Exam 1- Dr. A's Stuff Flashcards
Molarity
M
moles of solute/ 1 L of solution
Molality
m
moles of solute / 1000g (1kg) of solvent
Mole Fraction
ratio of moles of one constituent to total moles
X = moles of solute/ (moles of solute + moles of solvent)
X must = 1
Percent by weight
% w/w
grams of solute / 100g of solution
Percent by volume
% v/v
mL of solute / 100mL of solution
Percent weight-in-volume
% w/v
grams of solute/ 100mL of solution
Density
grams of solution /1 mL of solution
density = mass/volume
p=m/v
g/cm3
(1 mL = 1g = 1cm3)
ad
up to
-or-
quantity sufficient
TPN
Total parenteral nutrition
Why is age frequently considered in determining the proper dosage?
Because renal function develops over the first 2 years of life. Thus newborns are very sensitive to certain drugs.
BSA
- The body surface area (BSA) method of calculating drug doses is widely used in pediatric patients (except newborns) and cancer patients receiving chemotherapy.
- For precise calculations based on both height and weight, we can refer to a standard nomogram.
- The BSA in square meters (m2) is indicated where a straight line drawn to connect the height and weight of the child intersects the surface area column.
Child’s BSA Equation
(BSA of child in m2 )/(1.73m2) X adult dose = child’s dose
1.73m2 =average adult BSA
Drug definition
A drug is defined as an agent intended for use in the diagnosis, mitigation, treatment, cure, or prevention of disease in humans or in other animals.
The only difference between a drug and a poison is?
The dose
Drugs usually require…
- Stability (make it in bulk, want 2 year shelf life)
- Components must be physically and chemically compatible
- Protected from microbial contamination, heat, light, moisture, etc.
- Therapeutic ingredients must be released in proper amount at proper time
- Attractive flavor, color, texture (helps patient compliance, especially with kids)
Drugs date back to?
Approximately 3000 BC
Disease was often believed to be caused by?
The entrance of demons or evil spirits into the body
- In the early apothecaries, it was believed that a drug had magical associations.
- This meant that its action, bad or good, did not depend on its qualities alone; a compassionate god, the absence of evil spirits, and the healing intent of the dispenser were important.
- Because of this, the tribal apothecary was one to be feared, respected, and revered due to the need for spiritual intervention.
- With time, the art of apothecary combined with priestly functions, and the priest-magician became the healer of the body as well as the soul.
What is the most famous ancient writing on drugs?
The Ebers Papyrus that is 60 feet long and has more than 800 formulas and 700 drugs dating back to 1550 BC
What delivery vehicles were used back in the day?
Commonly beer, wine, milk, honey
Hippocrates
- 460-377 BC
- Described hundreds of drugs
- The term “pharmakon” came to mean a purifying remedy for good only.
- This was different from the previous belief that a charm or drug could be used for evil or good
4 humors
Any sickness was due to an imbalance in the 4 humors, the 4 fluids in the body
- Black bile
- Yellow bile
- Blood
- Phlegm
Dioscorides
- 1st century
- Studied pharmaceutical botany and described collection and proper storage.
- Also had means of detecting contaminants, and set standards.
Galen
- 130-200 AD
- Wrote about numerous drugs and described preparations of vegetable drugs by mixing and compounding.
- The field of pharmacy was once commonly referred to as “Galenic Pharmacy”.
Avicenna
- 981-1037
- Wrote the Canon of Medicine in Persia that remained a common medical text in Europe until the 18th century.
- The text stated that disease could be spread through water, soil or air.
- Introduced the ideas of quarantine (to limit disease), evidence-based medicine, and randomized clinical trials.
Pharmacy was officially separated from medicine in?
1240 by Emperor Frederick II of Germany
Pharmacists were required to prepare?
Reliable drugs of uniform quality.
Side note: Any exploitation of the patient through business relations between the pharmacist and the physician were forbidden.
Aureolus Theophrastus Bombastus von Hohenheim
Aka. Paracelsus
- 1493-1541
- Transformed the profession from one based on botany to one based on chemistry.
- He believed it was possible to cure any disease with a specific medicinal agent.
The Pharmacopeia of London was published in?
- 1618
- It contained descriptions of how to mix components and contained standards.
1698
The first patent- epsom salts
When was morphine isolated from opium?
