Pharmacodynamics Notes PDF

INTRODUCTION TO PHARMACODYNAMICS LAWRENCE MICAH-AMUAH OBJECTIVES By the end on the lecture, you should be able to 1. Understand the general concept of Pharmacodynamics 2. Explain the principles of drug action 3. Understand the role of receptors in drug action and response 4. Define some phar...

INTRODUCTION TO PHARMACODYNAMICS LAWRENCE MICAH-AMUAH OBJECTIVES By the end on the lecture, you should be able to 1. Understand the general concept of Pharmacodynamics 2. Explain the principles of drug action 3. Understand the role of receptors in drug action and response 4. Define some pharmacodynamic terms 5. Discuss the relevance of pharmacodynamics to professional nursing practice 6. Employ the pharmacodynamics of drugs to improve benefits as well as minimize risks of drugs BENEFITS OF PHARMACODYNAMICS To participate rationally in achieving the therapeutic objective, nurses need a basic understanding of pharmacodynamics. Nurses must know about drug actions to ✓educate patients about their medications ✓make PRN decisions, and ✓evaluate patients for beneficial and harmful drug effects. Nurses also need to understand drug actions when conferring with prescribers about drug therapy. PHARMACODYNAMICS Pharmacodynamics is defined as the study of the biochemical and physiological effects of drugs on the body and the molecular mechanisms by which those effects are produced. In short, pharmacodynamics is the study of what drugs do to the body and how they do it. Drug-induced changes in normal physiologic functions are explained by the principles of pharmacodynamics.  After administration, most drugs enter the systemic circulation and expose almost all body tissues to possible effects of the drug. All drugs produce more than one effect in the body. Drug response can cause a primary or secondary physiologic effect, or both. The primary effect is desirable and called the therapeutic effect The secondary effect may be desirable or undesirable A positive change in a faulty physiologic system, called a therapeutic effect of a drug is the goal of drug therapy.  Drugs can produce actions (therapeutic effects) in several ways. The effects of a particular drug depend on the characteristics of the cells or tissue targeted by the drug. Once the drug is at the site of action, it can modify (increase or decrease) the rate at which that cell or tissue functions, or it can modify the strength of function of that cell or tissue. A drug cannot, however, cause a cell or tissue to perform a function that is not part of its natural physiology. Drugs usually work in one of four ways: 1. To replace or act as substitutes for missing biochemicals Eg. : Insulin in DM, hormones and their congeners in deficiency states 2. To increase or stimulate certain cellular activities Eg.: adrenaline, dobutamine and dopamine stimulate the heart to contract harder (inotropy) or beat faster (chronotropy) 3. To depress or slow cellular activities Eg. :Quinidine depresses heart rate in arrythmias, antihypertensives like nifedipine reduces high blood pressure. 4. To interfere with the functioning of foreign cells, such as invading microorganisms or neoplasms (drugs that act in this way are called chemotherapeutic agents). Eg. :Antibiotics/anticancer drugs Drugs can act in several different ways to achieve these results. MECHANISMS OF DRUG ACTION There are two main mechanisms of action: 1. Alteration in cellular environment – non receptor mediated 1. Alteration in cellular function – receptor mediated  Alteration in Cellular Environment Some drugs act in the body by changing the cellular environment, either physically or chemically. Physical changes in the cellular environment include changes in: 1. Osmotic pressures e.g. Mannitol 2. Lubrication e.g. liquid paraffin, arachis oil 3. Absorption e.g. Activated charcoal or 4. the conditions on the surface of the cell membrane. Examples of the physical changes An example of a drug that changes osmotic pressure is mannitol, which produces a change in the osmotic pressure in brain cells, causing a reduction in cerebral edema. A drug that acts by altering the cellular environment by lubrication is liquid paraffin, arachis oil and docusate. These are lubricating laxatives An example of a drug that acts by altering absorption is activated charcoal, which is administered orally to absorb a toxic chemical ingested into the gastrointestinal tract. Examples of the Chemical changes Chemical changes in the cellular environment include: inactivation of cellular functions or the alteration of the chemical components of body fluid, such as a change in the pH. For example, antacids neutralize gastric acidity in patients with peptic ulcers. Alteration in Cellular Function Most drugs act on the body by altering cellular function. Pharmacological effect is due to the alteration of an intrinsic physiologic process and not the creation of a new process A drug that alters cellular function can increase or decrease certain physiologic functions, such as: ✓Increasing or decreasing heart rate, ✓Increasing or decreasing blood pressure, ✓Increasing or decreasing GI motility or ✓Increasing or decreasing urine output. TARGETS OF DRUG ACTION Majority of drugs