Drug Interactions

PHARMACODYNAMIC D-ITXN ENZYME SYSTEMS, DRUG METABOLISM AND D-ITXN CYP Enzyme INHIBITOR
- Pharmacodynamic Definition: Effect or change that a drug -CYTOCHROME P450 Enzymes: catalyze Phase I reactions that either produce essential compounds
(e.g., cholesterol and cortisol) or uncover or insert a POLAR (i.e., water-loving) group on a compound to
has on the body.
- Additive Effects: Agonists Binding to the SAME receptor.
facilitate renal excretion. CYP450 enzymes are primarily expressed in the liver.
G-PACMA
- (E.g., 2 opioids- morphine and oxycodone, taken together=
excessive sedation, respiratory depression, and death)
- Additive Effects: Agonists Binding to DIFFERENT Grapefruit
receptors. (Similar end effects through different Protease Inhibitors (PIs) Ritonavir, b
mechanisms/receptors can cause additive effects.) potent inhib
- (E.g., Risk with concurrent use of Benzodiazepines and Fluconazole
Opioids that may cause fatality risk are taken together) Azole antifungals
ketoconazo
- WARNINGS: Risks from concomitant use with opioids may voriconazol
result in sedation, respiratory depression, coma, and death. isavuconaz
- Non-CYP450 Enzymes: Phase II enzyme, N-acetyltransferase (NAT)
- Antagonists Block the Action of Agonists Cyclosporine/cobicistat
- Antagonist blocks the agonis from binding to its receptor. Macrolides Clarithromy
- Prodrugs- Inactive Drugs converted by CYP Enzymes to active drugs: Prodrugs are taken by the
erythromyc
- Agonist is unable to initiate a change. patient in an inactive form and are converted by CYP450 enzymes into the ACTIVE form.
- Amiodarone/Dronedarone
- Synergistic Effects Prodrugs are used by drug manufacturers to:
Diltiazem a
- Non- DHP CCBs
- Synergism is present when two drugs take together= Extend the dosing interval. An example of this is valacyclovir, which is metabolized to the
active drug acyclovir= higher bioavailability than acyclovir and is dosed less frequently.
greater effect.
- Prevent drug abuse. An example of this is lisdexamfetamine (Vyvanse)= formulated with an
PHARMACOKINETICS D-ITXN amino acid (lysine) attached to the amphetamine. This renders the amphetamine inactive, until
the lysine is detached by enzymatic cleavage, which prevents the crushing and snorting of the
- Pharmacokinetics Definition: the effect the body has on the drug.
drug as it goes through the absorption, distribution, Common Prodrugs and Example Safety Considerations
metabolism, and excretion (ADME) processes. Prodrug and Active Metabolite Example Safety Considerations Examples: CASE SCENARIO: TOXICITY W
- Absorption (typically occurring in the small intestine with Capecitabine ➔ Fluorouracil A 76-year-old male presents to the pharmacy w
Clopidogrel ➔ Active metabolite Clopidogrel (Plavix): includes betaxolol 1 drop OU BID, simvastatin 4
oral drugs)
Recognizing the Problem
- Reduced Absorption- Chelation occurs when a drug - Risk with CYP2C19 inhibitors, which can block Voriconazole is a strong CYP3A4 inhibitor and s
conversion to the active form. Voriconazole will increase the simvastatin level,
binds to polyvalent cations (e.g., Mg2+, Ca2+. Fe2+) in
another compound (e.g., antacids or iron supplements). - Do not use with CYP2C19 inhibitors, including Pharmacist Actions
The combination of voriconazole and simvastati
- E.g., Quinolone + Calcium Containing drugs and Dairy omeprazole and esomeprazole (can decrease
antiplatelet effects). Ensure that the drugs are not used concurrently
Products= INFXN may not be treated Recommend an alternative statin, such as rosuv
- Risk with PMs of CYP2C19 (low conversion to the
- E.g., Antacids, MV, Sucralfate, Bild acid resins, Al, Ca, active form, with reduced antiplatelet activity).
Iron, Mg, Zn, Phos should be separated from quinolones, CYP Enzyme INDUCERS D
Tetracyclines, Levothyroxine, and oral bisphosphonates.
- Use an alternative P2Y12 inhibitor in patients
identified as PMs of 2C19.
- Distribution (through the blood and dispersed throughout
PS PORCS
Codeine ➔ Morphine Codeine, by itself, and in combination products
the tissues) such as Tylenol #3:
- Metabolism (including enzymatic reactions) - Risk of toxicity with ultra-rapid metabolizers (UMs)
of CYP2D6 due to a more rapid conversion to
- Most metabolism occurs in the liver.
- Excretion [removal of the drug or end products
morphine. Phenytoin
- Do not use codeine in UMs of 2D6. Smoking
(metabolites) from the body]
 - Renal excretion is the primary route - Risk of poor analgesia with poor metabolizers
of drug excretion (PMs) of CYP2D6.
- PK drug interactions occur when one drug alters the - Use an alternative analgesic in patients identified
absorption, distribution, metabolism, or excretion of another as PMs of 2D6.
drug. PK drug interactions can be beneficial or harmful. Colistimethate ➔ Colistin
Cortisone ➔ Cortisol
Famciclovir ➔ Penciclovir
“Lag” Time for Enzyme Induction Fosphenytoin ➔ Phenytoin
lsavuconazonium sulfate ➔
- Induction most often requires additional enzyme lsavuconazole
production, which takes time. Levodopa ➔ Dopamine
Lisdexamfetamine ➔
- Full effect on drug levels may not be seen for up to Dextroamphetamine
four weeks. Prednisone ➔ Prednisolone
- When the inducer is stopped, it could take 2 - 4 weeks Primidone ➔ Phenobarbital
for the induction effects to disappear completely. Tramadol ➔ Active metabolite
Valacyclovir ➔ Acyclovir
- Excess enzymes will degrade based on their half-lives. Valganciclovir ➔ Ganciclovir

