Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Pamela - Naplex 2023 > Chapter 3 - Drug Interaction > Flashcards

Chapter 3 - Drug Interaction Flashcards

1
Q

List types of drug interaction

A

1) PHARMACODYNAMIC DRUG INTERACTIONS
- Additive Effects: Agonists Binding to the Same Receptor
- Additive Effects: Agonists Binding to Different Receptors
- Antagonists Block the Action of Agonists
- Synergistic Effects

2) PHARMACOKINETIC DRUG INTERACTIONS (ADME)
- Reduced Absorption
- Induction or Inhibition of Metabolism
- Decreased or Increased Excretion

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Define Pharmacodynamics and Pharmacodynamic Drug Interaction

A

Pharmacodynamics refers to the effect or change that a drug has on the body or some other type of organism
(Drug on body)

A pharmacodynamic (PD) drug interaction occurs when two or more drugs are given together, and their end effects impact each other. (Drugs on each other in body)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Define Drug Interactions with Additive Effects: Agonists Binding to the Same Receptor (PD)

A

Multiple drugs that are agonists at the same receptor can cause additive effects.

Example:
- opioids (mu-receptor agonists), providing analgesia, but with a risk of fatal toxicity when overdosed.
If two opioids (morphine and oxycodone) are taken together, the effects would be additive, with increased side effects (excessive sedation, respiratory depression and death).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Define Drug Interactions with Additive Effects: Agonists Binding to Different Receptors (PD)

A

Drugs that have similar end effects through different mechanisms/receptors can cause additive effects.

Example 1:
- BDZ with opioids –> increase the risk of a fatal overdose. (Respiratory suppression)
(use alternative/ minimum dose & duration/ monitor Sx of resp depression & sedation)

Example 2: Warfarin + Aspirin –> inc risk of bleeding

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Define DI where Antagonists Block the Action of Agonists (PD)

A

An antagonist blocks the agonist from binding to its receptor.

Example:
- naloxone is a mu-receptor antagonist, and floods the mu-receptor, which blocks the opioid from binding.
- Naloxone is used to reverse respiratory depression, but will also reverse the analgesic effect.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Define DI through Synergistic Effects (PD)

A

Synergism is present when two drugs taken in combination have a greater effect than that obtained by simply adding the two individual effects together.

Example: Oxycodone (mu-receptor agonist) + APAP –> greater analgesia effect

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Define Pharmacokinetics and Pharmacokinetic Drug Interaction

A

Pharmacokinetics = the effect the body has on the drug

■ Absorption (with oral drugs, typically occurring in the small intestine)
■ Distribution (through the blood and dispersed throughout the tissues)
■ Metabolism (including enzymatic reactions)
■ Excretion [removal of the drug or end products (metabolites) from the body]

PK drug interactions occur when one drug alters the absorption, distribution, metabolism or excretion of another drug.
PK drug interactions can be beneficial or harmful.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Reduced Absorption (PK)

A

1) Chelation: drug binds to polyvalent cations (Mg, Ca, Fe) in another compound (antacids or iron supplements).
The chelated complex cannot dissolve in the gut fluid and will pass out in the stool.

  • Example: Quinolones bind to calcium-containing drugs and dairy products (Space).
  • Drugs with polyvalent cations or other binding properties:
    – Aluminium
    – Antacid
    – Bile acid resins
    – Calcium
    – Iron
    – Magnesium
    – Multivitamins
    – Phosphate binders
    – Sucralfate
    – Zinc
  • should be separated from
    – Quinolones
    – Tetracyclines
    – Levothyroxine
    – Oral Bisphosphonate

2) Some drugs require an acidic gut for adequate absorption. If GI pH is increased, absorption will be decreased.

  • Ex: acid-suppressing drugs (H2RAs, PPIs) decrease the absorption of some antifungals (itraconazole) if taken together.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Induction or Inhibition of Metabolism (PK)

A

Majority during metabolism (Phase I or Phase II reactions) in the liver.

Example of a beneficial interaction: Ritonavir + Darunavir
- Ritonavir inhibits the metabolism of darunavir, which “boosts” the level of darunavir and increases its efficacy in treating HIV.

Examples of harmful interactions:
- Clarithromycin inhibits warfarin metabolism (inc INR & risk of bleeding), and rifampin induces warfarin metabolism (dec INR and inc risk for blood clots).
Increase/ decrease to keep the INR in the desired range.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Decreased or Increased Excretion (PK)

A
  • Renal excretion: primary route of drug excretion

Example of decreased renal excretion:
- Probenecid (treats gout) blocks the renal excretion of penicillin.
- Giving probenecid with penicillin can be beneficial when high penicillin levels are needed to cross the blood-brain barrier (BBB) and provide effective treatment of neurosyphilis.

Example of increased renal excretion:
- Salicylate (aspirin) overdose results in toxicity.
- IV Sodium bicarbonate alkalinizes the urine, which causes the salicylate to become ionized.
- Ionized compounds are more hydrophilic and will stay in the urine.
- Less will be reabsorbed through the renal tubules (across a lipid membrane) back into the blood.
- Compounds that stay in the urine will be renally excreted.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

ENZYME SYSTEMS, DRUG METABOLISM AND DRUG INTERACTIONS

A

1) CYTOCHROME P450 ENZYMES

2) PRODRUGS: INACTIVE DRUGS CONVERTED BY CYP ENZYMES TO ACTIVE DRUGS

3) NON-CYP450 ENZYMES

4) CYP ENZYME INHIBITORS INCREASE THE CONCENTRATION OF SUBSTRATE DRUGS

5) CYP ENZYME INDUCERS DECREASE THE CONCENTRATION OF SUBSTRATE DRUGS

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

1) What is the purpose of CYTOCHROME P450 ENZYMES?

