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Pharmacology > Introduction to Pharmacology > Flashcards

Introduction to Pharmacology Flashcards

1
Q

Pharmacology

A
  • The study of the effects of drugs on the function of
    living systems
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2
Q

Drug

A
  • A chemical substance of known structure, other
    than a nutrient or an essential dietary ingredient,
    which, when administered to a living organism,
    produces a biological effect
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3
Q

510 BC
* Pythagoras
(2)

A

— fava bean ingestion was dangerous for some
* now known to be G6PDH deficient individuals
— Pythagoras would not eat beans

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4
Q

SKIPPED
De Materia Medica (“Concerning
Medical Substances”)
(3)

A
  • 1st Century AD
  • Pedanius Dioscorides (90-40 AD)
    — Greek botantist/pharmacologist/physician
    — served in Nero’s army as a botantist
  • Five volume collection on medicinal
    plants
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5
Q

SKIPPED
Shennong Bencao Jing (“The Divine
Farmer’s Herb-Root Classic”)
(2)

A
  • 1st Century AD
  • Han Dynasty
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6
Q

SKIPPED
Medieval Times
* Robert Boyle (1627-1691)
(3)

A

— Scientific foundations of chemistry beginning to
be established in 17th century
— Surprisingly content with lack of scientific
approach to therapeutics
— A Collection of Choice Remedies, 1692 (Robert
Boyle)

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7
Q
  • Boyle’s Law:
A

inverse proportionality between
pressure and volume of gas

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8
Q

SKIPPED
Colchicine
* history
(2)

A

— history dating back to Dioscorides
— isolated from the Autumn Crocus plant in
1820

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9
Q

SKIPPED
Benjamin Franklin –

A

world traveler and gout
sufferer; introduced colchicine to the U.S.

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10
Q

Paul Ehrlich (1854-1915)
* Modern Chemotherapy
(5)

A

— German physician-scientist
— How to differentiate healthy
tissue from invading pathogen?
— Staining techniques led
eventually to Gram staining
— arsphenamine (Salvasan)
— 1908 Nobel Prize
* contributions to immunology

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11
Q

— arsphenamine (Salvasan)
* Treatment of

A

syphilis

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12
Q

SKIPPED
Gerhard Domagk (1895-1964)
* German pathologist (Bayer)
* 1908—

A

synthesis of azo dyes (German patents)

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13
Q

SKIPPED
Gerhard Domagk (1895-1964)
* German pathologist (Bayer)
* 1932—

A

Klarer & Mietzsch* patent for azo dyes containing sulfonamide group
— Domagk studied synthetic azo dyes for action against Streptococci and Staphylococci

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14
Q

SKIPPED
Gerhard Domagk (1895-1964)
* German pathologist (Bayer)
* 1933—

A

Prontosil (a red dye with the active metabolite = sulfanilamide) given to 10 month old infant with Staphylococcus septicemia* dramatic cure, but little credit given
— Domagk treats his own daughter with prontosil* dramatic cure, but he doesn’t tell anyone until later

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15
Q

SKIPPED
Gerhard Domagk (1895-1964)
* German pathologist (Bayer)
* 1939—

A

Nobel Prize awarded to Domagk

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16
Q

SKIPPED
1928: Alexander Fleming
(2)

A
  • St. Mary’s in London
  • Staphylococcus cultures contaminated with mold
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17
Q

SKIPPED
1940: Oxford University
(1)

A
  • Crude mold extract administered to Strep.-infected mice
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18
Q

SKIPPED
1941: Clinical Trial
(4)

A
  • Severely ill with Staphylococcus or Streptococcus infections
  • 100L of broth required for 1 patient (24 hr regimen)
  • Crude drug recovered in urine
  • “remarkable substance grown in bedpans and purified through the Oxford police force”
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19
Q

SKIPPED
Mold identified as Penicillium notatum

A

 1943: U.S. Surgeon General
* allowed trials in military forces
 First marketable penicillin
* several dollars/100,000 Units
 1950s-1970s: Research
* discovery of penicillin began world wide search
 Present:
* 100,000 Units of penicillin V potassium costs several cents notatum

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20
Q

SKIPPED
1930’s to 2016

A
  • 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
  • Kinch et al
    — Drug Discov Today. 2014 Aug;19(8):1033-9
  • On average, 25-30 New Molecular Entities (NME)
    approved by FDA every year
  • Over 500 drugs approved since 1990
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21
Q
  • Basic & Clinical Pharmacology
A

— Pharmacokinetics & Pharmacodynamics (PKPD)

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22
Q
  • Organ System Pharmacology
    (5)
A

— Cardiovascular pharmacology
— Immunopharmacology
— Neuropharmacology
— Gastrointestinal Pharmacology
— Respiratory Pharmacology

