Exam 1 Flashcards
What is pharmacology?
scientific discipline that investigates the interactions between living organisms and drugs; includes several subdisciplines that investigate different aspects of these interactions (e.g., pharmacokinetics, pharmacodynamics, etc.)
When did pharmacology become the primary way to understand drugs in Western Medicine?
19th century
What are the two primary branches of pharmacology that analyze drug-body interactions?
- Pharmacokinetics
- Pharmacodynamics
What are drugs?
- chemical substances used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental wellbeing
- can vary greatly in complexity from simple organic molecules to large and complex organic molecules
- use by humans pre-dates earliest historical records
drugs vs. poisons
Drugs - chemical substances used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental wellbeing
Poisons - chemical substances that cause injury, illness, or even death in living organisms
Drugs can act as poisons when the level of the drug in the body exceeds a toxic threshold
What is toxicology?
sub-discipline of pharmacology that investigates the adverse effects of chemicals on living organisms
Where does tobacco (nicotine) originate?
New World
Where does caffeine originate?
Coffee from Ethiopia
Tea from China
Cocoa from the New World
Where do beer and wine (ethyl alcohol) originate?
Unsure, widespread in pre-history
How is Chinese medicine an example of a pre-pharmalogical success?
“The Divine Farmer’s Herb-Root Classic” is a book that lists 365 medicines derived from natural sources, many of which are still medicines today
The most prominent of these is Ephedra sinica (now known as ephedrine), which is used as a stimulant to improve breathing
How is Peruvian Indian medicine an example of a pre-pharmalogical success?
Peruvian Indians used bark extracts from the cinchona tree (now called quinine) to treat fever and malaria; this is still used today for the same purposes
How is Eastern Mediterranean medicine an example of a pre-pharmalogical success?
Eastern Mediterranean people used opium (which contains morphine and codeine) for pain relief; both are on the WHO’s list for essential medicines, and codeine is thought to be the most commonly used drug today
Why were many pre-pharmacological “medicinal drugs” ineffective and/or dangerous?
Marketed/used without evidence for efficacy and often compounded in the home
Who was Francois Magendie?
19th century scientist who rejected theory-only based explanations for drugs in favor of facts gathered through experimentation; established the value of experimental animals and established experimental approaches such as IV injection
2 advances in other sciences that facilitated 19th century pharmacology
- Chemists isolated active drug compounds from plant-based medicines
- New instruments were invented that aided investigation of the responses to drugs (e.g., mercury manometer to measure blood pressure changes)
Who was Claude Bernard?
19th century scientist known as the “father of experimental medicine;” his research on curare and carbon monoxide poisoning pioneered the concept of investigating the mechanism of action for drugs
Claude Bernard’s 4 thoughts on the scientific method
- Goal is to discover new facts and formulate new theories to explain diseases and the responses to drugs and poisons
- Theories should try to explain cause and effect relationships
- Theories should be testable and continuously tested by experimentation
- Observable reality is the ONLY AUTHORITY and theories must be reformulated if contradicted by experimentally observed facts (the common practice before this was to rely on the authority of past physicians, like Hippocrates)
How is Aspirin an example of a 19th century pharmacological success?
Extracts of willow and similar plant had been used to treat fever and pain for thousands of years, but in the 19th century, salicylates (the active compounds in these plants that are chemically related to Aspirin) were isolated and studied
3 common features of non-steroidal anti-inflammatory drugs (NSAIDs)
- Anti-inflammatory effects
- Analgesic effect: reduction of pain
- Antipyretic effect: lowering of a raised temperature
What was the 1937 Elixir Sulfanilamide disaster, and why was it significant to pharmacology?
Sulfanilamide was an early antibiotic used to treat infections, and S.E. Massengill Co. created an elixir of sulfanilamide using diethylene glycol (a poison similar to antifreeze) as the solvent, causing hundreds of painful deaths from kidney failure.
This prompted passage of the 1938 Federal Food, Drug, and Cosmetic Act that remains the basis for FDA regulation of drugs
What is the role of pharmacology in the 21st century?
central role in the development and improvement of medicines (e.g., discovery of cyclooxygenase inhibitors)
How are cyclooxygenase inhibitors an example of a 21st century pharmacological success?
