Drug Induced Diseases HL Exam 1

Which meds are discussed in this section?

Haloperidiol,

Phenothiazines,

Azole Antifungals,

Heparin, Low Molecular Weight heparin,

Argatroban,

Amiodarone,

Nitrofurantoin,

Bleomycin,

Methotrexate

What is Torsades de Pointes (TdP)?

specific type of ventricular tachycardia and is typically in response to a medication or condition

What is the most important risk factor of TdP?

QT prolongation

What is the measurement or marker on an EKG for TdP?

QT prolongation

True or False: QT prolongation makes the heart more susceptible to an arrhythmia

True

it appears as a rapid, polymorphic rhythm with a characteristic 'twisting' of the QRS complexes around the baseline

An absolute QT (or corrected QT, QTC) greater than ________ is considered a significant risk of TdP

500 ms

How is TdP risk best assessed?

plotting QT vs HR on a QT nomogram

Which drug classes are considered high risk for QT prolongation and TdP?

cardiac, antidepressants, antipsychotics, antihistamines, antimicrobials, and other drugs

Which cardiac meds are considered high risk for QT prolongation and TdP?

amiodarone, sotalol, disopyramide, procainamide, quinidine

Which antidepressants are considered high risk for QT prolongation and TdP?

SSRIs (citalopram, escitalopram, fluoxetine) Moclobemide, TCAs, Lithium

Which antipsychotics are considered high risk for QT prolongation and TdP?

Amisulpride, Chlorpromazine, QTidol, Thiordazine

Which antihistamines are considered high risk for QT prolongation and TdP?

Loratadine, Astemizole, Diphenhydramine

Which 'other drugs' are considered high risk for QT prolongation and TdP?

Chloroquine, Cisspride, Dolesatron, Methadone, Arsenic

What patient factors increase risk for QT prolongation and TdP?

Females (longer QT interval),

Increasing age,

Electrolyte disturbances (hypo- K, Ca, Mg),

Hypoglycemia,

CV (myocardial ischemia, cardiomyopathies, HTN),

Hypothyroidism,

Obesity,

Genetic predispositions (congenital long QT syndromes or other variants)

What is heparin induced thrombocytopenia (HIT)?

Immune mediated adverse rxn to heparin

What is the mechanism of HIT?

IgG antibodies form against complexes of heparin and platelet factor 4 (PF4)

→ activates platelets

→ thrombocytopenia (low platelets)

AND → pro-thrombotic state (increased clotting risk)

What are detrimental effects of HIT?

Despite causing low platelet counts, HIT triggers thrombosis (blood clots) which can affect any vascular bed

True or False: HIT can cause venous thrombosis at sites of catheters

True

Other atypical presentations include

- bilateral adrenal hemorrhage

- venous limb gangrene

- skin necrosis

How is HIT diagnosed?

clinical assessment + lab testing

What's the 4Ts score?

estimates the probability of HIT

What are the 4Ts?

Thrombocytopenia, Thrombosis, Timing, and oTher causes

True or False: thrombocytopenia manifests as an increase in platelet counts

False

manifests as a drop or relative decline in platelet counts that is often moderate and NOT associated with bleeding complications

What does the severity of thrombocytopenia correlate to?

thrombotic risk

patients with marked thrombocytopenia have 8x more risk of thrombosis vs patients with a 'relative decline' (

What is the most severe complication of HIT?

thrombosis

Can you be asymptomatic and have thrombosis?

Yes

Some seropositive patients are asymptomatic vs others progress to severe disease, but this is unclear because there are NO differences in traditional markers (i.e., protein C, protein S, antithrombin, or factor V) → Some newer studies state that serologic features may be associated with thrombotic risk (i.e., IgG isotype, capacity to activate platelets, and high antibody levels)

How long does the thrombosis risk remain elevated for after diagnosis?

4-6 weeks due to circulating antibodies

What is the most important diagnostic element of HIT?

timing

What is the timing if you are a heparin virgin (first time having heparin)?

PF4 and heparin antibodies appear around 4 days after starting therapy

What is the timing if you had recent heparin exposure (within 100 days)?

thrombocytopenia develops within 24 hours of re-exposure

What is the timing of clinical manifestations of HIT?

thrombocytopenia +/- thrombosis develops 5-14 days after initial heparin therapy (usually 2 days after antibody detection)

What is the timing of delayed HIT?

days to weeks after D/C of heparin

What causes delayed HIT?

Antibodies that are cross-reactive with PF4/GAG complexes found on cell surfaces can trigger heparin-independent platelet activation in functional assays

How long does it take for HIT antibodies to clear the body?

50 days via platelet activation assays

OR 85-90 days by immunoassays

True or False: HIT antibodies can stay in the body for 2 years

False, some stay for ONE year

What is the timing for platelets to rebound after HIT?

within 1 week of D/C heparin

What is the function of lab tests for HIT?

detects HIT antibodies and/or platelet activation

What are the types of lab tests for HIT?

immunoassays and functional assays

What is another name for functional assays?

platelet activation assays

How do immunoassays work for HIT?

measures the presence of anti-PF4/heparin antibodies using a variety of antibody capture platforms

What are the +/- of immunoassays for HIT?

+ simply, high sensitivity

- low specificity (low positives that can be increased through IgG detection and quantifications of OD +/- titers)

How do functional assays work for HIT?

detects antibodies capable of binding and cross-linking platelet FcgRIIA

What are the +/- of functional assays for HIT?

+ high specificity, high PPVs

- low sensitivity (depends on functional end points of the assay), more challenging, not routinely performed

What is the first step of HIT treatment?

D/C all forms of heparin

What are the following steps of HIT treatment?

initiate parenteral alternative agents and you can also overlap with warfarin

How long should parenteral alternative agents be administered for isolated HIT?

4 weeks

How long should parenteral alternative agents be administered for HIT + thrombosis?

3 months

When would overlapping with warfarin be appropriate for HIT treatment?

after platelet counts recover to a stable baseline or greater

How should we treat a patient if they are on warfarin at time of HIT diagnosis?

reversal with vitamin K

Which meds most commonly cause drug induced lung disease (DILD)?

cancer drugs > DMARDs > amiodarone > antibiotics

What is the full list of meds that cause DILD?

1. cancer meds

2. DMARDs

3. antibiotics

4. NSAIDS

5. psychiatrics

6. antiarrhythmic

Which cancer meds cause DILD?

Bleomycin, gemcitabine, epidermal growth factor receptor (EGFR)- directed therapies, mechanistic target of rapamycin protein (MTOR) inhibitors, and immune checkpoint inhibitors, MTX

Which DMARDs cause DILD?

MTX, leflunomide, TNFi

Which antibiotics cause DILD?

nitrofurantoin, daptomycin

What is an important risk factor for amiodarone-related DILD?

cumulative dose and combination of high doses over longer periods

How does amiodarone cause DILD?

amiodarone is highly lipophilic and accumulates in lung tissue, where it can cause direct cytotoxic injury & immune-mediated inflammation through generating toxic oxygen radicals & phospholipid accumulation (phospholipidosis) → lung injury

True or False: Drug-induced interstitial lung disease (DIILD) occurs when exposure to a drug causes inflammation and eventually fibrosis of the lung interstitium

True

What are types of ILD?

most common: chronic interstitial pneumonitis