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- liver disease
- kidney disease
- thyroid disease
- heart or blood vessel disease
- blood disease
- brain disease
- problems with urination
- current or past alcohol abuse
- clumsiness or unsteadiness
- slurred speech or stuttering
- unusual excitement, irritability, or nervousness
- uncontrolled eye movements
- blurred or double vision
- mood or mental changes
- increase in seizures
- bleeding, tender, or swollen gums
- skin rash or itching
- enlarged glands in neck or armpits
- muscle weakness or pain
- airway opening drugs (bronchodilators) such as aminophylline, theophylline (Theo-Dur and other brands), and oxtriphylline (Choledyl and other brands)
- medicines that contain calcium, such as antacids and calcium supplements
- blood thinning drugs
- antibiotics such as clarithromycin (Biaxin), erythromycins, and sulfonamides (sulfa drugs)
- disulfiram (Antabuse), used to treat alcohol abuse
- fluoxetine (Prozac)
- monoamine oxidase inhibitors (MAO inhibitors) such as phenelzine (Nardil) or tranylcypromine (Parnate), used to treat conditions including depression and Parkinson's disease
- tricyclic antidepressants such as imipramine (Tofranil) or desipramine (Norpramin)
- acetaminophen (Tylenol)
- female hormones (estrogens)
- male hormones (androgens)
- cimetidine (Tagamet)
- central nervous system (CNS) depressants such as medicine for allergies, colds, hay fever, and asthma; sedatives; tranquilizers; prescription pain medicine; muscle relaxants; medicine for seizures; sleep aids; barbiturates; and anesthetics
- other anticonvulsant drugs
Anticonvulsant Drugs: Carbamazepine, Ethosuximide, Lamotrigine, Phenobarbital, Phenytoin, Primidone, Valproic Acid
SpecimenSerum (1 mL) collected in a red-top tube.
|Drug*||Route of Administration|
|Drug||Therapeutic Range Conventional Units||Conversion to SI units||Therapeutic Range SI Units||Half-Life (hr)||Volume of Distribution (L/kg)||Protein Binding (%)||Excretion|
|Carbamazepine||4–12 mcg/mL||SI units = Conventional Units × 4.23||17–51 micromol/L||15–40||0.8–1.8||60–80||Hepatic|
|Ethosuximide||40–100 mcg/mL||SI units = Conventional Units × 7.08||283–708 micromol/L||25–70||0.7||0–5||Renal|
|Lamotrigine||1–4 mcg/mL||SI units = Conventional Units × 3.9||4–16 micromol/L||25–33||0.9–1.3||50–5||Hepatic|
|Phenobarbital||Adult: 15–40 mcg/mL||SI units = Conventional Units × 4.31||Adult: 65–172 micromol/L||Adult: 50–140||0.5–1||40–50||80% Hepatic and 20% Renal|
|Child: 15–30 mcg/mL||SI units = Conventional Units × 4.31||Child: 65–129 micromol/L||Child: 40–70||80% Hepatic and 20% Renal|
|Phenytoin||10–20 mcg/mL||SI units = Conventional Units × 3.96||40–79 micromol/L||20–40||0.6–0.7||85–95||Hepatic|
|Primidone||Adult: 5–12 mcg/mL||SI units = Conventional Units × 4.58||Adult: 23–55 micromol/L||4–12||0.5–1||0–20||Hepatic|
|Child: 7–10 mcg/mL||SI units = Conventional Units × 4.58||Child: 32–46 micromol/L|
|Valproic acid||50–125 mcg/mL||SI units = Conventional Units × 6.93||347–866 micromol/L||8–15||0.1–0.5||85–95||Hepatic|
Many factors must be considered in effective dosing and monitoring of therapeutic drugs, including patient age, patient weight, interacting medications, electrolyte balance, protein levels, water balance, conditions that affect absorption and excretion, and the ingestion of substances (e.g., foods, herbals, vitamins, and minerals) that can either potentiate or inhibit the intended target concentration. Peak and trough collection times should be documented carefully in relation to the time of medication administration.