Aspirin was discovered to act as a cyclooxygenase inhibitor, and other NSAIDs have been developed as cyclooxygenase inhibitors such as celecoxib, which has several advantages over Aspirin for long-term pain management
What are international non-proprietary names (INN)?
Generic names for drugs that are set by the WHO, are the same worldwide, and are in the same public domain (e.g., celecoxib)
Drugs with similar structures and actions tend to have similar INN names
5 main questions that pharmacology experiments try to answer
- What routes can be used to administer the drug (oral, injection, inhalation, etc.)?
- How long does the drug last in the body?
- What are the molecular targets of the drug?
- What doses are effective to treat a medical condition?
- What doses cause unacceptable side effects?
4 benefits of laboratory based pre-clinical research in pharmacology
- Pharmacologist has more complete control over the experimental subjects
- Human safety not at risk
- Animal experimentation can predict safe and effective drug dosing for human trials
- Mechanism based studies can lead to better drugs
What is clinical pharmacology?
the science of using drugs in humans; subjects must provide informed consent to be part of clinical research and the work of clinical pharmacology is usually based on laboratory science and seeks to understand if and how a drug should be used in medical practice
What are Phase I clinical trials?
Phase I clinical trials are usually the first time the drug has been evaluated in human subjects, and its purpose is to evaluate the SAFETY of a drug and the maximum dose that does not cause unacceptable side effects. May also evaluate the interactions between the drug, food intake, and metabolism.
Usually conducted on a small group (tens) of healthy volunteers who are paid to participate.
What are Phase II clinical trials?
Phase II clinical trials continue safety testing and provide the first test of DRUG EFFICACY. Efficacy often judged in a randomized and blinded trial which compares the drug to a placebo.
Usually conducted on an intermediate sized group (tens to hundreds) of volunteers who have a medical condition that may be treatable by the drug.
What is the placebo effect?
a psychological phenomenon where individuals experience real changes in their health or symptoms after receiving a treatment that has no therapeutic effect; this outcome occurs because the person believes the treatment is real and expects it to work, which can trigger physiological responses in the body
What are Phase III clinical trials?
Phase III clinical trials are designed to be a DEFINITIVE TEST OF DRUG EFFICACY, providing the final required tests needed in support of an application for FDA approval of a new drug.
Studies a large total patient population (often thousands) usually at multiple medical centers around the country or world; involves the majority of the total costs to bring a new drug to the market
What is a Phase IV clinical trial?
Phase IV clinical trials are additional human trials for a drug that is already approved in the marketplace.
These can occur for several reasons:
1. Additional evaluation of drug safety and side effects
2. Study of long-term risks and benefits
3. Investigation of a drug efficacy for new medical conditions or in patient populations not enrolled in initial clinical trials (e.g., pregnant women)
High profile example is the withdrawal of rofecoxib (Vioxx) from the market following phase IV trials.
What is rofecoxib (Vioxx)?
COX2-selective NSAID that was approved as an arthritis drug in 1999 until a phase IV trial investigating Vioxx in colon cancer uncovered a 2-fold increased risk for heart attakcs and strokes for patients taking the drug.
Likely caused ~100,000 heart attacks while on the market from 1999-2004.
3 requirements for informed consent in clinical trials
- Must be mentally competent
- Must be informed of the details of the study, its benefits, and its risks
- Must agree to be part of the trial and able to withdraw consent
What is the Belmont Report, and what are its 3 main principles?
A report used to provide research subjects with protections, based on past subject abuses like the Tuskegee Syphilis Experiments
Principles:
1. Respect for persons - voluntary and informed participation
2. Beneficence - study must have the possibility of producing good for subjects, society, etc.
3. Justice - subjects must not be chosen to selectively provide benefit or put at risk selected social groups
What was the TGN1412 phase I clinical trial?
