Pharmacodynamics PDF

Introduction to Pharmacodynamics Evi Sovia Faculty of Medicine Universitas Jenderal Achmad Yani  Learning outcome Setelah mengikuti kuliah ini, mahasiswa mampu: 1. Memahami pengertian farmakodinamik 2. Menjelaskan tentang reseptor, lokasi reseptor, jenis-jenis re...

Introduction to Pharmacodynamics Evi Sovia Faculty of Medicine Universitas Jenderal Achmad Yani  Learning outcome Setelah mengikuti kuliah ini, mahasiswa mampu: 1. Memahami pengertian farmakodinamik 2. Menjelaskan tentang reseptor, lokasi reseptor, jenis-jenis reseptor dan regulasi reseptor 3. Menjelaskan ikatan obat-reseptor agonis dan antagonis 4. Memahami kurva dosis respon dan faktor-faktor yang mempengaruhi respon farmakologi 5. Mengetahui toleransi, potensi obat dan efek kombinasi obat  Introduction Pharmacodynamics is the study of a drug's molecular, biochemical, and physiologic effects or actions. Pharmacodynamics refers to the relationship between drug concentration at the site of action and the resulting effect, including the time course (OOA and DOA) and intensity of therapeutic and adverse effects.  Pharmacodynamics is about all those matters that are concerned with the pharmacological actions of drugs when they get to their sites of action, whether they be determinants of beneficial or adverse effects.  The effect of a drug present at the site of action is determined by that drug’s binding with a receptor All drugs produce their effects → interacting with biological structures or targets at the molecular level → induce a change in how the target molecule functions in regards to subsequent intermolecular interactions  Types of interactions 1. Drugs binding to an active site of an enzyme 2. Drugs that interact with cell surface signaling proteins to disrupt downstream signaling 3. Drugs that act by binding molecules like tumor necrosis factor (TNF)  Subsequent to the drug-target interaction occurring → effects are elicited which can be measured by biochemical or clinical means Examples of this include the: – inhibition of platelet aggregation after administering aspirin – the reduction of blood pressure after ACE inhibitors – the blood-glucose-lowering effect of insulin Receptors The component of a cell or organism that interacts with a drug and initiates the chain of events leading to the drug’s observed effects May be present on: – Neurons in the central nervous system (i.e., opiate receptors) → depress pain sensation – Cardiac muscle → affect the intensity of contraction – Within bacteria → disrupt maintenance of the bacterial cell wall.  Cellular receptors: proteins either inside a cell or on its surface which receive a signal. In normal physiology, this is a chemical signal where a protein-ligand binds a protein receptor. The ligand is a chemical messenger released by one cell to signal either itself or a different cell. Types of Ligands Ligands are the signaling molecule used by the body for various cells to communicate with other cells. The adrenal gland can release a hormone such as cortisol The effect of the ligand is dependent on both the ligand itself and the receptor it targets. For example, small and hydrophobic ligands such as steroids like cortisol often target internal receptors as they are capable of passing through the plasma membrane without help. On the other hand, large or hydrophilic ligands such as GABA are unable to pass through the cell membrane and must target cell surface receptors. Classes of proteins that have been clearly identified as drug receptors: – Enzymes, which may be inhibited (or, less commonly, activated) by binding a drug (eg, dihydrofolate reductase, the receptor for the antineoplastic drug methotrexate) – Transport proteins (eg, Na+/K+-ATPase, the membrane receptor for cardioactive digitalis glycosides) – Structural proteins (eg, tubulin, the receptor for colchicine, an anti-inflammatory agent).  Receptors Receptors largely determine the quantitative relations between dose or concentration of drug and pharmacologic effects. The receptor’s affinity for binding a drug determines the concentration of drug required to form a significant number of drug receptor complexes The total number of receptors may limit the maximal effect a drug may produce. Receptors are responsible for selectivity of drug action. The molecular size, shape, and electrical charge of a drug determine whether—and with what affinity—it will bind to a particular receptor among the vast array of chemically different binding sites available in a cell, tissue, or patient. Accordingly, changes in the chemical structure of a drug → can dramatically increase or decrease a new drug’s affinities for different classes of receptors, with resulting alterations in therapeutic and toxic effects.  Receptors mediate the actions of pharmacologic agonists and antagonists Agonist Some drugs and many natural ligands, such as hormones and neurotransmitters, regulate the function of receptor macromolecules as agonists This means that they activate the receptor to signal as a direct result of binding to it. Some agonists activate a single kind of receptor to produce all their biologic functions, whereas others selectively promote one receptor function more than another. Antagonists Other drugs act as pharmacologic antagonists → they bind to receptors but do not activate generation of a signal Interfere with the ability of an agonist to activate the receptor The effect of a so-called “pure” antagonist on a cell or in a patient depends entirely on its preventing the binding of agonist molecules and blocking their biologic actions. Other antagonists, in addition to preventing agonist binding, suppress the “constitutive” activity (basal signaling) of receptors. Some of the most useful drugs in clinical medicine are pharmacologic antagonists.  