Pharmacology Notes Chapter 1 Introduction
Pharmacology
Study of substances that interact with living sys tems through chemical processes; binding to regulatory molecules and activating/ inactivating normal body processes Achieve beneficial therapeutic effect or toxic effects on o regulatory processes in parasi tes Medical pharmacology science of s ubstances used to prevent, diagnose , treat disease Toxicology branch of pharmacology specializing in undesirable effects of chemicals on living sys tems
History of Pharmacology Early use of medicines in China , Egypt, India Sporadic attempts to introduce rational methods into medicine , none were s uccessf ul due to philosophies that explain biology and disease wi thout need for experimentation and observation th End of 17 century Reliance on observation and experimentation replace d o theorizing in me dicines Methods were applie d on traditional drugs o Materia medica o Science of drug preparation and medicinal use of drugs Precursor to pharmacology Mechanisms of action were no t understood due to o absence of methods to purify active ingredients from crude materials, lack of methods to test hypotheses th th Late 18 and 19 centuries o Francois Magendie and student Claude Bernard developed experimental physiology an d pharmacology eeded for understanding how drugs work at organ an d o tissue levels Real advances in basic pharmacology accompanie d by o outburst of unscientific claims by manufacturers Controlled clinical trials rein troduced into medicine, 60 o years ago to accurately eval uate therapeutic drugs Major expansion of research in all areas of biology Informa tion about drug action and receptors o o ew drug groups and new members of old groups introduced Molecular mechanisms i dentified, numerous receptors o isolated, structurally characterized, and cloned Discover of orphan recep tors receptors with no known o ligand and hypothesized f unction Receptors and effectors strongly infl uenced by o companion reg ulatory proteins Pharmacogenomics rela tion of individuals gene tic make up to his or her response to specific drugs o Recogni tion of unsuspected relationships between receptor families an d way receptor proteins have evolve d Alternative heal th care in dustry Irrational use of inn umerable, expensive, ineffective, o sometimes harmf ul remedies o Medication-cons uming public exposed to inaccurate, incomplete, unscientific information regarding pharmacological effec ts All substances can be toxic, chemicals in botanicals are no differen t that chemicals in man ufactured drugs except for propor tion of impurities
All dietary supplements and health-enhancing therapies should meet same standards of efficacy and safety as conven tional drugs and medical therapies o artificial separa tion between scien tific medicine an d alternative/ complemen tary medicine
Pharmacology and Pharmaceutical Industry Big pharma m ultibillion dollar corpora tions that specialize in drug discovery an d development Exploiting discoveries from aca demic and governmental o laboratories and translating findings into commercially successf ul therapeutic breakthroughs Escalating costs of drugs is significan t contributor to inflationary increase in cos t of health care Drug developmen t is expensive; companies pay cos ts of o drug development and marketing and return profi t to sharehol ders o Costs of developmen t and marketing grossly inflated by marketing procedures Profi t margins have excee d all other industries o Pricing sche dules vary dramatically from co untries and within countries Nature of Drugs Drug any s ubstance that brings about a change in biologic f unction through chemical ac tions Agonis t activator o o Antagonist inhi bitor Specific to a receptor o Chemical antagonists interact directly with drugs Osmotic agents interact with water o Drugs synthesized in body hormones o Not synthesized in body xenobiotics Poisons drugs with almost exclusively harmf ul effects o Paracels us the dose makes the poison Any substance is harmf ul if taken in wrong dosage o Toxins poisons of biologic origin , synthesized by plants o or animals Inorganic poisons lea d, arsenic, heavy metals o To interact with receptor, drug must have appropria te size, charge , shape, atomic composition Must have necessary proper ties to be transported from site of admin to site of action Should be inactivated or excreted so that actions will be of appropria te duration Drug
Characteristics 1. Physical nature a. Solid, liquid, gaseous b. Of ten determine best route of administration c. Inorganic elemen ts or organic drugs (weakly aci dic/ basic) d. pH differences in body may alter degree of ionization 2. Drug size a. Molec ular size from very small ( Lithium, MW 7 to alteplase MW 59,050) b. Most drugs between MW 100-1000 c. Lower limi t is set by requirements for specifici ty of action To be good fit to one receptor must be sufficien tly i. unique in shape, charge, and other properties to prevent binding to other receptors
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d.