2) Where are they primarily expressed?

3) How CYP450 Enzymes Metabolize Drugs

A

1) Purpose: catalyze Phase I reactions that either produce essential compounds (cholesterol and cortisol) or uncover or insert a polar (water-loving) group on a compound to facilitate renal excretion.

2) Liver

3) Drug binds to the CYP enzyme to form a complex –> more polar metabolites
- CYP3A4 metabolizes -34% of all CYP450 drug substrates.
- The function of CYP450 enzymes can be affected by genetics and other drugs that act as enzyme inhibitors or inducers.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

1) What are PRODRUGS?

2) What is their purpose?

A

1) Prodrugs are taken by the patient in an inactive form and are converted by CYP450 enzymes into the active form.

2) Purpose:

a) Extend the dosing interval:
- Valacyclovir (active drug form: acyclovir).
- Valacyclovir has higher bioavailability than acyclovir and is dosed less frequently .

b) Prevent drug abuse
- Lisdexamfetamine (Vyvanse) which is formulated with an 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 drug

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Prodrug: Capecitabine

A

Active: Fluorouracil

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Prodrug: Clopidogrel

A

Active: metabolite

Metabolized by CYP2C19

1) Risk with CYP2C19 inhibitors, which can block conversion to the active form.
–> Do not use with CYP2C19 inhibitors, including omeprazole and esomeprazole (can decrease antiplatelet effects).

2) Risk with PMs of CYP2C19 (low conversion to the active form, with reduced antiplatelet activity).
–> Use an alternative P2Y12 inhibitor in patients identified as PMs of 2C19.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Prodrug: Codeine

A

Active: Morphine

Codeine, by itself, and in combination products (Tylenol 3):

1) Risk of toxicity with ultra-rapid metabolizers (UMs) of CYP2D6 due to a more rapid conversion to morphine.
–> Do not use codeine in UMs of 2D6.

2) Risk of poor analgesia with poor metabolizers (PMs) of CYP2D6.
–> Use an alternative analgesicin patients identified as PMs of 2D6.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Prodrug: Colistimethate

A

Active: Colistin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Prodrug: Cortisone

A

Active: Cortisol

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Prodrug: Famciclovir

A

Active: Penciclovir

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Prodrug: Fosphenytoin

A

Active: Phenytoin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Prodrug: Isavuconazonium sulfate

A

Active: Isvuconazole

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Prodrug: Levodopa

A

Active: Dopamine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

Prodrug: Lisdexamfetamine

A

Active: Dextroamphetamine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

Prodrug: Prednisone

A

Active: Prednisolone

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

Prodrug: Primidone

A

Active: Phenobarbital

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

Prodrug: Tramadol

A

Active metabolite

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

Prodrug: Valacyclovir

A

Active: Acyclovir

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

Prodrug: Valganciclovir

A

Active: Ganciclovir

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

NON-CYP450 ENZYMES

A

CYPs –> Phase I
Other enzymes, including those active in Phase II reactions, can also alter drug levels.

Examples
1) Bictegravir, an antiretroviral drug for HIV, is a substrate of CYP3A4 and the Phase II enzyme uridine diphosphate glucuronosyl transferase (UGT) lAl. Inducers or inhibitors of CYP3A4 or UGTlAl will change the metabolism of bictegravir.

2) Another type of Phase II enzyme, N-acetyltransferase (NAT).
NATs are highly polymorphic; differences in the degree of isoniazid toxicity were found to be due to differences in the rate of acetylation by NAT enzymes.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

CYP ENZYME INHIBITORS –> INCREASE THE CONCENTRATION OF SUBSTRATE DRUGS

1) What are the common cyp inhibitors involved in drug interactions?

2) Whats the effects on substrates?

3) Whats the effects on prodrugs?

4) Recognizing the Problem

5) Possible Actions

A

1) G + PACMAN
- Grapefruit
- Protease inhibitors, especially ritonavir
- Azole antifungals
(fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole and isavuconazonium)
- Cyclosporine, cobicistat
- Macrolides (clarithromycin and erythromycin, but NOT azithromycin)
- Amiodarone (and dronedarone)
- Non-DHP CCBs (diltiazem and verapamil)

2) Effect on Substrates
- Decreased metabolism
- Increased serum concentrations and increased clinical effect
- INhibitors ; INcreased effects/ levels/ADRs/toxicities of substrates

3) Effect on Prodrugs
Decreased conversion to the active drug (and dec levels)

4) Recognizing the Problem
■ Review labs for therapeutic drug monitoring
■ Monitor for therapeutic effect, ADRs, toxicity

5) Possible Actions: decrease dose of substrate (unless a prodrug), use alternate drug to avoid combination

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

CASE SCENARIO:
A 76-year-old male presents to the pharmacy with a voriconazole prescription to treat aspergillosis.

His medication profile includes
- betaxolol 1 drop OU BID
- simvastatin 40 mg PO QHS
- hydrochlorothiazide 25 mg PO QAM

A

1) Recognizing the Problem
Voriconazole is a strong CYP3A4 inhibitor
and simvastatin is a major CYP3A4 substrate.
Voriconazole will increase the simvastatin level, increasing the risk of muscle toxicity and rhabdomyolysis.

Pharmacist Actions
The combination of voriconazole and simvastatin is contraindicated.

Ensure that the drugs are not used concurrently. Recommend an alternative statin, such as rosuvastatin.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

CYP ENZYME INDUCERS –> DECREASE THE CONCENTRATION OF SUBSTRATE DRUGS

1) What are the common cyp inducers involved in drug interactions?

