Pharmacokinetics Flashcards
1
Q
Cell Membrane Polarity
A
Charged heads (hydrophilic) Uncharged tails (lipophilic)
2
Q
Types of compounds that diffuse passively through membrane
A
Lipophilic (uncharged)
3
Q
Determinants of passive diffusion
A
Partition coefficent
Concentration gradient
4
Q
Form of weak acid that diffuses
A
HA
5
Q
Form of weak base that diffuses
A
B
6
Q
Definition of pKa
A
pH where ratio of unprotonated to protonated is equal
7
Q
Henderson-Hasselbach equation
A
log([protonated]/[unprotonated]) = pKa - pH
8
Q
Ion trapping of drugs
A
Acidic drugs accumulate on the side of the membrane that is more basic
Basic drugs accumulate on the side of the membrane that is more acidic
9
Q
Characteristics of passive diffusion
A
Bidirectional
Driven by concentration gradient
10
Q
Definition of carrier mediated transport
A
Molecule across a barrier is mediated by the binding of solute to protein transporter
11
Q
Purposes of carrier mediated transport
A
Hydrophilic molecule movements
Molecules against gradient
Providing specificity
12
Q
Characteristics of facilitated diffusion
A
Carrier mediated
Concentration gradient driven
Not active energy
Example: Glucose transport
13
Q
Characteristics of active transport
A
Carrier mediated
Moves solute against its concentration gradient
Active energy
14
Q
What is p-glycoprotein?
A
ATP binding cassette (ABC) carrier or pump
Binds to lipophilic drugs to promote their efflux (removal) from cell
Energy from ATP hydrolysis
Encoded by multidrug resistance gene
15
Q
Characteristics of secondary active transport
A
Carrier mediated
Multiple solutes in same (symport) or opposite (antiport) directions
Requires moving one solute down its gradient to drive the movement of the other against its concentration gradient
16
Q
Most often driving solute for secondary active transport
A
Sodium or hydrogen
17
Q
Name of symport and antiport proteins
A
Symport: Co-transporter
Antiport: Exchangers
18
Q
Definition of bioavailability
A
F - Fraction of the administered dose of drug that reaches circulation
19
Q
What is an F = 1 defined to be?
A
IV delivery
20
Q
Bioavailability of oral drugs
A
F < 1
Incomplete absorption, first pass effect
21
Q
Definition of first pass effect
A
Orally administered drugs are metabolized by liver or excreted into intestine via biliary excretion (enterohepatic circulation)
Results in not reaching systemic circulation
22
Q
Propranolol’s bioavailability
A
Loss during first pass
Causes it to have low potency
23
Q
Therapeutic considerations of first pass effect
A
More for older, established drugs
Newer drugs are designed with this in mind so structure minimizes the effect
24
Q
Definition of bioequivalence
A
Same drug
Same route of administration
Same amount of drug enters the circulation
Drug enters the circulation at same rate
Standard for comparing formulations (generics)
25
Absorption of orally administered drugs
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Passive diffusion in GI tract
Unionized form (No not the auto workers)
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26
Characteristics of Stomach Absorption
Very acidic, thick mucous, small surface area
| Limited absorption of even weak acids
27
Characteristics of Upper Intestine Absorption
pH of about 7
Large absorptive surface area (200 sq meters)
Moving blood prevents formation of an equilibrium (Le Chatelier all day to the blood)
28
Gastric emptying impact on drug absorption
Increased emptying increases the rate of absorption
29
Effect of dissolution of a solid drug
Affect the rate of absorption
| Coatings, particle sizes need to be considered
30
How to achieve controlled release solid drug?
Hard-to-dissolve agents for slow uniform dissolution and absorption
31
Advantages of controlled release solid drug
Slower absorption results in decreased frequency of dosing, more uniform concentration of drug in the blood
32
Disadvantages of controlled release solid drug
Greater variability among patients (Grapefruit and dat Cytochrome P450 action)
Greater toxicity if incorrectly absorbed (Chewing the pill)
33
Purpose of enteric coatings
Protect the drug from the stomach acid and stomach from drug (e.g. aspirin)
Better taste
34
Sublingual delivery definition
Under the tongue (e.g. nitroglycerin for angina)
| Rapid absorption
35
Buccal delivery definition
Beneath gum and cheek
36
Characteristics of sublingual/buccal delivery
Blood drains into the sup. vena cava
Avoids liver for first pass
Small surface area so drug is lipophilic
37
Rectal administration advantages
Useful if patient cannot or won't swallow (unconscious, vomiting, pediatric, etc.)
