Chapter 3- Drug Interactions Flashcards
Pharmacodynamics
The effect or change that the drug has on the body
Additive effect toxicity
Drugs that have similar end effects through different mechanisms/receptors can cause additive effects.
Risk with concurrent use of benzodiazepines and opioids
Due to the heightened fatality risk when opioids and benzodiazepines are taken together, the FDA placed a boxed warning to all drugs in both classes.
Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.
Aspirin + warfarin interaction
Warfarin causes anticoagulation through inhibition of vitamin K dependent clotting factors. Aspirin blocks the effects of platelets. They both cause increased bleeding and this effect is greater when taken together.
Antagonist
Blocks the agonist from binding to its receptor.
Naloxone as an antagonist
Naloxone is a mu-receptor antagonist; it saturates the mu receptors and blocks the opioid from binding. Naloxone is used to reverse respiratory depression, but will also reverse the analgesic effect.
Synergism
Present when two drugs taken in combination have a greater effect than obtained by simply adding the two individual drugs together.
Oxcodone + Acetaminophen synergy
The mechanisms of analgesia between oxycodone and acetaminophen are different and do not overlap. When taking the drugs together the effect is greater than the individual drugs
Pharmacokinetics
The effect the body has on the drug (ADME)
Chelation
Occurs when a drug binds to polyvalent cations (ex, Mg++, Ca++, Fe++) in another compound
Example of chelation
antacids or iron supplements
Chelation of quinolone antibiotics
Occurs when quinolones bind to calcium-containing drugs and dairy products. When taken together, the antibiotic will not dissolve, will not be absorbed, and the infection may not be adequately treated.
Examples of drugs with polyvalent cations or other binding properties
Antacids, multivitamins, sucralfate, bile acid resins, aluminum, calcium, iron, magnesium, zinc, phosphate binders
Polyvalent cations should be separated from what drugs?
Quinolones, tetracyclines, levothyroxine. oral bisphosphonates
The majority of PK drug reactions occur during
metabolism in the liver
Ritonavir and darunavir interaction
Ritonavir inhibits the metabolism of darunavir, which “boosts” darunavir levels and increases its efficacy in treating HIV.
Clarithromycin + warfarin interaction
Clarithromycin inhibits warfarin metabolism, increasing the INR and risk of bleeding.
Warfarin would need to be decreased.
Rifampin + warfarin interactions
Rifampin induces warfarin metabolism, decreasing the INR and increasing the risk for blood clots.
Warfarin would need to be increased.
Primary route of drug excretion
Renal
Probenacid + penicillin interaction
Probenacid blocks the renal excretion of penicillin. Giving probenacid with penicillin can be beneficial when high penicillin levels are needed to cross the BBB and provide effective treatment of neurosyphilis.
Sodium bicarbonate + aspirin interaction
Salicylate overdose results in toxicity.
IV sodium bicarb alkalinizes the urine, causing salicylate to become ionized. Ionized compounds are more hydrophilic and will stay in the urine, causing less to be reabsorbed in the renal tubules. Compounds that stay in the urine will be renally excreted.
What is the purpose of CYP450 enzymes?
catalyze Phase I reactions that either produce essential compounds or uncover or insert a polar group on a compound to facilitate renal excretion.
Prodrugs
Taken in an inactive form and are converted by CYP450 into the active form.
Why are prodrugs used?
To extend the dosing interval and to prevent drug abuse
Prodrug and active metabolite
Capecitabine
Fluorouracil
Prodrug and active metabolite
Clopidogrel
Active metabolite
Prodrug and active metabolite
Codeine
Morphine
Prodrug and active metabolite
Colistimethate
Colistin
Prodrug and active metabolite
Cortisone
Cortisol
Prodrug and active metabolite
Famciclovir
Penciclovir
Prodrug and active metabolite
Fosphenytoin
Phenytoin
Prodrug and active metabolite
Isavuconazonium sulfate
Isavuconazole
Prodrug and active metabolite
Levodopa
Dopamine
Prodrug and active metabolite
Lisdexamfetamine
Dextroamphetamine
Prodrug and active metabolite
Prednisone
Prednisolone
Prodrug and active metabolite
Primidone
Phenobarbital
Prodrug and active metabolite
Tramadol
Active metabolite
Prodrug and active metabolite
Valacyclovir
Acyclovir
Prodrug and active metabolite
Valganciclovir
Ganciclovir
Do not use codeine in
UMs of 2D6
Do not use clopidogrel with
PMs of CYP2C19 or CYP2C19 inhibitors
NATs are highly
Polymorphic
CYP enzyme inhibitors
Decrease enzyme function and the ability to metabolize compounds.
