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phm 501: foundation > drug interactions > Flashcards

drug interactions Flashcards

1
Q

drug interactions

A
  • phenomena that occurs when the effects (pharmacodynamics) our pharmacokinetics of a drug are altered by prior administration or co-administration of a 2nd drug
  • a situation in which a substance (usually another drug) affects the activity of a drug when both are administered together
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2
Q

when do drug interactions occur?

A
  • pharmacologic or clinical response to the administration of a drug combination is different from the anticipated from the known effects of the 2 agents when given alone
  • effect of a drug is modified by the presence of another agent including: drugs-prescription, OTC; herbal, smoking, drinking, and foods
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3
Q

mechanistic drug interactions

A
  • pharmaceutical
  • pharmacokinetic
  • pharmacodynamic
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4
Q

pharmaceutical

A

prior to administration

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5
Q

pharmacokinetic

A

ADME (absorption, distribution, metabolism, excretion)

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6
Q

pharmcodynamic

A

response

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7
Q

drug interactions based on interacting subjects

A
  • drug
  • food
  • disease
  • herbal
  • laboratory result
  • endogenous substance
  • chemical
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8
Q

what are the components of drug interactions?

A

precipitant drug and object drug

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9
Q

precipitant drug

A
  • drug that causes the interaction
  • interacting drug
  • “doer”
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10
Q

object drug

A
  • drug whose activity is changed
  • index drug
  • “receiver”
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11
Q

summation

A

sum of A + B drugs

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12
Q

synergy

A

response of drugs A + B that is greater than the summation

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13
Q

antagonism

A

less than the response from each agent

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14
Q

idiosyncratic

A
  • cannot be explained

- random and unpredictable

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15
Q

object vs precipitant

A
  • one drug may be an object in one interaction but a precipitant in another
  • both drugs may affect each other
  • most interactions involve synergistic or antagonistic effects with no specific object or precipitant
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16
Q

drug or neurotransmitter reuptake

A

one drug induces a change in a patient’s response to a drug without altering the object drug’s pharmacokinetics

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17
Q

potentiation & antagonism

A
  • extension of underlying pharmacology/toxicology (physiologic effects)
  • ex. potentiation: benzodiazepines and muscle relaxants
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18
Q

examples of pharmacodynamic effects

A
  • CNS depression
  • additive anticholinergic effect
  • potentiation of neuromuscular blockade
  • additive cardiac depression
  • changes in various components of coagulation system
  • changes in blood sugar
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19
Q

warfarin & leafy green vegetables

A
  • leafy greens are rich in vitamin k which decreases its effect
  • maintain balanced diet, without abrupt changes in amount of leafy greens
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20
Q

isoniazid with foods containing tyramine

A
  • tyramine: blue cheese
  • provokes epinephrine/norepinephrine release
  • leads to hypertensive crisis
  • recommended to avoid tyramine containing foods in patients taking this agent
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21
Q

what are pharmaceutical interactions?

A
  • interactions that occur prior to systemic administration
  • ex. incompatibility between two drugs mixed in an IV fluid
  • these interactions can be physical (e.g. with a visible precipitate) or chemical with no visible sign of a problem
  • check chemical compatibility when pharmaceutical interactions are suspected
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22
Q

~80-90% of drug interactions are?

A

pharmacokinetic drug interactions

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23
Q

what are the assumptions that are the foundation of pharmacokinetic effects?

A
  • one drug alters the rate or extent of absorption, distribution, metabolism, or excretion (ADME) of the other drug
  • a change in blood concentrations of the other drug causes a change in the drug’s effect
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24
Q

absorption: acidity (pH)

A
  • increasing GI pH: decreases absorption of weak acids, increases absorption of weak bases
  • decreasing GI pH: increases absorption of weak acids, decreases absorption of weak bases
  • ex. 1: ketoconazole needs acidic conditions in gut, avoidance of H2As or PPIs
  • ex. 2: H2 antagonists (H2As) increase absorption of drugs that need alkaline environment
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25
Q

absorption: nonspecific binding

A
  • anionic binding resins (colestipol, cholestyramine)

- activated charcoal

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26
Q

absorption: chelation

A
  • metal ions in drugs form complex with other drugs, preventing absorption of both: Mg2+, Ca2+, Al3+
  • calcium and tetracycline complex decreases antibiotic effects
  • EDTA: chelating agent
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27
Q

how to prevent drug interactions due to absorption?

