Lectures 3&4 Flashcards
how do you define pharmacology
the basic and clinical applied science that deals with the fate and actions of drugs in the body
what are drugs
Any substance used in the diagnosis, prevention, or treatment of disease
drugs are made of
chemicals
what is pharmakon
poison or drugs
logos
study or discourse of
Humans have sough ___ and ___ roducts since the earliest of times to combat sickness and death
plant & animal
what has been common since religion and men have existed
Mixture of religion and use of plant substances
what is the doctrine of signatures (1500s)
Plant parts that resembled human body parts, animals, or other objects were thought to have useful relevance to those parts, animals, or objects
People thought that God had made herbs for the use of men and given them particular Signatures that could be read to cure disease, such as
Walnuts were good to cure ailments of the head because they had a perfect signature for the head!
The holes in the leaves of Saint Johns Wort resemble pores of the skin and, therefore, can treat disease and wounds of the skin
Oldest prescriptions were found on clay tablets written by _____ physicians around ____ BC
Sumerian
3000
one of the earliest urban societies to emerge in the world, in Southern Mesopotamia (modern day Iraq), more than 5000 years ago
Sumerians
What did hippocrates say
5th century BC) promoted the idea that disease results from natural causes rather than evil spirits
He believed that the body had abilities to recuperate from disease
In the early years, medicines were developed by isolation and use of nature substances from
botanical, mineral, and animal sources
In modern times, medicines are developed by
chemical synthesis of compounds that have biological activity
what is quinine
Bark of some trees contained quinine
Quinine is still used today as a drug of choice against malaria
The first specific drug used to treat an infectious disease
first successful drug used against malaria
quinine
when did synthesis of arsenicals come about
1910
Sahachiro Hata and Paul Ehrlich’s synthesized arsenicals by
attaching an arsenic atom to a carbon atom
(Salvarsan-first chemotherapeutic agent) to treat syphilis
arsphenamine
what is the primary use of digitalis
heart disease
William Withering’s use of purple foxglove (digitalis purpurea) in 1783, lead to
the isolation of digitalis
He made a tea to treat the edema of cardiac
“dropsy” (congestive heart failure)
Digitalis is still the drug of choice for
congestive heart failure
Today the drug is still isolated from plants (digitalis lanata leaves rather than digitalis purpurea seeds) because
it is too difficult and expensive to synthesize chemically
a narcotic is used for pain control
opium
had been used as a medical and recreational drug since prehistoric times
opium
most powerful pain killers
opium
The source of opium is th
poppy plant (Papavir somniferum)
Growth of poppy plants for medicinal use in the U. S. is highly regulated
true
The German chemist, Friedrich Serturner, isolated the alkaloid _______ from ______ in 1805
morphine
opium
By 1820, the isolation of morphine had lead the way to techniques for the isolation of
caffeine, atropine, & strychnine
the way we regulated morphine from poppy seeds was the same technique to regulate caffeine
true
atropine is used to
dilate your eyes
what is strychnine
poison
The history of coffee goes at least as far back as the _____ century
13th
The original native population of coffee is thought to have come from ______ specifically from ______
East Africa
Ethiopia
It was first cultivated by _____ from the 14th century and onward
Arabs
Caffeine is extracted from the coffee plant,
Coffea arabica
Caffeine works by stimulating the
CNS, heart, and muscles
It relieves mental and physical fatigue and increases mental alertness
caffeinr
an enchantress of exceeding loveliness
belladona
Devil’s cherries
Atropa belladonna
what are the two alkaloid substances isolated from a plant
atropine
scopolamine
can be used topically but not swallowed
atropa belladonna
what is atropine used for
(medicinal use)
Belladonna plasters often applied after a fall to the injured or sprained part
Ingestion in excess amounts is a poison
what is scopolamine used for
Used for motion sickness (Transderm Scōp - patch), sedative, truth serum, and mydriasis (prolonged or excessive pupil dilation)
what is salicylic acid
Willow bark is a source of salicin, which is metabolized to salicylic acid in the body
a precursor to aspirin (popular analgesic/anti-inflammatory agent)
salicin & salicylic acid
Acetylsalicylic acid,
aspirin
increase the risk of bleeding, ulcers, and tinnitus
Willow bark and salicylates
adrenaline
epinephrine
hormone & NT
Epinephrine, also known as adrenaline
first hormone isolated in 1897, by John Jacob Abel, a researcher at Johns Hopkins University and the father of modern pharmacology
Epinephrine, also known as adrenaline
where is epinephrine produced
Some neurons of the CNS
The chromaffin cells of the adrenal medulla from the amino acids, phenylalanine and tyrosine
who is the father of modern pharmacology
jacob abel
what is in the epipens?