- 1805
- Was developed as a pain killer; a “miracle drug”.
- It eliminated pain and produced a dream like state, so named ‘Morphine” after Morpheus, the Greek God of dreams
Quinine, caffeine, codeine…
- Isolated in the early 1800s.
- The extraction and isolation of active constituents led to the development of dosage forms of uniform strength.
United States Pharmacopeia (USP) was first published in?
- 1820
- Published in English and Latin
- Pharmakon (drug) was combined with “poiein” (make). This provided standards to insure drug quality.
- 272 pages and 217 drugs considered worthy of recognition.
- This document reflected the fact that the apothecary was competent at collecting and identifying botanical drugs, and preparing mixtures required by the physician.
First pharmacy school in the nation?
- The Philadelphia College of Pharmacy
- 1821
What was the first organic molecule to be synthesized?
- Urea
- 1828
1858
- American doctors first experimented with the hypodermic needle to directly inject morphine into the bloodstream.
- The hypodermic needle was perfected by mid -1800s, and a common instrument in 1870.
- Because pain could be controlled with less morphine, it was concluded that injection was less likely to foster addiction.
Cocaine
- 1860
- Pure cocaine powder extracted from coca, and was tried on almost every illness known to man.
- It was observed that cocaine made workers more productive.
- In general, opiates and cocaine were regarded as compounds that were helpful in everyday life. Like coffee, cigarettes, massage, beer today.
- Edgar Allen Poe and Ben Franklin used extensively.
Germ theory was developed in?
- 1865
- By Pasteur
1880
Industrial manufacturing and synthesis became possible.
1884
- Purified cocaine became commercially available in the US (25 cents/gram; average wage 20 cents/hr).
- Medical experts depicted cocaine as a harmless stimulant that was “no more habit forming than coffee or tea”
- Coke- cocaine without alcohol
1885
Rabies Vaccine
1888
The National Formulary (NF) was created and included some drugs that were not included in the USP.
1898
- Bayer aggressively marketed diacetylmorphine to doctors and patients as “safe, non-addictive” substitute for morphine …coined brand name “heroin”.
- A “miracle drug” cure-all for whatever ails you.
- Free samples of tablets were given to physicians.
1899
Acetylsalicylic acid (aspirin) was introduced by Bayer.
Opium and cocaine were more readily available in America because?
- The Constitution gave individual states responsibility for health issues, regulation of medical practice, and availability of “pharmacological products”.
- Many states chose to have no controls at all in the spirit of “free enterprise”.
1906
- Theodore Roosevelt signed the first Pure Food and Drug Act which designated that drugs labeled USP or NF must conform to the standards set forth.
- These two texts were officially combined in 1980.
- The Food and Drug Act of 1906 required accurate labeling, but did not prevent sales of drugs.
- Claims of therapeutic benefits were still not regulated.
- Drugs are not thought to be curative!
- American Medical Association approved heroin for use “in place of morphine in various painful infections” - creates huge addiction problem; approximately 5% of the US population is addicted due to prevalence of opium, morphine, heroin and cocaine in various products.
Test available for syphilis in?
1906
1910
- Arsphenamine was found to cure syphilis.
- First drug to be curative.
1912
Sherley Amendment prohibited false claims.
1914
- Harrison Act required strict accounting of opium and cocoa from entry into US to patient; these products were taxed at each transfer except the patient.
- Forbade any trace of cocaine in other remedies (cocaine was available only by prescription); in contrast, heroin could be used in small amounts in non-prescription cough medicine.
- This is the first law where the federal government controls prescribing practices.
1920
Prohibition (“the noble experiment”) banned the sale, manufacture, and transportation of alcohol for consumption until 1933.
1922
Insulin was isolated
Penicllin
- Discovered in 1928
- Commercially available in 1944
- Won the Noble Prize in 1945
1937
Marijuana Tax Act controlled and taxed marijuana
The Sulfanilamide Disaster
- 1938
- Sulfanilamide was the new wonder drug, but it was not soluble in most solvents.
- One manufacturer started using diethylene glycol in an elixir to improve solubility, and more than 100 people died.
- Congress passed the Federal Food, Drug, and Cosmetic Act of 1938 and created the FDA.
