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
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
3
Q
variation is a different response to same:
A
concentration
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
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
6
Q
medication variations are due to
A
- half life
- lipophilicity
- metabolic pathway
- metabolite activity
- elimination
7
Q
what is half life
A
time it takes for serum concentrations to reduce by half in the elimination phase
8
Q
how many half lives does it take to reach steady state
A
4.5-5 half lives
9
Q
what is lipophilicty and what can it affect
A
ability to cross into fatty tissue, may increase volume of distribution
10
Q
what are the metabolic pathways that contribute to medication variations
A
- cytochrome P450
- polymorphisms
- SNPs
- genetic polymorphisms
- HLAB 1502 allele
- membrane transporters
11
Q
what are polymorphisms
A
alternative sequences at a locus within a DNA strand (allele) that persists in a population
12
Q
what are SNPs
A
DNA sequence variations occur when a single nucleotide in the genome sequence is altered
13
Q
if the HLAB1502 allele is present:
A
increases risk of SJS/TEN with carbapenzamine (tegratol)
14
Q
HLAB1502 allele is common in:
A
chinese ancestry
15
Q
what is the membrane transporter we are concerned with in metabolic pathway
A
p-glycoprotein
16
Q
what are the type of metabolic activity
A
active and inactive metabolites
17
Q
what are the types of elimination
A
renal and hepatic
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
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)
20
Q
qualitative responses can be different because of:
A
genetic and immune responses
21
Q
what is an example of qualitative repsonse
A
hemolytic anemia secondary to methyldopa and response to antidrug antibodies that get formed
22
Q
what are the factors contributing to quantitavie and qualitative variation
A
- ethnicity
- age
- pregnancy
- disease
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
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
25
what are the age considerations in ADME
- 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
26
what are the pregnancy considerations
- reduced maternal plasma albumin
- increased CO
- increased renal blood flow and GFR
- increased transfer of lipophilic drugs
27
what are the disease considerations
- may result in pharmacodynamic and pharmacokinetic variation
- renal function
- hepatic function
- gastric stasis
- pancreatic disease
28
what is the concern with increased concentration of free drug in pregnant patients
toxicity
29
what are the idiosyncratic reactions
- typically harmful
- do not require large drug doses
- genetic connectino
- immunological factors
30
what are the considerations with drug interactions
- dietary considerations
- cytochrome P450- phase 1 metabolism
- P-glycoproteins
31
what are the dietary considerations we should be concerned with
- grapefruit juice inhibits CYP3A4
- vitamin K increases clotting and impacts warfarin
32
what is codeine broken down into
demethylated to norcodeine and morphine
33
what are the pharmacodynamic interactions with beta blockers
agents like propranolol reduce effectiveness of beta agonists used for asthma treatment (albuterol)
34
what is an example of a pharmacodynamic interaction with diuretics
agents that decrease potassium ( hydrochlorothiazide) predispose to digoxin toxicity
35
what is an example of a pharmacodynamic interaction with MAOIs
inhibit the breakdown of pressor agents- tyramine
36
what is an example of a pharmacodynamic interaction with ASA/warfarin
increased bleeding
37
what is an example of a pharmacodynamic interaction with NSAIDs
increase the risk of hypertension by inhibiting prostaglandin
38
what is an example of a pharmacodynamic interaction with antihistamines, opiates, ETOH
additive sedative effects
39
what is an example of a pharmacodynamic interaction with anticonvulsants
Depakote inhibits platelet formation
40
what is an example of a pharmacodynamic interaction with dopamine blockers
impacted by dopamine agonists ( levodopa/carbidopa)
41
what is an example of a pharmacodynamic interaction with anticholinergics
cogentin may decrease the effectiveness of AChE inhibitors
42
GI absorption slowed by meds that inhibit gastric empyting such as:
atropine, anticholinergics, opiates
43
GI absorption increased by meds that increase gastric emptying such as:
metoclopramide (reglan)
44
what are examples of interactions within the gut
- 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
what happens when a drug is distributed
- competition for protein binding sites
- alterations in free drug concentrations
