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Transcript
Introduction to Pharmacology Pharmacology 2 Pharmacology • Pharmacology – the study of drugs and their interactions with living systems – The study of physical and chemical properties of drugs and their biochemical and physiologic effects – Knowledge of the history, sources, and uses of drugs 3 What Do We Need to Know About Drugs? 4 What Do We Need to Know About Drugs? • Pharmacokinetics • Pharmacodynamics 5 Pharmacokinetics 6 Pharmacokinetics • Pharmacokinetics - How a particular drug gets into the body and is distributed throughout the body • Determine how much of an administered dose gets to its sites of action • The impact of the body on drugs • Components of pharmacokinetics • • • • Absorption Distribution Metabolism Excretion 7 Pharmacodynamics 8 Pharmacodynamics • Pharmacodynamics: How a particular drug affects body processes • The impact of the drug on the body • Includes: • Therapeutic or desirable effects • Side or undesirable effects • Steps in pharmacodynamics • The initial step leading to a response is the binding of a drug to its receptor • The patient’s functional state has an influence • Ex. tolerance, placebo 9 What Do You Need to Know About How Drugs Interact with the Patient? 10 What Do You Need to Know About How Drugs Interact with the Patient? • Patient-specific factors • Alter the drug’s ability to produce its therapeutic effects • Increase the drug’s side effects • Might cause an idiosyncratic reaction, like a drug allergy, or other effect particular to that patient • How to evaluate a patient to identify patient-specific factors that will impinge on drug administration or activity – Ex. if the person is in a coma, you cannot give them a pill 11 Drug-Patient Interactions 12 Drug-Patient Interactions •Other drugs that the patient is taking •Sources of individual variation •Particular characteristics of the patient •Pregnancy •Age •Other characteristics that would affect that patient’s ability to respond to a drug 13 Drug-Patient Interactions Sources of Individual Variation 14 Drug-Patient Interactions Sources of Individual Variation • Physiologic variables – Age, gender, weight • Pathologic variables – Diminished kidney function, diminished liver function • Genetic variables – Alter the metabolism of the drug and can predispose the patient to unique drug reactions 15 Patient Evaluation 16 Patient Evaluation Health status, including cognitive function Life span and gender Lifestyle, diet and habits: • Use of over-the-counter (OTC) medications, herbals, dietary substances etc. • Substance abuse. • Health insurance/prescription drug coverage. • Support system: family, significant other, etc • Will affect their adherence to the drug regimen Environment: • Occupational or other exposure to toxic substances. • Setting in which the drug will be administered. Culture/Ethnicity: • Some cultures have a negative view of taking medication • Religious, social and ethnic background • Genetic traits. 17 Where Does Patient Information Come From? 18 Where Does Patient Information Come From? • Patient interview • Observation of the patient • History and physical examination • Performed by you or another individual • Medical record • Lab values • Family members, friends, etc. 19 The Nursing Process Introduction 20 The Nursing Process Introduction • Assessment • Diagnosis • Planning • Implementing • Evaluation 21 The Nursing Process Assessment 22 The Nursing Process Assessment • Includes patient factors and drug information • Involves collecting data about the patient that is used to identify actual and potential health problems • Establishes a database 23 The Nursing Process Diagnosis 24 The Nursing Process Diagnosis • Identify deficits in patient, known as the medical diagnosis • Include a statement of the health problem and of the problem’s probable cause or risk factors 25 The Nursing Process Planning 26 The Nursing Process Planning • Maximize therapeutic effects, minimize adverse effects • Include the patient/family in the planning 27 The Nursing Process Implementing 28 The Nursing Process Implementing • • The rights of drug administration – – – – – Right route Right patient Right drug Right dose Right time – – – – – Right assessment Right education Right to refuse Right documentation Right situation/reason Patient education must be a part of the intervention • So that the patient understands why they are taking the drug and why it is important 29 The Nursing Process Evaluation 30 The Nursing Process Evaluation • Is the patient taking the drug as prescribed? • Is the drug producing the effect it is supposed to? • Are the adverse effects acceptable? • Should the dose be increased or decreased, or a different drug substituted? • Does the patient need to continue this therapy? 31 Important Things to Know about Drugs 32 Important Things to Know about Drugs • How drugs are named and classified • How drugs are developed • The legal requirements for drug administration and dispensing 33 Naming and Classification of Drugs 34 Naming and Classification of Drugs • Every drug has at least three names • Chemical Name • Generic Name • Trade Name • This system is very confusing and could lead to the patient receiving the same drug more than once • Patient knows the drug by two different names and do not realize that it is the same drug 35 Chemical Name 36 Chemical Name • Not used by health care providers • Describes the chemical structure of the drug. • This is usually irrelevant to health care practitioners and patients because we want to know what the drug does, not its structure. • Drugs with different chemical structures can do the same thing. 37 Generic Name 38 Generic Name • Most important name • Constant, printed on the label or bottle, not capitalized • Assigned to the drug when it is first given to humans. • The drug is always known by this generic name. • The generic name printed on a bottle or in an advertisement might be in parentheses and is not capitalized. • Sometimes generic names are hard to say. • Only one per drug 39 Trade Name 40 Trade Name • This name is given to the drug by the drug company that markets it. • If more than one drug company markets a particular drug, it will have a different name for each company. • This name is capitalized. 