TGN1412 was a candidate drug for arthritis and leukemia that had been evaluated in non-human primates. In the phase I trial with humans, all 6 who took the drug became extremely ill, and 4 developed multi-organ failure. All 6 survived, but one was hospitalized for three months, one developed cancer, and one had his toes and parts of his fingers amputated.
How many cells are in the human body?
10^14 (or 100,000,000,000,000) cells
What is the composition of a cell by weight?
30% chemicals (proteins, DNA, RNA, ions, etc.)
70% H2O
From where does most of a cell’s “dry weight” derive?
Most of a cell’s “dry weight” derives from 4 families of organic biomolecules:
1. Polyaccharides (carbs)
2. Lipids, membranes
3. Proteins
4. Nucleic acids
What are ionic bonds?
relatively weak bonds occurring between atoms that can easily become charged (ions); water-soluble
What are covalent bonds?
strong chemical bonds made by the sharing of a pair of electrons between two atoms (vs. donating ionic bond); can be non-polar or polar based on equal or unequal distribution of electrons that may result in partial charges
What are hydrogen bonds?
form between molecules because of the attraction between areas of partial negative and positive charge that result from polar covalent bonds; very weak compared to covalent bonds
Common examples are water (H2O) molecules
What are hydrophobic interactions?
arrangements of molecules that minimize interaction with water (non-polar molecules, AKA hydrophobic molecules)
What bonds typically form interactions among biomolecules and between cells and their environment?
Mostly hydrogen and ionic bonds (chemical interactions), but hydrophobic interactions are also important
Prokaryotic cell (bacterial cell) vs. Eukaryotic cell (plants, animals, people)
What is the chemical basis for cell membranes?
Phospholipids with a hydrophilic head and two hydrophobic tails compose the semipermeable lipid bilayer cell membrane
How do drugs cross the cell membrane (phospholipid bilayer)?
Hydrophobic molecules can freely cross (some drugs)
Many molecules are hydrophilic (many drugs), and proteins help transport such molecules into the cell
Why are proteins on the phospholipid bilayer important?
Many serve as receptors and transporters that can be important for drug availability and action
What are the respective functions of DNA, RNA, and proteins within cells?
Together, DNA, RNA, and proteins are responsible for the flow of biological information within cells…
DNA: function is long-term storage of information
RNA: function is short-term transmission of information and sometimes catalysis
Protein: functions include providing physical structure, transmission of information, transport of materials, and catalysis
Drugs could target any of these, but mostly target proteins
What type of bonds hold the two strands of DNA together in a double helix?
Hydrogen bonds; this is how complimentary base pairing works
What drugs damage DNA?
Some chemotherapy drugs chemically damage DNA by mimicing subunits and disrupting replication
What is the role of mRNA?
Provides a template for protein synthesis in translation (RNA –> amino acid sequence)
What is transcription?
RNA is synthesized from a DNA template based on complementary base pairing
What drugs disrupt transcription and translation of RNA?
Some antibiotic drugs, specifically in bacteria
How are proteins formed?
Initially formed as a linear polymer, and the amino acid sequence is directly determined by mRNA based on information in DNA (AKA translation)
How many amino acids make up the proteins found in the human body?
20
How many proteins are in the human body?
> 20^300 potential proteins, but probably a few hundred thousand actually found in humans
What is the primary cellular target of most drugs?
most drugs target or mimic proteins
What are carbohydrates?
The class of organic molecules characterized by a ratio of 1:2:1 carbon:hydrogen:oxygen (e.g., glucose C6H12O6)
Functions are composition of structural elements, communication (ABO blood type), building blocks (nucleotides contain a carb compound), ENERGY SOURCE
Certain drugs (e.g., type 2 diabetes drugs) mimic carbohydrates to alter nutrient absorption
4 protein-based processes in cells that make good drug targets
- Receptor-Ligand binding: drugs can bind the receptor to mimic or block the ligand
- Enzymes and the process of catalysis: drugs can block catalysis by mimicking the enzyme substrate
- Ion channels: drugs can change the conformation to open or close the channel
- Macromolecule synthesis: drugs can mimic the monomer subunits to poison the process
What is the role of enzymes in cell metabolism?
