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
Qualitative responses can be different in some individuals because of
genetic or immunologic differences. * e.g. Hemolytic anemia secondary to methyldopa and response to antidrug antibodies that get formed
25
Qualitative responses can be different in some individuals because of
genetic or immunologic differences. * e.g. Hemolytic anemia secondary to methyldopa and response to antidrug antibodies that get formed
25
Qualitative responses can be different in some individuals because of
genetic or immunologic differences. * e.g. Hemolytic anemia secondary to methyldopa and response to antidrug antibodies that get formed
26
Qualitative responses can be different in some individuals because of
genetic or immunologic differences. * e.g. Hemolytic anemia secondary to methyldopa and response to antidrug antibodies that get formed
27
Quantitative and Qualitative Variation (4)
* Ethnicity – relates to “race”, variation in population responses * Age * Pregnancy * Disease
28
Ethnic Variation African-American (2)
* 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
29
Ethnic Variation Chinese (2)
* 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
30
* Absorption –
e.g. hypothermia reduces drug clearance
31
* Distribution –
reduced total body water, increased lipid distribution with age (increased body fat)
32
* Metabolism –
impaired Phase 1 metabolism (e.g. oxidation, reduction, hydrolysis) = accumulation * Example: lorazepam (Ativan ™), temazepam (Restoril ™), and oxazepam (Serax ™) undergo Phase 2 metabolism
33
Excretion –
less efficient in newborns and over the age of 65
34
Pregnancy Considerations (4)
* Reduced maternal plasma albumin * Increased cardiac output * Increased renal blood flow and GFR * Increased transfer of lipophilic drugs
35
Disease Considerations (5)
* May result in both pharmacokinetic and pharmacodynamic variation * Renal function * Hepatic function * Gastric stasis * Pancreatic disease * Others
36
Idiosyncratic Reactions (4)
*Typically harmful *Do not require large drug doses *Genetic connection *Immunological factors
37
Drug Interactions (3)
* Dietary considerations * Cytochrome P450 - Phase 1 Metabolism * P-glycoproteins
38
* Dietary considerations grapefruit juice
inhibits CYP3A4; Vitamin K increases clotting and impacts warfarin (Coumadin ™)
38
* Beta Blockers –
agents like propranolol (Inderal™) reduce effectiveness of Beta agonists used for asthma treatment (e.g. albuterol [Ventolin™], salmeterol [Serevent™])
39
* Diuretics –
agents that decrease K+ (e.g. hydrochlorothiazide) predispose to digoxin toxicity
40
* MAOIs –
inhibit the breakdown of “pressor” agents (e.g. tyramine)
41
* ASA/Warfarin –
increased bleeding
42
* NSAIDs –
increase the risk of hypertension by inhibiting prostaglandin
43
* Antihistamines, Opiates, ETOH –
additive sedative effects
44
* Anticonvulsants –
e.g. valproic acid (Depakote ™) inhibits platelet formation
45
* Dopamine Blockers –
impacted by dopamine agonists (e.g. levodopa/carbidopa [Sinemet™])
46
* Anticholinergics –
Cogentin may decrease the effectiveness of AChE Inhibitors (e.g. donepezil [Aricept ™])
47
Pharmacokinetic Interactions (4)
* Absorption * Distribution * Metabolism * Excretion
48
Absorption * GI absorption slowed by meds that * GI absorption increased by meds that * Interactions within the gut
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
Distribution * Competition for * Alterations in * Impact secondarily on
protein binding sites "free" drug concentrations elimination
50
Metabolism * Enzyme (2)
* Enzyme induction (phenytoin, carbamazepine, rifampin, theophylline) * Enzyme inhibition (allopurinol, ciprofloxacin, paroxetine, fluoxetine, cimetidine)
51
Excretion (2)
