Term
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Definition
The study of the relationship between the nature and intensity of a drug’s effects and various drug formulation or administration factors”
“The science that examines the interrelationship of the physicochemical properties of the drug, the dosage form in which the drug is given, and the route of administration on the rate and extent of systemic drug absorption”
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Term
Formulation and Administration Factors |
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Definition
•Chemical nature
–Solubility, pKa, partition coefficient, polymorphism, chirality, hydrates, complex formation potential
•Physiological environment
–pH, GI motility, vasculature
•Inert formulation substances
–Can affect drug release, permeation and metabolism
•Pharmaceutical processes used to manufacture the dosage form
–Tablets, capsule, liquids, suspension, liposomes, emulsions, targeted drug delivery
•Routes of administration
Type and concentration of enzymes, blood flow, barrier properties of the tissue |
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Term
Drug Transport and Absorption |
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Definition
1. Transcellular - (passive diffusion, carrier mediated, and vesicular)
2. Paracellular - (passive diffusion)
3. Carrier Mediated - (active transport, facilitated diffusion)
4. Cellular Efflux |
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Term
3 Mechanisms of Transcellular Transport |
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Definition
1. Partitioning and passive diffusion
2. Carrier-mediated transport
3. Vesicular transport
(can be influx into the cell or effluxed out of the cell)
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Term
2 Types of Carrier Mediated Transcellular Transport |
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Definition
1. Active
2. Facilitated Diffusion |
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Term
Carrier-Mediated Active Transport |
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Definition
•Involves carrier proteins or transporters
•Drug can be transported against a concentration gradient i.e. from low to high
•Process requires energy
•Carrier may be selective
•Carrier system is saturable
•Process may be competitive
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Term
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Definition
| P-glycoprotein and multidrug resistant proteins |
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Term
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Definition
| amino acid transporters and peptide transporters |
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Term
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Definition
–Pinocytosis – small solute or fluid volumes
–Phagocytosis – larger particles or macromolecules
–Endocytosis – receptor mediated
–Exocytosis – movement out of the cell
–Budding
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Term
Different Drugs with Different Absorption Rates |
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Definition
1. Quickly absorbed=Quicker onset= More intense effect
2. Quickly absorbed=Quicker onset=less duration of effect
3. Metabolism and elimination of individual patient can also effect the absorption |
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Term
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Definition
The “rate and extent” to which an active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action (true definition)
Bioavailability refers the fraction (extent) of the drug dose that reaches the systemic circulation.
Bioavailability is commonly referred to as “F” where F stands for “Fraction reaching systemic circulation”.
Disintegration, Dissolution, Diffusion, Metabolism in intestinal wall, metabolism in liver are all rate determining steps of bioavailability.
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Term
How would you create a dosage form that has the highest possible dissolution?
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Definition
You’d give it as an oral liquid. That way it’s already dissolved. Even then, much of the drug may not make it all the way into the blood.
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Term
What’s the most obvious step where those who design dosage forms can influence this process?
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Definition
Probably disintegration. The diffusion and absorption of a drug depends mostly on the nature of the drug molecule. It depends on the solubility of the molecule and it’s pka. The disintegration step depends more on what the people who design the dosage form do in terms of adding inert ingredients and the altering the pharmaceutical processes used to manufacture the dosage form.
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Term
Administering the same amount of drug |
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Definition
Bioavailability is directly proportional to AUC. If product A has a larger AUC than product B, the bioavailability of product A must be greater than that of product B.
Furthermore, if the AUC of product A is twice that of the AUC of product B, the bioavailability of Product A is twice the bioavailability of product B. |
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Term
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Definition
| the systemic availability of a drug after extravascular administration (oral, rectal, transdermal, SQ) compared to IV dosing |
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Term
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Definition
| the availability of the drug from a drug product (A) as compared to a recognized standard (B) |
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Term
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Definition
•The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action.
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Term
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Definition
| Absorption rate constant. It is the percent absorbed per unit of time. As a general rule if Ka > 1 hr-1, then absorption is rapid and extensive. |
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Term
Steps of 2-compartment Calculation of absorption and distribution with residual lines. |
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Definition
Step 1. Find the straight-line portion of the curve from the terminal phase and extrapolate back to time zero.
Step 2. Find extrapolated concentrations corresponding to measured concentrations in the uphill region.
