Case Study Case Study

Initial Question Initial Question

Are there any drug interactions between labetalol, clonidine, amlodipine, lorazepam, and minoxidil?

Potential Response in the Absence of Relevant Potential Response in the Absence of Relevant Background InformationBackground Information

An extensive search of tertiary, and secondary An extensive search of tertiary, and secondary (MEDLINE®, EMBASE, and so forth) literature (MEDLINE®, EMBASE, and so forth) literature sources did not reveal any significant drug-sources did not reveal any significant drug-drug interactions between labetalol, clonidine, drug interactions between labetalol, clonidine, amlodipine, lorazepam, and minoxidil. amlodipine, lorazepam, and minoxidil. However, concomitant therapy with a However, concomitant therapy with a beta-beta-adrenergic antagonist, an alpha-2 agonist, a adrenergic antagonist, an alpha-2 agonist, a calcium-channel antagonist, and a periperal calcium-channel antagonist, and a periperal vasodilatorvasodilator may increase the potential for may increase the potential for additive additive hypotension.hypotension.

Pertinent Background Pertinent Background Information Information

The requestor is a physician who is caring for a The requestor is a physician who is caring for a patient with severe hypertension patient with severe hypertension

The physician plans to add minoxidil to the The physician plans to add minoxidil to the antihypertensive regimen because the patient's antihypertensive regimen because the patient's morning blood pressure is not optimally morning blood pressure is not optimally controlled. controlled.

He would like to make sure that there are no He would like to make sure that there are no drug interactions between minoxidil and the drug interactions between minoxidil and the patient's other medications. patient's other medications.

Pertinent Patient FactorsPertinent Patient Factors

S.L. is a 40-year-old HIV-infected man S.L. is a 40-year-old HIV-infected man with with severe hypertensionsevere hypertension and and renal renal dysfunction. dysfunction.

Past Medical HistoryPast Medical History HIV infection (2003) HIV infection (2003) Hepatitis C (2001) Hepatitis C (2001) Hypertension x 4 years Hypertension x 4 years Renal dysfunctionRenal dysfunction

Social History Social History 1 to 2 pints of vodka daily x 12 years 1 to 2 pints of vodka daily x 12 years 1 pack per day (PPD) of cigarettes x 25 years 1 pack per day (PPD) of cigarettes x 25 years History of intravenous drug abuseHistory of intravenous drug abuse

Current MedicationsCurrent Medications Labetalol 400 mg orally qd (@9 AM) Labetalol 400 mg orally qd (@9 AM) Clonidine transdermal patch 0.3 mg/day Clonidine transdermal patch 0.3 mg/day Amlodipine 10 mg orally daily (@9 AM) Amlodipine 10 mg orally daily (@9 AM) Lorazepam 1 mg orally as needed for Lorazepam 1 mg orally as needed for

anxiety anxiety Multiple vitamin tablet orally daily Multiple vitamin tablet orally daily

Allergies/IntolerancesAllergies/Intolerances Lisinopril (angioedema)Lisinopril (angioedema)

Laboratory ResultsLaboratory Results Sodium 136 mmol/L, potassium 4.7 mmol/L, Sodium 136 mmol/L, potassium 4.7 mmol/L,

chloride 102 mmol/L, CO2 24 mmol/L, creatinine 2.9 chloride 102 mmol/L, CO2 24 mmol/L, creatinine 2.9 mg/dL, glucose 98 mg/dL, BUN 14 mg/dL mg/dL, glucose 98 mg/dL, BUN 14 mg/dL

Viral DNA < 100 copies/mL Viral DNA < 100 copies/mL Cluster designation 4 (CD4) count 900 cells/mm3Cluster designation 4 (CD4) count 900 cells/mm3

Blood Pressure Blood Pressure Measurements (mmHg)Measurements (mmHg)

4/15 4/15 @ 6 AM 172/116 @ 6 AM 172/116 @ noon 121/81 @ noon 121/81 @ 8 PM 158/100 @ 8 PM 158/100

4/164/16 @ 6 AM 168/110 @ noon 116/86 @ 8 PM 150/104

•4/17 •@ 6 AM 178/114 •@ noon 119/84 •@ 8 PM 166/100

Pertinent Disease FactorsPertinent Disease Factors

It is not known whether patients with HIV It is not known whether patients with HIV infection respond differently to infection respond differently to antihypertensive medications.antihypertensive medications.

