Chapter 2: Pharmacokinetics

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1

What is pharmacokinetics?

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The processes of absorption, distribution, metabolism, and excretion, which dictate the passage of drugs through the body.

2

What is the cell membrane composed of?

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A bimolecular sheet of lipids (primarily phospholipids and cholesterol) with proteins interspersed.

3

What is the is the most common mechanism of passage of drugs across biological membranes?

passive diffusion

4

What is the defining characteristic of passive diffusion?

That the drug moves down its electrochemical gradient when crossing the membrane.

5

What is aqueous diffusion?

Simple diffusion of hydrophilic drugs between epithelial tight junctions or through aqueous pores.

6

What is lipid diffusion?

Simple diffusion of lipophilic drugs directly through the lipid barrier of the cell membrane.

7

What is the partition coefficient and how is it related to diffusion of drugs?

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The relative solubility of an agent in a fat solvent versus in water, which determines how readily a drug will pass through the lipid phase of the membrane.

8

What is hydrophobic bonding and how does it relate to diffusion of drugs?

The tendency for water-insoluble molecules to be drawn together, which is responsible for the tendency of lipid-soluble drugs to penetrate cell membranes.

9

What is governs the rate of movement of drugs consisting of charged molecules?

The partition coefficient of the neutral species versus the ionized species.

10

What is hydrogen bonding and how does it relate to drug solubility?

Bonds between water and organic residues containing oxygen, nitrogen, or sulfur, which provide some degree of aqueous solubility.

11

What is "lipid trapping"?

Drugs with very high partition coefficients may be so lipid-soluble that they have little tendency to diffuse out of the membrane once they have entered it.

12

What is the paracellular pathway?

An aqueous pathway formed by clefts between endothelial cells of capillaries, which permits aqueous simple diffusion of water-soluble drugs.

13

What enables hydrophilic molecules to cross plasma membranes more readily than would be predicted by simple diffusion?

facilitated diffusion

14

What are aquaporins?

Transmembrane pores that allow diffusion of water and sometimes other small molecoles.

15

What are ion channels?

Gated transmembrane channels, regulated by the electric potential across the membrane or specific ligands, which allow diffusion of ions.

16

What are carrier proteins?

Transmembrane proteins that selectively transport lipid-insoluble substances across the membrane.

17

What is active transport?

Carrier-mediated transfer of a drug against its electrochemical gradient, requiring expenditure of energy.

18

What are the two superfamilies of transporters of special significance to pharmacokinetics?

  1. ATP-binding cassette (ABC) transporters
  2. solute carrier (SLC) transporters
19

What are ABC transporters?

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Primary active transporters that hydrolyze ATP to provide the energy directly needed for molecular transport (e.g. P-glycoprotein, MRP transporters).

20

What are SLC transporters?

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Secondary active transporters which depend on the Na+ pump to produce an electrochemical gradient down which solutes can move (e.g. GLUT, OATs).

21

What are symporters?

Secondary active transporters that move coupled substances in the same direction as the linked ion.

22

What are antiporters?

Secondary active transporters that move the coupled substances in the opposite direction as the linked ion.

23

What is endocytosis?

The process by which a substance is engulfed and internalized by the cell.

24

What is phagocytosis?

A variant of endocytosis associated with the removal of particulate matter by macrophages.

25

What is the role of the protein clathrin in endocytosis?

It attaches to the internal surface of the plasma membrane and captures the ligand-bound receptors within coated pit, excluding other surface proteins.

26

What is the role of the protein dynaminin endocytosis?

It congregates around the collar of the invaginated coated bud that forms from the coated pit and initiates it separation from the membrane.

27

What is exocytosis?

The process by which vesicles fuse with the plasma membrane and discharge their contents outside the cell.

28

What is transcytosis?

A coupled form of endocytosis and exocytosis leading to the transfer of drug from one epithelial surface of a cell to another.

29

What is absorption?

