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Fixed Pros II > Lecture 8 - Drug Variability and Harmful Effects > Flashcards

Lecture 8 - Drug Variability and Harmful Effects Flashcards

1
Q

what is variation

A

most often quantitative as a drug produces a larger or smaller effect and/or lasts for a longer or short 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

variation is a different response to same:

A

concentration

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4
Q

what are the 3 reasons there is individual variation

A
  • pharmacodynamic - ADME: pharmacogenomics and personalized medicine
  • pharmacodynamic
  • idiosyncratic - because of genetic difference or immunologic response
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5
Q

what are the implications of variaiton

A
  • clinical impact- repsonse vs toxicity
  • lack of efficacy
  • side effects and drug toxicity
  • including unexpected side effects
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6
Q

medication variations are due to

A
  • half life
  • lipophilicity
  • metabolic pathway
  • metabolite activity
  • elimination
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7
Q

what is half life

A

time it takes for serum concentrations to reduce by half in the elimination phase

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8
Q

how many half lives does it take to reach steady state

A

4.5-5 half lives

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9
Q

what is lipophilicty and what can it affect

A

ability to cross into fatty tissue, may increase volume of distribution

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10
Q

what are the metabolic pathways that contribute to medication variations

A
  • cytochrome P450
  • polymorphisms
  • SNPs
  • genetic polymorphisms
  • HLAB 1502 allele
  • membrane transporters
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11
Q

what are polymorphisms

A

alternative sequences at a locus within a DNA strand (allele) that persists in a population

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12
Q

what are SNPs

A

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

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13
Q

if the HLAB1502 allele is present:

A

increases risk of SJS/TEN with carbapenzamine (tegratol)

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14
Q

HLAB1502 allele is common in:

A

chinese ancestry

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15
Q

what is the membrane transporter we are concerned with in metabolic pathway

A

p-glycoprotein

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16
Q

what are the type of metabolic activity

A

active and inactive metabolites

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17
Q

what are the types of elimination

A

renal and hepatic

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18
Q

what contributes to drug related response variations

A
  • age related changes
  • genetics- influence PK by altering the expression of proteins involved in drug ADME- genetic polymorphism
  • immunological
  • concurrent disease- commonly renal and hepatic
  • drug interactions - think CYP 450
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19
Q

quantitative and qualitative variation results when:

A

the drug produces 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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20
Q

qualitative responses can be different because of:

A

genetic and immune responses

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21
Q

what is an example of qualitative repsonse

A

hemolytic anemia secondary to methyldopa and response to antidrug antibodies that get formed

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22
Q

what are the factors contributing to quantitavie and qualitative variation

A
  • ethnicity
  • age
  • pregnancy
  • disease
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23
Q

what are the examples of ethnic variation in african americans

A
  • hydralazine and nitrates offer better mortality benefit in heart failure vs caucasian
  • ACEi (enalapril/Vasotec) do not work as well because of lower renin concentrations
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24
Q

what is an example of ethnic variation in chinese

A
  • dont metabolize alcohol as well, results in increased plasma concentrations of acetylaldehyde
  • increased sensitivity to the beta blocker propranolol even though metabolized faster
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25
Q

what are the age considerations in ADME

A
  • absorption: hypothermia reduces drug clearance, age lowers core body temp
  • distribution- reduced total body water, increased lipid distribution with age- increased body fat
  • metabolism- impaired phase 1 metabolism (oxidation, reduction, hydrolysis) = accumulation
  • excretion: less efficient in newborns and over the age of 65
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26
Q

what are the pregnancy considerations

A
  • reduced maternal plasma albumin
  • increased CO
  • increased renal blood flow and GFR
  • increased transfer of lipophilic drugs
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27
Q

what are the disease considerations

A
  • may result in pharmacodynamic and pharmacokinetic variation
  • renal function
  • hepatic function
  • gastric stasis
  • pancreatic disease
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28
Q

what is the concern with increased concentration of free drug in pregnant patients

A

toxicity

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29
Q

what are the idiosyncratic reactions

A
  • typically harmful
  • do not require large drug doses
  • genetic connectino
  • immunological factors
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30
Q

what are the considerations with drug interactions

A
  • dietary considerations
  • cytochrome P450- phase 1 metabolism
  • P-glycoproteins
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31
Q

what are the dietary considerations we should be concerned with

A
  • grapefruit juice inhibits CYP3A4
  • vitamin K increases clotting and impacts warfarin
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32
Q

what is codeine broken down into

A

demethylated to norcodeine and morphine

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33
Q

what are the pharmacodynamic interactions with beta blockers

A

agents like propranolol reduce effectiveness of beta agonists used for asthma treatment (albuterol)

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34
Q

what is an example of a pharmacodynamic interaction with diuretics

A

agents that decrease potassium ( hydrochlorothiazide) predispose to digoxin toxicity

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35
Q

what is an example of a pharmacodynamic interaction with MAOIs

A

inhibit the breakdown of pressor agents- tyramine

36
Q

what is an example of a pharmacodynamic interaction with ASA/warfarin

A

increased bleeding

37
Q

what is an example of a pharmacodynamic interaction with NSAIDs

A

increase the risk of hypertension by inhibiting prostaglandin

38
Q

what is an example of a pharmacodynamic interaction with antihistamines, opiates, ETOH

A

additive sedative effects

39
Q

what is an example of a pharmacodynamic interaction with anticonvulsants

A

Depakote inhibits platelet formation

40
Q

what is an example of a pharmacodynamic interaction with dopamine blockers

A

impacted by dopamine agonists ( levodopa/carbidopa)