Pertinent Medication Pertinent Medication FactorsFactors

There are no primary or tertiary literature There are no primary or tertiary literature reports describing drug interactions between reports describing drug interactions between minoxidil and any of S.L.'s current medications minoxidil and any of S.L.'s current medications

A review of the patient's current A review of the patient's current antihypertensive medications suggests that the antihypertensive medications suggests that the dose of each agent is appropriate for achieving dose of each agent is appropriate for achieving adequate blood pressure control in the face of adequate blood pressure control in the face of significant renal compromise significant renal compromise

However, the duration of action of labetalol is 8 However, the duration of action of labetalol is 8 to 12 hours, and this agent is typically dosed to 12 hours, and this agent is typically dosed twice dailytwice daily. S.L. is receiving 400 mg of labetalol . S.L. is receiving 400 mg of labetalol daily at 9 AM. daily at 9 AM.

Analysis and SynthesisAnalysis and Synthesis S.L.'s blood pressure appears to be highest in S.L.'s blood pressure appears to be highest in

the morning, just before the daily doses of the morning, just before the daily doses of labetalol and amlodipine are administeredlabetalol and amlodipine are administered

Because the duration of action of labetalol is Because the duration of action of labetalol is 8 to 12 hours, and the usual maintenance 8 to 12 hours, and the usual maintenance dose is 200 to 400 mg twice daily, the dose is 200 to 400 mg twice daily, the increase in blood pressure observed in the increase in blood pressure observed in the morning could be due, at least in part, to morning could be due, at least in part, to inappropriate dosing of labetalol. inappropriate dosing of labetalol.

Labetalol should generally be administered Labetalol should generally be administered twice daily to achieve maximal benefit twice daily to achieve maximal benefit

Adjustment of the labetalol dose should Adjustment of the labetalol dose should precede the addition of other antihypertensive precede the addition of other antihypertensive agents to this patient's medication regimen.agents to this patient's medication regimen.

Although long-term cigarette smoking can Although long-term cigarette smoking can increase the cardiovascular risk associated increase the cardiovascular risk associated with hypertension, there is no indication that with hypertension, there is no indication that smoking or alcohol ingestion are contributing to smoking or alcohol ingestion are contributing to this patient's present problem. this patient's present problem.

Response and Response and RecommendationsRecommendations

There do not appear to be any significant drug There do not appear to be any significant drug interactions between any of S.L.'s current interactions between any of S.L.'s current medications and minoxidil medications and minoxidil

dosing of labetalol is inappropriate dosing of labetalol is inappropriate

Because S.L. is receiving 400 mg of labetalol Because S.L. is receiving 400 mg of labetalol once daily at 9 AM, the increase in blood once daily at 9 AM, the increase in blood pressure observed in the morning could be due pressure observed in the morning could be due to inappropriate labetalol dosing. to inappropriate labetalol dosing.

The physician was directed to optimize The physician was directed to optimize labetalol therapy before the addition of labetalol therapy before the addition of another antihypertensive agent another antihypertensive agent

If the patient's blood pressure is not If the patient's blood pressure is not controlled with proper dosing of labetalol and controlled with proper dosing of labetalol and minoxidil therapy is required, the physician minoxidil therapy is required, the physician should be advised that minoxidil is usually should be advised that minoxidil is usually administered with a diuretic to prevent fluid administered with a diuretic to prevent fluid retention. retention.

Questions for Questions for Obtaining Obtaining Background Background Information from Information from Requestors Requestors

Availability of Dosage Availability of Dosage Forms Forms

1. What is the dosage form desired? 1. What is the dosage form desired? 2. What administration routes are feasible 2. What administration routes are feasible

with this patient? with this patient? 3. Is this patient alert and oriented? 3. Is this patient alert and oriented? 4. Does the patient have a water or sodium 4. Does the patient have a water or sodium

restriction? restriction? 5. What other special factors regarding drug 5. What other special factors regarding drug

administration should be considered?administration should be considered?

