Pharmacology Handout 2024 PDF

Pharmacology Dr. Ruth Hannon [email protected] Resources (MAC Library Access)  RxTx (CPS full Access)/Micromedex online Books: - Brunton, L., & Knollmann, B. (2022). Goodman & Gilman’s The pharmacological basis of therapeutics (14th ed.). McGraw-Hill Medical. - Katzung, B.G. & Vanderah, T.W. (Eds...

Pharmacology Dr. Ruth Hannon [email protected] Resources (MAC Library Access)  RxTx (CPS full Access)/Micromedex online Books: - Brunton, L., & Knollmann, B. (2022). Goodman & Gilman’s The pharmacological basis of therapeutics (14th ed.). McGraw-Hill Medical. - Katzung, B.G. & Vanderah, T.W. (Eds). (2024). Basic and clinical pharmacology (16th ed.). McGraw-Hill. - Wainman, B., McDonald, H., & Murray-Davis, B. (2019). Pharmacology revealed: An interactive ebook (3rd ed.). The e-Book Foundry @McMaster University. Labels! Terms Pharmacology – Science of drugs  Pharmacokinetics  Pharmacodynamics  Study of interactions of drugs and living tissues Pharmacotherapeutics  Study of movements of drugs in the body Study of clinical effects of drugs Toxicology Study of toxic substances Dose of formulated drug Administration Pharmacology I: Pharmaceutical phase Disintegration of dosage form Dissolution of drug Drug available for absorption II: Pharmacokinetic phase [ADME] Absorption, Distribution, Metabolism, Excretion Drug available for action III: Pharmacodynamic phase Pharmacotherapeutics Pharmacoeconomics Pharmacogenomics Adapted from McKenry, Tessier & Hogan (2006) Figure 3.1 Drug‐receptor interaction Effect Toxicology Pharmacovigilance Interactions of Drugs and Body Tissues #1 - Routes  Routes of administration Interactions of Drugs and Body Tissues #2 - Process  Process by which the drug travels to the site of action and is removed from site of action     Absorption – movement of a drug from its site of administration across body membranes and into circulating fluids Distribution – process by which drug reversibly leaves bloodstream and enters cells +/- ECF and rate Metabolism – chemical biotransformation of drugs usually to inactive form that is easily excreted Excretion – clearance/removal of the drug from the body Absorption Relative Absorption Rates Liquids, elixirs, syrups Rapid-dissolving tablets Suspensions Powders Capsules Tablets Coated tablets Sustained-release formulations McKenry, Tessier & Hogan (2006) Figure 3.2 Fastest Slowest Complicated process - First must dissolve - Drugs bound to particles (excipients) - To enter circulation must be absorbed - Influencing factors Remember the barriers! Solubility very important! - lipid based drugs vs - charged or ionized molecules Adams et al. (2021) Figure 3.1 Dissolving drugs in biological fluids  Biological fluids dissolve drugs that share the same physico-chemical characteristics –  “like dissolves like” Biological fluids consist mostly of water, which is a polar or ionized liquid H2O OH- + H+ Polar molecules are “charge” and have separate regions of positive and negative electronic densities Enteral vs Parenteral Administration  If a drug is highly water-soluble (i.e. polar or ionized) then the drug can be administered via the parenteral route   IV drug administration skips the process of absorption and a fast onset of action can be expected If a drug is poorly water-soluble (i.e. mostly non-polar or non-ionized) then the drug must be administered enterally  Orally administered drugs must be absorbed and a slower onset of action can be expected All drugs are weak acids or bases Part 1: Acids   An acid is a compound that ionizes in water to produce a proton Most acidic drugs used in pharmacology are weak acids –  As pure compounds they are solid materials and are uncharged (electronically neutral) When dissolved in water, these drugs dissociate into a negatively charged anion and a proton AH + H2O  A- + H+ + H2O AH is the neutral or non-polar form of the