Drug Induced AW

Examples of drug induced diseases

-HIT: heparin induced thrombocytopenia

-TdP: Torsades de Pointes

-ILD: interstitial lung disease

HIT pathophys

-Heparin induced thrombocytopenia

-Immune complication of heparin therapy caused by antibodies to complexes of platelet factor 4 (PF4) and heparin

-Antibodies cause the platelet complexes to clump together and form thrombi

Risks of HIT

-Thrombosis: usually venous thrombi

-Atypical presentations: bilateral adrenal hemorrhage, venous limb gangrene, skin necrosis

Diagnosing HIT

-Occurs ~5-14 days from start of heparin therapy (within 1 day if heparin reexposure occurring

4T scoring system calculation

-Timing of heparin therapy

-Complications of thrombocytopenia and thrombosis

-Exclusion of other causes

-Categorizes HIT likelihood based on cumulative score

-0-3: low risk

-4-5: intermediate risk

-6-8: high risk

4T scoring system accuracy

-Low risk outcome is usually accurate

-Intermediate to high risk outcome may be less accurate at predicting disease

HIT expert probability score

-Developed by Cuker and colleagues

-Utilizes 8 clinical features and broad expert opinion to assign clinical significance

HIT expert probability score accuracy

-Still undergoing prospective validation

-Tentative improved correlation with serologic HIT testing and improved inter-observer agreement compared to 4Ts score

Lab diagnostics of HIT

-Necessary for diagnosis

-Platelet activation assays

-Immunoassays

Platelet activation assays

-AKA functional assays

-C-SRA, platelet aggregation

-High specificity >95% (correctly rules out people who don't have HIT)

-Lower sensitivity 56-100% (low ability to identify people who have HIT)

Immunoassays

-Measure presence of anti-PF4/heparin antibodies

-Use enzyme-linked immunosorbent assays, particle gel, immunoturbidimetric, etc.

-High sensitivity >99% (correctly identifies those with HIT)

-Low specificity 30-70% (low ability to rule out those without HIT)

Treating acute HIT

-D/C heparin

-IV direct thrombin inhibitors are preferred agents in critically ill

-Overlap with vitamin K antagonist only after platelets recover to stable baseline or > 150x10^9 (heightened risk of gangrene if given too early)

-Long term therapy: anticoagulation for 4 weeks if isolated HIT, and 3 months for HIT with thrombosis

Aragatroban

-Direct thrombin inhibitor for the treatment of HIT

-Hepatically cleared, need dose adjustment in liver impairment

Monitoring argatroban

-Monitor aPPT to decide dose adjustments

-Hemoglobin, hematocrit, s/s of bleeding

Torsades de Pointes

-Twisting of the Points

-Life threatening rapid heart rhythm in the lower chambers of the heart that create a twisting pattern in an ECG

-Caused by excessive QT prolongation

TdP ECG

Risk factors for TdP

-Electrolyte imbalances (hypokalemia, hyponatremia, hypocalcemia, hypomagnesaemia)

-Female

-Increasing age

-Time of day (diurnal variation)

-Myocardial ischemia, cardiomyopathies

-Hypothyroidism

-Obseity

-HTN

Drugs affecting QT interval

-Haloperidol

-Phenothiazines (chlorpromazine, promazine, fluphenazine, etc.)

-Azole antifungals

-Amiodarone (rarely causes TdP)

-And many more

Normal vs abnormal QTc

-Abnormal in men: QTc >450 ms

-Abnormal in women: QTC > 470 ms

-QTc >5000 is significant risk of TdP

Correction of the QT interval

-IV mag sulfate

-Electrical cardioversion

-D/C medications that prolong QT interval

DIILD

-Drug induced interstitial lung disease

-Exposure to a drug causes inflammation and eventually fibrosis of the lung interstitium

Drugs likely to cause ILD

-Amiodarone

-Nitrofurantoin

-Bleomycin

-Methotrexate

Bleomycin

-Treats Hodgkin's lymphoma

-6.8-21% risk, 48% mortality rate

-May be asymptomatic

MTX

-0.3-2.1% risk

Nitrofurantoin

-Accounts for 16-48% of the adverse events

-Reaction can occur within days to hours of nitrofurantoin exposure

Amiodarone

-One of the most common causes of DIILD

-1.2-8.8% incidence

-Especially with high doses of over longer periods of time

Types of ILD amiodarone can cause

-Subacute DIILD is most common

-Acute frequently fatal form can occur

-37% mortality rate

ILD treatment

-Remove offending agent

-Corticosteroids: limited data

-Wide variety of efficacy with GC

Glucocorticoids in treatment of amiodarone induced ILD

-1 mg/kg

-76% response but no obvious difference in survival outcomes