41 Acetaminophen 42 Chemical Structure Chemical Name N-Acetyl-para-aminophenol Generic Name Acetaminophen Trade Name Acephen, Aceta, Anacin-3, Apacet, Arthritis Pain Formula Aspirin Free, Aspirin Free Pain Relief, Banesin, Bromo Seltzer, Dapa, Datril, Dolane, Dorcol Children’s Fever & Pain Reducer, Feverall, Genapap, Genebs, Halenol, Liquiprin Elixir, Meda Tab, Myapap, Neopap, Oraphen-PD, Panadol, Panex, Panex 500, Phenaphen Caplets, SnapletsFR Granules, St. Joseph Aspirin-Free for Children, Suppap-325, Tapanol Extra Strength, Tempra, Tylenol Lehne, RA, Pharmacology for Nursing Care, 6th ed., 2007, Elsevier, p. 19 43 In the drugstore, you see pill bottles with the following names: 1. 2. 3. 4. Advil (ibuprofen) 200 mg Ibuprofen, 200 mg Motrin (ibuprofen) 200 mg Nuprin (ibuprofen) 200 mg Which of the following is true? 1. 2. 3. 4. 1. 2. Advil (ibuprofen) 200 mg, Ibuprofen, 200 mg Motrin (ibuprofen) 200 mg Nuprin (ibuprofen) 200 mg. 25% 25% 25% 25% They all contain the same drug. People with muscle pain should only take Motrin. - Could take any of the medications is rin up N ot rin ... fo rh on ly ge ne e th is ith w le op Pe ric p. .. cl e m us ta in on al lc - Can be used for any type of pain ey Nuprin is only for headaches. Th 4. th e. .. - Motrin is the trade name ... Motrin is the generic name M 3. Generic vs. Trade Names 46 Generic vs. Trade Names • Generic names are international and avoid confusion. • In clinical practice, trade names might be used but you should always try to look at the generic name too. • That way, you may avoid giving the same drug twice. • In this course, we will try to stick to generic names, although trade names may creep in. 47 Methods of Classifying Drugs 48 Methods of Classifying Drugs • According to their use (antihypertensives, for instance): • This may be confusing because many drugs have more than one use. • However, this is a classification system used by many people • One of the most common ways to classify drugs • According to their mechanism of action: • This is the most useful classification since it explains all the actions of the drug • According to their chemical structure: • This is of limited usefulness for health care providers 49 Advantages of Classifying According to Mechanism of Action: Example of Calcium Channel Blockers 50 Advantages of Classifying According to Mechanism of Action: Example of Calcium Channel Blockers • Calcium channel blockers block calcium channels in smooth and cardiac muscles •When they block calcium channels in vascular smooth muscle, they dilate vessels and reduce blood pressure. •When they block calcium channels in the heart, they slow conduction and so are used for cardiac arrhythmias. • If we classified them based on their use, we would have to learn about them at least twice. •But if we classify them by their mechanism of action, we can learn about them once and then apply that knowledge to different uses. 51 Classifying by Mechanism of Action 52 Classifying by Mechanism of Action • Classification by mechanism enables us to know what a new drug will do – Can put it into a class whose mechanism of action we know • Allows us to organize drugs in our head and understand what they do • Example - if a new calcium channel blocker were introduced, you would know what it could be used for and what its side effects might be because you already knew about other drugs with that same mechanism of action 53 Classifying Drugs in the Pathopharmacology Course 54 Classifying Drugs in the Pathopharmacology Course • We will use a “blend” of classification by use and classification by mechanisms in this course • The first time we encounter a particular drug, we will explain its mechanism of action along with its use in relation to the body system we are talking about • If we encounter the same drug later, we will refer you back to its mechanism and explain how that drug works in the new body system • Please read Lehne, p. 21: “What if peas were marketed like drugs?” 55 Sources of Drug Information Changes in Drugs 56 Sources of Drug Information Changes in Drugs • Drug information changes almost daily • New drugs are constantly being introduced • New dosage forms or routes of administration may be approved for older drugs • New adverse events may be uncovered and new warnings may be issued • Drugs may be taken off the market 57 Sources of Drug Information 58 Sources of Drug Information 1. Pharmacology book (Lehne) - Goes into detail about the use and actions of the drug 2. Physicians’ Desk Reference (PDR) for prescription drugs and for OTC drugs - Compendium of the prescribing information for each drug - Written by lawyers who write it defensively - All of the side effects of the drug are stated - Includes only what the FDA has approved the drug company to say about the drug 3. Formularies - In hospitals - Includes drugs used in the agency - Lists of drugs that are approved for use in the hospital and agency and include standards for how they are to be used 4. Drug compendiums - Quick and dirty reference - Includes the dose, type of pills, strength 5. Web sites - There are good and bad websites - Example of a good website – NIH, CDC, FDA - Example of a poor website – blogs 6. Drug companies - Cannot tell you anything that has not been approved by their lawyers 7. People, such as health care personnel 59 How Drugs are Developed 60 How Drugs are Developed • In order to be marketed, a drug must be approved by the Food and Drug Administration. • Vitamins and other dietary supplements are not drugs; they are foods • They are approved in the same way as drugs • The drug company must show evidence of efficacy. • Must show that the drug works in order to help a particular condition • The development process can only be conducted with respect to one particular condition or disease (indication) • The drug company must have an indication – a disease or condition that the drug is supposed to make better. • A particular drug might be good for more than one thing, but the drug company has to choose for which use they want to seek approval. • If the drug is ultimately approved, the approval will be for that indication only. • Later, the FDA may approve the drug to treat a different