drug – the species that can be absorbed All drugs are weak acids or bases Part 1: Bases   A base is a compound that accepts cations (protons) in water Most basic drugs used in pharmacology are weak bases –  As pure compounds they are solid materials and are uncharged (electronically neutral) When dissolved in water, these drugs associate with a proton and become positively charged B + H2 O  BH+ + OH- B is the neutral or non-polar form of the drug – the species that can be absorbed In acidic environments, weakly acidic drugs remain in the non-polar form   In an acidic environment such as the stomach, the pH is very low (pH = 2) As such, the electrically neutral non-polar form of the drug is favoured AH + H2O  A- + H+ + H2O Weakly acidic drugs are absorbed in the stomach In basic environments, weakly acidic drugs become polar   In a basic environment such as the intestines, the pH is very high (pH = 8) As such, the electrically charged polar form of the drug is favoured AH + H2O  A- + H+ + H2O Weakly acidic drugs are poorly absorbed in the intestines Henderson-Hasselbalch Equation  The finding that weakly acidic drugs remain in their non-polar form in acidic environments can be summarized by the following equation [A-] pH = pKa + log [AH]   As the pH of a solution decreases, the concentration of the AH increases Increased absorption of the weakly acidic drug results Conversely: Basic drugs  In basic environments, weakly basic drugs remain in their non-polar form and these drugs are absorbed in the intestines B + H+  BH+ + OH- In acidic environments, weakly basic drugs become polar and these drugs are poorly absorbed in the stomach B + H+ BH+ + OH- Stomach vs Intestines Summary Weakly acidic drugs – – –  Exist in a non-polar, nonionized form in the stomach Exist in a polar, ionized form in the intestines Absorbed in the stomach Percentage  Weakly basic drugs – – – Exist in a polar, ionized form in the stomach Exist in a non-polar, nonionized form in the intestines Absorbed in the intestines 100 80 60 % AH Ionized 40 % B Ionized 20 0 0 2 4 6 pH 8 10 Distribution       Process by which a drug reversibly leaves the blood stream and enters body tissues Factors influencing this include blood flow, capillary permeability, plasma protein binding, drug structure Only drugs in free or ‘unbound’ state can be distributed Non-polar, fat-soluble drugs are easily distributed Volume of distribution is a theoretical volume into which a drug is distributed in the body (remember different fluid compartments!) Apparent Volume of Distribution (Vd) = the volume into which a drug is known to distribute with the body – – – Expressed in L or L/kg Every drug has its own unique Vd Importance Body Compartments Katzung & Vanderah (2024) Table 3.2 Vd verses Low Vd High Vd Wainman, McDonald & Murray-Davis (2019) Figures 14.1, 14.2, 143. & 14.4 t½  Half-life (t½ ) – – Time required for serum concentrations to decrease by one-half after absorption and distribution are complete Each drug has a measured t½ The Concept of Drug Half-Life Different Perspectives Drug Concentration (mg/L) Changing Values 100 50 25 12.5 6.25 3.125 Hours after peak concentration 0 8 16 24 32 40 Number of half-lives 0 1 2 3 4 5 Percentage of drug removed 0 50 75 88 94 97 Adapted from Lilley, Aucker & Albanese (1996) Table 3.3 Metabolism      Process by which drugs are biotransformed Major mechanism of drug elimination Drug converted to inactive, reactive intermediate, active Oxidation, reduction, hydrolysis, conjugation reactions Sites – –  Primary: liver Others: plasma, lung, kidney, intestinal mucosa, adrenals, skin, placenta Enzymes in the liver – – #1 – cytochrome P450 system (CYP) Major isoenzymes: – CYP3A4, CYP2D6, CYP2C9, CYP1A2, CYP2C19 – Genetic variation Cytochrome P-450 (FYI only!) Raffa, Rawls, Beyzarov & Netter (2013) Figure 1.30 Metabolism of Drugs Clinical Importance!! Adams et