Ammonia Levels

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C3.1 R4(e): Perform & document a pharmacokinetic interpretation (OTHER drug)

Interpretation #1 of SB:

MAR 1/ 17 (1000hr) Clinical Pharmacy Note RE: Valproic Acid Level

ID: 24 yo female, 40kg with atypical Angelman’s Syndrome, admitted for uncontrolled status epilepticus

S/O:
Currently on VPA 250mg via G-tube AM and 500mg via G-tube PM. During hospital stay, was started on valproic acid and given varying doses at different times as detailed below:

  • Feb 25, 2350hr: 800mg IV → Feb 26, 250hr: 400mg IV
  • Feb 27, 1130hr: 750mg via G-tube and 2200hr: 500mg via G-tube
  • Feb 28, 800hr: (↓) 250mg via G-tube
    → level taken 30 mins prior to 2100hr dose of 500mg: 277 umol/L (target: 350-700)

Previous levels:
Feb 26, 448hr: 815 umol/L (random level)
Feb 26, 1255hr: 629 umol/L (10 hr post-dose)
Other labs: Alb (Feb 26) : 32 g/L; PLTs (Feb 28): 114 (↓142 from 26th); eGFR: >150mL/min (stable), LFTs WNL

  • Difficult to assess safety of valproic acid as patient is non-verbal and RASS -3
  • Unclear to neurology if any EEG changes with short episodes of grinning but thought to have no epileptiform activity on EEG for the past 24 hours

A:

  • Trough level taken appropriately 30 mins prior to dose, and subtherapeutic
  • Not a true steady state level of current dose
  • Potential drug interaction with topiramate: ↓ levels of topiramate and valproic acid and ↑ risk of encephalopathy, hyperammonemia, ↓ platelets

P:

  • Discussed with neurology and plan is to wean off valproic acid after extubation or sooner. No changes to other anti-epileptics (clobazam, topiramate, levetiracetam)
  • Continue to monitor for AEs while on valproic acid, such as tremors, confusion, drowsiness, nausea, diarrhea and thrombocytopenia

Reflection and feedback:

  • Important to provide own assessment of appropriateness and efficacy of VPA and all notes regarding levels → at this point in time, it seemed that valproic acid while appropriate may not be doing much for epilepsy management as levels are currently sub-therapeutic

Progression in hospital: Valproic acid was titrated down to 250mg via G-tube BID, and levetiracetam was increased from 1000mg BID to 1500mg BID. On Mar 2, epileptologist (who was following SB as out-patient) noted EEG changes consistent with seizures. Parents are also observing seizures (presenting as arrhythmic mouth opening and grinning). Valproic acid load was given, maintenance dose was increased and propofol (previously weaned off) was restarted. Valproic peak level (2hrs post IV load dose was given, daily valproic acid levels prior to AM dose, and ammonia levels were ordered.


Interpretation #2 of SB:

Mar 3, 2017 (1000hr) Clinical Pharmacy Note RE: Valproic Acid Levels

ID: 24 yo female, 40kg admitted with status epilepticus
HPI: EEG changes found to be reflective of seizure activity and valproic acid was increased and propofol restarted

S/O:
Valproic acid dose changes since last note:

  • Feb 28: 250mg G-tube AM, 500mg G-tube PM
  • Mar 1: 250mg G-tube AM, 250mg G-tube PM
  • Mar 2: 250mg G-tube at 800hr
    → 600mg IV loading dose at 1200hr and VPA ↑ to 750mg BID at 600hr and 1800hr
  • Valproic acid levels:
    • 2 hours post loading dose: 543 umol/L
    • 30 mins pre AM 750mg dose: 295 umol/L
  • Ammonia levels: Mar 2: 54 umol/L → Mar 3: 44 umol/L
  • LFTs (last done on Feb 26): WNL
  • RASS -4 and still on propofol → difficult to assess efficacy and safety of valproic acid

A:

  • Valproic acid appropriate for seizures and currently titrating up to therapeutic levels
  • Recent ↑ in VPA is appropriate as peak level post load was only in therapeutic range for a trough level
  • Steady state of valproic acid (half life: 9-19 hrs) tends to take 2-4 days
  • Ammonia is elevated but not significantly. VPA-associated hyperammonemia is typically associated with ammonia levels of 75-283 umol/L. Hyperammonemia can also be asymptomatic

P: Discussed with doctor

  • Continue current VPA dose and daily VPA levels
  • Monitor for AEs of VPA: drowsiness, tremors, N/V/D, thrombocytopenia
  • Monitor ammonia and LFTs daily while in ICU
  • Monitor for valproate-induced hyperammonemic encephalopathy: confusion, lethargy, vomiting, increased seizure frequency

Reflection and Feedback:

