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PHARM > intro > Flashcards

intro 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

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

 De Materia Medica (“Concerning Medical Substances”)

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

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

A
  • 1st Century AD
  • Han Dynasty
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6
Q

 Colchicine

A
  • history
    — history dating back to Dioscorides
    — isolated from the Autumn Crocus plant in 1820
  • Benjamin Franklin – world traveler and gout sufferer; introduced colchicine to the U.S.
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7
Q

 Paul Ehrlich (1854-1915)

A
  • Modern Chemotherapy
    — German physician-scientist
    — How to differentiate healthy
    tissue from invading pathogen?
    — Staining techniques led
    eventually to Gram staining
    — arsphenamine (Salvasan)
  • Treatment of syphilis
    — 1908 Nobel Prize
  • contributions to immunology
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8
Q

FDA

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
  • On average, 25-30 New Molecular Entities (NME)
    approved by FDA every year
  • Over 500 drugs approved since 1990
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9
Q

Pharmacology divisions

A
  • Basic & Clinical Pharmacology
    — Pharmacokinetics & Pharmacodynamics (PKPD)
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10
Q

Organ System Pharmacology

A

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

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11
Q

— Pharmacokinetics

A
  • Absorption
  • Distribution
  • Metabolism
  • Excretion
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12
Q

— Pharmacodynamics components

A
  • Drug-receptor interactions
  • Signal transduction
  • Drug effects
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13
Q

Pharmacogenetics

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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14
Q

Pharmacogenomics

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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15
Q

Pharmacoepidemiology

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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16
Q

Pharmacoeconomics

A
  • The study of cost and benefits/detriments
    of drugs used clinically
  • Made possible with “Big Data” sets
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17
Q

Drug Development
associations/process

A

 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 USDA
— FDA shares responsibility with USDA for food safety

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18
Q

Key Legislations

A

Pure Food and Drug Act of 1906
Food, Drug, and Cosmetic Act of 1938
Durham-Humphrey Act of 1952
Dietary Supplement Health and Education Act (1994)
FDA Safety and Innovation Act of 2012

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19
Q

Dietary Supplement Health and Education Act (1994)

A

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

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20
Q

“Drug” as defined by FDA
* A substance recognized by?
* A substance intended for use in?
* A substance (other than food) intended to?
* A substance intended for use as a _____ of a medicine but not a______
* Biological products? laws and regulations?differences?

A
  • A substance recognized by an official pharmacopoeia or formulary
  • 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 are 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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21
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:
* The FDA bases evaluations of:
* By law, a generic drug product must contain:
* Drug products evaluated as “therapeutically equivalent” can be expected to have:

A
  • A generic drug is the same as a brand name drug in dosage, safety, strength, how it is taken, quality, performance, and intended use
  • Before approving a generic drug product, FDA requires many rigorous tests and procedures to assure that the generic drug
    can be substituted for the brand name drug
  • The FDA bases evaluations of substitutability, or therapeutic equivalence of generic drugs on scientific evaluations
  • By law, a generic drug product must contain the identical amounts of the same active ingredient(s) as the brand name product
  • Drug products 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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22
Q

Drug Development Process (trials)

A
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23
Q

 Protein Targets for Drug Binding

A
  • Receptors
  • Enzymes
  • Carrier Molecules (Transporters)
  • Ion Channels
  • Specific Circulating Plasma Proteins
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24
Q

 Nucleic Acid Targets for Drug Binding

A
  • RNA & DNA
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25
Q

 Other Targets

A
  • Ion Chelators
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26
Q

 Receptor

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
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27
Q

receptor classification based on?

A
  • Classified based on ligands
    — increasing focus on developing new classification system based on genomics
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28
Q

 Receptors (e.g. G-Protein Coupled common locations)

A

ANS and vasucular receptors

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29
Q
  • Autonomic Nervous System receptor targets
A

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

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30
Q

vascular system receptor targets

A

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

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31
Q

nuclear receptor targets

A
  • Steroid Receptors, intracellular
32
Q

 Drug Specificity

A
  • 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, etc
33
Q

Angiotensin II Specificity example

A
  • Selectively activates angiotensin II receptors in vascular smooth muscle to cause contraction
    — does not affect smooth muscle in the gastrointestinal tract, genitourinary tract, or uterus
  • Angiotensin II receptors selectively bind angiotensin II
    — do not bind angiotensinogen (precursor to AT-II) or angiotensin IV (AT-II metabolite with 1 aa removed, Phe)
34
Q

Receptor “Binding” or “Bonding” forms

A
  • Electrostatic (most common)
  • Hydrophobic (less common)
    Covalent (relatively rare)
35
Q

Electrostatic bonding

A

— weaker: hydrogen bonding and van der Waals forces (dipoles)
— stronger: ionic bonding

36
Q

Hydrophobic bonding

A

— weak associations of hydrophobic compounds with hydrophobic domains of receptors

37
Q

Covalent bonding
examples?