CYP enzyme substrates
Drugs that are substrates for the same CYP enzyme will have a decreased rate of drug metabolism and an increased serum drug level. In some cases, less drug will be lose to first pass metabolism.
Enzyme inhibition
Very fast. Effects are seen within a few days and will end quickly when the inhibitor is discontinued.
Common CYP inhibitors
G PACMAN
Grapefruit
Protease inhibitors (especially ritonavir)
Azole antifungals
Cyclosporine, cobicistat
Macrolides (Clarithromycin and erythromycin, NOT azithromycin)
Amiodarone and dronedarone
Non-DHP CCBs (diltiazem and verapamil)
CYP inhibition effect on substrates
Decreased metabolism
Increased serum levels and clinical effects
INhibitors=INcreased effects/levels/ADRs/toxicities
CYP inhibition effect on prodrugs
Decreased conversion to the active drug (decreased serum levels and clinical effects)
Possible actions for CYP inhibition of a substrate
Decrease dose of substrate (unless a prodrug), use alternate drug to avoid combination.
CYP enzyme inducers ________ the concentration of substrate drugs
Decrease
Drug enzyme inducers _________ enzyme production or activity
Increase
Common CYP inducers involved in drug interactions
PS PORCS
Phenytoin
Smoking
Phenobarbital
Oxcarbazepine
Rifampin, rifabutin, rifapentine
Carbamazepine (also an auto inducer)
St. Johns Wort
CYP inducers effect on substrates
Increased metabolism
Decreased serum levels and clinical effects
InDucers=Decreased effects/levels
CYP inducer effects on prodrugs
Increased conversion to the active drugs (increase serum levels and clinical effects)
CYP inducers solution
Increase the dose of the substrate (unless a prodrug), use alternative drug to avoid combination.
Timing for enzyme induction
Lag time. Induction most often requires additional enzyme production, which takes time. The full effect on drug levels may not be seen for up to 4 weeks. When the inducer is stopped in could take 2-4 weeks for the induction effects to disappear completely; the excess enzyme will degrade based on their half lives.
What do P-gp efflux pumps do?
Protect against foreign substances by moving them out of critical areas
Where do P-gp pumps transport drugs?
P-gp pumps in the cell membranes of the GI tract transport drugs and their metabolites out of the body by pumping then into the gut where they can be excreted in the stool.
When a drug blocks or inhibits P-gp, a drug that is a P-gp substrate will
have increased absorption (less drug is pumped into the gut) and the substrate drug level will increase
Common P-gp substrates
Anticoagulants- apixaban, edoxaban, dabigatran, rivaroxaban
Cardiovascular drugs- digoxin, diltiazem, carvedilol, ranolazine, verapamil
Immunosuppressants- cyclosporine, sirolimus, tacrolimus
HCV drugs- dasabuvir, ombitasvir, paritaprevir, sofosbuvir
Others- atazanavir, colchicine, dolutegravir, posaconazole, raltegravir, saxagliptin
Common P-gp inducers
Carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, St. Johns wort, tipranavir
Common P-gp inhibitors
Antiinfectives- clarithromycin, itraconazole, posaconazole
Cardiovascular drugs- amiodarone, carvedilol, conivaptan, diltiazem, dronedarone, quinidine, verapamil
HIV drugs- cobicistat, ritonavir
HCV drugs- ledipasvir, paritaprevir
Others- cyclosporine, flibanserin, ticagrelor
Enterohepatic recycling
After a drug has been metabolized in the liver, it can be transported through the bile back to the gut. From the gut, the drug can be reabsorbed (primarily in the small intestine), enter into the portal vein and travel back to the liver. The recycling of an already metabolized drug is called enterohepatic recycling, which increases the duration of action of many drugs, including some abx, NSAIDs, and ezetimibe.
Amiodarone + Warfarin drug interaction
Amiodarone inhibits multiple enzymes, including CYP2C9, which metabolizes the more potent warfarin isomer.
Decreased warfarin metabolism causes increased INR and bleeding risk.
Amiodarone + Warfarin drug interaction actions by pharmacists
If using amiodarone 1st and adding warfarin- start warfarin at a lower dose </= 5 mg
If using warfarin 1st and adding amiodarone- Decrease warfarin dose 30-50% depending on INR
If taking both- monitor INR and adjust as needed
When can amiodarone and warfarin be used together?
Can be used together for Afib.
Amiodarone for rhythm control and warfarin to reduce clot risk
Amiodarone + Digoxin drug interaction
Amiodarone inhibits P-gp; digoxin is a P-gp substrate.
