Cases in Primary Care

Lauren Foy, D.O.APN Pharmacology UpdateMarch 28, 2014Cases in Primary CareObjectivesIdentify the appropriate treatment for hypothyroidism, including appropriate medication dosing & monitoringAppropriately prescribe & monitor statins, including differentiating between moderate & high intensity statins according to the 2013 ACC/AHA hyperlipidemia guidelinesAppropriately prescribe and manage antiviral treatment for shingles, including length of treatment and choice of agentCase 145 year old female presents to the officeCC: I want my thyroid checkedROS: +fatigue, constipation, dry skin, steady weight gain over last few yearsFHx: +thyroid disorder (mom, MGM)PE: unremarkable, no thyromegaly or nodules palpatedLabs: TSH 7.5, FT4 35% reduction in LDL: suggest treatment with rosuvastatin, atorvastatin, or simvastatin cause the greatest percentage change in LDL-CPts with CKD: suggest treatment with atorvastatin or fluvastatindo NOT require dose adjustmentPts with chronic liver disease who require a statin because of high cardiovascular risk: suggest complete abstinence from alcohol and the use of pravastatin at a low dose Pts on multiple medications: consider pravastatin, fluvastatin, rosuvastatin, and pitavastatin because they are not metabolized through the CYP3A4 & fewer pharmacokinetic drug interactions are likely to occur

Case 366 year old female presents to the officeCC: I have a rash for the last 2 daysROS: +burning, itchy, painful rash on side, HA yesterday, resolved now, +malaise, denies fevers/chills, recent illnessPMHx: HTN, anxietyFHx: unremarkablePE: VSS, afebrilePhysical Exam

Case 3, continuedDx: Shingles (Zoster)Treatment: start antiviral medication & monitor response

What antiviral do I choose? What dose do start?Are there any labs I need to monitor?What are the adverse effects?

Clinical Presentation of Herpes ZosterCharacterized by painful vesicular eruptions in a dermatomal distributionMay be preceded by a prodromal phase with fever and malaise or pain over the affected dermatomeLesions continue to form over a period of 3 to 5 days, and disappear, often with a degree of scarring, after 10 to 15 daysChronic pain that may persist after the rash has healed is termed postherpetic neuralgia occurs in about 10% of patientsInvolvement of the trigeminal nerve can lead to sight-threatening ophthalmic herpes zosterHerpes zoster may be more severe and extensive in immunocompromised patients but is rarely fatalVZV PhysiologyMember of herpesviridae familyCauses 2 separate diseases: chickenpox (varicella) and herpes zoster (zoster, shingles)Primary infection with VZV usually occurs in childhood and results in chickenpoxIn immunocompetent persons, chickenpox is self-limiting and results in lifelong immunityVirus is not eliminated and remains dormant within sensory nerve gangliaIn later life or in immunocompromised persons, reactivation of the virus from the sensory nerve may occur and give rise to nerve pain and a dermatomal rash Immunocompromised patients may develop a second episode of chickenpox Infection may be acquired through the respiratory tract via airborne droplets or by close contact with infected individualsVZV Physiology

Antiviral treatmentCan reduce the severity and duration of acute pain, minimize complications and propagation of the rash, and reduce viral sheddingSystemic antivirals are recommended for:all immunocompetent patients who are over 50 years of agehave moderate to severe pain or rashhave non-truncal involvement. Treatment should be started within 72 hours of the onset of the rash and is usually continued for 7 to 10 days. Antiviral therapy may also be considered in those presenting 72 hours after the onset of the rash when:there are skin, motor, neurological, or ocular complicationswhen new vesicles are still formingin the elderlythose with severe pain.Topical antivirals are not recommended.Timing of TherapyAntiviral therapy should be initiated within 72 hours of clinical presentation in patients greater than 50 years of age to maximize the potential benefits of treatmentClinical utility of initiatingacyclovirtherapy more than 72 hours after the onset of lesions in the immunocompetent host is unknownTreatment should be considered if new lesions are still appearing at that time of clinical presentation, indicating ongoing viral replication Likely minimal benefit of antiviral therapy in the patient who has lesions that have encrusted.The rapid initiation of therapy is particularly critical in the severely immunocompromised patient, such as the organ transplant recipientAntiviral therapy should be initiated in all immunocompromised patients, even if they present after 72 hoursImmunocompromised hosts with disseminated zoster should be hospitalized for intravenousacyclovirtherapy.