- The act prohibits the distribution and use of any new drug without the prior filing of a new drug application (NOA).
- The FDA became responsible for granting or denying permission to distribute a new product.
- The act required that the new product be safe for human use, but it did not require efficacy.
1951
DNA double helix described by Watson and Crick
1952
- Durham-Humphrey Amendment limited new drugs to prescription-only dispensing.
- Prescriptions could not be refilled without the consent of the physician.
Polio Vaccine
1954
Birth control pill
Approved by the FDA in 1960
1962
- A new drug, thalidomide, was being sold OTC in Europe as a sedative and tranquilizer.
- It was promising because it appeared to lack toxicity even at high doses.
- As a pharmaceutical company waited for US approval from the FDA, birth defects associated with the drug were reported in Europe.
- Congress passed the Kefauver-Harris Drug Amendments which required that drugs were both safe and effective before FDA would approve for marketing.
- Drug sponsors were now required to submit an investigational new drug application (IND) before testing in humans.
Measles Vaccine
1963
Mumps Vaccine
1967
1970
- Insert describing risks and benefits was required by FDA for oral contraception
- Comprehensive Drug Abuse Act made marijuana illegal.
Tamper-resistant packaging
1982
1994
- Congress passed the Dietary Supplement Health and Education Act (OSHEA) which differentiated between regulated, FDA-approved drugs and herbal/dietary supplements.
- Supplements were not allowed to have labels claiming that the product can cure or prevent a specific disease.
- However, the law does permit claims of benefit relating to nutritional deficiency and general well-being.
- Labels and promotions must be submitted to the FDA.
Sources of new drugs
- Plants; vinblastine, cortisone, estrogens, taxol
- Animal; estrogen from pregnant mares, hormones, factor VIII
- Cell cultures; vaccines grown in monkey tissue, chick embryos
- Recombinant DNA technology; insulin, EPO, growth hormone, interferon
- Antibody technology; diagnostics, many in clinical trials for cancer
- Gene therapy; replacement of defective genes, Vitravene, SCIO
- Combinatorial chemistry allows rapid screening of compounds
lnvestigational New Drug Application
The IND contains
- Contact information for sponsor, researchers, etc.
- Drug’s structural formula, dosage form, etc
- Rationale for study and indications to be studied
- Previous human experience
- hemistry, manufacturing, and quality control information
- Pharmacology and toxicology, e.g., mechanism of action, ADME
- Clinical protocol
- Approval and commitment from an Institutional Review Board (IRB)
Clinical Trials
- It takes I 0-15 years on average for an experimental drug to travel from the 1<1b to U.S. patients.
- Only five in 5,000 compounds that enter preclinical testing make it lo human testing.
- One of these five tested in people is approved.
- 3 phases
Phase I of Clinical Trials
- Healthy volunteers
- Determine safety and dosage
- The initial dose is usually low, typically one-tenth of the highest no-effect dose observed during animal studies.
- If this is well tolerated , progressively greater doses are given to new subjects untilsome effects are observed.
Phase II of Clinical Trials
- 100-500 sick patient volunteers
- Evaluate effectiveness
- Look for side effects
Phase III of Clinical Trials
- 1,000-5,000 sick patient volunteers
- Confirm effectiveness
- Monitior adverse reactions from long-term use
Blood levels are considered to be a measure of?
Bioavailability
The Orphan Drug Act
Passed in 1983 to facilitate the development of drugs for treating diseases that affect less than 200,000 people in the US.
New Drug Application
- If safety and efficacy were demonstrated in the clinical trials, a New Drug Application (NDA) is filed.
- This application presents all the data from preclinical and clinical trials (Typically at least 100,000 pages).
- The FDA is given 6 months to review, but the average review time is over a year.
- Funds can be provided by the pharmaceutical companies to expedite review.
Postmarketing Surveillance
Phase 4 studies continue to monitor the safety and efficacy of the drug after marketing. These studies may suggest new indication or reveal additional side effects
The Drug Price Competition and Patent Term Restoration Act of 1984
- Allows applications for generic copies of approved drugs to be filed thorough an abbreviated new drug application (ANDA) after 17 years.
