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Flashcards in ADME Deck (102):
1

The therapeutic window lies between what 2 values?

Minimum toxic concentration and minimum effective concentration

2

What is the difference between pharmacodynamics and pharmacokinetics?

pharmacodynamics describes the effect of a drug on a specific receptor in the body
pharmacokinetics describes the effect that the body has on a drug

3

What are the 4 features of drug dynamics that determine pharmacokinetics?

Absorption
Distribution
Metabolism
Excretion

4

Pharmacokinetics govern what 3 features of drug action?

Onset
Intensity
Duration

5

What are the methods clinicians use to effect a drug's concentration v. time profile?

Selecting different:
doses
frequencies of administration

6

What is the therapeutic index?

MTC/MEC

7

What types of drugs are allowed to pass through cellular membranes?

low molecular weight (100-200 Da)
Lipophilic
Non polar/Non ionized compounds

8

What are the two major process by which drugs cross biological membranes?

1) Passive diffusion** MAJOR
2) Carrier-Mediated Transport

9

What law governs rate of diffusion?

Fick's Law

10

What is Fick's Law?

Diffusion rate= -DAK(Cout-Cin)/deltaX

11

What does D stand for in Fick's law?

Diffusion coefficient

12

Diffusion coefficient is related to what feature of drugs?

INVERSELY related to size

13

What does K stand for in Fick's law?

Partition Coefficient

14

Partition coefficient is related to what feature of drugs?

TWO FEATURES:
Lipid solubility (oil:water)
Ionization (dictated by pH)

15

An ionized drug has higher or lower partition coefficient?

LOWER, diffusion rate is therefore slower

16

What does A stand for in Fick's law?

surface area (larger means more diffusion

17

True or false: thinner membranes promote higher rates of diffusion.

TRUE!

18

Name 2 types of carrier mediated transportation.

Facilitated Diffusion
Active Transport

19

True or false: carrier mediated transportation are saturable.

True!

20

What is the name of the major transporter of chemotherapeutic agents?

MDR1 (P-glycoprotein)

21

What assumption does the pH-partition theory make?

Drugs are absorbed only when they are non-ionized and therefore have a higher lipid solubility

22

What is the Henderson-Hasselbalch equation?

log(protonated form/unprotonated form)=pKa-pH

23

Acidic drugs accumulate on what side of a membrane?

the basic side (where they will dissociate into their unprotonated, ionized form)

24

Basic drugs accumulate on what side of a membrane?

the acidic side (because the protonated form is ionized)

25

Acidic drugs are absorbed best where?

in stomach

26

Basic drugs are absorbed best where?

in intestines

27

How do you promote excretion of an acidic dug?

alkalinize the urine (by giving bicarbonate so drug dissociates into its ionized form and cannot be absorbed back into the blood from the renal tubule)

28

What term describes the rate at which a drug leaves its side of administration and the extent to which that occurs?

absorption

29

What term describes the fractional extent to which a given dose of a drug reaches either its site of action or a biological compartment from which the drug has free access to its site of action?

bioavailability

30

What has a bioavailability of 1?

IV drugs

31

First pass metabolism has what affect on bioavailability?

severely limits it

32

What is the most common form of drug administration?

oral

33

List the enteral routes of administration.

oral, sublingual, rectal

34

What must occur before drugs taken via the enteral rate are absorbed?

dissolution

35

How can absorption be modified?

-Delayed/sustained release tablets
-Depot preparations
-Rapid release formulations
-Transdermal patches

36

Why is the small intestine a generally better place for drug absorption?

larger surface area (A)

37

What greatly increases drug absorption in the small intestine?

increasing gastric emptying

38

What factors SLOW gastric emptying?

-Eating large volumes or bulky food
-Fatty foods
-Lying on left side
-Drugs (narcotics, anticholinergics, analgesics)

39

List the 6 forms of parenteral routes of administration.

1) IV
2) Subcutaneous
3) IM
4) IA
5) Inhalation
6) topical

40

What is the maximum dose that can be given subcutaneously?

2 mL

41

What is the maximum does that can be given IM?

4-5 mL

42

Where is the best place to give an IM injection?

deltoid muscle

43

Name the 3 major factors that affect the rate of distribution of a drug?

1) Blood Perfusion Rate (CO and regional blood flow)
2) Tissue Volume
3) Capillary permeability

44

Which organs receive the highest total blood flow/highest perfusion rates?

brain
kidney
liver
muscles (heart)

45

Drugs larger than 25 kD are transported via what mechanism?

pinocytosis

46

Describe the permeability of renal capillaries.

Renal capillaries have increased permeability due to large spaces between endothelial cells. Good at filtering drugs.

47

Describe the permeability of brain capillaries.

tight junctions between cells make the brain capillaries relatively impermeable and restrict the transfer of molecules from blood to brain tissue

48

List the 2 major factors affecting the extent of distribution.

Intracellular binding
Plasma protein binding (most common)

49

Plasma protein binding causes drug to stay in what compartment?

central blood compartment

50

What plasma protein binds to acidic drugs?

Albumin

51

What plasma protein is in highest concentration?

albumin

52

What plasma protein binds to basic drugs?

Globulins

53

What factors influence the total fraction of drug bound at any given time?

