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Flashcards in Pharmacokinetics Deck (111)
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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
Q

Absorption of orally administered drugs

A
Passive diffusion in GI tract
Unionized form (No not the auto workers)
26
Q

Characteristics of Stomach Absorption

A

Very acidic, thick mucous, small surface area

Limited absorption of even weak acids

27
Q

Characteristics of Upper Intestine Absorption

A

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
Q

Gastric emptying impact on drug absorption

A

Increased emptying increases the rate of absorption

29
Q

Effect of dissolution of a solid drug

A

Affect the rate of absorption

Coatings, particle sizes need to be considered

30
Q

How to achieve controlled release solid drug?

A

Hard-to-dissolve agents for slow uniform dissolution and absorption

31
Q

Advantages of controlled release solid drug

A

Slower absorption results in decreased frequency of dosing, more uniform concentration of drug in the blood

32
Q

Disadvantages of controlled release solid drug

A

Greater variability among patients (Grapefruit and dat Cytochrome P450 action)
Greater toxicity if incorrectly absorbed (Chewing the pill)

33
Q

Purpose of enteric coatings

A

Protect the drug from the stomach acid and stomach from drug (e.g. aspirin)
Better taste

34
Q

Sublingual delivery definition

A

Under the tongue (e.g. nitroglycerin for angina)

Rapid absorption

35
Q

Buccal delivery definition

A

Beneath gum and cheek

36
Q

Characteristics of sublingual/buccal delivery

A

Blood drains into the sup. vena cava
Avoids liver for first pass
Small surface area so drug is lipophilic

37
Q

Rectal administration advantages

A

Useful if patient cannot or won’t swallow (unconscious, vomiting, pediatric, etc.)
50% less first pass than orally administered agents

38
Q

Rectal administration disadvantages

A

Variable absorption, can be incomplete, irritating to rectal mucosa, uncomfortable

39
Q

Transdermal administration definition

A

Through the skin

40
Q

Characteristics of transdermal

A

Epidermis is impermeable to hydrophilic, but permeable to lipophilic
Best if hydrated
Examples are nicotine, estrogen/progesterone

41
Q

Definition of parenteral injection

A

Without the intestine

Include IV, subcut, and intramuscular

42
Q

Mechanism of subcutaneous and intramuscular delivery

A

Injection results in a depot of drug in dermis or muscle

Drug diffuses to nearby capillaries

43
Q

Rate of absorption of lipophilic drugs via injection

A

Depends on drug solubility in interstitial fluid

Area of capillary bed in vicinity

44
Q

Mechanism of absorption of large hydrophilic drugs via injection

A

Pass through large, aqueous channels in the capilaries

Example insulin

45
Q

Mechanism of absorption of proteins via injection

A

Enter via the lymphatic system

Example: Antigens in vaccination

46
Q

Where do the parenterally drugs distribute to first?

A

The Lungs

47
Q

Characteristics of lung during drug absorption

A

Metabolically active organ, large capillary bed
Filters particulates
Volatile agents can diffuse into the expired air (breathilizer test)
Lipophilic agents can accumulate; redistribute

48
Q

Characteristics of IV injection

A

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
Q

Advantages of IV injections

A

Control over dosage

Control over rate of administration (Bolus. slow infusion)

50
Q

Disadvantages

A

Route of no return, hard to remove once in circulation

Need close monitoring, experienced staff

51
Q

Subcutaneous control of absorption

A

Add vasoconstrictors to delay absorption

52
Q

Variability of intramuscular absorption

A

Blood flow based on muscle demand

53
Q

Airway administration purposes

A

Volatile agents; rapid access to the circulation

Treatment of the airway (targeted delivery in brachoconstriction)

54
Q

Topical targets for drugs

A

Mucous membranes

Eye

55
Q

Definition of drug eluting stents

A

Placing a scaffold into the artery (stent) with drugs bound onto the stent for controlled release
Example: Anticoagulants post balloon angioplasty

56
Q

Drug delivery targeting of cells via ________

A

Antibodies

Possible treatment for tumor cells

57
Q

Prodrug delivery

A

Inactive drugs that are activated by enzymes at target site

Example; Heroin in the brain

58
Q

Blood flow phases of drug delivery

A

First phase: Highly perfused organs receive most of the drug; equilibration is rapid
Second phase: More poorly perfused organs; equilibration is very slow

59
Q

Role of capillary permeability of drug delivery

A

Endothelial junctions are loose so paracellular delivery (except in brain) - Driven by hydrostatic pressures
Lipids can transfer transceullularly

60
Q

Role of plasma proteins in drug delivery

A

Drug binding to plasma proteins (low affinity, easily reversible)
Follows mass action

61
Q

Specific proteins for acidic and basic drugs

A

Albumin - Acidic (Has positive charge sites)

Alpha-1-Acid-Glycoprotein - Basic (Has negative charge sites)

62
Q

Equation for drug binding

A

[DP] = [Total protein]*[Drug]/(Kd+[Drug])

[DP] remains constant if drug is repeatedly delivered ([Drug] = constant)

63
Q

Method of disease altering protein binding

A

Alters concentration of plasma binding proteins long term

64
Q

Liver disease effect on protein binding

A

Reduced albumin and reduced binding

Need to decrease the dose of drug

65
Q

Immune activation effect on protein binding

A

Increase α-1-acid glycoprotein

Need to increase drug dosage

66
Q

Examples of tissue reservoirs for drugs

A

Fat - Lipophilic drugs for long periods

Bone - Divalent cations (tetracycline) and heavy metals

67
Q

Definition of redistribution

A

Mechanism of termination of action of a drug

Redistribution from active site (tissue) to inactive site

68
Q

Examples of redistribution

A

Highly lipid soluble drugs
Drugs acting on a highly perfused organ (brain or heart)
Drugs administered by IV or inhalation (general anesthetics)

