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drug variability and harmful Flashcards

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1
Q

Variation
* Most often qualitative or quantitative? drug produces?
* Variation can result from?

A
  • Most often quantitative 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.
  • Variation can result from a different drug
    concentration at sites of drug action OR by different
    responses to the same drug concentration.
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2
Q

variations and concentrations

A

people may respond differently to the same concentrations

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3
Q

forms of Individual Variation

A
  • Pharmacokinetic – ADME- Pharmacogenomics and Personalized Medicine
  • Pharmacodynamic
  • Idiosyncratic – because of genetic differences or
    immunologic response
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4
Q

Implications of Variation

A
  • Clinical Impact – “response” vs. “toxicity”
  • Lack of efficacy
  • Side effects and drug toxicity: Including unexpected side effects
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5
Q

Half-life

A

Half-life – 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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6
Q

Lipophilicity

examples of very lipophilic drugs?

A

Lipophilicity – ability to cross into fatty tissue, may increase Volume of Distribution
* Examples: (diazepam, carbamazepine, trazodone)

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7
Q

how can there be metabolic variations?

A

– Cytochrome P450 (e.g. CYP3A4, CYP2D6)
* Polymorphisms – alternative sequences at a locus within a DNA strand (alleles) that persist in a population
* Single nucleotide polymorphisms (SNPs) – DNA sequence variations occur when a single nucleotide in the genome sequence is altered
* Genetic polymorphisms
* HLAB*1502 Allele if present (Chinese ancestry) increases risk of SJS / TEN with carbamazepine
* Membrane transporters – P-glycoprotein (delivery and elimination)

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8
Q

Metabolite Activity

A

active and inactive metabolites

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9
Q

elimination variabilty?

A

renal/hepatic

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10
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”= Personalized Medicine
  • Immunological
  • Concurrent disease – commonly renal and hepatic
  • Drug interactions – “think” CYP450
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11
Q

Quantitative and Qualitative Variation
* Results when?
* Qualitative responses can be different in individuals why?
* factors?

A
  • Results when 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).
  • Qualitative responses can be different in some individuals because of genetic or immunologic differences.
  • Ethnicity – relates to “race”, variation in population responses
  • Age
  • Pregnancy
  • Disease
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12
Q

what sedatives can be given to older individuals safely and why?

A

LOT
loreazepam, oxazepam, temazepam
DO NOT ACCUMULATE, will undergo phase 2 not phase 1 which is decreased

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13
Q

African-American variations
* Hydralazine and Nitrates?
* ACE inhibitors (enalapril [Vasotec ™ ]?

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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14
Q

Chinese variations
* alc?
* Increased sensitivity to?

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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15
Q

Age Considerations of pharmokenetic variations

A
  • Absorption – hypothermia reduces drug clearance
  • Distribution – reduced total body water, increased lipid distribution with age (increased body fat)
  • Metabolism – impaired Phase 1 metabolism (e.g. oxidation, reduction, hydrolysis) = accumulation
  • Excretion – less efficient in newborns and over the age of 65
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16
Q

Pregnancy physio Considerations and their implications

A
  • Reduced maternal plasma albumin, increased free fraction
  • Increased cardiac output
  • Increased renal blood flow and GFR, increased elimination
  • Increased transfer of lipophilic drugs, crosses the placenta
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17
Q

Disease Considerations of variations
* May result in what variations?
* Renal?
* Hepatic ?
* Gastric?
* Pancreatic?
* Others:

A
  • May result in both pharmacokinetic and pharmacodynamic variation
  • Renal function: elim
  • Hepatic function: metab
  • Gastric stasis: slows absorbtion
  • Pancreatic disease: decreased Absorb
  • Others: MG
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18
Q

Idiosyncratic Reactions

A

*Typically harmful= fatal
*Do not require large drug doses
*usual causes: Genetic connection and Immunological factors

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19
Q

Drug Interactions
dietary with warfarin?
often affected systems/proteins?

A
  • Dietary considerations: grapefruit juice inhibits CYP3A4; Vitamin K increases clotting and impacts warfarin (Coumadin ™)
  • Cytochrome P450 - Phase 1 Metabolism
  • P-glycoproteins
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20
Q
  • Non-specific Beta Blockers pharmycodynamic interactions
A

