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Unformatted text preview: Overview of Pharmaceutical Industry Login and password: “marijuana” (Legal Drug Mfg from Lec 2) Drug nomenclature and classification Pharmacokinetics Pharmacodynamics Pharmacodynamics WEBSITE http://mocolab.org/Courses/Psyc181.html Psych 181: Lecture 3 Professor Anagnostaras Legal Drug Manufacturing in the World • There are 24,000 drugs on the market in the US, with about 1100 different ingredients (up 7x since 1990) • About 300 are commonly prescribed 2 3 QuickTimeª and a TIFF (Uncompressed) decompressor are needed to see this picture. 4 QuickTimeª and a TIFF (Uncompressed) decompressor are needed to see this picture. 5 6 Legal Drug Manufacturing in the World • Typical profit margin of a Pharmaceutical company is three times that of any other industry represented by Fortune • For every year since 1982, Pharmaceutical industry has had the highest profit margin of any industry. • In 2008, US Drug sales were $305 billion, about 40% of world total of $745 billion (US is about 5% of world population). • In 1999, NIH spent $17.8 billion for 7research and pharms spent $22.7 billion, according to 8 9 10 QuickTimeª and a TIFF (Uncompressed) decompressor are needed to see this picture. 11 12 Market Share & Competition Market Pharmaceutical Automobile Source: IMS Health. Figures for 2000 Express Scripts Drug Trend Report, 1997 Health Patents by Country of Inventor Health Based on nearly 40,000 triadic patent families filed from 1988 to 1995 Frank Lichtenberg and Suchin Verabhak, Using Patent Data to Map Technical Change in Health-Related Areas, Organization for Economic Cooperation and Development, STI Working Papers, Jan. 16, 2003 Demographics • Highly prevalent neuro-psychochological disorders: Highly - Insomnia (60 million) - Migraine (40 million) - Depression (20 million) - Anxiety Disorders (19 million) - Alzheimer's (4 million) - Schizophrenia (3 million) - Stroke (3 million) - Head Injury (2.5 million) - Parkinson's disease (1.5 million) - Pain (#1 Patients' complaint) Pricing Determine margins, research capacity, and internationalization. internationalization. U.S. is the only country globally with a“free U.S. pricing policy” -- new drugs cost about $2-3 per pill or "whatever the market will bear” per This results in higher R&D success and This higher profits. higher US VS. CANADA DRUG PRICES (VERMONT VS MONTREAL) XXX Azmacort $50.70 US $18.85 CA $31.85 63% Celebrex, 100 mg/cap, 60 $77.15 US $33.75 CA $43.40 56% Flonase Nasal $46.00 US $23.00 CA $23.00 50% Lipitor, 20 mg., 90 $229.93 US $164.00 CA $65.93 29% Methotrexate, 2.5 mg., 28 $47.84 US $21.00 CA $26.84 56% Pravachol, 20 mg., 30 $64.38 US $47.50 CA $16.88 26% Prozac, 20 mg., 45 $105.64 US $43.00 CA $62.64 59% Welbutrin, 1 2x daily SR150 mg, 60 $81.98 US $45.00 CA $36.98 45% Prilosec, 20 mg, 90Zocor, 80 mg, 30 $360.50 US $101.82 US $170.36 CA $60.00 CA $190.14 $41.82 53% 41% Propulsid, 20 mg, 200 $289.20 US $200.00 CA $89.20 31% Zoloft, 50 mg., 30 $62.00 US $31.00 CA $31.00 50% http://bernie.house.gov/prescriptions/drugsheet.asp Average US to Canadian Price Ratios, Patented Drug Products, 2002 (with alternative exchange rates) Outline of Drug Development Discern unmet medical need Discern Discover mechanism of action of disease Identify target protein Screen known compounds against target Chemically develop promising leads Find 1-2 potential drugs Toxicity, pharmacology Clinical Trials Approaches to drug discovery • Successful candidate drug in rats (or mice) • Test in monkeys for toxicity and efficacy • Market evaluation - jobs from entire unit can be lost in a day - big problem for scientist retention • Clinical trials • Approval - every aspect of drug is regulated - e.g., specific manufacturing process can take years to approve (Regulatory affairs dept). Pharmacology: overview Nomenclature & Classification Pharmacokinetics Pharmacodynamics Principles of Pharmacology Principles Pharmacology q “The branch of medicine that The deals with the uses, effects, and modes of actions of drugs”. modes (The New Shorter Oxford English Dictionary) Principles of Pharmacology Principles Drug Nomenclature What is a drug? (Pharmakon (G.), poisons and medicines) Substance that is used, "primarily to bring Substance about a change in some existing process or state, be it psychological, physiological or biochemical" or Sources of psychoactive agents Sources 1. Naturally occurring 1. Examples: Ephedrine, which is extracted from plant which indigenous to China, ma huang (Ephedra equisetina). equisetina). Cocaine, from the leaves of the coca plant Opium, extracted from the unripe seed extracted pods of the opium poppy pods Sources of psychoactive agents Sources 2. Semisynthetics Examples: Heroin (from morphine) LSD (from fungi that grow on grain) grain) Sources of psychoactive agents Sources 3. Synthetics Examples: Methadone (synthetic opiate) Amphetamine (powerful stimulant) stimulant) Sources of psychoactive agents Sources q Opium q Morphine q Heroin Methadone q Naming Pharmaceuticals q q q q q q q Chemical name Manufacturer's laboratory designation Chemical group