Identification of ProductIdentification of Product

1. What is the generic or trade name of the product? 1. What is the generic or trade name of the product? 2. Who is the manufacturer? What country of origin? 2. Who is the manufacturer? What country of origin? 3. What is the suspected use of this product? 3. What is the suspected use of this product? 4. Under what circumstances was this product 4. Under what circumstances was this product

found? Who found the product? found? Who found the product? 5. What is the dosage form, color markings, size, 5. What is the dosage form, color markings, size,

and so on? and so on? 6. What was your source of information? Was it 6. What was your source of information? Was it

reliable?reliable?

General Product General Product InformationInformation

1. Why is there a particular concern for this 1. Why is there a particular concern for this product? product?

2. Is written patient information required? 2. Is written patient information required? 3. What type of information do you need? 3. What type of information do you need? 4. Is this for an inpatient, outpatient, or 4. Is this for an inpatient, outpatient, or

private patient?private patient?

Foreign Drug Foreign Drug IdentificationIdentification

1. What is the drug's generic name, trade name, 1. What is the drug's generic name, trade name, manufacturer, and/or country of origin? manufacturer, and/or country of origin?

2. What is the dosage form, markings, color, 2. What is the dosage form, markings, color, strength, or size? strength, or size?

3. What is the suspected use of the drug? How 3. What is the suspected use of the drug? How often is the patient taking it? What is the patient's often is the patient taking it? What is the patient's response to the drug? Is the patient male or female? response to the drug? Is the patient male or female?

4. If the medication was found, what were the 4. If the medication was found, what were the circumstances/conditions at the time of discovery? circumstances/conditions at the time of discovery?

5. Is the patient just visiting, or planning on staying?5. Is the patient just visiting, or planning on staying?

Investigational Drug Investigational Drug InformationInformation

1. Why do you need this information? Is the patient 1. Why do you need this information? Is the patient in need of the drug or currently enrolled in a in need of the drug or currently enrolled in a protocol? protocol?

2. If a drug is to be identified, what is the dosage 2. If a drug is to be identified, what is the dosage form, markings, color, strength, or size of the form, markings, color, strength, or size of the product? product?

3. Why was the patient receiving the drug? What 3. Why was the patient receiving the drug? What was the response when the patient was on the was the response when the patient was on the drug? What are the patient's pathological drug? What are the patient's pathological conditions? conditions?

4. If a drug is desired what approved or accepted 4. If a drug is desired what approved or accepted therapies have been tried? Was therapy maximized therapies have been tried? Was therapy maximized before discontinued?before discontinued?

Method and Rate of Method and Rate of AdministrationAdministration

1. What dosage form or preparation is being used (if 1. What dosage form or preparation is being used (if multiple salt forms are available)? multiple salt forms are available)?

2. What is the dose ordered? Is the drug a one-time 2. What is the dose ordered? Is the drug a one-time dose or standing orders? dose or standing orders?

3. What is the clinical status of the patients? Could 3. What is the clinical status of the patients? Could the patients tolerate a fluid push of XX mL? Is the the patients tolerate a fluid push of XX mL? Is the patient fluid or sodium restricted? Does the patient patient fluid or sodium restricted? Does the patient have congestive heart failure (CHF) or edema? have congestive heart failure (CHF) or edema?

4. What possible delivery routes are available? 4. What possible delivery routes are available? 5. What other drugs are the patient receiving 5. What other drugs are the patient receiving

currently? Are any by the same route?currently? Are any by the same route?

