Drug Interactions

How do inhibitors affect drug levels?

If substrate:

• decreased metabolism

• increased serum levels and effects: INhibitors= Increased ADRs

If prodrug:

• decreased conversion to the active drug(↓ serum levels and clinical effects)

How do inducers affect drug levels

If substrate:

• increased metabolism

• decreased serum levels and effects: InDucers= Decreased effects

If prodrug:

• increased conversion to the active drug( increased serum levels and clinical effects)

How long does it take to see effect of inducer?

There is a lag period of effect

When d/c, the effect of inducer can take 2-4 weeks to disappear

What are CYP inhibitors?

G PACMAN

Grapefruit

Protease inhibitors

Azole antifungals

Cyclosporine, cobicistat

Macrolides

• not Azithromycin

Amiodarone(Droneadrone)

Non DHP CCBs

What are the CYP inducers?

PS PORCS

Phenytoin

Smoking

Phenobarbital

Oxcarbazepine

Rifampin(Rifabutin, Rifapentine)

Carbamazepine

St. Johns wort

P-GP substrates

• DOACs

• Cardiovascular Drugs: Digoxin, Diltazem, Verapamil

• Immunosuppressants: Cyclosporine, Tacrolimus, Sirolimus

• HIV / HCV Medications: Sofosbuvir

• Others: Colchicine

PG-P inducers

• carbamazepine

• Phenobarbital

• Phenytoin

• Rifampin

• St. Johns Wort

no smoking or oxcabazepine

PgP inhibitors

• Anti-infectives

• Amiodarone, Diltiazem, verapamil

• HCV/HIV: Ledipasvir, ritonavir, cobicistat

• Cyclopsporine

Patient on Amiodarone prior and Warfarin is being added

• Use lower dose of warfarin

• Monitor INR

Patient on Warfarin prior and Amiodarone is being added

decrease Warfarin dose by 30-50%

Monitor INR

Patient on Amiodarone prior and Digoxin is being added

• Start digoxin at low dose

• Monitor HR and check for other drugs that can lower HR(i.e B_B, clonidine, Non DHP CCBs)

Patient on Digoxin prior and Amiodarone is being added

• decrease Digoxin dose by 30-50%

• Monitor HR and check for other drugs that can lower HR(i.e B_B, clonidine, Non DHP CCBs)

Patient is on Digoxin and Loop diuretic

• monitor electrolytes

• if renal impairment: decrease Digoxin dose, frequency, or discontinue use

Patient is on Statin + Strong 3A4 inhibitor(G-PACMAN)

• levels of lovastatin(Altoprev), simvastatin(Zocor), and atorvastatin(Lipitor) increase

• simvastatin and lovastatin are CI with strong 3A4 inhibitors

Patient is on Warfarin + CYP2C9 inhibitors and inducers

Inducers: St. Johns wort, Rifampin

• Decreased INR (Lower INR) → Increased risk of clotting / thrombosis.

Inhibitors: Azoles, SMX/TMP, Amiodarone

• Increased INR (Higher INR) → Increased risk of bleeding.

Strong 3A4 inhibitors/inducers + 3A4 substrate

Inhibitors

• decreased substrate metabolism leads to increased drug levels/toxicity(i.e sedation)

• do not use opioids with 3A4= sedation

• Grapefruit: AVOID Amiodarone, Simvastain, Lovastatin, Nifedipine, and Tacrolimus

Inducers:

• opioids=analgesia effect decrease

Valproate and Lamotrigene

Initiate Lamotrigene starter kit that begins with lower dose

Anti-seizure medications and inducers

• carbamazepine is known to be an auto inducer

• if using lamotrigine with other ASM—> use higher dose

MAOI + Drugs/foods that increase NE, Epi, DA + Drugs that increase 5HT

• do not use together

• use 2 week washout period

  • fluoxetine requires 5 weeks due to long half life

CYP3A4, Pgp + CNIs(tacrolimus/Cyclosporine) or mTORI(sirolimus, everolimus)

• if inhibitors: avoid use due to increased toxicity concerns

• if inducers: avoid use due to increased risk of transplant rejection

Smoking status +1A2

• current smoker: decreases levels; needs higher doses to achieve effect

• former smoker: increase levels; needs lower doses to achieve effect

NRT does not induce 1A2

What drugs have additive serotonergic effect?

