Pharmacology Dr Yahya Lecture 1 PDF

University of Alkafeel, College of Medicine, Year 1, Course 1 16/09/2024 1  Learning Objective 1. Introduction and history of the pharmacology. 2. Source and nature of drugs 3. DRUG DEVELOPMEN...

University of Alkafeel, College of Medicine, Year 1, Course 1 16/09/2024 1  Learning Objective 1. Introduction and history of the pharmacology. 2. Source and nature of drugs 3. DRUG DEVELOPMENT & REGULATION. 4. Drug -Receptors & Pharmacodynamics 5. Know how drugs to act. 6. Safety & efficacy of the drugs. 02/01/2024 Email :[email protected] Website :http://Alkafeel.edu.iq 2  Introduction to Pharmacology Pharmacology is the body of knowledge concerned with the action of chemicals on biological systems. Medical pharmacology is the area of pharmacology concerned with using chemicals to prevent, diagnose, and treat disease, especially in humans. Toxicology is the area of pharmacology concerned with the undesirable effects of chemicals on biological systems. Pharmacokinetics describes the effects of the body on drugs, eg, absorption, metabolism, and excretion. Pharmacodynamics denotes the drug’s actions on the body, such as mechanism of action and therapeutic and toxic effects. 02/01/2024 Email :[email protected] Website :http://Alkafeel.edu.iq 3  Introduction to Pharmacology Placebo An inactive “dummy” medication made up to resemble the active investigational formulation as much as possible but lacking therapeutic effect. Single-blind study A clinical trial in which the investigators— but not the subjects—know which subjects are receiving active drugs and which are receiving placebos Double-blind study A clinical trial in which neither the subjects nor the investigators know which subjects are receiving placebos; the code is held by a third party Orphan drugs Drugs developed for diseases in which the expected number of patients is small. Email :[email protected] Dr. Yahya Ibrahim Website :http://Alkafeel.edu.iq Ph.D. Pharmacology (1) Synthetic drugs: Aspirin , Paracetamol, antidiabetics, antihistaminic (2) Natural Drugs : (a) Plant: morphine, codeine, quinine. (b) Animal: gonadotropins, heparin, enzymes. (c) Microorganisms: penicillin, streptomycin. (d) Minerals: iron, calcium, Magnesium. (3) Semi-synthetic drugs: Ampicillin, Amoxicillin, Cloxacillin (4) Biosynthetic drugs: -Biosynthesis of insulin by inserting the human pro insulin gene cDNA in E. coli. -Growth hormone, -hepatitis vaccine Email :[email protected] Dr. Yahya Ibrahim 2 Website :http://Alkafeel.edu.iq Ph.D. Pharmacology Introduction to Pharmacology Email :[email protected] Website :http://Alkafeel.edu.iq  THE NATURE OF DRUGS A. Size and Molecular Weight Drugs vary in size from molecular weight (MW) 7 (lithium) to over MW 50,000 (thrombolytic enzymes, antibodies, other proteins). Most drugs, however, have MWs between 100 and 1000. Drugs smaller than MW 100 are rarely sufficiently selective in their actions, whereas drugs much larger than MW 1000 are often poorly absorbed and poorly distributed in the body. Email :[email protected] Website :http://Alkafeel.edu.iq  THE NATURE OF DRUGS B. Drug-Receptor Bonds Drugs bind to receptors with a variety of chemical bonds. These include very strong covalent bonds (which usually result in irreversible action), somewhat weaker reversible electrostatic bonds (eg, between a cation and an anion), and (eg, hydrogen, van der Waals, and hydrophobic bonds). Email :[email protected] Website :http://Alkafeel.edu.iq  THE NATURE OF DRUGS Affinity: the tendency of a drug to bind to the receptor, the higher the affinity, the lower the concentration required to produce a given level of receptor occupancy. Several types of bonds are involved in drug-receptor interaction: Van der Waals bonds Hydrogen bonds Reversible binding Electrostatic bonds Covalent bonds → Irreversible binding Email :[email protected] Website :http://Alkafeel.edu.iq  II. DRUG DEVELOPMENT & REGULATION The sale and use of drugs are regulated in most countries by governmental agencies. In