Incompatibility and Incompatibility and StabilityStability

1. What are the routes for the patient's medications? 1. What are the routes for the patient's medications? 2. What are the doses (in mg), concentrations, and 2. What are the doses (in mg), concentrations, and

volumes for all pertinent medications? volumes for all pertinent medications? 3. What are the infusion times/rates expected or 3. What are the infusion times/rates expected or

desired? desired? 4. What is the base solution or diluent used? 4. What is the base solution or diluent used? 5. Was the product stored in a refrigerator or at 5. Was the product stored in a refrigerator or at

room temperature? For how long? room temperature? For how long? 6. Was the product exposed to sunlight? For how 6. Was the product exposed to sunlight? For how

long? long? 7. Was the product frozen? For how long? 7. Was the product frozen? For how long? 8. When was the product compounded/prepared?8. When was the product compounded/prepared?

Drug InteractionsDrug Interactions

1. What event(s) suggest that an interaction 1. What event(s) suggest that an interaction occurred? Please describe. occurred? Please describe.

2. For the drugs in question, what are the doses, 2. For the drugs in question, what are the doses, volumes, concentrations, rate of administration, volumes, concentrations, rate of administration, administration schedules, and length of therapies? administration schedules, and length of therapies?

3. What is the temporal relationship between the 3. What is the temporal relationship between the drugs in question? drugs in question?

4. Has the patient received this combination or a 4. Has the patient received this combination or a similar combination in the past? similar combination in the past?

5. Other than the drugs in question, what other 5. Other than the drugs in question, what other drugs is the patient receiving currently? When were drugs is the patient receiving currently? When were these started?these started?

Drug-Laboratory Test Drug-Laboratory Test InterferenceInterference

1. What event(s) suggest an interaction occurred? 1. What event(s) suggest an interaction occurred? Please describe. Please describe.

2. For the drug in question, what is the dose, 2. For the drug in question, what is the dose, volume, concentration, rate of administration, volume, concentration, rate of administration, administration schedule, and length of therapy? administration schedule, and length of therapy?

3. What is the temporal relationship between drug 3. What is the temporal relationship between drug administration and laboratory test sampling? administration and laboratory test sampling?

4. What other drugs are the patient receiving? 4. What other drugs are the patient receiving? 5. Has clinical chemistry (or the appropriate 5. Has clinical chemistry (or the appropriate

laboratory) been contacted? Are they aware of any laboratory) been contacted? Are they aware of any known interference similar to this event? known interference similar to this event?

6. Was this one isolated test or a trend in results?6. Was this one isolated test or a trend in results?

Pharmacokinetics Pharmacokinetics

1. What is the generic name, dose, and route of the 1. What is the generic name, dose, and route of the drug? drug?

2. What is the patient's age, gender, height, and 2. What is the patient's age, gender, height, and weight? weight?

3. What are the diseases being treated and the 3. What are the diseases being treated and the severity of the illness? severity of the illness?

4. What are the patient's hepatic and renal 4. What are the patient's hepatic and renal functions? functions?

5. What other medications are the patient receiving? 5. What other medications are the patient receiving? 6. What physiologic conditions exist (e.g., 6. What physiologic conditions exist (e.g.,

pneumonia, severe burns, or obesity)? pneumonia, severe burns, or obesity)? 7. What are the patient's dietary and ethanol habits?7. What are the patient's dietary and ethanol habits?

Serum or Urine Serum or Urine Therapeutic LevelsTherapeutic Levels

1. Is the patient currently receiving the drug? Have samples 1. Is the patient currently receiving the drug? Have samples already been drawn? At what time? already been drawn? At what time?

2. What is the disease or underlying pathology being treated? 2. What is the disease or underlying pathology being treated? If infectious in nature, what is the suspected/cultured If infectious in nature, what is the suspected/cultured organism? organism?

3. If not stated in the question, what was the source of the 3. If not stated in the question, what was the source of the sample (blood, urine, saliva; venous or arterial blood)? sample (blood, urine, saliva; venous or arterial blood)?

4. What was the timing of the samples relative to drug 4. What was the timing of the samples relative to drug administration? Over what period of time was the drug administration? Over what period of time was the drug administered and by what route? administered and by what route?

5. What were the previous concentrations for this patient? Was 5. What were the previous concentrations for this patient? Was the patient receiving the same dose then? the patient receiving the same dose then?

6. How long has the patient received the drug? Is the patient at 6. How long has the patient received the drug? Is the patient at steady state?steady state?

