Pharmacology Notes – Chapter 1 Introduction

Pharmacology Study of substances that interact with living systems through

chemical processes; binding to regulatory molecules and activating/ inactivating normal body processeso Achieve beneficial therapeutic effect or toxic effects on

regulatory processes in parasites Medical pharmacology – science of substances used to

prevent, diagnose, treat disease Toxicology – branch of pharmacology specializing in

undesirable effects of chemicals on living systems

History of Pharmacology Early use of medicines in China, Egypt, India Sporadic attempts to introduce rational methods into

medicine, none were successful due to philosophies that explain biology and disease without need for experimentation and observation

End of 17th century o Reliance on observation and experimentation replaced

theorizing in medicineso Methods were applied on traditional drugso Materia medica

Science of drug preparation and medicinal use of drugs

Precursor to pharmacology o Mechanisms of action were not understood due to

absence of methods to purify active ingredients from crude materials, lack of methods to test hypotheses

Late 18th and 19th centurieso Francois Magendie and student Claude Bernard

developed experimental physiology and pharmacology o Needed for understanding how drugs work at organ and

tissue levelso Real advances in basic pharmacology accompanied by

outburst of unscientific claims by manufacturers o Controlled clinical trials reintroduced into medicine, 60

years ago to accurately evaluate therapeutic drugs Major expansion of research in all areas of biology

o Information about drug action and receptors o New drug groups and new members of old groups

introducedo Molecular mechanisms identified, numerous receptors

isolated, structurally characterized, and clonedo Discover of orphan receptors – receptors with no known

ligand and hypothesized function o Receptors and effectors strongly influenced by

companion regulatory proteins Pharmacogenomics – relation of individual’s genetic make up

to his or her response to specific drugs o Recognition of unsuspected relationships between

receptor families and way receptor proteins have evolved Alternative health care industry

o Irrational use of innumerable, expensive, ineffective, sometimes harmful remedies

o Medication-consuming public exposed to inaccurate, incomplete, unscientific information regarding pharmacological effects

All substances can be toxic, chemicals in botanicals are no different that chemicals in manufactured drugs except for proportion of impurities

All dietary supplements and health-enhancing therapies should meet same standards of efficacy and safety as conventional drugs and medical therapies

No artificial separation between scientific medicine and alternative/ complementary medicine

Pharmacology and Pharmaceutical Industry Big pharma – multibillion dollar corporations that specialize in

drug discovery and developmento Exploiting discoveries from academic and governmental

laboratories and translating findings into commercially successful therapeutic breakthroughs

Escalating costs of drugs is significant contributor to inflationary increase in cost of health careo Drug development is expensive; companies pay costs of

drug development and marketing and return profit to shareholders

o Costs of development and marketing grossly inflated by marketing procedures

o Profit margins have exceed all other industries Pricing schedules vary dramatically from countries and within

countries

Nature of Drugs Drug – any substance that brings about a change in biologic

function through chemical actionso Agonist – activatoro Antagonist – inhibitor o Specific to a receptor

Chemical antagonists – interact directly with drugso Osmotic agents – interact with water

Drugs synthesized in body – hormones o Not synthesized in body – xenobiotics

Poisons – drugs with almost exclusively harmful effectso Paracelsus – the dose makes the poisono Any substance is harmful if taken in wrong dosageo Toxins – poisons of biologic origin, synthesized by plants

or animals o Inorganic poisons – lead, arsenic, heavy metals

To interact with receptor, drug must have appropriate size, charge, shape, atomic composition

Must have necessary properties to be transported from site of admin to site of action

Should be inactivated or excreted so that actions will be of appropriate duration

Drug Characteristics1. Physical nature

a. Solid, liquid, gaseous b. Often determine best route of administration c. Inorganic elements or organic drugs (weakly acidic/ basic)d. pH differences in body may alter degree of ionization

2. Drug sizea. Molecular size from very small (Lithium, MW 7 to

alteplase MW 59,050)b. Most drugs between MW 100-1000c. Lower limit is set by requirements for specificity of action

i. To be good fit to one receptor – must be sufficiently unique in shape, charge, and other properties to prevent binding to other receptors