- To gain approval , the generic form must have:
- The same active ingredients (inactive ingredients can vary)
- Identical strength, dosage form, and route of administration
- The same indications and precautions for use and other labeling instructions
- Bioequivalency
- The same batch-to-batch requirements for identity, strength, purity, and quality
- Strict manufacturing conditions that conform to FDA’s CGMP
Why do we need dosage forms?
- Amount of drug is too small for people to administer
- Protect the drug substance from air, moisture, stomach acid
- Hide bad taste or odor
- Increase solubility and/or stability
- Alter release profile to optimize drug action
- Improve patient compliance
Bioavailability
Describes the rate and extent to which an active drug is absorbed from a dosage form and becomes available at the site of action.
- Can be portrayed graphically by a concentration vs. time curve
Bioequivalence
Bioequivalence refers to the comparison of bioavailabilities of different formulations and/or dosage forms.
If we followed the drug in the body over time, we would typically see the drug be?
Absorbed, distributed, metabolized and excreted (ADME).
The dosage form can…
- Different dosage forms can dramatically alter the bioavailability even when the same amount of drug is administered.
- The dosage form can have a large impact on the effectiveness of the drug even if the AUC (bioavailability) is the same.
- The dose (as well as the dosage form) will affect drug performance. This is why different doses are investigated in clinical trials.
Milliequivalents
- This unit of measure is related to the total number of ionic charges in solution (not the number of particles), when quantifying electrolytes in solution
- Milliequivalents are not used to calculate whether a solution i s isosmotic, and should not be confused with sodium chloride equivalents (E values)! !
The total concentration of cations always?
Equals the total concentration of anions
- Any number of milliequivalents of Na+, K+, or any cations always reacts with precisely the same number of milliequivalents of Cl- ,HC03-, or any anion.
The equivalent weight of a substance is?
Its atomic weight divided by its valence (number of charges). Therefore, the number of equivalents is equal to the moles of charges in solution.
Milliequivalents is the number of?
Milliequivalents is the number of millimoles of charges (not millimoles) in solution.
Ca2+ has two charges (divalent) and therefore…
Ca2+ has two charges (divalent) and therefore
68 millimoles Ca2+ = 136 mEq Ca2+
If the ions are monovalent, the number of mEq is equal to?
If the ions are monovalent, the number of mEq is equal to the number of millimoles.
Why is mMol/L (instead of mEq/L) used to describe phosphate concentration?
It’s charge varies- the pH changes it
Colligative properties depend on the?
- Colligative properties depend on the number of particles in solution.
- # of dissolved species in solution
Free energy…
- Free energy causes some molecules to leave the solution and enter the vapor phase.
- At equilibrium, the rate of molecules leaving the solution is equal to the rate of molecules returning to the solution from the vapor phase.
- The molecules in the vapor phase exert a pressure on the solution called the vapor pressure.
- Free energy is highest in pure liquids and lower in mixtures.
- Therefore, when two liquids are mixed (for example water and ethanol), the free energy of each liquid is reduced due to the presence of the other.
- As a result, the vapor pressure of each solvent is reduced in proportion to its mole fraction (X).
If nA equals the number of moles of liquid A, nB equals the number of moles of liquid B then…
XA + XB = 1.
Therefore, XA = 1 - XB and XB = 1 - XA
Raoult’s law states
Raoult’s law states that the vapor pressure of component A (pA) is equal to the mole fraction of component A in the mixture times the vapor pressure of pure component A (p°A)
pA =
pA = XA • p°A = (1-XB) p °A
pB=
pB = XB • p°B = (1-XA) p °B
Lowering the vapor pressure
- Adding solutes to water lowers the vapor pressure and increases the boiling point
- Changes are usually small
- Dependent on the number of particles in solution
- A colligative property
What happens when you add a drug to a solution?
The vapor pressure is lowered
Ex: With other molecules in the water it causes enough disorder that the water doesn’t want to leave as much
⇒Frat boys want to go out and party but frat boys stay in when a few sorority girls are added to the mix
The laws governing colligative properties were?
The laws governing colligative properties were developed for ideal solutions and are therefore only accurate for real solutions that are dilute.
The boiling point is the point at which?
The boiling point is the point at which the vapor pressure of the solution equals the external (environmental) pressure.
At sea level, pext = 1 atm = 760 mm Hg
Boiling point elevation
(Non-electrolytes)
ΔTb=kbm
- Tb is the boiling temperature
- kb is the molal boiling elevation constant (equals 0.51°C/m for water)
- m is molality.
