Unwanted drug side effects can complicate care. Adverse neurologic effects of commonly used medications is a chapter of case series and clinical pearls of potential adverse drug events and clinical considerations to best prevent or manage these complications as a neurohospitalist. It includes 6 cases with questions to review in detail, including life-threatening bleeding, medications that reduce seizure threshold, drug-induced cognitive impairment, medication overuse headache, Parkinson disease, and statin induced myopathy. Clinical pearls are discussed in the chapter for medications that are most concerning for abrupt discontinuation and clinical presentation for drug-induced neuropathies with an emphasis on chemotherapeutic agents.

Unwanted side effects can complicate care. Knowing the likelihood and risks associated with specific medications or medication combinations can assist in the efforts of minimizing unwanted side effects for your patients. Considering the timeline of the clinical presentation with the timing of commencement of a medication is essential for diagnosis of a drug-induced syndrome. Polypharmacy increases the risk for potential adverse effects and drug interactions. Patients with comorbidities are also at an increased risk for adverse effects and may require continuation with a different therapy. Depending on comorbidities, use a consult service to collaborate on an alternative best plan for the patient. This chapter focuses on identifying the most likely offending agents and management strategies.

A short discontinuation of the most likely offending agent(s) should be considered when possible for assessing possible cause and effect. Reintroduction can be a method to confirm a drug-induced problem; however, the potential risk of the reoccurrence should be considered. The recovery phase from the drug-induced problem depends on the etiology of the drug-induced problem.

In many cases, possible sources of historical information include the primary physician, the local pharmacy used by the patient, or the pharmacist at the institution where the patient has previously or is currently hospitalized. A dose-related response is often typical of most drug-induced conditions.

What options are recommended for reversing warfarin and novel oral anticoagulants (NOACs) in the setting of a life-threatening bleeding episode?

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  The following interventions have been recommended for life-threatening bleeding associated with direct thrombin inhibitor (DTI) use:

  
  
  
  
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    An antibody fragment (idarucizamab) that binds to dabigatran yielding it inactive has recently been granted US Food and Drug Administration (FDA) approval. Idarucizamab has been shown to completely reverse the effects of dabigatran within minutes when administered as two 2.5-g (5 g) intravenous bolus doses no more than 15 minutes apart. The product must be given within 1 hour of admixture. The maximum percentage reversal of the anticoagulant effect of dabigatran occurred within 4 hours after the administration of idarucizumab, on the basis of the determination at a central laboratory of the dilute thrombin time or ecarin clotting time.¹ One thrombotic event in 90 patients occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated.¹

    
    
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    Activated charcoal if it has been less than 2 hours since the patient received the last dose of a DTI

    
    
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    Maintain adequate hydration and diuresis

    
    
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    Hemodialysis especially if the patient has kidney failure (consult Nephrology and Toxicology)

    
    
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    Platelet transfusion if the patient was receiving a concomitant antiplatelet medication

  
  

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  Reversal of warfarin typically involves administration of intravenous vitamin K 5–10 mg administered over 30 minutes PLUS administration of a clotting factor concentrate:²

  
  
  
  
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    Prothrombin complex concentrates (PCCs)

    
    
    
    
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      3-factor products contain coagulation factors II, IX, and X with little or no factor VII (eg, Profilnine, Bebulin)

      
      
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      4-factor products contain factors II, VII, IX, and X (eg, KCentra, FEIBA)

    
    
    
    
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    Fresh-frozen plasma (FFP)—generally not recommended for emergent reversal due to slow or incomplete INR reversal

  
  
  
  
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  At present, there is no approved antidote for the reversal of factor Xa inhibitors such as Xarelto (rivaroxaban) or Eliquis (apixaban). However, the following interventions have been recommended for life-threatening bleeding associated with factor Xa inhibitors:

  
  
  
  
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    Activated charcoal if it has been <1 hour since the patient received the last dose

    
    
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    Hemodialysis is likely to be ineffective, since these drugs are highly protein bound

