Exam 1 Flashcards
(172 cards)
1
Q
Define pharmacokinetics
A
the kinetics of drug (1) absorption, (2) distribution and (3) elimination from the body
2
Q
Define pharmacodynamics
A
the relationship between (1) the drug concentration at the receptor and (2) the physiologic response
3
Q
Define therapeutic window (2 components)
A
the plasma drug concentration at which (a) the drug is effective (b) without [1] exceeding the minimum toxic concentration (MTC)OR [2] falling below the minimum effective concentration (MEC)
4
Q
Define bioavailability (F)
A
the amount of therapeutically active drug that reaches the systemic circulation
5
Q
Define biopharmaceutics (4 components)
A
the interrelationship between (1) physicochemical properties of the drug, (2) the dosage form, (3) the route of administration and (4) how these affect systemic drug absorption
6
Q
Define drug substance
A
FDA definition: substance intended for the use in diagnosis, cure, mitigation, treatment or prevention of disease.
7
Q
What are three (3) synonyms for drug substance?
A
- Active ingredient
- active pharmaceutical ingredient (API)
- active constituent
8
Q
By what two (2) properties is a drug substance selected by
A
- Physicochemical
2. pharmacological efficacy
9
Q
By what two (2) properties is a drug vehicle selected by?
A
- ability to overcome physiological barriers
2. enable therapeutically relevant drug delivery from site of administration
10
Q
Define drug formulation
A
- Active drug substance
2. Active or inactive substances (excipients) in a preparation that is ready to be administered.
11
Q
Define excipient
A
A usually inert substance that forms a vehicle (as for a drug)
12
Q
Define drug product
A
Finished dosage form including:
- formulation
- deliver mechanism
- packaging
13
Q
Define drug product performance (2 components)
A
the release of the drug substance from the drug product either for (1) local drug action or (2) drug absorption into plasma for systemic drug therapeutic activity
14
Q
What are three (3) factors affecting drug product performance?
A
- drug (physicochemical)
- dosage form (drug product)
- body (individual patient)
15
Q
Drug Product Performance is divided into what four (4) phases?
A
- Absorption - drug enter blood
- Distribution - drug moves between blood and tissue
- Metabolism - biochemical drug conversion
- Excretion - irreversible removal of chemically intact drug
16
Q
What is disposition?
A
A phase in performance including distribution and elimination.
17
Q
What is elimination?
A
A phase in performance including metabolism and excretion.
18
Q
How are the phases of drug product performance quantified?
A
Plasma concentration vs Time Curves
19
Q
What are Critical Quality Attributes (CQAs)? (4 components)
A
Critical Quality Attributes (CQA) are (1) chemical, (2) physical, (3) biological and (4) microbiological attributes that can be defined, measured, and continually monitored to ensure final product outputs remain within acceptable quality limits.
20
Q
What are Product Quality Attributes?
A
parameters in the manufacturing process
21
Q
What is drug delivery?
A
A mechanism of the drug product designed to transport a drug to a specific part of the body
22
Q
Define drug absorption
A
Series of events leading up to drug appearance in systemic circulation including:
- loss before absorption
- dissolution and drug release from product
- absorption of soluble drug through membranes
23
Q
What are three (3) factors affecting drug absorption?
A
- Physicochemical properties of the drug substance
- Drug product
- Anatomy of the target site of absorption and action
24
Q
Why does intravascular (ex. intravenous) administration not involve administration?
A
The drug is delivered directly to blood stream (systemic circulation) and thus does not need to be absorbed.
25
Define the two (2) types of movement a drug can do
1. Transcellular movement: movement across cells
| 2. Paracellular movement: movement between cells
26
What are three (3) transport mechanisms?
1. Passive diffusion
2. Facilitated diffusion
3. Active transport
27
What is permeability?
how easy it is for a substance to pass through a membrane
28
What is flux and in what units is it expressed?