Interact with target biomolecules: Usually A Protein 1. ENZYMES 2. ION CHANNELS 3. TRANSPORTERS 4. RECEPTORS ENZYMES AS DRUG TARGETS Almost all Biological reactions are carried out under catalytic influence of enzymes – major drug target Drugs – increases/decreases enzyme mediated reactions In physiological system enzyme activities are optimally set Enzyme stimulation is less common by drugs Enzyme inhibition is the most common mode of drug action – specific or nonspecific or may be selective or non selective to a specific enzyme system Enzymes – drug targets Acetazolamide is a diuretic that blocks the enzyme carbonic anhydrase, which subsequently causes alterations in the hydrogen ion and water exchange system in the kidney, as well as in the eye. Lisinopril (ACEi): Inhibit synthesis of Angiotensin II – decrease in peripheral resistance and blood volume NSAIDs like Aspirin, diclofenac, ibuprofen and Naproxen inhibit the COX enzyme to exert their anti-inflammatory and hence analgesic effect Clorygyline used as an antidepressant by inhibiting MAO, an enzyme ION CHANNELS Some drugs act on specific ion channels to exert their pharmacological action. This includes the activation (opening) or inactivation (closure) of their channels to cause an action or inhibit an action respectively Egs: 1. Calcium Channel Blockers (antagonist) eg. Nifedipine, Amlodipine and Felodipine, exert their antihypertensive effect by blocking Calcium entry into the cells of the heart and arteries. 2. Diuretics like Furosemide (Lasix) and Bendrofluazide act by blocking the Na/K/2Cl and Na/Cl channels respectively. This leads to inhibition of reabsorption of salt and water leading to the production of more urine (diuresis) 3. Anaesthetic agents like Lidocaine (ligdocaine) and Bupivacaine inhibit Na channels to prevent the generation/conduction of nerve impulses. TRANSPORTERS Drugs acting on transporters either enhance the activity of carrier or transport proteins or inhibit their activities. Egs. Calcitriol works by enhancing absorption of dietary calcium and phosphate from the GIT and promoting the renal tubular reabsorption of calcium in the kidneys Monoamine reuptake inhibitors (MRIs) reduce the reuptake of serotonin, noradrenaline and dopamine by inhibiting the transporters responsible for their reuptake from the synaptic cleft. Such drugs can be used as antidepressants eg. TCAs (eg. Amitriptylline), SSRIs (eg. Fluoxetine) SGLT2 inhibitors also act on the renal glucose reabsorption channel. These drugs are now used in the treatment of Diabetes and Heart failure. Eg. are Dapagliflozin, Empagliflozin and Canagliflozin.  DRUG RECEPTORS WHAT IS A RECEPTOR A receptor can be defined as a reactive site on the surface or inside of a cell. It is defined as a macromolecule or binding site located on cell surface or inside the effector cell that serves to recognize the signal molecule/drug and initiate the response to it, but itself has no other function. There are finite number of receptors in a given cell. They are usually proteins or glycoproteins Itself has no function Most receptors, protein in structure, are found on cell membranes. Drug Receptors The interaction between the drug and the receptor site affects certain biochemical systems within the cell. The affected biochemical processes then produce certain effects, such as: Increased or decreased cellular activity, Changes in cell membrane permeability, or Alterations in cellular metabolism. Drug Receptors For a drug–receptor reaction to occur, a drug must be attracted to a particular receptor. Drugs bind to a receptor much like a piece of a puzzle. The closer the shape, the better the fit, and the better the therapeutic response. The intensity of a drug response is related to how good the “fit” of the drug molecule is and the number of receptor sites occupied The binding can be considered to analogous to a key and lock - Emil Fisher (1899) LOCK AND KEY MODEL The three-dimensional shape of the drug molecule acts like the key and must fit exactly into the structure of the target (receptor), the lock, in order to activate it. Therefore, just like locks and their keys, the interactions between drugs and their targets are highly specific and based on physical shape interactions. Also, drugs should have significant binding and adequate binding time in order to elicit a response. Drug–receptor interactions involve all known types of bond: ionic, hydrogen, van der Waals, covalent. Drugs with short duration of action generally have weaker bonds; long- duration or irreversible drug–receptor interactions may have stronger bonds such as covalent. Much of the work of drug development is concerned with designing or refining the shape of drug molecules so that they have an ever-closer fit with the target molecule. Parts of the Drug-Receptor complex Pharmacophore is the part of the drug molecule - the atoms and groups - that bind to the receptor Auxophore are the parts of the drug molecule that are not directly involved in binding, but may rather interfere with binding, be essential for the arrangement of pharmacophoric elements, or may be irrelevant. DRUG RECEPTOR INTERACTION Drug-receptor interaction is the joining of the drug molecule