indication after conducting a second set of trials 61 Stages of Drug Development 62 Stages of Drug Development - Preclinical testing - - Performed in animals Drugs are tested for toxicity May take one-five years If successful, the drug is awarded new drug status and begins clinical testing Clinical testing - Performed in humans - May take two-ten years - Phase one - Conducted in healthy volunteers - Evaluate drug metabolism, pharmacokinetics, pharmacodynamics - Aim to determine the maximum tolerated dose - Phases two and three - Tested in 500-5,000 patients - Goal is to determine therapeutic effects, dosage range, safety, and effectiveness - At the end, the drug company applies for conditional approval and begins phase four - Phase four: postmarketing surveillance - New drug is released for general use - Observe the effects of the drug in the general population 63 Randomized Control Trial 64 Randomized Control Trial • The development and testing of new drugs requires 612 years to complete • Thousands of compounds undergo testing, a few enter clinical trials, and 20% gain approval • The cost of developing a new drug can exceed $800 million • Testing can guarantee effectiveness but cannot guarantee that a drug will be safe – Adverse effects may appear after the drug has been released for general use • Randomized control trials (RCTs) are the most reliable way to objectively assess all new drugs 65 Distinguishing Features of Randomized Control Trials 66 Distinguishing Features of Randomized Control Trials • Use of controls • Randomization • Blinding 67 Off-Label Use 68 Off-Label Use • Once a drug is approved for marketing, it can be prescribed for anything by anyone authorized to prescribe drugs. • Off-label use - if the prescriber gives a drug for a use for which it is not approved • There is nothing illegal about giving a drug for an off-label use, but if an adverse event occurred, the provider could be sued for malpractice. • Typically, when drugs are prescribed off-label, there is evidence in the literature that supports the off-label use so that an individual provider can say that the use is supported. 69 Safety Cost-Benefit Assessment 70 Safety Cost-Benefit Assessment • Drug companies must also provide evidence that the drug being developed is safe, but there is no such thing as a completely safe drug. •Every drug possesses adverse effects • The danger presented by the drug has to be balanced against the benefits. •We (and the FDA) are willing to compromise on safety if the benefits are great. •A life-saving drug that will cure cancer might have a lot of adverse effects, but if your life were saved, it would be worth it. •We do not want a very dangerous drug for a trivial health problem. 71 Safety Long-term and Over-the-counter Drugs 72 Safety Long-term and Over-the-counter Drugs • We would expect a drug that is to be taken for a long period of time—such as an antihypertensive drug—to be safer than one that would be taken for a short time or only once. • Over-the-counter drugs should be safer than prescription drugs because we expect the prescriber of a prescription drug to monitor the patient, whereas this does not occur with overthe-counter drugs. 73 Pre-Clinical Studies 74 Pre-Clinical Studies • Provide evidence of efficacy in the animal. • Provide a rough idea of an effective dose that can be upscaled for humans. • In order to receive permission from the FDA to administer the drug to humans in a clinical trial and garner data for safety and efficacy, the drug company must have pre-clinical data. • The drug will be given to animals • There is an understanding that it is meant for eventual use in humans (although it could also have veterinary use). • Initial studies are often done in mice or rats, but sometimes in other animals. • Ex. you cannot test an anti-emetic drug in mice or rats, because they can’t vomit; hence, cats, dogs, or ferrets are used in that case. 75 Safety Studies in Animals 76 Safety Studies in Animals • Adverse effects •Increasing doses of the drug •How the drug is distributed in the body and how it is eliminated •Blood, urine and organs •Safety data of different time courses •Short and long-term administration •Animals on long-term administration are monitored for the development of cancer •Terotogenicity in pregnant animals 77 Use of Primates in Animal Studies 78 Use of Primates in Animal Studies • Primates may be given the drug to show that effects in them are similar to smaller (cheaper) animals. • The use of primates in animal research is becoming more rare; used only when necessary • Ex. when a smaller animal does not have a disease found in humans, such as HIV 79 Investigative New Drug (IND) 80 Investigative New Drug (IND) • The drug company presents all this pre-clinical data to the FDA in an IND application. • The IND application is a request to the FDA for approval to enter clinical trials on humans. • The IND also includes a plan of how human testing will be conducted. 81 Testing New Drugs in Humans Phase I 82 Testing New Drugs in Humans Phase I • Determine the dose to be used in future studies. • Normal people—not people with the condition that the drug is to be used for—are used. • The exception is for cancer and some AIDS drugs • Most Phase I trials have fewer than 50 subjects, sometimes only 10 or so. • A low dose is started and if the people tolerate it, the dose is increased. • The dose is increased in a stepwise fashion until intolerable adverse events occur – this is called the maximum tolerated dose (MTD). • Measurements of blood and urine are taken to determine how the drug is distributed and eliminated. – Pharmacokinetics 83 Testing New Drugs in Humans Phase II 84 Testing New Drugs in Humans Phase II • Patients with the condition to be treated are used. • Phase II trials typically include fewer than 50 subjects. • At the end of Phase II, we would expect to know: • A lot about drug distribution and elimination and • A dosage range that is effective for the condition being treated. • Blood and urine are taken to determine the distribution and elimination. • Dosages are adjusted based on response. 