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Neurologic Complications of Organ Transplantation Medication

  • Author: Jasvinder Chawla, MD, MBA; Chief Editor: Stephen A Berman, MD, PhD, MBA  more...
 
Updated: Feb 09, 2015
 

Medication Summary

Principles of medical therapy of neurologic complications in transplant patients are not altered by their transplant status. Nevertheless, additional attention must be paid to complex drug interactions and possible neurotoxicity so that the immunosuppression regimen and allograft function are not compromised.

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Antibiotics

Class Summary

Bacterial CNS infections are relatively uncommon in transplant recipients and are usually caused by opportunistic pathogens rare in immunocompetent individuals.

Ampicillin (Marcillin, Omnipen, Polycillin, Principen, Totacillin)

 

Bactericidal activity against susceptible organisms.

Gentamicin (Garamycin, I-Gent, Jenamicin)

 

Aminoglycoside antibiotic for gram-negative coverage. Used in combination with both an agent against gram-positive organisms and one that covers anaerobes.

Not the DOC. Consider if penicillins or other less toxic drugs are contraindicated, when clinically indicated, and in mixed infections caused by susceptible staphylococci and gram-negative organisms.

Dosing regimens are numerous; adjust dose based on CrCl and changes in volume of distribution. May be administered IV/IM.

Amoxicillin (Amoxil)

 

Derivative of ampicillin and has similar antibacterial spectrum, namely certain gram-positive and gram-negative organisms. Superior bioavailability and stability to gastric acid and has broader spectrum of activity than penicillin. Somewhat less active than that of penicillin against Streptococcus pneumococcus. Penicillin-resistant strains also resistant to amoxicillin, but higher doses may be effective. More effective against gram-negative organisms (eg, N meningitidis, H influenzae) than penicillin. Interferes with synthesis of cell wall mucopeptides during active multiplication resulting in bactericidal activity against susceptible bacteria.

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Antifungals

Class Summary

Fungal CNS infections are frequently fatal in transplant recipients, and early diagnosis and initiation of treatment are of uttermost importance.

Amphotericin (Amphocin, Fungizone)

 

Polyene antibiotic produced by a strain of Streptomyces nodosus. Can be fungistatic or fungicidal. Binds to sterols, such as ergosterol, in the fungal cell membrane, causing intracellular components to leak with subsequent fungal cell death.

Liposomal preparation is more expensive but is associated with less nephrotoxicity.

Voriconazole (VFEND)

 

Used for primary treatment of invasive aspergillosis and salvage treatment of Fusarium species or Scedosporium apiospermum infections. A triazole antifungal agent that inhibits fungal cytochrome P450-mediated 14-alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis. Also may be used in the treatment of coccidiosis and blastomycosis.

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Antiviral agents

Class Summary

Viral CNS infections in immunosuppressed transplant recipients are caused by a variety of pathogens, and early treatment is essential.

Acyclovir (Zovirax)

 

Has affinity for viral thymidine kinase and once phosphorylated causes DNA chain termination when acted on by DNA polymerase.

Has demonstrated inhibitory activity against both HSV-1 and HSV-2. Selectively incorporated into infected cells.

Ganciclovir (Cytovene, Vitrasert)

 

Used in the treatment of viral infections with limited response to acyclovir, particularly with CMV infections.

Synthetic guanine derivative active against CMV. An acyclic nucleoside analog of 2'-deoxyguanosine that inhibits replication of herpes viruses both in vitro and in vivo. Levels of ganciclovir-triphosphate are as much as 100-fold greater in CMV-infected cells than in uninfected cells, possibly because of preferential phosphorylation of ganciclovir in virus-infected cells.

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Immunomodulatory agents

Class Summary

Agents with targeted immunotherapy are emerging treatment options that may find wider use in the near future.

Rituximab (Rituxan)

 

Rituximab has been used in the treatment of PTLD and refractory myasthenia in transplant recipients and in the treatment of paraproteinemic neuropathies in nontransplant patients.

Antibody genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. Antibody is an IgG1 kappa immunoglobulin containing murine light and heavy chain variable region sequences and human constant region sequences.

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Anticonvulsant

Class Summary

Seizures in transplant recipients can be attributable to transient metabolic disturbances, drug neurotoxicity, focal CNS lesions, to the activation of a low seizure threshold, or to the exacerbation of a preexisting seizure disorder.

Long-term treatment with antiepileptic drugs (AEDs) may significantly complicate maintenance of immunosuppression because some AEDs (particularly phenytoin) may interfere with metabolism of cyclosporine and tacrolimus. Newer AEDs including topiramate, levetiracetam, and gabapentin seem to have a better adverse effect profile and may be better tolerated by transplant recipients.

Phenytoin (Dilantin)

 

First-line agent in the treatment of seizures and status epilepticus.

In transplant recipients, phenytoin may interfere with tacrolimus and cyclosporine metabolism.

Individualize dose. Administer larger dose before retiring if dose cannot be divided equally.

Fosphenytoin (Cerebyx)

 

Phenytoin derivative with better adverse effect profile.