The transfer of a drug from its site of administration into the bloodstream.

30

What are the three main advantages of oral drug administration?

  1. convenience
  2. economics
  3. safety
31

What are the three main disadvantages of oral drug administration?

  1. requires compliance
  2. delayed absorption
  3. metabolic inactivation
32

Where is absorption of acidic drugs (e.g. asprin) most favorable in the digestive tract?

Absorption of acidic drugs is favored in the stomach, where pH is low and they will be unionized.

33

What is "ion trapping"?

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Unequal distribution of drug molecules based on the pH gradient across a membrane (e.g. absorption of aspirin across the gastric membrane into the plasma)

34

Where is absorption of basic drugs (e.g. codiene) most favorable in the digestive tract?

Absorption of basic drugs is favored in the intestine, where pH is higher and they will be unionized

35

Why is ion trapping not as extensive for basic drugs as for acidic drugs?

Because the pH differential across the intestinal mucosa is small compared to that across the gastric mucosa.

36

Why does most absorption occur in the small intestine, even for acidic drugs whose absorption is favored in the stomach?

Due to the extensive surface area of the small intestine provided by folds, villi, and microvilli, even ionized drugs are effectively absorbed.

37

How does gastric emptying affect absorption?

Gastric emptying takes place over 40-minute periods with 1 hour quiescent periods between; a drug may be retained in the stomach for an hour or more.

38

How does fat intake affect absorption?

The presence of fat in chyme slows absorption by delaying gastric emptying, except for drugs that have a high lipid but low water solubility, in which case it promotes absorption.

39

When can the dissolution process of a drug be considered the rate limiting step?

Whenever a drug solution produces a systemic effect faster than a solid formulation of the same agent.

40

What is enteric coating?

A coating that is insoluble under the acidic conditions of the stomach, but break downs in the more alkaline environment of the small intestine.

41

How do sustained-release preparations work?

They use a drug-infused porous matrix, release a steady amount of drug for 12 to 24 hours as they dissolve in the gastrointestinal tract.

42

What are the two main causes of drug inactivation by the oral ingestion route?

  1. gastric acid
  2. enzymatic activity
43

What is first pass metabolism?

A reduction in drug concentration that reaches systemic circulation due to passage through the liver.

44

Why might sublingual drug administration be used?

Because gastric acid and intestinal and hepatic enzymes are bypassed, it can be more efficient overall for certain drugs than intestinal uptake.

45

When is rectal drug administration used?

When other enteral routes are precluded, as in an unconscious or nauseated patient.

46

What are aerosols?

Liquid or solid particles small enough to remain suspended in air for prolonged periods, which provide a route for inhaled drug administration.

47

What are the two main advantages of aerosols?

  1. rapid onset of effect
  2. minimize systemic exposure
48

When might drugs be given as a parenteral injection?

When oral ingestion is precluded, rapid onset is necessary, or blood concentrations greater than those obtainable with the enteral route are required.

49

When is intravenous (IV) route of injection used?

When immediate effects or exact blood concentrations are desired.

50

How long should most IV drugs should be administered over period of and why?

Over 1 minute; it approximates circulation time of blood through the body, thus avoiding high, transient concentrations and permitting discontinuance if any untoward effect is observed.

51

When is intramuscular (IM) route of injection used?

When drugs cannot be given orally because of slow or erratic absorption, high percentage of drug inactivation, or lack of patient cooperation.

52

Why might a practitioner give an IM injection in the shoulder rather that the gluteus maximus?

Muscles with high blood flows provide faster absorption rates than muscles with lesser flows.

53

When is subcutaneous (SQ) route of injection used?

For drugs that can be given in small volumes (≤2 mL) and are not locally damaging.

54

How does subcutaneous implantation of a drug work?

Compressed pellets of drugs, sometimes mixed with insoluble matrix material, are inserted to provide nearly constant drug release for weeks or months.

55

Why might a practitioner massage the site of an SQ injection after drug adminitration?