69
Q

Issues of drug distribution into CNS

A

Has to overcome tight capillary endothelial cell junctions (blood-brain barrier) and tight epithelial cell junctions (blood-CSF barrier)

70
Q

Drugs able to enter the brain

A

Unionized, not protein, bound, and highly lipophilic

Substrates for carriers (e.g. Levo-dopa)

71
Q

Brain efflux mechanisms

A

P-glycoprotein (lipophilic drugs; inducible)

Organic anion transporting polypeptide (OATP; negatively charged molecules)

72
Q

Why does loperamide (an opioid) not have any CNS effects?

A

OATP

73
Q

Factors for placental transfer of drug

A

Lipophilicity, unionized drug, protein binding for passive
Fetal plasma is more acidic than maternal; trapping of basic drugs
Carriers are present

74
Q

Renal excretion processes

A

Glomerular filtration - Unbound drug enters the tubular lumen
Active tubular secretion (Proximal tubule)
Passive tubular reabsorption (proximal and distal tubules)

75
Q

Methods of active tubular secretion

A

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
Q

Clinical importance of passive tubular reabsorption

A

Treating overdoses or poisonings (altering pH of urine) to hasten excretion

77
Q

Methods of biliary and fecal excretion

A

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
Q

Other Routes of Excretion

A

Sweat, saliva, tears, hair, skin (useful for drug detection)
Milk (Lipophilic drugs enter easily)
Slightly acidic compared to blood; trapping of weak bases

79
Q

Definition of rate of absorption

A

Peak height/Time to peak = Cmax/tmax

80
Q

Definition of lag time

A

Time to peak = tmax

81
Q

Definition of extent of absorption

A

Area under concentration curve

82
Q

Definition of therapeutic window

A

Amount of time where drug concentration is between minimum effective concentration and minimum toxic concentration

83
Q

Definition of volume of distribution

A

Amount of volume in the body that contains the drug

84
Q

Equation of volume of distribution (Vd)

A

Amount of drug in the body = Vd * [Drug]

Vd = D/C0; D is the dosage

85
Q

Definition of C0

A

Concentration of drug at time zero

Determined by extrapolating the elimination phase

86
Q

Definition of accumulation phase/elimination phase

A

Accumulation - Drug plasma curve pre-peak

Elimination - Drug plasma curve post-peak (linear in log-range)

87
Q

Assumption for determining Vd

A

Concentration of drug throughout body is the same as its concentration in plasma/serum (likely incorrect)

88
Q

Notable Vd values

A

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
Q

How is Vd given in dosing tables?

A

Usually as a rate dependent on patient body weight (Liters/kg)

90
Q

Drug dosage equation with bioavailability factored in

A

D = Vd * C0/F

91
Q

What does bioavailability change in a drug response curve?

A

Cmax and area under curve are directly proportional to F

Rate of accumulations and elimination are unfaffected

92
Q

Definition of clearance of drug

A

CL = rate of elimination/concentration (Volume/time)
CLs are additive if multiple routes
CL_total = CL_renal + CL_liver

93
Q

When is clearance constant?

A

If clearance processes are not saturated.

Common at therapeutic concentraions

94
Q

What order process are drugs cleared through?

A

First order-decay

Log-linear

95
Q

Slope of drug clearance in a log10 curve

A

-k_el/2.3

96
Q

Half-life of drug

A

T1/2 = 0.69/k_el
Time needed to reduce the amount of drug by one half
Constant for a first order process

97
Q

Definitions of IV phases

A

Alpha Phase - Distribution: From circulation to tissues instead of accumulation phase for oral
Beta Phase - Elimination: Same concepts as oral drug elimination phase

98
Q

Zero-order kinetics

A

Saturated elimination processes (via Michaelis-Menten kinetics)
Clearance is not a constant

99
Q

Effect on CL, k_el, T1/2 with increasing concentration in zero-order kinetics

A

CL decreases
k_el decreases
half-life increases

100
Q

Drugs that show zero-order kinetics

A

Ethanol, aspirin, phenytoin

101
Q

Therapeutic concern for zero-order kinetics

A

Drugs accumulate due to lack of elimination

102
Q

Relationship between CL and T1/2

A

CL = k_el * Vd
T1/2 = 0.69/k_el
Therefore: T1/2 = 0.69 * Vd/CL

103
Q

Effect of repeat dosing on first-order kinetics

A

Body reaches steady state where amount added and the amount eliminated are equal

104
Q

Equation of steady state concentration of drug

A

F*Dose/dosing interval = CL * Css

Rate in = Rate out

105
Q

What is a desirable value for Css?

A

Somewhere in the therapeutic window

106
Q

Definition of maintenance dose

A

Dose that keeps the Css

107
Q

How long does it take for a maintenance dose to reach Css?

A

4-5 half-lives

108
Q

How to reach Css more quickly?

A

Loading dose - Large dose which is used to reach Co

109
Q

4 Important Equations

A

Henderson-Hasselbach
Loading dose
Half-life/clearance relationship
Maintenance dose

110
Q

Effect of decreased renal function on drug response

A

Elimination rate and clearance decrease
Half-life increases
New higher steady state if same dosage maintained

111
Q

Effect of decreased dose interval (assuming accompanied decrease in dosage)

A

Narrows concentration window while keeps the same Css (same concept for controlled release)
Useful if therapeutic window is narrow