al. (2021) Figures 3.2, 3.6 Metabolism: First Order Kinetics     Lose a constant PERCENTAGE of what you have per unit of time Essentially based on concentrations Most drugs Not saturated Metabolism: Zero Order Kinetics   Lose a constant AMOUNT per unit time Saturated Mixed Order Kinetics    Dose dependent kinetics Smaller doses are handled by first order As the plasma concentration reaches higher values, rates of elimination becomes zero order (as metabolizing enzymes or elimination processes become saturated) – Examples: aspirin, phenytoin, digoxin, warfarin, ethanol, caffeine Excretion  Routes – – – – –  Kidneys – primary site, drugs must be ionized and polar (remember polarity of drugs can be manipulated by changing pH of urine) Lungs GI – fecal (more for highly fat-soluble metabolites) Breast milk Skin Clearance – measure of elimination per unit of time (i.e. L/hr) Clr = k x Vd k = elimination rate constant (k=0.693 / t ½) Vd = apparent volume of distribution of the drug Interactions of Drugs and Body Tissues #3 – Bioavailability  Bioavailability – fraction of administered drug that reaches the systemic circulation in a chemically unchanged and biologically active form AUCIV Cp AUCIM Cp Time AUCPO Cp Time Time Bioavailability  Therapeutic concentration range ([D]th) – – – Therapeutic response Adverse effects Little effects Adams et al. (2021) Figure 3.8 Dosing Intervals Adams et al. (2021) Figure 3.9 Dosing to Reach Steady State Loading dose Maintenance dose Wd = [D]o x Vd Wd = [D]pl x T x Clr McKenry, Tessier & Hogan (2006) Figure 3.14 Plateau Principle    The t ½ of a drug provides a useful measure called the Plateau Principle: 94% of the steady state will be reached after 4 half lives This means that after you start, stop, or change a dosage regimen, it will usually take 4 halflives for the concentration of the drug in plasma to be stable Exceptions? Multiple Dosing Brophy, Scarlett-Ferguson & Webber (2008) Figure 2.3b Avoid Prescribing Complicated Regimes Paauw, Pangilinan & Scudder (2018) Figure 9 Formulas – Online tutorial!     Loading dose Maintenance dose Clearance Wd = [D]o x Vd Wd = [D]pl x T x Clr Clr = k x Vd Dosing interval [D] log [D] = - (k/2.303) x T o Wd = weight of drug administered Vd = apparent volume of distribution [D] = bottom of therapeutic range [D]pl = middle of therapeutic range [D]o = top of therapeutic range T = dose interval Clr = clearance k = elimination constant (k = 0.693/t ½) Pharmacokinetics Summary Brunton & Knollmann (2022) Figure 2.1 Pharmacodynamics - How Drugs Produce Effects    Chemical alterations Drug-Enzyme interaction Drug-Receptor interactions Drug-Receptor Interactions     Receptor Affinity Agonist types Antagonist types     Threshold Plateau Potency Efficacy Drug or natural ligand Drug-receptor complex Drugs normally have to bind receptors before they have an effect. This drug would have its effect through a second messenger system but only after it bound to its receptor Marieb & Hoehn (2019) Focus Figure 3.3 Agonists Affinity Efficacy Raffa, Rawls, Beyzarov & Netter (2013) Figure 1.8 Concentration – Response Curve Agonist = Drug/natural substance that binds reversibly to receptor and produces effects by stimulating receptor Adams et al. (2018) Figure 4.3 Dose – Response Curve EC50 = Concentration that elicits half the maximal effect Wainman, McDonald & Murray-Davis (2019) Figure 2.1 Potency Adams et al. (2021) Figure 4.4a Efficacy Adams et al. (2021) Figure 4.4b Comparing Drugs Wainman, McDonald & Murray-Davis (2019) Figure 2.2 Percent of Maximum Biological Effect 100% 50% 0% Log of Drug Concentration Wainman, McDonald & Murray-Davis (2019) Figure 2.4 Antagonists Raffa, Rawls, Beyzarov & Netter (2013) Figure 1.9 Antagonists    They bind to similar receptors as the endogenous compound but do not produce the same effect as the endogenous compound Antagonists have no efficacy Types – Competitive (binds to the same receptor)  – This can be reversible or irreversible Noncompetitive (binds to a different receptor) Drug Interactions  Synergism – increase effect of the drug caused by the second drug – – –  Summation, additively Supraadditively Potentiation (2 + 2 = 4) (2 + 2 = 5) (2 + 0 = 3) Antagonism – a drug effect is decreased or eliminated by a second drug – – – Chemical Physiological Pharmacological – Competitive vs. noncompetitive Drug-Drug Interactions Altering Absorption Paauw, Pangilinan & Scudder (2018) Figure 7 Drug Effects  Desired: Therapeutic –  Expected, predictable, dose related Undesired: Side effects or adverse effects – Predictable – dose related – – – Toxic – too much Secondary or unwanted effects on other systems Unpredictable – – Idiosyncrasies – unusual individual reactions Allergic Overall Summary McKenry, Tessier & Hogan (2006) Figure 3.8 Pediatrics          Gastric pH less acidic, gastric emptying slower Topical absorption faster TBW much greater but fat content less Immature blood brain barrier First-pass elimination by liver reduced Microsomal enzymes decreased Protein binding decreased GFR decreased Increased metabolism Older Adults McKenry, Tessier & Hogan (2006) Figure 8.1 Terms    Therapeutic Index – rough indication of the relative safely of a drug Tolerance – a decreasing response to repetitive drug doses Dependence – a physiologic or psychological need for a drug Therapeutic Window LD50 = lethal dose in 50% of population Therapeutic Index = ED50/LD50 Wainman, McDonald & Murray-Davis (2019) Figure 3.6 & 3.7 Pharmacogenetics / genomics   Certain groups of medications only 30-60% chance of working Personalized drug therapy of the future – Drug response variability – – –   Environment Heredity Combination Single nucleotide polymorphisms (SNPs) Genetic profiling – – Oncology Codeine Medication Safety  Drug administration is a key nursing responsibility   One study showed that nurses intercepted 86% of all medication errors made by others Medication errors   How they occur Common types References – 1 Adams, M., Urban, C., Sutter, R.E., El-Hussein, M., & Osuji, J. (2021). Pharmacology for Nurses, Third Canadian Edition. Pearson Canada. Brophy, K., Scarlett-Ferguson, H. & Webber, K. (2008). Clinical drug therapy for Canadian practice (1st ed.). Lippincott Williams & Wilkins. Brunton, L. & Knollmann, B. (2022). Goodman & Gilman’s: The pharmacological basis of therapeutics (14th ed.) (Online). McGraw Hill. Greenstein, B. & Greenstein, A. (2007). Concise clinical pharmacology (Online). Pharmaceutical Press. Katzung, B.G. & Vanderah, T.W. (Eds) (2024). Basic and clinical pharmacology (16th ed.). McGraw-Hill. Koren, G., Cairns, J., Chitayat, D., Gaedigk, A., & Leeder, S.J. (2006. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeineprescribed mother. Lancet, 368(9536), 704. Lilley, l., Aucker, R. & Albanese, J. (1996). Pharmacology and the nursing process. Mosby. References – 2 Merel, S.E & Paauw, D.S. (2017). Common drug side effects and drug-drug interactions in elderly adults in primary care. Journal of the American Geriatrics Society, 65 (7), 1578-1585. McKenry, L., Tessier, E., & Hogan M. (2006) Mosby’s pharmacology in nursing (22nd ed.). Mosby, Inc. Marieb, E., & Hoehn, K. (2019). Human anatomy and physiology (11th ed.). Pearson Education Inc. Mycek, M., Harvey, R. & Champe, P. (2000). Pharmacology (2nd ed.). Lippincott Williams & Wilkins. Paauw, D., Pangilinan, J., & Scudder, L. (2018). Common prescribing blunders: Are you making any of these? Medscape [Online]. https://www.medscape.com/slideshow/common-prescribing-blunders-6010111 Raffa, R.B., Rawls, S.M., Beyzarov, E.P. & Netter, F. (2013). Netter’s illustrated pharmacology (2nd ed.). Saunders. Wainman, B., McDonald, H., & Murray-Davis, B. (2019). Pharmacology revealed: An interactive ebook (3rd ed). The e-Book Foundry @McMaster University.