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d. Upper limit determined by ability to move within the body

i. Large MW of 1000 do not diffuse readily ii. Very large drugs (proteins) administrated directly

into compartment to have effect iii. Alteplase directly into vascular compartment via IV

or intra-arterial infusion 3. Drug reactivity and drug-receptor bonds

a. Covalent bonds i. Strong, not reversible under biological conditions

ii. Ex. Bond between ASA and cyclooxgenase in platelets 1. Platelet aggregation blocking effect lasts long

after free ASA has disappeared from blood, reversed only through synthesis of new enzyme in new platelets

iii. Ex. DNA-alkylating agents in cancer chemotherapy to disrupt cell division in tumor

b. Electrostatic bondsi. More common, form relatively strong linkages,

weaker than covalentii. Bonds between permanently charged ionic

molecules, weak hydrogen bonds, very weak induced dipole interactions (Van der Waals forces)

c. Hydrophobic bondsi. Quite weak

ii. Important in interactions of highly lipid-soluble drugs with lipids in cell membranes and interaction with internal walls of receptor pockets

d. Drugs that bind through weak bonds are generally more selective than those that bind with strong bonds

i. Weak bonds require very precise fit; only few receptor types provide such a precise fit

ii. To make highly selective short-acting drug, avoid highly reactive molecules that form covalent bonds

e. Few substances are almost completely inerti. May still have significant pharmacologic effects

ii. Xenon – inert gas, anesthetic effects at high pressures

4. Drug shapesa. Shape must permit binding to its receptor site via bonds b. Shape must be complementary to that of the receptorc. Chirality – stereoisomerism

i. More than half of all useful drugs exist in enantiomeric pairs

ii. Most cases only one enantiomer is more potent than the other, better fit to receptor

d. More active enantiomer at one type of receptor may not be more active at another receptor, type may be responsible for some other effect

i. Ex. Carvedilol – interacts with adrenoreceptors, one chiral center

ii. S-isomer is potent β-receptor blockeriii. R-isomer is 100 fold weaker at the β-receptor

e. Some isomers are approximately equipotent as α-receptor blockers

i. Ketamine, IV anestheticii. R-isomer more potent anesthetic and less toxic than

S-isomeriii. Still used as racemic mixture

f. Enzymes are usually steroselective, one enantiomer more susceptible than other to metabolism

i. Duration of action of one enantiomer differs than other

ii. Drug transporters may also be steroselective g. Most studies of clinical efficacy done with racemic

mixtures rather than with separate enantiomers i. Small percentage of chiral drugs used are marketed

as the active isomer, others only available as racemic mixtures

ii. Many patients receive drug which is only 50% or more is less active, inactive, or actively toxic

h. Administration of pure, active enantiomer decreases adverse effects relative to racemic mixture not firmly supported

i. More chiral drugs available as active enantiomers through scientific and regulatory levels

5. Rational drug designa. Ability to predict appropriate molecular structure on

basis of information of biological receptor b. Drugs developed through random testing of chemicals or

modification of drugs know to have some effectc. Few drugs developed through molecular design based on

knowledge of 3D structure of receptor 6. Receptor nomenclature

a. Newer, more efficient ways to identify and characterize receptors resulted in different naming systems

b. International Union of Pharmacology committee on Receptor Nomenclature and Drug Classification

Drug-body Interactions Pharmacodynamic processes – actions of drug on the body

o Determine group which drug is classified, play major role in deciding whether the group is appropriate therapy

Pharmacokinetic processes – actions of body on drugo Absorption, distribution, metabolism