Phenobarbital
Oxcarbazepine
Rifampin/Rifabutin/Rifapentine
Carbamazepine
St. John’s Wort

Examples: CASE SCENARIO: SUBTHE

A 34-year-old female with a mechanical mitral v
Warfarin dose: 5 mg PO daily
INR range for the past 6 months: 2.6-3.1 (INR g
She was admitted for infective endocarditis and
Recognizing the Problem
Rifampin is an inducer of P-gp, CYP2C9, 3A4, 1
Warfarin is metabolized by CYP2C9 (major), 1A
Pharmacist Actions
Monitor INR more frequently; increase warfarin
 Drug Interactions
GUT Excretion by P-gp Common Substrates, Inducers, and CYP450 Enzymes: Common Substrates, Inducers, and
Drug Transporters Inhibitors Inhibitors
- P-Glycoprotein Substrates Inducers Inhibitors CYP Substrates Inducers Inhibitors
Anti-infectives Carbamazepi -Anti-
Efflux Pumps:
Anticoagulants Carbamazepine (clarithromycin, 3A4 - Analgesics (buprenorphine, ne, efavirenz, infectives
aka Permeability {apixaban, edoxaban, Dexamethasone itraconazole, diclofenac, fentanyl,
etravirine, (clarithromycin,
glycoprotein (P-gp) dabigatran, Phenobarbital posaconazole) hydrocodone, meloxicam,
oxcarbazepin erythromycin,
methadone, oxycodone,
Efflux pumps (or rivaroxaban) Phenytoin
tramadol)
e, azole
Rifampin phenobarbital, antifungals,
transporters).
Cardiovascular drugs St. John's wort Cardiovascular - Anticoagulants (apixaban, phenytoin, isoniazid}
- Protect against (digoxin, diltiazem, Tipranavir drugs (amiodarone, rivaroxaban, R-warfarin} primidone,
foreign carvedilol, ranolazine, carvedilol, - Cardiovascular drugs rifabutin, -
substances by verapamil) conivaptan, diltiazem, rifampin Cardiovascula
{amiodarone, amlodipine,
dronedarone, rifapentine, r drugs
moving them out lmmunosuppressants quinidine, verapamil)
bosentan, diltiazem,
smoking, St. (amiodarone,
(efflux) of critical eplerenone, ivabradine,
(cyclosporine, John's wort diltiazem,
nifedipine, quinidine,
areas. sirolimus, tacrolimus) HIV drugs
ranolazine, tolvaptan, dronedarone,
(cobicistat, ritonavir) quinidine -
- P-gp pumps in verapamil}
ranolazine,
the cell HCV drugs - lmmunosuppressants verapamil}
membranes of HCV drugs (ledipasvir, (cyclosporine, tacrolimus,
(dasabuvir, ombitasvir, paritaprevir) sirolimus)
the GI tract -Key HIV
paritaprevir,
transport drugs sofosbuvir) Others
- Statins (atorvastatin, lovastatin, drugs
simvastatin) (cobicistat,
and their (cyclosporine, efavirenz,
metabolites out Others flibanserin, ticagrelor) - Key HIV drugs (atazanavir, ritonavir and
of the body by (atazanavir, colchicine, efavirenz and other NNRTls, other protease
dolutegravir, ritonavir, tipranavir} inhibitors}
pumping them posaconazole,
into the gut,
- PDE-5 inhibitors (avanafil,
raltegravir, saxagliptin) -Others
sildenafil, tadalafil, vardenafil)
where they can {aprepitant,
be excreted in
- Others (alfuzosin, aprepitant, cimetidine,
aripiprazole, cyclosporine,
the stool. benzodiazepines, fluvoxamine,
- When a drug brexpiprazole, buspirone, grapefruit juice,
carbamazepine, citalopram,
blocks (or haloperidol,
clarithromycin, colchicine, nefazodone,
inhibits) P-gp, a dapsone, dutasteride, sertraline)
drug that is a P- erythromycin, escitalopram,
gp ethinyl estradiol, felbamate,
haloperidol, ketoconazole,
substrate=increa levonorgestrel, mirtazapine,
sed absorption modafinil, ondansetron,
(less drug is paritaprevir, progesterone,
pumped into the quetiapine, tamoxifen,
trazodone, venlafaxine,
gut) = substrate zolpidem}
drug level will
 increase.