Rate of transport for diffusion expressed as (quantity)*(time)^-1*(area)^-1 (how much water flows from a cross section in a river in a certain time)
29
Express Fick's First Law of Diffusion
dQ/dt = [(DAK)/h] (Cgi - Cp)
dQ/dt = rate of diffusion
D = diffusion coefficient (area/time)
A = surface area of membrane
K = drug limit water partition coefficient
h = membrane thickness (length of diffusion path)
Cgi - Cp = difference in drug concentration between GI tract and plasma
30
Describe passive diffusion as an equation for net rate of penetration
Net rate of penetration = Permeability * Surface Area * Concentration Gradient
31
What is osmosis?
The passive diffusion of water
32
What is a saturable process
There is a maximum rate (e.g. all channels are full)
33
What is an influx transporter?
Transfers substrate into cell
34
What is an efflux transporter?
Transfers substrate out of cells
35
What is an absorptive transporter?
Transfers substrate into system circulation
36
What is a secretive transporter?
Transfers substrate from system circulation into bile, urine and/or GI lumen.
37
Define facilitated diffusion
Passive transport of a drug (across a membrane) by specific transmembrane proteins.
38
Define active transport
Characterized by the ability to transport a drug against its concentration gradient at the cost of energy.
39
What is a notable influx transporter in the GI tract?
PepT1 - influx transporter that can enhance the absorption of peptide drugs.
40
What is a notable efflux transporter in the GI tract?
P-gp efflux transporter (also called MDR1): has the ability to efflux many different drug molecules out of cells and into the GI lumen.
41
MDR1 efflux transporters are especially important in these three (3) areas:
1. GI Lumen
2. Blood-brain barrier
3. Drug resistant cancer cells
42
Pharmacodynamics is studied using what type of measurements?
Exposure-response measurements
43
What is drug exposure?
the dose that is input to the body and the measure of drug concentrations in the plasma and other biological fluids
44
What is drug response?
measurement of the physiologic effect that the drug has on the body (measured by clinical markers such as blood pressure, cholesterol elvel, etc.)
45
What are two (2) factors that affect both drug exposure and drug response?
1. Disease state
| 2. patient-specific factors (age, race, sex, exercise level, etc.)
46
Define dosing regimen
Amount and interval of drug administration
47
What are four (4) invasive methods for measuring drug concentration?
1/2. Blood from peripheral vein/artery
3. Tissue biopsy
4. CNS fluid
48
What are peripheral veins/arteries?
Veins/arteries that are not part of the abdomen/drunk.
49
What are six (6) noninvasive methods for measuring drug concentration?
1. Urine
2. Feces
3. Tears
4. Sweat
5. Saliva
6. Breast milk
50
What is a major difference between whole blood and serum or plasma?
Serum and plasma do not contain cellular elements
51
What is a major difference between serum and plasma?
Serum does not contain clotting proteins.
52
Why are plasma drug concentrations useful for calculating drug kinetics?
Plasma perfuses all tissues of the body, thus changes in the plasma drug concentration will reflect changes in tissue drug concentrations.
ASSUMPTION: drug in plasma is in equilibrium with the tissues
53
What are two (2) different states that a drug may exist while in plasma (systemic circulation)?
Protein-bound or free (unbound)
54
What is AUC and what does it represent?
1. Area Under Curve for a plasma drug [c]-time curve.
| 2. Represents the calculation of total drug exposure
55
What is Cmax and what three (3) factors is related to?
Peak concentration:
1. dose
2. rate constant for absorption
3. rate constant for elimination
56
What is Tmax and how can it be interpreted?
Time of Peak Concentration: Is a very rough marker of average rate of drug absorption (for oral delivery)
57
IV Push gives a simple means for calculating pharmacokinetic parameters. What are two (2) assumptions made in these calculations?
1. No absorption. Drug distributes and equilibrates instantaneously.
2. Elimination begins to occur immediately.
58
In a typical plasma drug [c]-time curve, explain three notable regions in terms of input rate and output rate.