Pharmacodynamic Principles Drugs must bind to receptor to bring an effect, series of

complicated steps o D+R-> D-R complex -> effecto D+R-> D-R complex -> effector molecule -> effecto D+R-> D-R complex -> activation of coupling molecule ->

effector molecule -> effecto Inhibition of metabolism of endogenous activator ->

increased activator -> increased effect Final change in function through effector mechanism

o May be part of receptor or separate molecule Large number of receptor communicate with effectors

through coupling molecules

Pharmacodynamics1. Types of drug-receptor interactions

a. Agonists – bind to and activate the receptor to directly or indirectly bring an effect

i. Activation results in change in conformationii. Some receptors have effector machinery so that

drug binding brings about effect directly iii. Can be linked through coupling molecules to a

separate effector molecule b. Pharmacological antagonist drugs – bind to receptor,

compete and prevent binding by other moleculesi. Acetylcholine receptor blockers – atropine, prevent

access of acetylcholine and cholinergic drugs to acetylcholine receptor and stabilize receptor in its inactive state

ii. Reduce effects of acetylcholine, action overcome by increasing dosage of agonist

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iii. Some bind so tightly to receptor that irreversible or pseudoirreversiblly and cannot be displaced

c. Allosteric inhibition – drugs that bind to receptor molecule but do not prevent binding of agonist

i. Can enhance or inhibit agonist molecule ii. Not overcome by increasing dose of agonist

2. Agonists that inhibit binding moleculesa. Inhibit molecules responsible for terminating action of

endogenous agonist b. Acetylcholinesterase inhibitors – slow destruction of

endogenous acetylcholine cause cholinomimetic effects resembling actions of cholinoceptor agonist although cholinesterase inhibitors do not bind or only incidentally bind to cholinoreceptors

c. Amplify effects of physiologically released agonist ligandsd. Effects can be more selective, less toxic than exogenous

agonists 3. Agonists, partial agonists, inverse agonists

a. Receptor can exist in inactive, nonfunctional form and activated form

b. Constitutive activity In the absence of any agonist, receptor pool must exist in Ra form and may produce same physiologic effect as agonist-induced activity

i. Constitutive activity depends on receptor density, concentration of coupling molecules, number of effectors

c. Agonists – have higher affinity for Ra configuration and stabilize it, large percentage resides in Ra-D form and produces large effect

d. Full agonists – activate receptor-effector systems to maximum extent, shift almost all of pool to Ra-D form

e. Partial agonists – bind to receptors and activate them but do not evoke great response, no matter how high the concentration

i. Do not fully stabilize Ra configuration as full agonists, significant fraction exists in Ri-D form; have low intrinsic efficacy

i. Pindolol - β-adrenoreceptor partial agonist; may act as agonist if no full agonist is present or antagonist if full agonist is present

ii. Independent of affinity to receptor c. Conventional antagonist action by fixing Ri and Ra

fractions in same amounts so that no change will be observed

d. Neutral antagonism – presence of antagonist at receptor will block access of agonist to receptor and prevent agonistic effect

e. Inverse agonists – drugs that have stronger affinity for Ri state and stabilizes pool as Ri-D, reduce constitutive activity, opposite of effects produce by conventional agonists

i. γ-aminobutyric acid receptor-effectorii. Activated by endogenous transmitter GABA,

inhibition of postsynaptic cellsiii. Exogenous agonists – benzodiazepins, facilitate

receptor-effector system to cause GABA-like inhibition with sedation as therapeutic result

iv. Inhibition blocked by conventional neutral antagonists – flumazenil

v. Also found that cause anxiety and agitation, inverse of sedation

vi. Found for β-receptors, H1 and H2 receptors, etc

4. Duration of action a. Effect lasts only as long as drug occupies receptor,

disassociation terminates effectb. Action may persist after 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. Incorporate desensitization mechanisms for preventing excessive activation when agonists are present for long periods of time

5. Receptors and inert binding sitesa. Endogenous molecule must be selective in choosing

ligands to bind i. Selectivity required to avoid constant activation of

receptor by excessive binding of different ligandsb. Change function upon binding

i. Necessary if ligand is to cause pharmacologic effect c. Not all endogenous molecules are regulatory

i. Inert binding site – binding to nonregulatory molecule will result in no detectable change

ii. Binding will affect distribution of drug in body and determines amount of free drug is in circulation

