back to basics: a review of pharmacology and drug action...

Back to Basics: A Review of Pharmacology and Drug ActionPharMEDium Lunch and Learn Series

ProCE, Inc.www.ProCE.com 1

Back to Basics:A Review of Pharmacology and Drug Action

November 11, 2016

Featured Speaker: Russell B. Melchert, PhD, RPh

Dean and ProfessorUniversity of Missouri‐Kansas City School of Pharmacy

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Russell B. Melchert, Ph.D.Dean, UMKC School of PharmacyProfessor, Division of Pharmacology and ToxicologyUniversity of Missouri‐Kansas CitySchool of Pharmacy

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Back to Basics: A Review of Pharmacology and Drug Action

Learning Objectives

• Define pharmacology and its related sub‐disciplines

• Describe the drug development process in the U.S.

• Describe drug‐receptor interactions and factors affecting drug‐receptor interactions

• List at least 5 major types of targets for drug action

• Describe one example of how drugs function using an opioid agonist and an antagonist

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What is Pharmacology Anyway?

Pharmacology

• The study of the effects of drugs on the function of living systems

Drug

• “A drug may be broadly defined as any chemical agent that affects living protoplasm, and few substances would escape inclusion by this definition”— Goodman and Gilman’s Pharmacological Basis of

Therapeutics, 12th Edition (2011)

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History of Pharmacology Prehistoric People

• Eat this, Not That

Pythagoras (500 BC)• Fava bean ingestion was dangerous for some

— now known to be G6PDH deficient individuals

Materia Medica (“Concerning Medical Substances”)

• Pedanius Dioscorides (90‐40 AD)— Greek botantist/pharmacologist/physician— served in Nero’s army as a botanist

• Five volume collection on medicinal plants

Shennong Bencao Jing (“The Divine Farmer’s Herb‐Root Classic”)

• 1st Century AD• Han Dynasty

a2 + b2 = c2

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History of Pharmacology Historically Significant Legislation

• Pure Food and Drug Act of 1906— Prohibited mislabeling

• Food, Drug, and Cosmetic Act of 1938— Required that new drugs be safe as well as pure— Did not require efficacy— Required enforcement by FDA

• Durham‐Humphrey Act of 1952— Vested in the FDA power to determine which products could be

sold without prescription

• Dietary Supplement Health and Education Act (1994)— Prohibited full FDA review of supplements and botanicals as

drugs— Established labeling requirements for dietary supplements

• FDA Safety and Innovation Act of 2012— Established new accelerated process for “breakthrough

therapy”, “priority review”, and “fast‐track” procedures

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History of Pharmacology

1938 to 2016• U.S. Food & Drug Administration (FDA) created in

1938

• Over 1,500 “drugs” have been reviewed and approved by the FDA

• Many drugs in wide use prior to FDA— aspirin, colchicine, morphine, etc.

• On average, 25‐30 New Molecular Entities (NME) approved by FDA every year

• Over 500 drugs approved since 1990

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Pharmacology & “Sub‐Disciplines”

Pharmacology• Basic & Clinical Pharmacology

— Pharmacokinetics & Pharmacodynamics (PKPD)

• Organ System Pharmacology— Cardiovascular pharmacology

— Immunopharmacology

— Neuropharmacology

— Gastrointestinal Pharmacology

— Respiratory Pharmacology

Pharmacogenomics

Pharmacoepidemiology

Pharmacoeconomics

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Pharmacology (Toxicology)

• Basic & Clinical Pharmacology (Toxicology)


— Toxicokinetics & Toxicodynamics

• Organ System Pharmacology (Toxicology)

— Cardiovascular Pharmacology (Toxicology)

— Immunopharmacology (Immunotoxicology)

— Neuropharmacology (Neurotoxicology)

— Gastrointestinal Pharmacology (Toxicology)

— Respiratory Pharmacology (Toxicology)

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Pharmacology

• Basic & Clinical Pharmacology


— Pharmacokinetics* Absorption

* Distribution

* Metabolism

* Excretion

— Pharmacodynamics* Drug‐receptor interactions

* Signal transduction

* Drug effects

pharm = drugology = studykinetic = movementdynamic = force

creating action

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Pharmacogenomics

• The genetic basis of a drug’s absorption, distribution, metabolism, excretion, and receptor‐target affinity

— the genetic basis of a drug’s pharmacokinetics and pharmacodynamics

— an extension of pharmacogenetics

• Use of genetic information to guide the choice of drug therapy on an individual basis

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Pharmacoepidemiology• The study of drug effects at the population

level

• Concerned with variability of drug effects between individuals in a population and between populations