2) Whats the effects on substrates?

3) Whats the effects on prodrugs?

4) Recognizing the Problem

5) Possible Actions

A

1) PS PORCS
- Phenytoin
- Smoking
- Phenobarbital
- Oxcarbazepine (and eslicarbazepine)
- Rifampin (rifabutin, rifapentine)
- Carbamazepine (also an auto-inducer)
- St. John’s wort

2) Effect on Substrates
■ Increased metabolism
■ Decreased serum concentrations and decreased clinical effect
■ lnDucers = Decreased effects/levels of substrates

3) Effect on Prodrugs
Increased conversion to the active drug (inc levels)

4) Recognizing the Problem
■ Review labs for therapeutic drug monitoring
■ Monitor for therapeutic effect

5) Possible Actions: increase dose of substrate (unless a prodrug), use alternate drug to avoid combination

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

CASE SCENARIO

A 34-year-old female with a mechanical mitral valve has been taking warfarin chronically to prevent thrombosis.
Warfarin dose: 5 mg PO daily
INR range for the past 6 months: 2.6 - 3.1
(INR goal 2.5 - 3.5)

She was admitted for infective endocarditis and started on gentamicin, ceftriaxone, rifampin and vancomycin.

A

Recognizingthe Problem
Rifampin is a broad-spectrum inducer of P-gp, CYP2C9, 3A4, 1A2 and 2C19.
Warfarin is metabolized by CYP2C9 (major), 1A2, 2C19 and 3A4.

Pharmacist Actions
Monitor INR more frequently; increase warfarin dose PRN.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

“Lag” Time for Enzyme Induction

A
  • 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, it could take 2 - 4 weeks for the induction effects to disappear completely; the excess enzymes will degrade based on their half-lives.
35
Q

GUT EXCRETION BY DRUG TRANSPORTERS

A

1) P- GLYCOPROTEIN EFFLUX PUMPS

2) ENTERO HEPATIC RECYCLING

36
Q

P-gp: Permeability - GLYCOPROTEIN EFFLUX PUMPS (or transporters)

1) their function

2) Substrates

3) Inducers

4) Inhibitors

A

1) Protect against foreign substances by moving them out of critical areas.
- P-gp pumps in cell membranes of GI tract transport drugs and their metabolites out of the body by pumping them into the gut, where they can be excreted in the stool.

2) Substrates:
_ Anticoagulants (apixaban, edoxaban. dabigatran, rivaroxaban)
_ Cardiovascular drugs (digoxin, diltiazem, carvedilol, ranolazine, verapamil)
_ lmmunosuppressants (cyclosporine, sirolimus, tacrolimus)
_ HCV drugs (dasabuvir, ombitasvir, paritaprevir, sofosbuvir)
_ Others (atazanavir, colchicine, dolutegravir, posaconazole, raltegravir, saxagliptin)

3) Inducers:
Carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, St.John’s wort, tipranavir

4) Inhibitors:
_ Anti-infectives (clarithromycin, itraconazole, posaconazole)
_ Cardiovascular drugs (amiodarone, carvedilol, conivaptan, diltiazem, dronedarone, quinidine, verapamil)
_ HIV drugs (cobicistat, ritonavir)
_ HCV drugs (ledipasvir, paritaprevir)
_ Others (cyclosporine, flibanserin, ticagrelor)

37
Q

ENTEROHEPATIC RECYCLING

A
  • 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, where most drugs are absorbed), 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 antibiotics, some NSAIDs and the cholesterol-lowering drug ezetimibe.
38
Q

COMMON CARDIOVASCULAR DRUG INTERACTIONS

A
39
Q

COMMON CARDIOVASCULAR DRUG INTERACTIONS

AMIODARONE (Dronedarone)
+ Warfarin

A

Atrial fibrillation treatment: amiodarone (rhythm), warfarin (to reduce clot risk).

RISK
- Warfarin: Metabolized by CYP 2C9
- Amiodarone: Inhibits CYP 2C9
- Dec warfarin metabolism –> Inc warfarin conc –> inc INR & bleeding risk

ACTION:

  • If using amiodarone 1st:
    ■ Start warfarin at a lower dose of <= 5 mg
  • If using warfarin 1st:
    ■ Dec warfarin dose 30-50%, depending on the INR
  • Taking both
    ■ Monitor INR; adjust as needed
40
Q

COMMON CARDIOVASCULAR DRUG INTERACTIONS

AMIODARONE
+ Digoxin

A

Arrhythmia treatment: Amiodarone (for rhythm), digoxin [for rate control (dec HR), or for symptom improvement in a patient with HF]

RISK:
- Amiodarone: inhibits P-gp
- Digoxin is a P-gp substrate
- Dec digoxin excretion –> inc ADRs/toxicity
- Amiodarone and digoxin both dec HR, inc risk of bradycardia, arrhythmia, fatality.

ACTION:

  • If using amiodarone 1st:
    ■ Start oral digoxin at a low dose, such as 0.125 mg daily instead of 0.25 mg daily.
  • If using digoxin 1st:
    ■ Dec oral digoxin dose 50% (change 0.25 mg daily to 0.125 mg daily, or change 0.125 mg daily to 0.125 mg every other day)

Taking both amiodarone and digoxin
■ Instruct patient to monitor for symptoms of digoxin toxicity: nausea, vomiting, vision changes; if present, contact prescriber.
■ Monitor HR; normal is 60-100 BPM
■ Check for other drugs that.dec HR: beta blockers, clonidine, diltiazem, verapamil, dexmedetomidine (Precedex).

■ If digoxin is being used for rate control, inform prescribers to consider beta-blockers or non-DHP CCBs (preferred).