with a reactive site on the surface of a cell or tissue. Once a drug binds to and interacts with the receptor, a pharmacologic response is produced Drug Receptor Interactions Affinity Affinity refers to the strength (extent) of binding between a drug and receptor Affinity is how well a drug can bind to a receptor (Fast/strong binding = higher affinity). The affinity of a drug can be evaluated by determining the Dissociation constant (KD) A drug becomes bound to the receptor through the formation of chemical bonds between the receptor on the cell and the active site on the drug molecule. Once a drug binds to and interacts with the receptor, a pharmacologic response is produced Number of occupied receptors is a function of a balance between bound and free drug  AFFINITY Dissociation constant (KD) Measure of a drug’s affinity for a given receptor Defined as the concentration of drug required in solution to achieve 50% occupancy of its receptors the smaller the KD, the greater the affinity of the drug to the receptor; the smaller the KD for a reaction, the lower the concentration of drug required in order to produce half maximal binding Drug effects can be evaluated in terms of POTENCY and EFFICACY EFFICACY Is the relationship between receptor occupancy and the ability to initiate a response at the molecular, cellular, tissue or system level. In other words, efficacy refers to how well an action is taken after the drug is bound to a receptor. In pharmacology, a high efficacy usually means that a drug has worked since the drug caused the receptor to initiate or perform an action extremely well. POTENCY Potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A highly potent drug elicits a given response at low concentrations, while a drug of lower potency does same only at higher concentrations. The potency depends on both the affinity and efficacy. The more potent a drug is, the less the amount of the drug needed to produce a pharmacological response and vice versa DRUG-RECEPTOR EFFECTS Some drugs produce effects in minutes, but others may take hours or days. Measurement of drug receptor effect is done using either a dose-response or a time-response curve A time – response curve evaluates three parameters of drug action: 1. The onset of drug action 2. Peak action 3. Duration of Action T1 = onset of action, T2 = Peak, T3 = duration MEC: Minimum effective concentration MTC: Minimum toxic concentration BASIC TERMINOLOGIES Minimum Effective Concentration Is the minimum (lowest) plasma concentration of a drug needed to achieve sufficient drug concentration at the receptor site to produce the desired pharmacologic response Can be also defined as the lowest concentration of the drug required to achieve the therapeutic benefit or effect. Minimum Effective dose is the minimum dose of a drug that produces a biological or therapeutic effect Minimum Toxic Concentration Is defined as the minimum plasma concentration of a drug at which toxic effects occurs Is the concentration at which a drug produces unwanted side effects The minimum dose required to produce toxic effect is called Minimum Toxic Dose  If the drug plasma or plasma level decreases below threshold or MEC, adequate drug dosing is not achieved; Too high a drug level, above the minimum toxic concentration (MTC), can result in toxicity. The aim of drug therapy is to achieve plasma concentrations between the MEC and MTC. The range between the MTC and the MEC represents the Therapeutic Window of a drug. The wider the therapeutic window, the safer drug dosing is and vice versa. Nursing Consideration Narrow therapeutic window drugs should be carefully administered by the nurse by checking the dose and rate of drug administration in order to avoid toxicity. Assignment 1. What is therapeutic Index? 2. What is the formula for measuring Therapeutic Index? 3. How does therapeutic index relate to the safety of drugs? - low therapeutic index - high therapeutic index 4. What are the nursing considerations when administering drugs low therapeutic index? Onset, Peak, and Duration of Action Onset of action: This is time it takes to reach the minimum effective concentration (MEC) after a drug is administered. Peak action: This is the highest point of drug effect or action. It usually occurs when the drug reaches its highest blood or plasma concentration. Duration of action: This is the length of time the drug has a pharmacologic effect. DOSE RESPONSE CURVES A DOSE RESPONSE CURVE is a graph illustrating the effect of various drug concentrations (doses) on drug receptors. Dose response data are typically graphed with the dose or dose function (e.g. log10 dose) on the X-axis and the measured effect (response) on the Y-axis. Measured effects are frequently recorded as maximal at time of peak effect Drug effects may be quantified at the level of molecule, cell, tissue, organ, organ system, or organism. A dose Response curve of Isoflurane (General Anaesthetic agent) FEATURES OF A DOSE RESPONSE CURVE The dose response curve has the following features 1. Minimum effective dose or Concentration 2. Maximal efficacy or ceiling effect 3. Slope (change in response per unit dose) 4. Potency 5. Efficacy PHASES OF THE DOSE RESPONSE CURVE