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23
Q

Pharmacology & “Sub-Disciplines”
(5)

A

 Pharmacology
 Pharmacogenetics
 Pharmacogenomics
 Pharmacoepidemiology
 Pharmacoeconomics

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24
Q
  • Basic & Clinical Pharmacology
    (3)
A

— Pharmacokinetics & Pharmacodynamics (PKPD)
— Pharmacokinetics
— Pharmacodynamics

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25
Q

— Pharmacokinetics
(4)

A
  • Absorption
  • Distribution
  • Metabolism
  • Excretion
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26
Q

— Pharmacodynamics
(3)

A
  • Drug-receptor interactions
  • Signal transduction
  • Drug effects
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27
Q

Pharmacogenetics
(2)

A
  • the metabolic fate of a drug based on individual genetic differences
  • study of genetic influences on the responses to drugs
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28
Q

Pharmacogenomics
(2)

A
  • 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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29
Q

Pharmacoepidemiology
(3)

A
  • 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
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30
Q

Pharmacoeconomics
(2)

A
  • The study of cost and benefits/detriments
    of drugs used clinically
  • Made possible with “Big Data” sets
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31
Q

U.S. Food & Drug Administration (FDA)

A

— administrative body that oversees drug
evaluation process

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32
Q
  • FDA grants approval for marketing new
    drug products
  • FDA approval for marketing
    (2)
A

— evidence of safety and efficacy
— “safe” does not mean complete absence of risk

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33
Q

FDA and USDA

A

— FDA shares responsibility with USDA for food
safety

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34
Q

SKIPPED
* Pure Food and Drug Act of 1906
(1)

A

— prohibited mislabeling

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35
Q

SKIPPED
* Food, Drug, and Cosmetic Act of 1938
(3)

A

— required that new drugs be safe as well as pure
— did not require efficacy
— required enforcement by FDA

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36
Q

SKIPPED
* Durham-Humphrey Act of 1952
(1)

A

— Vested in the FDA power to determine which products could be sold without Rx

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37
Q
  • Dietary Supplement Health and Education Act (1994)
    (2)
A

— prohibited full FDA review of supplements and botanicals as drugs
— established labeling requirements for dietary supplements

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38
Q

SKIPPED
* FDA Safety and Innovation Act of 2012
(1)

A

— established new accelerated process for “breakthrough therapy”, “priority review”, and “fast-track” procedures

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39
Q

“Drug” as defined by FDA
* A substance recognized by
* A substance intended for use in the
* A substance (other than food) intended to affect the
* A substance intended for use as a
* Biological products are included within this definition
and are generally covered by the same laws and
regulations, but differences exist regarding their

A

an official pharmacopoeia or formulary
diagnosis, cure, mitigation, treatment, or prevention of disease
structure or any function of the body
component of a medicine but not a device or a component, part or
accessory of a device
manufacturing processes (chemical process versus
biological process.)

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40
Q

“Generic Drug” as defined by FDA
* A generic drug is the same as a brand name drug in
* Before approving a generic drug product, FDA requires many
* The FDA bases evaluations of
* By law, a generic drug product must contain the identical
amounts of the same — as the brand name
product
* Drug products evaluated as “therapeutically equivalent” can
be expected to have

A

dosage, safety, strength, how it is taken, quality, performance, and
intended use
rigorous tests and procedures to assure that the generic drug can be substituted for the brand name drug
substitutability, or therapeutic equivalence of generic drugs on scientific evaluations
active ingredient(s)
equal effect and no difference when substituted for the brand name product

41
Q

Paul Ehrlich (1854-1915)
* Modern Chemotherapy
— Drug actions not result of magical
— Drug action explained by
— “A drug will not work unless it is
—”
— Must develop a “—”

A

“vital forces”
conventional chemical
interactions between drugs and
tissues
bound
Magic Bullet

42
Q

Protein Targets for Drug Binding
(5)

A
  • Receptors
  • Enzymes
  • Carrier Molecules (Transporters)
  • Ion Channels
  • Specific Circulating Plasma Proteins
43
Q

Nucleic Acid Targets for Drug Binding

A
  • RNA & DNA
44
Q

Other Targets

A
  • Ion Chelators
45
Q

Receptors

A
  • Protein molecule which function to
    recognize and respond to
    endogenous chemical signals
    — protein molecules which function to
    recognize specific endogenous ligands
    — may also recognize/bind xenobiotics
46
Q

Receptors
* Classified based on

A

ligands
— increasing focus on developing new
classification system based on
genomics

47
Q

Receptors (e.g. G-Protein Coupled)
* Autonomic Nervous System
(2)

A

— Adrenergic Receptors
* a1, a2, b1, b2, b3
— Cholinergic
* muscarinic (M)