Step 3 . Subtract measured concentration values from corresponding extrapolated concentration values.
Step 4 . Plot the values obtained from subtractions at corresponding times. Then draw a line that best fits the new points (Residual Line).
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Term
Controlled-Release Products
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Definition
•Prolonged-release usually means the drug is always released at a controlled rate from beginning to end.
•Includes enteric-coated products but these are a little different. Here the rate of release is not controlled. But where release occurs is controlled.
•Repeat-action formulations; release an initial dose followed by another dose later but the rate of the release is not controlled.
Sustained release formulations; usually release initial dose followed by controlled-release
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Term
Common Formulations for ORAL Controlled-Release Products
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Definition
•Wax matrix tablets
•Coated pellets in tablets
•Coated pellets in capsules
•Osmotic pumps
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Term
Factors That Affect Distribution |
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Definition
A.Body tissue characteristics
B.Disease states
C.Lipid solubility of drug
D.Regional differences in pH
E.Extent of protein binding
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Term
Diseases That Decrease Perfusion |
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Definition
•Liver failure
•CHF
•Renal failure
•Highly perfused organs tend to get a higher distribution of the drug. So, diseases that decrease the perfusion will decrease the distribution.
•If affected organ is an organ of elimination you could actually see a build up of drug in the body.
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Term
Differences in Solubility |
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Definition
•Lipophilic
–Crosses membranes easily
–Distributes into fat
•Hydrophilic
–Polar or charged molecules
–Don’t cross membranes easily
–Doesn’t distribute much into fat
–Example: gentamicin
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Term
Changes in Protein Binding |
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Definition
•Changes in protein concentration
•Displacement by other substances
•Changes due to disease states
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Term
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Definition
| elimination rate constant for hepatic metabolism of drug X |
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Term
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Definition
| elimination rate constant for renal excretion of metabolite Y |
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Term
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Definition
•Inactive
•Bioactive after biotransformation or metabolism
•Levodopa
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Term
Factors to Affect Biotransformation
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Definition
•Functioning of metabolic enzyme systems: Neonates may have incomplete enzyme systems for chloramphenicol.
•Social habits: Alcohol or smoking
•Diseases: Cirrhosis, hepatitis and reduced hepatic blood flow affect drug metabolism
•Concomitant drug use: Inhibition or induction of enzymes
•Genetic variation: Genetic polymorphism
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Term
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Definition
| The efficiency of the liver in removing drug from the bloodstream. It is the fraction of drug removed in one pass. |
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Term
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Definition
| represents the liver’s innate ability to clear unbound drug from intracellular water via metabolism or biliary excretion |
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Term
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Definition
•This is significant for drugs with high extraction ratio.
•It is the removal of drug by the liver AFTER absorption but BEFORE reaching systemic circulation.
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Term
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Definition
| Made up of metabolism and excretion |
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Term
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Definition
1 of 3 types of renal excretion:
Passive diffusion of fluids and solutes.
Influenced by molecular size(≤60,000), protein binding (only free fraction), integrity of and number of nephrons.
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Term
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Definition
1 of 3 types of renal excretion:
Active process therefore may be subject to competition e.g to enhance half-life of penicillin coadminister probenecid. |
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Term
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Definition
Depends on the effect of pH on the drug.
Drugs that are ionized in the urine have less reabsorption so they stay in the urine and are excreted. Urine flow rate may also be important for some compounds e.g. urea (low flow rate higher reabsorption).
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Term
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Definition
Michaelis constant = drug concentration when the rate of the process is half the maximum rate
has units of concentration and in simple terms represents the concentration above which saturation of drug elimination is likely. |
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Term
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Definition
theroretical Maximum Rate of the process.
