DDI, Inducers, Substrates

What are the different types of pharmacodynamic interactions between drugs?

• Additive effects

• synergistic

• antagonistic

Additive effects definition

The combined effect of two drugs is approximately equal to the sum of their individual effects.

• Can occur when:

  • Drugs act as agonists at the same receptor

    • Example: Morphine + oxycodone → increased opioid effects/adverse effects

  • Drugs act through different mechanisms or receptors but produce similar effects

    • Example: Benzodiazepines + opioids → profound sedation and respiratory depression

    • Example: Warfarin + aspirin → increased bleeding risk

Synergistic effects definition

The combined effect of two drugs is greater than the sum of their individual effects.

• Example: Oxycodone + acetaminophen → greater analgesia than either drug alone

Antagonistic effects definition

One drug reduces or blocks the effect of another drug.

• Example: Naloxone blocks opioid effects

What drugs are should be avoided with polyvalent ions?

• Quinolones

• Tetracyclines

• Levothyroxine

• oral bisphosphonates

What are CYP enzymes and Pgp pumps?

Cytochrome P450 (CYP) enzymes metabolize drugs and chemicals in the body, while

P-glycoprotein (P-gp) acts as a cellular pump that moves drugs across cell membranes and out of tissues. 

What are common CYP inhibitors?

G-PACMAN

Grapefruit

Protease inhibitors(i.e ritonavir)

Azole antifungals

Cyclosporine, cobicstat

Macrolides(except Azithromycin)

Non DHP CCBs

Effects of CYP inhibitors

What are Common CYP inducers

PS PORCS

Phenytoin

Smoking

Phenobarbital

Oxcarbazepine

Rifampin

Carbmazapine

St Johns Wort

effects of CYP inducers

T/F: Inducers have quick on and off times for their effects

Inducers have a lag time before you see effect; when you stop it it takes 2-4 weeks to see effect disappear completely

What are Common Pgp substrates

• Anticoagulants 

• Cardiovascular drugs(Digoxin, Non DHP CCBs)

• HCV drugs(Sofosbuvir)

• Immunospuressants(Cyclosporine, Tacrolimus)

• Colcichine 

What are Common Pgp inducers 

• Carbamazepine 

• Phenobarbital 

• Phenytoin 

• Rifampin 

• St. Johns wort 

What are common PgP inhibitors 

• Anti-infectives 

• Cardiovascular drugs(Amiadrone, Non DHP CCBs)

• HCV drugs(Ledipasvir)

• HIV drugs(Cobicstat, ritonavir)

• Cyclosporine

What is the risk of using Amiodarone + Warfarin and how can we address it?

Risk: Amiodarone inhibits 2C9 which metabolizes Warfarin slower(increased INR and bleeding risk)

Action:

• if adding on Warfarin: use low dose

• if adding on amiodarone: decrease Warfarin dose by 30-50%

• if taking both: monitor INR

What is the risk of using Amiodarone + Digoxin risk and how can we address it?

Risk: Amiodarone inhibits Pgp and Digoxin is a Pgp substrate(decreases excretion and increases ADRs) and both increase risk of bradycardia

Actions

• if adding on digoxin: use low dose

• if adding on amiodarone: decrease oral digoxin dose by 50%

• when taking both:

  • look for s/sx of digoxin toxicity

  • monitor HR and look out for BB, Clonidine, or Non DHP CCBs

What is the risk of using Loop Diuretics and Digoxin and how can address it?

Risk:

• Loop diuretics decrease K+ and Mg+ and Digoxin toxicity increases with low levels

• Loop diuretics can cause renal impairment and Digoxin can be less excreted

Action:

• check electrolytes

• if Renal impairment: decrease either dose of digoxin or frequency

What drugs when used together decrease HR and how can we address it?

Drugs: BB, Non DHP CCB, Clonidine, Amiodarone, and or Digoxin

Action: monitor HR

What is the risk of using Statins and Strong 3A4 inhibitors and how can we address it?

Risk:

• decreased metabolism of lovastatin, simvastatin, or atorvastatin levels; higher drug levels

Action:

• Avoid simvastatin and lovastatin if on concurrently; they are CI

What is the risk of using Warfarin with either 2C9 inducers and inhibitors risk and how can we address it?

Risk:

• inhibitors: increase levels of warfarin(higher INR and higher bleeding risk)

• inducers: decrease levels of warfarin(lower INR and higher clotting risk)

Action: Monitor INR

What is the risk of using 3A4 inhibitors +3A4 substrates that are opioids(i.e fentanyl, oxycodone) and how can we address it?

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

Action: do not use 3A4 inhibitor with opioid

Which medications are known for the counseling point of avoiding grapefruit juice when taking them?

• amiodarone

• simvastin

• lovastatin

• nifedipine

• tacrolimus

What is the risk of using Valproate and Lamotrigene and how can we address it?

risk: Valporate decreases Lamotrigene metabolism and increases levels of lamotrigine= increased risk of SJS/TENS

Action: use starter kit of lamotrigine that uses lower dose

What is the risk of concurrently using MAOI+ Drugs/Foods that increase NE/epi/dopamine+ Drugs that increase 5HT and how can we address it?

risk:

• blocking MAOI will increase epinephrine, norepinephrine, dopamine, and dopamine

• HTN crisis

• high 5HT can cause serotonin syndrome

Actions:

• do not use together

• use 2 week washout period for everything except fluoxetine(Need to wait 5 weeks)

• avoid aged cheeses, air-dried meats, and sauerkraut

What is the risk of using CYP2 D6 inhibtors+ 2D6 substrates risk and how can we address it?