48
Q

Receptors (e.g. G-Protein Coupled)
* Vascular System
(4)

A

— angiotensin II receptors (AT1, AT2)
— endothelin receptors (ETA, ETB)
— prostaglandin receptors (DP, EP, FP, IP, TP)
— histamine receptors (H1, H2, H3)

49
Q

Receptors (e.g. Nuclear)
* Steroid Receptors
(6)

A

— Estrogen Receptor (ER)
* ERa, ERb
— Androgen Receptor
— Glucocorticoid Receptor (cortisol)
— Mineralocorticoid Receptor (aldosterone)
— Retinoid X Receptor (RXR)
— Constitutive Androstane Receptor (CAR)

50
Q

Drug Specificity
* For a drug to be useful:
(2)

A

— must act selectively on particular cells and
tissues
— must show a high degree of binding site
specificity

51
Q

For a protein to function as a receptor:
(2)

A

— generally shows a high degree of ligand
specificity
— bind only molecules of certain physico-
chemical properties
* size, shape, charge, lipophilicity, etc

52
Q

Angiotensin II
* Selectively activates angiotensin II
receptors in vascular smooth muscle
to cause contraction

A

— does not affect smooth muscle in the
gastrointestinal tract, genitourinary
tract, or uterus

53
Q

Angiotensin II receptors selectively
bind angiotensin II

A

— do not bind angiotensinogen (precursor
to AT-II) or angiotensin IV (AT-II
metabolite with 1 aa removed, Phe)

54
Q

Receptor “Binding” or “Bonding”
* Electrostatic (most common)
— weaker:
— stronger:

A

hydrogen bonding and van der Waals forces (dipoles)
ionic bonding

55
Q

Hydrophobic (less common)

A

— weak associations of hydrophobic compounds with hydrophobic domains of receptors

56
Q

Covalent (relatively rare)
(3)

A

— permanent, lasting bonding
— aspirin and cyclooxygenase
— omeprazole and proton pump

57
Q

Physico-Chemical Properties of
Drugs
* size

A

— molecular weight ranging from 7 to
hundreds of thousands

Li+: MW = 7
Alirocumab: MW ~ 146,000

58
Q

Lipophilicity
(4)

A

— more soluble in oil than water
* i.e. more soluble in fat than blood
— steroids
— readily diffuse across membranes
— more likely to by metabolized by gut and liver

59
Q

Hydrophilic
(4)

A

— more soluble in water than oil
* i.e. more soluble in blood than fat
— small molecules, weak acids/bases
* ionized at physiologic pH (7.4)
— not as easy to diffuse across plasma membranes
— more likely to be excreted unchanged by kidney

60
Q

Physico-Chemical Properties of
Drugs
* ionic charge

A

— weak acids (e.g. aspirin, pKa 3.5)
* pKa is the pH at which the concentrations of
ionized and unionized species are equal

61
Q

Physico-Chemical Properties of Drugs
* chirality (stereoisomerism)
(4)

A

— enantiomers: 1 pair for each chiral carbon
— most drugs used as “racemic” mixtures
— carvedilol: a1, b1, b2 adrenergic receptor antagonist used to treat heart failure
— sometimes only one stereoisomer is active and the others produce adverse effects

62
Q

R(+) Carvedilol:

A

blocks a adrenergic receptors

63
Q

S(-) Carvedilol:

A

blocks b adrenergic receptors

64
Q

R,S(+) Carvedilol:

A

blocks a, b adrenergic receptors

65
Q

Affinity
(3)

A

— 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 (nM), lower the affinity

66
Q

Efficacy
(2)

A

— tendency of a drug to activate the receptor once bound
— generally expressed as dose-response curves or concentration-effect curves

67
Q
  • highly effective (potent) drugs generally have high
A

affinity

68
Q

Agonist
(3)

A

— posses significant efficacy
— full agonist = elicits maximal response
— partial agonist = elicits partial response, even when 100% of receptors are occupied

69
Q

Antagonist efficacy

A

— possess zero efficacy

70
Q

Allosteric Agonists and Antagonists
(2)

A

— bind to the same receptor, but do not prevent binding of the agonist
— can may enhance or inhibit the action of agonists

71
Q

Hyperbolic Relation
Model of Receptor Actions
(3)

A
  • Inactive (Ri) and Active (Ra) Receptors
  • Cells express many thousands of receptors
  • Agonists (D) have high affinity for activated state and stablize it
72
Q

Cells express many thousands of receptors
(2)

A

— absent any agonist, some would be in activated (Ra) state (constitutively active), but most in Ri state
— minimal effect produced

73
Q

Agonists (D) have high affinity for activated state and stablize it
(2)