A

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

38
Q

Physico-Chemical Properties of
Drugs

A
  • size
  • Lipophilicity
  • Hydrophilic
  • ionic charge
  • chirality (stereoisomerism)
39
Q

drug size

A
  • size
    — molecular weight ranging from 7 to
    hundreds of thousands
40
Q
  • Lipophilicity of drugs
    — more soluble in?
    — example molecule?
    — membranes?
    — more likely to by metabolized by?
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

41
Q
  • Hydrophilic
    — more soluble in?
    — example molecules?
    — plasma membranes?
    — more likely to be excreted how?
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

42
Q
  • ionic charges of drugs
    examples? pKa?
A

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

— weak bases (e.g. epinephrine, pKa 8.7)
pKa follows same rule

43
Q
  • chirality (stereoisomerism)
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

44
Q

R(+) Carvedilol:
S(-) Carvedilol:
R,S(+) Carvedilol:

A

R(+) Carvedilol: blocks a adrenergic receptors
S(-) Carvedilol: blocks b adrenergic receptors
R,S(+) Carvedilol: blocks a, b adrenergic receptors

45
Q
  • Affinity
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

46
Q

Efficacy
usually expressed as?

A

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

47
Q
  • highly effective (potent) drugs generally have?
A
  • highly effective (potent) drugs generally have high affinity
48
Q

Types of Drug-Receptor Interactions

A

Agonist
Antagonist
Allosteric Agonists and Antagonists

49
Q

Agonist
efficacy?
full or partial?

A

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

50
Q
  • Antagonist efficacy
A

— possess zero efficacy

51
Q

agonist with and without antagonist response curve

A
52
Q
  • Allosteric Agonists and Antagonists
A

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

53
Q

Drug-Receptor Interactions diagrammed

A
54
Q

Model of Receptor Actions basics/agonist

A
  • Inactive (Ri) and Active (Ra) Receptors
  • Cells express many thousands of receptors
    — absent any agonist, some would be in activated (Ra) state (constitutively active), but most in Ri state
    — minimal effect produced
  • Agonists (D) have high affinity for activated state and stablize it
    — large percentage of total receptor pool resides in Ra-D state
    — large effect is produced
55
Q

Model of Receptor Actions
* Full Agonist

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

56
Q

Model of Receptor Actions
* Partial Agonist

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)

57
Q

 Model of Receptor Actions
* Antagonist

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)

58
Q

 Model of Receptor Actions
* Inverse Agonist

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

59
Q

 Drug-Receptor Binding calculation

A
60
Q

Concentration-Effect (Dose-Response)

A
  • In Vitro/In Vivo (Cells vs Animals or Patients)
    — effect/response of low concentrations/doses of a drug usually increases in direct proportion to concentration/dose
  • E = effect observed at given concentration (C)
    — As “dose” increases, the effect/response increment diminishes
  • Emax = point at which at which no further effect/response is achieved as “dose” increases further
  • EC50 = concentration of drug that produces 50% of maximal effect/response
  • Hyperbolic Relation
61
Q

Drug-Receptor Interactions: agonist with incrasing antagonist

A
62
Q

 Model of Receptor Actions
* Competitive Antagonist

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

63
Q

 Model of Receptor Actions
* Noncompetitive Antagonist

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

64
Q

Drug-Receptor Interactions: agonist with comp and noncomp antag

A
65
Q

 Other Mechanisms of Drug Antagonism

A
  • Chemical Antagonist
  • Physiologic Antagonist
  • Pharmacokinetic Antagonist
66
Q
  • Chemical Antagonist
A
  • Chemical Antagonist
    — for example: ionic interaction between positively charged protamine and negatively charged heparin
  • protamine antagonizes heparin
67
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

68
Q
  • Pharmacokinetic Antagonist
A

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

69
Q

 Termination of Drug-Receptor Actions forms

A
  • Dissociation of drug from receptor
  • Dissociation of drug from receptor but effects continue for some time
    — downstream activation of effectors
  • e.g. kinase phosphorylation of downstream proteins
    — activated effectors have to be deactivated
  • e.g. phosphatase dephosphorylation of downstream proteins
  • Covalently bound drugs require destruction of the drug-receptor complex and synthesis of new receptors
    — platelets and aspirin; omeprazole and proton pump
  • Desensitization
70
Q
  • Desensitization (a.k.a. Tachyphylaxis) mechanisms
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)

71
Q

 Timing of Drug Effects

A

Rapid, intermediate, and delayed Responses

72
Q
  • Rapid Responses
A

(seconds to minutes)
—b-adrenergic receptor activation
— nicotinic-acetylcholine receptor activation in nerve synapse

73
Q
  • Intermediate Responses
    may be due to what process?
A

(minutes to hours)
— receptor desensitization

74
Q

Delayed Responses

A

(hours to days)
— steroid-induced increase in gene
expression

75
Q

agonist with and without antagonist response curve

A
76
Q

Drug-Receptor Interactions response curves for full/partial agonsits, antag and inverse agonist

A
77
Q

competitive vs noncampetitive dose response curves

A

PHARM (15 decks)

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