85 Testing New Drugs in Humans Phase III 86 Testing New Drugs in Humans Phase III • A large clinical trial is conducted with several hundred subjects who have the condition • Demonstrate safety and efficacy of the drug in treating that indication • The drug must be compared with something – either a placebo, or if that is not ethical, with the standard treatment for that condition. • • Subjects are randomized to receive either the investigational drug or the comparator (placebo or standard treatment). The design is usually double blinded (neither the subject nor the person administering the drug knows whether it is the experimental drug or the comparator). • Randomized control trial • The trial may last several months or even years. • Subjects are monitored very carefully for progression of their disease and for adverse events. • There may be more than one Phase III trial if the FDA thinks it is necessary. • If the drug company wants to market the drug for more than one indication, there would be a87 Phase III trial for each indication. Phase III Inclusion and Exclusion Criteria 88 Phase III Inclusion and Exclusion Criteria • Inclusion criteria for subjects • Make sure that the subjects actually have the disease in question • Subjects are likely to be helped by the therapy • Exclusion criteria exclude people likely to be harmed by the therapy • Ex. Pregnant women and people with serious comorbidities. • The problem with this is that it causes the research on the effect of drugs on pregnant women and fetuses to be scant 89 Clinical Testing 90 Clinical Testing • The FDA or the drug company can stop the process at any time. • At the end of the Phase III trials, the company can submit a new drug application (NDA). • Data from Phase I, Phase II and Phase III are presented. • A draft of the prescribing information is proposed—the material to be published in the PDR and included on the package insert. • The drug company and the FDA negotiate the prescribing information, warnings about particular adverse effects, etc. • The prescribing information is a legal document 91 Testing New Drugs in Humans Phase IV: Postmarketing Surveillance 92 Testing New Drugs in Humans Phase IV: Postmarketing Surveillance • It is imperative to continue surveillance after approval. • You could have a post-marketing study – this would be called a Phase IV study. Most of the time, there is not a formal study. • Usually is not done because it costs the drug company money • Unfortunately, post marketing surveillance relies on spontaneous reports from practitioners or patients about adverse events. • A particular adverse event may not be attributed to a drug until the drug has been on the market a number of years and a significant number of people have taken the drug. • Since there is no control group, it is very hard to show that a particular adverse event is due to the drug and is not just a coincidence. 93 New Drug Approvals 94 New Drug Approvals • If all goes well, the company gets permission to market the drug for the indication used in the clinical trials. • In Phase I, Phase II, and Phase III, the drug may have been given to fewer than 1000 people, maybe fewer than 500. • When it is marketed, it may be given to millions of people. • Since the drug was given to relatively few people before it was approved, rare adverse events may not be evident before approval. • If an adverse effect has a one in a million chance, it may not show up often or at all in the clinical trial but likely will when it is marketed to the general public 95 In Which Stage of Drug Development are Researchers Concerned with the Drug’s Maximum Tolerated Dose? 96 In which Stage of Drug Development are Researchers Concerned with the Drug’s Maximum Tolerated Dose? e as Ph Ph as e IV . II Ph as e e as 25% 25% III 25% I Phase I Phase II Phase III Phase IV. Ph 1. 2. 3. 4. 25% Difference between Generic and Brand Name Drugs 98 Difference between Generic and Brand Name Drugs • At this time, there is NO difference between generic drugs and brand name drugs and NO reason to buy the brand name over the generic. • The FDA has standards that force the company marketing the generic to make sure the generic drug is the same as the trade name drug in terms of its activity and purity. 99 Patents 100 Patents • When a drug is first approved, it is protected by a patent issued to the drug company that developed it. • No one else can produce the drug and they can charge whatever they want • The patent length is variable • It is marketed under that company’s brand name with the generic name in parenthesis. • After the patent expires, anyone can make the drug (as long as they satisfy the FDA’s manufacturing standards). • If the original drug company comes out with some improvement, however, they can get a patent on the improvement and therefore extend their ability to charge a high price for the drug. • Example – long-acting preparations of short-acting medications can be eligible for a new patent. 101 Drug Pricing 102 Drug Pricing • The drug company typically charges a really high price because they are trying to recoup their cost of developing the drug. • At that point, one or more other companies usually make the drug available as a generic – it only has the generic name and no trade name. • Usually is much cheaper 103 Controlled Substances 104 Controlled Substances • Controlled substances are those that have a potential to be abused. • Controlled substances are regulated by the Drug Enforcement Administration, NOT the FDA. • Each prescriber must have a DEA number that is on the prescription and every prescriber must comply with DEA regulations. However, who can be a prescriber is generally regulated by each state. • Ex. NPs in most states can prescribe, but their limitations varies by state • Nurses, pharmacies and hospitals must also comply with DEA regulations to handle controlled substances. • The regulations include keeping track of quantities of controlled substances and who receives them. 105 Drug Schedules 106 Drug Schedules Schedule Abuse Potential Dependence Liability Examples Rules I High Severe Heroin, LSD No acceptable use Research only II High Severe Amphetamines, some opioids Triplicate prescriptions, no refills, limit the quantity of drugs/number of pills, typed or ink-written prescriptions III Moderate Moderate Some opioids, some stimulants, anabolic steroids Written or telephone prescription every 6 months, up to five refills allowed IV Low Limited Tranquilizers, weak opioids ex. valum Same as schedule III V Limited Lowest Antidiarrheals (Lomodium) drugs that contain small amounts of opioid in a medication mixture Many OTC 107 Definition Pharmacology 108 Definition Pharmacology The study of drugs and their interactions with living systems 109 Definition Drug 110 Definition Drug A drug is any chemical that can affect a living process. 