1. Input rate > output rate (part of curve before Cmax)
2. Input rate = output rate (Cmax)
3. Input rate
59
Explain why the phase of the plasma drug [c]-time curve where input rate > output rate increases at a decreasing rate.
Disposition occurs shortly after administration, lowering plasma drug [c] by movement into tissues and elimination.
60
Define apparent volume of distribution
Vd is the volume in which the drug appears to be distributed at equilibrium.
61
From what two (2) parameters is the apparent volume of distribution calculated?
1. injected amount of drug
2. plasma drug concentration immediately after injection
[based on first assumption of IVPush kinetics]
62
Define clearance
describes the process by which a drug is eliminated from the body without identifying the individual processes
63
In what units is clearance reported?
Volume of fluid cleared of drug from the body per unit of time (e.g. mL/min, L/hr)
64
What two parameters characterize the elimination phase?
1. Elimination half-life
| 2. Volume of distribution
65
How is elimination half-life determined?
k = ln2/half-life
66
How is total clearance determined?
Total Clearance = k*Vd
67
Define drug excretion
Removal of intact drug
68
Define drug metabolism (biotransformation)
the drug is chemically converted to a metabolite in the body
69
Is the body modeled in the calculation of drug clearance?
The body is considered as one compartment.
70
What is the elimination rate constant in drug clearance calculation?
Sum of all different rate constants for drug elimination
71
What is elimination half-life?
The time taken for the plasma concentration to fall by 1/2.
72
How many half-lives must occur for total elimination?
5 half-lives eliminate about 97% of drug.
73
What is the kinetic order of the process for the elimination of most drugs?
The rate of elimination from the body followers a first-order process.
74
The rate of elimination is proportional to what in first order elimination?
Proportional to the plasma [c].
75
When the plasma [c] is plotted vs. time in a first-order process, what is the shape of the curve?
Decrease at decreasing rate.
76
When the plasma [c] is plotted vs time on a semi-log graph in a first-order process, what is the shape of the curve?
Linear with slope= (-k)/2.3
77
What are three (3) major sites of excretion of the drug/metabolite?
1. Kidney
2. Liver
3. Intestine
78
What are three (3) minor sites of excretion of the drug/metabolite?
1. Skin
2. Lungs
3. Salivary glands
79
What is steady-state concentration?
When the rate of drug input = rate of drug output and the plasma [c] plateaus.
80
What drug administration can easily result in a steady-state concentration?
IV Infusion, because the drug will be infused slowly at a constant rate (zero order rate of delivery).
81
What are three (3) advantages of IV infusion?
1. Avoid large peaks and troughs.
2. Can give the drug with IV fluids
3. Easy to maintain/adjust or terminate therapy as needed.
82
How does IV infusion induce steady-state concentration? (4 steps)
1. Infusion can be thought of as multiple doses.
2. Drug accumulates as successive doses are administered.
3. Rate of elimination increases as plasma [c] increases.
4. Rate of elimination approaches rate of administration until max and min drug concentrations are the same for two successive doses.
83
On what four (4) parameters does plasma [c] depend on during steady state?
1. Clearance
2. Volume of distribution
3. Dose
4. Dosing interval
84
Define local administration
exerts its effect where applied
85
Define systemic administration
intended to produce an effect throughout the body; blood circulation required to deliver the drug to its site of action
86
What are three (3) factors on which route of delivery is chosen?
1. Intended site of action
2. Properties of the drug compound
3. Patient and disease-specific factors
87
What are three routes of delivery?
1. Parenteral (must be injectable)
2. Enteral
3. Other
88
List two (2) classifications of parenteral administrations and give examples for each
1. Intravascular: intravenous, intrarterial
| 2. Extravascular: intradermal, intramuscular, subcutaneous
89
Give four (4) examples of enteral routes of delivery
1. Oral
2. Rectal
3. Sublingual
4. Buccal
90
Give three (3) examples of "other" routes of delivery
1. Topical
2. Transdermal
3. Pulmonary
91
What is the primary goal of Biopharmaceutics?
