Individual Drug Variation, Drug Interactions, AND Harmful Effects of Drugs

Question 1

Most often ___________ as a drug produces a “larger” or “smaller” effect and/or lasts for a longer or shorter period of time….while qualitatively exerting the same effect

Answer 1

quantitative

Question 2

How does variation of drug response to the same concentration occur?

Answer 2

• a different drug concentration at sites of drug action
• by different responses to the same drug concentration

Question 3

Variants exist in the gene that produces aldehyde dehydrogenase 2 enzymes (ALDH2), if two copies are present you will get a __________ response

Answer 3

negative
- Impacts an estimated 5-10% of those who are of Asian descent.

Question 4

What does idiosyncratic mean?

Answer 4

because of genetic differences or
immunologic response

Question 5

What are the implications of variation?

Answer 5

• Clinical Impact – “response” vs. “toxicity”
• Lack of efficacy
• Side effects and drug toxicity

Question 6

What is half-life?

Answer 6

time it takes for serum concentrations to reduce by half in the elimination phase (it takes 4.5 to 5 half-lives to reach steady-state)

Question 7

What is lipophilicity?

Answer 7

ability to cross into fatty tissue, may increase Volume of Distribution

Examples: (diazepam [Valium], carbamazepine [Tegretol], trazodone [Desyrel])

Question 8

What is a polymorphism?

Answer 8

alternative sequences at a locus within a DNA strand (alleles) that persist in a population

Question 9

What is a single nucleotide polymorphism (SNP)?

Answer 9

DNA sequence variations occur when a single nucleotide in the genome sequence is altered

Question 10

What should you think about for the metabolic pathway and variation?

Answer 10

cytochrome P450

Question 11

What is the membrane transporter for delivery and elimination that has some variation?

Answer 11

P-glycoprotein
- Biological barrier that extrudes toxins and xenobiotics out of cells playing a roles in both absorption and disposition of medications
- Limits cellular uptake of drugs from blood circulation in the brain and from the intestinal lumen into epithelial cells than on increasing the elimination of medications out of hepatocytes and renal tubules and into the luminal space

Question 12

HLAB*1502 Allele if present (Chinese ancestry) increases risk of SJS / TEN with ______________

Answer 12

carbamazepine
(Tegretol)

Question 13

What Contributes to Drug Related
Response Variations?

Answer 13

• Age related changes
• Genetics– influence PK by altering the expression of proteins involved in drug ADME - “genetic polymorphism”
  — Personalized Medicine
• Immunological
• Concurrent disease– commonly renal and hepatic
• Drug interactions– “think” CYP450

Question 14

Quantitivative variation results when the drug produces a larger or smaller effect, acts longer or shorter in duration, while from a qualitative standpoint still demonstrating the…

Answer 14

same effect (receptor level)

Question 15

Qualitative responses can be different in some individuals because of ___________________ differences

Answer 15

genetic or immunologic

Question 16

What type of ethnicity associated variation is important to know in African-Americans?

Answer 16

• Hydralazine and Nitrates offer better mortality benefit in heart failure vs. Caucasian
• ACE inhibitors (enalapril [Vasotec])do not work as well because of lower renin concentrations

Question 17

What type of ethnicity associated variation is important to know in people of Asian decent?

Answer 17

• Don’t metabolize alcohol as well, results in increase plasma concentration of acetaldehyde
• Increased sensitivity to the beta-blocker propranolol (Inderal) even though metabolized faster

Question 18

How does age consideration affect absorption?

Answer 18

hypothermia reduces drug clearance

Question 19

How does age consideration affect distribution?

Answer 19

reduced total body water, increased lipid distribution with age (increased body fat)

Question 20

How does age consideration affect Metabolism?

Answer 20

impaired Phase 1 metabolism (e.g. oxidation,
reduction, hydrolysis) = accumulation

Question 21

How does age consideration affect excretion?

Answer 21

less efficient in newborns and over the age of 65

Question 22

What should you consider for drug variation and pregnancy considerations?

Answer 22

• Reduced maternal plasma albumin
• Increased cardiac output
• Increased renal blood flow and GFR
• Increased transfer of lipophilic drugs

Question 23

Lipophilic drugs go to the fetus faster or slower?

Answer 23

faster

Question 24

What should you consider for drug variation and disease considerations?

Answer 24

• May result in both pharmacokinetic and
  pharmacodynamic variation
• Renal function*
• Hepatic function*
• Gastric stasis
• Pancreatic disease
• Others

Question 25

What are the features of idiosyncratic reactions?

Answer 25

- Typically harmful - Do not require large drug doses - Genetic connection - Immunological factors

Question 26

Are idiosyncractic reactions dose dependent?

Answer 26

NO

Question 27

What dietary considerations do you need to worry about?

Answer 27

- grapefruit juice inhibits CYP3A4 - Vitamin K increases clotting and impacts warfarin (Coumadin)

Question 28

What are the pharmacodynamic interactions with beta blockers?

Answer 28

agents like propranolol (Inderal) reduce effectiveness of Beta agonists used for asthma treatment (e.g. albuterol [Ventolin], salmeterol [Serevent])

Question 29

What are the pharmacodynamic interactions with diuretics?