The metabolism of many commonly prescribed medications is driven by the cytochrome P450 (CYP450) family of enzymes. Genetic variants can alter enzymatic activity that results in a spectrum of effects ranging from the total absence of drug metabolism to ultrafast metabolism. Impaired drug metabolism can prevent the intended therapeutic effect or even lead to serious adverse drug reactions. Poor metabolizers (PM) are at increased risk for drug-induced side effects due to accumulation of drug in the blood, while ultra-rapid metabolizers (UM) require a higher than normal dosage because the drug is metabolized over a shorter duration than intended. In the case of pro-drugs, which require activation prior to metabolism, the opposite occurs: PM may require a higher dose because the activated drug becomes available more slowly than intended, and UM requires less because the activated drug becomes available sooner than intended. Other genetic phenotypes used to report CYP450 results are intermediate metabolizer (IM) and extensive metabolizer (EM). Genetic testing can be performed on blood samples submitted to a laboratory. The test method commonly used is polymerase chain reaction. Counseling and informed written consent are generally required for genetic testing. CYP2C9 is a gene in the CYP450 family that metabolizes pro-drugs like phenytoin as well as other drugs like phenobarbital; the anticoagulant warfarin; and opioid analgesics like codeine, hydrocodone, dihydrocodeine, oxycodone, and tramadol. Testing for the most common genetic variants of CYP2C9 is used to predict altered enzyme activity and anticipate the most effective therapeutic plan. Incidence of the PM phenotype is estimated to be less than 0.04% of African Americans and less than 0.1% of Caucasians and Asians.
These medications are metabolized and excreted by the liver and kidneys and are therefore contraindicated in patients with hepatic or renal disease. Caution is advised for patients with renal impairment. Information regarding medications must be clearly and accurately communicated to avoid misunderstanding of the dose time in relation to the collection time. Miscommunication between the individual administering the medication and the individual collecting the specimen is the most frequent cause of subtherapeutic levels, toxic levels, and misleading information used in calculation of future doses. If administration of the drug is delayed, notify the appropriate department(s) to reschedule the blood draw and notify the requesting health-care provider (HCP) if the delay has caused any real or perceived therapeutic harm.
This procedure is contraindicated for
- Assist in the diagnosis of and prevention of toxicity
- Evaluate overdose, especially in combination with ethanol
- Monitor compliance with therapeutic regimen
|Normal levels||Therapeutic effect|
|Subtherapeutic levels||Adjust dose as indicated|
|Toxic levels||Adjust dose as indicated|
|Phenobarbital||Hepatic or renal impairment|
|Valproic acid||Hepatic impairment|
It is important to note the adverse effects of toxic and subtherapeutic levels. Care must be taken to investigate signs and symptoms of not enough medication and too much medication. Note and immediately report to the HCP any critically increased or subtherapeutic values and related symptoms.
It is essential that a critical finding be communicated immediately to the requesting HCP. A listing of these findings varies among facilities.
Timely notification of a critical finding for lab or diagnostic studies is a role expectation of the professional nurse. The notification processes will vary among facilities. Upon receipt of the critical finding the information should be read back to the caller to verify accuracy. Most policies require immediate notification of the primary HCP, hospitalist, or on-call HCP. Reported information includes the patient’s name, unique identifiers, critical finding, name of the person giving the report, and name of the person receiving the report. Documentation of notification should be made in the medical record with the name of the HCP notified, time and date of notification, and any orders received. Any delay in a timely report of a critical finding may require completion of a notification form with review by Risk Management.
Signs and symptoms of carbamazepine toxicity include respiratory depression, seizures, leukopenia, hyponatremia, hypotension, stupor, and possible coma. Possible interventions include gastric lavage (contraindicated if ileus is present); airway protection; administration of fluids and vasopressors for hypotension; treatment of seizures with diazepam, phenobarbital, or phenytoin; cardiac monitoring; monitoring of vital signs; and discontinuing the medication. Emetics are contraindicated.
Signs and symptoms of ethosuximide toxicity include nausea, vomiting, and lethargy. Possible interventions include administration of activated charcoal, administration of saline cathartic and gastric lavage (contraindicated if ileus is present), airway protection, hourly assessment of neurologic function, and discontinuing the medication.
Signs and symptoms of lamotrigine toxicity include severe skin rash, nausea, vomiting, ataxia, decreased levels of consciousness, coma, increased seizures, nystagmus. Possible interventions include administration of activated charcoal, administration of saline cathartic and gastric lavage (contraindicated if ileus is present), airway protection, hourly assessment of neurologic function, and discontinuing the medication
Signs and symptoms of phenobarbital toxicity include cold, clammy skin; ataxia; central nervous system (CNS) depression; hypothermia; hypotension; cyanosis; Cheyne-Stokes respiration; tachycardia; possible coma; and possible renal impairment. Possible interventions include gastric lavage, administration of activated charcoal with cathartic, airway protection, possible intubation and mechanical ventilation (especially during gastric lavage if there is no gag reflex), monitoring for hypotension, and discontinuing the medication.