Risk: decreased substrate metabolism, and increased ADR metabolism

Action: avoid using together if possible

What is the risk of using 3A4 inhibitors or PgP inhibitors with CNIs or mTOR kinase inhibitors(everolimus or sirolimus) interaction and how can we address it?

risk: decreased substrate metabolism

Action: avoid using together

What is the risk of using ASM CYP inducers + other drugs metabolized by CYP enzymes and how can we address it?

risk:

• increased substrate metabolism will cause drug levels to decrease

• decreased drug effects with ASMs lead to loss of seizure control

Action:

• monitor drug levels

• if substrate is lamotrigine, use the starter kit that begins with higher lamotrigine doses

What is the risk of using rifampin + CYP and Pgp substrates risk

risk: increased substrate metabolism will cause drug levels to decrease

What is the risk of CYP3A4 inducers + opioids that are 3A4 substrates

Risk: increased metabolism results in decreased opioid concentration; analgesia will decrease

What is the risk of using CYP3A4 or Pgp Inducers with CNIs or MTOR inhibitors?

Risk: Increased drug metabolism of CNIs or MTORs leads to lower levels in body= increased risk of transplant rejection

How does smoking affect Antipsychotics, Antidepressants, Anxiolytics, or Theophylline

smoking induces 1A2

risk:

• current smoker: 1A2 substrates will have low levels

• smokers who quit: when inducer is stopped, drug concentrations will increase toxicity

Note: NRT products do not induce CYP

What meds carry serotonergic toxicity?

Medications:

• Antidepressants

• MAOI

• Opioids

• triptans

• St. Johns wort

• Buspirone, Lithium, DXM

What do we do for meds that have additive risk of serotnergic toxicity?

• avoid serotonergic agents together

• need washout period

What meds carry bleeding when added together and actions

Meds:

• Anticoagulants

• Antiplatets

• NSAIDs

• SSRIs/SNRIs

• Natural Products

What do we do for meds that have additive bleeding risk?

Actions: avoid generally unless if:

• NSAID PRN with SSRI/SNRI

• ASA and NSAID PRN

• dual antiplatet therapy

• bridging overlap

What meds carry hyperkalemia when added together, their risk, and actions

Meds:

• RAAS

• Potassium sparing diuretics

What do we do for meds that have additive hyperkalemia risk?

Actions:

• do not use ACE with ARBS or ARNI

• avoid salt substitutes

What meds carry QTc prolongation risk and actions?

Meds:

• Antiarrythmtics

• anti-infectives

  • except isavuconazium

• antidepressants

  • highest risk with citalopram

• antipsychotics

  • highest risk with ziprasidone/Second gen AP

• Oncology meds

• droperidol

What do we use for meds that have additive QT prolongation effect?

• limit QT prolongation unless amiodarone for arrhythmia in HF

• do not exceed:

  • Citalopram:

    • 20 mg for citalopram in elderly

    • 40mg daily

  • Escitalopram:

    • 10 mg for elderly

    • 20 mg daily

• swap to seterlaine if need; the most safe

• do not use droperidol for inpatient N/V

What meds carry the highest risk CNS depression?

Opioids + BZDs

Actions for meds with additive CNS depression risk?

• do not use alcohol

• avoid combining CNS depressants

• For opioids:

  • do not combine with BZDs

  • XR have risk when taken with alcohol

What meds carry additive ototoxicity risk?

• Aminoglycosides(i. gentamicin, neomycin)

• Cisplatin

• Loop diuretics

• Salicylates

• Vancomycin

Risk: hearing loss

What to do for meds that have additive ototoxicity effect?

consult audiology, avoid using multiple drugs

meds that carry additive effect of nephrotoxicity

• anti-infectives

• cisplatin

• CNI(Cyclopsporine, tacrolimus)

• loop diuretics

• NSAIDs

• Radiographic dyes

Actions of meds with additive effects of nephrotoxicity

• maintain adequate hydration

• monitor drug levels

• If using Cisplatin-→use amifostine concurrently

Meds with hypotensive/orthostasis additive risk?

PDE5 inhibitors + 3A4 inhibitors or Nitrates or Alpha 1 blockers

actions for meds with hypotensive/orthostasis additive risk?

• for 3A4 inhibitors: start with half the dose of PDE5 inhibitor

• PDE5 and nitrates: CI from concurrent use

• PDE5 and alpha 1 blocker: start with half the dose when adding a drug from either class

CYP3A4 Substrates

• Analgesics

• Anticoagulants

• Cardiovascular drugs: amiodarone, CCB, or ranolazine

• Immunosuppressants: CNI

• Statins: atorvastatin, lovastatin, simvastatin

• NNRTIs

• PDE-5 inhibitors:

CYP3A4 inducers

PS PORCS

CYP3A4 inhibitors

G-PACMAN

1A2 substrates

R-warfarin, theophylline

1A2 inhibitors

Ciprofloxacin, fluvoxamine

1A2 inducers

Carbamazepine, phenobarbital, phenytoin, primidone, rifampin, smoking, St. John's wort

2C9 substrates

S-warfarin

2C9 inhibitors

Amiodarone, fluconazole, metronidazole, SMX/TMP

“2C9 hates ABX”

2C9 inducers

PS PORCS

2D6 substrate

analgesics: codeine, meperidine, tramadol

Tamoxifen

2D6 inhibitors

Amiodaorone, Bupropion, fluoxetine, duloxetine, and paroxetine

“2D6 hates Antidepressants”