41
Q

COMMON CARDIOVASCULAR DRUG INTERACTIONS

DIGOXIN
+ Loop diuretic

A

Caution:
- HF and renal impairment often occur together
- Digoxin is cleared by P-gp and excreted by the kidneys; renal impairment inc digoxin levels and toxicity risk.

RISK:
- Loops dec K, Mg, Ca and Na.
(Even without the use of a loop, electrolyte deficiencies are common with CVD)
- Low K, Mg or Ca will worsen arrhythmias
- Digoxin toxicity risk is increased with dec K and Mg levels and inc Ca levels.

ACTION:
Taking digoxin and a loop diuretic
■ Monitor electrolytes and correct if abnormal.
■ Renal impairment: Dec digoxin dose or frequency, or discontinue.

42
Q

COMMON CARDIOVASCULAR DRUG INTERACTIONS

DRUGS THAT DECREASE HEART RATE

  • Diltiazem/verapamil or beta- blockers for rate control;
  • Clonidine and beta-blockers to lower blood pressure.
A
  • Additive effects when drugs that dec HR are used together, including amiodarone, digoxin, beta-blockers, clonidine and dexmedetomidine (Precedex).

Monitor HR; normal is 60-100 BPM (can be lower, based on patient’s history and physical state).

43
Q

COMMON CARDIOVASCULAR DRUG INTERACTIONS

STATINS
+ Strong CYP3A4 inhibitors

A

Cyp Inhibitors: ritonavir and other Pis, cobicistat, clarithromycin, erythromycin, azole antifungals, cyclosporine, grapefruit juice/fruit

RISK:
- Inc levels of CYP3A4 substrates: lovastatin, simvastatin, atorvastatin.
- Inc myopathy risk; if severe (with high CPK), can cause rhabdomyolysis with acute renal failure (ARF).

ACTION:
- Simvastatin and lovastatin are CI with strong CYP3A4 inhib.
- Recommend a statin not metabolized by CYP enzymes (pitavastatin, pravastatin, rosuvastatin)

(bravo rosy aam tekul pita bread –> not metabolized by cyp))

44
Q

COMMON CARDIOVASCULAR DRUG INTERACTIONS

WARFARIN
+ CYP2C9 inhibitors and inducers

Inhibitors: azole antifungals, sulfamethoxazole/trimethoprim, amiodarone, metronidazole

Inducers: rifampin, St. John’s wort

A
  • Inc levels of warfarin (inc INR and bleeding risk) with CYP2C9 inhibitors.
  • Dec levels of warfarin (dec INR and inc clotting risk) with CYP2C9 inducers

ACTION:
- Monitor INR; therapeutic range is 2-3 for most conditions (2.5-3.5 for some high-risk indications, such as mechanical mitral valve).
- Some drugs (e.g., amiodarone) require prophylactic warfarin dose adjustment when started.

45
Q

INHIBITORS INCREASE SUBSTRATE DRUGS

A
46
Q

INHIBITORS INCREASE SUBSTRATE DRUGS

CYP3A4 INHIBITORS + CYP3A4 substrates (many)

Includes the opioids fentanyl, hydrocodone, oxycodone, methadone.

A

RISK
- CYP3A4 substrate metabolism will cause inc drug levels and inc toxicity.
- If an opioid is the substrate, sedation will increase, followed by respiratory depression –> Fatal

ACTION

  • Do not use a CYP3A4 inhibitor with an opioid metabolized by CYP3A4
  • Grapefruit/juice: do not take with CYP3A4 substrates.
  • Drugs that specifically include instructions not to take with grapefruit include:
    – Amiodarone
    – Simvastatin
    – Lovastatin
    – Nifedipine
    – Tacrolimus
47
Q

INHIBITORS INCREASE SUBSTRATE DRUGS

VALPROATE + lamotrigine

A
  • Valproate is an inhibitor of lamotrigine metabolism

RISK
- Valproate dec lamotrigine metabolism and inc lamotrigine levels causing inc risk of serious skin reactions, including SJS/TEN (can be fatal)

ACTION
- Initiate lamotrigine using the starter kit that begins with lower lamotrigine doses.
- Titrate carefully every 2 weeks.
- Counsel patients to get emergency help if rash develops.

48
Q

INHIBITORS INCREASE SUBSTRATE DRUGS

MONOAMINE OXIDASE (MAO) INHIBITORS
+
Drugs/foods that inc epinephrine, norepinephrine, dopamine
+
Drugs that inc serotonin (5-HT) Antidepressants:

A

MONOAMINE OXIDASE (MAO) INHIBITORS
lsocarboxazid, phenelzine, tranylcypromine, rasagiline, selegiline, linezolid, methylene blue

+

Drugs/foods that inc epinephrine, norepinephrine, dopamine, SNRls, TCAs, bupropion, levodopa, stimulants, including amphetamines used for ADHD (methylphenidate, lisdexamfetamine, dextroamphetamine), tyramine (from foods)

+

Drugs that inc serotonin (S-HT) Antidepressants: SSRls, SNRls, TCAs, mirtazapine, trazodone
Opioids and analgesics: fentanyl, methadone, tramadol
Others: buspirone, dextromethorphan (high doses taken as drug of abuse), lithium, St.John’swort

RISK
- The MAO enzyme metabolizes Epi, NE, DA, tyramine and 5-HT.
- MAO-inhibitor will inc Epi, NE, DA and 5-HT.
- High Epi, NE and DA can cause hypertensive crisis.
- High 5-HT can cause serotonin syndrome

ACTION
- Do not use together.
- Use a 2-week washout period when switching between drugs with MAO inhibitor or serotonergic properties (except with FLUOXETINE, wait 5 weeks).
- Tyramine-rich foods have been aged, pickled, fermented or smoked, including aged cheeses, air-dried meats, sauerkraut, some wines and beers.