Cell metabolism is organized by enzymes, which accelerate, or catalyze, a chemical reaction
What is the implication of drugs in catalysis (+ statin example)?
Enzymes are often organized into networks to achieve their purpose, and drugs can target any of the enzymes to stop the process.
An example is statin drugs, which target an enzyme network that leads to cholesterol synthesis. Hydrogen bonds that normally form between the catalytic site and the enzyme’s substrates can’t occur because the enzyme forms hydrogen bonds with the statin drug instead. This is known as competitive inhibition.
How does an enzyme act as a catalyst for a chemical reaction?
The catalytic site often makes hydrogen and/or ionic bonds with the substrate to promote a chemical reaction
Why is x-ray crystallography important with regard to biomolecule interactions?
X-ray crystallography can be used to observe the 3-dimensional atomic structure and interations among biomolecules (and between biomolecules and drugs)
What is the implication of competitive inhibitors and enzyme catalytic sites?
Drugs that bind enzyme catalytic sites are often competitive inhibitors that inhibit catalysis by competing with natural enzyme substrates for binding to the catalytic site.
This is usually a reversible process that ceases when concentration of a drug falls (e.g., stop taking drug), but can be irreversible for some drugs that covalently modify their target.
How does Aspirin act on catalytic sites?
Aspirin is an irreversible competitive inhibitor of COX-1 and COX-2, as it causes acetylation near the catalytic sites
What is pharmacokinetics?
the branch of pharmacology that examines the distribution and fate of drugs administered to the body; includes altered kinetics caused by drug interactions and/or disease status and is important for designing a drug-based therapy that will keep the levels of a drug within therapeutic range
What 2 things does drug fate depend on?
- Route of Administration
- Formulation
4 important pharmacokinetic parameters
- Absorption of drug
- Distribution of drug
- Metabolism of drug
- Excretion of drug
How do most drugs reach their target tissues?
Through the circulatory system by way of one of many routes of administration
What is the role of capillaries in drug action?
Absorb drugs at sites of delivery and release drugs into tissues throughout the body
What does the area under the curve (AUC) measure in pharmacokinetics?
The level and duration of a drug in systemic circulation; it is a measure of extent of exposure of the body to the drug.
AUC is proportional to bioavailability and inversely proportional to clearance.
`What is bioavailability (F), and how is it calculated for different routes of administration?
Fraction of a drug dose that reaches systemic circulation; directly proportional to AUC
For IV injection: F = 1
For oral dosing: F = (fraction absorbed)(fraction escaping first-pass clearance)
At equal doses, F= oral AUC / IV AUC
When can a drug be given orally on the basis of bioavailability (F value)?
Drugs with higher F value (closer to 1) can easily be given orally.
Drugs with F value < 0.01 cannot be given orally and typically require injection.
Why might a drug be delivered by IV injection instead of orally or topically?
With IV injection, absorption is immediate and complete, and IV injection gives 100% bioavailability (F=1).
Good for drugs that need to act quickly (critical care) and drugs that can’t survive the digestive tract or first-pass metabolism or have F < 0.01.
What is a formulation?
Concoction of the drug together with other chemicals to control the pH and act as preservatives; in liquid form for IV injection and pill/capsule form for oral.
Oral formulation can control the rate and location of absorption from the digestive tract.
Why might a drug be given orally instead of via IV injection or topically?
Less invasive, very convenient for patients and good for drugs that can survive the digestive tract and first-pass metabolism
Why might a drug be given topically instead of via IV injection or orally?
Good for small hydrophobic drugs that can be formulated to pass through the skin or other body surfaces (e.g., steroids, nicotine, antibiotics).
Good for local drug delivery.
Can achieve very slow and sustained drug absorption.
How do the pharmacokinetic curves differ between a drug injected via IV and a drug taken orally?
IV injection has faster time to effect (immediate) and a much greater peak concentration
Describe skin epithelium and how drugs are implicated
In the skin…
1. Epithelium has multiple cell layers
2. Thin layer of dead cells
Abosrption barrier = high, epithelial cells create a barrier between the environment and circulation, and drugs must cross this barrier if they are not injected or are not small hydrophobic drugs (classic in topical administration); they are held tightly together by protein-based junctions so most drugs must pass through the cells rather than around them, limiting drug absorption
What are the types of epithelium?
