drug interactions

what is a drug interaction?

occurs when the pharmacological activity of one drug is altered by the concomitant use of another drug or by the presence of some other substance

what is the importance of interactions?

up to 3-7% of hospitalizations are due to drug interactions

what are factors that contribute to drug interactions?

• polypharmacy
• multiple prescribers
• multiple pharmacological effects of medications
• disease states
• advancing age
• narrow therapeutic index drugs (digoxin, warfarin, lithium, cyclosporine

what is pharmacist monitoring?

• during drug utilization review (DUR), you will need to assess the severity of the interactions (minor, moderate, and major/life-threatening)
• beware of patients with polypharmacy, many concomitant diseases, and advancing age

what is the object/victim drug?

drug that is affected by the interaction

what is the precipitant/perpetrator drug?

drug/chemical that causes the interaction

what are potential interaction outcomes?

• typically most interactions are quantitative leading to an increased/decreased effect
• rarely are the interactions qualitative leading to a rapid/slower effect
• there is a potential for a new/enhanced adverse effect
• the majority of drug interactions are undesirable

what are the exceptions of desired effects?

• ritonavir: inhibition of CYP3A4-mediated metabolism of protease inhibitors
• probenecid: prevent renal secretion of penicillin (WWII)

what are the mechanisms of interactions?

pharmaceutical ↔ pharmacokinetic ↔ pharmacodynamic

what is pharmaceutical incompatibility?

results from physicochemical interactions when drugs are co-administered:

• addition of multiple drugs in an IV solutions that cause chemical precipitation/inactivation of drugs
• potential to form toxic products, lead to particulate emboli from formation of crystallization, tissue irritation, and therapeutic failure
• not all incompatibilities are normal

what are absorption interactions?

lead to:

• faster/slower drug absorption

• more/less completed drug absorption

• examples are typically for orally administered drugs that are in immediate-release formulations

what happens with altered pH levels in absorption interactions?

• some medications require acidic environment for absorption
• increasing pH to neutral or alkaline will reduce absorption
• e.g. ciprofloxacin (victim drug: antibiotic) and antacid (perpetrator)

what happens with altered bacterial flora in absorption interactions?

• bacteria in the intestines metabolize some drugs
• antibiotics that eliminate flora can affect absorption
• e.g. digoxin (victim drug: treat congestive heart failure) and erythromycin (perpetrator: antibiotic)

what happens with damage to GI mucosa in absorption interactions?

• antineoplastic drugs will directly kill proliferating enterocytes needed for drug absorption
• e.g. cyclophosphamide, vincristine

what happens with the formation of insoluble complexes in absorption interactions?

• chelation/adsorption of drugs with other chemicals
• complexes are poorly soluble and drug becomes unabsorbable
• e.g. tetracyclin and quinolone antibiotics (victim drugs) and divalent and trivalent ions (perpetrators: Ca2+, Al3+, Mg2+, Fe3+, Zn2+, antacids, milk)
• e.g.,anionic drugs (victim drugs: warfarin) are bound to cationic resins (perpetrator: cholestyramine*)

what happens with altered GI motility in absorption interactions?

• based on the physicochemical properties of a drug (solubility and permeability), changes in GI motility can increase/decrease its absorption

• site of absorption (stomach vs intestine) is important

increase gastric emptying and GI motility:

• 'prokinetic' drugs

• perpetrator examples: metoclopramide, cisapride (Canada), domperidone (outside US)

decrease gastric emptying and GI motility:

• perpetrator examples: anticholinergic drugs such as diphenhydramine

what happens with competition for protein binding in distribution interactions?

• important for drugs with low Vd
• e.g. warfarin, phenytoin, salicylic acid, gentamicin, phenoarbital
• e.g. anticoagulant (victim: warfarin, 99% binding) and phenybutazone (perpetrator): increased clotting time, risk of hemorrhage
• e.g. diabetic drug (victim: tolbutamide, 96% binding) and sulfonamides (perpetrator): enhance hypoglycemia

what happens with enzyme induction in metabolism interactions?

enhance the amount of CYP enzymes expressed:

• increase victim drug metabolism
• onset of induction is typically slow (days to weeks) because new protein is being produced by the liver
• slow to resolve induction
• may need to increase dose of victim drug
• e.g. corticosteroids, oral contraceptives, warfarin, phenytoin (victim drugs) and phenoarbital, rifampin (perpetrator): decrease plasma levels and efficacy

what P450 inducers are there?

1A2:

• banzo(a)pyrene*: from tobacco smoke and charcoal

• omeprazole, phenoarbital, rifampin***, carbamazepine

2C19:

• phenoarbital, rifampin, phenytoin***, carbamazepine

2C9:

• phenoarbital, rifampin, phenytoin***, secobarbital

2E1:

• chronic ethanol*, isoniazid

3A4:

• phenoarbital, rifampin, phenytoin, St. John's Wort****

• carbamazepine, dexamethasone, efavirenz, pioglitazone, prednisone

what happens with enzyme inhibition in metabolism interactions?

competitive/noncompetitive blockade of activity and decrease drug metabolism:

• more common than enzyme induction

• usually observed in 2-3 days

• need to determine whether changes in metabolism are clinically relevant: does the interaction alter serum levels outside of the therapeutic range?

examples:

• tyramine-rich foods (victim drugs) and MAO inhibitor (perpetrator drugs): enhanced absorption of tyramine

• warfarin (victim drugs) and metronidazole (perpetrator drugs): increased anticoagulant activity

• alcohol (victim drugs) and disulfiram, metronidazole (perpetrator drugs): increased acetaldehyde levels (flushing reaction)

what are monoamine oxidase inhibitors (MAOIs)?

treat depression by preventing breakdown of neurotransmitters

what is hypertensive crisis precipitated by?

drugs and foods rich in tyramine (cheese, wine, preserved meats)

what are flushing reactions?