  • Important to understand and assess appropriateness of what is happening for patient prior to assessing the level
  • Questions to ask yourself while assessing drug levels:
    • In what situations should a peak level be ordered (esp, for a drug where monitoring is usually done with trough levels)?
      → In this case, varying doses have been given and patient has been on a relatively low dose of VPA, so a peak level was done post-dose to see if it was in therapeutic range. If peak level is sub-therapeutic, current dose is probably not sufficient. If peak level is therapeutic or above therapeutic level, the appropriateness of current dose is more difficult to assess.
    • If a peak level is warranted, when should it be ordered?
      → Consider: volume of distribution and required time for the drug to distribute throughout the body
    • How often should you monitor levels?
      → Consider: urgency, severity of clinical situation, and what will help dictate therapy and dose adjustments
    • What are the pharmacokinetics of the drug you are monitoring? And, how does it affect your interpretation of the levels?

Follow-up:

Mar 6, 2017

S/O:
Propofol increased to 100 mcg/kg/min IV infusion (FYI: feeds had to be decreased as feeding “fat” with propofol) 
Valproic Acid doses since last note:

  • Mar 3: (pre-AM level: 295 umol/L) 750mg Gtube at 600hr, 600mg IV at 1025hr, 750mg Gtube at 1800hr
  • Mar 4: (pre-AM level: 260 umol/L) 750mg Gtube at 600hr, 500mg IV at 1200hr, 750mg Gtube at 1800hr
  • Mar 5: (pre-AM level: 282 umol/L) 750mg G tube at 600hr, 500mg IV at 1200hr, (↑) 1000mg Gtube at 1800hr
  • Mar 6: (pre-AM level: 358 umol/L) 1000mg Gtube at 600hr and 1800hr

Neurology to d/w EEG and assess if any seizures on the weekend. Plan is to wean off propofol. Continue daily VPA levels – unlikely to be therapeutic with 1g BID as therapeutic level reached with multiple IV loading doses.


Valproic Acid:chemically related to free fatty acids and is used in the treatment of generalized, partial, and absence (petit mal) seizures. Has a broad spectrum of activity

Pharmacokinetics:

  • Kinetics: NON-linear
    • Due to concentration-dependent protein binding of valproic acid
  • Distribution: CSF at concentration similar to unbound concentration in plasma
    (i.e. ~10% of total plasma concentration)

    • Vd = 0.15L/kg
  • Protein binding (concentration dependent): 80-90%
    • Decreased in elderly and patients with hepatic or renal impairment
    • Due to concentration-dependent protein binding: may take several week to achieve a therapeutic effect despite already reaching therapeutic range at ss
  • Metabolism: extensively hepatic
  • Bio-availability:
    • Depakote ER: ~90% relative to IV and ~89% relative to delayed release formulation
  • Time to peak:
    • Depakote tablet and sprinkle capsules: ~ 4 hrs
    • Depakote ER: 4-17 hrs
    • Epival: 4 hrs
  • Half-life elimination:
    • Adults: 9-19 hours

Levels:

  • Trough within 30 mins prior to dose
  • Sampling should ideally be done prior to same dose, preferably AM dose – due to effects of diurnal variation on clearance
  • Initially after reading steady state (usually 2-4 days) and after each dosing adjustment at steady state

Free VPA levels: indicated if:

  • Total VPA dose is >60mg/kg/day (max dose)
    OR
  • Seizure-free at a total level of <350 umol/L and need to determine whether a dosage increase is necessary
    OR
  • exhibiting signs of toxicity at a dosage of <60mg/kg/day
    OR
  • unique subpopulation (e.g. pregnant female, patient on multiple anticonvulsant therapy, etc)

Other monitoring:

  • Adverse reactions: tremors, confusion, drowsiness, insomnia, nausea, vomiting, diarrhea
  • Hepatotoxicity (LFTs), CBCs (dose-related thrombocytopenia), Ammonia (if suspect encephalopathy) – ammonia should be sent on ice and stat!

References:

C3.1 R4(e): Perform & document a pharmacokinetic interpretation (OTHER drug)

ID: 72 yo female with bipolar type II disorder and mild Alzheimer’s

s/o:

  • Taking divalproex EC 1000mg po daily at 800hr since Sept 28, 2016 (no compliance issue in hospital)
    • As per P’net, patient was also on divalproex EC 1000mg po daily PTA (but likely non-compliant as valproic acid level on admission (Sept 26) was 36 umol/L)
  • Valproic acid level: 513 umol/L (350-835 umol/L)
    • Taken on Oct 5, 2016 (12 hours post 800 hr dose)
      SPH lab bases on 12 hr-post dose trough concentration, regardless of dosing frequency as studies have shown that its best for interpretation
  • Oct 5, 2016 Labs:
    Alb: 30g/L, AST = 20, ALT = 12, GGT = 8, ALP = 57, total bilirubin = 5 umol/L
  • As of Oct 6, 2016 – patient denies any concerns or side effects with divalproex (e.g. no tremors, weakness, dizziness, stomach upset). Patient feels that her mood is stable (denies low or elevated mood, issues with sleep and energy)

