the absorption surface Oral route starts at 0, then absorbed and excreted in the body Not all oral medication is absorbed due to the First-pass effect in Anything that delays the transport of the drug from the stomach to the liver the intestine delays the rate of absorption Presence of food in the stomach A. FACTORS THAT INFLUENCE BIOAVAILABILITY → Both dilutes the drug and slows gastric emptying → A drug taken with a meal is generally absorbed more slowly First-Pass Hepatic Metabolism Increase contact time, increase absorption A drug absorbed from the Gl tract enters the portal circulation before entering the systemic circulation Expression of P-glycoprotein → If the drug is rapidly metabolized in the liver or gut wall during this P-glycoprotein initial passage → A transmembrane transporter protein responsible for transporting ▪ Amount of unchanged drug entering the systemic circulation is various molecules across cell membranes decreased → Involved in transportation of drugs from tissue to blood First-pass metabolism by the intestine or liver limits the efficacy of ▪ "Pumps" drugs out of cells many oral medications → Reduces drug absorption → Associated with multidrug resistance Solubility of the Drug Very Hydrophilic drugs C. DRUG SOLUBILITY → Poorly absorbed pKa ▪ Because of the inability to cross lipid-rich cell membranes pH at which a drug is 50% protonated and 50% non-protonated Extremely Lipophilic drugs the smaller the value of pKa, the stronger the acid → Poorly absorbed Table 2. Drug Solubility ▪ Because they are insoluble in aqueous body fluids Largely Lipophilic, some solubility in aqueous solutions Weak Bases Weak Acids → Readily absorbed lonized Non-ionized Chemical Instability Penicillin G More polar when protonated Less polar when protonated → Unstable in the pH of gastric contents More soluble when Less soluble when Insulin protonated protonated → Destroyed in the Gl tract by degradative enzymes CM 109 B1: Espeña, Llorando, Magsaysay, Mendoza, Mirandilla, R., Mirandilla, T., Pedarios, Peña, Poche, Ramos, Siao, Villanueva 3 of 7  Nature of the Drug Formulation Particle size, salt form, crystal polymorphism, enteric coatings, and the presence of excipients → Can influence the ease of dissolution → alter rate of absorption IV. DRUG ADMINISTRATION A. ROUTES OF DRUG ADMINISTRATION Figure 13.“Schematic Representation of Subcutaneous and Intramuscular Injection” Retrieved from Trans - Batch 2026. NOTES: Route of Administration table, see appendix B. BIOEQUIVALENCE VS. THERAPEUTIC EQUIVALENCE Bioequivalence Two drug formulations are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentrations Figure 12. “Commonly Used Routes of Drug Administration” IV = intravenous; IM = intramuscular; SC = subcutaneous Therapeutic Equivalence Retrieved from Doc Buela's PPT (2024). Two drug formulations are therapeutically equivalent if they are Enteral pharmaceutically equivalent: By mouth → Same dosage form Oral → Same active ingredient → Enteric-coated preparations → Same route of administration → Extended-release preparations → Similar clinical and safety profiles Sublingual - place under the tongue Requires that drug products are bioequivalent and pharmaceutically Buccal - place inside the mouth between gums and cheek equivalent V. DRUG CLEARANCE THROUGH METABOLISM Parenteral Introduces drugs directly into the systemic circulation Clearance (CL) → Intravenous (IV) Estimates the volume of blood from which the drug is cleared per → Intramuscular (IM) unit of time → Subcutaneous (SC) Total CL → the composite estimate reflecting all mechanisms of drug → Intradermal (ID) elimination Others The Three Major Routes Of Elimination Oral Inhalation Hepatic Elimination Nasal Inhalation Biliary Elimination Otic - ears Urinary Elimination Intrathecal - directly to bones Topical - skin Transdermal Rectal Intra - vaginal Which drug administration route is fastest? Figure 14.“Biotransformation of Drugs” Table 3. Rate of Different Administration Route Retrieved from Trans - Batch 2026. Administration Route Rate Some drugs directly go to phase 2 Intravenous 30 - 60 seconds A. CYTOCHROME P450 CYP ISOFORMS Intraosseous 30 - 60 seconds Endotracheal 2 -3 minutes Inhalation 2 -3 minutes Sublingual 3 - 5 minutes Intramuscular 10 - 20 minutes Subcutaneous 15 - 30 minutes Rectal 5 - 30 minutes Ingestion 30 - 90 minutes Transdermal (topical) Variable (minutes to hours) Figure 15. “Relative contribution of cytochrome P450 (CYP) isoforms to drug biotransformation” Retrieved from Trans - Batch 2026. CM 109 B1: Espeña, Llorando, Magsaysay, Mendoza, Mirandilla, R., Mirandilla, T., Pedarios, Peña, Poche, Ramos, Siao, Villanueva 4 of 7  The phase I reactions most frequently involved in drug metabolism are catalyzed by the cytochrome P450 system (also called Microsomal Mixed-Function Oxidases) Secreted by liver B. HALF-LIFE = HALF THE DRUG The half-life of a drug is the time it takes for one-half of the drug to be eliminated by the body Knowing half life guide the clinician the amount of drug and timing of administration Factors that Affect a Drug's Half-Life: → Rate of Absorption → Metabolism → Excretion V. DRUG DEVELOPMENT PROCESS Drug Discovery → Identification of new drug targets or promising molecules through screening,chemical modification, or rational design Preclinical Testing → Safety and efficacy studies in cell cultures and animals to determine pharmacologic profile and toxicity Clinical Trials → Testing in humans through phase 1 (safety), phase 2 (efficacy), and phase 3 (large-scale) trials FDA Review → Submission of New Drug Application (NDA) with all preclinical