Pharmacodynamics Lecture Notes PDF

PHARMACODYNAMICS   Review the presentation Pharmacodynamics located on Brightspace.  Read Chapter 1 (pp 1-14), Chapter 5 (pp 81-87) and Chapter 7 (pp 110-122). You should be able to answer the following chapter questions:...

PHARMACODYNAMICS   Review the presentation Pharmacodynamics located on Brightspace.  Read Chapter 1 (pp 1-14), Chapter 5 (pp 81-87) and Chapter 7 (pp 110-122). You should be able to answer the following chapter questions:  Chapter 1: 1, 2, 3, 4, 5, 7, 8, 10, 11, 12, 15 REQUIREMENT  Chapter 5: 1, 2, 4, 9, 10, 12, 13, 14, 15 S  Chapter 7: 1, 5, 6, 7, 8, 9, 10, 11, 15  Watch the following Khan Academy videos:  Membrane Receptors (7:59)  Ligand Gated Ion Channels (7:23)  G Protein Coupled Receptors (12:48)  Enzyme Linked Receptors (8:50)   Define the pharmacologic terms highlighted in maroon throughout this presentation.  Explain, and give examples of, the four major receptor families.  Explain drug binding and its physiologic effects.  List and explain the types of drug therapy.  Discuss the factors to be considered when OBJECTIVES administering a drug.  Explain the various ways drug administration is monitored.  Define and identify the different types of adverse drug reaction.  List factors that affect the likelihood of developing an adverse drug reaction. PHARMACODYNAMICS - DEFINITIONS  Pharmacodynamics: The actions of a drug on the body.1 Most drugs exert their actions by binding to a receptor present on or in a cell.  Receptor: Specialized macromolecule present on or in a cell. Cells have many different types of receptors, each of which is specific for a particular agonist and produces a unique response.1  Drug-receptor complex: Binding of a drug to a receptor initiates alterations in biochemical and/or molecular activity of a cell by a process called signal transduction.  Agonist: Binding to a receptor site activates the receptor and initiates an intra-cellular process  Second-messenger: Molecules that act as signal relayers between the drug-receptor complex and the target intra-cellular mechanism. 4 MAJOR RECEPTOR FAMILIES LIGAND-GATED ION CHANNELS Drug receptor site on extracellular side of  Drug binds to receptor that causes a transmembrane change in channel protein shape thus ligand-gated ion opening the channel to ion flow. channel  Ions are able to flow uni-directional or Channel closes Drug binds to bi-directional depending on the channel receptor site type. after several causing channel to milliseconds  Net ion flow causes a local change in open membrane polarization. This may result in depolarization or hyperpolarization.  Similar binding sites can be found on voltage-gated ion channels.  Neurotransmission and muscle Membrane Ions flow through contraction are examples of ligand or polarization the channel changes voltage-gated ion channels at work. TRANSMEMBRANE G PROTEIN-COUPLED RECEPTORS Receptor binding site Drug binds to receptor Activation of Gs Effects last seconds to located on the site causing receptor protein uncouples G minutes. Unbinding of extracellular side of protein shape change. protein subunits the drug causes the cell membrane Intracellular portion of making them available receptor to return to adjacent to Gs receptor now interacts to interact with its inactive shape and transmembrane with adjacent Gs intracellular enzymes the G protein to return protein protein or transmembrane ion to its membrane- channels. These bound form. This step “effector molecules” requires energy to may provoke an effect complete. by themselves or may Adrenaline is an activate second example of a drug that messenger molecules. acts via G protein receptor ENZYME-LINKED RECEPTORS Phosphorylation Response lasts Binding of drug acts as a from minutes to to receptor Drug binding “molecular hours. causes site on switch” turning Unbinding of intracellular extracellular on target drug to receptor portion of side of proteins. This stops the receptor to transmembrane has a cascade- phosphorylation phosphorylate receptor like effect on process. itself and other target protein specific proteins E.g. Insulin activation. INTRA-CELLULAR RECEPTOR Lipid soluble drug diffuses through the cell membrane into the cell Receptor with drug-binding site is in the cytoplasm. Drug binds to intracellular receptor creating a drug-receptor complex. Drug-receptor complex enters the nucleus and affects gene transcription (activates or inactivates). The drug-receptor complex may also target structural proteins, enzymes, RNA, and ribosomes. Unbinding of the drug from the receptor halts gene transcription and other activities. The effects of intracellular–acting drugs takes hours to days to occur. Steroids are an example of drugs that act via intra-cellular receptors. DRUG BINDING  For a drug to elicit a physiologic response, it must bind to a receptor. Tissues and organs have many different types of receptors. The type of receptors on a particular cell is dependent on the intended function of the cell. Drugs are not able to elicit a cellular response if that cell does not have the correct receptors.  