Module 1: Drug Interactions and Adverse Effects

Question 1

Drug-Drug Interactions (DDIs)

Answer 1

When one drug modifies the blood concentration, magnitude, or duration of effect of another drug

Can occur when a drug is added or removed from a therapeutic regimen

DDIs can elicit both desired & unintended effects:
1. Desired effect: i.e. Probenecid is admin. with PCN to decrease the amount of PCN needed

2. Unintended effect: i.e. Metronidazole (an antibiotic) interacts with Warfarin and causes severe bleeding

Question 2

Consequence of DDIs #1: Intensification of Effects

Answer 2

Good — Increased therapeutic effects:

1. Sulbactam prevents bacteria from becoming resistant to ampicillin
2. Protease inhibitors “boost” other HIV and Hep C drugs

Bad — Increased AEs:

1. Aspirin and Warfarin (excessive bleeding)
2. Benzodiazepines (i.e. Zanax for anxiety) and opioids can cause excessive CNS depression and death

Question 3

Consequence of DDIs #2: Reduction of Effects

Answer 3

Bad — Reduced therapeutic effects:

1. Propranolol (a beta blocker) blocks beta receptors in the heart and lungs, while albuterol (a beta agonist) activates these receptors (counteraction)
2. Calcium binds to antibiotics in the GI tract, inhibiting their absorption into the bloodstream

Good — Reduced AEs:
1. Naloxone (Narcan) blocks the same receptor that morphine acts on (used to treat morphine overdose)

Question 4

Consequence of DDIs #3: Creation of a Unique Response

Answer 4

i.e. Alcohol, when consumed with Disulfiram (used to treat alcohol use disorder), can cause very unpleasant constellation of effects (i.e. increased HR, flushing, diaphoresis)

Question 5

Direct Chemical or Physical Interactions

Answer 5

Never combine IV solutions unless they have been established to be safe

Combining IV solution can cause crystallization and AEs

Question 6

PK Interactions: Absorption

Answer 6

Increased or decreased extent of drug absorption:
1. Elevated gastric pH impairs absorption — i.e. Antifungal drugs require low gastric pH (acidic)

2. Laxatives speed up the passage of substances through the GI tract, reducing drug absorption
3. Drugs that depress peristalsis decrease absorption
4. Drugs that induce vomiting impair absorption
5. Absorbent drugs (drugs that bind together) — i.e. Calcium and antibiotics lead to impaired absorption
6. Drugs that reduce regional blood flow decrease absorption

Question 7

PK Interactions: Distribution

Answer 7

Unbound free drugs are more likely to go to receptor sites and increase therapeutic and AEs

Question 8

PK Interactions: Metabolism

Answer 8

Most important and most complex mechanism in which drugs interact

Cytochrome P450 (CYP) group of enzymes (convert drugs to more water-soluble, polar metabolites): 
1. Inducing agents: INCREASE the metabolism of other drugs; need to increase dose — i.e. Phenytoin, phenobarbital, carbamazepine, rifampin

2. Inhibiting agents: DECREASE the metabolism of other drugs; need to decrease dose — i.e. Protease inhibitors, azole antifungals, cimetidine

Question 9

PK Interactions: Excretion

Answer 9

Decreased renal secretion

Question 10

PD Interactions

Answer 10

Relationship between drug concentration and response

One drug alters the effects of another drug (but not through ADME PK processes)

Effects could be:
1. Additive: may lead to excess response or toxicity — i.e. Benzodiazepines used along with other CNS depressants such as opioids)

2. Antagonistic: reduce or block the effects (either therapeutic or toxic) of the other drug — i.e. Potassium-sparing diuretics offset the effects of potassium loss caused by thiazide diuretics
3. Combined toxicity at the same organ — i.e. Isoniazid and rifampin are some of the most effective drugs used to treat TB infections; both are toxic to the liver and require intense LFT monitoring to prevent cirrhosis

Question 11

Drug-Food Interactions (DFIs)

Answer 11

Factors:
1. Decreased/increased absorption or extent of absorption — i.e. Calcium (milk) can decrease the absorption of tetracyclines (large group of antibiotics)

2. Metabolism — i.e. Grapefruit juice can inhibit the metabolism of many drugs via CYP inhibition
3. Drug action — i.e. Vitamin K decreases the effects of warfarin
4. Timing of meals — i.e. Admin. on empty stomach = 1 hour before eating OR 2 hours after eating

Question 12

Drug-CAM Interactions

Answer 12

Conventional drugs can interact with CAMs; interactions are just as likely as they are with prescription meds.