Signs and symptoms of phenytoin toxicity include double vision, nystagmus, lethargy, CNS depression, and possible coma. Possible interventions include airway support, electrocardiographic monitoring, administration of activated charcoal, gastric lavage with warm saline or tap water, administration of saline or sorbitol cathartic, and discontinuing the medication.
Signs and symptoms of primidone toxicity include ataxia, anemia, CNS depression, lethargy, somnolence, vertigo, and visual disturbances. Possible interventions include airway protection, treatment of anemia with vitamin B12 and folate, and discontinuing the medication.
Signs and symptoms of valproic acid toxicity include loss of appetite, mental changes, numbness, tingling, and weakness. Possible interventions include administration of activated charcoal and naloxone and discontinuing the medication.
Carbamazepine: Greater Than 20 mcg/mL (SI: Greater Than 85 micromol/L)
Ethosuximide: Greater Than 200 mcg/mL (SI: Greater Than 1,416 micromol/L)
Lamotrigine: Greater Than 20 mcg/mL (SI: Greater Than 78 micromol/L)
Phenobarbital: Greater Than 60 mcg/mL (SI: Greater Than 259 micromol/L)
Phenytoin (Adults): Greater Than 40 mcg/mL (SI: Greater Than 158 micromol/L)
Primidone: Greater Than 15 mcg/mL (SI: Greater Than 69 micromol/L)
Valproic Acid: Greater Than 200 mcg/mL (SI: Greater Than 1,386 micromol/L)
- Blood drawn in serum separator tubes (gel tubes).
- Drugs that may increase carbamazepine levels or increase risk of toxicity include acetazolamide, azithromycin, bepridil, cimetidine, danazol, diltiazem, erythromycin, felodipine, fluoxetine, flurithromycin, fluvoxamine, gemfibrozil, isoniazid, itraconazole, josamycin, ketoconazole, loratadine, macrolides, niacinamide, nicardipine, nifedipine, nimodipine, nisoldipine, propoxyphene, ritonavir, terfenadine, troleandomycin, valproic acid, verapamil, and viloxazine.
- Drugs that may decrease carbamazepine levels include phenobarbital, phenytoin, and primidone.
- Carbamazepine may affect other body chemistries as seen by a decrease in calcium, sodium, T3, T4 levels, and WBC count and increase in ALT, alkaline phosphatase, ammonia, AST, and bilirubin levels.
- Drugs that may increase ethosuximide levels include isoniazid, ritonavir, and valproic acid.
- Drugs that may decrease ethosuximide levels include phenobarbital, phenytoin, and primidone.
- Drugs that may increase lamotrigine levels include valproic acid.
- Drugs that may decrease lamotrigine levels include acetaminophen, carbamazepine, hydantoins (e.g., phenytoin), oral contraceptives, orlistat, oxcarbazepine, phenobarbital, primidone, protease inhibitors (e.g., ritonavir), rifamycins (e.g., rifampin), and succinimides (e.g., ethosuximide).
- Drugs that may increase phenobarbital levels or increase risk of toxicity include barbital drugs, furosemide, primidone, salicylates, and valproic acid.
- Phenobarbital may affect the metabolism of other drugs, increasing their effectiveness, such as β-blockers, chloramphenicol, corticosteroids, doxycycline, griseofulvin, haloperidol, methylphenidate, phenothiazines, phenylbutazone, propoxyphene, quinidine, theophylline, tricyclic antidepressants, and valproic acid.
- Phenobarbital may affect the metabolism of other drugs, decreasing their effectiveness, such as chloramphenicol, cyclosporine, ethosuximide, oral anticoagulants, oral contraceptives, phenytoin, theophylline, vitamin D, and vitamin K.
- Phenobarbital is an active metabolite of primidone, and both drug levels should be monitored while the patient is receiving primidone to avoid either toxic or subtherapeutic levels of both medications.
- Phenobarbital may affect other body chemistries as seen by a decrease in bilirubin and calcium levels and increase in alkaline phosphatase, ammonia, and gamma glutamyl transferase levels.
- Drugs that may increase phenytoin levels or increase the risk of phenytoin toxicity include amiodarone, azapropazone, carbamazepine, chloramphenicol, cimetidine, disulfiram, ethanol, fluconazole, halothane, ibuprofen, imipramine, levodopa, metronidazole, miconazole, nifedipine, phenylbutazone, sulfonamides, trazodone, tricyclic antidepressants, and trimethoprim. Small changes in formulation (i.e., changes in brand) also may increase phenytoin levels or increase the risk of phenytoin toxicity.