It stimulates blood flow, which increases absorption, and also helps spread the drug, providing an increased surface area for absorption.

56

When might an intraarterial injection be used?

When a localized effect on a particular organ or area of the body is desired (e.g. radiopaque dyes or antineoplastic agents).

57

When might an intrathecal injection be used?

When the direct access of drug to the central nervous system (CNS) is necessary (e.g. local anesthetics or antibiotics)

58

When might an intraperitoneal injection be used?

For the infusion of fluids, as a substitute for hemodialysis in the treatment of drug poisoning.

59

When might an intraosseous injection be used?

For injection of emergency drugs can be used when intravenous access cannot be obtained quickly.

60

How does keratinization affect absorption of topical drugs across the epithelium?

The stratum corneum is densely packed with keratin, creating a thick layer impervious to water and water-soluble drugs, and even some lipophilic agents.

61

What is a “transdermal therapeutic system”?

A patch consisting of an outer impermeable backing, a reservoir containing a drug suspension, a semipermeable membrane, and an inner adhesive seal; provides continuous systemic uptake of the drug.

62

What is iontophoresis?

Electric transport of charged drugs across surface tissues, which involves passing a direct electric current through the drug solution and patient.

63

What is distribution?

The movement of drugs throughout the body.

64

How does pKa affect a drugs tendency to enter cells?

Acids with a pKa less than 8.0 tend to remain outside the cell, whereas basic drugs with a pKa greater than 6.0 tend to accumulate within it.

65

How does the blood-brain barrier restrict distribution to the CNS?

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  1. capillaries of the brain do not have fenestrations and are characterized by tight junctions
  2. a cellular sheath composed of astrocytic processes surrounds the capillaries
  3. P-glycoproteins actively transport drugs out of the brain
  4. choroid plexus cells provide an avenue to pump drugs out of the cerebrospinal fluid
66

How is distribution restricted to the fetus?

Fetal blood vessels projecting into sinuses filled with maternal blood are covered by a single syncytium of cells called trophoblasts, which limits movement of drugs across the placenta.

67

What is the volume of distribution (Vd)?

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The hypothetical amount of water by which a particular dose would have to be diluted to produce a given plasma concentration.

68

What would be to the approximate Vd expected for drugs confined within the blood?

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3 L

69

What would be to the approximate Vd expected for drugs distributed in extracellular volume?

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12 L

70

What would be to the approximate Vd expected for drugs that can freely penetrate all membranes?

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41 L

71

Why does calculated Vd often differ from true Vd?

Dissimilarities arise when ions are distributed across electrically polarized membranes, weak electrolytes are present in fluids of different pH, or drugs are actively transported into or out of a water space.

72

What is albumin?

The predominant protein in plasma, which contains ionized functional groups and has the capacity to bind many different substances concurrently.

73

What is α1-acid glycoprotein?

A plasma protein that is major “acceptor” of basic, or cationic, agents.

74

How does the law of mass action apply to plasma protein binding binding and drug distribution?

Binding within the vascular compartment removes available free drug, reducing the concentration gradient across the capillary membrane, slowing egress from the plasma into the extravascular space.

75

How does plasma protein binding affect drug metabolism and excretion?

Glomerular filtration and passive hepatic uptake involve only free drug; significant binding may depress the metabolism and excretion of drugs.

76

How do individual differences in plasma protein binding affect drug dosage?

Individual differences affecting the concentration of free drug within the bloodstream may lead to insufficient therapy in one patient and overdosage in another.

77

Where else may drugs bind besides plasma proteins?

Drugs that bind with plasma proteins are also likely to bind to tissue protein constituents; this does not impede distribution, but it does slow elimination.

78

What is drug storing?

When the association between drugs and tissue elements is sometimes so stable that it is better to think of them as stored rather than transiently bound.

79

What is drug redistribution?

