Drug Drug Interactions (Cut off for Exam 4) Flashcards
Drug-Drug Interactions
- 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
Nature Alterations
Effect that isn’t expected from either of the drugs alone.
Magnitude/Duration Alterations
Increased or decreased effect or duration of drug(s).
FDA Adverse Event
- 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
Adverse Event Frequencies
- Frequent: > 1/100
- Infrequent: < 1/100 but > 1/1000
- Rare: < 1/1000
Adverse Event Severities
- Mild - dry mouth
- Moderate/Severe - myocardial infarction
Serious Adverse Effects
-Death
-Disability
-Birth defect
-Cancer
-Overdose
Etc…
Cerivastatin
- Baycol
- Caused 31 deaths from rhabdomyolysis
Terfernadine
- Seldane
- Caused 250 deaths from Torsade des Pointes
- Interacted with Ketoconazoles/Itraconazole - overdose risk
- Interacted with Clarithromycin, Erythromycin, and Troleandomycin - significant hepatic dysfunction
Areas for DDIs
- Stomach/Intestine
- Liver - metabolism
- Absorption Intestine - OATPs, P-gp, and P-450s
- Blood - binding proteins
- Kidneys - secretion/elimination
GI DDIs
-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)
Tetracycline/Ciprofloxacin
- Absorption impaired by antacids with aluminum, calcium or magnesium
- Also preparations with iron, zinc, or sodium bicarbonate
Iron
-Forms insoluble complex with other drugs with bisphosphonates and quinolones (Cirpo)
OATPs
- 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)
Grapefruit/Orange/Apple Juice
- 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
Nadolol
- Avoid green tea and green tea supplements
- 12 oz of green tea twice a day decreased its absorption via OATPs by 85%
P-gp
- 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
Epithelial P-gp
- Small intestine
- Proximal tubules in kidney
- Limits drugs to blood (bioavailability)
Capillary P-gp
- Barrier function to protect brain (BBB)
- Provides similar function to fetus, placenta, testes, and uterus
Other Cells’ P-gp
- Surface of cancer cells and HIV-infected macrophages
- Contributes to multi-drug resistance in cancer/HIV
P450s
- 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
CYP2D6 Inhibitors
- 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
Fluoxetine
- 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
Paroxetine
- 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
Statin + Myopathy
- 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
Enzyme Inhibition + Potentiation
- 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**
Induction Reactions
- 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
Irreversible Inhibition
-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
Grapefruit Juice + CYP450s
- 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
Loperamide
- 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
DDI in Blood
- Acidic drugs - albumin
- Basic drugs - alpha-gp
- Equilibrium established of bound to free drugs
Competition for Binding Proteins
-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
Increased Amounts of Binding Proteins
- 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
DDI in Blood Meaning
- 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
DDI in Kidney
- 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
Organic Anion Transporter
- 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
Organic Cation Transporter
- Few DDIs
- Cimetidine + Triamterene - inhibits secretion of procainamide which can cause cardiac toxicity
Furosemide
- 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)