Decreases digoxin excretion and increases ADRs/toxicity
Amiodarone and digoxin both decrease heart rate, increase risk of bradycardia, arrhythmia, fatality
Amiodarone + Digoxin actions by pharmacists
If using amiodarone 1st:
-Start oral digoxin at low dose, such as 0.125 mg daily
If using digoxin 1st:
-Decrease digoxin dose by 50%
Taking both:
-Monitor for signs of digoxin toxicity; nausea, vomiting, vision changes
-Monitor HR, check for other drugs that decrease HR
-If digoxin is being used for rate control, recommend beta blockers or non-DHP CCBs instead
Drugs that decrease HR
Digoxin, amiodarone, beta blockers, clonidine, diltiazem, verapamil, Precedex
When would amiodarone and digoxin be used together?
Can be given together for Afib treatment.
Amiodarone- rhythm control
Digoxin- rate control or for symptom management in heart failure
Digoxin + Loop diuretic interaction
Loop diuretics decrease K, Mg, Ca, and Na.
Low K, Mg, or Ca worsen arrhythmias.
Digoxin toxicity risk increases with decreased K and Mg levels and increased Ca levels.
Another caution- HF and renal impairment commonly occur together. Digoxin is cleared by P-gp and excreted by the kidneys. Renal impairment (exacerbated by loop diuretics) increases digoxin levels and toxicity risk.
Digoxin + loop diuretic pharmacists action
Monitor electrolytes and correct if abnormal.
Renal impairment: Decrease digoxin dose or frequency, or discontinue
When would digoxin and loop diuretics be used together?
For heart failure treatment
Digoxin is for symptom improvement and loop diuretics alleviate fluid overload.
Statins + Strong 3A4 inhibitor interaction
Increase levels of 3A4 substrates: lovastatin, simvastatin, and atorvastatin
Increased myopathy risk; if severe (with high CPK), can cause rhabdomyolysis with acute renal failure
Statins + Strong 3A4 inhibitor pharmacist action
Simvastatin and lovastatin are contraindicated with strong 3A4 inhibitors. Recommend a statin not metabolized by CYP450 enzymes.
Pitavastatin, pravastatin, rosuvastatin
Warfarin + CYP2C9 inhibitors and inducers
Increased levels of warfarin (increased INR and bleeding risk) with CYP2C9 inducers
Decreased levels of warfarin (decreased INR and increased clotting risk) with CYP2C9 inducers
CYP2C9 inhibitors
Azole antifungals, sulfamethoxazole/trimethoprim, amiodarone, metronidazole
CYP2C9 inducers
Rifampin, St.Johns wort
Warfarin + CYP2C9 inhibitors or inducer pharmacist action
Monitor INR
Some drugs (amiodarone) requires prophylactic warfarin dose adjustment before started
CYP3A4 substrates +CYP3A4 inhibitors DDI
Decreased 3A4 substrate (drug) metabolism will cause increased levels and toxicity.
Do not use a CYP3A4 inhibitor with an opioid metabolized by
CYP3A4
Do not take grapefruit with
CYP3A4 substrates
Including simvastatin, lovastatin, amiodarone, nifedipine, tacrolimus
Valproate + Lamotrigine DDI
Valproate is an inhibitor of Lamotrigine metabolism.
This increases lamotrigine levels and increases risk of serious skin infections SJS/TEN
Valproate + Lamotrigine DDI Pharmacist action
Initiate lamotrigine using the starter kit that begins with lower lamotrigine doses. Titrate carefully every 2 weeks and counsel on rash
Monoamine oxidase inhibitors
Isocarboxazid, phenelzine, tranylcypromine, rasagiline, selegiline, linezolid, methylene blue
Drugs that increase Epi/NE/DA
SNRIs, TCAs, bupropion, levodopa, stimulants, tyramine
Drugs that increase serotonin
Antidepressants, fentanyl, methadone, tramadol, buspirone, dextromethorphan (when abused), lithium, St. Johns wort
MAO inhibitors with drugs/food that increase Epi/NE/DA or 5-HT3
MAO enzyme metabolizes Epi, NE, DA, tyramine, and 5-HT.