Optimize therapeutic activity and safety outcomes of a drug product using basic sciences.
92
What is Quality by Design?
Approach in pharmaceutical development that is systematic and scientific with the final product being kept in mind throughout the process.
93
How do Critical Quality Attributes relate to routes of administration?
Different CQAs will apply to each route of administration for therapeutic efficacy and patient safety.
94
Give five (5) examples of performance attributes
1. In vitro: Purity
2. In Vivo: Efficacy/Safety
3. Sensory: Taste
4. Utility: Storage
5. Administration: Ease of injection
95
What are three (3) Raw material CQAs
1. Particle size and distribution
2. Bulk density of the material
3. Hardness of a tablet
96
What are three (3) factors affecting the Critical Quality Attribute of Stability?
1. Environmental factors
2. Packaging materials
3. Microbial contamination
97
What are four (4) environmental factors that affect stability?
1. Temperature
2. Light
3. Air
4. Humidity
98
What are the first three rate steps (processes) involved solid oral drug absorption?
1. Disintegration and subsequent drug release
2. Dissolution of the drug in an aqueous environment
3. Absorption across membranes
99
Define disintegration
The process by which aggregated small particles are liberated, releasing the drug
100
Define dissolution
The process by which a chemical or drug becomes dissolved in a solvent
101
Define solubility
static property that refers to how much mass of a solute can dissolve in mass or volume of solvent at a given temperature (e.g. 10 g/L)
102
What are five (5) drug product design considerations to meet desired bioavailability and therapeutic objectives?
1. physicochemical properties of molecule
2. type of drug product
3. nature of excipients
4. method of manufacturing
5. route of drug administration
103
How does biopharmaceutics aid the use of drugs?
It allows for the rational design of drug products.
104
What are seven (7) factors for the rational design of drug products?
1. Physicochemical properties of substance
2. Route of administration
3. Desired pharmacodynamic effect
4. Toxicologic properties
5. Safety of excipients
6. Effect of excipients and dosage form on drug product performance
7. Manufacturing processes
105
What is purpose of the Noyes-Whitney Equation?
Equation describing the rate of dissolution in terms of properties of the solute and solvent.
106
Write the Noyes-Whitney Equation
dC/dt = (DA/h) * (Cs-C)
```
dC/dt = rate of dissolution
D = diffusion rate constant
A = surface area of particle
h = thickness of stagnant layer
Cs = concentration of drug in stagnant layer (equal to solubility)
C = concentration of drug in the rest of the solvent
```
107
Why is the concentration of drug in the stagnant layer equal to the solubility?
The stagnant layer is a saturated solution at the surface of the particle.
108
Describe a pH-solubility plot
Plot of drug solubility at various pH values.
109
Describe a pH-stability plot
Describes the reaction rate constant for degradation of the drug at various pH values
110
How does pH formulation affect drug performance?
pH affects solubility and stability.
111
How does particle size affect drug performance?
1. Decreasing particle size will increase surface area that is available for dissolution.
2. Increased surface area will increase rate of dissolution.
[Noyes-Whitney Equation]
112
What are three (3) common excipients that affect bioavailability?
1. Disintegrants
2. Coatings
3. Lubricants
113
How do disintegrants affect bioavailability?
enhance the rate of disintegration and dissolution
114
How do coatings affect bioavailability?
control release of the drug (affect diffusion rate constants)
115
How do lubricants affect bioavailability?
Can slow dissolution rates
116
What are five (5) formulation factors affecting absorption?
1. Dosage form design (drug product)
2. Rate of drug release from dosage form
3. Dose
4. Pharmacokinetics
5. Route of administration
117
Define duration of effect
Timeframe at which plasma [c] exceeds minimum effective concentration.
118
Define onset time
Time at which plasma [c] first reaches minimum effective concentration.
119
Describe the relationship between volume of distribution, amount of drug in body and plasma drug [c].