50% less first pass than orally administered agents
38
Rectal administration disadvantages
Variable absorption, can be incomplete, irritating to rectal mucosa, uncomfortable
39
Transdermal administration definition
Through the skin
40
Characteristics of transdermal
Epidermis is impermeable to hydrophilic, but permeable to lipophilic
Best if hydrated
Examples are nicotine, estrogen/progesterone
41
Definition of parenteral injection
Without the intestine
| Include IV, subcut, and intramuscular
42
Mechanism of subcutaneous and intramuscular delivery
Injection results in a depot of drug in dermis or muscle
| Drug diffuses to nearby capillaries
43
Rate of absorption of lipophilic drugs via injection
Depends on drug solubility in interstitial fluid
| Area of capillary bed in vicinity
44
Mechanism of absorption of large hydrophilic drugs via injection
Pass through large, aqueous channels in the capilaries
| Example insulin
45
Mechanism of absorption of proteins via injection
Enter via the lymphatic system
| Example: Antigens in vaccination
46
Where do the parenterally drugs distribute to first?
The Lungs
47
Characteristics of lung during drug absorption
Metabolically active organ, large capillary bed
Filters particulates
Volatile agents can diffuse into the expired air (breathilizer test)
Lipophilic agents can accumulate; redistribute
48
Characteristics of IV injection
Completely bioavailable (F = 1)
Achieve immediate action; drug delivery can be highly controlled
Dose and rate of delivery can be rapidly adjusted
Anesthetics; emergency treatments
Irritating agents are diluted by the entire blood volume
49
Advantages of IV injections
Control over dosage
| Control over rate of administration (Bolus. slow infusion)
50
Disadvantages
Route of no return, hard to remove once in circulation
| Need close monitoring, experienced staff
51
Subcutaneous control of absorption
Add vasoconstrictors to delay absorption
52
Variability of intramuscular absorption
Blood flow based on muscle demand
53
Airway administration purposes
Volatile agents; rapid access to the circulation
| Treatment of the airway (targeted delivery in brachoconstriction)
54
Topical targets for drugs
Mucous membranes
| Eye
55
Definition of drug eluting stents
Placing a scaffold into the artery (stent) with drugs bound onto the stent for controlled release
Example: Anticoagulants post balloon angioplasty
56
Drug delivery targeting of cells via ________
Antibodies
| Possible treatment for tumor cells
57
Prodrug delivery
Inactive drugs that are activated by enzymes at target site
| Example; Heroin in the brain
58
Blood flow phases of drug delivery
First phase: Highly perfused organs receive most of the drug; equilibration is rapid
Second phase: More poorly perfused organs; equilibration is very slow
59
Role of capillary permeability of drug delivery
Endothelial junctions are loose so paracellular delivery (except in brain) - Driven by hydrostatic pressures
Lipids can transfer transceullularly
60
Role of plasma proteins in drug delivery
Drug binding to plasma proteins (low affinity, easily reversible)
Follows mass action
61
Specific proteins for acidic and basic drugs
Albumin - Acidic (Has positive charge sites)
| Alpha-1-Acid-Glycoprotein - Basic (Has negative charge sites)
62
Equation for drug binding
[DP] = [Total protein]*[Drug]/(Kd+[Drug])
| [DP] remains constant if drug is repeatedly delivered ([Drug] = constant)
63
Method of disease altering protein binding
Alters concentration of plasma binding proteins long term
64
Liver disease effect on protein binding
Reduced albumin and reduced binding
| Need to decrease the dose of drug
65
Immune activation effect on protein binding
Increase α-1-acid glycoprotein
| Need to increase drug dosage
66
Examples of tissue reservoirs for drugs
Fat - Lipophilic drugs for long periods
| Bone - Divalent cations (tetracycline) and heavy metals
67
Definition of redistribution
Mechanism of termination of action of a drug
| Redistribution from active site (tissue) to inactive site
68
Examples of redistribution
Highly lipid soluble drugs
Drugs acting on a highly perfused organ (brain or heart)
Drugs administered by IV or inhalation (general anesthetics)
69
Issues of drug distribution into CNS
Has to overcome tight capillary endothelial cell junctions (blood-brain barrier) and tight epithelial cell junctions (blood-CSF barrier)
70
Drugs able to enter the brain
Unionized, not protein, bound, and highly lipophilic
| Substrates for carriers (e.g. Levo-dopa)
71
Brain efflux mechanisms
P-glycoprotein (lipophilic drugs; inducible)
| Organic anion transporting polypeptide (OATP; negatively charged molecules)
72
Why does loperamide (an opioid) not have any CNS effects?