    
    
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    PCC

    
    
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    Platelet transfusion if the patient is receiving concomitant antiplatelets

  
  

Andexant alpha is a factor Xa variant (andexanet alpha) that binds with affinity similar to that of native factor Xa and inactivates direct and indirect factor Xa inhibitors including low-molecular-weight heparins (LMWH) and fondaparinux. This is currently under investigation, and has been granted FDA breakthrough therapy designation. The factor Xa decoy is a recombinant, modified version of human factor Xa.³

Aripazine is a small water-soluble new molecular entity. It is a synthetic cationic peptide (D-arginine compound) that has broad activity. It purportedly reverses dabigatran and factor Xa inhibitors as well as some of the established anticoagulants heparin and LMWH. The “universal reversal agent” directly combines with the direct Xa- and IIa-inhibitors, fondaparinux, LMWH, and unfractionated heparins, allowing rapid re-establishment of a normal blood coagulation state.³

How do you know if you have achieved successful reversal?

Correction of laboratory values does not imply reversal; thus, laboratory values should be correlated with clinical and radiographic evidence of hemostasis (for reversal treatment details, see Chapter 52). Point-of-care laboratory tests such as thromboelastography (TEG) that measures global coagulation may provide additional information to determine the adequacy of reversal but may not be available in most centers. The following strategies may be used in relation to the individual classes of anticoagulants to judge the success of reversal:

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  Warfarin: Correction of INR depends on the INR value and severity of bleeding as to what agent(s) to use.

  
  
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  DTI—Correction of thrombin time (TT) AND activated partial thromboplastin time (aPTT):

  
  
  
  
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    If TT and aPTT are normal, direct thrombin inhibitors (DTI) concentration is likely very low.

    
    
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    If TT is normal and aPTT is slightly elevated, DTI concentration is likely very low.

    
    
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    If TT or aPTT is elevated, suggests presence of DTI.

  
  
  
  
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  Anti-Xa medications: Correction of anti-Xa level, or prothrombin time (PT)

  
  
  
  
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    Anti-Xa level has the strongest relationship between factor Xa concentration but is not routinely available

    
    
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    PT may be normal despite “on therapy” concentrations of factor Xa inhibitors

  
  

Should you restart anticoagulation after intracranial hemorrhage in patients with a history of A Fib? If so, when?

The decision whether to resume anticoagulation should always balance the risks of ischemic (cardioembolic) stroke due to A Fib versus the risk of recurrent bleeding. The following should be considered:

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  Location of the bleed

  
  
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  The risk of rebleeding likely outweighs the benefits of resuming anticoagulation in patients with lobar hemorrhage or cerebral amyloid angiopathy (CAA).

  
  
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  Risk/benefit analysis should be individualized in patients with deep brain hemorrhages (eg, putamen, thalamus, pons, or cerebellum). Some authors recommend restarting anticoagulation when CHADS2 score is ≥4, or CHA2Ds2-VASc ≥5.^4,5 A delay of 10 weeks is often recommended.

  
  
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  Hypertension is a risk factor for recurrent ICH regardless of location; treatment with antihypertensive medications decreases this risk.

  
  
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  In patients with subarachnoid hemorrhage (SAH), subdural hematoma (SDH), and intracerebral hemorrhage (ICH), the risk of ischemic stroke appears to be low in the weeks following the initial bleeding. Some authors recommend waiting at least 10 weeks to resume anticoagulation, although this decision should be individualized.^4,6

To minimize the risk of new or recurrent ICH, is there a preferred anticoagulant?

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  NOACs have generally been shown to have a lower risk of a first ICH than warfarin. Of the available NOACs, apixaban appears to have the most favorable pharmacokinetics in elderly patients compared to dabigatran and rivaroxaban.⁷

  
  
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  There are no studies comparing the risk of recurrent ICH in patients restarted on warfarin compared to NOACs.

  
  
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  The dose of NOACs may need to be adjusted for decreased renal function, advanced age, low body weight, and potential drug interactions.