Types of Receptors 1. Ligand gated ion channels 2. G protein coupled receptors (GPCRs) 3. Voltage dependent ion channels 4. Enzyme linked membrane receptors 5. Intracellular receptors 6. Cytokine Receptors  Types of Receptors 1. Ligand gated ion channels are specialized membrane pores made of multisubunit proteins  Ligand- and Voltage-Gated Channels Many of the most useful drugs in clinical medicine act by mimicking or blocking the actions of endogenous ligands that regulate the flow of ions through plasma membrane channels. The natural ligands of such receptors include acetylcholine, serotonin, GABA, and glutamate. All of these agents are synaptic transmitters. 2. G protein coupled receptors (GPCRs) Guanine nucleotide binding proteins (G protein) are transducers of information between ligand receptor binding to GPCRs and the formation of several intracellular second messengers that culminate in a cellular response  G Proteins & Second Messengers Many extracellular ligands act by increasing the intracellular concentrations of second messengers such as: – cyclic adenosine-3′,5′-monophosphate (cAMP) – calcium ion – phosphoinositides  In most cases, they use a transmembrane signaling system with three separate components: – First, the extracellular ligand is selectively detected by a cell-surface receptor.  – The receptor in turn triggers the activation of a GTP-binding protein (G protein) located on the cytoplasmic face of the plasma membrane. – The activated G protein then changes the activity of an effector element, usually an enzyme or ion channel. This element then changes the concentration of the intracellular second messenger.  For cAMP, the effector enzyme is adenylyl cyclase, a membrane protein that converts intracellular adenosine triphosphate (ATP) to cAMP. The corresponding G protein, G s, stimulates adenylyl cyclase after being activated by hormones and neurotransmitters that act via specific Gs-coupled receptors. There are many examples of such receptors, including β adrenoceptors, glucagon receptors, thyrotropin receptors, and certain subtypes of dopamine and serotonin receptors 3. Voltage dependent ion channels normally open or close in response to changes in the membrane potential, but they can also function as receptors for drugs 4. Enzyme linked membrane receptors These receptors are polypeptides consisting of an extracellular hormone-binding domain and a cytoplasmic enzyme domain, which may be a protein tyrosine kinase, a serine kinase, or a guanylyl cyclase In all these receptors, the two domains are connected by a hydrophobic segment of the polypeptide that crosses the lipid bilayer of the plasma membrane.  Ligand-Regulated Transmembrane Enzymes Including Receptor Tyrosine Kinases This class of receptor molecules mediates the first steps in signaling by : – Insulin – epidermal growth factor (EGF) – platelet-derived growth factor (PDGF), – atrial natriuretic peptide (ANP), – transforming growth factor-β (TGF-β), – and many other trophic hormones. 5. Intracellular receptors Intracellular Receptors for Lipid-Soluble Agents Several biologic ligands are sufficiently lipid- soluble to cross the plasma membrane and act on intracellular receptors. Steroids (corticosteroids, mineralocorticoids, sex steroids, vitamin D) Thyroid hormone, whose receptors stimulate the transcription of genes by binding to specific DNA sequences (often called response elements) near the gene whose expression is to be regulated. The mechanism used by hormones that act by regulating gene expression has two therapeutically important consequences: 1. All of these hormones produce their effects after a characteristic lag period of 30 minutes to several hours—the time required for the synthesis of new proteins. – This means that the gene-active hormones cannot be expected to alter a pathologic state within minutes (eg, glucocorticoids will not immediately relieve the symptoms of bronchial asthma). 2. The effects of these agents can persist for hours or days after the agonist concentration has been reduced to zero. – The persistence of effect is primarily due to the relatively slow turnover of most enzymes and proteins, which can remain active in cells for hours or days after they have been synthesized. – Consequently, it means that the beneficial (or toxic) effects of a gene- active hormone usually decrease slowly when administration of the hormone is stopped.  6. Cytokine Receptors Cytokine receptors respond to a heterogeneous group of peptide ligands, which include growth hormone, erythropoietin, several kinds of interferon, and other regulators of growth and differentiation. These receptors use a mechanism closely resembling that of receptor tyrosine kinases, except that in this case, the protein tyrosine kinase activity is not intrinsic to the receptor molecule.  Drugs produce their effects by interacting with biologic targets The time course of the pharmacodynamic effect is dependent on the mechanism and biochemical pathway of the target.  Effects can be classified: – direct and indirect – immediate and delayed.  