111 Pharmacokinetics 112 Pharmacokinetics: - The effect of the body on the drug 1. The study of how a drug gets to its receptor in the body. This is broken down into absorption and distribution. 2. The study of how a drug is changed or excreted by body processes. This is called elimination. - Includes metabolism and elimination 113 Pharmacodynamics 114 Pharmacodynamics: The study of the interaction between a drug and its receptor to produce an effect. -What drugs do in the body -The effect of the drug on the body 115 Receptor Theory 116 Receptor Theory 1. Drugs interact with the receptors, which are physiologically important macromolecules. 2. Drugs alter the rate – either up or down – of the natural function of the macromolecule. 117 Drugs Cause Effects by Binding to Receptors 118 Drugs Cause Effects by Binding to Receptors Lehne, RA, Pharmacology for Nursing Care, 7th ed., 2009, Elsevier, p. 50 119 What Types of Physiologically Important Macromolecules Serve as Drug Receptors? 120 What Types of Physiologically Important Macromolecules Serve as Drug Receptors •Almost any molecule in the body can serve as a drug receptor. •Ex. enzymes, neurotransmitter receptors, ion channels, transport proteins, etc, can be drug receptors. 121 Use of the Term “Receptor” by Pharmacologists 122 Use of the Term “Receptor” by Pharmacologists • Receptor - a macromolecule with an endogenous ligand • Ligand - a chemical that binds to a receptor and activates it, causing some change to occur • Ex. in the previous slide, acetylcholine is the ligand • There are four classes of macromolecule that are usually defined as receptors 123 Classes of Macromolecules Defined as Receptors Classical Receptors 124 Classes of Macromolecules Defined as Receptors Classical Receptors • Membrane-bound enzymes with activating ligands. • Ligand-gated ion channels • G-protein coupled neurotransmitter receptors • Transcription factors with activating ligands 125 Examples of Endogenous Ligands 126 Examples of Endogenous Ligands • Neurotransmitters bind to neurotransmitter receptors, which can be of several types. •Ex. norepinephrine binds to the beta-1 receptor and acts as an agonist, causing effects •Causes the heart to speed up • Steroids bind to their respective receptors which are transcription factors. 127 Lehne, RA, Pharmacology for Nursing Care, 7th ed., 2009, Elsevier, p. 48 128 Receptors with Endogenous Ligands Lehne, RA, Pharmacology for Nursing Care, 7th ed., 2009, Elsevier, p. 49 129 Four Primary Receptor Families 130 Four Primary Receptor Families • Cell-membrane embedded enzymes • Ligand gated ion channels • G-Protein coupled receptor system • Transcription factors 131 Cell-membrane Embedded Enzymes 132 Cell-membrane Embedded Enzymes • Cell membrane-embedded enzymes span the cell membrane • The ligand-binding domain is located on the cell surface • The enzyme’s catalytic site is located inside – Binding of an endogenous regulatory molecule or agonist drug (one that mimics the action of the endogenous regulatory molecule) activates the enzyme, thereby increasing its catalytic activity • Responses to activation of these receptors occur in seconds • Ex. insulin is an endogenous ligand that acts through this type of receptor 133 Ligand Gated Ion Channels 134 Ligand Gated Ion Channels • Span the cell membrane • Function to regulate the flow of ions into and out of cells – Each ligand-gated channel is specific for a particular ion • When an endogenous ligand or agonist binds the receptor, the channel opens, allowing ions to flow inward or outward – The direction of flow is determined by the concentration gradient of the ion across the membrane • Responses to activation of the channel are extremely fast, occurring in milliseconds • Ex. neurotransmitters, such as GABA 135 G-Protein Coupled Receptor System 136 G-Protein Coupled Receptor System • Possess three components – The receptor itself – G protein (named because it binds GTP) – An effector (typically an ion channel or an enzyme) • Binding of an endogenous ligand or agonist drug activates the receptor, which in turn activates G protein, which in turn activates the effector • Responses develop rapidly • Ex. many endogenous ligands act through G protein-couples receptor systems, such as NE, serotonin, histamine, and many peptide hormones • The receptors that couple to G proteins are serpentine structures that traverse the cell membrane seven times – The ligand-binding domain may be on the cell surface or located in a pocket accessible from the cell surface 137 Transcription Factors 138 Transcription Factors • Differences from other receptors – Found within the cell rather than on the surface • Situated on the DNA in the cell nucleus – Responses to activation are delayed – may take several hours to days • Transcription factors function to regulate protein synthesis • Activation by endogenous ligands or by agonist drugs stimulates transcription of messenger RNA molecules, which then act as templates for synthesis of specific proteins • Because transcription factors are intracellular, they can only be activated by ligands that are sufficiently lipid soluble to cross the cell membrane • Ex. thyroid hormone, steroid hormones (progesterone, cortisol, testosterone) 139 Other Macromolecules that Drugs Can Bind to 140 Other Macromolecules that Drugs Can Bind to • Enzymes • Ribosomes • Tubulin • DNA or RNA • Transporters • Others 141 Drug Specificity Binding to One Receptor 142 Drug Specificity Binding to One Receptor • If a drug only binds to one receptor type, it will be very specific in its effects. •Will only cause an effect in places in the body where the specific receptor is located 143 Drug Specificity Binding to Multiple Receptor 144 Drug Specificity Binding to Multiple Receptor • Many drugs bind to more than one receptor type and have effects due to activity at all those receptors. • If a drug has activity at more than one receptor, that might be good --- for instance a drug that blocks both β and α receptors might be a good anti-hypertensive agent. • For instance, many beta blockers bind to both β1 and β2 receptors. These drugs can cause bronchiolar constriction at beta-2 receptors in the bronchi as well as slowing of heart rate at beta-1 receptors at the SA node in the heart. • Conversely, activity at a second receptor might be undesired—for instance a β blocker might also block serotonin receptors and cause bad dreams. 