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Pharmacology Pharmacodynamic part 1 PharmDr. Davoud Ahmadimoghaddam, Ph.D. Department of Pharmacology & Toxicology School of Pharmacy, Hamadan University of Medical Sciences  :‫منابع آموزشی‬ Basic And Cli...

Pharmacology Pharmacodynamic part 1 PharmDr. Davoud Ahmadimoghaddam, Ph.D. Department of Pharmacology & Toxicology School of Pharmacy, Hamadan University of Medical Sciences  :‫منابع آموزشی‬ Basic And Clinical Pharmacology Book by Bertram G. Katzung Rang & Dale's Pharmacology Goodman & Gilman's The Pharmacological Basis of Therapeutics  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.  Pharmacology Such deliberate therapeutic applications may be considered the proper role of medical pharmacology, which is often defined as the science of substances used to prevent, diagnose, and treat disease. 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.  Drug-body Interactions Pharmacodynamic processes The actions of the drug on the body Pharmacokinetic processes The actions of the body on the drug Pharmacokinetic processes govern the absorption, distribution, elimination of drugs are of great practical importance in the choice and administration of a particular drug for a particular patient, eg, a patient with impaired renal function  General Principles Of Pharmacology drug ► any substance that brings about a change in biologic function through its chemical actions. In most cases, the drug molecule interacts as an agonist (activator) or antagonist (inhibitor) with a specific molecule in the biologic system that plays a regulatory role. This target molecule is called a receptor!  General Principles Of Pharmacology To interact chemically with its receptor, a drug molecule must have the appropriate : size electrical charge shape 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.  The Physical Nature of Drugs Solid → aspirin, atropine Liquid → nicotine, ethanol Gaseous → nitrous oxide, halothane, amyl nitrite These factors often determine the best route of administration! The most common routes of administration: intravenous (IV), Intramuscular (IM), Subcutaneous (Sc), Oral (PO), Rectal (PR), Inhalation, Transdermal A number of useful or dangerous drugs are inorganic elements, eg, lithium, iron, heavy metals Many organic drugs are weak acids or bases! The various classes of organic compounds—carbohydrates, proteins, lipids, and their constituents—are all represented in pharmacology  Drug size Lithium ion MW 7 – Alteplase (t-PA) MW 59,050 Majority between 100 – 1000 MW Good fit to only one receptor ↔ sufficiently unique in shape, charge, etc → to prevent its binding to other receptors (at least 100 MW in most cases) Larger than > 1000 MW no diffusion readily between compartments of body → admin. Directly into their site of action! eg. Alteplase, a clot-dissolving enzyme, iv  Drug reactivity & drug-receptor bonds Drugs interact with receptors by means of chemical forces or bonds covalent, electrostatic, and hydrophobic Covalent Not readily broken Last longer after the free drug has disappeared form blood Phenoxybenzamine + α receptor of norepinephrine = blockade of the receptor Reversed only the synthesis of new α receptors (48hrs)  acetyl group of acetylsalicylic acid (aspirin) and cyclooxygenase = platelet aggregation–blocking effect  Reversed only by the synthesis of new enzyme cyclooxygenase in new platelets, a process that takes several days Other e.g. DNA- alkylating agents: Cyclophosphamide, Cisplatin  Drug reactivity & drug-receptor bonds Electrostatic bond  much more common than covalent bonding in drug-receptor interactions  Strong linkage between permanently charged ionic molecules  Weak hydrogen bonds  Very weak induced dipole interactions : van der waals forces  Weaker than covalent bonds  Drug reactivity & drug-receptor bonds Hydrophobic bonds quite weak Important in the interaction on highly lipid-soluble drugs with lipids of cell membrane  interactions of drugs with the internal walls of receptor pockets  Drug reactivity & drug-receptor bonds Drugs which bind through weak bond to their receptors are generally more selective then drugs which bind through very strong bonds → this is bcz weak bonds require a very precise fit of the drug to its receptor if an interaction is to occur. How to design a highly selective short-acting drug for a particular receptor?  avoid highly reactive molecule that form covalent bonds  instead choose molecules that from weaker bonds  Drug reactivity & drug-receptor bonds A few substances that are almost completely inert in the chemical sense nevertheless have significant pharmacologic effects. eg., xenon, an “inert” gas, has anesthetic effects at elevated pressures  Drug shape Must be such as to permit binding to its receptor site Is complementary to that of the receptor site (key & lock) More than half of all useful drugs are chiral molecules! (enantiomer pairs) (stereoisomerism) Ephedrine → 2 asymmetric centers → 4 diasteromers ↔ one enantiomer is more potent »» reflecting a better fit to the receptor molecule. (S) (+) methacholine (parasympathomimetic) 250x more potent > (R) (-) enantiomer The more active enantiomer at one type of receptor site may not be more active at another type! e.g. a receptor type that are responsible for some unwanted effect → Carvediol (nonselective βB & α), has a single chiral center ↔ 2enantiomers → (S)(-) isomer = potent βB , (R)(+) isomer = 100x weaker at β receptor! two stereoisomers of carvedilol on the β receptor  Drug shape Ketamine (i.v. anesthetic) → (+) enantiomer more potent >>> and less toxic