* Tubular secretion * Altered urine flow and urine pH
52
What is polypharmacy? (2)
* Use of multiple medications by a patient * ≥ 5 medications
53
Adverse Effects: Pharmacological Action * Result from -- * Often addressed with -- * Usually -- * Some events more --
main pharmacological action and can reasonably be expected dose reduction reversible discrete
54
Adverse Effects: Independent of Main Pharmacological Action * Can be predictable when dose is excessive (3)
* Aspirin and tinnitus * Clozapine (Clozaril ™ ) and seizures * Bupropion (Wellbutrin ™) and seizures
55
Adverse Effects: Independent of Main Pharmacological Action * Unpredictable idiosyncratic reactions (2)
* Penicillin and anaphylaxis * Clozapine and aplastic anemia
56
Drug Toxicity Testing (4)
* Animal testing * Doses significantly above therapeutic range * Identify organ toxicity * "acceptable" toxicity differences dependent upon targeted disease state
57
Toxin Induced Cell Damage Drug Metabolites * Non-Covalent Interactions (4)
Lipid peroxidation Reactive oxygen species Depletion of glutathione Modification of sulfhydryl groups
58
Lipid peroxidation –
peroxidation of unsaturated lipids, hydroperoxides (ROOH) are formed and break down lipid membranes
59
Reactive oxygen species –
formation of hydrogen peroxide and are excitotoxic, cytotoxic, and neurodegenerative
60
Depletion of glutathione –
disrupts normal cellular defense
61
Modification of sulfhydryl groups –
result in cell death from acute calcium overload and activation of degrading enzymes
62
Covalent Interactions – (3)
targets DNA, proteins, peptides, lipids, and carbohydrates Hepatotoxicity Nephrotoxicity
63
* Mutagenesis –
results from covalent modification of DNA
64
* Alteration of DNA –
sequence codes for proteins that regulate cell growth
65
* More than one mutation is required for
malignancy proto-oncogenes or tumor suppressor genes
66
* Carcinogens –
chemical substances that cause cancer
67
Teratogenesis –
result is gross structural malformations during fetal development and is different than other forms of fetal damage (e.g. growth retardation)
68
Mutagenesis and Teratogenicity Mechanism (3)
Blastocyte formation – cell division occurring Organogenesis – structural formation Histogenesis and maturation of function – nutrient supply
69
Known Teratogens (5)
* Thalidomide – * Cytotoxic Medications * Vitamin A Derivatives – * Antiepileptics * Anticoagulants
70
* Thalidomide –
sedative/hypnotic – shortened long bone development
71
* Cytotoxic Medications (2)
* Alkylating agents and antimetabolites – cyclophosphamide * Folate antagonists – valproic acid (Depakote ™)
72
* Vitamin A Derivatives –
tretinoin and isotretinoin
73
* Antiepileptics
* Phenytoin (Dilantin™), valproic acid (Depkaote™), carbamazepine (Tegretol™), lamotrigine (Lamictal™)
74
* Anticoagulants
* Warfarin (Coumadin™)
75
Allergic Reactions (5)
* May be immediate or delayed following exposure * Dose doesn’t matter * Not related to primary drug MOA * Incidence < 25% * Skin reactions most common
76
Allergic Responses (2)
Anaphylactic shock Hematological reactions
77
Anaphylactic shock –
release of histamine and leukotrienes (sudden onset)
78
Anaphylactic shock – ex (3)
* Penicillins * Adrenocorticotropin * Heparin
79
Hematological reactions (5)
* Sulfonamides – hemolytic anemia * Clozapine - agranulocytosis * Sulfonamides - agranulocytosis * Thiazide diuretics - agranulocytosis * Valproic Acid - thrombocytopenia
80
anaphylaxis
a serious allergic rxn and should be treated as a medical emergency it can occur within minutes of exposure or take serveral hours
81
Anaphylaxis signs (5)
* Swelling of mouth, face, neck, or tongue * Red skin, rash, hives * Difficulty breathing * Wheezing * Rapid Pulse