49
Q

INHIBITORS INCREASE SUBSTRATE DRUGS

CYP2D6 INHIBITORS
Amiodarone, fluoxetine, paroxetine, fluvoxamine

+ CYP2D6 substrates (many)

A

RISK
Dec drug metabolism, inc ADRs/ toxicity.

ACTION
Avoid using together or dec dose of the substrate.

50
Q

INHIBITORS INCREASE SUBSTRATE DRUGS

CYP3A4, P-GP INHIBITORS

+

Calcineurin inhibitors (CNls): Tacrolimus, cyclosporine
or
mTOR kinase inhibitors: Sirolimus, everolimus

A

RISK
- Dec drug metabolism, inc ADRs/ toxicity, including inc blood pressure, nephrotoxicity, metabolic syndrome and other adverse effects

ACTION:
- Avoid using together or dec dose of CNI or mTOR kinase inhibitor cautiously and based on drug levels.
- Monitor transplant drug level (trough).

51
Q

INDUCERS DECREASE SUBSTRATE DRUGS

A
52
Q

INDUCERS DECREASE SUBSTRATE DRUGS

ANTIEPILEPTIC DRUG (AED) CYP INDUCERS:
Phenytoin, phenobarbital, primidone, carbamazepine, oxcarbazepine

+

Other drugs metabolized by CYP enzymes:
Oral contraceptives, other AEDs, carbamazepine (auto- inducer, induces its own metabolism)

A

RISK
- Inc substrate (drug) metabolism will cause dec drug levels.
- Dec drug effects; with AEDs, loss of seizure control.

ACTION:
- Monitor drug levels; induction takes up to 4 weeks for the full effect.
- Consider increasing the dose of the substrate drug.
- If substrate is lamotrigine, use the starter kit that begins with higher lamotrigine doses.

53
Q

INDUCERS DECREASE SUBSTRATE DRUGS

RIFAMPIN
+ CYP and P-gp substrates

A

RISK
- The concentration of substrate drugs will greatly decrease.

ACTION
- Monitor drug levels or appropriate monitoring parameter, such as an INR with warfarin.
- Increase the dose of the substrate drug as necessary.

54
Q

INDUCERS DECREASE SUBSTRATE DRUGS

CYP3A4 INDUCERS
+
Opioids that are CYP3A4 substrates
Fentanyl, hydrocodone, oxycodone, methadone

A

RISK
- inc metabolism results in dec opioid concentration; analgesia (pain relief) will decrease.

ACTION
- Assess the patient’s use of breakthrough pain medication to determine if an increased maintenance dose is necessary.
- Use caution; opioids cause respiratory depression when overdosed, and induction has a lag time.

55
Q

INDUCERS DECREASE SUBSTRATE DRUGS

CYP2D6UMs
+
Prodrugs that are CYP2D6 substrates
Codeine, tramadol

A

RISK

  • There are no CYP2D6 inducers (not an inducible enzyme).
  • With 2D6 UMs (who produce about twice as many enzymes), the effect is similar to the effect from an inducer and the prodrug will be converted more rapidly to the active drug.
  • Inc active drug concentration, which can cause toxicity/risk and possible fatality.

ACTION

  • Do not use codeine or tramadol in patients < 12 yrs and in children < 18 years following tonsillectomy and/or adenoidectomy (CI).
  • Do not use an opioid prodrug that is metabolized by CYP2D6 (codeine, tramadol) in a breast-feeding mother unless it is known that she is not a 2D6 UM.
56
Q

INDUCERS DECREASE SUBSTRATE DRUGS

CYP3A4, P·GP INDUCERS +
Calcineurin inhibitors (CNls) Tacrolimus, cyclosporine
or
mTOR kinase inhibitors
Sirolimus, everolimus

A

RISK
- inc drug metabolism results in J, transplant drug level and i risk of transplant (organ) rejection.

ACTION
- Avoid using together or inc dose of CNI or mTORkinase inhibitor carefully.
- Monitor transplant drug level (trough) for efficacy.

57
Q

INDUCERS DECREASE SUBSTRATE DRUGS

SMOKING
Primarily induces CYP1A2; includes smoking tobacco and marijuana
+
Some antipsychotics, antidepressants, hypnotics, anxiolytics, caffeine, theophylline, warfarin (R-isomer)

A

1) Smokers who quit

  • When the inducer (cigarettes) is stopped, drug concentrations (primarily CYP1A2 substrates) will inc causing toxicity.
  • When a smoker quits, monitor the INR if taking warfarin;
    – the R-isomer of warfarin (less potent isomer) is metabolized by CYP1A2, but the therapeutic range is narrow and could be affected.
  • Nicotine replacement products (NRT, such as the patch and gum) do not induce CYP enzymes.