- impact secondarily on elimination
46
what drugs cause enzyme induction in metabolism
- phenytoin
- carbamazepine
- rifampin
- theophylline
47
what drugs cause enzyme inhibition in metabolism
- allopurinol
- ciprofloxacin
- paroxetine
- fluoxetine
- cimetidine
48
what are reasons that affect how other medications are eliminated
- tubular secretion
- urine pH
49
what is the lithium pharmacodynamic interaction with NSAIDS
NSAIDS vasoconstrict the afferent renal tubule causing less renal blood flow and higher lithium
50
what is the lithium pharmacodynamic interaction with ACEi
inhibit conversion of ANG I to ANG II so we vasodilate and cause less renal clearance and lithium levels go up
51
what is the pharmacodynamic interaction between thiazide diuretics and lithium
causes increased lithium reabsorption
52
what is the pharmacodynamic interaction between methylxanthines and lithium
decreased lithium levels
53
what is polypharmacy
use of 5 or more medications
54
describe the adverse effects of pharmacological action
- result from main pharmacological action and reasonable be expected
- often addressed with dose reduction
- usually reversible
- some events more discrete
55
describe adverse effects independent of main pharmacological action
- can be predictable when dose is excessive
- unpredictable idiosyncratic reactions
56
what drugs can be predictable when dose is excessive
- aspirin and tinnitus
- clozapine and seizures
- bupropion and seizures
57
what drugs can cause unpredictable idiosyncratic reactions
- penicillin and anaphylaxis
- clozapine and aplastic anemia
58
what is considered in drug toxicity testing
- animal testing
- doses significantly above therapeutic range
- identify organ toxicity
- acceptable toxicity differences dependent upon targeted disease state
59
what are examples of non covalent interactions in toxin induced cell damage
- lipid peroxidation
- reactive oxygen species
- depletion of glutathione
- modification of sulfhydryl groups
60
what is lipid peroxidation
peroxidation of unsaturated lipids, hydroperoxides (ROOH) are formed and break down lipid membranes
61
what are reactive oxygen species
formation of hydrogen peroxide and are excitotoxic, cytotoxic, and neurodegenerative
62
what does depletion of glutathione do
disrupts normal cellular defense
63
what does modification of sulfhydryl groups do
result in cell death from acute calcium overload and activation of degrading enzymes
64
what are examples of covalent interactions in toxin induced cell damage
- targets DNA, proteins, peptides, lipids and carbohydrates
- hepatotoxicity
- nephrotoxicity
65
what does mutagenesis result from
covalent modification of DNA
66
what does alternation of DNA do
sequence codes for proteins that regulate cell growth
67
how many mutations are required for malignancy
more than one
68
what mutations cause malignancy
proto-oncogenes or tumor suppressor genes
69
what are carcinogens
chemical substances that cause cancer
70
what is the result of teratogenesis
gross structural malformations during fetal development and is different than other forms of fetal damage - growth retardation
71
what is the mechanism of teratogenesis
- blastocyte formation: cell division occurring
- organogenesis: structural formation
- histogenesis and maturation of function - nutrient supply
72
what are the known teratogens
- thalidomide
- cytotoxic medications
- vitamin A derivatives
- antiepileptics
- anticoagulants
73
what is the result of thalidomide
sedative/hypnotic
- shortened long bone development
74
what are the cytotoxic medications that are teratogens
- alkylating agents and antimetabolites- cyclophosphamide
- folate antagonists- valproic acid (depakote)
75
what are the vitamin A derivatives that are teratogens
tertinoin and isotretinoin
76
what antiepileptics are teratogens
- phenytoin
- valproic acid
- carbamazepine
- iamotrigine
77
what anticoagulants are teratogens
warfarin
78
describe allergic reactions
- 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
what are the 2 types of allergic reactions
- anaphylactic shock
- hematological reactionsw
80
what happens in anaphylactic shock
release of histamines and leukotrienes
81
what drugs can cause anaphylactic shock
penicillins
- adrenocorticotropin
- heparin
82
what are the drugs that can cause hematological reactions and what reaction do they cause
- sulfonamides- hemolytic anemia
- clozapine- agranulocytosis
- sulfonamides- agranulocytosis
- thiazide diuretics- agranulocytosis
- valproic acid- thrombocytopenia
83
what are the symptoms of anaphylaxis
- swelling of mouth, face, neck or tongue
- red skin, rash, hives
- difficulty breathing
- wheezing
- rapid pulse
84
anaphylaxis is a:
sudden onset
85