Freezing point
The freezing point is defined as the point at which the free energy of the liquid equals the free energy of the solid. For example, when water and ice are in equilibrium.
- If we add a solute, the free energy, and therefore the vapor pressure, of the solution is reduced.
Freezing Point Depression
(Non-electrolytes)
ΔTf= kfm
kf = the molal freezing point depression constant = 1.86°C/m for water.
Osmotic Pressure
Water flows to the region of higher solute concentration due to the reduced free energy of more concentrated solutions.
The pressure that must be applied to the more concentrated solution in order to prevent this flow of water is defined as the osmotic pressure.
The ideal gas law
The ideal gas law can be used to calculate osmotic pressure.
PV = nRT
PV = mRT (for dilute solutions)
R = 0.082 liter•atm/mole•K
Temperature is in kelvin
Colligative properties- Electrolytes
- Electrolytes dissociate into ions in aqueous solutions, e.g., NaCl dissociates to form Na+ and Cl-
- Remember that colligative properties depend on the number of particles in solution.
- Therefore, dissociation of electrolytes will affect colligative properties differently than non-electrolytes, and we must consider both the concentration of the electrolyte and its degree of dissociation .
Colligative properties- Electrolytes
Correction Factor
- Correction factor (i) to correct for dissociation of electrolytes .
- For salts that produce two particles (e.g., NaCl), i = 1.8. For salts that produce three particles (e.g., MgCl2), i = 2.6.
- For non-electrolytes (e.g., dextrose, ethanol), i= 1.
Therefore, the equations for freezing point depression and boiling point elevation become:
ΔTf = i kf m and ΔTb = i kb m
For non-electrolytes, molarity and osmolarity are?
Equivalent
- 1 M = 1 Osm/L (particle concentration) because no dissociation occurs.
- The number of particles (i.e., millimoles of particles) is often expressed as milliOsmoles. 1 Osm = 1000 mOsm
For electrolytes, we use P = i mRT to correct for dissociation. Therefore…
Osmolal = i m = Osm/kg
P = (Osm/kg) RT
Osmolar = i M = Osm/L
What is the osmolarity of 0.9% NaCl?
277mOsm•L-1
(Isotonic Saline)
Considered the same osmolarity as blood
E value
How much osmotic pressure is contributed by 1 gram of the drug or how much osm pressure exerts thes same pressure as 1 gram of drug
=NaCl equivalent (this has nothing to do with charge- all about osmotic pressure)
How much NaCl do you know to leave out by using the E value?
(g of drug)(E value) = How much NaCl to leave out because the drug exerts this pressure
For intravenous infusion, solutions that are much more concentrated than isosmotic can cause?
- For intravenous infusion, solutions that are much more concentrated than isosmotic can cause phlebitis and tissue damage.
- This presents less of a problem in a central vein infusion because the solutions are diluted very rapidly in a large volume of blood.
For peripheral vein TPN infusions it is important that solutions not exceed?
900 mOsm/L
According to the Bronsted-Lowry theory,
An acid is a substance?
An acid is a substance, charged or uncharged, that is capable of donating a proton.
According to the Bronsted-Lowry theory,
A base is a substance?
A base is a substance, charged or uncharged, that is capable of accepting a proton from the acid.
Equilibrium may be defined as a?
Equilibrium may be defined as a balance between two opposing forces or actions. This does not mean that opposing reactions have stopped, but that their rates are equal.
The dissociation constant for an acid
x = [H3O+] ≈ √(Kac)
*Not used for buffers
Ka = dissociation constant for acids
The dissociation constant for a base
x = [OH-] ≈ √(kbc)
The dissociation constant (also known as the ion product) of water is:
Kw = [H3O+] [OH-]
In pure water at 24°C the hydronium and hydroxyl ion concentrations are equal,and they each are at a concentration of 10·7 M.
Therefore, at 24°C in pure water:
Kw= [10-7] [10-7] = 10-14
- When an acid is added to pure water, some hydroxyl ions, provided by the ionization of water, must always remain. The increase in hydronium ions is offset by a decrease in hydroxyl ions so that Kw remains constant.
- Therefore, you can calculate the concentration of either of these ions at a given temperature if you know the other. (Note: the temperature dependence of Kw).