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

non-specific blockers

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21
Q

diuretics pharmycodynmaic interactions

A

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

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22
Q

MAOIs pharmycodynamic interaction

A

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

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23
Q

ASA/warfarin pharmycodynamic interaction

A

increase bleeding

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24
Q

NSAIDS pharmycodynamic interaction

A

increase HTN risk with inhbition of PG production

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25
Antihistamines, Opiates, ETOH pharmycodynamic effect
additive sedative effects
26
Anticonvulsants pharmycodynamic effects
e.g. valproic acid (Depakote ™) inhibits platelet formation
27
Dopamine Blockers pharmycodynamic interactions
impacted by dopamine agonists (e.g. levodopa/carbidopa)
28
Anticholinergics pharmycodynamic effect (cogentin effect?)
– Cogentin may decrease the effectiveness of AChE Inhibitors (e.g. donepezil, ALZ tx )
29
Pharmacokinetic Interactions
* Absorption * Distribution * Metabolism * Excretion
30
Absorption * GI absorption slowed by meds that? examples? * GI absorption increased by meds that? examples?
* GI absorption slowed by meds that inhibit gastric emptying (atropine, anticholinergics, opiates) * GI absorption increased by meds that increase gastric emptying (metoclopramide (reglan))
31
absorption interations within the gut? | examples?
* 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
32
important Li drug rxns to know
33
distribution interactions Competition for? * Alterations in? * Impact secondarily on?
Competition for protein binding sites * Alterations in "free" drug concentrations (albumin levels) * Impact secondarily on elimination (increased elim can decrease total drug reduction), protein displacing drugs (Abx) can displace other drugs creating greater serum con.= toxicity
34
Metabolism interactions | examples?
* Enzyme induction (phenytoin, carbamazepine, rifampin, theophylline) * Enzyme inhibition (allopurinol, ciprofloxacin, paroxetine, fluoxetine, cimetidine)
35
Excretion interactions
* Tubular secretion alterations * Altered urine flow and urine pH
36
* What is polypharmacy?
* Use of multiple medications by a patient * ≥ 5 medications
37
Adverse Effects: Pharmacological Action * Result from? * Often addressed with? * Usually? * Some events more?
* Result from main pharmacological action and can reasonably be expected (A1 blockers=ortho hypo, -zosin) * Often addressed with dose reduction * Usually reversible * Some events more discrete
38
Adverse Effects: Independent of Main pharmacological Action * Can be? | ASA. clozapine, buproion, PCN?
* Can be predictable when dose is excessive: * Aspirin and tinnitus * Clozapine and seizures * Bupropion and seizures * Unpredictable idiosyncratic reactions: * Penicillin and anaphylaxis * Clozapine and aplastic anemia
39
phenytoin oral adverse effect?
ging hyper
40
Drug Toxicity Testing procedure? * tests on? * Doses? * Identify? * "acceptable" toxicity?
* Animal testing * Doses significantly above therapeutic range * Identify organ toxicity * "acceptable" toxicity differences dependent upon targeted disease state (more severe dx=more acceptable)
41
Toxin Induced Cell Damage Drug Metabolites forms?
covalent and non-covalent interactions
42
* Non-Covalent Interactions of toxin induced cell damage via metabolites examples
Lipid peroxidation Reactive oxygen species Depletion of glutathione modification of sulfahydral groups
43
lipid peroxidation toxin induced cell damage
a non-covalent toxin induced cell damage – peroxidation of unsaturated lipids, hydroperoxides (ROOH) are formed and break down lipid membranes
44
ROS as toxin induced cell damage
as a non-covalent toxin induced cell – formation of hydrogen peroxide and are excitotoxic, cytotoxic, and neurodegenerative
45
Depletion of glutathione toxin induced cell damage
non-covalent toxin induced cell damage disrupts normal cellular defense
46
Modification of sulfhydryl groups toxin induced cell damage
non-covalent toxin induced cell damage result in cell death from acute calcium overload and activation of degrading enzymes
47
Toxin Induced Cell Damage Drug Metabolites Covalent Interactions
– targets DNA, proteins, peptides, lipids, and carbohydrates: Hepatotoxicity Nephrotoxicity
48
Mutagenesis and Carcinogenicity * Mutagenesis def * how many mutations needed? * Carcinogens def
* Mutagenesis – results from covalent modification of DNA * Alteration of DNA – sequence codes for proteins that regulate cell growth * **More than one mutation** is required for malignancy proto-oncogenes or tumor suppressor genes * Carcinogens – chemical substances that cause cancer
49
Mutagenesis and Teratogenicity
* Teratogenesis – result is gross structural malformations during fetal development and is different than other forms of fetal damage (e.g. growth retardation)
50
teratogenesis potential stages to occur in:
Blastocyte formation – cell division occurring, days 0-16 Organogenesis – structural formation, 17-60 Histogenesis and maturation of function – nutrient supply' 60-term
51
Known Teratogens (classes and drug names?)
* **Thalidomide** – sedative/hypnotic – shortened long bone development * **Cytotoxic Medications**: Alkylating agents and antimetabolites – cyclophosphamide, Folate antagonists – valproic acid *** Vitamin A Derivatives** – tretinoin and isotretinoin *** Antiepileptics:** Phenytoin, valproic acid, carbamazepine, lamotrigine *** Anticoagulants**: Warfarin
52
Allergic Reactions * timing? * Dose? * Not related to? * Incidence% * reactions most common?
* May be immediate or delayed following exposure * Dose doesn’t matter * Not related to primary drug MOA * Incidence < 25% * Skin reactions most common
53
common allergic responses
anaphylaxis and hematological rxns
54
* Anaphylactic shock | release of, onset, common drugs
– release of histamine and leukotrienes (sudden onset) * Penicillins * Adrenocorticotropin * Heparin
55
* Hematological reactions * Sulfonamides? * Clozapine? * Sulfonamides? * Thiazide diuretics ? * Valproic Acid?
affect hematologic balance * Sulfonamides – hemolytic anemia * Clozapine - agranulocytosis * Sulfonamides - agranulocytosis * Thiazide diuretics - agranulocytosis * Valproic Acid - thrombocytopenia
56
CNS signs anaphylaxis
anx lightheadedness LOC confusion headache
57
CV anaphylaxis signs
low bp brady/tachycardia
58
anaphylaxis at skin
flushing hives itching
59
GI signs anaphylaxis
diarrhea vomiting cramping
60
res signs anaphylaxis
cough dysphagia hoarseness SOB wheezing runny nose
61
swelling with anaphylaxis
swelling of lips, tongue and/or throat
62
Anaphylaxis simple signs
* Swelling of mouth, face, neck, or tongue * Red skin, rash, hives * Difficulty breathing * Wheezing * Rapid Pulse
63
PCN allergic rxn presentation
commonly rash
64
what other common Abx can cause rash/allergic rxn
amoxicillin
65
phase 1 and 2 with age
phase 1 will be decreased and phase 2 will be unaffected
66
what allele can cause SJS/TEN with carbamazepine? ethnicity?
HLAB 1502, chinese ancestry
67
GFR with age
decreases
68
why can there be ethic differences
genetic polymorphisms

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