2) Current smoker

  • The substrate drugs (primarily CYP1A2 substrates) will have dec levels.
  • When a current smoker starts a drug (primarily CYP1A2 substrates), a higher dose can be required.
58
Q

ADDITIVE SIDE EFFECTS:
SEROTONERGIC TOXICITY

A

1- Antidepressants:
– SSRls, SNRls, TCAs, mirtazapine, trazodone

2- MAO inhibitors
– Antidepressants: isocarboxazid, phenelzine, tranylcypromine
– Selective MAO-B inhibitors: selegiline, rasagiline
– Others: linezolid, methylene blue

3- Opioids
– Fentanyl, meperidine, methadone, tramadol, tapentadol (and risk with any other opioids when used in combination with serotonergic drugs)

4- Triptans
– Occasional (PRN) triptan use may be safe; more frequent use can increase risk

5- Natural products:
– St. John’s wort, 1-tryptophan

6- Others:
– Buspirone, lithium, dextromethorphan (when taken in excess as a drug of abuse)

Risk:

  • Serotonin syndrome risk increases when two or more drugs that affect serotonin are used together.
  • Higher doses inc risk.
  • 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 seizures)

Action:

  • Avoid using serotonergic drugs together; if used, doses should be within recommended ranges.
  • Check for inhibitors of serotonergic drugs.
  • Counsel to report sx, even mild.
  • If severe symptoms, counsel to go to the emergency department.
  • Recommend eliminating an initial serotonergic drug prior to starting a new serotonergic drug by using a washout period:
    – use 2 weeks between the drugs, or
    – use 5 weeks for drugs with a longer duration of action, such as fluoxetine.
59
Q

BLEEDING RISK

A

1- Anticoagulants
– Warfarin, dabigatran, apixaban, edoxaban, rivaroxaban, heparin, enoxaparin, dalteparin, fondaparinux, argatroban, bivalirudin

2- Anti platelets
– Salicylates, including aspirin, dipyridamole, clopidogrel, prasugrel, ticagrelor

3- NSAIDs
– Ibuprofen, naproxen, diclofenac, indomethacin,
others

4- SSRls, SNRls
– Citalopram, escitalopram, fluoxetine, paroxetine, sertraline, duloxetine, venlafaxine, others

5- Natural products
- 5G’s: garlic, ginger, ginkgo biloba, ginseng, glucosamine
Vitamin E, willow bark, fish oils (high doses)

inc bleeding risk; can occur with or without changing an anticoagulation monitoring parameter, such as the INR (with warfarin)

Avoid using in combination, with a few exceptions:
■ Aspirin (for cardioprotection) and occasional NSAID
use for pain, fever or inflammation.
■ SSRI/SNRI use and occasional NSAID use for pain,
fever or inflammation.
■ Dual antiplatelets, when recommended.
■ Bridging/overlap treatment, such as enoxaparin + warfarin, until INR therapeutic >= 24 hrs.

60
Q

HYPERKALEMIA RISK

A

1- Renin-angiotensin-aldosterone system drugs
– ACE inhibitors, ARBs, aliskiren, sacubitril/valsartan, spironolactone, eplerenone (highest risk with aldosterone receptor antagonists)

2- Potassium-sparing diuretics
– Amiloride, triamterene

3- Others
– Salt substitutes (KCI), calcineurin inhibitors (tacrolimus and cyclosporine), SMX/TMP, canagliflozin, drospirenone-containing oral contraceptives

Risk:
- Hyperkalemia; symptoms include weakness, heart palpitations, arrhythmia.
- Higher risk with renal impairment.

Action:
- Do not use ACE inhibitors with ARBs.
- Do not use sacubitril/valsartan with ACE inhibitors or ARBs.
- If risk of hyperkalemia, suggest alternatives to canagliflozin (for diabetes), SMX/TMP (for infection) and drospirenone-containing oral contraceptives.
Counsel patient to avoid salt substitutes that contain KCI.
- Monitor potassium.

61
Q

QT PROLONGATION

A

1- Antiarrhythmics
– Including amiodarone, dofetilide, dronedarone, ibutilide, sotalol

2- Antibiotics/antifungals
– Quinolones and macrolides

3- Azole antifungals, except isavuconazonium
(Cresemba)

4- Antidepressants
– SSRls: highest risk with citalopram, escitalopram
– SNRls
– TCAs
– Mirtazapine
– Trazodone

5- Antipsychotics (most)
– Including phenothiazines (end in -azine, such as thioridazine), haloperidol, ziprasidone

6- Antiemetics
– 5-HT3 receptor antagonists (ondansetron), droperidol and phenothiazines (prochlorperazine)

7- Others
Donepezil, fingolimod, methadone

Risk:
- QT prolongation inc the risk of torsades de pointes (TdP), an often fatal arrhythmia. The risk increases with:
■ Higher doses.
■ Higher drug levels due to concurrent enzyme inhibitors.
■ Higher drug levels due to reduced drug clearance, such as with renal or liver disease.
■ Multiple QT-prolonging drugs.
■ Elderly(> 60 years) and patients with CVD, including arrhythmias, HF, MI

Action:
With all QT-prolonging drugs, avoid/reduce risk of TdP:

■ If possible, do not use QT-prolonging drugs at all or select drugs with lower QT risk, especially with arrhythmias, CVD or CVD risk (exception: amiodarone is the drug of choice to treat an arrhythmia in patients with HF).

■ Carefully dose QT-prolonging drugs; do not use excessive doses. Use lower doses/caution use in elderly patients.
- Do not exceed citalopram 40 mg daily or 20 mg daily in elderly (> 60 years), liver disease or with enzyme inhibitors that decrease clearance.
- Do not exceed escitalopram 20 mg daily or 10 mg daily in elderly.
- Among SSRls, sertraline is considered safer with CVD.

■ Avoid concurrent QT-prolonging drugs, if possible.

■ Avoid use of inhibitors that block a QT-prolonging
drug’s metabolism.

■ Do not use droperidol for inpatient N/V (droperidol is injection only and has restricted use due to QT prolongation risk).