Charge is critical for virtually everyhting in pharmacy because?
The charge on the drug is going to affect the absorption, solubility, everything!
Remember that when salt and acid concentrations are equal
(i. e [salt] / [acid] = 1)
that. ..
pH= pKa
Buffers
Counteracts the change in pH of a solution
What can affect the pH of buffer solutions?
- Temperature
- Dilution
- Presence of drugs
- Effect of ionic strength from a neutral salt, i.e., NaCl
By adding a base (OH) the pH should?
Go up!
Atomic Nucleus
Composed of protons and neutrons
Number of protons equals
The atomic number in the periodic table
Electrons occupy
Discrete states called “orbitals”
Atoms like to fill
Their entire outer shell with electrons
Orbitals can carry
- s- 2 electrons
- p- 6 electrons
- d
- f
Noble Gases
- Some atoms naturally have their outer shells filled
- Therefore are not very reactive
- They do not need to share any electrons to fill their shell
Covalent Bonds
- When atoms SHARE electrons
- Very energetically favorable
- Relatively strong- the strength of a covalent bond is strongly dependent on the bond length
- SHORTER BONDS= STRONGER BONDS
Ionic Bonds
- The transfer of electrons between atoms
- Cation (+)
- Anion (-)
- Ions interact due to their opposite charge
- Referred to as “salts”
- The strength varies depending on the relative electronegativities of the atoms involved
- Typically weaker than covalent bonds
When identical atoms are involved in covalent bonds, the sharing of electrons is?
Equal (each atom pulls on electrons with the same force due to the same number of protons in their nuclei)
When different atoms are involved in a covalent bond the electrons are shared?
Unequal-
Unequal sharing of the electrons that creates a polarity
Polarity
When one atom has a partial positive charge and one atom has a partial negative charge
A difference in charge creates a?
Permanent dipole that can interact with other molecules via dipole-dipole interactions
The geometry of the molecule is?
Very important! Some molecules composed of different atoms fo not have a permanent dipole because of their orientation (Ex: CO2)
London Forces or Van der Waals Interactions
- Molecules can induce dipoles in other molecules (“polarizability”) and associate via induced dipole-dipole interactions
- The strength of these induced dipole interactions is very weak (0.1-1 kcal/mole)
- These electrostatic interactions are very dependent on distance
- Repulsion- too close together and their electron clouds start running into each other –> Strong repulsion
- Attraction- close enough that the molecules are pulling together
- If too far away- nada happens
Which atoms are strongly electronegative?
Nitrogen
Oxygen
Fluorine
Nitrogen, Oxygen, and Fluorine can participate in?
A polar interaction involving a hydrogen atom–> hydrogen bonding
Hydrogen Bonds
- Are much stronger than van der Waals interactions
- Not as strong as covalent bonds
Hydrogen bonds are very prevalent in?
Biological molecules!
They play an emnormous role in the structure of DNA and proteins
Hydrogen bonds and water molecules
- Dipoles in the water molecule are satisfied by participating in hydrogen bonds with other water molecules
- This hydrogen bonded network is energetically favorable (lower free energy)
- The disruption of water-water hydrogen bonds is therefore unfavorable
Hydrophobic interaction
- When nonpolar molecules that cannot participate in hydrogen bonds are introduced into water, the hydrogen bonding network is disrupted
- In order to minimize this disruption, the nonpolar molecules become sequestered together by a hydrophobic interaction
→ The kids nobody wants to hang out with become sequestered together, even if they don’t really want to hang out together, they have to.
The association between nonpolar molecules in water is?
Not due to any attraction or “bond” between them, it results from the tendency of the water to maintain its favorable hydrogen bonds with other molecules
Due to the hydrophobic interaction?
- Fewer water molecules are in contact with the nonpolar molecules
- The water molecules can better maintain their freedom to move and exchange hydrogen bonds
- This is an entropy-driven process
Molecular interactions turn out to be?
Important for solubility- if we’re going to dissolve a molecule in a solvent, it’s going to have to interact with that solvent
Ideal Solubility
Accounts for how close we are to the melting point and how much energy it actually takes to melt that material
What is the most common pharmaceutical solvent?
Water
Isotonic Saline
- 9% NaCl
- 9g / 100ml of solution