• Made possible with “Big Data” sets

Pharmacoeconomics• The study of cost and benefits/detriments

of drugs used clinically

• Made possible with “Big Data” sets

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Drug Development Process

U.S. Food & Drug Administration (FDA)— administrative body that oversees drug evaluation

process

• FDA grants approval for marketing new drug products

• FDA approval for marketing

— evidence of safety and efficacy

— “safe” does not mean complete absence of risk

• FDA and U.S. Department of Agriculture (USDA)

— FDA shares responsibility with USDA for food safety

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Drug Development Process “Drug” as defined by FDA

• A substance recognized by an official pharmacopoeia or formulary— United States Pharmacopoeia

• A substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease

• A substance (other than food) intended to affect the structure or any function of the body

• A substance intended for use as a component of a medicine— but not a device or a component, part or accessory of a

device

• Biological products— included within this definition and are generally covered by

the same laws and regulations— but differences exist regarding their manufacturing

processes (chemical process versus biological process)

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“Generic Drug” as defined by FDA• A generic drug is the same as a brand name drug in

dosage, safety, strength, how it is taken, quality, performance, and intended use— must contain the identical amounts of the same active

ingredient(s) as the brand name product

— FDA requires many rigorous tests and procedures to assure that the generic drug can be substituted for the brand name drug

— FDA bases evaluations of substitutability, or therapeutic equivalence of generic drugs on scientific evaluations

• By law, a generic drug product evaluated as "therapeutically equivalent”— can be expected to have equal effect and no difference

when substituted for the brand name product

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Chemical Synthesis & In Vitro Screening

(Thousands of Compounds)

Preclinical Testing

Phase IV (1)

Phase I (1‐5)

Phase III (1‐2)

Phase II (1‐5)

(Tens of Compounds)

PatentLife (yrs)

4

0

8

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IND(Investigational New Drug)

NDA(New Drug Application)

Marketing&Post‐Marketing Surveillance

Healthy Subjects(10‐100)

Disease Subjects(100‐500)

Broad Testing(1,000‐10,000)

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Drug Targets

Paul Ehrlich (1854‐1915)

• Modern Chemotherapy

— Drug actions not result of magical “vital forces”

— Drug action explained by conventional chemical interactions between drugs and tissues

— “A drug will not work unless it is bound”

— Must develop a “Magic Bullet”

Corpora non agunt nisi fixata

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Drug Targets

Protein Targets for Drug Binding• Receptors

• Enzymes

• Specific Circulating Plasma Proteins

• Carrier Molecules (Transporters)

• Ion Channels

Nucleic Acid Targets for Drug Binding• RNA & DNA

Other Targets• Ion Chelators

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Drug Targets

Receptors• Protein molecules which function to

recognize and respond to endogenous chemical signals— protein molecules which function to

recognize specific endogenous ligands

— may also recognize/bind xenobiotics

• Classified based on ligands— increasing focus on developing new

classification system based on genomics

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Drug Targets

Drug Specificity

• For a drug to be useful:

— must act selectively on particular cells and tissues

— must show a high degree of binding site specificity

• For a protein to function as a receptor:

— generally shows a high degree of ligand specificity

— bind only molecules of certain physico‐chemical properties

* size, shape, charge, lipophilicity, etc24



Drug‐Receptor Interactions Binding Affinity & Drug Efficacy

• Affinity— tendency of a drug to bind to the receptor— dissociation constant (Kd) = concentration required

for 50% saturation of available receptors— inversely proportional to affinity

* higher the Kd, lower the affinity

• Efficacy— tendency of a drug to activate the receptor once

bound— generally expressed as dose‐response curves or

concentration‐effect curves

• Highly effective (potent) drugs generally have high affinity

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Drug‐Receptor Interactions

Types of Drug‐Receptor Interactions• Agonist

— posses significant efficacy— full agonist = elicits maximal response— partial agonist = elicits partial response, even

when 100% of receptors are occupied

• Antagonist— possess zero efficacy— block or reduce efficacy of agonist

• Allosteric Agonists and Antagonists— bind to the same receptor, but do not prevent

binding of the agonist— may enhance or inhibit the action of agonists

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Model of Receptor Actions• Competitive Antagonist

— bind to same site on receptor as agonist— compete with agonist for binding— with fixed agonist concentration, progressive

increases in antagonist will progressively decrease effect up to completely abolishing it

— increasing agonist concentration can overcome competitive antagonist

• Noncompetitive Antagonist— often bind covalently and irreversibly— often allosteric inhibition but can be same

binding site as agonist— increasing agonist concentration may not

overcome noncompetitive antagonist27


Drug Concentration

Drug Response Agonist Agonist + Antagonist

Y

X 2X

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Other Mechanisms of Drug Antagonism• Chemical Antagonist

— for example: ionic interaction between positively charged protamine and negatively charged heparin* protamine antagonizes heparin