145 Dose-Response Curves Lehne, RA, Pharmacology for Nursing Care, 7th ed., 2009, Elsevier, p. 47 146 Dose-Response Curve 1. Before the threshold, few receptors are bound by drug and such a small response is produced, it is not detectable in a whole animal or person. Threshold occurs between phase one and phase two 2. After the threshold is reached and a response can be detected, more drug produces a bigger effect because more receptors are bound. 3. At the plateau, all receptors are bound by drug, and no matter how much more drug is given, no additional 147 response is produced. Basic Features of the DoseResponse Curve 148 Basic Features of the DoseResponse Curve • Dose-response relationship – the relationship between the size of an administered dose and the intensity of the response produced • The dose-response relationship is graded • As the dosage increases, the response becomes progressively larger • To tailor treatment to a patient, need to raise or lower the dosage until a response of the desired intensity is achieved 149 Phases of the Dose-Response Curve 150 Phases of the Dose-Response Curve • Phase I occurs at low doses – The curve is flat during this phase because doses are too low to elicit a measurable response • Phase II – An increase in dose elicits a corresponding increase in the response – The phase during which the dose-response relationship is graded • Phase III – The curve flattens out again – Point where an increase in dose is unable to elicit a further increase in response 151 Simple Occupancy Theory Lehne, RA, Pharmacology for Nursing Care, 7th ed., 2009, Elsevier, p. 51 152 Simple Occupancy Theory • The intensity of the response to a drug is proportional to the number of receptors occupied by that drug – Presumably, all receptors are occupied when the dose-response curve starts to level off – A maximal response will occur when all available receptors have been occupied 153 Simple Occupancy Theory Important Points 154 Simple Occupancy Theory Important Points • The receptors through which drugs act are normal points of control of physiologic processes • Under physiologic conditions, receptor function is regulated by molecules supplied by the body • All that drugs can do at receptors is mimic or block the action of the body’s own regulatory molecules • Drugs cannot give cells new functions, but rather can only alter the rate of pre-existing processes (except with gene therapy) 155 Simple Occupancy Theory Things that are Not Explained 156 Simple Occupancy Theory Things that are Not Explained • Things that are not explained – Why one drug is more potent than another drug – How one drug can have higher maximal efficacy than another • Assumes that all drugs acting at a particular receptor are identical with respect to – The ability to bind to the receptor – The ability to influence receptor function once binding has taken place 157 Efficacy vs. Potency Lehne, RA, Pharmacology for Nursing Care, 7th ed., 2009, Elsevier, p. 47 158 Potency vs. Efficacy Explanation 159 Potency vs. Efficacy Explanation 1. A more potent drug binds the receptors more avidly, so that a high proportion of receptors are bound with drug even at low doses. This produces a response at low doses. 2. The second drug that is less potent is not attracted to the receptors to the same extent and it takes higher doses to produce the same degree of receptor occupancy. 160 Potency 161 Potency • Potency – the amount of drug necessary in order to produce an effect – Indicated by the relative position of the dose-response curve along the x (dose) axis – The closer to 0 on the axis, the more potent the drug – A more potent drug produces its effects at low doses • In diagram B, both drugs are 100% efficacious because they produce the same effect, but morphine is more potent because it produces it at a lower dose • Potency refers to the dose, while efficacy refers to the maximal effect • Potency is rarely an important characteristic of a drug • Potency does not make a drug superior; it only means that the drug can be given in smaller doses 162 Efficacy 163 Efficacy • Efficacy- the ability of a drug to produce an effect • In diagram A, the maximum effect of meperidine is much higher than that of pentazocine so it is more efficacious – They are equally potent but not equally efficacious • Maiximal efficacy – the largest effect that a drug can produce – Indicated by the height of the dose-response curve • A drug with very high maximal efficacy is not always more desirable than a drug with a lower maximal efficacy 164 Modified Occupancy Theory 165 Modified Occupancy Theory • Modified occupancy theory takes into account that a drug binding to a particular receptor may: 1. Mimic the endogenous ligand’s activity at that receptor to produce activity 2. Produce a lesser effect than the endogenous ligand ex. pentazocine in the last diagram 3. Produce no effect. • A drug that produces no effect at the receptor will produce an effect in the body by preventing the binding of the endogenous ligand. 