Therapy Evaluation/Drug Therapy Evaluation/Drug of Choiceof Choice

1. What medications, including doses and routes of administration, 1. What medications, including doses and routes of administration, are the patient receiving? are the patient receiving?

2. What are the patient's pathology(ies) and disease(s) severity? 2. What are the patient's pathology(ies) and disease(s) severity? 3. What are the patient's specifics: age, weight, height, gender, 3. What are the patient's specifics: age, weight, height, gender,

organ function/dysfunction? organ function/dysfunction? 4. Has the patient received the drug previously? Was response 4. Has the patient received the drug previously? Was response

similar? similar? 5. Has the patient been compliant? 5. Has the patient been compliant? 6. What alternative therapies has the patient received? Was 6. What alternative therapies has the patient received? Was

therapy maximized for each of these before discontinuation? What therapy maximized for each of these before discontinuation? What other therapies are being considered? other therapies are being considered?

7. What monitoring parameters have been followed (serum 7. What monitoring parameters have been followed (serum concentrations/levels, clinical status, other clinical lab results, concentrations/levels, clinical status, other clinical lab results, objective measurements, and subjective assessment). objective measurements, and subjective assessment).

8. What is the patient's name and location?8. What is the patient's name and location?

Dosage Dosage RecommendationsRecommendations 1. What disease is being treated? What is the extent/severity 1. What disease is being treated? What is the extent/severity

of the illness? of the illness? 2. What are the drugs being prescribed? What drugs have the 2. What are the drugs being prescribed? What drugs have the

patient received to date? patient received to date? 3. Does the patient have any insufficiency of the renal, hepatic, 3. Does the patient have any insufficiency of the renal, hepatic,

or cardiac system? or cardiac system? 4. For drugs with renal elimination, what are the serum 4. For drugs with renal elimination, what are the serum

creatinine/creatinine clearance, blood urea nitrogen (BUN), creatinine/creatinine clearance, blood urea nitrogen (BUN), and/or during output? Is the patient receiving peritoneal and/or during output? Is the patient receiving peritoneal dialysis or hemodialysis? dialysis or hemodialysis?

5. For drugs with hepatic elimination, what are the liver 5. For drugs with hepatic elimination, what are the liver function tests (LFTs), bilirubin (direct and indirect), and/or function tests (LFTs), bilirubin (direct and indirect), and/or albumin? albumin?

6. For drugs with serum level monitoring utility, characterized 6. For drugs with serum level monitoring utility, characterized the most recent levels per timing relative to dose and results. the most recent levels per timing relative to dose and results.

7. Are these lab values recent? Is the patient's condition 7. Are these lab values recent? Is the patient's condition stable? stable?

8. Does this patient have a known factor that could affect drug 8. Does this patient have a known factor that could affect drug metabolism (ethnic background, such as Japanese or metabolism (ethnic background, such as Japanese or Chinese, or acetylator status)?Chinese, or acetylator status)?

Adverse EffectsAdverse Effects 1. What is the name, dosage, and route for all 1. What is the name, dosage, and route for all

drugs currently and recently prescribed? drugs currently and recently prescribed? 2. What are the patient specifics (age, gender, 2. What are the patient specifics (age, gender,

height, weight, organ dysfunction, and height, weight, organ dysfunction, and indication for drug use)? indication for drug use)?

3. What is the temporal relationship with the 3. What is the temporal relationship with the drug? drug?

4. Has the patient experienced this adverse 4. Has the patient experienced this adverse relationship (or a similar event) with this drug relationship (or a similar event) with this drug (or similar agent) previously? (or similar agent) previously?

5. Was the suspected drug ever administered 5. Was the suspected drug ever administered before? Why was it discontinued then? before? Why was it discontinued then?

6. What were the events/findings that 6. What were the events/findings that characterize this adverse drug reaction (ADR) characterize this adverse drug reaction (ADR) (include onset and duration)? (include onset and duration)?