the United States, regulation is by the Food and Drug Administration (FDA). New drugs are developed in industrial or academic laboratories. Before a new drug can be approved for regular therapeutic use in humans, a series of animal and experimental human studies (clinical trials) must be carried out. Preclinical study: Intact animal study ( in Vivo) Isolated organ or tissue (in Vitro) Email :[email protected] Website :http://Alkafeel.edu.iq  II. DRUG DEVELOPMENT & REGULATION SAFETY & EFFICACY evidence of relative safety (derived from acute and subacute toxicity testing in animals) and probable therapeutic action (from the pharmacologic profile in animals) before human testing is permitted A. Acute Toxicity These studies involve the administration of incrementing doses of the agent up to the lethal level in at least 2 species (eg, 1 rodent and 1 non rodent). B. Subacute and Chronic Toxicity testing is required for most agents, especially those intended for chronic use. Doses are selected based on the results of acute tests. Tests are usually conducted for 2–4 weeks (subacute) and 6–24 months (chronic), in at least 2 species. Email :[email protected] Website :http://Alkafeel.edu.iq II. DRUG DEVELOPMENT & REGULATION Email :[email protected] Website :http://Alkafeel.edu.iq Drug -Receptors & Pharmacodynamics Email :[email protected] Website :http://Alkafeel.edu.iq Pharmacodynamics & Pharmacokinetics Email :[email protected] 14 Website :http://Alkafeel.edu.iq Pharmacodynamic phase Email :[email protected] 15 Website :http://Alkafeel.edu.iq Action vs effect Email :[email protected] 16 Website :http://Alkafeel.edu.iq Action vs effect Email :[email protected] 17 Website :http://Alkafeel.edu.iq How drug to act Email :[email protected] 18 Website :http://Alkafeel.edu.iq 2 5 S e p RECEPTORS t e m b e Receptors are the specific molecules in a biological system r 2 0 with which drugs interact to produce changes in the function 2 3 of the system. Receptors must be selective in their ligand-binding characteristics (to respond to the proper chemical signal and not to meaningless ones). Receptors must also be modifiable when they bind a drug molecule (to bring about the functional change). The term “ligand” refers to a small molecule that binds to a specific site on the receptor and activates the receptor (the ligand may be a naturally occurring molecule or a drug). Email :[email protected] 19 Website :http://Alkafeel.edu.iq RECEPTORS Email :[email protected] 20 Website :http://Alkafeel.edu.iq Email :[email protected] 21 Website :http://Alkafeel.edu.iq  EFFECTORS Effectors are molecules that translate the drug-receptor interaction into a change in cellular activity. The best examples of effectors are enzymes such as adenylyl cyclase. Some receptors are also effectors in that a single molecule may incorporate both the drug-binding site and the effector mechanism. For example, a tyrosine kinase effector is part of the insulin receptor molecule, and a sodium-potassium channel is the effector part of the nicotinic acetylcholine receptor. Email :[email protected] 22 Website :http://Alkafeel.edu.iq  GRADED DOSE-RESPONSE RELATIONSHIPS When the response of receptor-effector system is measured against increasing concentrations of a drug, the graph of the response versus the drug concentration or dose is called a graded dose- response curve. The efficacy (Emax) and potency (EC50 or ED50) parameters are derived from these data. The smaller theEC50 (or ED50), the greater the potency of the drug. Email :[email protected] 23 Website :http://Alkafeel.edu.iq GRADED DOSE-RESPONSE RELATIONSHIPS Email :[email protected] 24 Website :http://Alkafeel.edu.iq  GRADED DOSE-RESPONSE RELATIONSHIPS B. Same data, logarithmic dose axis. The dose or concentration at which the effect is half-maximal is denoted EC50, whereas the maximal effect is Emax. Email :[email protected] 25 Website :http://Alkafeel.edu.iq  GRADED DOSE-BINDING RELATIONSHIP & BINDING AFFINITY If the percentage of receptors that bind drugs