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810 > Drug Drug Interactions (Cut off for Exam 4) > Flashcards

Drug Drug Interactions (Cut off for Exam 4) Flashcards

1
Q

Drug-Drug Interactions

A
  • Second drug alters the nature, magnitude, or duration of the first drug’s dose
  • Physicians may not be aware of them or Black Box Warnings
  • EX: Warning for Seldane before it was removed from the market for QT prolongation and Ventricular Arrhythmia
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2
Q

Nature Alterations

A

Effect that isn’t expected from either of the drugs alone.

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3
Q

Magnitude/Duration Alterations

A

Increased or decreased effect or duration of drug(s).

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4
Q

FDA Adverse Event

A
  • Any unfavorable/unintended sign/symptom/disease that is temporarily causes by a drug
  • Categorized by frequency, severity/seriousness
  • Examples: Black Box Warnings
  • Drugs are usually removed from the market if they cause death, even rarely
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5
Q

Adverse Event Frequencies

A
  • Frequent: > 1/100
  • Infrequent: < 1/100 but > 1/1000
  • Rare: < 1/1000
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6
Q

Adverse Event Severities

A
  • Mild - dry mouth

- Moderate/Severe - myocardial infarction

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7
Q

Serious Adverse Effects

A

-Death
-Disability
-Birth defect
-Cancer
-Overdose
Etc…

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8
Q

Cerivastatin

A
  • Baycol

- Caused 31 deaths from rhabdomyolysis

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9
Q

Terfernadine

A
  • Seldane
  • Caused 250 deaths from Torsade des Pointes
  • Interacted with Ketoconazoles/Itraconazole - overdose risk
  • Interacted with Clarithromycin, Erythromycin, and Troleandomycin - significant hepatic dysfunction
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10
Q

Areas for DDIs

A
  • Stomach/Intestine
  • Liver - metabolism
  • Absorption Intestine - OATPs, P-gp, and P-450s
  • Blood - binding proteins
  • Kidneys - secretion/elimination
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11
Q

GI DDIs

A

-Drugs that bind and decrease or prevent absorption
EX: Cholestyramine (bile acid binder), Ferrous sulfate, sucralfate (peptic ulcer disease), aluminum hydroxide antacids, calcium (antacids and milk)

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12
Q

Tetracycline/Ciprofloxacin

A
  • Absorption impaired by antacids with aluminum, calcium or magnesium
  • Also preparations with iron, zinc, or sodium bicarbonate
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13
Q

Iron

A

-Forms insoluble complex with other drugs with bisphosphonates and quinolones (Cirpo)

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14
Q

OATPs

A
  • Membrane transport proteins in intestines and hepatocytes that transport endogenous and exogenous compounds into cell
  • Work antagonistically to P-gp
  • Affected by grapefruit/apple/orange juice (inhibits absorption)
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15
Q

Grapefruit/Orange/Apple Juice

A
  • Affects absorption of drugs like Aliskiren (antihypertensive renin inhibtor), Beta blockers (atenolol), and fexofenadine (OTC, Allegra, Mucinex)
  • Need to separate these out by at least for hours
  • Main interaction effect is within 2 hours of drug administration
  • No evidence that eating these fruits effects absorption
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16
Q

Nadolol

A
  • Avoid green tea and green tea supplements

- 12 oz of green tea twice a day decreased its absorption via OATPs by 85%

17
Q

P-gp

A
  • LOTS of substrates
  • Actively transports drugs OUT of cell against concentration gradients
  • Uses ATP
  • Potential defense against poisons
  • Changes oral bioavailability, elimination, and CNS penetration
18
Q

Epithelial P-gp

A
  • Small intestine
  • Proximal tubules in kidney
  • Limits drugs to blood (bioavailability)
19
Q

Capillary P-gp

A
  • Barrier function to protect brain (BBB)

- Provides similar function to fetus, placenta, testes, and uterus

20
Q

Other Cells’ P-gp

A
  • Surface of cancer cells and HIV-infected macrophages

- Contributes to multi-drug resistance in cancer/HIV

21
Q

P450s

A
  • Abundant in liver and small intestine
  • CYP3A4 metabolizes 50% or more of drugs
  • MOST COMMON/IMPORTANT DDI IS THE INHIBITION OF P450S
  • These interactions increase the amount of drug in the plasma which increases drug response and its toxicity
  • Occur quickly (hours) and full effect is dependent on concentration and half life of the inhibiting drug
22
Q

CYP2D6 Inhibitors

A
  • Fluoxetine/Paroxetine
  • Same inhibitory effect, different durations
  • Inhibited for as long as drug is in the body (t1/2 is important)
  • Take care when adding a second antidepressant
23
Q

Fluoxetine

A
  • Prozac
  • CYP2D6 inhibitor
  • Inhibits rapidly, 16 days to full effect
  • Half life: 3.5 days, so reaction can last 1-1.5 months
  • Tapers themselves off
24
Q

