intro Flashcards
Pharmacology
- The study of the effects of drugs on the function of
living systems
Drug
- 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
510 BC
* Pythagoras
— fava bean ingestion was dangerous for some
* now known to be G6PDH deficient individuals
— Pythagoras would not eat beans
De Materia Medica (“Concerning Medical Substances”)
- 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
Shennong Bencao Jing (“The Divine Farmer’s Herb-Root Classic”)
- 1st Century AD
- Han Dynasty
Colchicine
- 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.
Paul Ehrlich (1854-1915)
- 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
FDA
- 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
Pharmacology divisions
- Basic & Clinical Pharmacology
— Pharmacokinetics & Pharmacodynamics (PKPD)
Organ System Pharmacology
— Cardiovascular pharmacology
— Immunopharmacology
— Neuropharmacology
— Gastrointestinal Pharmacology
— Respiratory Pharmacology
— Pharmacokinetics
- Absorption
- Distribution
- Metabolism
- Excretion
— Pharmacodynamics components
- Drug-receptor interactions
- Signal transduction
- Drug effects
Pharmacogenetics
- the metabolic fate of a drug based on individual genetic differences
- study of genetic influences on the responses to drugs
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
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
Drug Development
associations/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 USDA
— FDA shares responsibility with USDA for food safety
Key Legislations
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
Dietary Supplement Health and Education Act (1994)
— prohibited full FDA review of supplements and botanicals as drugs
— established labeling requirements for dietary supplements
“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 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.)
“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 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
Drug Development Process (trials)
Protein Targets for Drug Binding
- Receptors
- Enzymes
- Carrier Molecules (Transporters)
- Ion Channels
- Specific Circulating Plasma Proteins
Nucleic Acid Targets for Drug Binding
- RNA & DNA
Other Targets
- Ion Chelators
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
receptor classification based on?
- Classified based on ligands
— increasing focus on developing new classification system based on genomics
Receptors (e.g. G-Protein Coupled common locations)
ANS and vasucular receptors
- Autonomic Nervous System receptor targets
— Adrenergic Receptors
* a1, a2, b1, b2, b3
— Cholinergic
* muscarinic (M)
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)
nuclear receptor targets
- Steroid Receptors, intracellular
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
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)
Receptor “Binding” or “Bonding” forms
- Electrostatic (most common)
- Hydrophobic (less common)
Covalent (relatively rare)
Electrostatic bonding
— weaker: hydrogen bonding and van der Waals forces (dipoles)
— stronger: ionic bonding
Hydrophobic bonding
— weak associations of hydrophobic compounds with hydrophobic domains of receptors
Covalent bonding
examples?
— permanent, lasting bonding
— aspirin and cyclooxygenase
— omeprazole and proton pump
Physico-Chemical Properties of
Drugs
- size
- Lipophilicity
- Hydrophilic
- ionic charge
- chirality (stereoisomerism)
drug size
- size
— molecular weight ranging from 7 to
hundreds of thousands
- 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
- 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
- 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
- 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
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
- 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
Efficacy
usually expressed as?
— 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?
- highly effective (potent) drugs generally have high affinity
Types of Drug-Receptor Interactions
Agonist
Antagonist
Allosteric Agonists and Antagonists
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
- Antagonist efficacy
— possess zero efficacy
agonist with and without antagonist response curve
- 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
Drug-Receptor Interactions diagrammed
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
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
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)
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)
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
Drug-Receptor Binding calculation
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
Drug-Receptor Interactions: agonist with incrasing antagonist
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
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
Drug-Receptor Interactions: agonist with comp and noncomp antag
Other Mechanisms of Drug Antagonism
- Chemical Antagonist
- Physiologic Antagonist
- Pharmacokinetic Antagonist
- Chemical Antagonist
- 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 b-blockers on heart rate
- Pharmacokinetic Antagonist
— one drug increases the metabolism of the other
* rifampin increases metabolism of many drugs
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
- 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)
Timing of Drug Effects
Rapid, intermediate, and delayed Responses
- Rapid Responses
(seconds to minutes)
—b-adrenergic receptor activation
— nicotinic-acetylcholine receptor activation in nerve synapse
- Intermediate Responses
may be due to what process?
(minutes to hours)
— receptor desensitization
Delayed Responses
(hours to days)
— steroid-induced increase in gene
expression
agonist with and without antagonist response curve
Drug-Receptor Interactions response curves for full/partial agonsits, antag and inverse agonist
competitive vs noncampetitive dose response curves