The units are amount per time (e.g. mg/day) and represents the maximum amount of drug that can be eliminated in a given time period |
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Term
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Definition
| process that allows Nonlinear Elimination of a drug to occur. |
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Term
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Definition
| The time it takes to reach 90% of the steady state concentration. There is no such thing as a true half life for non-linear elimination so this is what we use instead. |
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Term
Nonlinear pharmacokinetics |
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Definition
refer to several different processes, including absorption, distribution, and renal or hepatic elimination. For example, with nonlinear absorption, the fraction of drug in the GI tract that is absorbed per minute changes with the amount of drug present. Even though absorption and distribution can be nonlinear, the term nonlinear pharmacokinetics usually refers to the processes of drug elimination
Many drugs exhibit mixed-order pharmacokinetics, displaying first-order pharmacokinetics at low drug concentrations and zero-order pharmacokinetics at high concentrations. It is important to know the drug concentration at which a drug "order" switches from first to zero. Phenytoin is an example of a drug that switches order at therapeutic concentrations, whereas theophylline does not switch until concentrations reach the toxic range |
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Term
The kinetics of Non-linear elimination |
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Definition
| After a large dose is administered, an initial slow elimination phase (clearance decreases with higher plasma concentration) is followed by a much more rapid elimination at lower concentrations (curve A). However, when a small dose is administered (curve B), the capacity of the elimination process is not reached, and the elimination rate remains constant. At high concentrations, the elimination rate approaches that of a zero-order process (i.e., the amount of drug eliminated over a given period remains constant, but the fraction eliminated changes). At low concentrations, the elimination rate approaches that of a first-order process (i.e., the amount of drug eliminated over a given time changes, but the fraction of drug eliminated remains constant). |
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Term
Sources of Pharmacokinetic Variation |
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Definition
•Age
•Disease states
•Genetic factors
•Obesity
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Term
Sources of Error in Samples |
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Definition
•Sample collection and handling
•Physicochemical factors
•Instrument calibration and controls
•Drug administration and sampling times
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Term
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Definition
| The fluid portion of a sample of whole blood allowed to clot for 30 min before centrifugation. |
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Term
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Definition
| The fluid portion of whole blood centrifuged before clot formation |
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Term
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Definition
| Refers to diminished assay performances by structurally related drug compounds or metabolites for which the assay method measures as if they were the desired assay compound |
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Term
serum separator tube (SST) |
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Definition
To measure drug concentrations, whole blood is usually collected in this blood collection tube.
It contains a gel barrier that separates the fluid portion of blood from the solid portion. After collection, the blood is first allowed to clot, which takes approximately 30 minutes, and is then centrifuged for at least 15 minutes to separate the solid components of the blood (blood cells, fibrin, fibrinogen, etc.) from the fluid component. This fluid component is then called . If whole blood is centrifuged before it clots, then only the blood cells are separated from the fluid component, which is then called |
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Term
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Definition
•Lower limits of drug detection
•Upper limit of drug detection
•Assay interference
–Cross-reactivity
–Physiologic interference
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Term
Upper Limit of Drug Detection |
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Definition
| The upper limit of drug detection indicates the highest drug concentration that can be accurately measured. Plasma drug concentrations above the upper limit will often be reported as higher than this value. If this occurs, assay parameters can be adjusted to increase the dilution volume of the plasma sample, thus allowing higher drug concentrations to be measured |
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Term
Lower Limit of Drug Detection |
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Definition
| The lower limit of drug detection indicates the lowest drug concentration that the assay can reliably report. This is a function of the particular assay instrument and is called assay sensitivity. Assay sensitivity is the lowest measurable drug concentration that can be distinguished from zero with 95% confidence. Plasma drug concentrations lower than this concentration should be reported as less than this value |
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Term
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Definition
| Assay interferences are generally categorized as cross-reactivity and physiologic interferences. The degree of cross-reactivity with other structurally similar compounds is called assay specificity. Cross-reactivity is a function of the specificity of the antibody used to bind to the drug. Often, this antibody will also at least partially bind to other compounds that are structurally related to the desired analyte, such as metabolites and chemical analogues of the analyte |
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Term
Drug Administration and Sampling Errors |
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Definition
•Deviations in drug administration times
•Accurate sampling times
•Other medications
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Term
Most frequently used model-independent parameters |
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Definition
•AUC
•Elimination rate constant
•Elimination half-life
•Total Body Clearance
•Mean Residence Time
•Volume of distribution at steady state
•Formation Clearance
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Term
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Definition
Average time intact drug molecules transit or reside in the body
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Term
Volume of Distribution at Steady State |
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Definition
| Relates total amount of drug in the body to a particular plasma concentration after a single dose. |
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Term
Formation Clearance (CLP→Mx) |
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Definition
| Provides a meaningful estimate of the portion of total body clearance that is accounted for by production of a specific metabolite |
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