How do you prevent bleeding in patients receiving NOACs scheduled for invasive procedures or surgery?⁸

Delay elective surgery or procedure after last anticoagulant dose based on:

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  Type of procedure

  
  
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  Agent

  
  
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  Renal function

High-risk surgery (eg, spinal or neurosurgery, vascular, abdominal, or cardiac surgery)

2 days: Dabigatran creatinine clearance (CrCl) >50 mL/min, or rivaroxaban and apixaban CrCl >30 mL/min

4 days: Dabigatran CrCl 31–50 mL/min, or rivaroxaban and apixaban CrCl <30 mL/min

6 days: Dabigatran CrCl <30 mL/min

Low-risk surgery (eg, diagnostic endoscopy, breast biopsy, cardiac catheterization, or minor orthopedic surgery)

24 hours: Dabigatran CrCl >50 mL/min or rivaroxaban and apixaban CrCl >30 mL/min

2 days: Dabigatran CrCl 31–50 mL/min or rivaroxaban and apixaban CrCl <30 mL/min

4 days: Dabigatran CrCl <30 mL/min

The influence of drug interactions on excretion is undetermined at present. However, those labeled as strong inducers or inhibitors of the medication should be considered, as in Table 50-1, for increased risk for bleeding or lack of coagulation protectiveness if held for more than 3 days. Medications cleared by CYP450 3A4 are often also impacted by the P-glycoprotein (P-gp) flux pump. The Hanston and Horn top 100 drug interactions is a good quick clinical reference. Drug pharmacokinetic monographs also list the route of metabolism and their ability to either inhibit or induce.

It was determined that the patient in case 1 was also receiving aspirin 325 mg daily. What options are available to “reverse” the effects of antiplatelet medications?⁹

There is a paucity of evidence for any intervention to improve outcomes in this setting. Options that may improve platelet function in the setting of cerebral hemorrhage include platelet transfusions and administration of desmopressin 0.3 µg/kg intravenously. Consultation with a hematologist is recommended.

Drug-induced seizures

What drug interactions may have increased the risk of seizures by lowering the seizure threshold in this case?

Carbapenem antibiotics have been shown in numerous cases to decrease valproic acid concentrations to undetectable levels. Although the proposed mechanism is unknown, decreased enterohepatic circulation and inhibition of hydrolysis of valproic acid–glucuronide to valproic acid have been reported. As such, this combination should be avoided, or alternatively, frequent monitoring of valproic acid concentrations if this combination cannot be avoided.

When should drug-induced seizures be suspected?

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  In patients who are stabilized and have well-controlled seizures, or in those with no history of seizures, the potential for drug-induced seizures should be investigated with any new-onset seizures in hospitalized patients

  
  
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  Temporal relationship between onset of seizures (or increase in seizure frequency) and drugs with known association with seizures

  
  
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  Administration of high doses or inappropriate adjustment for organ dysfunction of medications with known association with seizures

  
  
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  Seizures not responding to treatment with traditional antiepileptic drugs (AEDs), since these are generally ineffective in this setting

What medications are associated with seizures?

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  Anti-infective medications have been frequently implicated as a cause of drug-induced seizures.

  
  
  
  
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    Penicillins and structurally related antibiotics (eg, cephalosporins, carbapenems, and monobactams) and fluoroquinolones have been most commonly associated with drug-induced seizures.

    
    
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    Carbapenem antibiotics have the highest reported rates of seizures, with an incidence of 0.3–33%.¹⁰ Seizures may occur less frequently with the newer carbapenems (doripenem, meropenem, and ertapenem), although trials reporting higher seizure rates of imipenem–cilastatin included patients with other possible explanations for seizures.

    
    
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    The antituberculosis agent isoniazid (INH) has also been implicated in drug-induced seizures, mostly in cases of overdose. However, seizures have been reported in patients receiving INH at therapeutic doses.¹¹

  
  
  
  
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  Psychotropic medications such as phenothiazines, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and bupropion have also been associated with seizures.