Tx: Patients over 50 years of age

Recommend antiviral therapy for patients >50 years of age with uncomplicated herpes zoster who present within 72 hours of clinical symptomsAcyclovir,famciclovir, and valacyclovirhave all demonstrated clinical benefit and safety in the treatment of herpes zoster in immunocompetent patientsPrefer valacyclovir or famciclovir compared with acyclovir based on the convenience of less frequent dosing selection of drug may also be influenced by cost considerations. Duration of treatment is seven daysDosing is as follows:Acyclovir800 mg five times dailyFamciclovir500 mg three times dailyValacyclovir1000 mg three times daily

Tx: Patients under 50 years of ageEfficacy of antiviral therapy in patients less than 50 years of age has not been as well studied Risk of adverse events secondary to antiviral therapy is very low, and early treatment can decrease symptoms of acute neuritis and hasten resolution of cutaneous lesions Generally give antiviral therapy to patients 50 lesions) to promote more rapid healing and in those with acute neuritis to lessen the severity and duration of pain

Tx: Recurrent ZosterEpisodes of recurrent zoster are uncommonPatients with recurrent zoster should be treated with antiviral therapy with similar dosing and duration as for a primary episodeIn addition, patients who present with recurrent herpes simplex outside of the mouth or genital areas may be misdiagnosed with recurrent zosterviral cultures or other detection assays should be performed when a diagnosis of recurrent zoster is being considered

Acyclovir (Zovirax)Administration within 48 to 72 hours of the onset of rash has demonstrated clinical benefit in the treatment of acute neuritis and in the prevention of post-herpetic neuralgiaHas been the mainstay of herpes zoster txNeed for frequent daily dosing800mg PO 5 times daily x7-10days

Acyclovir: Mechanism of Action9-[2-hydroxymethyl]guanine; a nucleoside analogSelectively inhibits the replication of herpes simplex virus types 1 and 2 (HSV 1 & 2) and varicella-zoster virus (VZV)After intracellular uptake, it is converted to acyclovir monophosphate by virally-encoded thymidine kinaseThis step does not occur to any significant degree in uninfected cells and thereby lends specificity to the drug's activityThe monophosphate derivative is subsequently converted to acyclovir triphosphate by cellular enzymesAcyclovir triphosphate competitively inhibits viral DNA polymerase by acting as an analog to deoxyguanosine triphosphate (dGTP)Incorporation of acyclovir triphosphate into DNA results in chain termination since the absence of a 3' hydroxyl group prevents the attachment of additional nucleosides Acyclovir triphosphate has a much higher affinity for viral DNA polymerase than for the cellular homolog, yielding a high therapeutic ratio

Acyclovir: MOA, continued

Acyclovir: PharmacokineticsModest oral bioavailability, ~15- 30%decreases with higher dosesmultiple oral doses of 200 to 800 mg yield steady-state peak plasma concentrations of 0.6 to 1.6 mcg/mLIV doses at 5 to 10 mg/kg every eight hours results in concentrations of 10 to 20 mcg/mLIV formulation should be used for serious infections such as disseminated varicella in an immunocompromised hostNot highly bound to plasma protein (~15%) Achieves widespread tissue and fluid penetrationincluding the CSF, in which acyclovir concentrations are ~50%of those in plasmaExcretion is predominantly renal, both by glomerular filtration and tubular secretionPlasma half-life is 2-3 hours in patients with normal renal functiondosage modifications are required in the presence of renal insufficiency, which is a risk factor for acyclovir-related neurotoxicity

Acyclovir: ToxicityAcute Renal Failureproduced by the precipitation of relatively insoluble acyclovir crystals in the renal tubulesan occasional complication of intravenous therapy Risk can be minimized by prior hydration (with the urine output maintained above 75 mL/hour) and slow drug infusion over one to two hoursNeurotoxicityRare reports of neurologic toxicity, particularly in patients with underlying renal failure, have included agitation, tremors, delirium, hallucinations, and myoclonus Severe neurotoxicity, characterized by delirium and coma, has been described at doses as low as 800 mg twice daily in patients requiring dialysis The potential for this complication is greater in patients treated with peritoneal dialysis, which is associated with minimal removal of acyclovir Peritoneal Dialysis Pts: daily doses of 600 to 800 mg/day should lead to safe serum acyclovir concentrations HD Pts: a loading dose of 400 mg followed by maintenance dosing of 200 mg twice daily plus 400 mg after each dialysis is recommended Patients who develop serious neurotoxicity should be treated with hemodialysis to remove the drug.

Acyclovir: Dose Adjustment in Renal ImpairmentCrCl 10-25 mLNormal dosing regimen 800 mg 5 times daily Administer 800 mg every 8 hours

CrCl