62
Q

CNS DEPRESSION

A
  • Opioids
  • Skeletal muscle relaxants
  • Antiepileptic drugs
  • Benzodiazepines
  • Barbiturates
  • Hypnotics
  • Antidepressants: mirtazapine, trazodone
  • Antihypertensives: propranolol, clonidine
  • Cannabis-related drugs: dronabinol, nabilone
  • Sedating antihistamines
  • Cough syrups with an antihistamine or opioid
  • Some NSAIDs

Highest risk for fatality when used in combination:
Opioids + Benzodiazepines or other CNS depressants

Risk:
- CNS depressant-effects: somnolence, dizziness, confusion/ cognitive impairment, altered consciousness/delirium, gait instability/imbalance/risk of falls/ accidents, including motor vehicle accidents.

  • BDZ are a drug of abuse, and are often prescribed inappropriately (for anxiety or insomnia), adding unnecessary risk of CNS depression.
  • Benzodiazepines are appropriate for status epilepticus, alcohol withdrawal, as an antidote for stimulant overdose, prior to medical procedures, in acute high-anxiety situations and for anticipatory emesis with chemotherapy.
  • Opioids: due to the risks of abuse, dependence and addiction, , reserve for severe pain that is not responsive to other measures.

Action:
■ Do not use alcohol.
■ Do not operate a car or other potentially dangerous vehicles/machines.
■ Can increase risk of falls, confusion.

  • Monitor for sedation, slow and shallow breathing and shortness of breath. Avoid combining CNS depressants when possible.
  • Suggest alternatives for anxiety (SSRI, SNRI, buspirone), insomnia (lifestyle treatments preferred) or pain (acetaminophen, NSAIDs, antiepileptic drugs, antidepressants, physical therapy, acupuncture).

For opioids specifically:
■ Do not use in combination with benzodiazepines; use of other CNS depressants, including alcohol, have a high risk of fatality with opioids.
■ Extended-release formulations have additional risk: several become shorter-acting when taken with alcohol, which increases the risk of fatality.
■ Recommend naloxone for at-risk patients, including anyone using high doses, receiving rapid dose increases or with reduced clearance (e.g.,renal impairment with morphine).
■ Avoid codeine if pharmacogenomic profile is unknown (highest risk with CYP2D6 UMs).

63
Q

OTOTOXICITY

A

1- Aminoglycosides
Gentamicin, tobramycin, amikacin, others
2- Cisplatin
3- Loop diuretics
Furosemide, bumetanide, ethacrynic acid (especially rapid IV administration)
4- Salicylates
Aspirin, salsalate, magnesium salicylate, others
5- Vancomycin

Risk: Hearing loss, tinnitus, vertigo.

Action:
- Consider an audiology consult at start of treatment for baseline hearing assessment, continue to monitor.
- Avoid using multiple ototoxic drugs at the same time, when possible.

64
Q

NEPHROTOXICITY

A

1- Anti-infectives
Aminoglycosides, amphotericin B, polymyxins, vancomycin
Cisplatin
Calcineurin inhibitors
Cyclosporine, tacrolimus
loop diuretics
Furosemide, torsemide, bumetanide, ethacrynic acid
Radiographic-contrast dye
nsaids

risk:
Worsening renal function/
acute renal failure (ARF),can be evidenced by .Ji.n urine output and i SCr/BUN.

action:
Cisplatin: use amifostine (Ethyol)to protect kidneys. Maintain adequate hydration (avoid dehydration
which can worsen kidney function).
Monitor drug levels (e.g.,aminoglycosides, vancomycin, tacrolimus), asappropriate.
Discontinue offending drugs if acute renal failure occurs.
Monitor urine output, SCr/BUN.

65
Q

’ ANTICHOLINERGIC TOXICITY

A

Antidepressants/antipsychotics
Paroxetine, TCAs, first-generation
antipsychotics
Sedating antihistamines
Diphenhydramine, brompheniramine, chlorpheniramine, doxylamine, hydroxyzine, cyproheptadine, meclizine
Centrally-acting anticholinergics Benztropine, trihexyphenidyl
Muscle relaxants
Baclofen, carisoprodol, cyclobenzaprine
Antimuscarinics (for urinary incontinence)
Oxybutynin, darifenacin, tolterodine
Others
Atropine, belladonna, dicyclomine

risk:
Anticholinergic symptoms: CNS depression, including sedation, and peripheral anticholinergic side effects of dry mouth, dry eyes/ blurry vision, constipation, urinary retention.
Highest risk in elderly.

action:
Recommend alternatives to sedating antihistamines, such as loratadine, fexofenadine, cetirizine, or suggest saline nasal spray/drops that clear allergens out of the nasal passages.
If using diphenhydramine or other sedating antihistamines for sleep, suggest lifestyle changes (sleep hygiene).
Recommend treatments for dry mouth, dry eyes (see Sjogren’s Syndrome in Systemic Steroids & Autoimmune Conditions chapter); recommend laxatives for constipation (see Constipation & Diarrhea chapter).

66
Q

HYPOTENSION/ORTHOSTASIS

A

PDE-5 inhibitor: Sildenafil, tadalafil, avanafil, vardenafil
+
CYP3A4 inhibitors or
Nitrates
or
Alpha-1 blockers
Non-selective (e.g.,doxazosin, terazosin) or selective (e.g.,tamsulosin)

risk:
With CYP3A4 inhibitors: PDE-5 inhibitor metabolism causesi sideeffects, including headache, dizziness, flushing (causing i risk of falls/injury).
PDE-5 inhibitors, nitrates and alpha-1 blockers all cause vasodilation. Additive effects can lead to hypotension/orthostasis, dizziness and falls.
With nitrates, severe hypotension can cause chest pain and CV events, which can be fatal.

action:
If taking a CYP3A4 inhibitor
■ Start with half the usual starting dose of the PDE-5
inhibitor (seeSexualDysfunction chapter). PDE-5 inhibitors and nitrates
■ Do not use together (contraindicated); check for use of sublingual nitroglycerin PRNfor chest pain; can consider use of nitroglycerin in emergent situations (UA/NSTEMI/STEMI) with close monitoring.
PDE-5 inhibitors and alpha-1 blockers
■ Start with a low dose when adding a drug from either class (e.g., if taking an alpha-1 blocker, start at half the usual PDE-5 inhibitor starting dose). Do not start a PDE-S inhibitor unless stable (e.g., no symptoms of hypotension) on an alpha-1 blocker.