-Drug concentration
-Drug's affinity for binding sites (esp. at low conc.)
-Number of binding sites (esp. at high conc.)

54

What can lead to drug reservoirs? What is the effect of having a reservoir of drug?

trapping of free, nonionized forms of a drug (ex. basic drugs trapped in stomach)
-This leads to a prolonged duration of response

55

Describe volume of distribution.

Vd indicates the apparent body volume that a given drug is located within and is generally indicative of the compartment to which it distributes

56

What is the equation for volume of distribution?

Vd= amount of drug administered/plasma drug concentration

57

What is the volume of extracellular fluid?

around 14 L

58

What is the volume of plasma?

~4 L

59

What is the volume to total body water?

~40 L

60

What does it mean if a drug has a Vd much higher than total body water?

it is concentrating in organs! (this lowers the plasma concentration and makes the Vd look HUGE

61

What two processes determine elimination of drug from the body?

metabolism and excretion

62

What term describes chemical modifications of xenobiotics by endogenous enzymes?

biotransformation

63

What term describes the chemical transformation of both endogenous and exogenous agents?

metabolism

64

True or False: inactivation of a drug converts it to a less lipid soluble, more polar form.

TRUE! this form favors drug excretion

65

Where do biotransformation reactions usually take place?

liver

66

Where do phase I reactions typically take place in the cell?

ER which fragments into mirosomes

67

Describe what a phase I reaction is.

Reaction that converts a parent drug to an inactive metabolite/or activates a prodrug by introducing or unmasking a functional group

68

Products of phase I reactions often have what characteristics?

highly reactive free radicals that are potentially toxic

69

Name 3 examples of phase I reactions.

1) oxidation (add oxygen, remove hydrogen)
2) reduction (add hydrogen, remove oxygen)
3) hydrolysis (add water and break-down molecule)

70

Where do phase II reactions typically take place in the cell?

cytosol

71

Describe what a phase II reaction is.

covalent addition of a functional group onto a parent compound or reactive product of phase I reaction

72

Products of phase II reactions often have what characteristics?

more water soluble and less lipid soluble (less drug is reabsorbed, inactive drug is readily excreted)

73

What is the major conjugation (phase II) reaction in the body?

glucuronidation

74

What catalyzes glucuronidation?

UGTs

75

List other phase II reactions.

Acetylation
Glycine addition
Sulfoxidation
Glutathione conjugation

76

Name an example of when a phase II reaction produces a product that is more reactive than the reactant.

morphine metabolite is a more potent analgesic than morphine

77

What is the major catalyst for phase I reactions?

CYP450 family

78

Where are CYP450 enzymes located?

smooth ER of numerous tissues (highest concentration in the liver)

79

What is the major CYP involved in metabolization of drugs absorbed from the GI tract?

CYP3A
(3A4 and 3A5 can metabolize around 50% of drugs)

80

What makes up the CYP450 enzyme complex?

CYP450 enzyme and CYP450 reductase

81

True or false: drugs bind to the reduced form of the CYP450 enzyme complex?

FALSE: they bind to the oxidized form of the complex and the complex gets reduced by CYP450 reductase

82

What returns CYP450 reductase to its original reduced form after molecular oxygen oxidizes the drug bound to the CYP450 complex?

NADPH

83

What is the term for the genetic basis for differences among the population in drug responses?

pharmacogenetics

84

What is the term for application of genomic information towards the discovery/development of novel specific drugs?

pharmacogenomics

85

What is a genetic polymorphism?

a variation in DNA sequence between individuals that can be propogated to the protein sequence

86

What type of phenotypic variation has two or three discrete distributions?

monogenic trait

87

What type of phenotypic variation hasone broad population distribution?

polygenic trait

88

What is the major organ for excretion of drugs?

KIDNEY

89

What is the glomerular filtration rate?

around 20% of blood which enters the glomeruli of the nephron is filtered. GFR is usually 110-130 mL/min

90

How to you measure GFR?

renal clearance of creatinine

91

What prevents drugs from being filtered at the glomerulus?

if they are bound to plasma proteins or RBCs

92

How much of filtrate is reabsorbed typically?

90%

93

Where does tubular secretion occur? By what method?

proximal tubule by active secretion

94

What is the transporter involved in tubular secretion?

MDR2 and energy supply work to secrete weak electrolytes (removes organic anions and cations--as well as most drugs from blood)

95

Where does tubular reabsorption occur? By what method?

distal tubules by passive diffusion

96

What types of things can be reabsorbed in the distal tubule?

nonionized forms of weak acids and bases

97

What is a major factor in what gets reabsorbed in the distal tubule?

pH of urine

98

What value quantifies the renal excretion of a drug?

renal clearance value

99

What does a renal clearance value of 120 mL/min tell you?

drug is neither secreted or reabsorbed

100

What does a renal clearance value of less than 120 mL/min tell you?

drug shows NET reabsorption

101

What does a renal clearance value of greater than 120 mL/min tell you?

drug must be having tubular secretion contributing to elimination process

102

What is enterohepatic cycling?

when conjugated byproducts of drugs metabolized by the liver are hydrolyzed into parent compound by normal flora in intestines and are reabsorbed to travel back to the liver via the portal circulation