Vd is the plasma volume in which the drug appears to be distributed at equilibrium. Therefore, Vd times the plasma drug [c] gives the amount of drug in body.
Dose = V*[C]
120
What are three (3) factors that can affect apparent volume of distribution
1. Tissue affinity
2. Protein binding
3. Transporters
121
Define lag time
the delay that occurs between drug administration and the beginning of absorption.
122
What are three factors that oral dose absorption depends on?
1. Physicochemical properties of the drug
2. Drug product/formulation
3. Physiology of the site of absorption (small intestine favored)
123
What are three (3) factors contributing to the high rate of absorption in the small intestine?
1. Immense surface area
2. Blood flow
3. Permeability
124
What is the First-Pass Effect?
A phenomenon where a large amount of drug is eliminated on the first pass through the hepatic portal vein before entering the systemic circulation.
125
What is hepatic biotransformation?
Metabolism in the liver.
126
What family of enzymes are especially important in hepatic biotransformation?
Cytochrome P450 Enzymes
127
In general, describe the electronic structure of metabolites compared to their parent compound.
Metabolites are more polar than their parent compound.
128
Describe phases I and II of Biotransformation
Phase I: Chemical Modification of Drug compound (oxidation, reduction, hydrolysis)
Phase 2: chemical addition of functional groups (sulphation, glucoronidation)
129
What are three (3) functions of the Enteral System?
1. Secretion
2. Digestion
3. Absorption
130
What is transit time?
Time from point A to point B in GI tract. Ingestion to excretion by GI tract is approx. 5 days (total transit time)
131
What is the small intestine transit time?
3-4 hours
132
What is the fasted pH of the stomach?
about 2-6
133
Describe the pH changes that occur in stomach as food enters
1. Food buffers the stomach, raising pH
| 2. Parietal cells release HCl, lowering pH
134
Define gastric emptying time
How long it takes stomach to empty contents into duodenum
135
Describe the relative gastric emptying times of liquids and solids
Liquids empty faster than digested solids when ingested at the same time.
136
What are three (3) functions of the small intestine?
1. Mix food with enzymes to facilitate digestion
2. Mix intestinal contents with intestinal secretions (enables absorption)
3. Move unabsorbed materials towards large intestine
137
What is the shortest section of the small intestine?
Duodenum - 20-30 cm
138
What is the longest section of the small intestine?
Ileum (~3.5 meters)
139
What is the most important section of the small intestine and why? (2 reasons)
Duodenum - (1) releases bicarbonate and (2) is major site for passive drug absorption.
140
Define absorption window
Anatomic or temporal frame in which a drug is efficiently absorbed in GI tract.
141
What are four (4) factors affecting transit time of a drug in the GI tract
1. Physicochemical properties of the drug
2. Dosage form
3. State of the GI tract
4. Other physiologic factors, such as "fed" or "fasted" state.
142
Define alimentary canal
The canal from mouth to anus that food passes through.
143
What are three (3) factors affecting gastric emptying time?
1. Food, esp. Fatty meals
2. Cold beverages
3. Anticholinergic drugs
144
Tablets and capsules are delayed from emptying into the duodenum by how much time in the presence of food?
About 3 to 6 hours.
145
What three (3) effects can food have on absorption?
1. Enhance absorption
2. Delay absorption
3. Reduce absorption
146
In general, what is the relationship between food and bioavailability? (2 components)
1. Bioavailability is greater in a fasted state when a large volume (8 oz) of water is given.
2. Effects are food will be greatest 10-15 mins after a meal.
147
What are five (5) specific ways food can affect bioavailability?
1. Delay in gastric emptying
2. Change in the pH of GI tract
3. Stimulate bile flow
4. Physical or chemical interaction of the meal with drug substance/formulation
5. Change in luminal metabolism
148
What are six (6) factors influencing the interaction between food and drug absorption
1. drug substance
2. drug formulation
3. local pH
4. presence of food
5. transit time through various parts of GI tract
6. Disease states
149
What affect does food have on drugs with high first-pass metabolism?
