Exam #1 Flashcards
1
Q
Identify acidic (-COOH) and basic (-NR3) functional groups in a molecule and predict the ionization states of a molecule at physiological pH (~7.4)
A
- at physiological pH, carboxyic acids are expected to be deprotonated and amines to be protonated
- when a molecule enters our body, it is immediately subjected to aqueous solution with an average physiological pH 7.4
2
Q
Quinine
A
isolated from cinchona tree bark and is used to treat malaria
3
Q
morphine
A
anesthetic (pain relief) derived from opium poppies
4
Q
digoxin
A
treatment for various heart conditions, including heart failure, derived from foxglove plant and used to tret edema (swelling and fatigue)
5
Q
cocaine
A
numbing agent for mouth and nose, from erythorxylon coca plant
6
Q
Ephedrine
A
found in the ma huang plant (ephedra), used to treat cough, asthma and hay fever
7
Q
curcumin
A
found in the turmeric spice derived from rhizomes of the turmeric plant, used to treat cough, liver problems, rheumatism, inflammation, and anorexia
8
Q
caffeine
A
found in coffee, stimulatory effect appreciated but recognized as a diuretic
9
Q
theobromine
A
found in cacao seeds, more patent diuretic than caffeine
10
Q
theophylline
A
found in tea, more potent diuretic than caffeine
11
Q
nicotine
A
found in tobacco leaves, believed to have antispasmodic benefits
12
Q
vitamin C (ascorbic acid)
A
found in oranges and lemon juice, scurvy prevention
13
Q
First documented drug treatment for any disease?
A
first documented drug treatment can be traced to approx. 3000 BCE in China where ma huang was used to treat a number of conditions including cough
14
Q
First clinical trial?
A
the first clinical trial was related to vitamin C and conducted by James Lind (1747)
15
Q
Describe the first known controlled clinical trial (for scurvy)
A
Tested possible scruvy remedies. Used 5 possible control remedies with a control diet to observed the added benefits of various supplements. Only the sailors who received oranges and lemons showed improvement but juice was not part of standard fair until 1975 (around 50 years later)
16
Q
Discuss the significance of inorganic substances as early sources of drugs (organoarsenic drugs)
A
availability of pure inorganic substances allowed accurate quantification for proper dosing of patients
17
Q
Examples of inorganic substances
A
ferrous sulphate, arsenic trioxide, zinc sulphate, atoxyl
18
Q
ferrous sulphate
A
used to treat anemia
19
Q
arsenic trioxide
A
used to treat skin conditions, trypanosomes (a protozoan infection), toxicity prevented widespread acceptance
20
Q
zinc sulphate
A
used to induce vomiting (emetic), used today to treat ZN deficiency
21
Q
atoxyl
A
developed for trypanosome treatment, first organic arsenical drug (pure and mixtures of oligomers but found to be too toxic for human use)
22
Q
Be able to discuss at least 2 of the major contributions of Paul Ehrlich
A
- noted selective affinity of dyes for biological tissues → gram neg/pos, viability indicators
postulated existence of chemoreceptors, which lead to the birth of modern - chemotherapy → interact with chemicals to produce biological effect, chemoreceptors of microbes and cancer cells differ from host and differences could be used for therapeutic benefit (magic bullet)
- developed idea of chemotherapeutic index (CI), the ratio of maximum tolerated dose to minimum curative dose
- theorized that screening related compounds would optimize biological properties, an approach that laid the foundation for modern pharmaceutical research
23
Q
sulfa drug
A
used as antibiotics and paved the way for the antibiotic revolution in medicine
24
Q
sulfamidochrysoidine (prontosil)
A
he first commercially available antibacterial drug that has been found to have broad activity against many bacterial strains
25
sulfamethoxazole
actively prescribed sulfa drug that treats a range of bacterial infections, including many ear infections in children
26
pro drugs
compounds that are chemically altered in the body to form the biologically active drug
27
terfenadine
generally completely metabolized to the active form fexofenadine in the liver by the enzyme cytochrome P450 CYP3A4 isoform
28
antihistamine
drug used in the treatment of allergy symptoms such as hay fever and nasal congestion, effects limited to periphery, non-sedating
29
sulfasalazine
treat rheumatoid arthritis
30
Discuss the significance of atoxyl and other organic arsenicals
atoxyl and other organic arsenicals represent an important bridge between inorganic and organic chemistry in the development of pharmaceuticals