• Antidepressants

• MAOI(isocaboxazid, phenelzine, trancylporomine, Selegeline, rasagline)

• Opioids

• Triptans

• St. johns wort

• Others: Buspirone, Lithium, DXM

What drugs have increased bleeding risk?

• Anticoagulants

• Antiplatelets

• NSAIDs

• SSRI/SNRI

• 5Gs: ginger, garlic, ginseng, gingko, glucosamine

Drugs that cause Hyperkalemia

K+ BANKS DeaTH

• K – Potassium-sparing diuretics

• B – Bactrim and non-selective beta-blockers

• A – ACE inhibitors, ARBs, and ARNI

• N – NSAIDs

• K – Potassium supplements and salt substitutes

• S – SGLT2 inhibitors

• D – Drospirenone

• T – Tacrolimus and cyclosporine

• H – Heparin and LMWHs

Drugs that cause QT prolongation

ABCDE

• Antiarrythmitics

• AntiBiotics/ anti-infectives

• AntipsyChotics

• Depression meds

• AntiEmetics

How to minimize TdP:

• Limit QT prolongation unless amiodarone for arrhythmia in HF

• Do not exceed these doses:

  • Citalopram:

    • 40mg for everyone else

    • 20mg in elderly

  • Escitalopram

    • 20mg for everyone else

    • 10mg in elderly

• if need antidepressant: swap to Sertaline

• Do not use Droperidol for inpatient N/V

Meds that cause oto-toxicity

VALSC

• Vancomycin
• Aminoglycosides
• Loop diuretics
• Salicylates
• Cisplatin

Meds that cause nephrotoxicity

LANCr

• Loop Diuretics

• Anti-infectives

• NSAIDs

• Cisplatin, Cyclopsorine

• Radiographic dye

How to prevent nephrotoxicity

• if using cisplatin: use amifosetine

• maintain hydration

• monitor TDM

Drugs that are anticholinergic

• Antidepressants/Antipsychotics

• Antihistamines

• Muscle relaxants

• Antimuscaranics(for urinary incontience)

Drugs that can cause Hypotension/Orthostasis?

PDE5 inhibitors + 3A4 inhibitors(G-PACMAN)

PDE5 inhibitors + Nitrates

PDE5 inhibitors + Alpha 1 blockers( selective=tamsulosin or non selective= doxazosin)

if taking PDE5 and 3A4 inhibitor

start with half the usual dose of PDE5 inhibitor

PDE5+ nitrates

Absolute contraindication

PDE5 + Alpha 1 blocker

start with low dose when adding drug from either class

CYP3A4 substrates

• DOACs, R-warfarin
• Fentanyl, hydrocodone, methadone, oxycodone
• Amiodarone, amlodipine, dilt, verap
• CSA/TAC, sirolimus
• Statins (ASL)
• NNRTIs
• PDE-5 inhibitors
• Ethinyl estradiol

CYP3A4 inducers

PS PORCS

CYP3A4 inhibitors

GPACMAN

CYP1A2 substrates

• R warfarin
• Theophylline

CYP1A2 inhibitors

• Ciprofloxacin
• Fluvoxamine

Warfarin S vs R substrates

• R-warfarin: 1A2, 3A4
• S-warfarin: 2C9

2C19 inhibitors

• Esmopeprazole
• Omeprazole

2C19 substrate

Clopidogrel

2D6 substrates

Analgesics/opioids

Antipscyhotics/Antidepressants

Tamoxifen

2D6 inhibitors

Amiodarone

Bupropion

Antidepressants

2C9 substrate

S-Warfarin

2C9 inducer

PSPRS

phenytoin

smoking

rifampin, rifapentine

phenobarbital

Smoking, St. Johns wort

2C9 inhibitor

• Amiodarone

• Anti infectives