and clinical data for FDA evaluation and approval Post-Marketing Surveillance → Ongoing monitoring of drug safety and efficacy aftermarket release (phase 4) Figure 16. The development and testing process required to bring a drug to market in the USA. Some of the requirements may be different for drugs used in life-threatening diseases Retrieved from Katzung's Basic & Clinical Pharmacology, 16th Edition. PRECEPTOR NOTES Requiring permits that's why it takes years Animal testing-toxicity and efficacy Passed animal testing a drug is considered as investigational drugs Investigational drugs undergoes clinical testing After phase 3, called new drugs and to be approved by FDA/NDA Patent expires= generics alternatives VI. FUTURE OF PHARMACOLOGY Pharmacogenomics → Tailoring drug treatment based on individuals genetic profile to improve efficacy and reduce side effects Nanotechnology → Developing drug delivery systems at nano scale for more precise targeting and control The use of AI in drugs discovery → Accelerate identification and development of new drug, Gene therapy → Modify/replace faulty genes to cure genetic disorders IV. REFERENCES Buela, M. (2024). Basic Principles of Pharmacy. [Video Lecture]. CM 109: Integrated Basic Sciences II (Pharmacology). BUCM. Intro to Pharmacology.mp4 Katzung, B. G. (2023). Basic and Clinical Pharmacology (16th ed.). McGraw-Hill Education. CM 109 B1: Espeña, Llorando, Magsaysay, Mendoza, Mirandilla, R., Mirandilla, T., Pedarios, Peña, Poche, Ramos, Siao, Villanueva 5 of 7  APPENDIX Table 4. The Absorption Pattern, Advantages and Disadvantages of the most common routes of administration (Lippincott, Pharmacology 2019) Route of Administration Absorption Pattern Advantages Disadvantages Examples Oral Variable; affected by many Safest and most common, Limited absorption of Acetaminophen tablets factors convenient, and economical some drugs Amoxicillin suspension route of administration Food may affect absorption Patient compliance is necessary Drugs may be metabolized before systemic absorption Sublingual Depends on the drug: Bypasses first-pass effect Limited to certain types of Nitroglycerin Few drugs (for example, Bypasses destruction by drugs Buprenorphine nitroglycerin) have rapid, stomach acid Limited to drugs that can direct systemic absorption Drug stability maintained be taken in small doses Most drugs erratically or because the PH of saliva May lose part of the drug incompletely absorbed relatively neutral dose if swallowed May cause immediate pharmacological effects Intravenous Absorption not required Can have immediate Unsuitable for oily Vancomycin effects substances Heparin Ideal if dosed in large Bolus injection may result volumes in adverse effects Suitable for irritating Most substances must be substances and complex slowly injected mixture Strict aseptic techniques Valuable in emergency needed situations Dosage titration permissible Ideal for high molecular weight proteins and peptide drugs Intramuscular Depends on drug Suitable if drug volume is Affects certain lab tests Haloperidol diluents: Aqueous moderate (creatine kinase) Depot medroxy- solution: prompt Depot Suitable for oily vehicles Can be painful progesterone preparations: slow and and certain irritating Can cause intramuscular sustained substances hemorrhage (precluded Preferable to intravenous during anticoagulation if patient must therapy) self-administer Subcutaneous Depends on drug Suitable for slow-release Pain or necrosis if drug is Epinephrine diluents: Aqueous drugs irritating Insulin solution: prompt Depot Ideal for some poorly Unsuitable for drugs Heparin preparations: slow and soluble suspension administered in large sustained volumes Inhalation Systemic absorption may Absorption is rapid; can Most addictive route (drug Albuterol occur; this is not always have immediate effects can enter the brain Fluticasone desirable Ideal for gases quickly) Effective for patients with Patient may have respiratory problems difficulty regulating dose Dose can be titrated Some patients may have Localized effect to target difficulty using inhalers lungs; lower doses used compared to that with oral or parenteral administration Fewer systemic side effects Topical Variable; affected by skin Suitable when local effect Some systemic Clotrimazole cream condition, area of skin, of drug is desired absorption can occur Hydrocortisone cream and other factors May be used for skin, Unsuitable for drugs with Timolol eye drops eye, intra- vaginal, and high molecular weight or intranasal products poor lipid solubility Minimizes systemic absorption Easy for patient Transdermal (Patch) Slow and sustained Bypasses the first-pass Some patients are allergic Nitroglycerin effect to patches, which can Nicotine Convenient and painless cause irritation Scopolamine Ideal for drugs that are Drug must be highly lipophilic and have poor lipophilic oral bioavailability May cause delayed Ideal for drugs that are delivery of drug to quickly eliminated from pharmacological site of the body action Limited to drugs that can be taken in small daily doses Rectal Erratic and variable Partially bypasses Drugs may irritate the Bisacodyl first-pass effect rectal mucosa Promethazine Not a well-accepted route CM 109 B1: Espeña, Llorando, Magsaysay, Mendoza, Mirandilla, R., Mirandilla, T., Pedarios, Peña, Poche, Ramos, Siao, Villanueva 6 of 7  Bypasses destruction by stomach acid Ideal if drug causes vomiting Ideal in patients who are vomiting or comatose CM 109 B1: Espeña, Llorando, Magsaysay, Mendoza, Mirandilla, R., Mirandilla, T., Pedarios, Peña, Poche, Ramos, Siao, Villanueva 7 of 7