epinephrine
what are phenylalanine and tyrosine?
essential amino acids - produced in the body
what is acetylcholine
one of many neurotransmitters in the autonomic nervous system (ANS)
acts on both the peripheral and central nervous system
only neurotransmitter used in the motor division of the somatic nervous system
It was isolated by Otto Loewi in 1914, and Henry Hallet Dale in 1936, who found that it was present in the autonomic and peripheral nervous systems
acetylcholine
acetylcholine is an amino acid
false
hormones
In cardiac tissue, acetylcholine neurotransmission has an _____ effect, which lowers heart rate
inhibitory
also behaves as an excitatory neurotransmitter at neuromuscular junctions in skeletal muscle
acetylcholine
sulfa was founded by
Gerhard Johannes Paul Domagk,
germal biochemist in 1932
how did sulfa come about
tested a red dye, Prontosil
The dye had no antibacterial properties, but when Domagk slightly changed its chemical makeup, Prontosil was able to arrest infections in mice caused by streptococcal bacteria
He discovered the active antibacterial portion of the dye and named it sulfanilamide (one of the first antibiotics)
first effective treatments for pneumonia, meningitis, and other bacterial diseases
sullfa
pre-dated the clinical use of penicillin
sulfa drugs
One of the main components carried by combat medics during WWII was ______ and ______ that greatly reduced mortality
sulfa powder
sulfa tablets
used today to treat infections of the urinary tract
sulfas
who and when discovered penicillin
1928
Alexander Fleming
what did alexander fleming discover in 1928
He accidentally discovered that a mold known as penicillium notatum inhibited growth of staphylococcus aureus (a bacteria) in a petri dish in his lab
named the active ingredient penicillin
who in 1940, worked with penicillin and turned it into a usable product
Chain and Florey of Oxford University, U. K.,
what is the FDA
regulatory agency that is involved in regulation of drug development
evolved in response to a public need
The Pure Food and Drug Act -1906
Prompted by unsanitary and unsafe conditions in the meat packing industry, Congress created the FDA
Prior to and at the start of the 20th century, tampering and mislabeling of food and drugs was common
true
was used during WWII in 1941 and saved many live
penicillin
The Pure Food and Drug Act -1906 required that
drugs meet standards of strength and purity
burden of proof was on the FDA to show that the drug was false/fraudulent before it could be taken off the market
what are elixirs
syrups
what drug was only able to be mixed with diethylene glycol, antifreeze?
a sulfa drug called Strep-Elixir or Elixir Sulphonamide
In 1937, a 107 people, many of them children, had died from mass poisoning by this untested productdiethylene glycol, antifreeze
Strep-Elixir or Elixir Sulphonamide mixed with diethylene glycol, antifreeze
what was passed by congress in response to Strep-Elixir incident
In 1938, Congress passed the Food and Drug Cosmetic Act
what is the strep-elixir incident
Eli Lilly developed a sulfa drug called Strep-Elixir or Elixir Sulphonamide
But unknown to the public, while trying to make a mixture, they could not dissolve the drug molecule in anything other than diethylene glycol (a chemical analogue of antifreeze), which is toxic to the liver
In 1937, a 107 people, many of them children, had died from mass poisoning by this untested product
Food, Drug and Cosmetic Act of 1938
Required proof of a drug’s safety and purity
Mandated that manufacturers obtain pre-market approval from the FDA contingent on demonstrated safety
Regulated labeling and packaging of drug products
Durham-Humphrey Act of 1952
Granted the FDA authority to determine which drugs may be sold without a prescription
FDA examined a drug’s toxicity and the ability for someone to self-diagnose
OTC drugs are sold with lower dosage than their prescription counterparts and used primarily to treat symptoms, not cure diseases
alleve is otc for what medication
naproxen - decrease in pain, inflammation and fever
1962 Kefauver-Harris Amendments to the Food, Drug and Cosmetic Act
Required proof of efficacy as well as safety for new drugs and drugs approved since 1938
Established guidelines for adverse event reporting, clinical testing, and advertising (drugs must be appropriately labeled)
Orphan Drug Amendments of 1983
Provides manufacturers incentives, such as tax deductions for their clinical trials, to manufacture drugs that treat rare diseases (diseases that affect <200,000 people)
E.g., Lou Gehrig’s disease and Tourette’s syndrome
what is efficacy
how well it works, does it work
More commonly known as early access programs or compassionate use exemptions, began decades ago during the AIDS crisis
FDA Expanded Access program, 1987, streamlined in 2017-2018
Expedited Drug Approval Act of 1992
allowed accelerated FDA approval for drugs of significant medical need
Required detailed post-marketing surveillance (Phase IV-Clinical Trials)
when a drug is used for something else but was not approved for it
off label use
FDA Modernization Act of 1997
Allowed drug manufacturers to discuss unapproved or “off label” indications for drug products with practitioners
Provided for accelerated drug approvals for life-threatening medical disorders
Made provisions for pediatric drug research
Revised communications between FDA and researchers conducing clinical trials
Dietary Supplement Health and Education Act of 1994
Dietary supplements are defined as vitamins, minerals, herbs, botanicals, other plant-derived substances, amino acids, concentrates, metabolites and constituents and extracts of these substances