41
Q

what is an example of a pharmacodynamic interaction with anticholinergics

A

cogentin may decrease the effectiveness of AChE inhibitors

42
Q

GI absorption slowed by meds that inhibit gastric empyting such as:

A

atropine, anticholinergics, opiates

43
Q

GI absorption increased by meds that increase gastric emptying such as:

A

metoclopramide (reglan)

44
Q

what are examples of interactions within the gut

A
  • calcium and iron bind with tetracycline
  • cholestyramine binds digoxin and warfarin
  • reasons to separate doses of Maalox, Mylanta, and Metamucil from orally administered medications
45
Q

what happens when a drug is distributed

A
  • competition for protein binding sites
  • alterations in free drug concentrations
  • impact secondarily on elimination
46
Q

what drugs cause enzyme induction in metabolism

A
  • phenytoin
  • carbamazepine
  • rifampin
  • theophylline
47
Q

what drugs cause enzyme inhibition in metabolism

A
  • allopurinol
  • ciprofloxacin
  • paroxetine
  • fluoxetine
  • cimetidine
48
Q

what are reasons that affect how other medications are eliminated

A
  • tubular secretion
  • urine pH
49
Q

what is the lithium pharmacodynamic interaction with NSAIDS

A

NSAIDS vasoconstrict the afferent renal tubule causing less renal blood flow and higher lithium

50
Q

what is the lithium pharmacodynamic interaction with ACEi

A

inhibit conversion of ANG I to ANG II so we vasodilate and cause less renal clearance and lithium levels go up

51
Q

what is the pharmacodynamic interaction between thiazide diuretics and lithium

A

causes increased lithium reabsorption

52
Q

what is the pharmacodynamic interaction between methylxanthines and lithium

A

decreased lithium levels

53
Q

what is polypharmacy

A

use of 5 or more medications

54
Q

describe the adverse effects of pharmacological action

A
  • result from main pharmacological action and reasonable be expected
  • often addressed with dose reduction
  • usually reversible
  • some events more discrete
55
Q

describe adverse effects independent of main pharmacological action

A
  • can be predictable when dose is excessive
  • unpredictable idiosyncratic reactions
56
Q

what drugs can be predictable when dose is excessive

A
  • aspirin and tinnitus
  • clozapine and seizures
  • bupropion and seizures
57
Q

what drugs can cause unpredictable idiosyncratic reactions

A
  • penicillin and anaphylaxis
  • clozapine and aplastic anemia
58
Q

what is considered in drug toxicity testing

A
  • animal testing
  • doses significantly above therapeutic range
  • identify organ toxicity
  • acceptable toxicity differences dependent upon targeted disease state
59
Q

what are examples of non covalent interactions in toxin induced cell damage

A
  • lipid peroxidation
  • reactive oxygen species
  • depletion of glutathione
  • modification of sulfhydryl groups
60
Q

what is lipid peroxidation

A

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

61
Q

what are reactive oxygen species

A

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

62
Q

what does depletion of glutathione do

A

disrupts normal cellular defense

63
Q

what does modification of sulfhydryl groups do

A

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

64
Q

what are examples of covalent interactions in toxin induced cell damage

A
  • targets DNA, proteins, peptides, lipids and carbohydrates
  • hepatotoxicity
  • nephrotoxicity
65
Q

what does mutagenesis result from

A

covalent modification of DNA

66
Q

what does alternation of DNA do

A

sequence codes for proteins that regulate cell growth

67
Q

how many mutations are required for malignancy

A

more than one

68
Q

what mutations cause malignancy

A

proto-oncogenes or tumor suppressor genes

69
Q

what are carcinogens

A

chemical substances that cause cancer

70
Q

what is the result of teratogenesis

A

gross structural malformations during fetal development and is different than other forms of fetal damage - growth retardation

71
Q

what is the mechanism of teratogenesis

A
  • blastocyte formation: cell division occurring
  • organogenesis: structural formation
  • histogenesis and maturation of function - nutrient supply
72
Q

what are the known teratogens

A
  • thalidomide
  • cytotoxic medications
  • vitamin A derivatives
  • antiepileptics
  • anticoagulants
73
Q

what is the result of thalidomide

A

sedative/hypnotic
- shortened long bone development

74
Q

what are the cytotoxic medications that are teratogens

A
  • alkylating agents and antimetabolites- cyclophosphamide
  • folate antagonists- valproic acid (depakote)
75
Q

what are the vitamin A derivatives that are teratogens

A

tertinoin and isotretinoin

76
Q

what antiepileptics are teratogens

A
  • phenytoin
  • valproic acid
  • carbamazepine
  • iamotrigine
77
Q

what anticoagulants are teratogens

78
Q

describe allergic reactions

A
  • may be immediate or delayed following exposure
  • dose doesnt matter
  • not related to primary drug MOA
  • incidence less than 25%
  • skin reactions are most common
79
Q

what are the 2 types of allergic reactions

A
  • anaphylactic shock
  • hematological reactionsw
80
Q

what happens in anaphylactic shock

A

release of histamines and leukotrienes

81
Q

what drugs can cause anaphylactic shock

A

penicillins
- adrenocorticotropin
- heparin

82
Q

what are the drugs that can cause hematological reactions and what reaction do they cause

A
  • sulfonamides- hemolytic anemia
  • clozapine- agranulocytosis
  • sulfonamides- agranulocytosis
  • thiazide diuretics- agranulocytosis
  • valproic acid- thrombocytopenia
83
Q

what are the symptoms of anaphylaxis

A
  • swelling of mouth, face, neck or tongue
  • red skin, rash, hives
  • difficulty breathing
  • wheezing
  • rapid pulse
84
Q

anaphylaxis is a:

A

sudden onset

Fixed Pros II (13 decks)

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