3.
4.
Upper limi t determined by ability to move within the body Large MW of 1000 do not diff use readily i. ii. Very large drugs (proteins) administrated directly into compartment to have effect iii. Alteplase directly into vascular compartment via IV or intra-arterial inf usion Drug reactivity and drug-receptor bonds a. Covalent bonds i. Strong , not reversi ble under biological conditions ii. Ex. Bond between ASA and cyclooxgenase in platelets 1. Platelet aggregation blocking effect lasts long af ter free ASA has disappeared from blood, reversed only through synthesis of new enzyme in new platelets Ex. DNA-alkyla ting agen ts in cancer chemo therapy iii. to disrupt cell division in tumor b. Electrostatic bonds More common, form relatively s trong linkages , i. weaker than covalent ii. Bonds between permanently charged ionic molecules, weak hydrogen bonds, very weak induced dipole in teractions (Van der Waals forces) c. Hydrophobic bonds i. Q uite weak ii. Important in interactions of highly lipi d-soluble drugs with lipids in cell membranes and interaction with internal walls of recep tor pockets d. Drugs that bind through weak bonds are generally more selective than those that bind with strong bonds Weak bonds require very precise fi t; only few i. receptor types provi de such a precise fi t To make highly selec tive short-acting drug, avoid ii. highly reactive molecules that form covalent bonds e. Few substances are almost completely inert May still have significan t pharmacologic effec ts i. ii. Xenon inert gas, anesthetic effects at high pressures Drug shapes a. Shape must permit binding to its receptor site via bonds b. Shape must be complementary to that of the receptor c. Chirali ty stereoisomerism More than half of all usef ul drugs exist in i. enan tiomeric pairs Most cases only one enan tiomer is more po tent ii. than the other, better fit to receptor d. More active enan tiomer at one type of receptor may not be more active at another receptor, type may be responsi ble for some other effect Ex. Carvedilol in teracts with adrenoreceptors, one i. chiral center S-isomer is po tent -receptor blocker ii. iii. R-isomer is 100 fol d weaker at the -receptor e. Some isomers are approxima tely equipotent as receptor blockers i. Ketamine, IV anesthetic ii. R-isomer more po tent anesthetic and less toxic than S-isomer iii. Still used as racemic mix ture Enzymes are usually steroselective, one enantiomer more f. susceptible than other to metabolism Duration of action of one enan tiomer differs than i. other
ii.
transporters may also be steroselective studies of clinical efficacy done with racemic mixtures rather than with separate enantiomers Small percentage of chiral drugs used are marketed i. as the active isomer, others only availa ble as racemic mixtures Many patients receive drug which is only 50% or ii. more is less ac tive, inactive, or actively toxic d h. A ministration of pure, active enantiomer decreases adverse effec ts relative to racemic mixture not firmly supported More chiral drugs available as active enantiomers i. through scientific an d regulatory levels Rational drug design a. Ability to predict appropriate molecular structure on basis of informa tion of biological recep tor b. Drugs developed through random testing of chemicals or modification of drugs know to have some effect c. Few drugs developed through molecular design based on knowledge of 3D structure of receptor Recep tor nomenclature a. Newer, more efficient ways to identify and characterize receptors resulted in different naming sys tems b. International Union of Pharmacology commi ttee on Receptor Nomenclature and Drug Classifica tion
g.
5.
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Drug
Most
Drug-body
Interactions Pharmacodynamic processes ac tions of drug on the body Determine group which drug is classifie d, play major role o in deciding whether the group is appropria te therapy Pharmacokine tic processes ac tions of body on drug Absorption, distribution, metabolism o
Pharmacodynamic Principles Drugs must bind to receptor to bring an effec t, series of complica ted steps D+R-> D-R complex -> effec t o o D+R-> D-R complex -> effec tor molecule -> effect D+R-> D-R complex -> activation of co upling molecule -> o effector molecule -> effect Inhi bition of metabolism of endogenous activator -> o increase d activator -> increased effect Final change in f unction through effector mechanism May be part of receptor or separate molecule o Large number of recep tor communicate with effectors through coupling molecules Pharmacodynamics 1. Types of drug-receptor interactions a. Agonists bind to and activate the receptor to directly or indirectly bring an effec t Activation res ults in change in conforma tion i. Some receptors have effector machinery so that ii. drug binding brings about effect directly iii. Can be linked through coupling molecules to a separa te effector molecule b. Pharmacological antagonist drugs bind to receptor, compete and prevent binding by other molecules Acetylcholine receptor blockers atropine , prevent i. access of ace tylcholine an d cholinergic drugs to acetylcholine receptor and stabilize recep tor in its inactive state ii. Reduce effects of acetylcholine, action overcome by increasing dosage of agonis t
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iii.
