Pharmacology I Fall 2024 Lecture Notes PDF

Pharmacology I Prof. Mohamed Hamzawy Drug–Receptor Interactions and Pharmacodynamics Pharmacodynamics aims to study the actions of a drug on the body and the influence of drug concentrations on the degree of the response. Most drugs exert their effects, both beneficial and harmful, by...

Pharmacology I Prof. Mohamed Hamzawy Drug–Receptor Interactions and Pharmacodynamics Pharmacodynamics aims to study the actions of a drug on the body and the influence of drug concentrations on the degree of the response. Most drugs exert their effects, both beneficial and harmful, by interacting with receptors (that is, specialized target macromolecules) present on the cell surface or within the cell. The drug–receptor complex initiates series of modifications in biochemical and/or molecular activity of a cell by a process called signal transduction  Pharmacodynamics Most drugs exert their effects by interacting with receptors (that is, specialized target macromolecules) present on the cell surface or within the cell. The drug–receptor complex initiates alterations in biochemical and/or molecular activity of a cell by a process called signal transduction.  Signal Transduction Drugs act as signals, and their receptors act as signal detectors. Receptors transduce their recognition of a bound agonist by initiating a series of reactions that ultimately result in a specific intracellular response. Agonist refers to a naturally occurring small molecule or a drug that binds to a site on a receptor protein and activates it. Second messenger or effector molecules are part of the cascade of events that translates agonist binding into a cellular response.  Signal Transduction A. The drug–receptor complex Cells have many different types of receptors, each of which is specific for a particular agonist and produces a unique response. Cardiac cell membranes, for example, contain β receptors that bind and respond to epinephrine or norepinephrine, as well as muscarinic receptors specific for acetylcholine. These different receptor populations dynamically interact to control the heart’s vital functions.  Signal Transduction The magnitude of the response is proportional to the number of drug-receptor complexes. This concept is closely related to the formation of complexes between enzyme and substrate or antigen and antibody. These interactions have many common features, perhaps the most noteworthy being specificity of the receptor for a given agonist. Most receptors are named for the type of agonist that interacts best with it. For example, the receptor for histamine is called a histamine receptor.  Signal Transduction Although the effect of the drugs centers on the interaction of drugs with specific receptors, it is important to know that not all drugs exert their effects by interacting with a receptor. Antacids, for instance, chemically neutralize excess gastric acid, thereby reducing the symptoms of “heartburn.”.  Signal Transduction B. Receptor states Receptors exist in two states, inactive (R) and active (R*), that are in reversible equilibrium with one another, usually favoring the inactive state. Binding of agonists causes the equilibrium to shift from R to R* to produce a biologic effect. Antagonists occupy the receptor but do not increase the fraction of R* and may stabilize the receptor in the inactive state.  Signal Transduction B. Receptor states Some drugs (partial agonists) cause similar shifts in equilibrium from R to R*, but the fraction of R* is less than that caused by an agonist (but still more than that caused by an antagonist). The magnitude of biological effect is directly related to the fraction of R*. Agonists, antagonists, and partial agonists are examples of ligands, or molecules that bind to the activation site on the receptor.  Signal Transduction C. Major receptor families Receptor is any biologic molecule to which a drug binds and produces a measurable response. Enzymes, nucleic acids, and structural proteins can act as receptors for drugs or endogenous agonists. However, the richest sources of therapeutically relevant receptors are proteins that transduce extracellular signals into intracellular responses. C. Major receptor families Receptors may be divided into four families: 1) Ligand-gated ion channels 2) G protein–coupled receptors 3) Enzyme-linked receptors 4) Intracellular receptors Major receptor families  Signal Transduction The type of receptor a ligand interacts with depends on the chemical nature of the ligand. Hydrophilic ligands interact with receptors that are found on the cell surface (Figures A, B, C). Hydrophobic ligands enter cells through the lipid bilayers of the cell membrane to interact with receptors found inside cells (Figure D)  Signal Transduction 1. Transmembrane ligand-gated ion channels: The extracellular portion of ligand-gated ion channels usually contains the ligand binding site. This site regulates the shape of the pore through which ions can flow across cell membranes. The channel is usually closed until the receptor is activated by an agonist, which opens the channel briefly for a few milliseconds.  Signal Transduction 1. Transmembrane ligand-gated ion channels: Depending on the ion conducted through these channels, these receptors mediate diverse functions, including neurotransmission, and cardiac or muscle contraction. Example, stimulation of the nicotinic receptor by acetylcholine results in sodium influx and potassium outflux, generating an action potential in a neuron or contraction in skeletal muscle.  Signal Transduction 1. Transmembrane ligand-gated ion channels: Agonist stimulation of the γ-aminobutyric acid (GABA) receptor increases chloride influx and hyperpolarization of neurons. local anesthetics bind to the voltage-gated sodium channel, inhibiting sodium influx and decreasing neuronal conduction.  