Exam I: Medication Errors, Polymorphisms

Question 1

Define medication error

Answer 1

”Any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the healthcare professional, patient, or consumer”

Question 2

Define adverse drug event (ADE)

Answer 2

Patient harm from drug exposure (an ADE can occur in the absence of a medication error)

Question 3

Define a preventable ADE

Answer 3

Medication error that reaches the patient and causes harm (~50% of all ADEs)

Question 4

Define potential ADE

Answer 4

Medication error that does not cause harm (didn’t reach patient or just good luck)

Question 5

Define an adverse drug reaction (ADR)

Answer 5

A non-preventable ADE (no medication error occurred but patient still experienced harm from drug exposure)

Also called “side effects”

Question 6

What are the 4 classifications of an ADE from an IND Safety Report?

Answer 6

Life-threatening ADE

Serious ADE

Suspected ADE

Unexpected ADE

Question 7

Define what a life-threatening ADE is?

Answer 7

Places the patient at immediate risk of death

Question 8

A serious ADE results in (5) ?

Answer 8

1. Patient death
2. Life-threatening ADE
3. Hospitalization or prolongation of existing hospitalization
4. Persistent or significant incapacity or substantial disruption of normal daily life
5. Congenital anomaly or birth defect – this is why it is important for a subject not to get pregnant during a clinical trial. Most damage is done during the first trimester.

Question 9

What is an investigator brochure? How does it relate to unexpected ADE?

Answer 9

Investigator brochure is provided by the sponsor. It is the protocol and a summary of all the preclinical trial testing.

An ADE not already described in the IB or is more severe than what has been described is considered unexpected.

Question 10

What is a suspected ADE?

Answer 10

There is a reasonable possibility that the drug caused the adverse event.

Question 11

What is an unexpected ADE? (3)

Answer 11

1. Not included in the Investigator Brochure (IB)
2. Not described in the IB as occurring at the observed specificity or severity
3. Not consistent with the risk information described in the IB or general investigational plan (Study Protocol)

Question 12

Percentage of hospitalized patients that experience an ADE.

Answer 12

6.7%

Question 13

Provide 4 examples of ADEs during Transitions of Care (Hospital Discharge)

Answer 13

1. Medication adherence may suffer (patient anxiety, functional impairment)
2. Medications may have been stopped, replaced, or added during hospitalization
3. Poor healthcare provider communication and follow-up exacerbates these problems
4. Hospital readmission: ADR-related 20%; ADE-related 13%

Question 14

4,756 significant ADEs reported between 2009-2016 for children related to what types of medication?

Answer 14

OTC cough and cold meds

Question 15

What age range of children are at the highest risk of an ADE?

Answer 15

45.8% occurred in children < 6 years old between 2009-2016

Question 16

ADEs in Children: Dosing errors most common (93.2%)—wrong amount of liquid measured (45% by parent, 28.8% by another caregiver)

True/False

Answer 16

True

Question 17

Medication errors and ADEs can prolong hospitalization and require intervention

About how much money do these errors cost inpatient and outpatient?

Answer 17

Inpatient ADEs cost approximately $16.4 billion per year

Outpatient ADEs cost approximately $4.2 billion per year

Question 18

Most ADEs are not preventable.

True/False

Answer 18

False

Two-thirds of ADEs are preventable

Approximately 40% are the result of negligence

Question 19

Define medical negligence.

Answer 19

Failure to use reasonable care, resulting in damage or injury to another

Question 20

What is an adulterated drug?

Answer 20

Multiple points

• Consists in whole or in part of any filthy, putrid, or decomposed substance
• If it has been prepared, packed, or held under insanitary conditions
• If how it was produced, or stored does not conform with current good manufacturing practice

Question 21

Most common medication error in the pharmacy?

Answer 21

Transcribing—medication order interpreted incorrectly (wrong dose or quantity, 25.5%)

Question 22

Three strategies to reduce medication errors during the prescribing stage.

Answer 22

1. Avoid unnecessary medications
2. CPOE with clinical decision support system
3. Medication reconciliation during transitions of care

Question 23

One strategy to reduce medication errors during the transcribing stage.

Answer 23

CPOE to eliminate handwriting errors

Question 24

Three strategies to reduce medication errors in the dispensing stage.

Answer 24

1. Clinical pharmacist to manage medication dispensing
2. Use of tall man lettering to minimize confusion with LASA medications
3. Automated dispensing cabinets for high-risk medications

Question 25

What are the five rights? How does it affect medication error rate?

Answer 25

Right Medication, in the Right Dose, at the Right Time, by the Right Route, to the Right Patient Adherence to this reduces medication errors during administration

Question 26

Six ways that medication errors can be reduced during the administration stage.

Answer 26

1. Barcode bedside medication administration 2. Minimize nurse interruption 3. Smart infusion pumps 4. Multicompartment medication devices for patients on multiple medications 5. Patient education 6. Improved (easier to read and understand) medication labels

Question 27

What is polypharmacy? Give an example of how this can be problematic.

Answer 27

The use of multiple drugs or more than are medically necessary. Pt prescribed h2 blocker during NPO status to prevent a stress ulcer bleed. Pt discharged with h2 blocker script that they no longer need.

Question 28

What does LASA stand for?

Answer 28

Look alike sound alike

Question 29

Factors that can cause variability in drug metabolism from person to person.

Answer 29

1. Genetic factors 2. Epigenetic factors 3. Age 4. Gender 5. Ethnicity 6. Disease 7. Environmental factors

Question 30

What is a epigenetic factor for variability in drug metabolism?

Answer 30

Chemical modifications in gene activity (gene “turned on or off”) that do not change the DNA sequence (e.g., methylation of DNA turns the gene off)

Question 31

Name the examples that were provided for environmental factors that can cause variability in drug metabolism.

