Pharmacology_1st Lec.pdf

Ass.Prof Dr. Dlawer Abdul Hammed AL Jaff Ph.D Pharmacology and toxicology Head Of Pharmacology Department  Pharmacology can be defined as the study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecul...

Ass.Prof Dr. Dlawer Abdul Hammed AL Jaff Ph.D Pharmacology and toxicology Head Of Pharmacology Department  Pharmacology can be defined as the study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes.  These substances may be chemicals administered to achieve a beneficial therapeutic effect on some process within the patient or for their toxic effects on regulatory processes in parasites infecting the patient.  A drug may be defined as any substance that brings about a change in biologic function through its chemical actions.  In the great majority of cases, the drug molecule interacts with a specific molecule in the biologic system that plays a regulatory role. This molecules called a receptor.  Toxicology is the branch of pharmacology that deals with the undesirable effects of chemicals on living systems, from individual cells to humans to complex ecosystems  In order to interact chemically with its receptor, a drug molecule must have the appropriate size, electrical charge, shape, and atomic composition.  Furthermore, a drug is often administered at a location distant from its intended site of action, eg, a pill given orally to relieve a headache  Therefore, a useful drug must have the necessary properties to be transported from its site of administration to its site of action.  Finally, a practical drug should be inactivated or excreted from the body at a reasonable rate so that its actions will be of appropriate duration.  A placebo is any component of therapy that is without specific biological activity for the condition being treated.  Placebo medicines are used for two purposes:  As a control in scientific evaluation of drugs  To benefit or please a patient, not by any pharmacological actions but by psychological means  The interactions between a drug and the body are conveniently divided into two classes. The actions of the drug on the body are termed pharmacodynamic processes  Qualitative aspects: Receptors, Enzymes, Selectivity  Quantitative aspects: Dose response, Potency, Therapeutic efficacy, Tolerance  Pharmacodynamics describes the actions of a drug on the body and the influence of drug concentrations on the magnitude 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 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.  [Note: The term “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.  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.  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.  Receptor states  Receptors exist in at least 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. 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 pharmacokinetic  Pharmacokinetic processes govern the  Time course of drug concentration: Drug passage across cell membranes; Order of reaction; Plasma half-life and steady-state concentration; Therapeutic drug monitoring  Individual processes: Absorption, Distribution, Metabolism, Elimination  Drug dosage: Dosing schedules  Individual or biological variation: Variability due to inherited influences, environmental and host influences  Drug interactions: outside the body, at site of absorption, during distribution, directly on receptors, during metabolism, during excretion  MECHANISMS  drugs act on the cell membrane by:  Action on specific receptors, e.g. agonists and antagonists on adrenoceptors, histamine receptors, acetylcholine receptors  Interference with selective passage of ions across membranes, e.g. calcium entry (or channel) blockers  Inhibition of membrane bound enzymes and pumps, e.g. membrane bound ATPase by cardiac glycoside; tricyclic antidepressants block the pump by which amines are actively taken up from the exterior to the interior of nerve cells.  Drugs act on metabolic processes within the cell by:  Enzyme inhibition, e.g. platelet cyclo- oxygenase by aspirin, cholinesterase by pyridostigmine, xanthine oxidase by allopurinol  Inhibition of transport processes that carry substances across cells, e.g. blockade of anion transport in the renal tubule cell by probenecid can be used to delay excretion of penicillin, and to enhance elimination of urate  Incorporation into larger molecules, e.g. 5- fluorouracil, an anticancer drug, is incorporated into messenger-RNA in place of uracil  In the case of successful antimicrobial agents, altering metabolic processes unique to microorganisms e.g. penicillin interferes with formation of the bacterial cell wall, or by affecting a process common to both humans and microbes, e.g. inhibition of folic acid synthesis by trimethoprim.  Drugs act outside the cell by:  Direct chemical interaction, e.g. chelating agents, antacids  Osmosis, as with purgatives, e.g. magnesium sulphate, and diuretics, e.g. mannitol, which are active because neither they nor the water in which they are dissolved are absorbed by the cells lining the gut and kidney tubules respectively.  Four main kinds of regulatory protein are commonly involved as primary drug targets, namely:  receptors  enzymes  carrier molecules (transporters)  ion channels.  There are some exceptions, particularly among the new generation of biopharmaceutical drugs. Furthermore, many drugs bind (in addition to their primary targets) to plasma proteins and other tissue proteins, without producing any obvious physiological effect  RECEPTORS  Most receptors are protein macromolecules. When the agonist binds to the receptor, the proteins undergo an alteration in conformation which induces changes in systems within the cell that in turn bring about the response to the drug  Receptors are the sensing elements in the system of chemical communications that coordinates the function of all the different cells in the body, the chemical messengers being the various hormones, transmitters and other mediators.  A. Ligand-gated ion channels  The first receptor family comprises ligand-gated ion channels that are responsible for regulation of the flow of ions across cell membranes.  The activity of these channels is regulated by the binding of a ligand to the channel.  Response to these receptors is very rapid, having durations of a few milliseconds. The nicotinic receptor and the Gaba aminobutyric acid (GABA) receptor are important examples of ligand-gated receptors, the functions of which are modified by numerous drugs.  Stimulation of the nicotinic receptor by acetylcholine results in sodium influx, generation of an action potential, and activation of contraction in skeletal muscle. Benzodiazepines, on the other hand, enhance the stimulation of the GABA receptor by GABA, resulting in increased chloride influx and hyperpolarization of the respective cell  B. G protein coupled receptors  A second family of receptors consists of G protein coupled receptors. These receptors are comprised of a single peptide that has seven membrane-spanning regions, and these receptors are linked to a G protein (Gs and others)  that binds guanosine triphosphate (GTP). Binding of the appropriate ligand to the extracellular region of the receptor activates the G protein so that GTP replaces  guanosine diphosphate (GDP). Dissociation of the G protein occurs, and both the-GTP subunit and the subunit subsequently interact with other cellular effectors, usually an enzyme or ion channel.  These effectors then change the concentrations of second messengers that are responsible for further actions within the  cell. Stimulation of these receptors results in responses that last several seconds to minutes.  C. Enzyme-linked receptors  A third major family of receptors consists of those having cytosolic enzyme activity as an integral component of their structure or function. Binding of a ligand to an extracellular domain activates or inhibits this cytosolic enzyme activity.  Duration of responses to stimulation of these receptors is on the order of minutes to hours. The most common enzyme-linked receptors (epidermal growth factor, platelet-derived growth factor, atrial natriuretic peptide, insulin, and others) are those that have a tyrosine kinase activity as part of their structure.  Typically, upon binding of the ligand to receptor subunits, the receptor undergoes conformational changes, converting from its inactive form to an active kinase form. The activated receptor autophosphorylates, andphosphorylates tyrosine residues on specific proteins. The addition of a phosphate group can substantially modify the three- dimensional structure of the target protein, thereby acting as a molecular switch.  For example, when the peptide hormone insulin binds to two of its receptor subunits, their intrinsic tyrosine kinase activity causes autophosphorylation of the receptor itself. In turn, the phosphorylated receptor phosphorylated target molecules—insulin- receptor substrate peptides ”that subsequently activate other important cellular signals such as IP3 and the mitogen-activated protein kinase system.