Signal Transduction 2. Transmembrane G protein–coupled receptors: The extracellular domain of this receptor contains the ligand- binding area, and the intracellular domain interacts (when activated) with a G protein or effector molecule. There are many kinds of G proteins (for example, Gs, Gi, and Gq), but they all are composed of three protein subunits. The α subunit binds (GTP), and the β and γ subunits anchor the G protein in the cell membrane G protein–coupled receptors  Signal Transduction 3. Enzyme-linked receptors: This family of receptors consists of a protein that may form dimers or multisubunit complexes. When activated, these receptors undergo conformational changes resulting in increased cytosolic enzyme activity, depending on their structure and function. This response lasts on the order of minutes to hours. e.g. insulin receptor Enzyme-linked receptors:  Signal Transduction 4. Intracellular receptors: The fourth family of receptors differs considerably from the other three in that the receptor is entirely intracellular, and, therefore, the ligand must diffuse into the cell to interact with the receptor. In order to move across the target cell membrane, the ligand must have sufficient lipid solubility. Intracellular receptors:  Some characteristics of signal transduction Signal transduction has two important features: 1) The ability to amplify small signals 2) Mechanisms to protect the cell from excessive stimulation.  Some characteristics of signal transduction 1. Signal amplification: A characteristic of G protein–linked and enzyme-linked receptors is their ability to amplify signal intensity and duration. e.g., a single agonist–receptor complex can interact with many G proteins, thereby multiplying the original signal many fold. Additionally, activated G proteins persist for a longer duration than does the original agonist–receptor complex.  Some characteristics of signal transduction 1. Signal amplification: e.g. The binding of albuterol may only exist for a few milliseconds, but the subsequent activated G proteins may last for hundreds of milliseconds. Further prolongation and amplification of the initial signal are mediated by the interaction between G proteins and their respective intracellular targets. Because of this amplification, only a fraction of the total receptors for a specific ligand may need to be occupied to elicit a maximal response.  Some characteristics of signal transduction 1. Signal amplification: Systems that exhibit this behavior are said to have spare receptors. Spare receptors are exhibited by insulin receptors, where it is estimated that 99% of receptors are “spare.” This constitutes an immense functional reserve that ensures that adequate amounts of glucose enter the cell.  Some characteristics of signal transduction 1. Signal amplification: In the human heart, only about 5% to 10% of the total β-adrenoceptors are spare. An important implication of this observation is that little functional reserve exists in the failing heart, because most receptors must be occupied to obtain maximum contractility  Some characteristics of signal transduction 2. Desensitization and down-regulation of receptors: Repeated or continuous administration of an agonist (or an antagonist) may lead to changes in the responsiveness of the receptor. When a receptor is exposed to repeated administration of an agonist, the receptor becomes desensitized resulting in a diminished effect. This phenomenon, is called tachyphylaxis,  Some characteristics of signal transduction 2. Desensitization and down-regulation of receptors: In addition, receptors may be down-regulated such that they are internalized and sequestered within the cell, unavailable for further agonist interaction. These receptors may be recycled to the cell surface, restoring sensitivity, or, alternatively, may be further processed and degraded, decreasing the total number of receptors available.  Some characteristics of signal transduction 2. Desensitization and down-regulation of receptors: Some receptors, particularly ion channels, require a finite time following stimulation before they can be activated again. During this recovery phase, unresponsive receptors are said to be “refractory.” Repeated exposure of a receptor to an antagonist may result in up-regulation of receptors, in which receptor reserves are inserted into the membrane, increasing the total number of receptors available. Up-regulation of receptors can make the cells more sensitive to agonists and/or more resistant to the antagonist. Intrinsic activity: Drugs may be categorized according to their intrinsic activity and resulting Emax values (Figure 2-5): Full agonists It is the drug that produces a maximal biologic response, when it binds If a drug to a receptor and mimics the response to the endogenous ligand. Full agonists for a receptor population should produce the same Emax and stabilizing the receptor in its active state associated with intrinsic activity For example, phenylephrine is a full agonist at α1-adrenoceptors, because it produces the same Emax as does the endogenous ligand, norepinephrine. Partial agonists Partial agonists have intrinsic activities greater than zero but less than full agonist. Partial agonists cannot produce the same Emax as a full agonist. However, a partial agonist may have an affinity that is greater than, less than, or equivalent to that of a full agonist. When a receptor is exposed to both a partial agonist and a full agonist, the partial agonist may act as an antagonist of the full agonist. Figure (2-5): Effects of full agonists, partial agonists, and inverse agonists on receptor activity. Antagonists Antagonists bind to a receptor with high affinity but possess zero intrinsic activity. An antagonist has no effect in the absence of an agonist but can decrease the effect of an agonist when present. Antagonism may occur either by blocking the drug’s ability to bind to the receptor or by blocking its ability to activate the receptor (Figure 2-6). Competitive antagonists: The competitive antagonist competes with agonist, thus prevents an agonist from binding to its receptor, and maintains the receptor in its inactive state. For example, the antihypertensive drug terazosin competes with the endogenous ligand norepinephrine at α1-adrenoceptors, thus decreasing vascular smooth muscle tone and reducing blood pressure. However, this inhibition can be overcome by increasing the concentration of agonist relative to antagonist. Functional antagonism: An antagonist may act at a completely separate or other receptor, initiating effects that are functionally opposite those of the agonist. Such as functional antagonism by epinephrine to histamine-induced bronchoconstriction. Histamine binds to H1 histamine receptors on bronchial smooth muscle, causing bronchoconstriction of the bronchial tree. Epinephrine is an agonist at β2-adrenoceptors on bronchial smooth muscle, which causes the muscles to relax. This functional antagonism is also called “physiologic antagonism.”