Answer 31

1. Cigarette smoking, coffee, alcohol 2. Drug administration (drug interactions), herbals (St. John’s wort) 3. Exposure to DDT or gasoline fumes 4. Dietary factors (cruciferous vegetables, char-broiled beef, grapefruit juice)

Question 32

What enzyme metabolizes half of the drugs people can take?

Answer 32

Cytochrome P450 3A4 metabolizes half of all drugs people take

Question 33

What substance can inhibit the activity of cytochrome P450?

Answer 33

Grapefruit juice

Question 34

Describe Phase I of drug metabolism in humans.

Answer 34

1. Introduces or exposes a functional group | 2. Most reactions catalyzed by cytochrome 450 (CYP) enzymes

Question 35

Where is CYP450 located?

Answer 35

Located in the liver and intestine

Question 36

Describe Phase II of drug metabolism in humans.

Answer 36

1. Covalent linkage between a functional group on the parent compound with glucuronic acid, sulfate, glutathione 2. Leads to more rapid excretion

Question 37

Describe the final phase of drug metabolism

Answer 37

Pgp exists in the gut wall. Tries to absorb drug across the intestine and it pumps it right back out into the intestine and ends up being excreted in the feces

Question 38

Bioavailability (F) is the portion of the drug that makes it into _____? Where is some of the drug lost?

Answer 38

Bioavailability is the portion of the drug that makes it into the **systemic circulation**. Some can be lost in the gut wall and/or the liver

Question 39

What are the four phenotypic variants for the first two phases of drug metabolism?

Answer 39

1. Ultra-fast metabolizer (UM)—multiple copies of wt 2. Extensive metabolizer (EM) —homozygous wt/wt 3. Intermediate metabolizer (IM) —heterozygous wt/v 4. Poor metabolizer (PM)—homozygous v/v or heterozygous v1/v2 - V = variant (mutation) - Wt = wild type (normal)

Question 40

What is 6-mercaptopurine (6-MP)? What is it used to treat?

Answer 40

Purine antagonist used to treat childhood acute lymphoblastic leukemia (ALL) and (off-label) adult or childhood inflammatory bowel disease (like Crohn's disease)

Question 41

What is a major precaution that needs to be considered before prescribing 6-MP?

Answer 41

The biomarker for 6-MP is the enzyme TPMT There is a polymorphism present TPMT IMs and PMs are predisposed to 6-MP toxicity

Question 42

What side effect occurs in TPMT PMs who take 6-MP?

Answer 42

Fatal bone marrow suppression

Question 43

6-MP is never prescribed to patients who are PMs of TPMT. True/False

Answer 43

False Patients with childhood acute lymphoblastic leukemia (ALL) are sometimes prescribed this medication at very low doses because it is important in treating this disease

Question 44

Two inactivation pathways of 6-MP.

Answer 44

1. Inactivation to 6-thiouric acid (6-TU) by xanthine oxidase (XO) in gut wall and liver 2. Inactivation intracellularly (inside B and T cells) to 6-methyl mercaptopurine (6-MMP) by thiopurine methyltransferase (TPMT)

Question 45

What is the activation pathway for 6-MP?

Answer 45

1. 6-MP to 6-TIMP via HGPRT 2. 6-TIMP to 6-MMPR via TPMT 3. 6-MMPR to 6-TXMP via IMPDH 4. Activation of 6-TXMP to 6-TGNs via GMPS

Question 46

What are the inactive forms of 6-MP?

Answer 46

6-TU 6-MMP

Question 47

Why can't allopurinol be taken with 6-MP?

Answer 47

Drugs like allopurinol inhibits XO this is a contraindication

Question 48

PMs experience a shift in 6-MP metabolism that favors the pathway to 6-TGN (active) rather than 6-TU (inactive). Why is this bad?

Answer 48

The intermediate 6-MMPR is liver toxic (hepatoxic). A build of this metabolite 6-TGN is responsible for killing leukemia cells but is also toxic to bone marrow cells.

Question 49

Which form of 6-MP is responsible for killing leukemia cells but also bone marrow suppression in PMs?

Answer 49

6-TGNs

Question 50

Bioavailability of 6-MP in a normal metabolizer.

Answer 50

16%

Question 51

Myelotoxicity means?

Answer 51

Bone marrow suppression

Question 52

Describe TPMT activity and 6-MMPs production in PMs.

Answer 52

Little to no TPMT activity No 6-MMPs (Inactive)

Question 53

How long should a prescriber wait after each dose adjustment for an **EM** of TPMT to reach a steady dose adjustment?

Answer 53

Allow 2 weeks to reach steady state after each dose adjustment

Question 54

How long should a prescriber wait after each dose adjustment for an **IM** of TPMT to reach a steady dose adjustment?

Answer 54

Allow 2-4 weeks to reach steady state after each dose adjustment

Question 55

How long should a prescriber wait after each dose adjustment for an **PM** of TPMT to reach a steady dose adjustment?

Answer 55

Allow 4-6 weeks to reach steady state after each dose adjustment

Question 56

EMs for 6-MP begin with a normal dose (1.5mg/kg/d) then adjusts as needed. What percentage of a normal dose are IMs and PMs prescribed at first?

Answer 56

IMs - 30-70% of normal dose and adjust based on degree of myelosuppression and disease-specific guidelines PMs - Start with 10-fold lower daily dose given 3 times weekly instead of daily and adjust

Question 57

What is the biomarker for nortriptyline? How do PMs respond to this medication?

Answer 57

PMs— Reduced TCA metabolism causing higher than expected blood levels of all tricyclic antidepressants (TCAs)