Enterohepatic
Recycling

- After a drug has 1A2 Alosetron, aprepitant, clozapine, Carbamazepi Atazanavir,

cyclobenzaprine, duloxetine, ne, cimetidine,
been metabolized ethinyl estradiol, fluvoxamine, phenobarbital, ciprofloxacin,
in the liver  methadone, mirtazapine, phenytoin, fluvoxamine,
transported olanzapine, ondansetron, rimidone, zileuton
through the bile pimozide, propranolol, rifampin,
rasagiline, ropinirole, ritonavir,
back to the gut  theophylline, tizanidine, R- smoking, St.
From the gut, the warfarin, zolpidem John's wort
drug can be 2C8 Amiodarone, dasabuvir, Phenytoin, Amiodarone,
reabsorbed pioglitazone, repaglinide, rifampin atazanavir,
rosiglitazone clopidogrel,
(primarily in the gemfibrozil,
small intestine, ketoconazole,
where most drugs trimethoprim/
are absorbed)  sulfamethoxazo
le,
enter the portal ritonavir
vein  travel back Alosetron, carvedilol, celecoxib, Aprepitant, Amiodarone,
2C9
to the liver. diazepam, diclofenac, carbamazepin atazanavir,
fluvastatin, glyburide, glipizide, e, capecitabine,
- The recycling of an glimepiride, meloxicam, phenobarbital, cimetidine,
already- nateglinide, phenytoin, phenytoin, efavirenz,
metabolized drug ramelteon, S-warfarin, primidone, etravirine,
is called tamoxifen, zolpidem rifampin, gemfibrozil,
rifapentine, fluconazole,
enterohepatic ritonavir, fluvoxamine,
recycling, which smoking, fluorouracil,
increases the St. John's isoniazid,
duration of action wort ketoconazole,
metronidazole,
of many drugs, oritavancin,
including some tamoxifen,
antibiotics, some trimethoprim/
NSAIDs and the sulfamethoxazo
le,
cholesterol- valproic acid,
lowering drug voriconazole,
ezetimibe. zafirlukast
2C1 Clopidogrel, phenytoin, Carbamazepi Cimetidine,
thioridazine, voriconazole ne, esomeprazole,
9 phenobarbital, efavirenz,
phenytoin, etravirine,
rifampin fluoxetine,
 fluvoxamine,
isoniazid,
ketoconazole,
modafinil,
omeprazole,
topiramate,
voriconazole
2D6 - Analgesics (codeine, Amiodarone,
bupropion,
hydrocodone, meperidine,
cimetidine,
methadone, oxycodone,
cobicistat,
tramadol}
darifenacin,
Antipsychotics/Antidepress
dronedarone,
ants (aripiprazole,
duloxetine,
brexpiprazole, doxepin,
fluoxetine,
fluoxetine, haloperidol,
mirabegron,
mirtazapine, risperidone,
paroxetine,
thioridazine, trazodone,
propafenone,
tricyclic antidepressants,
quinidine,
venlafaxine}
ritonavir,
- Others (atomoxetine, carvedilol, sertraline
dextromethorphan, flecainide,
methamphetamine,
metoprolol, propafenone,
propranolol, tamoxifen}