FDA oversees the safety, manufacturing and health claims made by dietary supplements
FDA does NOT evaluate efficacy of supplements
FDA must demonstrate that a supplement is unsafe before taking action against it
Federal Food, Drug, and Cosmetic Act of 2006
Required the dietary supplement industry to report all serious dietary supplement-related adverse drug events to the FDA
FDA Amendments ACT (FDAA – 2007)
In response to the safety issues of COX-2 inhibitors (anti-inflammatory drugs) that led to cardiac issues and strokes
Gave enhanced authority to FDA to manage safety of approved drugs
Focused on Risk Evaluation and Mitigation Strategies (REMS) for new and already approved drugs
FDA regulates drugs sold without a prescription
FDA reviews OTC drugs for misbranding and adulteration
FDA sets guidelines to which OTC drugs are safe and effective
FDA has authority to prevent sales and to withdraw OTC drugs from the market
Controlled substances are drugs that have some potential for
abuse or dependence
FDA also regulates
controlled substances
Controlled Substances Act (CSA) (1970)
The Drug Enforcement Administration (DEA) administers the CSA and regulates manufacture and distribution of substances with potential for abuse including
Opioids (narcotics), stimulants, and sedatives
Before these laws, mixtures containing opium and cocaine were sold over-the-counter (OTC)
true
strongest warning the FDA has
black bbox
Opioids are powerful pain relievers and include
morpine, hydrocodone, and codeine
FDA is responsible for protecting the public health by
Assuring the safety, efficacy and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation
Today’s FDA is one of the strictest and most respected drug regulatory bodies in the world
tru
FDA is responsible for advancing the public health by
Helping to speed innovations that make medicines more effective, safer, and more affordable and by helping the public get the accurate, science-based information they need to use medicines and foods to maintain and improve their health
FDA has responsibility for regulating the f
Manufacturing, marketing and distribution of tobacco products to protect the public health and to reduce tobacco use by minors
FDA plays a significant role in the Nation’s counterterrorism capability by
By ensuring the security of the food supply and by fostering development of medical products to respond to deliberate and naturally emerging public health threats
In the U. S., the time necessary to develop a new drug is approximately ______ years, with an average of ____ years
10 to 15
~12
The clinical development phase of drug development is ______ years
~ 6 to 7
why was the covid vaccine remarkable
The clinical development phase of drug development is ~ 6 to 7 years
Which makes the <1 year development of the mRNA COVID-19 vaccine truly remarkable
The estimated cost of developing a drug in the U. S. from invention to pharmacy is ~ $________depending on what the drug is for (this includes the cost of failed compounds)
$1 to 2 billion
Only ______ drugs that enter clinical testing is approved & marketed
But then big commercial drug successes gross billions in annual drug revenues
1 of 10
general phases of drug development
Synthesis or discovery of new chemicals from the test tube or plant(s)
Safety evaluation in animals and humans
Effectiveness evaluation in humans
Review of new drug application
Post-marketing surveillance to report all adverse effects
Drug Discovery phase
This phase produces a new molecule
First patents are filed at this stage and granted several years later
Drug Development phase
The process requires that biological characterization and toxicology animal studies be conducted prior to filing an Investigational New Drug (IND) application
An IND is required at the start of clinical (human) trials (Phase I to III)
At the conclusion of successful clinical trials, the drug company files a New Drug Application (NDA), which is reviewed by the FDA
Post Approval Regulation
Once approved, a drug must be monitored for the remainder of its life span (Phase IV)
The first of the drug’s patents expires 20 years after its application
Abbreviated New Drug Application (ANDA) can be filed before expiration of original patent
what is a patent
something is going to be of value and file this and only that specific company can produce that medicine
LD50
Determination of the lethal dose
dose of the drug that kills 50% of the total numbers of mice that received it
ED50
Determination of effectiveness dose
does of a drug that causes an effect in 50% of the total numbers of mice that received it
What is the margin of safety
LD50 ÷ ED50
If LD50 is 10 mg and ED50 is 2 mg then the margin of safety is
only 5
10 divided by 2 = 5
acceptable margin of drug safety in humans is
> /= 2000
waht does a margin of safety of 5 mean
that the lethal dose is only 5x the effective dose, which may be predictive of a low margin of safety in humans
Short-term toxicity testing
Testing in animals
General profile screen in mice
Determination of the lethal dose = LD50
Determination of effectiveness dose = ED50
Long-term toxicity
Also known as chronic toxicity studies
Daily dosing to rats and dogs from 3 months to 2 years
Observe for toxicities, evaluate blood chemistries
Sacrifice the animal, then evaluate histopathology
Many toxic effects appear only after repeated dosing over many months or years
That is the reason why post approval regulation is required
Studies on reproduction
can females who are pregnant or trying to affect the fetus?
does the drug prevent ovulation
does the drug prevent fertilization
does the drug cause the expulsion of embryo from the uterus?