67
Q

cyp 3a4 substrate

A

Analgesics {buprenorphine, diclofenac, fentanyl, hydrocodone, meloxicam, methadone, oxycodone, tramadol)
Anticoagulants (apixaban, rivaroxaban, R-warfarin)
Cardiovascular drugs (amiodarone, amlodipine, bosentan, diltiazem, eplerenone, ivabradine, nifedipine, quinidine, ranolazine, tolvaptan, verapamil)
lmmunosuppressants (cyclosporine, tacrolimus, sirolimus) Statins (atorvastatin, lovastatin, simvastatin)
Key HIV drugs (atazanavir, efavirenz, ritonavir, tipranavir) PDE-5 inhibitors (avanafil, sildenafil, tadalafil, vardenafil)
Others (alfuzosin, aprepitant, aripiprazole, benzodiazepines, brexpiprazole, buspirone, carbamazepine, citalopram, clarithromycin, colchicine, dapsone, dutasteride, erythromycin, escitalopram, ethinyl estradiol, felbamate, haloperidol, ketoconazole, levonorgestrel, mirtazapine, modafinil, ondansetron, paritaprevir, progesterone, quetiapine, tamoxifen, trazodone, venlafaxine, zolpidem)

68
Q

cyp 3a4 inducer

A

ICarbamazepine, efavirenz, nevirapine, oxcarbazepine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, smoking, St. John’s wort

69
Q

cyp 3a4 inhibitor

A

Anti-infectives (clarithromycin, erythromycin, azole antifungals, isoniazid)
Cardiovascular drugs (amiodarone, diltiazem, dronedarone, quinidine, ranolazine, verapamil)
Key HIV drugs (cobicistat, efavirenz, ritonavir and other protease inhibitors)
Others (aprepitant, cimetidine, cyclosporine, fluvoxamine, grapefruit juice, haloperidol, nefazodone, sertraline)

70
Q

cyp 1a2 substrate

A

Alosetron, aprepitant, clozapine, cyclobenzaprine, duloxetine,
ethinyl estradiol, fluvoxamine, methadone, mirtazapine, olanzapine, ondansetron, pimozide, propranolol, rasagiline, ropinirole, theophylline, tizanidine, R-warfarin, zolpidem

71
Q

cyp 1a2 inducer

A

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

72
Q

cyp 1a2 inhibitor

A

Atazanavir, cimetidine, ciprofloxacin, fluvoxamine, zileuton

73
Q

cyp 2c8 substrate

A

Amiodarone, dasabuvir, pioglitazone, repaglinide, rosiglitazone

74
Q

cyp 2c8 inducer

A

Phenytoin, rifampin

75
Q

cyp 2c8 inhibitor

A

Amiodarone, atazanavir, clopidogrel, gemfibrozil, ketoconazole, trimethoprim/sulfamethoxazole, ritonavir

76
Q

cyp 2c9 substrate

A

S-warfarin

others: (ens) Alosetron, carvedilol, celecoxib, diazepam, diclofenac, fluvastatin, glyburide, glipizide, glimepiride, meloxicam, nateglinide, phenytoin, ramelteon, tamoxifen, zolpidem

77
Q

cyp 2c9 inducer

A

Aprepitant, carbamazepine, phenobarbital, phenytoin, primidone, rifampin, rifapentine, ritonavir, smoking, St. John’s wort

78
Q

cyp 2c9 inhibitor

A

Amiodarone, atazanavir, capecitabine, cimetidine, efavirenz, etravirine, gemfibrozil, fluconazole, fluvoxamine, fluorouracil, isoniazid, ketoconazole, metronidazole, oritavancin, tamoxifen, trimethoprim/sulfamethoxazole, valproic acid, voriconazole, zafirlukast

79
Q

cyp 2c19 substrate

A

Clopidogrel, phenytoin, thioridazine, voriconazole

80
Q

cyp 2c19 inducer

A

Carbamazepine,
phenobarbital, phenytoin, rifampin

81
Q

cyp 2c19 inhib

A

Omeprazole, esomeprazole,

others (ens): Cimetidine, efavirenz, etravirine, fluoxetine, fluvoxamine, isoniazid, ketoconazole, modafinil, topiramate, voriconazole

82
Q

cyp 2d6 substrate

A

Analgesics (codeine, hydrocodone, meperidine, methadone, oxycodone, tramadol)

antipsychotic/ antidepressant:
(aripiprazole, brexpiprazole, doxepin, fluoxetine, haloperidol, mirtazapine, risperidone, thioridazine,
trazodone, tricyclic antidepressants, venlafaxine)
Others (atomoxetine, carvedilol, dextromethorphan, flecainide, methamphetamine, metoprolol, propafenone, propranolol, tamoxifen)

83
Q

cyp 2d6 inhib

A

Amiodarone, bupropion, cimetidine, cobicistat, darifenacin, dronedarone, duloxetine, fluoxetine, mirabegron, paroxetine, propafenone, quinidine, ritonavir, sertraline

(no inducers)

Pamela - Naplex 2023 (32 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions