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Phar455 > Principles of Drug Interaction (Jenson) > Flashcards

Principles of Drug Interaction (Jenson) Flashcards

1
Q

drug interaction

A

modification in the action of a drug due to the presence of another agent

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2
Q

object drug

A

drug affected by the interaction (aka victim drug)

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3
Q

precipitant drug

A

drug responsible for the interaction (aka index drug, interacting drug, perpetrator drug)

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4
Q

Some harms of drug interaction

A
  • higher drug levels–> toxicity or increased rish of AE

- failed therapy

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5
Q

some benefits of drug interaction

A
  • synergistic
  • overdose (antidotes to displace)
  • counteract adverse effects of another drug
  • increase another drug’s serum level in order to decrease dose needed (toxic or expensive drugs)
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6
Q

Human reasons for bypassing computer alert systems

A
  • alert fatigue
  • topical/opthamalic formulations
  • broad definition of drug class
  • no differentiation between drugs within drug class
  • no differentiation for dose related DIs
  • alerts for drugs that have been discontinued
  • alerts for food-drug interactions
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7
Q

technology reasons for bypassing computer alert systems

A
  • failure to detect serious interactions (drug not linked in system to that drug class, system not updated, lack of standardization)
  • doesn’t include all drugs patient is on (OTCs, etc)
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8
Q

3 Steps for prevention of ADR due to DIs

A

1) ID DIs (understand the mechanism)
2) assess risk of ADR (both drug and patient specific factors)
3) select appropriate management strategy (either avoid or treat interaction)

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9
Q

PK drug interactions

A

drug-drug interaction that alter plasma concentration of one or both drugs

  • usually measurable
  • may or may not have physiological effect
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10
Q

Absorption can be altered by PK changes in

A
  • drug metabolizing enzymes

- drug transporters

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11
Q

Distribution can be altered by PK changes in

A

-drug transporters

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12
Q

Metabolism can be altered by PK changes in

A

-drug metabolizing enzymes

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13
Q

Elimination can be altered by PK changes in

A

-drug transporters

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14
Q

Main route of clearance for 70% of currently used drugs

A

Cytochrome P450 family (CYPs)

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15
Q

Phase 1 metabolizing enzymes

A
  • CYP P450 (predominant family of drug metabolizing enzymes)

- MOA, alcohol dehydrogenase, esterases, amidases

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16
Q

Phase 2 metabolizing enzymes

A
  • UGTs (glucuronidation)

- N-Acetyl transferase, methytransferases, sulfotransferases, etc

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17
Q

Where CYP450 enzymes are found

A
  • predominantly in liver

- also intestines, kidney, lung, placenta (PIKL)

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18
Q

what CYP450 enzymes do

A

catalyze redox reactions

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19
Q

CYP450 that metabolize xenobiotics

A

CYP 1,2,3,4

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20
Q

CYP450 that metabolizes steroid hormones

A

CYP 3

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21
Q

CYP450 that metabolizes mostly fatty acids

A

CYP 4

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22
Q

CYP450 that metabolizes bile acids, cholesterol, eicosanoids, vitamin D

A

CYP 7,8,24,27,51

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23
Q

CYP450 that metabolizes biosynthesis of steroid hormones from cholesterol

A

CYP 11, 17, 19, 21

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24
Q

most abundant CYP450

A

3A4

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25
Q

Classes of CYP450 that are most active

A

1,2,3,4

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26
Q

most actie subfamilies of gluronidases (UGTs)

A

1A and 2

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27
Q

major site of glucuronidation

A

liver

-also throughout GI

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28
Q

metabolic drug interaction

A

the activity of metabolizing enzymes is modified by drugs and or other agents

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29
Q

substrate

A

substance metabolizd by enzyme

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30
Q

inhibitor

A

agent that decreases enzyme activity

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31
Q

effect of an inhibitor on substrate

A

stays longer in body, increases half life, increases serum level, possibly increased effect/SEs

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32
Q

effect of an inducer on a substrate

A

more enzyme activity means more drug is broken down, decreased level of substrate and potentially decreased effect

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33
Q

inducer

A

agent that increases enzyme activity

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34
Q

more likely to cause clinically significant DIs- phase one or two?

A

one

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35
Q

what to drug transporters influence

A
  • GI absorption
  • hepatic uptake (therefore rate at which drugs are metabolizied)
  • biliary excretion
  • renal excretion
  • entry into brain and other organs
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36
Q

ATP binding Casette (ABC) transorters

A
  • export (mostly)

- ABCBI, p-gp, MDR1

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37
Q

Solute linked carriers (SLC)

A
  • export and uptake
  • all uptake transporters are in this family
  • SL01B1 (organic anion transporting polypeptide OATP)
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38
Q

Where is p-glycoprotein found

A
  • enterocytes in intestinal wall (large quantities)
  • biliary canulae in liver
  • proximal tubules in kidney
  • BBB
  • testes/uterus/placenta
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39
Q

what is p-glycoprotein’s mechanism

A

-to protect body and organs from harmful substance by being an efflux transporter

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40
Q

efflux mechanism alliance that p glycoprotein has and why

A
  • with CYP3A4 in intestine and liver

- p-gp recycles drugs to prevent saturation of 3A4

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41
Q

SLC transporters are (in or efflux)

A

-mostly influx, can be efflux too

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42
Q

OATP1B1 is an _____ located ____ and does _____

A
  • SLC influx transporter
  • portal vein side of liver
  • facilitates hepatic uptake of substrates
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43
Q

OATP2B1 in an_____ located ______ and does ______

A
  • SLC influx transporter
  • widespread in the body, a lot in apical (lumen) dise of intestinal enterocytes
  • facilitates absorption of substrates
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44
Q

In transporter drug interaction, if p-gp is inhibited, what will happen to substrate?

A

-p-gp is efflux (usually decreases absorption), it will inhibit ejection into intestinal lumen, etc and cause increased concentration of substrate therefore in GI tract–> increased absorption of substrate and may increase F

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45
Q

in transporter drug interaction, if OATP is inhibited, what will happen to the substrate?

A

-OATP is influx (usually increased absorption), so in GI you will get decreased absorption

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46
Q

In transporter drug interaction, if p-gp is induced, what will happen to substrate?

A

increased efflux –> decreased absorption and may decrease F of substrate

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47
Q

in transporter drug interaction, if OATP is induced, what will happen to the substrate?

A

increased influx –> increased absorption

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48
Q

what is the rate limiting step for absorption of a solid dosage form drug?

A

dissolution

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49
Q

what state does a drug dissolve most readily

A

ionized

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50
Q

major site of drug absorption

A

small intestine

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51
Q

average transit time for absorption

A

3 hours

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52
Q

for chronically administered drugs, is extent or speed of absorption important? What might be an exception?

A
  • extent. Once a drug reaches steady state it won’t really matter how fast
  • rate may be a factor for slow dissolving drugs or drugs degraded to inactive products in GI fluids
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53
Q

for drugs used for acute affect (i.e prn dosing), is extent or rate important?

A

both (drug needs to act quickly)

-if the rate is slowed, drug effect may be delayed

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54
Q

metabolic reactions in intestinal wall that decrease F (contribute to first pass effect in orally administered drugs)

A

-CYP450 oxidation, MAO, glucuronidation, sulfation

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55
Q

first pass effect

A

loss of active drug in GI tract and “first pass” through the liver before the drug enters the systemic circulation (bioavailability is amount that manages to make it unchanged and avoid first pass effect)

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56
Q

what determines F of orally administered drugs

A

first pass effect

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57
Q

intestinal flora (their enzymes produced naturally) can affect these drugs

A

drugs that undergo enterohepatic circulation

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58
Q

3 types of drug binding interactions

A
  • chelation
  • resin binding
  • adsorption
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59
Q

chelation

A

drug with di and tri valent cations that form insoluble complexes

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60
Q

resin binding

A

strongly basic anion exchange resins designed to complex with bile acids in the GI tract and reduce absorption of fat BUT they are not very specific and will bind with many other things as well

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61
Q

what will happen with an acidic complex and resin binding (anion exchange complex)

A

-form an ion exchange complex (insoluble) that is excreted in the feces

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62
Q

adsorption

A

some agents with alrge SA can adsorb other drugs on to this area and decrease the F of an object drug

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63
Q

how to manage binding drug interactions (and when it may not be effective):

A
  • separate doses of object and precipitant drugs by 2-4 hours
  • not effective (maybe) for slowly absorbed drugs, drugs with significant enterohepatic circulation
  • in this case, stop one, substitute different drug, or monitor closely
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64
Q

drugs that cause hypomotility

A

anticholinergic drugs

-drugs with anticholinergic side effects

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65
Q

effects of hypomotility

A
  • decreased rate of absorption
  • variable effect on F
  • delayed stomach emptying
  • decreased peristalsis
  • prolonged intestinal transit time
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66
Q

drugs susceptible to DI with hypomotility

A
  • slow dissolving drugs, especially in formulations with dissolution problems, will have increased F and serum [] (due to longer transit time and will get increased absorption)
  • drugs where rapid action is desired (decreased rate of absorption, no change in F) (will take longer to reach absorption site)
  • drugs with potential to cause GI irritation (mucosal damage due to longer contact)
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67
Q

effects of hypermotility

A
  • variable effect on F

- increased rate of absorption

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68
Q

drugs that cause hypermotility

A

-DA antagonists (domperidone, metoclopramide)

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69
Q

how to manage motility DIs

A

-systemic effect so separating doses may not prevent the interaction, but if you wait until GI motility has dissipated before administering object drug

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70
Q

dissolution is ____ dependent

A

pH

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71
Q

acidic drugs dissolve more readily in _____ medium

A

basic (and vice versa)

72
Q

what happens to some drugs at low pH?

A

they are degraded to inactive products

73
Q

which drugs in particular require an acidic medium to dissolve

A

antifungals (itraconazole, ketaconazole)

74
Q

what kinds of drugs will decrease the dissolution rate of a basic drug?

A
  • drugs that make the solution more basic therefore the drug stays in its unionized form resulting in no or less dissolution (decreased F)
  • antacids
  • H2 antagonists
  • proton pump inhibitors
75
Q

an acidic drug (such as some sulfonylureas and NSAIDs) may have an increased dissolution rate with this

A
  • antacids (or other drugs that increase pH)

- cinical importance is debatable

76
Q

enteric coated products undergo this theoretical risk if they are acidic and combined with antacids (or any drug that increases pH)

A

-premature release of drug (if used to protect stomach, can get increased risk of irritation or ulceration)

77
Q

changes in intestinal flora can affect these kinds of drugs

A
  • those not completely absorbed in small intestine (ie not likely to affect drugs absorbed mainly in the small intestine)
  • those drugs that undergo enterohepatic recycling
78
Q

how to counsel a patient on antibiotics and their oral contraceptives

A

-risk of contraceptive failure, but precautions probably not required for a short course of them unless the antibacterials cause vomiting or diarrhea

79
Q

what happens when you inhibit enzymes in the gut wall?

A

can get increased F of the object drug

-especially CYP450 (3a for sure)

80
Q

what are some examples of 3A4 inhibitors?

A
  • cimetidine
  • erythromycin
  • ketaconazole
  • clarithromycin
81
Q

what does MAO do?

A

-in the gut wall, it protects the body against tyramine and similar pressor agents in foods

82
Q

what do MAO inhibitors and foods rich in tyramine do? (non selective)

A

-risk a rapid increase in BP or hypertensive crisis

83
Q

how do you manage MAO inhibition?

A

-avoid foods high in tyramine content during and for 2 weeks after MAOI therapy

84
Q

what foods are high in tyramine content?

A
  • cheese
  • processed foods
  • pickled/fermented things
85
Q

levodopa and protein rich food- what happens?

A

-compete for active transport mechanism and the protein decreases the bioavailability of levodopa

86
Q

if you orally administer a p-gp substrate, what will happen?

A

-a portion of the drug will be secreted back in to the gut (efflux mechanism) and it will decrease the F of the substrate

87
Q

examples of inhibitors of p-gp

A
  • erythromycin
  • cyclosporine
  • verapamil
88
Q

examples of inducers of p-gp

A
  • rifampin
  • ritonavir
  • st john’s wort
89
Q

inhibitors of OATPs

A

-apple juice, orange juice, grapefruit juice, cyclosporine

90
Q

what do OATPs do

A

transport anionic substances from the intestinal lumen across the gut wall to increase F

91
Q

how fast will inhibition of GI absorption interfere with drug?

A
  • serum concentration of drug will decrease within hours

- rate of decline depends on half life of object drug

92
Q

how fast will interference with enterohepatic recycling take effect? What will happen to its half life?

A
  • decrease in serum concentration will occur rapidly (faster than inhibiting absorption)
  • half life of drug will be shortened
93
Q

how fast will changes in intestinal flora affect the drug (both onset and offset)?

A
  • onset is radual

- offset may be a long process too because of time required for bacteria to recolonize in intestine

94
Q

what is the purpose of hepatic metabolism

A

to change lipid soluble compounds into more water soluble metabolites to facilitate excretion via urine and bile

95
Q

metabolism of drugs often results in what

A

decrease of loss of pharmacologic activity (therefore metabolism plays a major role in determining the time course of drug activity)

96
Q

intrinsic hepatic clearance (and 2 things it does not factor in)

A

innate ability of the liver to metabolize a specific drug

-doesn’t factor in protein binding of a drug of liver blood flow

97
Q

hepatic extraction ratio

A

the proportion of drug extracted from the blood flowing through the liver

98
Q

high extraction drugs are restrictively or non restrictively metabolized?

A

non restrictively

99
Q

how much drug is removed from the blood by the liver if it is a high extraction drug?

A

60-70% (both protein and non protein bound)

100
Q

what does hepatic clearance for high E drugs depend on

A

the rate at which the drug is presented to the liver (ie hepatic/liver blood flow)

101
Q

what happens to the extraction ratio of high E drugs if there are enzyme inhibitors or inducers present?

A

no significant effect (this is because they are much more attracted to metabolizing enzymes than protein binding)

102
Q

low extraction drugs are restrictively or non restrictively metabolized? How much of the drug is removed?

A

restrictively- 30%

103
Q

what kind of drug is available for metabolism with low E drugs

A

only unbound (because they have a higher affinity for binding proteins than metabolizing enzymes)

104
Q

what does hepatic clearance for low E drugs depend on

A

unbound fraction of the drug in the blood and intrinsic clearance (capacity of liver to metabolize it)

105
Q

what happens to the extraction ratio of low E drugs if there are enzyme inhibitors or inducers

A

potential for large serum concentration changes

106
Q

how much of the drug is removed with intermediate extraction drugs, and are they affected by inhibition/induction?

A

30-60%

-may be affected by inhibition/induction, but to a lesser degree than drugs with a low E ratio

107
Q

when metabolism is affected, which phase is more likely and why

A

-phase 1- phase ????????????

108
Q

what is KI

A

inhibitory potential- quantifies a drug’s affinity for an enzyme

109
Q

what does a low ki mean in terms of affinity

A

higher affinity- and it will displace a drug with higher ki

110
Q

what ki value deems a drug a potent inhibitor

A

less than 2uM

111
Q

reversible inhibition is also called

A

competitive inhibition

112
Q

what is reversible inhibition

A

inhibiting drug competes with object drug for binding sites on the metabolizing enzyme and reduces the ability of the liver to metabolize object drug

113
Q

how to reverse reversible inhibition

A

increase concentration of one drug to displace the other

114
Q

non competitive inhibition

A

inhibitor binds to a different site other than substrate but still prevents substrate from binding to enzyme

115
Q

irreversible (aka mechanism based) inhibition

A

metabolism of inhibitor converts drug to reactive metabolite that forms irreversible bond with enzyme and enzyme is permanently inactivated (must be replaced by newly synthesized enzyme)

116
Q

which is the most likely mechanism of inhibition to cause clinically significant effects?

A

irreversible

117
Q

first pass effect affects low or high e drugs?

A

high E

118
Q

through the oral route, what will happen to a low E drug’s internal clearance, concentration at steady state and half life if it is inhibited?

A

internal clearance will decrease, concentration at steady state and half life will increase

119
Q

through the oral route, what will happen to a high E drug’s internal clearance, concentration at steady state and half life if it is inhibited?

A

-no change in internal clearance or half life, decrease in first pass effect, increase in bioavailability (not binding as well to enzymes), and increased serum concentration

120
Q

through the IV route, what will happen to a high E drug’s internal clearance, concentration at steady state and half life if it is inhibited?

A

no first pass effect possible, so no clange in Clint, Css or t1/2

121
Q

through the IV route, what will happen to a low E drug’s internal clearance, concentration at steady state and half life if it is inhibited?

A

same as through oral: internal clearance will decrease, concentration at steady state and half life will increase

122
Q

through the IV or oral route, what will happen to an intermediate E drug’s internal clearance, concentration at steady state and half life if it is

A

less marked decrease in internal clearance as compared to low E drugs, small to moderate increase in concentration at steady state and half life

123
Q

examples of low e drugs

A

carbamazepine, phenytoin, theophylline, warfarin

124
Q

examples of intermediate e drugs

A

ASA, codeine, metoprolol, quinidine

125
Q

examples of high e drugs

A

diltiazem, labetolol, felodipine, propranolol

126
Q

what percentage of change in clearance is usually required to produce observable effects

A

15-20%

127
Q

3 potential clinical effects of interaction

A
  • increased pharmacological activity of object drug
  • increased activity of both interacting drugs (each can potentially inhibit the other)
  • no change or decreased activity of object drug
128
Q

why would there be no change or decreased activity of the object drug in an interaction?

A
  • both the parent and metabolite of a drug are active
  • pro-drug (metabolite is the active form of the drug)
  • decreased production of toxic or chemically reactive metabolite
129
Q

what kinds of drugs are more likely to be excreted renally

A

hydrophilic

130
Q

what characteristics of drugs are more likely to be affected by enzyme inhibition?

A
  • lipophilic (hydrophilic would be more renally eliminated)
  • active drug primarilly eliminated by heatic mechanisms
  • metabolism primarily by one specific enzyme (more than one enzyme would give it options)
131
Q

on and off set for competitive inhibition

A
  • onset: as soon as sufficient concentrations of inhibitor reach liver, usually maximal within 24 hrs
  • offset: begins within 24 hours of withdrawal of inhibitor usually (serum levels of object drug will decline at a rate dependent on its half life)
132
Q

time for object drug to reach a new steady state once competitively inhibited depends on

A
  • the new (inhibited) half life of the drug
  • the pre existing serum concentration on the object drug
  • whether or not it displays concentration dependent PKs
133
Q

on and off set for non competitive inhibition

A
  • onset: delayed, effect increases with multiple doses of inhibiting drug
  • offset- prolonged, dependent on time required for regeneration of the enzyme (independent of kinetics of the inhibiting drug) (can be a day or two)
134
Q

list management options for inhibition DI

A
  • avoid or withdraw the inhibitor
  • switch to an alternative non interacting drug in the same or related class
  • no intervention, just monitor
135
Q

characteristics of hepatic metabolism inducers

A
  • highly lipid soluble
  • all induce 3A4
  • none induce 2D6
  • may be inhibitors transiently, but inducers with long term use
  • all are substrate of CYP
136
Q

potency of induction increases with; (for inducers of hepatic metabolism)

A
  • the dose or frequency of administration (ie dose-dependent induction effect)
  • lipid solubility
137
Q

if a low E drug is affected by an inducer, what happens to intrinsic clearance, steady state concentration and half life?

A

intrinsic clearance increases

steady state conc and half life decrease

138
Q

for a high E drug affected by induction, what happens to intrinsic clearance, half life, FPE, bioavailability and steady state concentration?

A

no chance in intrinsic clearance or half life

increased FPE and decreased F and steady state conc

139
Q

induction always (increases/decreases) concentration of the object drug and usually leads to

A

decreases

decreased therapeutic effect

140
Q

exceptions to effects of inducers

A
  • pro drugs (it will increase the concentration if the metabolite is the active form)
  • drugs with toxic or chemically inert metabolites (see an increase with increased metabolism)
  • both parent and metabolite are active
141
Q

how long does it take for induction DIs? what are the factors?

A

long time- gradual, less predictable as the liver is being stimulated to produce more enzymes, not chanigng their activity
-half life of precipitant and object drugs, length of time for new enzyme synthesis, time required for excess enzyme to decay

142
Q

management options for induction DIs

A
  • avoid or withdraw inducer
  • substitue a non interacting agent
  • monitor
143
Q

acidic drugs bind primarily to

A

albumin (which can also bind basic and neutral drugs)

144
Q

basic drugs bind primarily to

A

alpha acid glycoprotein

145
Q

when would levels of albumin be reduced

A

renal failure, hepatic disease, elderly

146
Q

when would levels of alpha 1 glycoprotein be increased?