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Lipophilic drugs go through an initial transfer into vessel-rich organs (brain, heart, kidneys, liver, and lungs) followed by redistribution to less highly vascularized tissues (muscle, skin, and fat).

80

What are two reasons why redistribution of drugs into saliva is of pharmacological interest?

  1. drugs gaining access to the oral environment can affect microorganisms or tissue surfaces
  2. noninvasive salivary drug measurements are correlated with free plasma concentration
81

What is substantivity?

The ability of a drug to remain for an extended time, due to the preparation or ability to form a retentive reservoir, on hard or soft tissue (e.g. fluoride).

82

What are four routes by which drugs may enter oral fluids?

  1. passive diffusion across cells of salivary glands
  2. active transport into saliva
  3. passive diffusion across the oral epithelium
  4. bulk flow of fluid from the gingival crevice
83

What is drug detoxification?

A term used historically to refer to drug metabolism.

84

What are two typical fates of a drug undergoing metabolism?

  1. conversion into pharmacologically inactive compounds by metabolic attack
  2. conversion into lipid-insoluble compounds for renal or biliary excretion
85

What are phase I reactions?

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Non-synthetic reactions of drug metabolism, include the transformations of molecular structure through oxidation, reduction, and hydrolysis.

86

What are phase II reactions?

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Synthetic reactions of drug metabolism, consisting of conjugation of drugs or metabolites with functional groups provided by endogenous cofactors.

87

What is the major organ of drug metabolism?

liver

88

What is the role of smooth endoplasmic reticulum in drug metabolism?

It forms an extensive network of in hepatocytes that catalyzes the metabolism of endogenous chemicals.

89

What are microsomes?

A subcellular organelle consisting of fragmented reticular elements and membrane structures containing enzymes for drug metabolism.

90

What is the outcome of drug oxidation?

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Compounds that tend to be more polar, relatively more hydrophilic, and less likely to penetrate cells and bind to tissue elements.

91

What is cytochrome P450?

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A hemoprotein, CYP enzyme that binds to drugs during microsomal oxidation (designated P450 because of its absorption peak at 450 Å when combined in the reduced state with CO).

92

What makes the CYP family of enzymes unique?

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Their capacity to react with an wide array of chemicals.

93

What are FMOs?

A superfamily of enzymes, flavin monooxygenases, whose substrates contain nucleophilic atoms (e.g. nicotine and cimetidine)

94

What is the outcome of drug reduction?

When reduction occurs at one site, oxidation usually takes place elsewhere, and the final product is more polar despite the initial addition of hydrogen atoms.

95

What is the outcome of drug hydrolysis?

Production of two smaller entities, each with a polar end.

96

What is the phase II reaction catalyzed by microsomal enzymes?

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The combination of compounds with glucuronic acid (glucuronide conjugation).

97

What is is the fate of glucuronide conjugates?

They are excreted, often with the help of active secretion, into the bile or urine.

98

What differentiates microsomal and non-microsomal metabolism?

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Drugs must resemble natural substrates to be metabolized by most non-microsomal enzymes; the lack of specificity displayed in microsomal oxidation is not characteristic of non-microsomal oxidation.

99

What are three important non-hepatic sites of drug metabolism?

  1. intestines
  2. kidneys
  3. lungs
100

How do drug metabolism inhibitors or inducers work?

By inactivating or activating CYP enzymes.

101

What is the role of the phenobarbitol in enzyme induction?

In activated the constitutive androstane receptor, which then migrates into the nucleus to activate genes associated with hepatic protein synthesis and expression of CYP enzymes.

102

What is the role of the rifampinin on enzyme induction?

It is a broad-spectrum inducer that binds to the pregnane X receptor, initiating a response similar to that of phenobarbitol.

103

What is pharmacokinetic tolerance?

Induction of microsomal enzymes leading to a loss of pharmacologic responsiveness.

104

Why is it that enzyme induction does not always decrease drug toxicity?

Because of the potential danger posed by highly reactive intermediary substances produced during microsomal oxidation.

