Introduction to Pharmacology! What is Pharmacology and How do Drugs Act? Flashcards
What is pharmacology?
The study of the effects of drugs on the function of living systems
What is a 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
Why did pythagoroas not eat beans?
— fava bean ingestion was dangerous for some
* now known to be G6PDH deficient individuals
What did Robert Boyles do for pharmacology?
- He kinda just made shit up
— Surprisingly content with lack of scientific approach to therapeutics
What did Benjamin Franklin bring to the US?
– world traveler and gout sufferer; introduced colchicine to the U.S.
What did Paul Ehrlich do for pharmacology?
Modern Chemotherapy
— How to differentiate healthy tissue from invading pathogen
— Staining techniques led eventually to Gram staining
— arsphenamine (Salvasan)
* Treatment of syphilis
— 1908 Nobel Prize
What did Gerhard Domagk do for pharmacology?
- 1908
— synthesis of azo dyes - 1932
— Klarer & Mietzsch - patent for azo dyes containing sulfonamide group
— Domagk studied synthetic azo dyes for action against Streptococci and Staphylococci - 1933
— Prontosil (a red dye with the active metabolite = sulfanilamide) given to 10 month old infant with Staph septicemia - dramatic cure, but little credit given
— Domagk treats his own daughter with prontosil - dramatic cure, but he doesn’t tell anyone until later
- 1939
— Nobel Prize awarded to Domagk
What did Alexander Fleming do for pharamcology?
- Staphylococcus cultures contaminated with mold
- Crude mold extract administered to Strep. infected mice
- Crude drug recovered in urine (people)
▪ Mold identified as Penicillium notatum
What is important to know about the Food and Drug Administration (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
What is PKPD?
Pharmacokinetics & Pharmacodynamics
What is pharmacokinetics?
- Absorption
- Distribution
- Metabolism
- Excretion
What is pharmacodynamics (part of pharmacology)?
- Drug-receptor interactions
- Signal transduction
- Drug effects
What is pharmacogenetics (part of pharmacology)?
- the metabolic fate of a drug based on individual genetic differences
- study of genetic influences on the responses to drugs
What is 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
What is 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
What is pharmacoeconomics?
- The study of cost and benefits/detriments of drugs used clinically
- Made possible with “Big Data” sets
What are all the branches of pharmacology?
- Biochemistry & Biotechnology
- Physiology & Pathophysiology
- Chemistry Medicinal Chemistry
- Pharmacogenetics & Pharmacogenomics
- Pharmacoepidemiology
- Pharmaceutics
- Pharmacoeconomics
What does the FDA do?
— administrative body that oversees drug evaluation process
* FDA grants approval for marketing new drug products
— evidence of safety and efficacy
— “safe” does not mean complete absence of risk
* FDA and USDA
— FDA shares responsibility with USDA for food safety
What is the dietary supplement health and education act (1994)?
— prohibited full FDA review of supplements and botanicals as drugs
— established labeling requirements for dietary supplements
What is “drug” as defined by FDA?
- A substance (other than food) recognized by an official pharmacopoeia or formulary intended:
— for use in the diagnosis, cure, mitigation, treatment, or prevention of disease
— to affect the structure or any function of the body
— for use as a component of a medicine but not a device - Biological products are included within this definition and are generally covered by the same laws and regulations
What is a generic drug?
A generic drug is the same as a brand name drug in dosage, safety, strength, how it is taken, quality, performance, and intended use
What are the steps of drug development process?
What did Pual Ehrlich believe in developing?
Magic Bullet
What are the protein targets for drug binding?
- Receptors
- Enzymes
- Carrier Molecules (Transporters)
- Ion Channels
- Specific Circulating Plasma Proteins
What are the nucleic acid targets for drug binding?
- RNA & DNA
What are receptors?
- Protein molecules which function to recognize and respond to endogenous chemical signals
- Classified based on ligands
What are the receptors (G-protein coupled) in the autonomic nervous system?
Adrenergic Receptors
— a1, a2, B1, B2, B3
Cholinergic
—muscarinic (M)
What are the receptors (G-protein coupled) in the vascular system?