Pharmacokinetic Principles Drug should reach site of action after admin Must be sufficiently lipid soluble and stable Prodrug – inactive precursor chemical converted to active

drug through metabolic processes Most situations require drug to be administered into another

compartment, must move to its site of actiono Must be absorbed in blood, distributed to site of action,

permeate through barriers, eliminated at reasonable rate by metabolic inactivation or excretion

Pharmacokinetics1. Permeation

a. Passive diffusion – common in aqueous/ lipid medium, active processes for most drugs

b. Aqueous diffusioni. Occurs within larger aqueous compartments, across

epithelial membrane tight junctionsii. Some tissues permit passage of large molecules of

MW 20-30Kiii. Driven by concentration gradient described by Fick’s

Lawiv. Drugs bound to plasma proteins do not permeatev. Flux of charged drugs influenced by electrical fields

(membrane/ transtubular potential)c. Lipid diffusion

i. Most important limiting factor for drug permeation ii. Lipid/water coefficient determines how readily drug

moves between the phasesiii. Weak acids/ bases’ movement dependent on pH of

medium, charged molecules attract water 1. Henderson-Hasselbalch equation

d. Special carriersi. For molecules too large or too insoluble in lipid to

diffuse profusely (peptides, amino acids, glucose) ii. Through active transport or facilitated diffusion

iii. Mechanisms are selective, saturable, inhibitable

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iv. ATP-binding cassette family 1. P-glycoprotein/ multidrug-resistance type 1

transporter found in brain, testes, drug-resistant neoplastic cells

2. Multidrug resistance-associated 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-ending membranes

e. Endo/exocytosisi. For substances very large, substance is bound at cell

surface receptor, engulfed by cell membrane, carried into cell by formation of a vesicle then released in cytosol 1. Transport of cyanocobalamin complexed with

intrinsic factor 2. Iron transported into hemoglobin-synthesizing

RBC precursors with transferring ii. Exocytosis responsible for secretion of

neurotransmitters1. Stored in vesicles in nerve endings to protect

from metabolic destruction 2. Activation of nerve ending causes fusion of

storage vesicle with cell membrane and expulsion of contents

2. Fick’s Law of Diffusion a. Fick’s Law – describes passive flux of molecules down

concentration gradient i. Permeability coefficient – measure of mobility of

drug molecules in medium of diffusion pathii. Thickness of diffusion path

b. Lipid diffusion – lipid/ water coefficient is major determinant of drug mobility

3. Ionization of Weak Acids/ Basesa. Electrostatic charge of ionized molecule attracts water

dipoles -> polar, relatively water soluble and lipid-soluble complex

i. Ionization reduces ability to permeate membranesb. Weak acid – neutral molecule that reversibly dissociates

into a conjugate base and proton i. Protonated form is neutral, lipid soluble

c. Weak base – neutral molecule that forms conjugate acid by combining with a proton

i. Unprotonated form is neutral, lipid soluble d. Reactions move left in an acid environment and to the

right in alkaline environment e. Henderson-Hasselbalch equation relates ratio of

protonated to unprotonated weak acid/base to molecule’s pKa and pH of the medium

i. Lower pH relative to pka, greater fraction in protonated form

ii. Weak acid will be lipid soluble at acid pH, weak base at alkaline pH

f. All drugs filtered at glomerulus i. Lipid soluble form will be reabsorbed by passive

diffusionii. Accelerate excretion by converting to ionized form

to prevent reabsorption by adjusting urine pH iii. Weak acids excreted faster in alkaline urine, weak

bases in acidic

g. pH differences from blood pH may cause trapping or reabsorption

h. Overdose of methamphetamine (weak base) countered with admin of ammonium chloride to acidify the urine to rapidly eliminate drug

i. Most drugs are weak bases containing aminesi. Primary, secondary, tertiary – reversible

protonation, vary lipid solubility on pH ii. Quaternary – permanently charged, always poorly

soluble

Drug Groups Drugs currently available arranged into about 70 groups Drugs within each group are similar in pharmacodynamic

actions and pharmacokinetic properties Prototype drugs identified to typify most important

characteristics

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