Diphosphate ester salt of phenytoin, which acts as water-soluble prodrug of phenytoin. Following administration, plasma esterases convert fosphenytoin to phosphate, formaldehyde, and phenytoin. Phenytoin in turn stabilizes neuronal membranes and decreases seizure activity. To avoid need to perform molecular weight–based adjustments when converting between fosphenytoin and phenytoin sodium doses, express dose as phenytoin sodium equivalents (PE). Although can be administered IV and IM, IV route is route of choice and should be used in emergency situations.

Concomitant administration of an IV benzodiazepine is usually necessary to control status epilepticus. The antiepileptic effect of phenytoin, whether administered as fosphenytoin or parenteral phenytoin, is not immediate.

Midazolam (Versed)

 

Short-acting benzodiazepine used for sedation and treatment of refractory status epilepticus.

Because midazolam is water soluble, reaching peak EEG effects takes approximately 3 times longer than diazepam. Thus, the clinician must wait 2-3 min to fully evaluate sedative effects before initiating procedure or repeating dose.

Lorazepam (Ativan)

 

First-line medication for immediate treatment of seizures and status epilepticus.

By increasing the action of gamma-aminobutyric acid (GABA), which is a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation. Important to monitor patient's blood pressure after administering dose. Adjust as necessary.

Propofol (Diprivan)

 

Used in treatment of refractory status epilepticus.

Phenolic compound unrelated to other types of anticonvulsants. Has general anesthetic properties when administered IV.

Levetiracetam (Keppra)

 

Used as adjunct therapy for partial seizures and myoclonic seizures. Also indicated for primary generalized tonic-clonic seizures. Mechanism of action is unknown. Useful in transplant patients as it has minimal drug-drug interactions.

Topiramate (Topamax)

 

Used as add-on therapy for partial seizures.

May be used in patients with hepatic impairment, but use is limited by lack of IV preparation.

Sulfamate-substituted monosaccharide with broad spectrum of antiepileptic activity that may have a state-dependent sodium channel blocking action. Potentiates the inhibitory activity of GABA. May block glutamate activity. Not necessary to monitor topiramate plasma concentrations to optimize topiramate therapy. On occasions, addition of topiramate to phenytoin may require an adjustment of the dose of phenytoin to achieve optimal clinical outcome.

Valproic acid (Depacon, Depakene, Depakote)

 

Because of potential hepatotoxicity, this drug is avoided in liver transplant recipients.

Chemically unrelated to other drugs that treat seizure disorders. Although the mechanism of action is not established, activity may be related to increased brain levels of GABA or enhanced GABA action. Valproate may also potentiate postsynaptic GABA responses, affect potassium channels, or have a direct membrane-stabilizing effect. For conversion to monotherapy, concomitant AED dosage can ordinarily be reduced by approximately 25% q2wk. This reduction may start at initiation of therapy or be delayed by 1-2 wk if concern exists that seizures may occur with a reduction. Monitor patients closely during this period for increased seizure frequency.

As adjunctive therapy, divalproex sodium may be added to the patient's regimen at 10-15 mg/kg/d. May increase by 5-10 mg/kg/wk to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses < 60 mg/kg/d.

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Contributor Information and Disclosures
Author

Jasvinder Chawla, MD, MBA Chief of Neurology, Hines Veterans Affairs Hospital; Professor of Neurology, Loyola University Medical Center

Jasvinder Chawla, MD, MBA is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Howard S Kirshner, MD Professor of Neurology, Psychiatry and Hearing and Speech Sciences, Vice Chairman, Department of Neurology, Vanderbilt University School of Medicine; Director, Vanderbilt Stroke Center; Program Director, Stroke Service, Vanderbilt Stallworth Rehabilitation Hospital; Consulting Staff, Department of Neurology, Nashville Veterans Affairs Medical Center

Howard S Kirshner, MD is a member of the following medical societies: Alpha Omega Alpha, American Neurological Association, American Society of Neurorehabilitation, American Academy of Neurology, American Heart Association, American Medical Association, National Stroke Association, Phi Beta Kappa, Tennessee Medical Association

Disclosure: Nothing to disclose.

Chief Editor

Stephen A Berman, MD, PhD, MBA Professor of Neurology, University of Central Florida College of Medicine

Stephen A Berman, MD, PhD, MBA is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, Phi Beta Kappa

Disclosure: Nothing to disclose.

Additional Contributors

Norman C Reynolds, Jr, MD Neurologist, Veterans Affairs Medical Center of Milwaukee; Clinical Professor, Medical College of Wisconsin

Norman C Reynolds, Jr, MD is a member of the following medical societies: American Academy of Neurology, Association of Military Surgeons of the US, International Parkinson and Movement Disorder Society, Sigma Xi, Society for Neuroscience

Disclosure: Nothing to disclose.

Acknowledgements

Sasa Zivkovic, MD, PhD Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, University of Pittsburgh and VA Pittsburgh Healthcare System

Sasa Zivkovic, MD, PhD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and Peripheral Nerve Society

Disclosure: Baxter Bioscience Meeting attendance expenses Attendee

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Neurotoxicity of calcineurin inhibitors manifests on MRI with predominantly posterior hyperintensities on T2-weighted and FLAIR imaging sequences (FLAIR; TE 175.0, TR 9002).
Muscle cryostat section at pH 4.6 shows decreased ATPase reactivity with reduced (arrows) and absent (asterisk) muscle fiber staining in critical illness myopathy (courtesy of Dr David Lacomis).
 
 
 
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