A

consider timing intervals to avoid interaction

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28
Q

absorption: GI motility and rate of absorption

A
  • drugs that affect GI motility affect rate of absorption not the amount of drug absorbed (clinical significance?)
  • metoclopramide and laxatives increase GI motility
  • anticholinergics and opiates decrease GI motility
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29
Q

absorption: changes in GI flora

A
  • bacteria in gut are responsible for some metabolism of drugs
  • ex. digoxin and erythromycin
  • erythromycin alters gut flora substantially, resulting in increased prothrombin time & digoxin concentrations to toxic levels
  • transporters such as P-gP might be involved
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30
Q

absorption: changes in blood flow

A
  • i.e., for non-oral routes
  • increasing blood flow increases drug absorption
  • decreasing blood flow decreases drug absorption
  • ex. epinephrine and local anesthetics decreases blood flow, decreasing absorption
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31
Q

food effects on absorption

A
  • can alter the extent of drug absorption, potentially altering bioavailability of drug (ex. milk and fluoroquinolones)
  • can serve as physical barrier, preventing absorption (access to the mucosa is reduced, delaying or decreasing drug absorption. reason for giving drug on empty stomach)
  • can increase absorption of drugs (high fat meals increasing absorption of lipophilic drugs, such as griseofulvin)
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32
Q

distribution: protein binding

A
  • unbound drug = active drug
  • displacement of a drug from its inactive binding site (such as albumin) may increase the serum concentrations of the free (and active)
  • unbound warfarin from albumin increases warfarin toxicity
  • free drug concentration must be monitored during warfarin therapy
33
Q

receptor binding

A
  • binding sites other than albumin: quinidine displaces digoxin from binding sites in skeletal muscle, increasing serum concentrations of digoxin
  • displacement of drugs from their receptor sites: beta blocker may displace beta agonist - increasing likelihood of asthmatic attack
34
Q

metabolism main sites

A
  • liver

- small intestine

35
Q

metabolism minor sites

A
  • kidney
  • lung
  • brain
36
Q

what happens in phase I metabolism in the liver?

A

-oxidation, reduction, hydrolysis

37
Q

what happens in phase II metabolism in the liver?

A

-glucuronidation, sulfation, acetylation, methylation

38
Q

what are the outcomes of liver metabolism?

A
  • addition of polar functional groups
  • makes drug more water soluble
  • phase I may be enough, but if not, conjugation in phase II leads to ionized, more water-soluble metabolites
39
Q

CYP isoenzymes

A
  • interact with molecular oxygen (O2) to form mono-oxygen (O)
  • mono-oxygen is inserted into drug molecules to form “oxidized” metabolites
  • different drugs are oxidized by different isozymes
40
Q

CYP450 Nomenclature

A
  • CYP: supergene family
  • 2: family
  • D: subfamily
  • 6: isozyme
41
Q

cytochrome p450 (CYP) enzymes

A
  • drugs that inhibit CYP isozymes decrease the metabolism and increase concentrations of drugs that are substrates for the isozymes
  • drugs that induce CYP isozymes increase the metabolism and decrease concentrations of drugs that are substrates for the isozymes
42
Q

Propafenone

A
  • inhibits CYP2D6

- decreases metabolism of metoprolol (metabolized by CYP2D6)

43
Q

carbamazepine

A
  • induces CYP2D6

- increases metabolism and decreases serum concentrations of phenytoin

44
Q

CYP inhibition

A
  • inhibition of drug metabolism occurs rapidly
  • competitive: two drugs metabolized by same isoenzyme, compete for same binding site
  • non-competitive: two drugs compete for same binding site on enzyme, but only one is metabolized by the enzyme
  • drug clearance of object drugs decrease
  • the t1/2 of object drugs increase
  • dose of object drug must be decreased
45
Q

considerations for inhibition: affinity

A

greater affinity of inhibiting drug for an enzyme, more it blocks binding of other drug molecules