• occur when aldehyde dehydrogenase is inhibited (due to genetics or antagonists)

• symptoms: flushing, erythema, throbbing, breathing difficulty, vomiting, hypotension

medications can cause flushing with alcohol:

• disulfiram

• antibiotics: cephalosporins, isoniazid, metronidazole, nitrofurantoin

• diabetic drugs: glyburide and tolbutamide

what is disulfiram?

• inhibits aldehyde dehydrogenase, causing accumulation of acetaldehyde
• with alcohol, leads to flushing effect
• intended effect to discourage drinking

what is terfenadine?

• used to treat allergic rhinitis
• inactive prodrug (cardiotoxic) that is converted by CYP3A4 to active fexofenadine (not cardiotoxic)
• inhibition of CYP metabolism by erythromycin increased terfenadine levels, which led to QT prolongation, Torsades de Pointes, and ventricular tachycardia

what P450 inhibitors are there?

1A2:

• cimetidine, macrolides

2C19:

• cimetidine, ritonavir, antidepressants (SSRIs)

2C9:

• cimetidine, amiodarone, ritonavir

• azole antifungals, antidepressants (SSRIs)

2D6:

• cimetidine, amiodarone, antidepressants (SSRIs and others)

3A4:

• cimetidine, amiodarone, ritonavir

• azole antifungals, antidepressants (SSRIs), macrolides, grapefruit juice

what happens when taking cyclosporine and rofampin (TB drug)?

• induction of CYP3A4
• increased cyclosporine metabolism
• transplant rejection

what happens when taking cyclosporine and itraconazole (antifungal drug)?

• inhibition of CYP3A4
• decreased cyclosporine metabolism
• cyclosporine nephrotoxicity

what happens with changes in active tubular secretion in excretion interactions?

• some medications compete for excretion

• interact with the same transporter

• changes level of drug in blood circulation examples: metformin (victim drug, diabetes) and cimetidine (perpetrator, ulcer medication)

• inhibit renal secretion (OCT2 and MATE1)

• increase risk of lactic acidosis adverse effect

what happens with interference with enterohepatic recirculation in excretion interactions?

• some medications circulate between the liver and intestines
• bacterial flora in the intestines modify drugs that allow for reabsorption
• e.g. oral contraceptive (victim drug) and penicillin (perpetrator)
• outcome: risk of pregnancy

what are MDR1/P-glycoprotein interactions?

• prevent absorption of medication in intestines
• important in hepatic/renal absorption
• affect oral absorption

what are the substrates, inhibitors, and inducers of P-glycoprotein interactions?

• substrates: cyclosporine, digoxin, doxorubicin, paclitaxel
• inhibitors: amiloride, amiodarone, atorvastatin, verapamil
• inducers: paclitaxel, rifampin (PXR), St John's Wort (PXR)

what is the relationship between drug bioavailability and MDR1?

• normal MDR1: low bioavailability
• impaired MDR1: high bioavailability

what are synergistic interactions?

• pharmacodynamic
• desired outcome: sulfonamides and trimethoprim are antibacterial drugs that work better together
• adverse outcome: potassium-sparing drugs (e.g. ACE inhibitors, some diuretics: victim drug) and potassium supplements (perpetrator) lead to hyperkalemia

what are antagonistic interactions?

• pharmacodynamic

• occurs when 2 chemicals have opposing effects

• e.g. warfarin (victim drug) and vitamin K (perpetrator)

what is glycyrrhizin?

• found in black licorice
• hydrolyzed in the intestine to glycyrrhetinic acid, which inhibits 11β-hydroxysteroid dehydrogenase and increases cortisol in the kidneys, leading to fluid retention, hypokalemia, and hypertension
• e.g. antihypertensive drugs (victim drugs) and licorice (perpetrator)

what are the components of grapefruit juice?

furanocoumarins: bergamottin, naringin

what are the mechanisms of grapefruit juice interactions?

• metabolism: decrease CYP3A4/5 in intestines
• transporter: inhibit OATP1A2 (intestine) and OAGTP1B1, 1B3, and 2B1 (liver)

what are the drug interactions with grapefruit juice?

• calcium channel blockers (e.g. felodipine)
• psychiatric medications (e.g. sertraline)
• cholesterol inhibitors (e.g. statins)
• erectile dysfunction (e.g. sildenafil)

what are smoking interactions?

• smoking and charcoal-broiled meats containing polyaromatic hydrocarbons can induce CYP1A2 expression
• increase metabolism of theophylline, olanzapine, diaszepam, phenacetin

what are alcohol interactions?

pharmacokinetic:

• chronic alcohol consumption can increase the protein stability of CYP2E1 (not transcriptional mechanism)

• increase metabolism of CYP2E1 substrates

pharmacodynamic:

• ethanol can enhance CNS depressive effects of medications (due to additive effects) and reduce anesthetic effects (due to receptor down-regulation)