• Physiologic Antagonist— for example: different regulatory pathways

mediated by different receptors resulting in opposing actions* anticholinergic atropine can physiologically antagonize

effects of ‐blockers on heart rate

• Pharmacokinetic Antagonist— one drug increases the metabolism of the other

* rifampin increases metabolism of many drugs

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Drug “Targets”

Protein Targets for Drug Binding and Drug Action

1. Receptors

2. Enzymes

3. Specific Circulating Plasma Proteins

4. Carrier Molecules (Transporters)

5. Ion Channels

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1. Receptors

Protein molecules which function to recognize and respond to endogenous chemical signals

• recognize/bind specific endogenous ligands

• may also recognize/bind xenobiotics

Classified based on ligands

Grouped into 4 major superfamilies

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1. Receptors

Receptor Subtypes

• receptors in given family generally occur in several molecular varieties or “subtypes”

— similar architecture

— significant differences in amino acid sequence

— often different pharmacologic properties

— nicotinic acetylcholine receptor subtypes occur in different brain regions and these differ from subtype in muscle

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1. Receptors Superfamilies of Receptors

• Ligand‐Gated Ion Channels— “ionotropic” receptors

• G‐Protein Coupled Receptors— “metabotropic” receptors— “7 trans‐membrane spanning domain”

receptors— “heptahelical” receptors— “serpentine” receptors

• Kinase‐Linked & Related Receptors— large and heterogeneous group— single trans‐membrane spanning domain

• Nuclear Receptors— “steroid superfamily”

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1. Receptors

Superfamilies of Receptors

• Ligand‐Gated Ion Channels

Ligand BindingDomain COOH

NH

PlasmaMembrane

*Ligand‐Gated Ion Channels Composed of 4‐5 of these subunits

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1. Receptors

Ligand‐Gated Ion Channels• share structural features with voltage‐

gated ion channels

• “ionotropic” receptors

• examples— nicotinic acetylcholine receptor (nAChR)

— gamma‐aminobutyric acid type A receptor (GABAA)* inhibitory neurotransmitter

— glutamate receptors [N‐methyl‐D‐aspartate (NMDA), ‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA), and kainate types]

* excitatory neurotransmitter

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1. Receptors


• G‐Protein Coupled Receptors

Ligand BindingDomain

G‐ProteinCoupling Domain

COOH

NH

PlasmaMembrane

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1. Receptors G‐Protein Coupled Receptors

• largest superfamily of receptors• “metabotropic” receptors• 7 transmembrane spanning domains• examples

— muscarinic acetylcholine receptor (mAChR)— gamma‐aminobutyric acid type B receptor

(GABAB)— serotonergic receptors (5‐hydroxytryptamine or

5‐HT, 1‐7 types)— adrenergic receptors ( and types)— angiotensin II receptors (1, 2, 3, 4 types)— endothelin receptors (A, B, C types)— histamine receptors (1, 2, 3 types)— photon receptors (retinal rod and cone)— opioid receptors ( types)

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1. Receptors


• Kinase‐Linked & Related Receptors

Ligand BindingDomain

CatalyticDomain

COOH

NH

PlasmaMembrane

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1. Receptors Kinase‐Linked & Related Receptors

• involved mainly in events controlling cell growth and differentiation

• act indirectly by regulating gene transcription• signal transduction generally involves

dimerization of two receptor molecules followed by autophosphorylation of tyrosine residues

• all have large extracellular ligand‐binding domain connected via single membrane spanning domain to an intracellular domain which has enzymatic activity

• examples— insulin receptors— epidermal growth factor receptors— cytokine receptors

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1. Receptors


• Nuclear ReceptorsLigand Binding

Domain HOOCHN

DNABinding Domain

NuclearMembraneLigand Binding

Domain HOOCHN

DNABinding Domain

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1. Receptors

Nuclear Receptors (“Steroid Superfamily”)• ligand‐activated transcription factors• ligand examples:

— estrogens, progestins, androgens, glucocorticoids, mineralocorticoids, vitamin D, vitamin A (retinoid receptors), fatty acids, etc.

• two main locations in the cell— cytoplasmic— nuclear

• ligand‐binding and DNA‐binding domains

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Drug “Targets”

Protein Targets for Drug Binding

1. Receptors

2. Enzymes



5. Ion Channels

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2. Enzymes Enzymes as Drug Targets

• Many enzymes serve as drug targets— enzymes that are key rate‐limiting steps in

biochemical reactions are the best drug targets— strategy is most often to reduce enzyme activity

through drug inhibition

• Non‐competitive enzyme inhibitors— drug may covalently modify enzyme

* aspirin acetylates Cyclooxygenase 1 & 2 (Cox 1 & 2)* non‐competitively and irreversibly inhibits Cox 1 & 2