  
  
  
  
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    Chlorpromazine has the highest incidence of seizures among the phenothiazines. This appears to be dose-related, more common among patients receiving >1000 mg/day.¹²

    
    
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    SSRIs have a lower incidence of seizures compared to bupropion (23%) and tricyclic antidepressants (7.7%).¹³

    
    
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    The highest rate of seizures among the antipsychotics is due to clozapine, with a reported cumulative risk of 10%. Clozapine-related seizures also appear to be dose-related, occurring more frequently among patients receiving doses ≥300 mg/day.^14,15

  
  
  
  
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  Analgesic medications have the potential to increase the risk of seizures, especially when combined with other medications or when used in patients with renal dysfunction.

  
  
  
  
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    Use of tramadol in patients receiving SSRIs, tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), or central nervous system (CNS) depressant medications is associated with high seizure risk. Caution should be used when administering tramadol to patients with CNS disorders (eg, history of seizures, stroke, or traumatic brain injury). Tramadol doses should be limited to no more than 200 mg daily administered no more frequently than every 12 hours in patients with renal or liver impairment.¹⁶

    
    
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    Meperidine should be avoided for routine use in ICU patients, as one of its active metabolites (normeperidine) has been associated with seizures, especially in patients with renal dysfunction. Moreover, meperidine within 14 days of MAOIs is contraindicated, since this combination may lead to a serotonin syndrome and related seizures.

  
  
  
  
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  Many other medications have been implicated in drug-induced seizures (Table 50-2).^17,18

Are there differences among classes of antibiotics in terms of seizure risk?

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  β-lactams

  
  
  
  
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    The β-lactam ring alone is epileptogenic. Structural differences among β-lactam and related antibiotics may be associated with convulsant activity:

    
    
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    Decreased convulsant activity

    
    
    
    
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      Addition of an amino group onto basic penicillin structure

      
      
      
      
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        Ampicillin

        
        
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        Amoxicillin

      
      
      
      
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      Addition of a ureido group onto basic penicillin structure

      
      
      
      
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        Piperacillin

      
      

    
    
    
    
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    No convulsant activity

    
    
    
    
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      Addition of a heterocyclic ring at position 7 on the basic cephalosporin structure

      
      
      
      
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        Cefoxitin

        
        
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        Cefuroxime

      
      

    
    
    
    
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    Increased convulsant activity

    
    
    
    
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      Addition of a tetrazole ring at position 7 on the basic cephalosporin structure

      
      
      
      
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        Cefazolin

      
      

    
    
    
    
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    Addition of a heterocyclic ring at position 3 and an aromatic nucleus at position 7 on the basic cephalosporin structure (moderately increased convulsant activity)

    
    
    
    
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      Ceftriaxone

      
      
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      Ceftazidime

      
      
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      Cefepime

      
      
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      Cefotetan

    
    
    
    
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    Increased basicity of the carbon-2 substitution on the carbapenem ring associated with greater affinity for the γ-aminobutyric acid (GABA) type A receptor complex

    
    
    
    
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      More basic

      
      
      
      
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        Imipenem

      
      
      
      
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      Less basic

      
      
      
      
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        Meropenem

        
        
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        Ertapenem

      
      

    
    

  
  
  
  
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  Fluoroquinolones

  
  
  
  
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    Piperazine ring substitutions at the 7 position on the parent fluoroquinolone molecule

    
    
    
    
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      Unsubstituted (increased convulsant activity)

      
      
      
      
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        Norfloxacin

        
        
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        Ciprofloxacin

      
      
      
      
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      Methyl substitution (less convulsant activity)

      
      
      
      
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        Ofloxacin

        
        
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        Levofloxacin

      
      

    
    

  
  

What is the mechanism of drug-induced seizures?

The mechanism of drug-induced seizures for the most common drugs can be found in Table 50-3. A clinical pharmacist or pharmacologist should be consulted for assessment of drug interactions and appropriate adjustments in patients with renal impairment.