Part 4 Flashcards
What is biopharmaceutics?
The area of pharmaceutics embracing the relationship between the physical, chemical, and biological sciences as they apply to drugs, dosage forms, and drug action
What is another word for metabolism
biotransformation
If a drug has an oral route of administration, explain its movement throughout the body
gastrointestinal tract. from there, some of the drug is absorbed into the circulatory system, from which the drug either enters the tissues (fluids and organs) or metabolic sites. At metabolic sites, the drug is excreted as metabolites. If excreted upon return to the circulatory system, it is excreted through the kidneys
Once a drug is administered and absorption begins, does the drug remain in a single body location?
no — it is distributed throughout the body until its ultimate elimination
Drugs administered by intravenous route are introduced where?
in the circulatory system, avoiding absorption (which is required in order for systemic effects to occur in all other routes of administration
In intramuscular and subcutaneous injections, where is the drug being introduced?
at the tissues. From there it goes into circulation/GI tract
Most drugs pass through biological membranes by….
PASSIVE DIFFUSION
Explain what passive diffusion is
The membrane does NOT actively participate in the process. The absorption process is driven by the concentration gradient— the drug comes from the side with high concentration
Explain what Fick’s first law is
Fick’s first law states that the rate of diffusion across a membrane is proportional to the difference in drug concentration on both sides of the membrane
-dc/dt = P(C1-C2)
C1 and C2 are the drug concentrations on each side of the membrane (C1 is the compartment with the greater concentration of the drug)
P is a permeability coefficient/constant
-dc/dt is the rate of diffusion/transport across the membrane
C1 usually represents ___ and c2 ___
C1 — compartment with higher drug concentration. ie: the absorption site
C2 — concentration of drug in the blood
C1 is usually MUCH greater due to the rapid dilution of the drug in the blood and its subsequent distribution into the tissues.
so, for practical purposes, fick’s law can just be:::
-dc/dt - PC1
The gastrointestinal absorption of most drugs occurs in accordance with _________ kinetics
1st order
the rate depends on drug concentration. Doubling the dose doubles the transfer rate
What is the permeability coefficient?
The rate at which a substance (drug) moves through a permeable membrane
What does a high permeability coefficient mean
that the drug will diffuse across the membrane very rapidly
Name 3 things that affect the permeability coefficient/constant
- The diffusion coefficient of the drug
- The thickness and area of the absorbing membrane
- The permeability of the membrane to the particular drug
The cell membrane is highly permeable to…
LIPID SOLUBLE SUBSTANCES
The Henderson-Hasselbach equation measures…
the extent of ionization of a drug
Are most drugs strong or weak acids/bases
most drugs are weak acids/bases because they are more lipid soluble and can cross the membrane easier
Explain how passive transport may be different from specialized transport
specialized transport may be slower. this is so because the carrier molecules across the membrane may become completely bound with the substance to be transported
What is active transport (absorption)
a subcategory of specialized transport.
the drug is carried AGAINST its concentration gradient
substrate forms a complex with the carrier in the membrane surface.
Substrate-carrier complex moves through the membrane. Substrate is released from the complex at the other side of the membrane
carrier molecule is now free and returns to the apical surface of the membrane, ready to bind further substrates
What is facilitated diffusion
along with active transport, the substance is moved across the membrane through a carrier molecule, but the process does NOT require energy as it is moving with its concentration gradient
Does active absorption require energy?
yes
For a drug to be absorbed it must first be….
dissolved in the fluid at the absorption site
the process by which a drug particle is dissolved is termed….
dissolution
Which has a larger surface area – the stomach or the small intestine
the small intestine
What is the MAJOR absorption site
the small intestine
What is gastric emptying time
the amount of time it takes for the drug to leave the stomach and begin absorption in the small intestine
Name 6 factors affecting dissolution (and hence drug absorption)
-particle size (smaller particle size = faster dissolution)
-surface area (larger surface area = fast dissolution)
-crystal or amorphous drug form (amorphous = fast dissolution. crystalline is more stable and requires more energy to dissolve)
-salt forms (salt forms are ionized and dissolve faster)
-state of hydration (anhydrous form is less stable and has a fast dissolution rate)
-condition of the environment (ie: pH, tetracycline forms a complex with calcium which causes solubility to decrease)
What does bioavailability mean
“bioavailability” describes the rate and extent to which an active drug ingredient is absorbed from a drug product and becomes available at the site of action
What does bioequivalence mean
the term bioequivalence refers to the COMPARISON of bioavailabilities of different formulations, drug products, or even batches of the same drug product
Graphically, bioavailability of a drug is portrayed by……
a blood, serum, or plasma concentration time curve
Give scenarios in which a bioavailability study would have to be submitted
NDA
ANDA
SNDA
Plasma profile has which 3 key features
-peak height (C max)
-time of peak (Tmax)
-Area under the serum-concentration time curve (AUC)
Most drugs exhibit their therapeutic effect through _____ circulation. Receptor sites are available through…
systemic
systemic circulation
Are we able to measure drug concentration at the receptor site?