Direct effects The result of drugs interacting with a receptor or enzyme that is central to the pathway of the effect Beta-blockers inhibit receptors that directly modulate cAMP levels in smooth muscle cells in the vasculature.  Drug action via a direct effect on a receptor Receptors → specific proteins, situated either in cell membranes or, in some cases, in the cellular cytoplasm. For each type of receptor, there is a specific group of drugs or endogenous substances (known as ligands) that are capable of binding to the receptor, producing a pharmacological effect. Most receptors are located on the cell surface. However, some drugs act on intracellular receptors; – these include corticosteroids, which act on cytoplasmic steroid receptors, The thiazolidinediones (such as pioglitazone), which activate peroxisome proliferator- activated receptor gamma (PPARy ), a nuclear receptor involved in the expression of genes involved in lipid metabolism and insulin sensitivity.  Indirect effects The result of drugs interacting with receptors, proteins of other biologic structures that significantly upstream from the end biochemical process that produces the drug effect. Corticosteroids bind to nuclear transcription factors in the cell cytosol which translocate to the nucleus and inhibit transcription of DNA to mRNA encoding for several inflammatory proteins  Immediate effects Secondary to direct drug effects. Neuromuscular blocking agents such as succinylcholine, which consists of two acetylcholine (ACh) molecules linked end to end by their acetyl groups, interact with the nicotinic acetylcholine receptor (nAChR) on skeletal muscle cells and leave the channel in an open state, resulting in membrane depolarization and generation of an action potential, muscle contraction and then paralysis within 60 seconds after administration.  Delayed effects Secondary to direct drug effects. Chemotherapy agents that interfere with DNA synthesis, like cytosine arabinoside which is used in acute myeloid leukemia → produce bone marrow suppression that occurs several days after administration.  Cumulative Effects Some drug effects are more obviously related to a cumulative action than to a rapidly reversible one. The renal toxicity of aminoglycoside antibiotics (eg, gentamicin) is greater when administered as a constant infusion than with intermittent dosing. It is the accumulation of aminoglycoside in the renal cortex that is thought to cause renal damage. Even though both dosing schemes produce the same average steady-state concentration, the intermittent dosing scheme produces much higher peak concentrations, which saturate an uptake mechanism into the cortex; thus, total aminoglycoside accumulation is less. The difference in toxicity is a predictable consequence of the different patterns of concentration and the saturable uptake mechanism.  Dosing Principles-Based Upon Pharmacodynamics The pharmacologic response depends on the drug binding to its target as well as the concentration of the drug at the receptor site. Kd measures how tightly a drug binds to its receptor. Kd → The ratio of rate constants for association (kon) and dissociation (koff) of the drug to and from the receptors  At equilibrium → the rate of receptor-drug complex formation is equal to the rate of dissociation into its components receptor + drug. The measurement of the reaction rate constants can be used to define an equilibrium or affinity constant (1/Kd). The smaller the Kd value → the greater the affinity of the antibody for its target. For example, albuterol has a Kd of 100 nanomolar (nM) for the beta-2 receptor while erlotinib has a Kd of 0.35 nM for the estimated glomerular filtration rate (EGFR) receptor indicating that erlotinib has approximately 300 times the receptor interaction than albuterol  Receptor Occupancy From the law of mass action → the more receptors that are occupied by the drug → the greater the pharmacodynamic response But all receptors do not need to be occupied in order to get a maximal response. The concept of spare receptors and occurs commonly to include muscarinic and nicotinic acetylcholine receptors, steroid receptors, and catecholamine receptors. Maximal effects are obtained by less than maximal receptor occupancy by signal amplification. Receptor Up- and Downregulation Chronic exposure of a receptor to an antagonist typically leads to upregulation (an increased number of receptors) The insulin receptor undergoes downregulation to chronic exposure to insulin. The number of surface receptors for insulin is gradually reduced by receptor internalization and degradation brought about by increased hormonal binding.  Chronic exposure of a receptor to an agonist causes downregulation (decreased number of receptors) Other mechanisms involving alteration of downstream receptor signaling may also be involved in up- or downmodulation without altering the receptor number on the cell membrane  An exception to the rule is the receptor for nicotine that demonstrates upregulation in receptor numbers upon extended exposure to nicotine, despite nicotine being an agonist, which explains some of its addictive properties.  Receptor Regulation G protein-mediated responses to drugs and hormonal agonists often attenuate with time After reaching an initial high level, the response (eg, cellular cAMP accumulation, Na+ influx, and contractility) diminishes over seconds or minutes, even in the continued presence of the agonist. This “desensitization” is often rapidly reversible; a second exposure to agonist, if provided a few minutes after termination of the first exposure, results in a response similar to the initial response.  