Intro to Pharm Flashcards
• The study of the effects of drugs on the function of
living systems
Pharmacology
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
Drug
inverse proportionality between pressure and volume of gas
Boyle’s Law:
• Father of 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
Paul Ehrlich (1854-1915)
- Absorption
- Distribution
- Metabolism
- Excretion of drugs
Pharmacokinetics
- Drug-receptor interactions
- Signal transduction
- Drug effects
Pharmacodynamics
- the metabolic fate of a drug based on individual genetic differences
- study of genetic influences on the responses to drugs
Pharmacogenetics
• 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
Pharmacogenomics
• 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
Pharmacoepidemiology
• The study of cost and benefits/detriments
of drugs used clinically
• Made possible with “Big Data” sets
Pharmacoeconomics
— administrative body that oversees drug
evaluation process
U.S. Food & Drug Administration (FDA)
____ grants approval for marketing new
drug products
— evidence of safety and efficacy
— “safe” does not mean complete absence of risk
FDA
— prohibited full FDA review of supplements and botanicals as drugs
— established labeling requirements for dietary supplements
- burden of proof of safety/effectiveness is on manufacturer not on FDA
Dietary Supplement Health and Education Act (1994)
________ as defined by FDA
• 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.)
Drug
________ as defined by FDA
• It 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
Generic drug
What are the 5 protein targets for drug binding?
- Receptors
- Enzymes
- Carrier Molecules (Transporters)
- Ion Channels
- Specific Circulating Plasma Proteins
• 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 • Classified based on ligands — increasing focus on developing new classification system based on genomics
Drug receptor
• For a drug to be useful:
— must act selectively on particular cells and
tissues
— must show a high degree of binding site
specificity
Drug Specificity
For a _____ 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
protein
(Drug-receptor interactions)
(most common)
— weaker: hydrogen bonding and van der Waals forces (dipoles)
— stronger: ionic bonding
Electrostatic
(Drug-receptor interactions)
(less common)
— weak associations of hydrophobic compounds with hydrophobic domains of receptors
Hydrophobic
(Drug-receptor interactions) (relatively rare) — permanent, lasting bonding — aspirin and cyclooxygenase — omeprazole and proton pump
Covalent
— 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
Lipophilicity
— 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
Hydrophilic
____ is the pH at which the concentrations of
ionized and unionized species are equal
pKa
— 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
Affinity
— tendency of a drug to activate the receptor once bound
— generally expressed as dose-response curves or concentration-effect curves
Efficacy
— posses significant efficacy
Agonist
= elicits maximal response
full agonist
= elicits partial response, even when 100% of receptors are occupied
partial agonist
— possess zero efficacy
Antagonist
— bind to the same receptor, but do not prevent binding of the agonist
— can may enhance or inhibit the action of agonists
Allosteric Agonists and Antagonists
If you add an antagonist to an agonist, how will the dose response curve shift?
Shifts to right
If you add an allosteric inhibitor to an agonist, how will the dose response curve shift?
Flattens curve
— 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
• Full Agonist
— do not stabilize 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”)
• Partial Agonist
— 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)
• Antagonist
— 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
Inverse Agonist
= equilibrium dissociation constant or concentration
of drug where 50% of receptors are bound
Kd
= concentration of drug that produces 50% of
maximal effect/response
EC50
— 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
• Competitive 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
Noncompetitive Antagonist
— for example: ionic interaction between positively charged protamine and negatively charged heparin
* protamine antagonizes heparin
Chemical 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
Physiologic Antagonist
— one drug increases the metabolism of the other
* rifampin increases metabolism of many drugs
Pharmacokinetic Antagonist
— 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) -down regulation
• Desensitization (a.k.a. Tachyphylaxis)