2.
3.
Some bind so tightly to receptor that irreversi ble or pseudoirreversi blly and cannot be displaced c. Allosteric inhi bition drugs that bind to receptor molecule but do not prevent binding of agonis t i. Can enhance or inhi bit agonist molecule ii. Not overcome by increasing dose of agonist Agonis ts that inhibit binding molecules a. Inhibit molecules responsible for terminating action of endogenous agonist b. Acetylcholinesterase inhibitors slow destruction of endogenous acetylcholine ca use cholinomimetic effects resembling actions of cholinocep tor agonist although cholines terase inhi bitors do not bind or only inci dentally bind to cholinoreceptors c. Amplify effects of physiologically release d agonist ligands d. Effects can be more selective, less toxic than exogenous agonists Agonis ts, partial agonis ts, inverse agonis ts a. Receptor can exis t in inactive, nonf unctional form and activated form b. Constitutive activity In the absence of any agonis t, receptor pool must exist in Ra form and may produce same physiologic effec t as agonist-induced activity i. Constitutive activity depends on receptor density, concentration of coupling molecules, number of effectors c. Agonists have higher affini ty for Ra config uration and stabilize it, large percentage resides in Ra-D form and produces large effec t d. Full agonists activate receptor-effector systems to maximum extent, shif t almost all of pool to Ra-D form e. Partial agonis ts bind to receptors and activate them but do not evoke great response, no matter how high the concentration i. Do not f ully stabilize Ra config uration as f ull agonists, significan t fraction exists in Ri- D form; have low intrinsic efficacy i. Pindolol - -adrenoreceptor partial agonist; may act as agonis t if no f ull agonist is present or antagonist if f ull agonist is present ii. Independent of affini ty to receptor c. Conventional antagonist action by fixing Ri and Ra fractions in same amo unts so that no change will be observed d. Neutral antagonism presence of an tagonist at receptor will block access of agonis t to receptor and prevent agonistic effect e. Inverse agonis ts drugs that have stronger affini ty for Ri state and stabilizes pool as Ri- D, reduce constitutive activity, opposite of effects produce by conventional agonists i. -amino butyric acid receptor-effector Activated by endogenous transmitter GABA, ii. inhibition of postsynaptic cells iii. Exogenous agonists benzodiazepins , facili tate receptor-effec tor system to cause GABA-like inhibition with sedation as therapeutic result iv. Inhi bition blocked by conventional ne utral antagonists flumazenil v. Also found that cause anxiety and agitation, inverse of sedation vi. Found for -receptors, H1 and H2 receptors, etc
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Duration
of action lasts only as long as drug occupies recep tor, disassocia tion terminates effect b. Action may persis t af ter dug as dissociated, coupling molecule still present in activated form c. Drug may be covalently bonded, effect persists until D-R complex is destroyed and new receptors/ enzymes are produced d. Incorpora te desensitization mechanisms for preven ting excessive activation when agonis ts are present for long periods of time Recep tors and inert binding sites a. Endogenous molecule must be selective in choosing ligands to bind i. Selectivity required to avoid constant activation of receptor by excessive binding of differen t ligands b. Change f unction upon binding i. Necessary if ligan d is to cause pharmacologic effec t c. Not all endogenous molecules are regulatory i. Inert binding site binding to nonregulatory molecule will result in no detectable change ii. Binding will affec t distribution of drug in body and determines amount of free drug is in circ ulation a.