166 Characteristics of the Modified Occupancy Theory 167 Characteristics of the Modified Occupancy Theory • The intensity of the response is related to the number of receptors occupied, but also to the ability of the drug to activate receptors once bound to them • Explains observations that cannot be explained by the simple occupancy theory • Components of the modified occupancy theory – Affinity – Intrinsic activity 168 Modified Occupancy Theory Affinity 169 Modified Occupancy Theory Affinity • Affinity – the strength of the attraction between a drug and its receptor – The higher the affinity, the stronger the attraction to the receptors • The affinity of a drug for its receptors is reflected in its potency • Drugs with high affinity can bind to their receptors when present in low concentrations and have greater potency 170 Modified Occupancy Theory Intrinsic Activity 171 Modified Occupancy Theory Intrinsic Activity • Intrinsic activity – the ability of a drug to activate the receptor following binding – Drugs with high intrinsic activity cause intense receptor activation • The intrinsic activity of a drug is reflected in its maximal efficacy • Drugs with high intrinsic activity have high maximal efficacy because they are able to cause intense responses by causing intense receptor activation 172 Intrinsic Activity Agonists and Partial Agonists 173 Intrinsic Activity Agonists and Partial Agonists • Intrinsic activity- The ability of a drug to activate a particular receptor when bound to it. • Endogenous ligands have full (100%) intrinsic activity. • Full agonists mimic the endogenous ligand and have full intrinsic activity. • Ex. meperidine in the previous example • Partial agonists have less than full intrinsic activity (they are less efficacious than full agonists). • Ex. pentazocine 174 Intrinsic Activity Antagonists 175 Intrinsic Activity Antagonists • Antagonists have no intrinsic activity. • Antagonists block the activity of the endogenous ligand by occupying the receptor and preventing the endogenous ligand from binding • The effect of an antagonist depends on the concentration of agonist (endogenous ligand) present. • If there is no agonist present, administration of an antagonist will have no observable effects • The drug will bind to its receptors but nothing will happen • *If receptors are undergoing activation by agonists, administration of an antagonist will shut the effects of the agonist down by blocking the receptor sites for the agonist • The effect of a competitive antagonist can be overcome by increasing the concentration of an agonist 176 Noncompetitive vs. Competitive Antagonism Lehne, RA, Pharmacology for Nursing Care, 7th ed., 2009, Elsevier, p. 53 177 Competitive vs. Noncompetitive Antagonism 1. A competitive antagonist binds reversibly to the receptor such that bound drug is in equilibrium with unbound drug. - The binding between an antagonist and the receptor in competitive binding is electrostatic and thus is reversible 2. As a given molecule of drug unbinds from the receptor, its place may be taken by another molecule of the same drug, or it may be taken by a molecule of the endogenous ligand. 3. If we’re trying to overcome the effect of the 1st drug (an antagonist), we could give a 2nd drug (an agonist) in high dose, increasing the chance that a vacant receptor will be occupied by the 2nd agonist drug in place of the 1st antagonist drug. - Can compete with a competitive antagonist by adding more agonist 4. At high enough concentrations of the agonist, we “win the competition”, ensuring that vacant receptors will always bind agonist. - The same maximum effect occurs because all of the receptors are bound 178 Competitive (Surmountable) Antagonism 179 Competitive (Surmountable) Antagonism • More common type of antagonist • Bind reversibly to receptors – Produce receptor blockage by competing with agonists for receptor binding • If an agonist and an antagonist have equal affinity for a receptor, it will occupied by whichever is in a higher concentration • Because binding is reversible, the inhibition that competitive antagonists cause can be surmountable by adding more agonists 180 Noncompetitive (Insurmountable) Antagonism 181 Noncompetitive (Insurmountable) Antagonism • Bind irreversibly to receptors – Reduces the total number of receptors available for activation by an agonist • Reduces the maximal response that an agonist can elicit • Because the binding of noncompetitive antagonists is irreversible, inhibition by these agents cannot be overcome, no matter how much agonist is given • Noncompetitive antagonists are rarely used therapeutically because they are irreversible • The effects of noncompetitive antagonists wear off as the receptors to which they are bound are replaced • The effects may subside in a few days 182 Which of the Following Terms is Defined as “the Ability of a Drug to Activate a Receptor upon Binding”? 183 Which of the Following Terms is Defined as “the Ability of a Drug to Activate a Receptor upon Binding”? cy te n ac y Po c tri ns i In Ef fic tiv ity ac ffi n A 1. Affinity - the strength of the attraction between a drug and its receptor 2. Intrinsic activity 3. Efficacy – maximum effect of the drug 4. Potency – dose of the drug needed to elicit a response ity 25% 25% 25% 25% Regulation of Receptor Sensitivity 185 Regulation of Receptor Sensitivity • Receptors continually exposed to agonist may downregulate their response. • Rapid downregulation: tachyphylaxis or desensitization. • Slower, more permanent downregulation: tolerance or tachyphylaxis. 186 Example of Downregulation or Tolerance 187 Example of Downregulation or Tolerance •Opioid tolerance - people who take opioid drugs for chronic pain gradually have to increase the dose because the dose they are taking becomes ineffective in relieving their pain. • Ultimately, they may be taking doses that will cause a respiratory arrest in a drug-naïve person. •They are able to remain active and alert because they have tolerance to the drug. 188 Other Causes of Decreased Drug Effect 189 Other Causes of Decreased Drug Effect •Receptor downregulation is not the only reason for loss of drug effect. •Anything that speeds up the elimination of the drug from the body will result in lower drug levels and less effect. 190 Receptor Upregulation 191 Receptor Upregulation • If a person takes an antagonist for a prolonged period, receptors may be upregulated so there are more of them per cell. •Increase in receptor number in order to have more receptors available for the agonist • The antagonist still has an effect if it is present in high enough concentration. •Supersensitivity - the problem comes when the person stops taking the antagonist—since there are more receptors, the endogenous agonist will have a pronounced effect. •Need to slowly lower the level of antagonist being taken 192 Receptor Regulation 193 Receptor Regulation • Sudden discontinuation of the drug allows the endogenous agonist to have access to the receptor. • In the case of desensitization following prolonged agonist administration, the endogenous agonist may have little effect, thereby producing a deficiency state. • In the case of increased sensitization following prolonged antagonist administration, the endogenous agonist may produce greatly exaggerated effects. 