31
atoxyl significance
first organic arsenical drug and its development marked an early attempt to move beyond traditional inorganic compounds by incorporating carbon based structures into drug design
32
arsphenamine significance
first example of “optimization,” where researchers developed related compounds with improved activity, active against the bacterium responsible for syphilis
33
Fluidextract Thimbleweed Incident
- fluidextract thimblweed was making people ill
- Lilly and company chemist, Ernest Eberhart decided to test a sample on themselves to determine its safety → Lilly was found unconscious
- fluidextract thimbleweed was quickly removed from Eli Lilly’s product list
34
Abbott Company
- produce dosimetric granules, a reference to the need for consistent dosing in the emerging field of pharmaceuticals
- made of ethanol and evaporates quickly → inconsistent amount of drug to ethanol ratio
35
animal testing and fluidextract of ergot
- ergot is a vasoconstrictor used to treat excessive bleeding following childbirth but too much is toxic
- gave roosters the extract that causes bluing of their red comb and wattle → evaluation of color change allowed quantification of the potency of the dose to establish the dosing amount
36
What is a patent drug? Describe what was concerning about some of these “drugs”?
- anything could be sold as a drug and chemicals that are now known to be harmful were marked as medicines
- syrups that were laced with opiates and addictive drugs were part of “patent medicines”
- there was no requirement for a listing of ingredients and secrete ingredients were common
- products were sold openly with colorful advertisements
37
Pure Food and Drug Act of 1906
- First attempt to ensure the safety of drugs and had far-reaching consequences for the pharmaceutical industry
- established the foundation upon which the FDA would be built
outlawed adultered and misbranded food and drugs
- said that dangerous drugs could not be used as secret ingredients but could be included as long as they were accurately labeled
US Department of Agriculture has the authority to enforce the laws
- inspectors could seize and destroy material found to be in violation of the new law and provide publication of all violations that occurred
- fines were modest but the prospect of negative publicity and physical loss of manufactured material became a major deterrent for enforcing the drug regulations
38
Food Drug and Cosmetic Act of 1938
- required companies to perform animal safety tests on new drug candidates, followed by submission of data/results to the FDA before being allowed to market
- set of laws passed by Congress in 1939 giving authority to the FDA to oversee the safety of food, drugs, and cosmetics
- New Drug Application (NDA) process → manufacturers required to submit an application for marketing approval to the FDA before new drugs could be brought to market (1st step of drug discovery)
- established the framework for the modern drug approval system
- companies did not need to demonstrate that their products were effective and the NDAs were automatically approved if the FDA did not act within a certain time frame
39
elixir sulfamide disaster
- spawned the requirements for drug safety
- 3 ingredients → sulfanilamide (antibiotic), ethylene glycol (solvant, toxic in kidneys), raspberry flavoring
- at this time, there was no law barring the sale of dangerous, untested or even poisonous drugs
- American medical association recieved reports that elixir sulfanilamide had been linked to a number of deaths
- ethylene glycol was the cause as it is is used at antifreeze and is a deadly poison
- many victims were children suffering from sore throats and died as a result of kidney failure brought on by ethylene glycol poising
- legal authority came from misbranding of the material as an “elixer” when it contained to alcohol (ethanol) in the product (not from the deaths it caused)
40
thalidomide story
- tranquilizer, pain killer, insomnia, coughs, colds, headaches, morning sickness (antimetic)
- withdrawn after being found to be the cause of birth defects
- teratogen → an agent that causes malformation of an embryo
- first recognition that drugs could cross the placental barrier
- first recognition of the importance of the chirality of drugs
- lead to greater safety requirements for all marketed drugs → Kefauver Harris Agreement of 1962
41
What is a “me too” drug? What is a category creator?