Maximal Efficacy and Relative Potency Dose-response curves reveal two characteristic properties of drugs: maximal efficacy and relative potency  EC - Effective Concentration (e.g. EC50: the drug concentration producing 50% of a maximal effect). ED - Effective Dose (e.g. ED50: the drug dose producing 50% of a maximal effect; or alternatively the dose producing the desired effect in 50% of the population. Which definition is appropriate depends on the context in which the abbreviation is being applied; i.e. it depends on whether the abbreviation is referring to the results of a population study, or drug effects on a single animal). Example: administering a 1000 mg dose of acetaminophen (ED50) orally will result in a plasma concentration of 15 ug/ml (EC50), which produces effective pain relief in 50% of adult patients. TD - Toxic Dose (e.g. TD50: the dose producing a toxic effect in 50% of the population). LD - Lethal Dose (e.g. LD50: the dose producing a lethal effect in 50% of the population). LD values almost always refer to animal studies, since lethal doses in humans are rarely known with any accuracy. POTENCY The term potency refers to the amount of drug we must give to elicit an effect. Potency is indicated by the relative position of the dose-response curve along the x (dose) axis. That is, a potent drug is one that produces its effects at low doses. It is important to note that the potency of a drug implies nothing about its maximal efficacy! Potency and efficacy are completely independent qualities. In everyday parlance, people often use the word potent to express the pharmacologic concept of effectiveness. That is, when most people say, “This drug is very potent,” what they mean is, “This drug produces very high effects.” They do not mean, “This drug produces its effects at low doses.” POTENCY Potency is measured by the position of the dose response curve on the x-axis. Curves closer to the ZERO MARK on the x-axis are relatively more potent than drugs seen further away. POTENCY  EFFICACY EFFICACY is the ability of a drug to elicit a response when it interacts with a receptor Efficacy is dependent on: 1. The number of drug-receptor complexes formed 2. The efficiency of the coupling of receptor activation to cellular response Maximal efficacy is defined as the largest effect that a drug can produce. Maximal efficacy assumes that all receptors are occupied by the drug and if more drugs are added, no additive response will be observed Maximal efficacy is indicated by the height of the dose-response curve. A drug with greater efficacy is more therapeutically beneficial than one that is more potent. ANY QUESTIONS DRUG –RECEPTOR INTERACTIONS There are 4 receptor families; 1. Cell membrane-embedded enzymes 2. Ligand-gated ion channels 3. G-protein-coupled receptor systems, and 4. Transcription factors. NOTE The term ligand-binding domain is the site on the receptor in which drugs bind. DRUG –RECEPTOR INTERACTIONS Characteristics of receptors Excellent ability to recognize a ligand (ie drug), Cause conformational change or biological effect. May cause a biologic response DRUG –RECEPTOR INTERACTIONS 1. Cell membrane-embedded enzymes The ligand-binding domain for drug binding is on the surface. The drug activates the enzyme (inside the cell) and a response is initiated. 2. Ligand-gated ion channels The receptor spans the cell membrane and, with this type of receptor, the channel opens, allowing for the flow of ions into and out of the cells. The ions are primarily sodium and calcium. 3. G-Protein-coupled receptor systems. There are three components to this receptor response. i. The receptor ii. G protein that binds with guanosine triphosphate (GTP), and iii. The effector that is either an enzyme ion channel  DRUG –RECEPTOR INTERACTIONS G-Protein-coupled receptor systems. The system works as follows: Drug ] activates Receptor activates G protein activates Effector  4. Transcription factors Transcription factors are proteins that regulates the transcription of genes on the DNA in the cell nucleus and not on the surface of the cell membrane. Transcription factors are proteins that help to turn specific genes “on” or “off” by binding to nearby DNA TRANSCRIPTION FACTORS interact with their binding sites using a combination of electrostatic and Van der Waals forces Activation of receptors through the transcription factors is prolonged. NOTE With the first three receptor groups, the activation of the receptors are rapid. DRUG –RECEPTOR INTERACTIONS Drugs that produce a response are called agonists, and drugs that block a response are called antagonists. An Agonist: a drug which combines with its specific receptor, activates it and produces an effect. An Antagonist: a drug which binds to a receptor without causing activation and thereby prevents the agonist from binding. When an antagonist interacts with receptor, no response is produced and the response of agonist is blocked. A partial agonist: binds to the receptor to produce sub- maximal tissue response but antagonizes the action of a full agonist. RECEPTOR THEORY RECEPTOR THEORY is the application of receptor models to explain drug behavior or action. These theories preceded accurate knowledge of