194 Patient Variability in Drug Responses 195 Patient Variability in Drug Responses • Up until now, the dose-response curves I have shown you were obtained in one animal or one person. • Drug response varies between individuals. • Frequency distribution curves show us how a population responds to a drug. 196 Frequency Distribution Curves 197 Frequency Distribution Curve ED50= Effective Dose 50% Lehne, RA, Pharmacology for Nursing Care, 7th ed., 2009, Elsevier, p. 54 198 How to Determine a Frequency Distribution Curve 199 How to Determine a Frequency Distribution Curve - Begin with a number of people who are receiving the drug - Define a response - This is an important step Need to have at least the response in order to qualify - Give a dose of drug and see how many people responded to that drug - Give the remaining people a higher dose of the drug (after the previous dose is eliminated from the body) - Continue increasing the dose until all individuals respond to the dose - People respond at varying doses - At the peak of the frequency distribution curve is the ED50, the effective dose 50% - 50% of the people responded with that dose 200 Frequency Distribution Curve Explanation 201 Frequency Distribution Curve Explanation 1. A response is strictly defined. For instance, it might be defined as a 10% reduction in BP for an antihypertensive. 2. If a low dose is given, a few people (2 in the example) will exhibit a response. (That doesn’t mean that the other people will have no change. It just means that the degree of change doesn’t meet the definition of a response.) The responders are removed from the mix. 3. As the dose is increased, more and more people will achieve the response. 4. At some dose, all of the subjects will achieve the response. 5. When the curve is plotted, there will be some dose at which 50% of the population tested will have achieved a response. This dose is called the “effective dose 50%” or ED50. 202 Therapeutic Index 203 Therapeutic Index • Therapeutic index – a measure of the drug’s safety – The ratio of a drug’s LD50 to its ED50 (therapeutic dose) • Average lethal dose – the dose that is lethal to 50% of the animals treated – The lethal dose is only tested in animals – A large therapeutic index indicates that a drug is relatively safe – LD50/ED50 • When there is overlap between the ED curve and the LD curve, it shows that the high dose needed to produce therapeutic effects in some people may be large enough to cause death in others • The larger the therapeutic index, the greater the space between the therapeutic dose and the lethal dose 204 Therapeutic Index LD50= Lethal Dose 50% Lehne, RA, Pharmacology for Nursing Care, 7th ed., 2009, Elsevier, p. 55 205 Therapeutic Index Maximum Tolerated Dose 206 Therapeutic Index Maximum Tolerated Dose • We do not usually determine LD50 in animals, but instead determine the maximum tolerated dose in humans. • Numerical values for TI are rarely spoken about, but the concept of a large therapeutic index being associated with a safer drug is frequently used. 207 Definitions Undesirable Drug Responses 208 Definitions Undesirable Drug Responses •Toxicity: an undesirable or dangerous effect of a drug brought about by high drug levels. •Side effect: an undesirable effect of a drug that occurs at therapeutic levels of the drug and is the result of the interaction of the drug with a receptor. •Allergic response: a response to a drug that is mediated by the immune system. 209 Choice of a particular drug is frequently dictated by side effects Beetle Bailey BY MORT WALKER © Copyright 2007 King Features Syndicate. All Rights Reserved Allergic Responses 211 Allergic Responses •Anaphylaxis, rashes, hives, etc, produced by the immune system interacting with the drug. •Patients who have allergic symptoms due to a drug should discontinue that drug right away. •The patient could be given another drug (usually from a different class or with a distinctly different chemical structure) that produced the same therapeutic effect in the hope that he/she would not be allergic to the new drug. •An exception to this is allergic reactions to nonsteroidal anti-inflammatory agents (NSAIDs), such as aspirin or ibuprofen. 212 •Will have allergic responses to all NSAIDs A frequency distribution curve for an antihypertensive agent shows an ED50 of 10 mg when the response is defined as a 10% lowering of blood pressure. What would happen if the response definition were changed to a 25% lowering of blood pressure? 213 A frequency distribution curve for an antihypertensive agent shows an ED50 of 10 mg when the response is defined as a 10% lowering of blood pressure. What would happen if the response definition were changed to a 25% lowering of blood pressure? The curve will shift to the right (toward higher doses) de n w ill br oa h. .. cu rv Th e e cu rv e Th e w ill no tc o ift t sh w ill e cu rv e w ill sh ift t o ... t.. 0% 0% 0% e 4. 0% Th 3. The curve will shift to the left (toward smaller doses. The curve will not change. The curve will broaden cu rv 2. Will make the response more difficult to obtain, so higher doses will be required e - Th 1. Things to Look Up • Slide 176 - If receptors are undergoing activation by agonists, administration of an antagonist will shut the effects of the agonist down by blocking the receptor sites for the agonist • Slide 178 – competitive vs. noncompetitive antagonism 215 Things to Ask • Slide 176 - If receptors are undergoing activation by agonists, administration of an antagonist will shut the effects of the agonist down by blocking the receptor sites for the agonist • Slide 178 – competitive vs. noncompetitive antagonism • Slide 192 - What determines whether a drug will result in receptor downregulation or upregulation? 216