A

— large percentage of total receptor pool resides in Ra-D state
— large effect is produced

74
Q

Full Agonist
(3)

A

— high affinity for Ra and stabilize Ra on binding
— shift nearly entire pool of receptors from Ri to Ra-D (Ra bound to drug)
— maximal effect is produced

75
Q

Partial Agonist
(4)

A

— do not stablize Ra as effectively
— significant fraction stays in Ri-D pool
— only partially effective no matter how high concentration
— some can act as agonist (if no full agonist is present) or antagonist (if if full agonist is present)
* e.g. pindolol, b-adrenergic receptor antagonist when epinephrine is present; agonist when absent (“intrinsic sympathomimetic activity”)

76
Q

Antagonist
(3)

A

— Ra-D and Ri-D stay in same relative amounts as in the absence of any drug
— no change in effect measured
— block effects of agonist (neutral antagonist)

77
Q

Inverse Agonist
(3)

A

— higher affinity for Ri than for Ra
— stabilize Ri on binding
— reduces any constitutive activity of receptor thus producing opposite effects as a conventional agonist
* e.g. g-aminobutyric acid (GABA) receptors; diazepam agonist, flumazenil antagonist, experimental compounds act as inverse agonist

78
Q

SKIPPED
In Vitro (Cells or Tissue Homogenates)
(2)

A

— Mass Action Law
— Drug agonists act by binding to (“occupying”) a distinct receptor

79
Q
  • B =
A

drug bound to receptors at given concentration (C)
— As “dose” increases, binding increment diminishes

80
Q
  • Bmax =
A

point at which at which all receptors are bound

81
Q
  • Kd =
A

equilibrium dissociation constant or concentration
of drug where 50% of receptors are bound
— low Kd = high binding affinity and vice versa

82
Q

Concentration-Effect (Dose-Response)
* In Vitro/In Vivo (Cells vs. Animals or Patients)

Hyperbolic Relation

A

— effect/response of low concentrations/doses of a drug usually
increases in direct proportion to concentration/dose

83
Q
  • E =
A

effect observed at given concentration (C)
— As “dose” increases, the effect/response increment diminishes

84
Q
  • Emax =
A

point at which at which no further
effect/response is achieved as “dose” increases further

85
Q
  • EC50 =
A

concentration of drug that produces 50% of
maximal effect/response

86
Q

Model of Receptor Actions
* Antagonist
(3)

A

— Ra-D and Ri-D stay in same relative
amounts as in the absence of any drug
— no change in effect measured
— block effects of agonist (neutral
antagonist)

87
Q

Model of Receptor Actions
* Competitive Antagonist
(4)

A

— 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

88
Q

Noncompetitive Antagonist
(3)

A

— often bind covalently and irreversibly
— often allosteric inhibition but can be same binding site as agonist
— increasing agonist concentration may not overcome noncompetitive antagonist

89
Q

Chemical Antagonist

A

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

90
Q

Physiologic Antagonist

A

— for example: different regulatory pathways mediated by different receptors resulting in opposing actions
* anticholinergic atropine can physiologically antagonize effects of b-blockers on heart rate

91
Q

Pharmacokinetic Antagonist

A

— one drug increases the metabolism of the other
* rifampin increases metabolism of many drugs

92
Q

Termination of Drug-Receptor Actions
(4)

A
  • Dissociation of drug from receptor
  • Dissociation of drug from receptor but effects continue for some time
  • Covalently bound drugs require destruction of the drug-receptor complex and synthesis of new receptors
  • Desensitization
93
Q
  • Dissociation of drug from receptor but effects continue for some time
A

— downstream activation of effectors
* e.g. kinase phosphorylation of downstream proteins
— activated effectors have to be deactivated
* e.g. phosphatase dephosphorylation of downstream proteins

94
Q

SKIPPED
* Covalently bound drugs require — of the drug-receptor complex and synthesis of new receptors

A

destruction
— platelets and aspirin; omeprazole and proton pump

95
Q

SKIPPED
Desensitization (a.k.a. Tachyphylaxis)

A

— change in receptors
* phosphorylation of receptor
— translocation of receptors
* b-adrenergic receptor internalization
— exhaustion of mediators
* neurotransmitter depletion
— increased drug metabolism
— physiologic adaptation
* blood pressure lowering from a diuretic
— active extrusion of drug from cell
* multi-drug resistance (P-glycoprotein)

96
Q

Rapid Responses (seconds to minutes)
(2)

A

—b-adrenergic receptor activation
— nicotinic-acetylcholine receptor
activation in nerve synapse

97
Q

Intermediate Responses (minutes to
hours)

A

— receptor desensitization

98
Q

Delayed Responses (hours to days)

A

— steroid-induced increase in gene
expression

Pharmacology (13 decks)

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