Paroxetine

A
  • Paxil
  • CYP2D6 inhibitor
  • Full effect takes 4-5 days
  • Half life: <24 hours
  • Short acting interaction once administration has stopped
  • Taper off slowly to avoid withdrawal symptoms
25
Q

Statin + Myopathy

A
  • Increased myopathy risk when given with a CYP3A4 inhibitor
  • Atorvastatin, Lovastatin, and Simvastatin are 5x more lifely to cause myopathy when given with these inhibs.
  • Rosuvastatin and Pitavastatin (Livalo) aren’t extensively P450 metabolized so they are safer alternatives
  • Also increase myopathy risk when given with fibric acid derivatives (Fenofibrate, Gemfibrozil), additive effect since these inhibit glucoridation of statin in liver
  • More of a risk with gemfibrozil
26
Q

Enzyme Inhibition + Potentiation

A
  • Saquinavir - protease inhibitor
  • HIV proteases cleave polypeptides needed for viral production
  • Inhibit these proteases = non-infectious HIV virions
  • Rapidly metabolized by CYP3A4 in GI/Liver
  • Ritonavir - used at low doses (non-therapeutic) to increase serum levels and decrease dosing frequency of protease inhibitors by inhibiting their metabolism by CYP3A4 and p-gp transport
  • *Increase Cmax and tmax SIGNIFICANTLY**
27
Q

Induction Reactions

A
  • Rarely produce problems unless it causes therapeutic failures
  • Rifampin - induces CYP3A4 in GI/liver and induces p-gp in intestine (oral contraceptives can be blocked leading to pregnancy)
  • Rifampin + Cyclosporine: Decreases cyclosporine concentrations which can lead to possible organ graft rejections
28
Q

Irreversible Inhibition

A

-Permanent inactivation of CYP enzymes
EX: Erythromycin, ketoconazole, spironolactone, GRAPEFRUIT JUICE
-Dependent on half life of inhibitory drug
-Synthesis of new CYP enzyme takes ~3-4 days at least

29
Q

Grapefruit Juice + CYP450s

A
  • Felodipine - antihypertensive drug, calcium channel blocker
  • Oral dose is 70% metabolized by CYP3A4 in intestine and further metabolized by 50% in liver
  • Only 15% of oral dose enters systemic circulation
  • Grapefruit juice inhibits the CYP3A4 metabolism, increasing the total bioavailability of the drug 3x
  • Also increases statins, immunosuppressants, benzos, and other neuralgic/psychiatric drug availabilities
  • Takes 3-4 days to recover
30
Q

Loperamide

A
  • OTC, anti-diarrhea
  • Poor absorption
  • Given with quinidine they compete with p-gp in the brain
  • Loperamide then can cause respiratory depression by crossing the BBB and not being effectively expelled
  • Also a substrate for CYP3A4 so also can be affected by grapefruit juice and cimetidine
31
Q

DDI in Blood

A
  • Acidic drugs - albumin
  • Basic drugs - alpha-gp
  • Equilibrium established of bound to free drugs
32
Q

Competition for Binding Proteins

A

-If BOTH are high protein bound (90%)
EX: T4/T3 is protected from inactivation by being bound and has a half life of 6-7 days, but phenytoin and other drugs compete and displace it giving it a shorter duration

33
Q

Increased Amounts of Binding Proteins

A
  • Estrogen increases the amount of binding proteins in blood

- May need to adjust doses for highly protein bound drugs like thyroid and warfarin (98-99% bound) when this occurs

34
Q

DDI in Blood Meaning

A
  • Initial effect may increase the free fraction available for ADME
  • Equilibrium will be reestablished however
  • Most drugs have a high TI as well, so these interactions tend to not be clinically significant
35
Q

DDI in Kidney

A
  • Competitive inhibition - 2+ drugs for one transporter
  • Induce or inhibit transporter production/function
  • P-gp drives hydrophilic substances (like digoxin) into proximal tube for elimination
  • P-gp is inhibited by drugs like Clarithromycin, itraconazole, and ritonavir: decreases digoxin elimination and increases its toxicity
36
Q

Organic Anion Transporter

A
  • Probenecid blocks secretion of penicillins, cidofovir, and other medications
  • This prolongs their actions and increases their plasma levels (Penicillin + Probenecid)
  • Cidofovir has decreased nephrotoxicity when given with Probenecid
37
Q

Organic Cation Transporter

A
  • Few DDIs

- Cimetidine + Triamterene - inhibits secretion of procainamide which can cause cardiac toxicity

38
Q

Furosemide

A
  • Secreted in renal tubules for therapeutic effect
  • Decreases blood flow and decreases effect (vasoconstrictor effect, indirect)
  • Competes with uric acid, increases its concentration, leads to gout attacks (Drug:endogenous compound interaction)
  • NSAIDs and Probenecid - compete with Furosemide for secretion which decreases its effects (competitive inhibition, DDI)

810 (22 decks)

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