receptors by many years The two renowned theories which explains the nature of drug-receptor interactions are: i. Receptor occupancy theory ii. Rate theory RECEPTOR OCCUPANCY THEORY Proposed by A. J. Clark in 1926 Theory states that Drugs act on binding sites and activate them, resulting in biological response. This theory also states that the intensity of response produced by a drug is proportional to the number of receptors occupied and maximal response occurs when all the receptors are occupied. The response ceases when the complex dissociates It is also stated that drugs exert an “ all or none’’ action on each receptor which means either a receptor is fully activated or not at all. The Receptor Occupancy theory does not fully account for the existence of partial or inverse agonist. It does not address the observation that the maximal response of some receptor systems was achieved well before theoretical saturation of the receptor binding Rate theory Proposed by Paton W.M.D. It states that drug effects are proportional to the rate of drug - receptor complex formation. Activation of receptors is proportional to the total number of encounters of a drug with its receptor According to this view, the duration of receptor occupation determines whether a molecule is an Agonist or partial Agonist That is response emanates from a receptor in proportion to the kinetic rate of onset and offset of drug binding to the receptor Other Drug Receptor Theories Induced-Fit theory Macromolecular Perturbation Theory Activation Aggregation Theory Two state receptor Model COMBINED EFFECT OF DRUGS SYNERGISM When two drugs are given simultaneously, and the action of one drug is increased by the other, they are treated as synergistic. In synergism, the drugs can have action in the same direction or when given alone, one may be inactive. Synergism can also be observed as supra-additive in nature. ADDITIVE When the effect of two drugs are in the same direction and the combined effect is comparable to the summation of their individual effects For example when aspirin is combined with paracetamol, the combined effect is analgesic/antipyretic. Another important example is the combination of theophyline and ephedrine as bronchodilator COMBINED EFFECT OF DRUGS SUPRAADDITIVE In this scenario, the effect of combined therapy is greater than the individual effect of only one of the drugs alone. Example: Levodopa and peripheral dopa-decarboxylase inhibitor, carbidopa or Benserazide in the treatment of parkinsonism. Drug Receptor Interaction Intrinsic activity- Ability of the drug to elicit a response after binding to a receptor  Drug Effects on Receptors Agonist These are drugs that bind with a receptor to produce a therapeutic response. The drug is able to stimulate a receptor, and therefore mimics the endogenous transmitter. If the drug mimics the effect of the naturally occurring substance at the receptor, the drug is known as an agonist. The key fits the lock, and opens the door. Has affinity+ IA Partial agonist A drug which does not produce maximal effect even when all of the receptors are occupied. Affinity + sub maximal I.A. E.g. Tramadol, Nalorphine DRUG ANTAGONISM DRUG ANTAGONISM This describes the situation, when one drug decreases or inhibits the action of another. The antagonism may be physical or chemical in which two drugs react physically or chemically and form a biologically inactive compound. This type of reaction may be used in the treatment of drug poisoning. Example: In morphine toxicity, Naloxone which is an opioid antagonist can be administered to counteract the effects of Morphine at the opioid receptors TYPES OF DRUG ANTAGONISM 1. Competitive antagonism 2. Non-competitive antagonism COMPETITIVE ANTAGONISM Here the antagonist binds at the same active site of the receptor as agonist. The competitive antagonist reduces affinity i.e. potency of the agonist. Higher doses of agonist can surmount the activity of the competitive antagonist Examples: Acetylcholine – as agonist and Atropine as antagonist Morphine vs Naloxone Noradrenaline vs Bisoprolol NON-COMPETITVE ANTAGONIST Binds to a site other than the agonist-binding domain Induces a conformation change in the receptor such that the agonist no longer “recognizes” the agonist binding site. High doses of an agonist do not overcome the antagonist in this situation Differences between agonist and antagonist AGONIST ANTAGONIST Agonist has affinity plus intrinsic Antagonist has affinity but NO activity intrinsic activity Partial agonist has affinity & (less) Competitive antagonists may be intrinsic activity overcome (surmountable) Agonists tend to desensitize Antagonists tend to up-regulate receptors receptors  Selective Toxicity Ideally, all chemotherapeutic agents would act only on enzyme systems that are essential for the life of a pathogen or neoplastic cell and would not affect healthy cells. The ability of a drug to attack only those systems found in foreign cells is known as selective toxicity. Penicillin, an antibiotic used to treat bacterial infections, has selective toxicity. It affects an enzyme system unique to bacteria, causing bacterial cell death without disrupting normal human cell functioning. THANK YOU