A:

  1. Level is drawn appropriately and at steady state
  2. Level is within therapeutic range. However, albumin is slightly low and also considering her age the protein binding to valproic acid might be lower and total valproic acid level might noe be reflective that free valproic acid level is within therapeutic range. Her free valproic acid level is likely higher than someone who is younger and have normal albumin levels.
  3. Patient denies any issues with her mood and there are no significant safety concerns with divalproex

P:

  1. Continue current dose of divalproex 1000mg EC po daily
  2. Monitor for adverse reactions of divalproex (e.g. tremors, dizziness, insomnia, stomach upset)

C3.1 R4(e): Perform & document a pharmacokinetic interpretation (OTHER drug) #2

ID: 47 yo male admitted on July 6, 2016 with unspecified psychosis

Medical conditions:

  • Schizoaffective disorder vs. Bipolar I manic disorder
  • (Previous?) Cluster B personality disorder
  • Methamphetamine use disorder
  • Opioid use disorder (on methadone for 20 years ago, started heroin at 15 yo)
  • Tobacco use disorder

Global Assessment Functining (GAF) = 20-25

Medications:

  • Nicotine patch 21mg/24hr apply 1 patch daily
  • Ferrous fumarate 300mg PO daily
  • ascorbic acid (vitamin C) 500mg PO daily
  • Vitamin D 1000 units PO daily
  • Multi-vitamins – 1 tab PO daily
  • Divalproex EC 500mg tab PO daily (800) and 2000mg PO hs (2200)
    ?Start date in hospital (as chart thinned), but has been on it at this dose at least since the end of Aug
  • Lithium carbonate 900mg PO hs (2200)
    Aug 23: started on 300mg PO hs, 24: ↑ 600mg hs, 29: ↑ 1050mg hs
    Sept 6: ↓ 900mg hs (RN noticed mild tremor, and ++ akathisia – marked restlessness, unable to sit, asking if he can pace, speech – N volume/speed, good eye contact) 

    • Last lithium levels:
      Sept 10: 0.7, Sept 4: 0.9, Aug 29: 0.5
  • Methadone 100mg po daily
  • Trazodone 250mg po hs
  • Quetiapine 800mg po hs
  • Mirtazapine 7.5mg po hs
  • Zuclopenthixol 20mg po hs

 


Levels drawn on Sept 28:

  • VPA level (drawn at 1000 hr, hold dose until drawn): 563
    • 12-hour post dose
    • AM dose was given at 1030 instead of 800
    • Therapeutic range: 350 – 835 umol/L
  • Lithium level (drawn at 1000hr): 0.70
    • 12-hour post dose
    • Maintenance therapeutic range: 0.6-0.8 mmol/L

LFTs, Sept 5:
AST: 49, ALT: 40, GGT: <5, ALP: 46, Total bilirubin: 4

Renal function:
Sept 5 (1007): eGFR: 84 mL/min, sCr: 93 umol/L
Sept 5 (2040): eGFR: 69 mL/min, sCr: 109 umol/L
Sept 10 (955): eGFR: 85 mL/min, sCr: 92 umol/L

Patient interview:

  • Feels restless, kept pacing during interview and unable to sit in the chair
  • Feels mood is “low” for ?some period of time
  • Showed affect during interview and was pleasant throughout interview
  • Feels that his tremor is resolving since medication change
  • Writer not able to see any tremors when patient raised his arms outwards
  • Denies N/V and any concerns/side effects with medications

Assessment:

  1. Levels drawn appropriately and at steady state
    (>5 days since starting on current dose)
  2. Level is within therapeutic range (0.6-0.8 mmol/L for maintenance)
  3. No significant safety concerns with current doses of valproic acid and lithium
    – No renal impairment
    – No liver impairment
    – Patient has minimal side effects and concerns with medication (no hand tremors)
  4. As per psychiatrist and nurse’s notes, patient is clinically improving and exhibits less aggression.