- similar structure, same mode of action → developed by competitors to cash in on large market
- analogs of different drug molecules by replacing functional groups
- few new drugs or drug classes are category creators
- example: H2 receptor antagonists
- to make an antagonist, you need enough structural similarity between your drug (the antagonist) and the natural substrate such that your drug will bind to the receptor
- you need enough difference such that your drug does not allow the receptor to carry out its function
42
Describe patents and patent protection. What is their function and how long do they last?
- patent is the grant of a property right to an inventor, issued by the United States Patent and Trademark Office (USPTO)
- the term of a new patent is 20 years from the date on which the application for the patent was filled
- right to exclude others from making, using, offering for sale, selling or importing the invention
43
utility patents
may be granted to anyone who invents or discovers any new and useful process, machine, article of manufacture, or compensation of matter, or any new and useful improvement thereof
44
design patents
may be granted to anyone who invents a new, original, and ornamental design for an article of manufacture
45
plant patents
may be granted to anyone who invents or discovered and asexually reproduces any distinct and new variety of plant
46
generics company
- can enter the marketplace with copies of the drug at a substantially lower cost because they did not have to pay for the initial discovery and development
- can use the abbreviated ANDA (from the Hatch-Waxman Act of 1984)
- lower research and development costs because they do not have to repeat the initial drug discovery and development process
- enter the market after the patent protection of the original drug has expired (the Hatch-Waxman Act of 1984 encourages the growth of generic drug industry)
- increase competition in the marketplace and can reduce healthcare costs
47
drug discovery company
- focus on discovering, developing, and bringing in new drugs to market, they bear the costs of identifying new therapeutics and gaining market approval for their new products
- must go through the NDA process
- substantial costs in research and development, including preclinical and clinical trials
- rely on patent protection to eliminate competition in the marketplace and recoup the costs of drug development
- have exclusive marketing rights to a particular drug until their composition of the patent expires
48
What funds drug discovery and development?
pharmaceutical companies fund drug discovery and development as they invest profits back into the company or distribute them to owners or investors
49
docking
- the likelihood of binding that is stimulated with computers
- protein of interest → chemical database → possible binding ligand
50
reverse docking
- compound library
- active compound or existing drug → protein target database → possible binding protein
51
What is ADME referring to?
ADME = Absorption, Distribution, Metabolism, Elimination
52
pharmacokinetics (PK)
what the body does to the drug (ADME)
53
absorption
- oral administration → gastrointestinal tract → drug in bloodstream
- intramuscular or subcutaneous injection → tissue deposits → drug in bloodstream
- intravenous injection → drug in bloodstream
- receptors for desired effects → drug metabolites
- mechanism of action, most direct route to the bloodstream, mechanism of action
54
distribution
distribution in the bloodstream
55
metabolism and elimination
- drug or drug metabolite (re-enters bloodstream) → liver (site of most drug metabolism) → intestinal tract → feeces
- pro drugs converted to active form in the liver
- drug metabolites → intetsinal tract → feeces
- drug metabolites → kidney → excretion of drug
- drug metabolites → receptor for undesired effects
56
What are the three major types of assays in drug discovery?