Answer 29

agents that decrease K+ (e.g. hydrochlorothiazide) predispose to digoxin toxicity

Question 30

What are the pharmacodynamic interactions with MAOIs?

Answer 30

inhibit the breakdown of “pressor” agents (e.g. tyramine)

Question 31

What are the pharmacodynamic interactions with ASA/Warfarin?

Answer 31

increased bleeding

Question 32

What are the pharmacodynamic interactions with NSAIDs?

Answer 32

increase the risk of hypertension by inhibiting prostaglandin

Question 33

What are the pharmacodynamic interactions with antihistamines, opiates, ETOH?

Answer 33

additive sedative effects

Question 34

What are the pharmacodynamic interactions with anticonvulsants?

Answer 34

e.g. valproic acid (Depakote) inhibits platelet formation

Question 35

What are the pharmacodynamic interactions with dopamine blockers?

Answer 35

impacted by dopamine agonists (e.g. levodopa/carbidopa [Sinemet])

Question 36

What are the pharmacodynamic interactions with anticholinergics?

Answer 36

Cogentin may decrease the effectiveness of AChE Inhibitors (e.g. donepezil [Aricept])

Question 37

What are the pharmacokinetic interactions?

Answer 37

Absorption Distribution Metabolism Excretion

Question 38

GI absorption slowed by meds that inhibit...

Answer 38

gastric emptying | atropine, anticholinergics, opiates

Question 40

GI absorption increased by meds that increase...

Answer 40

gastric emptying | metoclopramide [Reglan]

Question 41

What enzymes increase metabolism?

Answer 41

phenytoin, carbamazepine, rifampin, theophylline

Question 42

What enzymes decrease metabolism?

Answer 42

allopurinol, ciprofloxacin, paroxetine, fluoxetine, cimetidine

Question 43

What is polypharmacy?

Answer 43

- Use of multiple medications by a patient - ≥5 medications

Question 44

What adverse effects can occur through pharmacological action that are expected? | not an allergy/not a problem

Answer 44

- Result from main pharmacological action and can reasonably be expected - Often addressed with dose reduction - Usually reversible - Some events more discrete

Question 45

What types of adverse effects can be predictable when dose is excessive?

Answer 45

- Aspirin and tinnitus - Clozapine (Clozaril) and seizures - Bupropion (Wellbutrin) and seizures

Question 46

What types of adverse effects are unpredictable idiosyncratic reactions?

Answer 46

- Penicillin and anaphylaxis - Clozapine and aplastic anemia

Question 47

How do they test drug toxicity?

Answer 47

- Animal testing - Doses significantly above therapeutic range - Identify organ toxicity - "acceptable" toxicity differences dependent upon targeted disease state

Question 48

What are examples of non-covalent interactions?

Answer 48

- Lipid peroxidation - Reactive oxygen species - Depletion of glutathione (disrupts normal cellular defense) - Modification of sulfhydryl groups

Question 49

What do covalent interactions do?

Answer 49

targets DNA, proteins, peptides, lipids, and carbohydrates | Hepatotoxicity Nephrotoxicity

Question 51

What is mutagenesis?

Answer 51

results from covalent modification of DNA

Question 52

How many mutations are required for malignancy?

Answer 52

more than one | proto-oncogenes or tumor suppressor genes

Question 53

What are carcinogens?

Answer 53

chemical substances that cause cancer

Question 54

What is teratogenesis?

Answer 54

result is gross structural malformations during fetal development and is different than other forms of fetal damage (e.g. growth retardation)

Question 55

What is the mechanism of teratogenesis?

Answer 55

- Blastocyte formation – cell division occurring - Organogenesis – structural formation - Histogenesis and maturation of function – nutrient supply

Question 56

What are known teratogens?

Answer 56

- Thalidomide – sedative/hypnotic – shortened long bone development - Cytotoxic Medications --- Alkylating agents and antimetabolites – cyclophosphamide --- Folate antagonists – valproic acid (Depakote) - Vitamin A Derivatives – tretinoin and isotretinoin - Antiepileptics --- Phenytoin (Dilantin), valproic acid (Depkaote), carbamazepine (Tegretol), lamotrigine (Lamictal) - Anticoagulants --- Warfarin (Coumadin)

Question 57

What are the features of allergic reactions?

Answer 57

- May be immediate or delayed following exposure - Dose doesn’t matter - Not related to primary drug MOA - Incidence < 25% - Skin reactions most common

Question 58

What is anaphylactic shock?

Answer 58

release of histamine and leukotrienes (sudden onset) | Penicillins, Adrenocorticotropin, Heparin

Question 59

What are the signs of anaphylaxis?

Answer 59

- low blood pressure - fast/slow heart rate - flushing - hives, itchiness - vomiting, diarrhea, cramping - cough - shortness of breath, wheezing - runny nose - swelling of lips, tongue, throat - anxiety - lightheadedness - loss of consciousness

Question 60

What are examples of hematological reactions?

Answer 60

- Sulfonamides – hemolytic anemia - Clozapine - agranulocytosis - Sulfonamides - agranulocytosis - Thiazide diuretics - agranulocytosis - Valproic Acid - thrombocytopenia

Question 61

What are the main signs of anaphylaxis?

Answer 61

- Swelling of mouth, face, neck, or tongue - Red skin, rash, hives - Difficulty breathing - Wheezing - Rapid Pulse