name Generic or nonproprietary name Proprietary (brand) name General-use name Street names Drug classification q By Origin q By Action Relative to a By Prototype Prototype q Therapeutic Use q Mechanism of Action q Chemical Structure Drug classification Behavioral effects q CNS q q q q depressants - Sedative hypnotics - Anxiolytics Stimulants Stimulants Narcotic analgesics Narcotic Hallucinogens (psychedelics) Hallucinogens Others Others Drug classification Legal Classification (Drug Schedules) q q q q q q q Schedule I (heroin, psilocybin, LSD, THC, Schedule mescaline) mescaline) Schedule II (morphine, cocaine, amphetamines) Schedule III (ASA w/codeine, anabolic steroids) Schedule IV (diazepam, phenothiazines) Schedule V (cough syrup with codeine) Unscheduled Drugs (aspirin, tylenol, Prozac) Some states have Schedule VI (inhalants) Pharmacokinetics Area of pharmacology dealing Area with, "the absorption, distribution, biotransformation and excretion of drugs” and Pharmacokinetics Factors q Route of administration q Absorption and distribution q Inactivation q Elimination Routes of administration Routes q q q q Oral (p.o., per os, via the mouth) Parenteral injection (through the skin)  Subcutaneous (s.c., s.q., subq)  Intramuscular (i.m.)  Intravenous (i.v.)  Intraperitoneal (i.p., same as i.c.) Pulmonary absorption (inhalation) Topical application Common administration abbreviations (mostly latin) abbreviations q q q q q q q q q q q b.i.d. t.i.d. q.i.d. p.r.n. q_ u.d. r.t.c. m.g. n.p.o. h.s. h.s. p.c. Twice a day Three times a day Four times a day as needed every (e.g., q3h, qd, q3d) as directed round the clock milligram, mcg = microgram nothing by mouth At bedtime At after a meal Routes of administration Drug half-life varies as a function of route of administration of Half-life = time Half-life for plasma drug conc. to fall to half of peak level half Routes of administration Routes Effects of route of administration on rate of Effects absorption are due to many factors: absorption q Surface area available for absorption q Blood circulation at the site of Blood administration administration q Amount of drug destroyed immediately q Extent of binding to inert substances Drug distribution Drug Transport Across Membranes Drug q Most important factor in achieving active dose Most at site of action (e.g., brain) at Drug must pass through many cell membranes q (Cells in gut, blood vessels, glial cells, (Cells neurons) neurons) q Mechanism of transport Mechanism Passive diffusion Limits: • size and shape of drug molecule size • lipid solubility of drug lipid • degree drug is ionized (charged) degree Lipid solubility Ionization is the major factor: When drugs are ionized (charged) they When become much less lipid soluble, and drugs tend to become ionized when dissolved in solution dissolved More ionized > less lipid soluble > More less absorption > less effect less Degree of ionization Major factors: q Is the drug a weak acid or weak base (most drugs are weak acids or bases) Is the solvent an acid or a base (drugs that are weak acids ionize more in (drugs basic [alkaline] environments, and drugs that are weak bases ionize more in acidic environments) environments) q Ion trapping - aspirin Aspirin is a weak acid with a pKa of 3.5 q q q in stomach (pH 2-3), most aspirin not ionized in intestine (pH 5-6), more ionized aspirin better absorbed from stomach in blood (pH 7.4), most ionized once aspirin moves from stomach to blood once is trapped in blood (not move easily from trapped blood back to stomach) blood Absorption - Other factors q Drug must be able to survive low pH q Even if ionized and not very lipid Even soluble, digestive track has enormous surface area so may still get significant absorption absorption q Other special barriers Blood-Brain Barrier Limits the ability of drugs to Limits reach the brain, even when they can reach other tissues can Blood-Brain Barrier (a) Typical capillary Cell nucleus Basement membrane (b) Brain capillary Lipid-soluble transport Intercellular cleft Pinocytotic vesicle Lipid-soluble transport Carrier-mediated transport Tight junction Astrocytic process Fenestra 1.6 Astroglia: help comprise blood-brain barrier astroglia sends processes which cover blood vessel Pharmacokinetics Drug Inactivation and Elimination q q Inactivation usually by metabolism (biotransformation) to inactive forms (biotransformation) (liver major site) Elimination (metabolites or unchanged drug; kidney major site) drug; - but also lungs, sweat, saliva, feces or but milk milk Pharmacodynamics “The study of the biochemical The effects of drugs and their mechanism of action” mechanism Objective is identification of the Objective primary actions of a drug primary Receptors The initial site of action of biologically active The agents, including drugs agents, (The molecule a drug interacts with to initiate (The its biological effects) its To have an effect a drug must reach its To receptor receptor - Its ability to get to the receptor is the realm Its of pharmacokinetics of - What it does when it gets there is the realm What of pharmacodynamics of q Receptors D + R = DR > pharmacological