- Drugs that may decrease phenytoin levels include bleomycin, carbamazepine, cisplatin, disulfiram, folic acid, intravenous fluids containing glucose, nitrofurantoin, oxacillin, rifampin, salicylates, and vinblastine.
- Primidone decreases the effectiveness of carbamazepine, ethosuximide, felbamate, lamotrigine, oral anticoagulants, oxcarbazepine, topiramate, and valproate.
- Primidone may affect other body chemistries as seen by a decrease in calcium levels and increase in alkaline phosphatase levels.
- Drugs that may increase valproic acid levels or increase risk of toxicity include dicumarol, phenylbutazone, and high doses of salicylate.
- Drugs that may decrease valproic acid levels include carbamazepine, phenobarbital, phenytoin, and primidone.
Nursing Implications and Procedure
- Positively identify the patient using at least two unique identifiers before providing care, treatment, or services.
- Patient Teaching: Inform the patient this test can assist with monitoring for subtherapeutic, therapeutic, or toxic drug levels.
- Obtain a history of the patient’s complaints, including a list of known allergens, especially allergies or sensitivities to latex.
- These medications are metabolized and excreted by the kidneys and liver. Obtain a history of the patient’s genitourinary and hepatobiliary systems, symptoms, and results of previously performed laboratory tests and diagnostic and surgical procedures.
- Obtain a list of the patient’s current medications, including herbs, nutritional supplements, and nutraceuticals (see Effects of Natural Products on Laboratory Values online at DavisPlus). Note the last time and dose of medication taken.
- Review the procedure with the patient. Inform the patient that specimen collection takes approximately 5 to 10 min. Address concerns about pain and explain that there may be some discomfort during the venipuncture.
- Sensitivity to social and cultural issues, as well as concern for modesty, is important in providing psychological support before, during, and after the procedure.
- Note that there are no food, fluid, or medication restrictions unless by medical direction.
- Potential complications:
Lack of consideration for the proper collection time relative to the dosing schedule can provide misleading information that may result in erroneous interpretation of levels, creating the potential for a medication-error-related injury to the patient.
- Avoid the use of equipment containing latex if the patient has a history of allergic reaction to latex.
- Direct the patient to breathe normally and to avoid unnecessary movement.
- Observe standard precautions, and follow the general guidelines in Patient Preparation and Specimen Collection. Consider recommended collection time in relation to the dosing schedule. Positively identify the patient, and label the appropriate specimen container with the corresponding patient demographics, initials of the person collecting the specimen, date, and time of collection, noting the last dose of medication taken. Perform a venipuncture.
- Remove the needle and apply direct pressure with dry gauze to stop bleeding. Observe/assess venipuncture site for bleeding or hematoma formation and secure gauze with adhesive bandage.
- Promptly transport the specimen to the laboratory for processing and analysis.
- Inform the patient that a report of the results will be made available to the requesting HCP, who will discuss the results with the patient.
- Nutritional Considerations: Antiepileptic drugs antagonize folic acid, and there is a corresponding slight increase in the incidence of fetal malformations in children of epileptic mothers. Women of childbearing age who are taking carbamazepine, phenobarbital, phenytoin, primadone, and/or valproic acid should also be prescribed supplemental folic acid to reduce the incidence of neural tube defects. Neonates born to epileptic mothers taking antiseizure medications during pregnancy may experience a temporary drug-induced deficiency of vitamin K–dependent coagulation factors. This can be avoided by administration of vitamin K to the mother in the last few weeks of pregnancy and to the infant at birth.
- Reinforce information given by the patient’s HCP regarding further testing, treatment, or referral to another HCP. Explain to the patient the importance of following the medication regimen and instructions regarding drug interactions. Instruct the patient to immediately report any unusual sensations (e.g., ataxia, dizziness, dyspnea, lethargy, rash, tremors, mental changes, weakness, or visual disturbances) to his or her HCP. Answer any questions or address any concerns voiced by the patient or family.
- Instruct the patient to be prepared to provide the pharmacist with a list of other medications he or she is already taking in the event that the requesting HCP prescribes a medication.
- Depending on the results of this procedure, additional testing may be performed to evaluate or monitor progression of the disease process and determine the need for a change in therapy. Evaluate test results in relation to the patient’s symptoms and other tests performed.
- Related tests include ALT, albumin, AST, bilirubin, BUN, creatinine, electrolytes, GGT, and protein blood total and fractions.
- See the Genitourinary and Hepatobiliary systems tables at the end of the book for related tests by body system.