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intro Flashcards

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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
 Other Targets
* Ion Chelators
26
 Receptor
* 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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receptor classification based on?
* Classified based on ligands — increasing focus on developing new classification system based on genomics
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 Receptors (e.g. G-Protein Coupled common locations)
ANS and vasucular receptors
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* Autonomic Nervous System receptor targets
— Adrenergic Receptors * a1, a2, b1, b2, b3 — Cholinergic * muscarinic (M)
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vascular system receptor targets
— 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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nuclear receptor targets
* Steroid Receptors, intracellular
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 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, etc
33
Angiotensin II Specificity example
* 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
Receptor “Binding” or “Bonding” forms
* Electrostatic (most common) * Hydrophobic (less common) Covalent (relatively rare)
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Electrostatic bonding
— weaker: hydrogen bonding and van der Waals forces (dipoles) — stronger: ionic bonding
36
Hydrophobic bonding
— weak associations of hydrophobic compounds with hydrophobic domains of receptors
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Covalent bonding examples?
— permanent, lasting bonding — aspirin and cyclooxygenase — omeprazole and proton pump
38
Physico-Chemical Properties of Drugs
* size * Lipophilicity * Hydrophilic * ionic charge * chirality (stereoisomerism)
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drug size
* size — molecular weight ranging from 7 to hundreds of thousands
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* Lipophilicity of drugs — more soluble in? — example molecule? — membranes? — more likely to by metabolized by?
— 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
* Hydrophilic — more soluble in? — example molecules? — plasma membranes? — more likely to be excreted how?
— 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
* ionic charges of drugs examples? pKa?
— 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
* chirality (stereoisomerism)
— 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
R(+) Carvedilol: S(-) Carvedilol: R,S(+) Carvedilol:
R(+) Carvedilol: blocks a adrenergic receptors S(-) Carvedilol: blocks b adrenergic receptors R,S(+) Carvedilol: blocks a, b adrenergic receptors
45
* 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 (nM), lower the affinity
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Efficacy usually expressed as?
— tendency of a drug to activate the receptor once bound — generally expressed as dose-response curves or concentration-effect curves
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* highly effective (potent) drugs generally have?
* highly effective (potent) drugs generally have high affinity
48
Types of Drug-Receptor Interactions
Agonist Antagonist Allosteric Agonists and Antagonists
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Agonist efficacy? full or partial?
— posses significant efficacy — full agonist = elicits maximal response — partial agonist = elicits partial response, even when 100% of receptors are occupied
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* Antagonist efficacy
— possess zero efficacy
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agonist with and without antagonist response curve
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* Allosteric Agonists and Antagonists
— bind to the same receptor, but do not prevent binding of the agonist — can may enhance or inhibit the action of agonist
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Drug-Receptor Interactions diagrammed
54
Model of Receptor Actions basics/agonist
* 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
Model of Receptor Actions * Full Agonist
— 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
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Model of Receptor Actions * Partial Agonist
— 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)
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 Model of Receptor Actions * Antagonist
— 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)
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 Model of Receptor Actions * Inverse Agonist
— 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
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 Drug-Receptor Binding calculation
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Concentration-Effect (Dose-Response)
* 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
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Drug-Receptor Interactions: agonist with incrasing antagonist
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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
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 Model of Receptor Actions * 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 antagonist
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Drug-Receptor Interactions: agonist with comp and noncomp antag
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 Other Mechanisms of Drug Antagonism
* Chemical Antagonist * Physiologic Antagonist * Pharmacokinetic Antagonist
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* Chemical Antagonist
* Chemical Antagonist — for example: ionic interaction between positively charged protamine and negatively charged heparin * protamine antagonizes heparin
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* Physiologic Antagonist
— 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
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* Pharmacokinetic Antagonist
— one drug increases the metabolism of the other * rifampin increases metabolism of many drugs
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 Termination of Drug-Receptor Actions forms
* 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
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* Desensitization (a.k.a. Tachyphylaxis) mechanisms
— 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)
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 Timing of Drug Effects
Rapid, intermediate, and delayed Responses
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* Rapid Responses
(seconds to minutes) —b-adrenergic receptor activation — nicotinic-acetylcholine receptor activation in nerve synapse
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* Intermediate Responses may be due to what process?
(minutes to hours) — receptor desensitization
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Delayed Responses
(hours to days) — steroid-induced increase in gene expression
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agonist with and without antagonist response curve
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Drug-Receptor Interactions response curves for full/partial agonsits, antag and inverse agonist
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competitive vs noncampetitive dose response curves
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