effect Drug receptor interactions may involve many Drug different types of chemical bonds, but usually weak non-covalent interactions that are reversible reversible (For example, ionic or electrostatic (For interactions) interactions) Drug associates and then rapidly dissociates Law of Mass Action D + R = DR* > effect effect The active complex (DR*) leads to leads a cellular response that is in proportion to the fraction of receptors occupied receptors q Drugs do not produce new or unique Drugs cellular responses but only modify the rate of ongoing cellular events rate Law of Mass Action according to D + R = DR* > effect according DR effect q The magnitude of a drug effect should The be proportional to the number of receptors occupied by the drug, and receptors q A drug should have a maximal effect drug when all receptors are occupied when This relationship is described by the This dose-effect curve dose-effect Dose-effect curves Percent effect 100 75 50 25 1 10 100 1.7 Log dose (mg) The dose-effect curve For an AGONIST For AGONIST A drug that binds to receptor and has a drug pharmacological effect pharmacological Major characteristics are : q Potency Location (left-right) on a dose-effect curve q Maximum effect Dose where increases in dose produce no Dose further increase in effect further Potency More potent Less potent q % increase in pain threshold Accessibility Affinity (Kd, Affinity (K dissociation dissociation constant) constant) 100 75 50 25 1 10 100 Hydromorphine Morphine Codeine Aspirin q q Efficacy (intrinsic activity) Log dose (mg) 1.7 Potency hydromorphone (Dilaudid) morphine codeine 8-10X morphine 1/10– 1/20th morphine Potency Heroin (diacetylmorphine) fentanyl morphine 2-4X but much faster 100–1000X Potency etorphine (Immobilon) morphine tramadol (Ultram) 1/10-1/20th morphine but dua action 1000X-3000X 100 Drug A Potency 50 Desired effect Lethality q ED50 - Dose that produces an effect in 50% of a population population LD50 - Dose that kills 50% (TD = toxic dose) (TD Percent responding ED50 TD50 Low High Log drug dose Drug B q 100 q TI - Therapeutic Index TI (LD50 /ED50) (LD50 /ED Safety Margin = LD50 – ED50 ED 50 1.8 50 q ED50 TD50 Low Log drug dose High Maximum Effect Drugs vary in their Drugs ability to produce an effect effect They may act by They different mechdifferent anisms (at different anisms receptors) receptors) They may have more They or less efficacy at the same receptor the Max. effect 100 75 50 25 1 10 100 More Less Hydromorphine Morphine Codeine Aspirin q q Log dose (mg) 1.7 Side effects and specificity All drugs have multiple effects q All drugs are “dirty” q Degree depends on Degree dose, specificity etc. dose, Side effects are unwanted or Side undesirable effects (although are “real” effects) “real” Agonists vs Antagonists q q Agonist A drug that binds to receptor and has a drug cellular (pharmacological) effect cellular Antagonist A drug that binds to a receptor but drug produces no direct cellular effect produces Antagonists produce their effects by Antagonists blocking the action of an agonist, or an endogenous ligand (e.g., a transmitter), at that receptor that Competitive antagonists Competitive q Binds to same receptor as agonist q Shift dose-effect for agonist to right q Effect can be overcome by sufficient dose 100 Maximum % effect 50 Pretreated with competitive antagonist Low High Dose of morphine 1.9 Competitive antagonists Competitive naloxone (Narcan) -antagonist morphine Noncompetitive antagonists Noncompetitive q Shift dose-effect for agonist to right q Effect can not be overcome by Effect not sufficient dose (decrease in maximum sufficient Maximum 100 effect) e 100ffect) % effect Pretreated with competitive antagonist 50 50 Pretreated with noncompetitive antagonist 1.9 Low High Dose of morphine Low High Dose of morphine Noncompetitive antagonists Noncompetitive q Agonist can only act on the population of Agonist receptors not effected by the antagonist receptors (May be reversible or irreversible) Irreversible may form long-lasting bond with receptor receptor Reversible acts to prevent agonist-receptor Reversible coupling (e.g., on different site than agonist, through different mechanism) through q q Dose-effect curves Quiz: Percent Effect 100 A 75 50 25 1 10 B Z C 100 Log dose (mg) Tolerance and sensitization The effects of a drug may change The with repeated administration with Tolerance q Decreased Decreased response with repeated administration, or administration, q A higher dose is required to produce higher the original effect (shift to right) the Cross-tolerance Tolerance and sensitization Sensitization q Increased Increased response with repeated administration, or administration, q A lower dose is required to produce the lower original effect (shift to left) original q Cross sensitization Dose-effect curves Quiz: Percent Effect 100 A 75 50 25 1 10 B Z C 100 Log dose (mg) Tolerance and sensitization May involve multiple mechanisms May q q q Pharmacokinetic (dispositional) changes Pharmacodynamic changes (cellular adaptations) Behavioral (learning) factors ...
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