is plotted against drug concentration, a similar curve is obtained. The concentration at which 50% of the receptors are bound is denoted Kd, and the maximal number of receptors bound is termed Bmax. Email :[email protected] 26 Website :http://Alkafeel.edu.iq GRADED DOSE-RESPONSE RELATIONSHIPS Email :[email protected] 27 Website :http://Alkafeel.edu.iq  GRADED DOSE-RESPONSE RELATIONSHIPS The smaller the Kd, the greater the affinity of the drug for its receptor. If the number of binding sites on each receptor molecule is known, it is possible to determine the total number of receptors in the system from the Bmax. (drug-receptor binding) Drug + Receptor ↔ Drug–receptor complex → Biologic effect Email :[email protected] 28 Website :http://Alkafeel.edu.iq  QUANTAL DOSE-RESPONSE RELATIONSHIPS is defined as the minimum dose required to produce a specified response is determined in each member of a population. Quantal dose-response plots from a study of the therapeutic and lethal effects of a new drug in mice. The median effective (ED50), median toxic (TD50), and (in animals) median lethal (LD50) doses are derived from experiments carried out in this manner. Email :[email protected] 29 Website :http://Alkafeel.edu.iq QUANTAL DOSE-RESPONSE RELATIONSHIPS Email :[email protected] 30 Website :http://Alkafeel.edu.iq  QUANTAL DOSE-RESPONSE RELATIONSHIPS Quantal dose-response data provide information about the variation in sensitivity to the drug in a given population, and if the variation is small, the curve is steep. Email :[email protected] 31 Website :http://Alkafeel.edu.iq  Efficacy: the ability of a drug to elicit a response when it interacts with a receptor. Efficacy is dependent on the number of drug–receptor complexes. Efficacy is more important than drug potency. A drug with greater efficacy is more therapeutically beneficial than one that is more potent. Maximal efficacy assumes that all receptors are occupied by the drug, and no increase in response will be observed if more drugs are added. This concept holds true only if there are no "spare receptors" Email :[email protected] 32 Website :http://Alkafeel.edu.iq  Potency: The concentration of the drug producing an effect that is 50 percent of the maximum( EC50). Potency is determined mainly by the affinity of the receptor for the drug and the number of receptors available. In quantal dose-response measurements, ED50, TD50, and LD50 are also potency variables (median effective, toxic, and lethal doses, respectively( Email :[email protected] 33 Website :http://Alkafeel.edu.iq Email :[email protected] 34 Website :http://Alkafeel.edu.iq Email :[email protected] 35 Website :http://Alkafeel.edu.iq  SPARE RECEPTORS Spare receptors are exist if the maximal drug response (Emax) is obtained at less than 100% occupation of the receptors (Bmax). If the EC50 is ˂ Kd, spare receptors are said to exist. Email :[email protected] 36 Website :http://Alkafeel.edu.iq  SPARE RECEPTORS This might result from 1 of 2 mechanisms. First: the duration of the activation of the effector may be much greater than the duration of the drug-receptor interaction. Second: the actual number of receptors may exceed the number of effector molecules available. The presence of spare receptors increases sensitivity to the agonist Email :[email protected] 37 Website :http://Alkafeel.edu.iq  AGONISTS, PARTIAL AGONISTS, & INVERSE AGONISTS receptor to have at least 2 states—active )Ra) and inactive(Ri). Many receptor systems exhibit some activity in the absence of ligand, called constitutive activity. Full agonist a drug binds to a receptor and produces a maximal biological response that mimics the response to the endogenous ligand For example, phenylephrine is an agonist at α1- adrenoceptors, because it produces effects that resemble the action of the endogenous ligand, norepinephrine. Email :[email protected] Website :http://Alkafeel.edu.iq  AGONISTS, PARTIAL AGONISTS, & INVERSE AGONISTS Partial agonist A drug that binds to its receptor but produces a smaller