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Effect
Pharmacokine tic Principles Drug should reach site of action af ter admin Must be sufficien tly lipi d soluble and stable Prodrug inactive precursor chemical conver ted to active drug through metabolic processes Most situations req uire drug to be administered into another compartment, must move to its site of action Must be absorbed in blood, distributed to site of action, o permeate through barriers, elimina ted at reasonable rate by metabolic inactivation or excretion Pharmacokine tics 1. Permeation a. Passive diff usion common in aqueous/ lipid medium, active processes for mos t drugs b. Aqueous diff usion Occurs within larger aq ueous compartments, across i. epithelial membrane tight junctions ii. Some tissues permit passage of large molec ules of MW 20-30K iii. Driven by concen tration gradient descri bed by Ficks Law Drugs bound to plasma pro teins do not permeate iv. Flux of charge d drugs influenced by electrical fields v. (membrane/ transtubular potential) c. Lipid diff usion Most important limiting factor for drug permeation i. Lipid/water coefficien t determines how rea dily drug ii. moves between the phases Weak acids/ bases movement dependent on pH of iii. medium, charged molecules attract water 1. Henderson-Hassel balch equation d. Special carriers For molecules too large or too insoluble in lipi d to i. diff use prof usely (peptides, amino aci ds, glucose) ii. Through active transport or facili tated diff usion Mechanisms are selective, saturable, inhibitable iii.
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iv.
ATP-binding
cassette family P-glycopro tein/ multidrug-resis tance type 1 transporter found in brain, testes, drugresistant neoplastic cells 2. Multidrug resistance-associa ted protein transporters excrete some drugs, metabolites into urine and bile v. Some drugs do not bind ATP but use ion gradients for transport energy 1. Solute carrier family uptake of neurotransmitters across nerve-en ding membranes e. Endo/exocytosis For substances very large , substance is bound at cell i. surface receptor, engulfed by cell membrane, carrie d into cell by formation of a vesicle then release d in cytosol 1. Transport of cyanocobalamin complexe d with intrinsic factor 2. Iron transported into hemoglobin-synthesizing RBC precursors wi th transferring Exocytosis responsi ble for secretion of ii. neurotransmitters 1. Stored in vesicles in nerve en dings to protect from metabolic destruction 2. Activation of nerve ending causes f usion of storage vesicle with cell membrane and expulsion of contents Ficks Law of Diff usion a. Ficks Law describes passive fl ux of molecules down concentration gradient i. Permeability coefficient measure of mobility of drug molecules in medium of diff usion path Thickness of diff usion path ii. b. Lipid diff usion lipid/ water coefficien t is major determinant of drug mobility Ioniza tion of Weak Acids/ Bases a. Electrostatic charge of ionize d molecule attracts water dipoles -> polar , relatively water soluble and lipi d-soluble complex i. Ioniza tion reduces ability to permeate membranes b. Weak acid neutral molecule that reversi bly dissociates into a conjugate base and proton i. Protonated form is neutral, lipid soluble c. Weak base ne utral molecule that forms conjugate acid by combining with a proton i. Unprotonated form is neutral, lipid soluble d. Reactions move lef t in an aci d environmen t and to the righ t in alkaline environmen t e. Henderson-Hassel balch equation relates ratio of protonated to unprotonated weak acid/base to molecules pKa and pH of the medium Lower pH relative to pka, greater frac tion in i. protonated form ii. Weak aci d will be lipid soluble at acid pH, weak base at alkaline pH f. All drugs filtered at glomerulus Lipid soluble form will be reabsorbed by passive i. diff usion ii. Accelera te excretion by converting to ionized form to prevent reabsorption by ad justing urine pH iii. Weak aci ds excreted faster in alkaline urine, weak bases in aci dic
g.
pH differences from blood pH may cause trapping or reabsorption h. Overdose of methamphetamine (weak base) countered with admin of ammoni um chloride to acidify the urine to rapidly eliminate drug i. Most drugs are weak bases containing amines i. Primary , secondary, tertiary reversi ble protonation, vary lipi d solubility on pH ii. Q uaternary permanently charge d, always poorly soluble
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Drug
Groups Drugs currently availa ble arrange d into about 70 groups Drugs within each group are similar in pharmaco dynamic actions and pharmacokinetic properties Prototype drugs identified to typify most important charac teristics
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