Dose-response relationship: The magnitude of the drug effect depends on receptor sensitivity to the drug and the drug concentration at the receptor site, which, in turn, is determined by both the dose of drug administered and by the drug’s pharmacokinetic profile, such as rate of absorption, distribution, metabolism, and elimination.  Potency: a measure of the amount of drug necessary to produce an effect.  Efficacy: the magnitude of response a drug causes when it interacts with a receptor. NEARPOD QUESTION 1 NEARPOD QUESTION 1 Morphine and fentanyl are potent narcotic analgesics. A dose of 5 mg of morphine IV is expected to decrease a patient’s pain by about 2-3 points. A dose of 50 mcg of fentanyl IV is expected to decrease a patient’s pain by about 2-3 points. Based on this information, we can determine that morphine is MORE/LESS/EQUALLY effective as fentanyl, while fentanyl is MORE/LESS/EQUALLY potent than morphine. PHYSIOLOGIC RESPONSE TO DRUG BINDING  Agonist: A drug that binds to a receptor and causes the same action as the substance that normally binds to the receptor.  Full agonist: A drug that has high efficacy, producing a full response while occupying a relatively low proportion of receptors.  Partial agonist: A drug that binds to and activates a receptor but is not able to elicit the maximum possible response that is produced by full agonists.  Antagonist: A drug that binds to a receptor with high affinity but elicits no biological response.  Competitive antagonist: A drug that reversibly binds to the same site on the receptor as the agonist but elicits no biological response.  Irreversible (non-competitive) antagonist: A drug that irreversibly binds to the same site on the receptor as the agonist but elicits no biological response. A fundamental difference between competitive and noncompetitive antagonists is that competitive antagonists reduce agonist potency and noncompetitive antagonists reduce agonist efficacy  Functional antagonist: A drug that may act at a completely separate receptor, initiating effects that are functionally opposite those of the agonist. NEARPOD QUESTION 2  MATCH THE CORRECT TERM NEARPOD QUESTION 2 FOR THE DRUG ACTION DESCRIBED. PHARMACOTHERAPEUTICS PHARMACOTHERAPEUTICS  Pharmacotherapeutics:  Empirical therapeutics: Treatment given on the basis of a provider’s experience and observations without clear knowledge of the cause or nature of the disorder being treated. 2  Rational therapeutics: The use of drugs, which are efficient, safe, low-cost and easy to administer. It requires that health practitioners have adequate medical knowledge and appropriate skill for correct diagnosis and treatment.1  Types of therapies: Supplemen Maintenan tal/ Prophylacti Acute Palliative Supportive Empiric ce replaceme c nt DRUG ADMINISTRATION  Indications for administration: The clinical condition(s) for which a medication or treatment has evidence, or a reasonable expectation, of improving.  Desired effect: The intended biological response to the drug.  Side effect: any effect caused by a drug other than the intended therapeutic effect, whether beneficial, neutral or harmful.1 Sometimes side effects become intended effects.  Adverse effect: An effect that is harmful or unexpected.3  Toxic effect: an adverse effect of a drug produced by an exaggeration of the effect that produces the therapeutic response.2  Dose: a specified amount of medication taken at one time. By contrast, the dosage is the prescribed administration of a specific amount, number, and frequency of doses over a specific period of time. 4  Contraindications: A factor indicating that the use of a particular drug will cause harm. Contraindications may be absolute, meaning the drug should never be given when these factors exist, or relative, meaning the drug should only be given under extreme circumstances when these factors exist.3  Special considerations: Particular patient populations, co-administrations, or co-existing conditions that require modifications to dosages. NEARPOD QUESTION 3 NEARPOD QUESTION 3  Tylenol is a commonly used over-the-counter medication. Indication Most people don’t give much consideration to its general Special Side effect consideration use.  How many of you read the Tylen entire drug monograph for ol your medications? Contraindicati Adverse effect on  Can you fill in the drug administration info for Toxic effect Tylenol? MONITORING RESPONSE TO TREATMENT Therapeuti Clinical Drug levels c index response Tolerance and Interaction Adverse dependenc s effects e   As the concentration of drug increases, the number of receptor binding sites occupied increases until saturation occurs. Saturation of available receptors corresponds to the maximal biological effect of a drug.  Many drugs can bind to more than one type of receptor, thereby causing both desired therapeutic effects and undesired adverse effects.  