effect at full dosage than a full agonist. Partial agonists have efficacies (intrinsic activities) greater than zero but less than that of a full agonist. In the presence of a full agonist, a partial agonist acts as an inhibitor. In contrast, inverse agonists have a much higher affinity for the inactive Ri state than for Ra and decrease or abolish any constitutive activity. Email :[email protected] 39 Website :http://Alkafeel.edu.iq  ANTAGONISTS A. Competitive and Irreversible Pharmacologic Antagonists If both the antagonist and the agonist bind to the same site on the receptor, they are said to be “competitive.” The competitive antagonist will prevent an agonist from binding to its receptor and maintain the receptor in its inactive conformational 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. Email :[email protected] 40 Website :http://Alkafeel.edu.iq  ANTAGONISTS Irreversible antagonists An irreversible antagonist causes a downward shift of the maximum, with no shift of the curve on the dose axis unless spare receptors are present. The effects of competitive antagonists can be overcome by adding more agonists. Irreversible antagonists, by contrast, cannot be overcome by adding more agonists. Competitive antagonists increase the ED50, whereas irreversible antagonists do not (unless spare receptors are present). Email :[email protected] 41 Website :http://Alkafeel.edu.iq ANTAGONISTS Email :[email protected] 42 Website :http://Alkafeel.edu.iq  ANTAGONISTS There are two mechanisms by which an agent can act as a noncompetitive antagonist. I. The antagonist can bind covalently or II. with very high affinity to the active site of the receptor (irreversible antagonist). The second type of antagonist binds to a site ("allosteric site") other than the agonist binding site. This allosteric antagonist prevents the receptor from being activated even when the agonist is attached to the active site. Email :[email protected] 43 Website :http://Alkafeel.edu.iq  B. Physiologic Antagonists A physiologic antagonist binds to a different receptor molecule, producing an effect opposite to that produced by the drug it antagonizes. Thus, it differs from a pharmacologic antagonist, which interacts with the same receptor as the drug it inhibits. Familiar examples of physiologic antagonists are the antagonism of the bronchoconstrictor action of histamine by epinephrine’s bronchodilator action. Email :[email protected] 44 Website :http://Alkafeel.edu.iq  C. Chemical Antagonists A chemical antagonist interacts directly with the drug being antagonized to remove it or to prevent it from binding to its target. A chemical antagonist does not depend on interaction with the agonist’s receptor (although such interaction may occur). Common examples of chemical antagonists are dimercaprol, a chelator of lead and some other toxic metals, and pralidoxime, which combines with the phosphorus in organophosphate cholinesterase inhibitors. Email :[email protected] 45 Website :http://Alkafeel.edu.iq  THERAPEUTIC INDEX & THERAPEUTIC WINDOW ❖ Is a measure which relates the dose of a drug required to produce a desired effect to that which makes an undesired effect ❖ denotes the safety of the drugs ❖ TI=LD50 /ED50 （LC50 /EC50 ） The larger the value of the TI is, the wider the margin between effective dose and toxic dose is. For example, the drug TI=4 is safer than that of TI=2. Email :[email protected] 46 Website :http://Alkafeel.edu.iq  SIGNALING MECHANISMS The receptor-effector system may be 1) ligand-gated ion channels, eg. Cholinergic nicotinic receptors. 2) G protein-coupled receptors, eg. alpha and beta-adrenoceptors. 3) Enzyme-linked receptors, eg. Insulin receptors. 