biochemical, cellular, assays
57
biochemical in vitro
assays in tubes, dishes, glassware, plates without cells
58
cellular in vitro
assays in tubes, dishes, glassware, plates with cells
59
ex vivo
testing on tissue but outside of the organism
60
in vivo
testing in living organisms
61
biochemical assays
- binding to target
- performed in absence of cells
- give information only about drug target interaction
- assay development required considerable knowledge about the target and its related biological processes
- molecular biology team
- activity of drug in presence of enzyme
- high frequent screening
62
cellular assays
- enzyme with drug target
- drug with entire cell model (cancer, bacteria, fungi, noncancerous cells)
- cells are grown from an earlier cell culture → cell lines
- passage number → each new cell culture that grows is a new cel culture, higher number indicates higher chance of mutation and differences
- measure membrane permeability, cytotoxicity, serum protein binding
63
aminal experiments
- pre-clinicals or animal trials
- early pre clinical trails involve mice, rats, dogs, rabbits and monkeys
- tests must involve at least one rodent and one non rodent → goal is to determine whether the drug is safe to test in humans
- pharmaceutical company may meet with FDA an FDA may suggest additional specific animal tests
- long term animal trials can last up to two years and often overlap with phase I and phase II trials in humans
64
MTT/XTT
- mitochondrical metabolism and respiratory toxicity
- checks to see if mitochondria is working
added after drug treatment to check if cells are alive
- colorimetric assay → differences in color
- more live cells = darker purple
- more dead cells = lighter purple to yellow
64
alamar blue assays
- more live cells = pink (high fluorescence)
- more dead blue cells = blue (low fluorescence)
- fluorescence assay
- difference in color with spectroscopy
65
Be able to describe an EC50 value and estimate it from a dose-response curve
- EC50 → concentration required to kill 50% of all cells
- dose response curves consist of response plotted as a function of drug concentration
66
Complementarity
- biomolecules having an affinity for one another due to functional groups that are attracted to each other by intermolecular forces
- geometric, stereo, electronic
67
stages of early drug discovery
target discover, identifying hits, discovering leads, pre-clinical studies
68
target discovery
- design of small molecules that activate or inhibit the function of a biomolecule, such a protein, which results in therapeutic benefit to a patient
- begins with a hypothesis that modulation of a specific biological target may have therapeutic value
69
identifying hits
- screening hits are identified from intial hit dataset through physical or virtual screening
- library of compounds → screened in biological assays or screened in computer molecules
- each component to be tested can be tested at a wider range of concentrations once hits are identified
70
discovering leads
- find compounds that show modest activity in biological screens
- compounds showing activity beyond pre determined threshold are called hits
- a desirable hit range might be 0.1-10% spending on the drug and target class
- hits are further tested for their ability to cross membranes, cytotoxicity, and metabolism profile
- hits that pass these criteria are called leads, the goal is to find several promising leads
71
lead optimization
- activity of lead is increased by structural modification
- link between modification of a lead’s structure and changes in activity is called structure activity relationship (SAR)
- SARs guide med chem team as it seeks the best methods of increasing the lead’s activity
- once a lead has been adequate optimized and shows the desirable properties, it is elevated to the status of candidate
- candidates are then tested in animals (efficacy and safety)
72
pre clinical studies
- preclinical studies are independently conducted by whatever research group is doing the study
- preclinical trials are FDA mandated tests that seek to prove the safety of your drug
73
steps needed to take a lead from pre-clinical studies to market
patent filling, investigational new drug (IND), phase I, phase II, phase III, NDA application, phase IV
74
patent filling
after a lead discovery and optimization, file a patent to protect the intellectual property of the drug candidate
75
investigational New Drug (IND)
- contains a full summary of in house screening, animal trials, and information on the synthetic route for preparing the compound
- new chemical entities (NCE)
- if the drug seems safe and has promise being effective, the FDA approves the IND application and phase trials begin
76
Phase I (safety study)
- drug approved for testing in humans
- 20-80 healthy volunteered participants who are usually unpaid
- first introduction of an IND into humans
- determine safety and tolerance of the drug
- subjects are monitored for adverse side effects with increasing doses of the drug
- blood/fluid levels are monitored to determine properties such as half-life and metabolism of the drug
77
Phase II
- 100-300 participants of sick people
- determine effectiveness and proper dosing
- monitored for unwanted drug effects
sponsoring company often meets with the FDA to present clinical and late animal data collected
- FDA may recommend specific clinical tests or additional animal trials to clarify any questions
most drugs fail in the phase
78
Phase III
- 1,000-3,000 people
- increase sample size and diversity of patients
- mortality and chronic conditions with drug → problematic --> can have double or single blind studies with sick individuals
- sometimes optional depending on phase 2 and precedents set
- goal is effectiveness and long term safety
- the pharmaceutical company meets with the FDA to ensure that data collected to date is adequate for the IND to be considered for final approval
- few INDs die in this phase
79
NDA application
- all stages of IND, synthesis to clinical testing to formulation of package labeling are to be presented and reviewed by the FDA
- a smooth NDA may be completed within 12 months
80
Phase IV
- 1,000+ participants
- once a drug reaches market, its long term activity and safety continue to be monitored
- few drug candidates are actually launched as drugs → 20% of all drug candidates that reach IND status are eventually approved by the FDA