no - not at this point
That’s why we measure the amount of drug in the PLASMA and try to correlate that to the amount at the receptor site
What are the factors influencing drug availability (bioavailability)
rate and extent of absorption
Are we concerned with bioavailability in drugs with an intravenous route of administration?
NO
The drug is placed directly into systemic circulation. The bioavailability for intravenous routes is this almost always 100%
Are we concerned with bioavailability in drugs with an extravascular route of administration?
YES — because the drug doesn’t reach systemic circulation until after it is absorbed
the plasma profile curve is ___ vs ___
concentration vs time
What is Cmax
the peak concentration of the drug in the serum
what is tmax
the TIME at which cmax occurred (ie: 2 hours after administration)
plasma profile usually follows ____ order kinetics
1st order
Explain the concept of a half life of a drug
if the half life of a drug is 3 hours, after 3 hours, 50% of the drug will remain in the body. After another 3 hours, 25% of the drug will remain in the body, etc
In conducting a bioavailability study, we want the sampling time to be at least ____ half lives of the API
3
When drug concentration is decreasing at the absorption site, where is it going?
into the body
When a drug becomes a metabolite, what organ did this happen in
through the liver
A bioavailability study can be conducted using ___ or ___, and it is difficult to do with ___
a bioavailabilty study is conducted using blood or plasma, but it is difficult to do with urine
What factors on the plasma profile have to do with the RATE of absorption
Cmax
Tmax
What factor on the plasma profile has to do with the EXTENT of absorption
the area under the curve – tells the amount of drug absorbed into circulation
The smaller the AUC, the _____ drug being absorbed
LESS
Relative bioavailability is used for comparing bioavailability of drug products. Give 3 examples
-extravascular dose vs intravenous dose
-same product made by 2 diff manufacturers
-same drug in different dosage forms. ie: tab vs solution
How do we determine relative bioavailability
F = AUCtest/AUCreference
AUC test = product whose bioavailability is being determined
AUC reference - standard against which the test is being evaluated
BOTH PRODUCTS MUST BE ADMINISTERED AT THE SAME DOSE
For a NEW PRODUCT intended for extravascular administration, what will the reference AUC be to determine bioavailability?
the INTRAVENOUS DOSE of the product
This is called ABSOLUTE bioavailability
If testing drugs made by 2 different manufacturers, what will the reference bioavailability be?
the innovator’s product (brand name – co. who discovered it)
This is RELATIVE bioavailability
For the same drug marketed as different dosage forms, what will the reference bioavailability be?
the reference is the EXISTING dosage form of the product
This is RELATIVE BIOAVAILABILITY (absolute is extravascular compared to IV)
How do you determine absolute bioavailability
F = AUC test/D test / AUCIV/DIV
test product = product whose bioavailability is being determined
reference = intravenous dose of the product
F = fraction of dose administered that reaches systemic circulation
Name the drug substance physiochemical properties that influence the bioavailability of oral drugs
-particle size
-crystalline or amorphous form
-salt form
-hydration
-lipid or water solubility
-pH and pKa
Name the pharmaceutical ingredient factors that influence the bioavailability of oral drugs
-fillers
-binders
-coatings
-disintegrating agents
-lubricants
-suspending agents
-surface active agents
-flavoring agents
-coloring agents
-preservative agents
-stabilizing agents
Name the dosage form characteristics that influence the bioavailability of oral drugs
-disintegration rate (for tablets)
-dissolution time
-product age and storage conditions
Name the physiological factors and patient characteristics that influence the bioavailability of oral drugs
-gastric emptying time
-intestinal transit time
-gastrointestinal abnormality or pathologic condition
-gastric contents
-other drugs
-food (ie: tetracycline bonding to calcium)
-fluids
-gastrointestinal pH
The longer the gastric emptying time, the _____ the absorption
less