46
Q

considerations for inhibition: half life (t1/2)

A
  • longer the half life of inhibiting drug, the longer the drug interaction lasts
  • ketoconazole: t1/2 8 hours
  • amiodarone: t1/2 53 days
47
Q

considerations of inhibition: concentration

A

threshold concentration reached or exceeded to inhibit an isoenzyme

  • cimetidine (more potent) vs fluconazole
  • cimetidine: more potent for CYP3A4 inhibition, so requires lower concentration to achieve inhibition
48
Q

other considerations for inhibition: pro-drugs or active metabolites

A
  • drug metabolized to an active form to exert effect
  • clopidogrel (omeprazole)
  • tamoxifen (paroxetine)
48
Q

other considerations for inhibition: pro-drugs or active metabolites

A
  • drug metabolized to an active form to exert effect
  • clopidogrel (omeprazole)
  • tamoxifen (paroxetine)
49
Q

other considerations for inhibition: inactive metabolites

A
  • drugs metabolized to an inactive form to decrease toxicity
  • terfenadine and astemizole (erythromycin)
50
Q

CYP induction

A
  • induction of drug metabolism is slow with two potential mechanisms: increase in hepatic blood flow & increase in formation of hepatic enzymes
  • drug clearance of object drugs increase
  • the t1/2 of object drugs decrease
  • dose of object drugs must be increased (maintain therapeutic effect)
51
Q

considerations for induction: half life of inducer drug

A
  • rifampin: t1/2 ~4 hours; induction within 24 hours

- phenobarbital: t1/2 ~53-140 hours, induction within 7 days

52
Q

considerations for induction: half life of induced isoenzyme

A
  • takes 1-6 days for CYP enzyme to be degraded or produced
  • decrease of warfarin concentrations due to rifampin use could be observed within 1-6 days during. More CYP isoforms will be produced due to induction
53
Q

other considerations of induction: auto-induction

A
  • auto-induction: ability of a drug to increase its own metabolism (decrease t1/2)
  • leads to increased dose requirement
  • ex. carbamazepine and nevirapine
54
Q

drug transport: p-glycoprotein

A
  • biologic protective mechanism against hydrophobic substances (drugs)
  • found in large and small intestine, kidney, liver, endothelial cells and at the BBB
  • drugs excreted back into the GI lumen
  • drugs excreted back into bile and urine
  • drugs excreted out of brain
55
Q

p-glycoprotein

A
  • serves as an efflux pump
  • inhibition of p-gp: more drug absorbed, increasing plasma concentration of object drug
  • induction of p-gp: less drug absorbed, decreasing plasma concentration of object drug
56
Q

food effects on metabolism: grapefruit juice

A
  • due to flavinoid naringin
  • inhibits CYP3A4, increasing serum concentration of drugs dependent on CYP3A4 for metabolism
  • inhibits intestinal CYP3A4, not hepatic: only oral medications are altered
  • ex. 1: verapamil is dependent on CYP3A4, and so cannot be metabolized after oral administration (blood levels on verapamil may increase & cause lower BP & undesirable change in HR)
  • ex. 2: dihydropyridine
  • not diltiazem
57
Q

food effects on metabolism: pyridoxine (vitamin B6)

A
  • levodopa crosses BBB, dopamine does not
  • much of ingested levodopa is lost to metabolism
  • 1% of administered amount enters brain to be converted to dopamine
  • pyridoxine enhances metabolism of levodopa
  • decreasing drug efficacy
  • avoid foods rich in pyridoxine
58
Q

food effects on metabolism: charcoal broiled meats

A

-induce activity of CYP1A2

59
Q

excretion

A
  • drugs removed from bloodstream by kidneys
  • filtration or urinary excretion
  • ionization state of drug molecules is important in excretory process
  • lipophilic membranes are less permeable to hydrophilic (ionized) molecules; ionized molecules “trapped” in urine and excreted
  • non-ionized drugs may be reabsorbed and recirculated, decreasing elimination = increasing t1/2
60
Q

what is the effect of pH on excretion?