OATP
73
Factors for placental transfer of drug
Lipophilicity, unionized drug, protein binding for passive
Fetal plasma is more acidic than maternal; trapping of basic drugs
Carriers are present
74
Renal excretion processes
Glomerular filtration - Unbound drug enters the tubular lumen
Active tubular secretion (Proximal tubule)
Passive tubular reabsorption (proximal and distal tubules)
75
Methods of active tubular secretion
Moved into tubular lumen via pumps
P-glycoprotein; multi-drug resistance protein type 2 (MDRP-2, an ABC transporter)
Results in excretion rate that is greater than GFR
76
Clinical importance of passive tubular reabsorption
Treating overdoses or poisonings (altering pH of urine) to hasten excretion
77
Methods of biliary and fecal excretion
Canalicular membrane of hepatocytes ABC transporters to move drugs into bile
Carriers on enterocytes to move drugs from circulation into intestinal lumen
Role in enterohepatic recycling
78
Other Routes of Excretion
Sweat, saliva, tears, hair, skin (useful for drug detection)
Milk (Lipophilic drugs enter easily)
Slightly acidic compared to blood; trapping of weak bases
79
Definition of rate of absorption
Peak height/Time to peak = Cmax/tmax
80
Definition of lag time
Time to peak = tmax
81
Definition of extent of absorption
Area under concentration curve
82
Definition of therapeutic window
Amount of time where drug concentration is between minimum effective concentration and minimum toxic concentration
83
Definition of volume of distribution
Amount of volume in the body that contains the drug
84
Equation of volume of distribution (Vd)
Amount of drug in the body = Vd * [Drug]
| Vd = D/C0; D is the dosage
85
Definition of C0
Concentration of drug at time zero
| Determined by extrapolating the elimination phase
86
Definition of accumulation phase/elimination phase
Accumulation - Drug plasma curve pre-peak
| Elimination - Drug plasma curve post-peak (linear in log-range)
87
Assumption for determining Vd
Concentration of drug throughout body is the same as its concentration in plasma/serum (likely incorrect)
88
Notable Vd values
Small - Entirely in plasma (2.8 L/70kg person)
Total body volume - Moves like water (about 70 L)
Very large - Drug is being sequestered in non-plasma
89
How is Vd given in dosing tables?
Usually as a rate dependent on patient body weight (Liters/kg)
90
Drug dosage equation with bioavailability factored in
D = Vd * C0/F
91
What does bioavailability change in a drug response curve?
Cmax and area under curve are directly proportional to F
| Rate of accumulations and elimination are unfaffected
92
Definition of clearance of drug
CL = rate of elimination/concentration (Volume/time)
CLs are additive if multiple routes
CL_total = CL_renal + CL_liver
93
When is clearance constant?
If clearance processes are not saturated.
| Common at therapeutic concentraions
94
What order process are drugs cleared through?
First order-decay
| Log-linear
95
Slope of drug clearance in a log10 curve
-k_el/2.3
96
Half-life of drug
T1/2 = 0.69/k_el
Time needed to reduce the amount of drug by one half
Constant for a first order process
97
Definitions of IV phases
Alpha Phase - Distribution: From circulation to tissues instead of accumulation phase for oral
Beta Phase - Elimination: Same concepts as oral drug elimination phase
98
Zero-order kinetics
Saturated elimination processes (via Michaelis-Menten kinetics)
Clearance is not a constant
99
Effect on CL, k_el, T1/2 with increasing concentration in zero-order kinetics
CL decreases
k_el decreases
half-life increases
100
Drugs that show zero-order kinetics
Ethanol, aspirin, phenytoin
101
Therapeutic concern for zero-order kinetics
Drugs accumulate due to lack of elimination
102
Relationship between CL and T1/2
CL = k_el * Vd
T1/2 = 0.69/k_el
Therefore: T1/2 = 0.69 * Vd/CL
103
Effect of repeat dosing on first-order kinetics
Body reaches steady state where amount added and the amount eliminated are equal
104
Equation of steady state concentration of drug
F*Dose/dosing interval = CL * Css
| Rate in = Rate out
105
What is a desirable value for Css?
Somewhere in the therapeutic window
106
Definition of maintenance dose
Dose that keeps the Css
107
How long does it take for a maintenance dose to reach Css?
4-5 half-lives
108
How to reach Css more quickly?
Loading dose - Large dose which is used to reach Co
109
4 Important Equations
Henderson-Hasselbach
Loading dose
Half-life/clearance relationship
Maintenance dose
110
Effect of decreased renal function on drug response
Elimination rate and clearance decrease
Half-life increases
New higher steady state if same dosage maintained
111
Effect of decreased dose interval (assuming accompanied decrease in dosage)
Narrows concentration window while keeps the same Css (same concept for controlled release)
Useful if therapeutic window is narrow