7. Has any intervention been initiated at this 7. Has any intervention been initiated at this time? time?

8. Does the patient have any food intolerance? 8. Does the patient have any food intolerance? 9. Is there a family history for this ADR and/or 9. Is there a family history for this ADR and/or

drug allergy?drug allergy?

Toxicology InformationToxicology Information 1. What is your name, relationship to the patient, 1. What is your name, relationship to the patient,

and telephone number? and telephone number? 2. What are the patient specifics (age, gender, 2. What are the patient specifics (age, gender,

height, weight, organ dysfunction, and indication for height, weight, organ dysfunction, and indication for drug use)? drug use)?

3. Is this a suspected ingestion or exposure? 3. Is this a suspected ingestion or exposure? 4. What is the product suspected to have been 4. What is the product suspected to have been

ingested? What is the strength of the product and ingested? What is the strength of the product and the possible quantity ingested (e.g., how much was the possible quantity ingested (e.g., how much was in the bottle)? in the bottle)?

5. How long ago did the ingestion occur? 5. How long ago did the ingestion occur?

6. How much is on the child or surrounding floor? 6. How much is on the child or surrounding floor? 7. How much was removed from the child's hands and 7. How much was removed from the child's hands and

mouth? Was the ingestion in the same room where the mouth? Was the ingestion in the same room where the product was stored? product was stored?

8. What has been done for the patient already? Has the 8. What has been done for the patient already? Has the poison control center or emergency room (ER) been poison control center or emergency room (ER) been called? called?

9. Do you have syrup of ipecac available? Do you know 9. Do you have syrup of ipecac available? Do you know how to give it properly? how to give it properly?

10. What is the patient's condition (sensorium, heart rate, 10. What is the patient's condition (sensorium, heart rate, respiratory rate, temperature, skin color/turgor, pupils, respiratory rate, temperature, skin color/turgor, pupils, sweating/salvation, and so on)? sweating/salvation, and so on)?

11. Does the patient have any known illnesses or organ 11. Does the patient have any known illnesses or organ dysfunction?dysfunction?

Teratogenicity Teratogenicity 1. What was the drug the patient received and what was 1. What was the drug the patient received and what was

the dose? What was the duration of therapy? the dose? What was the duration of therapy? 2. Is the patient pregnant or planning to become pregnant? 2. Is the patient pregnant or planning to become pregnant? 3. When during pregnancy was the exposure (trimester or 3. When during pregnancy was the exposure (trimester or

weeks)? weeks)? 4. What are the patient specifics (age, height, weight, 4. What are the patient specifics (age, height, weight,

gender)? gender)? 5. What is the source of the case information? 5. What is the source of the case information? 6. Was the patient compliant? 6. Was the patient compliant? 7. For what indication was the drug being prescribed?7. For what indication was the drug being prescribed?

Drugs in Breast MilkDrugs in Breast Milk 1. What was the drug the patient received and what was the 1. What was the drug the patient received and what was the

dose? What was the duration of therapy? dose? What was the duration of therapy? 2. How long has the infant been breast-feeding? 2. How long has the infant been breast-feeding? 3. Has the infant ever received nonmaternal nutrition? Is 3. Has the infant ever received nonmaternal nutrition? Is

bottle-feeding a plausible alternative? bottle-feeding a plausible alternative? 4. What is the frequency of the breast-feeds? What is the 4. What is the frequency of the breast-feeds? What is the

milk volume? milk volume? 5. How old is the infant? 5. How old is the infant? 6. Does the mother have hepatic or renal insufficiency? 6. Does the mother have hepatic or renal insufficiency? 7. What was the indication for prescribing the drug? Was this 7. What was the indication for prescribing the drug? Was this

initial or alternate therapy? initial or alternate therapy? 8. Has the mother breast-fed previously while on the drug? 8. Has the mother breast-fed previously while on the drug?

QuizzQuizz

Labetalol is aLabetalol is a Ca channel blockerCa channel blocker Beta blockerBeta blocker DiureticDiuretic VasodilatorVasodilator

Clonidine is used to treat ------------Clonidine is used to treat ------------ Lorazepam is used to treat-----------Lorazepam is used to treat-----------