A
  • pH effects on the passive transport of weak acids or weak bases
  • decrease urine pH (increase acidity): acidic drugs non-ionized in acidic urine, basic drugs are ionized in acidic urine
  • increase urine pH (decrease acidity): acidic drugs are ionized in alkaline urine, basic drugs non-ionized in alkaline urine
61
Q

excretion: active transport pathways

A
  • limited capacity, may be saturated

- two drugs eliminated by the same pathway = “traffic jam”: elimination of one or both drugs is inhibited

62
Q

excretion: probenecid and penicillin

A
  • compete for secretion via organic acid pathway

- probenecid blocks secretion of penicillin: increasing therapeutic concentration of penicillin (yay)

63
Q

excretion: digoxin and verapamil

A
  • increasing therapeutic concentration of digoxin (boo)

- increases side effects of digoxin due to its narrow therapeutic window

64
Q

excretion: reabsorption

A
  • bases: antihistamines and amphetamines increased by sodium bicarbonate and decreased in ammonium chloride
  • acids: aspirin and phenobarbital increased by ammonium chloride and decreased by sodium bicarbonate
65
Q

excretion: biliary tract

A
  • elimination into feces
  • interaction of drugs that undergo entero-hepatic recirculation: drugs excreted into GI tract through biliary ducts, drugs could be reabsorbed through intestinal wall into bloodstream
  • some drugs depend on recirculation to achieve therapeutic concentrations: oral contraceptives, warfarin
66
Q

food effects on excretion: orange, tomato, grapefruit juice

A
  • metabolized to an alkaline residue

- increases urinary pH

67
Q

food effects on excretion: amphetamine (a weak base)

A

-increasing urine pH increases non-ionized drug, and enhances reabsorption of drug systemically

68
Q

effect of drugs on nutrients

A
  • drugs may cause nutrition depletion; orlistat with fat soluble vitamins and beta carotene, use caution if using with warfarin
  • drug induced malabsorption if pre-existing nutritional deficits: isoniazid and pyridoxine (vitamin B6) -> neuropathy
  • metformin and cyanocobalamin (vitamin B12) -> anemia
  • drugs can change nutrient excretion: loop diuretics and potassium -> hypokalemia
69
Q

drug-disease interactions: exacerbate

A

co-existing diseases: beta blockers and asthma

70
Q

drug-disease interactions: absorption

A

-diabetic gastroparesis, pyloric ulcers, hypothyroidism; diarrhea and vomiting

71
Q

drug-disease interactions: distribution

A

-burns, bone fractures, acute infections, liver or renal disease; benign tumors, gynecologic disorders, surgery

72
Q

drug-disease interactions: metabolism

A

-CHF

73
Q

drug-disease interactions: excretion

A

-uncontrolled HTN, diabetes

74
Q

smoking

A
  • can induce CYP1A2

- increases liver’s metabolism of certain drugs, e.g., diazepam, chlorpromazine, amitriptyline, and atazanavir

75
Q

drinking: alcohol acute use

A
  • can inhibit drug metabolism
  • pharmacodynamic CNS depression
  • increases risk of hypoglycemia (sulfonylureas)
76
Q

alcohol chronic use

A
  • can induce drug metabolism

- increases conversion of APAP to hepatotoxic metabolites

77
Q

particularly susceptible patients

A
  • elderly patients or the very young
  • acute illness
  • unstable disease
  • drug treatment-dependent
  • concurrent hepatic or renal disease
  • multiple prescribing physicians
78
Q

particularly susceptible drugs: narrow therapeutic window

A

-lithium, phenytoin, digoxin, warfarin, cyclosporine, theophylline

phm 501: foundation (3 decks)

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