Therapeutic index: The ratio of the dose that produces toxicity in half the population (TD50) to the dose that produces a THERAPEUTIC clinically desired or effective response (ED50) in half the population. This is a measure of drug safety whereby the wider INDEX the therapeutic index, the safer the drug. DRUG LEVEL MONITORING Therapeutic Toxic level Peak level Trough level level Amount of Too much Determine Determine drug present drug is in the serum levels serum levels in the body body and it when the when the to exert the is harming drug is at its drug is at its desired the patient peak action lowest level effect of action without any Drugs toxic with aeffects narrow therapeutic window, variable response between individuals, impaired clearance, or drugs used on a protective basis are often monitored through blood tests. These tests may be performed to determine adequate therapy, toxicity, maximum effect, or least effect. CLINICAL RESPONSE  Age: The extremes of life have different responses to drug therapy due to baseline Age organ function, total body water content, and metabolic rate.  Diseases: Chronic diseases may alter organ function and can affect the rates of absorption, Social Diseases distribution, and elimination of a drug. factors Patient  Individual differences: Body size, weight, respon muscle mass, nutrition and hydration status, se and genetic factors all contribute to an individual’s response to a drug.  Psychological factors: A drug is more likely to have a positive response if the patient believes Psychologi Individual that the drug will work. cal factors differences  Social factors: Lifestyle, drugs, alcohol, and smoking can all affect a drug’s metabolism. TOLERANCE AND DEPENDENCE  Drug tolerance: A decreased response to a drug that occurs as the dose is repeated.  Cross tolerance: Exposure to one drug can cause tolerance to other similarly-acting drugs.  Functional tolerance: Reduction in the reactivity of sites of drug action.  Drug dependence: A psychological or physiological need for the drug. NEARPOD QUESTION 4  MATCH THE NEARPOD TERM TO THE QUESTION 4 CLINICAL EXAMPLE. DRUG INTERACTIONS AND ADVERSE EFFECTS DRUG INTERACTIONS AND ADVERSE EFFECTS  Drugs may interact with other drugs or food.  These interactions may potentiate a drug’s effects (make stronger) Idiosyncratic or antagonize a drug’s effects (make weaker).  Additive effects: The sum of the effects of both drug together is the same as the sum of each drug independently.  Synergistic effects: The sum of the effects of both drugs together is greater than each drug independently. Adver  Sometimes one drug will impact the side effects of a second drug. This is often the primary reason for co-administration. se  Many drugs affect laboratory testing results and need to be considered when interpreting labs. effect  Adverse effects include:  Idiosyncratic: A response characteristic only to the patients having Allergy s Hypersensiti vity that response  Hypersensitivity: The patient is unusually sensitive to the unpleasant side effects of the drug but is not allergic.  Allergic: The patient has an allergic reaction to the drug FACTORS AFFECTING THE DEVELOPMENT OF ADVERSE REACTIONS Environme Age Gender Ethnicity ntal Polypharma Comorbiditi Pregnancy cy es TYPES OF ADVERSE DRUG REACTIONS Type A (augmented) Exaggerated presentation of expected drug response. Occurs at standard dosing. Resolves with dose reduction or stopping the drug. Type B (bizarre) Unexpected drug reaction Occurs at standard dosing. Type C (continuing) Long-lasting exaggerated effect of an expected drug response. May continue long after dose has been decreased or drug stopped. Type D (delayed) Exaggerated effect of an expected response that occurs after an unusually long period of time after starting the drug. Type E (end-of-use) A reaction associated with a dose reduction or stopping the drug. NEARPOD QUESTION 5  MATCH THE NEARPOD TERM TO THE QUESTION 5 CLINICAL EXAMPLE. RECOGNIZING TYPE B ADVERSE REACTIONS Anaphylaxis An exaggerated, life-threatening systemic immune response to a foreign antigen. Onset is generally within minutes of exposure and worsens over time or with repeatand Rashes exposures. skin eruptions May be an allergic reaction or other hypersensitivity response. Can present as a rash, bruising, blister, discolouration, swelling, or burn. Serum sickness A hypersensitivity reaction to animal proteins. Symptoms include rash, fever, joint pain, kidney dysfunction, weakness, and/or swollen lymph nodes. OTHER DRUG RELATED EFFECTS The Canadian Adverse Events Study showed that adverse events due to medication errors and other Medication causes occur in 7.5% of hospital admissions and are associated with a 20% risk of death and longer duration of hospital stay. errors Errors include wrong patient, wrong dose, wrong therapy, missed contraindications, medication interactions, administration error Teratogen An agent that can disturb the development of the embryo or fetus. Teratogens halt the pregnancy or produce a congenital malformation (a birth defect). An agent that causes a change in the DNA or chromosomes of an individual, potentially leading to the Mutagen development of disease or dysfunction. Carcinogen An agent that can cause cancer in humans. QUESTIONS? [email protected]