105

How does biotransformation capacity develop over the lifespan?

It is low in neonates due to lack of functional drug-metabolizing systems; children are often more adept at metabolizing drugs on a weight basis than young adults, but elderly individuals may often exhibit retarded rates of drug metabolism.

106

What is the major organ of drug excretion?

kidney

107

What three processes control urinary elimination of drugs?

  1. glomerular filtration
  2. tubular resorption
  3. active transpoprt
108

What is the glomerulus?

A tuft of capillaries in Bowman’s capsule of the kidney, uniquely modified for filtration.

109

What type of substances are most likely to undergo tubular resaborption?

Agents with a favorable partition coefficient will traverse the tubular epithelium and return to the bloodstream.

110

What determines tubular reabsorption of electrolytes?

pH; weak acids (e.g. aspirin) are reabsorbed under acidic conditions; weak bases (e.g. amphetamine and ephedrine) are reabsorbed under alkaline conditions.

111

What is the range of urinary pH?

4.5 to 8.0

112

How are anions secreted into urine?

They are taken up from interstitial fluid by OAT transporters and pumped into urine by NPT and ABC transporters.

113

How are cations secreted into urine?

They passively diffuse from the interstitial fluid into cells due to the electrochemical gradient, then are pumped into urine by P-glycoprotein, and SLC transporters.

114

What causes gout?

Excessive reuptake of uric acid by the kidneys, resulting in accumulation and crystallization.

115

What is clearance (CL)?

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The amount of drug removed from the body per unit of time

116

What is primarily responsible for fecal elimination of drugs?

biliary excretion

117

What is enterohepatic recycling and how does it affect the action of a drug?

Reabsorption of molecules excreted through the bile, which prolongs the duration of action of drugs.

118

What are three important routs of excretion besides urine and bile?

  1. breathing
  2. breast milk
  3. secretions
119

What are zero-order kinetic processes?

Processes that occur at a constant amount per unit of time (dC/dt = k0).

120

What are first-order kinetic processes?

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Processes that occur at a constant fractional rate per unit of time (dC/dt = k1Cp).

121

What is half-time (t½)?

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The time interval required for the plasma concentration to decrease by 50% of its original value.

122

How many half-times does it take for a drug to be nearly completely cleared (94%) assuming first-order kinetics?

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four

123

What are capacity-limited reactions?

Rates which display first-order kinetics at lower doses but zero order at higher doses (higher doses saturate the process).

124

What is the single-compartment model?

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A model that depicts the body as a single compartment whose size corresponds to the Vd and whose absorption and elimination are based on first-order kinetics.

125

What is the AUC?

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The area under the curve, which is used to compare the effect of different factors on the magnitude of drug effect.

126

How many half-times does it take to reach plateau (or steady-state) average plasma concentration assuming first order of elimination and no change in the dosing rate?

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four

127

How can the average steady-state concentration relative to the peak value obtainable after an initial dose can be calculated?

By multiplying the number of doses administered per elimination t½ by 1.44 (e.g. for a drug given 3 times per day with t½ of 2 days, the average steady-state concentration is 1.44 × 6 = 8.6 times the peak concentration of a single dose).

128

What is a loading dose?

A large, initial drug dose substituted for the normal amount to quickly produce a concentration approximating the steady state.

129

What is a maintenance dose?

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A drug dose that replaces the amount of drug lost due to elimination.

130

What is the two-compartment model?

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A model in which drugs are absorbed into and eliminated from a central compartment that is linked by distribution processes (having rate constants of kd and kr) to a second, peripheral compartment.

131

What is the value of the two-compartment model?

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It accounts for both the α phase, during which drug concentration decreases due to distribution out of the central compartment, and the β phase, during which metabolism and excretion predominate.

132

What context-sensitive t½?

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The time required for the plasma concentration of a drug to decrease by 50% when consideration is given to how long the drug has been infused.