- Simple: one layer
- Stratified: many layers
Can also be subdivided by shape:
1. Squamous
2. Cuboidal
3. Columnar
Describe the lung epithelium and how drugs are implicated
In the lungs…
1. Epithelium is one layer of very thin cells
2. Blood vessels are in very close contact with epithelial cells
Absorption barrier = very low, so for drugs that can be delivered as an aerosol or gas, inhalation is a very fast and efficient route for drug absorption; it also avoids first-pass metabolism in the liver
Describe drug absorption from the GI tract
Drug absorption in the GI tract affected by…
1. Epithelial barrier that varies along GI tract
2. pH changes significantly along the GI tract:
- neutral pH in mouth/esophagus
- very acidic pH in stomach
- moderately basic pH in small intestine
Drug formulations can often be designed to prevent absorption prior to the small intestine using pH-sensitive materials
Describe mouth and esophagus epithelium and how drugs are implicated
In the mouth and esophagus…
1. Epithelium is many layers
2. Also contains flattened cells but NO dead cells
Absorption barrier = moderate
Describe stomach epithelium and how drugs are implicated
In the stomach…
1. Single layer of columnar cells
2. Specialized for secretion
Abosrption barrier = low; the stomach is very acidic (low pH), but drug coatings can be made to resist the low pH environment
Describe small intestine epithelium and how drugs are implicated
In the small intestine…
1. Single layer of columnar cells
2. Many capillaries near the epithelium
3. Specialized for absorption of nutrients
Absorption barrier = very low, macroscopic villi and microscopic villi give the epithelium a very high surface area, and most oral drug absorption takes place in the small intestine
What is first-pass metabolism?
All drugs absorbed in the GI tract pass through the liver capillary bed prior to reaching general circulation. The liver has several enzyme systems that chemically modify drugs, and liver-modified drigs are often inactive and easy for the body to eliminate.
First-pass metabolism is why oral drugs have reduced potency.
What is clearance (CL)?
One of two primary pharmacokinetic parameters that describes the efficiency of irreversible elimination of a drug from the body, and is defined as the volume of blood cleared of drug per unit time
A CL value can be determined for the whole body or for a single organ like the liver
5 main types of irreversible elimination of a drug
Irreversible elimination can be by excretion of the drug into…
1. Urine
2. Gut contents
3. Expired air
4. Sweat
5. or by metabolic conversion of the drug into another chemical in the liver or other tissues
How are most drugs cleared from the body?
MOST clearance results from drug metabolism in the liver and/or drug and metabolite excretion in the kidneys
What is cytochrome p450 (CYP)?
Family of enzymes in the liver responsible for first-pass metabolism of drugs; most metabolic transformation of drugs (~75% of drugs) due to CYP450 actions
What determines the dosing needed to achieve a desired level of drug in the body?
Clearance; at steady state, the amount of the drug administered per unit time (dose rate) must equal the amount of drug eliminated per unit time (elimination rate)
A drug with higher CL value will achieve a lower steady state drug concentration for any given dose rate, meaning more drug must be given to achieve the same concentration
What determines the elimination rate of a drug?
Determined by the plasma drug concentration and the whole body clearance (CL) value
elimination rate = clearance*plasma drug concentration
What is the significance of serum albumin?
Each drug has an inherent tendency to interact with components of the blood (especially serum albumin) and/or other tissue types
I.e., serum albumin binds many drugs
What is volume of distribution (V)?
One of the two primary pharmacokinetic parameters, describes the relationship between the amount of drug in the plasma to the total amount of drug in the body; determined by the relative tendency of a drug to stay in the blood vs. reside in tissues of the body
V = total amount of drug in body / plasma drug concentration
Small V means most of the drug stays in the bloodstream
Large V means most of the drug resides in the tissues of the body
V can be used to plan a “loading dose” when medical care requires a drug to rapidly reach a therapeutic level
What is half life (t1/2)?