Plan:

  1. Continue current doses of valproic acid and lithium
  2. Monitor AEs of valproic acid: ataxia, tremors, visual changes, N/V/D, anorexia
  3. Monitor hepatic function (LFTs, albumin, bilirubin, INR) every 6 months or earlier if patient exhibits symptoms of hepatotoxicity (e.g. malaise, confusion, jaundice, vomiting, anorexia, abdominal distension/bloating, asterixis, spider veins)
  4. Monitor AEs of lithium: headache, tremor, N/V, polydipsia, polyuria, weight gain
  5. Monitor lithium levels and renal function monthly (may decrease frequency to every 3 months when dose is determined to be efficacious, safe and patient is stable)
  6. Monitor for efficacy:
    mood (+affect), thoughts, sleep, appetite, energy, auditory/visual hallucinations

FYI: Previous Pharmacist’s Clinical Note on Lithium on Sept 1, 2016

Baseline TSH 1.77, Cr 78

  • Lithium therapy started Aug 23 at 300mg HS, Aug 24 at 600mg HS
  • On Li 750 HS Aug 25-28, 2016
  • Li level = 0.5 on Aug 29, 2016 morning at 1000 hr
    • subtherapeutic as still titrating upwards
    • may be slightly early to consider this steady state level
    • dose increase to 1050mg HS
  • Met pt in dining room. denies headache. denies N/V. reports good appetite. No slurred speech. vision ✓, able to see clock on wall and tell me time accordingly
  • However, displaying fine tremor in hand bilaterally. per pt, been trembling for about a week (temporally, coincide with lithium start)
  • Drug interaction = Zuclopenthixol, Lithium, Methadone, Olanzapine, Trazodone can all prolong QT interval
    • pt July 28 ECG = 475ms
  • As pt likely experiencing minor hand tremor, secondary to Li
  • Suggest:
    1. Continue clinically monitoring with focus on tremor as escalating Li dose
    2. Repeat ECG x1 once reach a stable Li dose

 

C3.1 R4(e): Perform & document a phenytoin pharmacokinetic interpretation

Clinical Pharmacy Note RE: Phenytoin Levels

ID: 47 yo male with history of seizure disorders (?type of seizure ?unclear history)
(As per nurse, patient reports that last seizure, which was a petit mal seizure, was 2 months ago)

wt = 105.9kg, ht = 5 ft 10 inches, BMI = 33.4 kg/m2

Current regular medications:

  • Phenytoin 200mg extended release capsules PO BID (800hr, 2200hr)
    • Started on Sept 23, 2016 at HS
    • Was on same dose PTA but as per team care binder, did not take it on Sept 21/22
    • As per nurse, no issue swallowing capsules
  • Divalproex EC 250mg PO BID
    • Started on Sept 28, 2016 at HS
    • Dose ↑ on Sept 29, 2016 (today) to 250mg AM (same )and 500mg HS (↑)
  • Paliperidone 100mg IM q 4 weeks
  • Olanzapine 15mg PO HS
  • Nicotine Replacement Therapy

Phenytoin Levels (Target: 40-80 umol/L):

  • Sept 23, 2016: 5 umol/L (prior to 1st dose in hospital)
  • Sept 29, 2016: 11 umol/L at 1000hr (prior to Sept 29 AM dose)

Sept 29, 2016: Alb: 37 g/L        Sept 23, 2016:  sCr: 89umol/L,  eGFR: 92 mL/min

A:

  1. As per nurse, patient has not had a seizure during hospital stay.
  2. All doses given appropriately and on time.
  3. Phenytoin trough concentration drawn appropriately (12 hours post-dose)
  4. Level is likely not at steady state but trending upwards (average half-life: ~22 hrs, but can range from 7 to 42 hrs due to saturation kinetics. Time to steady state can range from 3 to 50 days)
  5. Using IBW (as patient is obese), maintenance dose should be 365-512 mg/day
  6. Drug interactions with phenytoin (Lexicomp):
    – Divalproex may ↓ the protein binding of phenytoin (as both compete for binding to albumin). This may lead to an initial ↑ in free phenytoin and to a ↓ in total phenytoin concentrations. With long-term concurrent use, total phenytoin concentrations may ↑.
    – Phenytoin may ↓ the serum concentration of divalproex. There is also a potential for hepatotoxicity due to the ↑ concentration of a hepatotoxic valproic metabolite if phenytoin dose is increased.
    – Phenytoin may ↓ the concentration of paliperidone and trazodone
    – Trazodone may ↑ the concentration of phenytoin
  7. As divalproex dose is being increased to pre-admission dose, total phenytoin levels may not accurately indicate that patient is on a therapeutic dose.

P: Suggest

  1. Continue current phenytoin dose, and monitor patient closely for seizures
  2. Monitor phenytoin concentrations weekly. Level next week will reflect a concentrations closer to steady state.
  3. Consider doing free phenytoin levels to assess efficacy and safety, if levels continue to remain subtherapeutic.
  4. Monitor AEs of phenytoin: ataxia, confusion, dizziness, somnolence, headache, slurred speech, N/V, nystagmus