— angiotensin II receptors (AT1, AT2)
— endothelin receptors (ETA, ETB)
— prostaglandin receptors (DP, EP, FP, IP, TP)
— histamine receptors (H1, H2, H3)
What are nuclear receptors?
- Steroid Receptors
—Estrogen Receptor (ERa, ERB)
—Androgen Receptor
—Glucocorticoid Receptor (cortisol)
—Mineralocorticoid Receptor (aldosterone)
—Retinoid X Receptor (RXR)
—Constitutive Androstane Receptor (CAR)
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 physicochemical properties (size, shape, charge, lipophilicity)
What does angiotensin II do?
- Selectively activates angiotensin II receptors in vascular smooth muscle to cause contraction
- Angiotensin II receptors selectively bind angiotensin II
What is the most common receptor binding?
Electrostatic
What is the most rare type of receptor binding?
Covalent
What is an electrostatic receptor bond?
- Electrostatic (most common)
— weaker: hydrogen bonding and van der Waals forces (dipoles)
— stronger: ionic bonding
What is an hydrophobic receptor bond?
- Hydrophobic (less common)
— weak associations of hydrophobic compounds with hydrophobic domains of receptors
What is an covalent receptor bond?
- Covalent (relatively rare)
— permanent, lasting bonding
— aspirin and cyclooxygenase
— omeprazole and proton pump
What is lipophilic?
— 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
What is hydrophilic?
— 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
___ is the pH at which the concentrations of ionized and unionized species are equal
pKa
If a drug is chiral (stereoisomeric) what does that mean?
— enantiomers: 1 pair for each chiral carbon
— most drugs used as “racemic” mixtures
— sometimes only one stereoisomer is active and the others produce adverse effects
What is dissociation constand (Kd)?
- concentration required for 50% saturation of available receptors
- inversely proportional to affinity
What is affinity?
— tendency of a drug to bind to the receptor
higher the Kd (nM), lower the _________
affinity
What is efficacy?
— 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 _____ affinity
high
What is an agonist?
— posses significant efficacy
— full agonist = elicits maximal response
— partial agonist = elicits partial response, even when 100% of receptors are occupied
What is an antagonist?
— possess zero efficacy
What is an alloseric agnosist or antagonist?
— bind to the same receptor, but do not prevent binding of the agonist
— may enhance or inhibit the action of agonists
On a drug response curve adding an antagonist leads to a _____ shift
right
- need more concentratin of agonist for the same effect
What are the characteristics of a 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
What are the characteristics of a 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 or antagonist
What are the characteristics of an 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
What are the characteristics of an 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
What is the drug-receptor binding equation in vitro?
- B = drug bound to receptors at given concentration (C)
- Bmax = point at which at which all receptors are bound
- Kd = equilibrium dissociation constant or concentration of drug where 50% of receptors are bound
What is Kd?
equilibrium dissociation constant or concentration of drug where 50% of receptors are bound
What is Bmax?
point at which at which all receptors are bound
What is the concentration-effect equation in vitro/in vivo?
- E = effect observed at given concentration (C)
- 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
What is EC50?
concentration of drug that produces 50% of maximal effect/response
What is Emax?
point at which at which no further effect/response is achieved as “dose” increases further
What are the characteristics of a 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
What are the characteristics of a 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
What are other mechanisms of drug antagonism besides competitive or noncompetitive?
- chemical antagonist
- physiologic antagonist
- pharmacokinetic antagonist
How do drug-receptor actions terminate?
- 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
What happens if there is dissociation of drug from receptor but effects continue for some time?
— downstream activation of effectors
— activated effectors have to be deactivated
How do drug-receptor actions become desensitized (tachyphylaxis)?
— change in receptors
— translocation of receptors
— exhaustion of mediators
— increased drug metabolism
— physiologic adaptation
— active extrusion of drug from cell
What are the different timings for drug effects?
- Rapid Responses (seconds to minutes)
- Intermediate Responses (minutes to hours)
- Delayed Responses (hours to days)