Effect compartment and indirect pharmacodynamics A delay between the appearance of drug in the plasma and its intended effect may be due to multiple factors to include transfer into the tissue or cell compartment in the body or a requirement for the inhibition or stimulation of a signal to be cascaded through intracellular pathways. These effects can be described by either using an effect compartment or using indirect pharmacodynamic response models, which describe the effect of the drug through indirect mechanisms such as inhibition or stimulation of the production or elimination of endogenous cellular components that control the effect pathway  key concepts and terms used in the description of pharmacodynamics Emax → the maximal effect of a drug on a parameter that is measured. EC50 → the concentration of the drug at a steady-state that produces half of the maximum effect Hill coefficient → the slope of the relationship between drug concentration and drug effect. In the simplest examples of drug effect, there is a relationship between the concentration of drug at the receptor site and the pharmacologic effect. If enough concentrations are tested, a maximum effect (E max) can be determined (Figure 1-5). When the logarithm of concentration is plotted versus effect (Figure 1-5), one can see that there is a concentration below which no effect is observed and a concentration above which no greater effect is achieved.  Potency One way of comparing drug potency is by the concentration at which 50% of the maximum effect is achieved (50% effective concentration or EC 50) When two drugs are tested in the same individual, the drug with a lower EC 50 would be considered more potent. This means that a lesser amount of a more potent drug is needed to achieve the same effect as a less potent drug. Tolerance The effectiveness can decrease with continued use → tolerance. Tolerance may be caused by pharmacokinetic factors, such as increased drug metabolism, that decrease the concentrations achieved with a given dose. There can also be pharmacodynamic tolerance, which occurs when the same concentration at the receptor site results in a reduced effect with repeated exposure. An example of drug tolerance is the use of opiates in the management of chronic pain. It is not uncommon to find these patients requiring increased doses of the opiate over time. Tolerance can be described in terms of the dose–response curve, as shown in Figure 1-6.  RELATION BETWEEN DRUG CONCENTRATION & RESPONSE Concentration-Effect Curves & Receptor Binding of Agonists Even in intact animals or patients, responses to low doses of a drug usually increase in direct proportion to dose. As doses increase, however, the response increment diminishes; finally, doses may be reached at which no further increase in response can be achieved. This relation between drug concentration and effect is traditionally described by a hyperbolic curve  Based on the maximal pharmacologic response that occurs when all receptors are occupied, agonists can be divided into two classes: partial agonists produce a lower response, at full receptor occupancy, than do full agonists. Partial agonists produce concentration effect curves that resemble those observed with full agonists in the presence of an antagonist that irreversibly blocks some of the receptor sites It is important to emphasize that the failure of partial agonists to produce a maximal response is not due to decreased affinity for binding to receptors. Indeed, a partial agonist’s inability to cause a maximal pharmacologic response, even when present at high concentrations that effectively saturate binding to all receptors, is indicated by the act that partial agonists competitively inhibit the responses produced by full agonists  Competitive & Irreversible Antagonists Receptor antagonists bind to receptors but do not activate them; the primary action of antagonists is to reduce the effects of agonists (other drugs or endogenous regulatory molecules) that normally activate receptors. While antagonists are traditionally thought to have no functional effect in the absence of an agonist, some antagonists exhibit “inverse agonist” activity because they also reduce receptor activity below basal levels observed in the absence of any agonist at all. Antagonist drugs are further divided into two classes depending on whether or not they act competitively or noncompetitively relative to an agonist present at the same time.  Not all mechanisms of antagonism involve interactions of drugs or endogenous ligands at a single type of receptor, and some types of antagonism do not involve a receptor at all. For example, protamine, a protein that is positively charged at physiologic pH, can be used clinically to counteract the effects of heparin, an anticoagulant that is negatively charged. In this case, one drug acts as a chemical antagonist of the other simply by ionic binding that makes the other drug unavailable for interactions with proteins involved in blood clotting. Physiologic antagonism  Enhancement of Drug Effect 1. Addition (Kotrimoxazole) 2. Synergism (Penicillin with Gentamicin) 3. Potentiation (Amoksiclav)  References 1. Basic and Clinical Pharmacology, Katzung 2. Introdction to Pharmacodynamic, Reza Karimi 3. Pharmacodynamic, StatPearls, NCBI 4. Pharmacodynamic, Howdrugswork 5. Introduction to Pharmacokinetics and Pharmacodynamics Thank You