4) intracellular receptors, eg. Steroid receptors. Email :[email protected] 47 Website :http://Alkafeel.edu.iq SIGNALING MECHANISMS Email :[email protected] 48 Website :http://Alkafeel.edu.iq  1- Transmembrane ligand-gated ion channels: The first receptor family comprises ligand-gated ion channels that are responsible for the regulation of the flow of ions across cell membranes. The activity is regulated by the binding of a ligand to the channel. Response to these receptors is very rapid (a few milliseconds). These receptors mediate diverse functions, including neurotransmission, cardiac conduction, and muscle contraction. Email :[email protected] 49 Website :http://Alkafeel.edu.iq  1- Transmembrane ligand-gated ion channels: For example, 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 γ-aminobutyric acid (GABA) receptor by GABA, resulting in increased chloride influx and hyperpolarization of the respective cell. Email :[email protected] 50 Website :http://Alkafeel.edu.iq  2. Transmembrane G protein-coupled receptors: ❖ These receptors are linked to a G protein (Gs, Gi, and others) having three subunits, an α subunit that binds guanosine triphosphate (GTP) and a βγ subunit ❖ Binding of the ligand activates the G protein so that GTP replaces (GDP) on the α subunit. ❖ Dissociation of the G protein occurs, and both the α-GTP subunit and the βγ subunit subsequently interact with other cellular effectors, usually an enzyme, a protein, or an ion channel. ❖ Stimulation of these receptors results in responses that last several seconds to minutes. Email :[email protected] 51 Website :http://Alkafeel.edu.iq Email :[email protected] 52 Website :http://Alkafeel.edu.iq 2 5 Second messengers S e p t e m b e r 2 The small molecule metabolite or ion. 0 2 3 Second messengers can diffuse through a cell and carry information to a wide variety of targets. Well-studied second messengers include cyclic AMP and cyclic GMP, Ca2+, phosphoinositides, and nitric oxide. Email :[email protected] 53 Website :http://Alkafeel.edu.iq 2 5 Second messengers S e p t e m b A. Cyclic AMP e r 2 0 Is the prototypical second messenger 2 3 Is synthesized by adenylyl cyclase under the control of many G protein-coupled receptors The activity of adenylyl cyclase can be modulated by phosphorylation and other regulatory influences Email :[email protected] 54 Website :http://Alkafeel.edu.iq  Second messengers B. Calcium and Phosphoinositides ❖Phospholipase C (PLC )splits the phosphatidylinositol-4,5- bisphosphate (PIP2) into diacylglycerol (DAG) and inositol- 1,4,5- trisphosphate (IP3) ❖DAG is limited to the membrane and activates a phospholipid- and calcium- sensitive protein kinase (protein kinase C). ❖IP3 triggers release of Ca2+ from internal storage vesicles Email :[email protected] 55 Website :http://Alkafeel.edu.iq  3. Enzyme-linked receptors: These receptors also have cytosolic enzyme activity as an integral component of their structure and function. 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, peptide, insulin, and others) that have a tyrosine kinase activity as part of their structure. Email :[email protected] 56 Website :http://Alkafeel.edu.iq  4. Intracellular receptors: the ligand must diffuse into the cell to interact with the receptor, & have lipid solubility to be able to move across the target cell membrane. The activation or inactivation of these factors causes the transcription of DNA into RNA and the translation of RNA into a group of proteins. For example, steroid hormones exert their action on target cells via this receptor mechanism. Email :[email protected] 57 Website :http://Alkafeel.edu.iq RECEPTOR REGULATION Frequent or continuous exposure to agonists results in short- term diminution of the receptor response, sometimes called tachyphylaxis. Several mechanisms are responsible for this phenomenon. Email :[email protected] 58 Website :http://Alkafeel.edu.iq RECEPTOR REGULATION Long-term reductions in receptor number (downregulation) may occur in response to continuous exposure to agonists. The opposite change (upregulation) occurs when receptor activation is blocked for prolonged periods (usually several days) by pharmacologic antagonists or by denervation. Email :[email protected] 59 Website :http://Alkafeel.edu.iq  The end Tuesday, Email :[email protected] Website :http://Alkafeel.edu.iq 60 August