• Competitive enzyme inhibitors— drug is often a structural analog of the naturally

occurring substrate— example: HMG‐CoA Reductase Inhibitors

“statins”

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Drug “Targets”


1. Receptors

2. Enzymes



5. Ion Channels

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3. Specific Circulating Plasma Proteins Disease and/or Symptoms Produced by Elevated

Circulating Plasma Proteins• Tumor Necrosis Factor‐

— elevated in rheumatoid arthritis (RA), Crohn’s disease, psoriasis, ankylosing spondylitis

— elevated in severe cases of aphthous ulcers

• Lowering TNF‐ in RA or Crohn’s patients decreases symptoms and may delay progression

• Infliximab and adalimumab— monoclonal antibodies that recognizes TNF‐— bind TNF‐ removing it from circulation

• Etanercept— soluble TNF‐ receptor that binds TNF‐

• Many other examples— daclizumab – antibody that binds interleukin‐2— mepolizumab – antibody that binds interleukin‐5

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Drug “Targets”


1. Receptors

2. Enzymes



5. Ion Channels

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4. Carrier Molecules (Transporters) Ion and Small Molecule Transporters

• important in moving substances across lipid bilayer membranes

• often good drug targets as they regulate key cellular events

Small Molecule Transporters• neurotransmitter uptake (norepinephrine, 5‐HT,

glutamate, etc.)• organic ion transporters (organic acids and bases)• p‐glycoprotein (Multi‐Drug Resistance)

— protective role in moving potential toxicants out of gastrointestinal epithelial cells back into lumen to prevent absorption

— overexpressed in certain tumor cells leading to drug resistance

— can be blocked by drugs* could increase absorption of some drugs* could potentially increase activity of anti‐cancer drugs

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4. Carrier Molecules (Transporters) Ion Transporters

• many transporters important in renal tubules— drives water reabsorption and concentration of

urine

• Na+/K+ ATPase important everywhere— establishes electrochemical gradient by moving

Na+ out and K+ in against concentration gradient

— requires energy (ATP) to function— key in all muscle contraction, nervous

conduction, ion gradient establishment, etc.— often provides the driving force for other ion

transporters— can be inhibited by drugs (e.g., digoxin, a

cardiac glycoside used for heart failure)48



Drug “Targets”


1. Receptors

2. Enzymes



5. Ion Channels

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5. Ion Channels

Voltage‐Gated Ion Channels• Structure

— very similar in structure and function to ligand‐gated ion channel receptors

• Ca++ channels (L, T, N types)

• Na+ channels (fast and slow types)

• K+ channels (voltage‐ and ligand‐gated types)— produce at least 9 different K+ currents

in heart, vascular smooth muscle, and other tissues such as pancreas

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5. Ion Channels

Voltage‐Gated Ion Channels• voltage‐dependent

— channels open or close depending upon the electrical gradient (voltage) across the plasma membrane* resting membrane potential ~ ‐90 mV

* depolarized membrane potential ~ 0 mV

— channels change opened/closed or activated/resting states as electrical potential changes from ‐90 mV to +10 mV (inside relative to outside)

— channels often susceptible to binding by various compounds, including xenobiotics

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Example of Drug‐Receptor Interactions

Opioid Pharmacology• Agonists of Opioid Receptors

— heroin, morphine, oxycodone, hydrocodone

• Competitive Antagonists of Opioid Receptors— naloxone, naltrexone

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Opioid type receptors (OR)

Ca++ Channelmorphine

OR

K+ Channel

Neuron

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OR

K+ Channel

(+)(‐)

Neuron

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OR

K+ Channelnaloxone

Neuron

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Morphine Concentration

Pain Relief Morphine Morphine + Naloxone

Y

X 2X

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Morphine Concentration

RespiratoryRate

Morphine Morphine + Naloxone

Y

X 2X

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Summary Pharmacology

• The study of the effects of drugs on the function of living systems

Drug Development• Begins with thousands of compounds and ends

with 1‐2 drugs with a useful patent life of 7‐10 years

Drug Targets• Include receptors, enzymes, specific circulating

plasma proteins, carrier molecules, and ion channels

Agonists‐Antagonists• Opioid receptors are competitively antagonized

by naloxone which can be life saving in preventing opioid‐induced respiratory arrest

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Useful References

Goodman & Gilman’sThe Pharmacological Basis of Therapeutics

2011, 12th Ed., Chapters 25‐31

Katzung’sBasic & Clinical Pharmacology2015, 13th Ed., Chapters 10‐15

Rang and Dale’sPharmacology

2012, 7th Ed., Chapters 1‐2

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Questions?

Russell B. Melchert, Ph.D.Dean, UMKC School of PharmacyProfessor, Division of Pharmacology and ToxicologyUniversity of Missouri‐Kansas CitySchool of Pharmacy

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