Reliable information about drug-CAM interactions is lacking

i.e. St. John’s wort induces drug-metabolizing enzymes and reduces the blood levels of many drugs

Question 13

Clinical Significance

Answer 13

Drug interactions:

1. Are not always bad
2. May cause a measurable change in a drug level without impacting a pt’s clinical status
3. May be clinically important in one pt and not so much in another

Promote:

1. Reduction in number of drugs pt takes
2. Thorough drug history
3. Dose adjustments and monitoring

Question 14

Patient Education to Avoid DDIs

Answer 14

Education about DDIs should include:
1. Why the pt is prescribed the med.

2. How to take the med.
3. Fill at the same pharmacy whenever possible
4. Be cautious with CAMs
5. Inform healthcare professionals about all meds., including OTC and CAMs
6. Avoid grapefruit juice
7. Limit alcohol
8. Talk to the pharmacist

Question 15

Adverse Drug Reactions (ADRs)

Answer 15

Any noxious, unintended, and undesired (mild to severe) effect that occurs at normal drug doses

Identification of ADRs:
1. Did symptoms appear soon after drug was started?

2. Did symptoms abate after discontinuation?
3. Did symptoms reappear when restarted?
4. Is there a pathophysiologic explanation for the symptoms?
5. Are other drugs to blame?

Question 16

Toxicities

Answer 16

Type of toxicity:
1. Hepatotoxicity — most common form of toxicity; drugs, when metabolized, may be converted to toxic products that cause injury to liver parenchyma; S/S: Jaundice, dark urine, light stools, N/V, appetite loss, abdominal discomfort

2. Nephrotoxicity — acute or chronic renal toxicity
3. Neurotoxicity — toxicity of the brain tissue
4. Cardiotoxicity — toxicity of the heart tissue (i.e. Anti-CA drugs like doxorubicin); Drugs that have the ability to prolong QT interval can result in serious dysrhythmias
5. Carcinogenic — able to cause CA (surprisingly, usually caused by anti-CA drugs)
6. Teratogenic — drugs that can cause birth defects; the embryonic period (first trimester, especially weeks 3-9) is the most concerning of all stages, and requires most caution

Question 17

Minimizing Risk of Teratogenic Drugs

Answer 17

Risk interventions:
1. Minimize use of drugs during pregnancy if possible

2. Discontinue drugs with high potential to cause teratogenesis
3. Use safer alternatives
4. Use reliable birth control

Question 18

FDA Pregnancy Risk Categories

Answer 18

Pregnancy risk categories:
1. A: Safest

2. B
3. C
4. D
5. X: Most dangerous; known to cause fetal harm

Question 19

Drug Therapy During Breast-Feeding

Answer 19

Drugs can be excreted in breast milk, and effects can occur in the infant

How to decrease risk to the infant:
1. Take drugs immediately AFTER breast-feeding

2. Avoid drugs that have long half-lives
3. Choose drugs that tend to be excluded from breast milk and that are least likely to affect the infant
4. Avoid drugs that are known to be hazardous (X drugs)

Question 20

Minimizing ADRs

Answer 20

Methods to minimize ADRS:

1. Anticipate ADRs
2. Balance risks vs. benefits of therapy
3. Individualize drug therapy
4. Education

FDA requirements:
1. Report ADRs

2. Medication guides: paper handouts that come with prescription meds. that address issues that are specific to particular drugs and drug classes; they contain FDA-approved information that can help pts avoid serious AEs
3. Black Box Warnings: required by the FDA for certain meds. that carry serious safety risks; these warning communicate potential rare, but dangerous side effects and/or communicate important instructions for safe drug use
4. Risk Evaluation and Mitigation Strategies (REMS): help ensure the benefits of the med. outweigh its risks if a serious safety concern is identified, before the med. is approved or after it is marketed