Studies on carcinogenicity
does a drug cause cancers
Drugs are given to laboratory rats for over 6 months
any signs of cancer are enough to stop testing of a drug
true
Investigational New Drug Application (IND)
Submitted if the drug has an impressive margin of safety in mice
Submitted if a drug lacks long-term toxicities
Submitted if a drug does not cause cancer, reproductive effects, or birth defects
A 30-day approval by the FDA (usually takes longer)
Contents of IND
Data acquired in animal studies
Protocols for human tests
Chemical structure of the drug
How the drug is synthesized
Formulation of dose form
Packaging information
Clinical Studies – Phase 1
Begins immediately after IND approval
20 to 100 healthy volunteers (usually healthy males)
Primarily evaluates safety of the drug in humans
Determines pharmacokinetics (what the body does with the drug)
Establishes the dose at which toxicity appears
Trial lasts for several months
Non-blinded trials
Clinical Studies – Phase 2
Given to patients having the condition for which drug is intended
Up to several hundred patients in the trial
Study of short-term effectiveness and safety
Establishes therapeutic efficacy, dose-response and dose range, kinetics, and metabolism
The trial lasts for several months to two years
Single-blind trial
desctibe phase two
looking for PTs that have that condition that the medicine acts on
is it effective? does it treat the condition?
is it working?
how high can we go? how high can we raise it before we see toxicity occurring
how is it excreted how is it metabollized? (urine & blood tests to monitor)
longer trial times
describe phase 2
no control, no experimental - just one group and the people know that they are getting the drug
want to see if it is dangerous or not
what level leads to issues but not death
Non-blinded trials
participant and investigator are both aware of what is being administered
Single-blind trial
drug of interest is evaluated against a placebo or existing therapy
participatn doesnt know if they are getting the drug or the placebo
control group - 2 groups of participants
Clinical Studies – Phase 3
Patient numbers in the study ranges from several hundred to several thousand and are more heterogenous
Confirms drug safety, dosage, and effectiveness
Tries to detect adverse effects undetected in prior studies
Trial lasts one to four years
Randomized, double-blind studies
Participants randomly assigned to either the drug or placebo group
heterogenous meaning in phase 3
mixture, more diverse
mixed gender, severity of disease can vary
more mixed group
double-blind studies
Participants randomly assigned to either the drug or placebo group
highest level of research in heirarchy of research
neither investigator or participants know who gets what
it is the most effective design to distill true effects from placebo effects and from natural fluctuations in course of the disease
Randomized, double-blind studies
what is one problem in phase 3
One problem is the small number of patients taking the drug for maybe up to four years compared to potentially millions who will take the drug long term
Drug toxicities which occur at less than 1 in 1000 exposures may not be revealed in Phase 3 clinical trials
true
These toxicities may only be revealed after marketing when millions of people would take drug long term
New Drug Application (NDA) Process
submitted after the successful conclusion of clinical trials
after approx 8-9 yrs of animal and human testing
Patent on drugs lasts _____ years after applying for the patent prior to Phase 1 of clinical testing
~ 20
Post-marketing Surveillance – Phase 4 Studies
Occurs after FDA approval
The drug is monitored for the remainder of its life span
drug is now used by much greater number of people than in clinical studies
A drug can be pulled off the market if new toxicities are uncovered. but what usually happens instead
if problems result that are not life threatening, they can be addressed by relabeling of the drug with new warnings or precautions
why monitored so long?
things can happen on the market that didn’t happen during clinical trials because more people are taking it
Clinical Phases of Drug Development (FDA Approval)
Phase 1
Involves 20 – 100 people in the clinical trial
Tested for safety in healthy volunteers
Phase 2
Up to several hundred people in the clinical trial with the disease
Tested for short-term safety and effectiveness
Phase 3
Several hundred to several thousand people involved in the trial
Tested for safety, dosage, effectiveness, adverse events
Phase 4
Post-marketing surveillance for adverse event monitoring for ever
The entire process can take 8 to 15 years and cost ~$1 to 2 billion.
true
