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Pharmacology > Drug Variability and Harmful Effects > Flashcards

Drug Variability and Harmful Effects Flashcards

1
Q

Variation
* Most often quantitative as a drug produces a

A

“larger”
or “smaller” effect and/or lasts for a longer or shorter
period of time….while qualitatively exerting the
same effect.

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2
Q

Variation can result from

A

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

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3
Q

Pharmacokinetic –

A

ADME
body on drug

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4
Q

Pharmacogenomics and — Medicine

A

Personalized

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5
Q

Pharmacodynamic

A

drug on body

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6
Q

Idiosyncratic –

A

because of genetic differences or
immunologic response

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7
Q

Implications of Variation
(3)

A
  • Clinical Impact – “response” vs. “toxicity”
  • Lack of efficacy
  • Side effects and drug toxicity
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8
Q

Side effects and drug toxicity
* Including – side effects

A

unexpected

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9
Q

Half-life –

A

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)

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10
Q

Lipophilicity –

A

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

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11
Q

Lipophilicity – ability to cross into fatty tissue, may increase Volume of Distribution
* Examples:

A

(diazepam [Valium™], carbamazepine [Tegretol ™], trazodone [Desyrel ™])

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12
Q

Metabolic Pathway –

A

Cytochrome P450 (e.g. CYP3A4, CYP2D6)

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13
Q

Polymorphisms –

A

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

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14
Q

Single nucleotide polymorphisms (SNPs) –

A

DNA sequence variations occur when a single nucleotide in the genome
sequence is altered (substitute one nucleotide for another, e.g. C for T)

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15
Q

Genetic polymorphisms

A

(e.g. 7% of Caucasians are deficient of 2C9, 20% of Japanese and Chinese are deficient of
2C19, 8% of Caucasians are deficient of 2D6, and 3% of African-Americans are deficient of 2D6)

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16
Q

HLAB*1502 Allele if present (Chinese ancestry)

A

increases risk of SJS / TEN with carbamazepine (Tegretol™)

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17
Q

Membrane transporters –

A

P-glycoprotein (delivery and elimination)

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18
Q

Metabolite Activity –

A

active and inactive metabolites

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19
Q

Elimination –

A

renal or hepatic

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20
Q

What Contributes to Drug Related
Response Variations
(6)

A
  • Age related changes
  • Genetics
  • Personalized Medicine
  • Immunological
  • Concurrent disease
  • Drug interactions
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21
Q

Genetics –

A

influence PK by altering the expression of
proteins involved in drug ADME - “genetic polymorphism”

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22
Q

Concurrent disease – commonly

A

renal and hepatic

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23
Q

Drug interactions – “think” –

A

CYP450

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24
Q

Quantitative and
Qualitative Variation
* Results when the drug produces a

A

larger or smaller effect, acts longer or
shorter in duration, while from a qualitative standpoint still demonstrating the
same effect (receptor level).

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25
Q

Qualitative responses can be different in some individuals because of

A

genetic
or immunologic differences.
* e.g. Hemolytic anemia secondary to methyldopa and response to antidrug
antibodies that get formed

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25
Q

Qualitative responses can be different in some individuals because of

A

genetic
or immunologic differences.
* e.g. Hemolytic anemia secondary to methyldopa and response to antidrug
antibodies that get formed

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25
Q

Qualitative responses can be different in some individuals because of

A

genetic
or immunologic differences.
* e.g. Hemolytic anemia secondary to methyldopa and response to antidrug
antibodies that get formed

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26
Q

Qualitative responses can be different in some individuals because of

A

genetic
or immunologic differences.
* e.g. Hemolytic anemia secondary to methyldopa and response to antidrug
antibodies that get formed

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27
Q

Quantitative and Qualitative Variation
(4)

A
  • Ethnicity – relates to “race”, variation in population responses
  • Age
  • Pregnancy
  • Disease
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28
Q

Ethnic Variation
African-American
(2)

A
  • 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
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29
Q

Ethnic Variation
Chinese
(2)

A
  • 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
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30
Q
  • Absorption –
A

e.g. hypothermia reduces drug clearance

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31
Q
  • Distribution –
A

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

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32
Q
  • Metabolism –
A

impaired Phase 1 metabolism (e.g. oxidation,
reduction, hydrolysis) = accumulation
* Example: lorazepam (Ativan ™), temazepam (Restoril ™),
and oxazepam (Serax ™) undergo Phase 2 metabolism

33
Q

Excretion –

A

less efficient in newborns and over the age of 65

34
Q

Pregnancy Considerations
(4)

A
  • Reduced maternal plasma albumin
  • Increased cardiac output
  • Increased renal blood flow and GFR
  • Increased transfer of lipophilic drugs
35
Q

Disease Considerations
(5)

A
  • May result in both pharmacokinetic and
    pharmacodynamic variation
  • Renal function
  • Hepatic function
  • Gastric stasis
  • Pancreatic disease
  • Others
36
Q

Idiosyncratic Reactions
(4)

A

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

37
Q

Drug Interactions
(3)

A
  • Dietary considerations
  • Cytochrome P450 - Phase 1 Metabolism
  • P-glycoproteins
38
Q
  • Dietary considerations
    grapefruit juice
A

inhibits CYP3A4; Vitamin K increases clotting and impacts warfarin (Coumadin ™)