A

inflammatory diseases, trauma, MI

147
Q

what form of the drug is able to bind to the receptor and exert and effect

A

unbound

148
Q

fraction unbound (free fraction or Fu) is determined by

A

-affinity for serum protein binding site
-concentration of binding protein
-binding capacity of protein
-drug concentration
ie if either want to bind, and how much there is

149
Q

for low E drugs, hepatic clearance is directly proportional to (depends on)

A

unbound fraction

150
Q

for low E drugs, what kind of drug is metabolized

A

only unbound (because it has higher affinity for plasma protein than metabolizing enzymes)

151
Q

what do physiological buffering systems do to low E drugs when the object drug is displaced?

A

decreases the Cu
increase hepatic clearance (because Fu was increased)
* eventually, Cu will go back to pre interaction level even though Cb was decreased and total concentration decreases and the Fu increases
-but the initial increase in Cu is usually very transient and doesn’t produce clinical effects

152
Q

for high E drugs, when unbound drug is metabolized, the bound drug….

A

dissociates and is available for metabolism

153
Q

for high E drugs, what is hepatic clearance dependent on

A

blood flow to the liver

154
Q

when a high E drug is displaced hepatically, what happens to clearance?

A

it doesn’t increase (because not dependent on unbound fraction of drug)

155
Q

what may be increased upon displacement of a high E drug?

A

FPE

156
Q

is protein binding displacement significant

A

in very few cases

  • if drug action is quickly after administered,
  • when doing TDM b/c dosing is based on total concentration vs free or unbound- this can cause mistakes
157
Q

if drug levels are being monitored and displacement interaction is suspected, any changes in dosage should be based on

A

unbound drug level (NOT total concentration)

158
Q

what kind of molecules are preferentially absorbed by passive tubular reabsorption

A

non ionized

159
Q

in acidic urine, which drugs would tend to be reabsorbed?

A

acidic

160
Q

in alkaline urine, which drugs are absorbed by PTR?

A

basic

161
Q

if there is an increase in unbound drug, what happens to renal excretion?

A

increased (only unbound drug is filtered through kidneys)

162
Q

if there is a change in filtration pressure, what happens to drug excretion through kidneys?

A

reduced blood pressure leading to decreased filtration and excretion

163
Q

what kind of interactions would affect the active tubular secretion?

A

competition for the same transport system (anionic ie acidic or cationic ie basic) resulting in saturation of the system
-may result in decreased excretion of the drug with lower affinity

164
Q

acidic urine +basic drug =

A

increased excretion of basic drug

165
Q

basic urine + acidic drug =

A

increased excretion of acidic drug

166
Q

how common are clinically significant DIs due to renal mechanisms?

A

not very
-usually only if renal elimination is an important path for drug, there is a narrow TI or drug is dosed to relatively high plasma concentrations

167
Q

how fast are renal DIs? How long to get back to normal?

A

rapid onset, and only takes 2-3 half lives to get back to normal after

168
Q

pharmacodynamic drug interaction

A

drug-drug interaction that modulates a drug’s effect t its receptor site in the absence of a corresponding change in plasma concentrations

169
Q

direct pharmacodynamic DI

A

interaction occurs via competition for the same receptor site

170
Q

indirect pharmacodynamic DI

A

interference with physiological mechanisms of the object drug’s effect
-interacting drugs affect different receptor sites

171
Q

seratonin syndrome clinical manifestations

A
  • GI (cramps, bloating diarrhoea)
  • psychiatric- manic, racing thoughts, hurried speech
  • neurologic- tremulousness, myoclonus, dysarthria, incoordination
  • cardiovascular- tachycardia, HT
  • autonomic- fever, excessive perspiration
  • rarely coma and death
172
Q

what happens if QT interval becomes long

A

ventricular arrhythmias including possibly fatal torsades de pointes could develops

173
Q

symptoms of rhabdomylysis

A
  • muscle pain/weakness, darkened urine
  • elevated CK (creatine kinase)
  • kidney failure
174
Q

anticholinergic toxicity symptoms

A

-blurred vision, dry mouth, constipation, difficulty breathing, reduced sweating, tachycardia
DRY EVERYTHING OUT, INCREASE HR, CONFUSION
-confusion, disorientation,hallucinations, agitation, memory problems

175
Q

simple additive or antagonistic pharmacodynamic interactions occur

A

quite quickly usually

Phar455 (6 decks)

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