Blocking MAO with an MAO inhibitor will increase Epi, NE, DA, and 5-HT
High EPI/NE/DA can cause hypertensive crisis
High 5-HT3 can cause serotonin syndrome
Do not use together. have a 2 week washout period
Tyramine rich foods
Aged cheeses, air-dried meats, sauerkraut, some wines/beers
Foods that have been aged, pickled, fermented, or smoked
CYP2D6 inhibitors
Amiodarone, fluoxetine, paroxetine, fluvoxamine
CYP2D6 substrates
Many, including codeine, meperidine, tramadol, tamoxifen
CYP2D substrates + inhibitors DDI
Decrease substrate metabolism increases ADR/toxicity
(or decreased clinical efficacy if prodrug)
Avoid using together if possible
CYP3A4, P-G inhibitors + calcineurin inhibitors or mTOR kinase inhibitors DDI
Decrease drug substrate metabolism, increases ADRs/toxicity’
Avoid
Antiepileptic drugs CYP inducers
Phenytoin, phenobarbital, primidone, carbamazepine, oxcarbazepine
Antiepileptic drugs CYP inducers + other drugs metabolized by CYP enzymes
Increases substrate metabolism and decreases drug levels and seizure control.
Monitor drug levels and consider increasing the dose. If substrate is lamotrigine, use starter kit
Rifampin + CYP and Pgp substrates
The concentration of the substrate drugs will greatly decrease.
Monitor
CYP2D6 UM + prodrugs that are 2D6 substrates (codeine, tramadol)
with 2D6 UMs, the prodrug will be converted more rapidly into its active drug, increasing active drug concentrations and causing toxicity
Are there any CYP2D6 inducers?
No
Do not use codeine or tramadol in
children <12 yo or <18 yo following tonsillectomy and/or adenoidectomy
Breastfeeding mothers unless it is known that she is not a 2D6 UM
CYP3A4, Pgp inducers + CNIs or mTOR kinase inhibitors
Increase drug metabolism results in decreased transplant drug level and increase risk of transplant rejection
Smoking (tobacco, marijuana) DDI
Smoking induces 1A2
When the inducer (cigarettes) is stopped, drug concentrations of CYP1A2 substrates will increase, causing toxicity.
In current smokers, 1A2 substrates will have decreased levels
Hyperkalemia symptoms
Weakness, heart palpitations, arrhythmias
Higher risk with renal impairment
What drugs have risk of hyperkalemia?
RAAS drugs- ACEi, ARBs, aliskiren, sacubitril/valsartan, spironolactone, eplerenone
Potassium sparing diuretics- amiloride, triamterene
Others- salt substitutes (KCl), calcineurin inhibitors (cyclosporine, tacrolimus), SMX/TMP, canagliflozin, drosperinone-containing oral contraceptives
Do not use sacubitril/valsartan with
ACEis or ARBs
Drugs with increase bleeding risk
Anticoagulants
Antiplatelets
NSAIDs
SNRIs/SSRIs
Natural products-
5Gs: Ginger, garlic, ginkgo biloba, ginseng, glucosamine
Vitamin E, willow bark, fish oils (high doses)
Drugs with risk of serotonergic toxicity
Antidepressants
MAOinhibitors
Opioids
Triptans
Natural products- St.Johns wort, L-tryptophan
Others- buspirone, lithium, dextromethorphan (in abuse)
Serotonin syndrome symptoms
Range from mild to severe and fatal
Autonomic dysfunction (diaphoresis, nausea, vomiting, hyperthermia)
Altered mental status (akathisia, anxiety, agitation, delirium)
Neuromuscular excitation: Hyperreflexia, tremor, rigidity, tonic-clonic seizure
Drugs that cause QTc prolongation
Antiarrhythmics, SSRIs, escitalopram, TCAs, trazodone, mirtazapine, venlafaxine, antimalarials, azole antifungals, lefamulin, macrolides, quinolones, 1st gen antipsychotics, 2nd gen antipsychotics, ondansetron, droperidol, metoclorpamide, promethazine, androgen deprivation therapy, methadone, tacrolimus
Do not exceed citalopram
40 mg QD or 20 mg QD in elderly (>60), liver disease, or with enzyme inhibitors
Do not use droperidol for
inpatient N/V
Which SSRI is safest for CVD?
Sertraline
Drugs with ototoxicity
Aminoglycosides- gentamicin, tobramycin, amikacin
Cisplatin
Loop diuretics (especially in rapid IV)
Salicylates
Vancomycin
Drugs with nephrotoxicity
Anti-infectives- aminoglycosides, amphotericin B, polymyxins, vancomycin
Cisplatin
Calcineurin inhibitors- tacrolimus, cyclosporine
Loop diuretics- furosemide, torsemide, bumetanide, ethacrynic acid
NSAIDs
Radiographic-contrast dye
What do you use with cisplatin to reduce nephrotoxicity?
Amifostine