Food can increase bioavailability, possibly by saturating portal vein enzymes with increased blood flow.
150
What are nine (9) ways disease can affect drug absorption?
Changes in:
1. Intestinal blood flow
2. GI motility
3. Stomach emptying time
4. gastric pH that affects solubility
5. intestinal pH that affects ionizaton
6. Permeability of the gut wall
7. Bile secretion
8. Secretion of digestive enzymes
9. Alternation of the normal GI flora
151
What are four (4) disease states that affect drug absorption?
1. Achlorhydria
2. Short bowel (gut) syndrome
3. HIV-AIDS
4. GI Disorders
152
What are two (2) GI disorders?
1. Celiac disease
| 2. Crohn's disease
153
How does HIV-AIDS impact drug absorption?
1. Increased gastric transit time
2. Diarrhea
3. Achlorhydria
154
What are 5 organs that can be targeted by drug delivery?
1. GI tract (small intestine)
2. Intravenous delivery
3. Skin
4. Brain
5. Lungs
155
What are four important CQAs of IV products?
1. Sterility
2. Volume
3. pH
4. Tonicity
156
What are three (3) ways to prepare a sterile IV product
1. autoclave
2. filtration through 0.22 micrometer filter
3. prepared in aseptic environment
157
How does the volume of IV administration affect pH and tonicity?
1. Small volume injections can be in pH range of 4-10 and hypo or hypertonic.
2. Large volumes (infusions) must be near pH 6-8 and tonicity varies.
158
What is the brick and mortar model of the skin?
A model wherein keratin filled cells lie within an intercellular lipid matrix.
159
What is the rate limiting step for absorption through skin?
Drug diffusion through the stratum corneum
160
What type of molecules are more easily absorbed through skin? (2 components)
1. Small molecules (
161
How do the concentrations of drug products delivered through the skin compare to other routes of delivery?
Low concentrations required for efficacy. Often very potent drugs on small surface area.
162
What four mechanisms (or lack thereof) form the blood-brain barrier?
1. Tight junctions between capillary and endothelial cells surrounding brain
2. NO paracellular transport possible
3. NO pinocytosis
4. P-gp efflux (MDR1) actively transport molecules out.
163
How do you cross the Blood-Brain barrier (2 ways)
1. highly lipid soluble and low molecular weight
| 2. specific transporters present
164
Describe the enzyme content of the liver
Nearly all of the enzymes for drug metabolism in the liver are found in the lungs
165
What are three (3) advantages of pulmonary delivery versus oral delivery?
1. More rapid onset of action
2. Less drug required
3. reduction in likelihood of systemic side effects
166
What happens if a drug particle is delivered to the lung and is too large?
Don't move past upper airways and are rapidly removed
167
What happens if a drug particle is delivered to the lungs and is too small?
Will be exhaled out before sedimentation in the alveoli
168
What is the rate-limited step in pulmonary absorption?
Transporting across the alveolar membrane
169
What are the three (3) primary physicochemical properties contributing to differential drug absorption
1. Molecular size (generally; small preferred)
2. Lipophilicity (generally; more lipophilic)
3. Ionization/charge (unionized more readily cross membrane)
170
What is the Biopharmaceutics Classification System?
```
A system that classifies drugs into Class I, II, III or IV based on intestinal permeability and solubility. Class I is highly permeable and soluble, class IV is poorly permeable and soluble.
{II, I }
{IV, III}
```
171
What is the pH partition hypothesis?
"absorption of a drug substance is based directly on the degree of ionization in the GI lumen and in the blood."
172
What is the logic behind the pH partition hypothesis?
Ion Trapping:
1. Unionized species travel through membranes more easily.
2. Many drugs are weak acids -- will be protonated in stomach, unprotonated (charged) in blood.
3. Drugs will cross membrane, become deprotonated, and be unable to recross membrane.