38
Q
  • Beta Blockers –
A

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

39
Q
  • Diuretics –
A

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

40
Q
  • MAOIs –
A

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

41
Q
  • ASA/Warfarin –
A

increased bleeding

42
Q
  • NSAIDs –
A

increase the risk of hypertension by inhibiting prostaglandin

43
Q
  • Antihistamines, Opiates, ETOH –
A

additive sedative effects

44
Q
  • Anticonvulsants –
A

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

45
Q
  • Dopamine Blockers –
A

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

46
Q
  • Anticholinergics –
A

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

47
Q

Pharmacokinetic
Interactions
(4)

A
  • Absorption
  • Distribution
  • Metabolism
  • Excretion
48
Q

Absorption
* GI absorption slowed by meds that
* GI absorption increased by meds that
* Interactions within the gut

A

inhibit gastric emptying (e.g. atropine, anticholinergics, opiates)
increase gastric emptying (e.g. metoclopramide [Reglan™])
(e.g. calcium and iron bind with
tetracycline; cholestyramine binds digoxin and warfarin;
reasons to separate doses of Maalox, Mylanta, and
Metamucil from orally administered medications)

49
Q

Distribution
* Competition for
* Alterations in
* Impact secondarily on

A

protein binding sites
“free” drug concentrations
elimination

50
Q

Metabolism
* Enzyme (2)

A
  • Enzyme induction (phenytoin, carbamazepine,
    rifampin, theophylline)
  • Enzyme inhibition (allopurinol, ciprofloxacin,
    paroxetine, fluoxetine, cimetidine)
51
Q

Excretion
(2)

A
  • Tubular secretion
  • Altered urine flow and urine pH
52
Q

What is polypharmacy?
(2)

A
  • Use of multiple medications by a patient
  • ≥ 5 medications
53
Q

Adverse Effects:
Pharmacological Action
* Result from –
* Often addressed with –
* Usually –
* Some events more –

A

main pharmacological action and can
reasonably be expected
dose reduction
reversible
discrete

54
Q

Adverse Effects:
Independent of Main
Pharmacological Action
* Can be predictable when dose is excessive
(3)

A
  • Aspirin and tinnitus
  • Clozapine (Clozaril ™ ) and seizures
  • Bupropion (Wellbutrin ™) and seizures
55
Q

Adverse Effects:
Independent of Main
Pharmacological Action
* Unpredictable idiosyncratic reactions
(2)

A
  • Penicillin and anaphylaxis
  • Clozapine and aplastic anemia
56
Q

Drug Toxicity Testing
(4)

A
  • Animal testing
  • Doses significantly above therapeutic range
  • Identify organ toxicity
  • “acceptable” toxicity differences dependent upon
    targeted disease state
57
Q

Toxin Induced Cell Damage
Drug Metabolites
* Non-Covalent Interactions
(4)

A

Lipid peroxidation
Reactive oxygen species
Depletion of glutathione
Modification of sulfhydryl groups

58
Q

Lipid peroxidation –

A

peroxidation of unsaturated lipids, hydroperoxides
(ROOH) are formed and break down lipid membranes

59
Q

Reactive oxygen species –

A

formation of hydrogen peroxide and are
excitotoxic, cytotoxic, and neurodegenerative

60
Q

Depletion of glutathione –

A

disrupts normal cellular defense

61
Q

Modification of sulfhydryl groups –

A

result in cell death from acute calcium
overload and activation of degrading enzymes

62
Q

Covalent Interactions –
(3)

A

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

63
Q
  • Mutagenesis –
A

results from covalent modification of
DNA

64
Q
  • Alteration of DNA –
A

sequence codes for proteins that
regulate cell growth

65
Q
  • More than one mutation is required for
A

malignancy
proto-oncogenes or tumor suppressor genes

66
Q
  • Carcinogens –
A

chemical substances that cause
cancer

67
Q

Teratogenesis –

A

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

68
Q

Mutagenesis and
Teratogenicity
Mechanism
(3)

A

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

69
Q

Known Teratogens
(5)

A
  • Thalidomide –
  • Cytotoxic Medications
  • Vitamin A Derivatives –
  • Antiepileptics
  • Anticoagulants
70
Q
  • Thalidomide –
A

sedative/hypnotic – shortened long bone development

71
Q
  • Cytotoxic Medications
    (2)
A
  • Alkylating agents and antimetabolites – cyclophosphamide
  • Folate antagonists – valproic acid (Depakote ™)
72
Q
  • Vitamin A Derivatives –
A

tretinoin and isotretinoin

73
Q
  • Antiepileptics
A
  • Phenytoin (Dilantin™), valproic acid (Depkaote™), carbamazepine (Tegretol™), lamotrigine (Lamictal™)
74
Q
  • Anticoagulants
A
  • Warfarin (Coumadin™)
75
Q

Allergic Reactions
(5)

A
  • May be immediate or delayed following exposure
  • Dose doesn’t matter
  • Not related to primary drug MOA
  • Incidence < 25%
  • Skin reactions most common
76
Q

Allergic Responses
(2)

A

Anaphylactic shock
Hematological reactions

77
Q

Anaphylactic shock –

A

release of histamine and leukotrienes (sudden onset)

78
Q

Anaphylactic shock – ex (3)

A
  • Penicillins
  • Adrenocorticotropin
  • Heparin
79
Q

Hematological reactions
(5)

A
  • Sulfonamides – hemolytic anemia
  • Clozapine - agranulocytosis
  • Sulfonamides - agranulocytosis
  • Thiazide diuretics - agranulocytosis
  • Valproic Acid - thrombocytopenia
80
Q

anaphylaxis

A

a serious allergic rxn and should be treated as a medical emergency
it can occur within minutes of exposure or take serveral hours

81
Q

Anaphylaxis
signs (5)

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

Pharmacology (13 decks)

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