A pharmacokinetic paramter that can be derived from clearance (CL) and volume of distribution (V) that can be described as the length of time for the drug plasma concentration to fall by 50%; also determines the length of time to reach a steady state plasma concentration (e.g., 1 dose per 24 hours can be established based on half life)
Half life applies for drugs with a plasma concentration that declines as exponential decay (most drugs), and may not apply when drug metabolizing enzymes are saturated (like alcohol during heavy drinking)
3 ways individualized medicine is pertinent to pharmacokinetics
- Half life of a drug for a given person may be longer or shorter than the population average, requiring differing doses and/or dose timing
- Individuals with diseases of the liver or kidneys (where metabolic alteration and excretion of drugs occurs) can have dramatically altered pharmacokinetics
- Individual polymorphisms for drug-metabolizing enzymes can also radically alter responses to drugs
In sum, pharmacokinetics can be variable between individuals
What is pharmacodynamics?
Branch of pharmacology concerned with what drugs do to the body (whereas pharmacokinetics is what the body does to drugs)
How do drugs do what they do?
“the pharmacological, physiological, or behavioral effects induced by a drug follow from their interaction with receptors”
What is a receptor?
a protein that is on the surface of (or within) a cell that provides the site(s) where biologically active, naturally occurring, endogenous compounds induce their normal biological effects; they are “sense organs” of a cell
How are receptor-ligand interactions like a “molecular switch?”
Ligand binding activates the receptor, allowing it to be turned “ON” like a light switch
Is receptor-ligand binding reversible?
Ligand binding is often reversible, and is more likely to be reversible if it binds with less affinity (more loosely)
2 determinants of signal intensity in receptor-ligand interactions (modulated signal intensity)
- Binding affinity (and subsequently time bound)
- how tight or loose a ligand binds, which affects how long it is bound - Number of receptors bound
How are receptor-ligand interactions like a “lock and key” mechanism?
Ligands are like a key in that they are specially shaped to fit with a given “lock,” or receptor; the ligand binds and “turns” like a key to flip the molecular switch
This is known as binding specificity, and the strength of binding (affinity) is structural
What determines a ligand’s receptor selection?
Ligand binding specificity, which is based on the structure of the ligand (think of the lock and key analogy)
How can binding affinity differ between a drug and its endogenous ligand?
A drug may be more specific to a given receptor than its endogenous ligand (higher binding affinity), which is how drugs can “win” competition with naturally produced compounds
What are side effects with regard to drugs?
Any result other than the therapeutic (or recreational) purpose of the drug
What is an agonist?
A ligand that binds to a receptor and triggers a response, often a drug mimicking the action of a naturally occurring substance
Agonists can either…
1. Mimic - act as an endogenous ligand
2. Facilitate - help the endogenous compound carry out its effects (called allosteric agonists)
What is an antagonist?
A ligand that binds to a receptor and blocks it, preventing the triggering of a response
4 types of drug targets (receptors) that regulate neuronal function
- Ion channels
- G-protein coupled receptors (GPCRs) (metabotropic receptors)
- Carriers or transporters
- Enzymes
How do drugs take effect at ion channels?
Ligand binding to an ion channel changes the voltage of the cell, inducing cellular action
How do drugs take effect at G-protein coupled receptors (GPCRs) (metabotropic receptors)?
Ligand binds to receptor, activating a G-protein. The G-protein then moves and triggers signal inside the cell.
How do drugs take effect at carrier or transporter proteins?
Ligand binds to transporter molecules and directly manipulates carrier/transporter action (e.g., cocaine binds and prevents the transporter from eliminating neurotransmitters, leading to neurotransmitter accumulation)
How do drugs take effect at enzymes?
Ligand binds to enzyme and can trigger the creation or disruption of neurotransmitter/molecule production (e.g., some drugs can bind to enzymes and catalyze ACh neurotransmitter breakdown)
What does the y-axis of a dose response curve describe?
Drug efficacy, or the intensity of drug response; this can plateau, meaning additional doses no longer have an effect