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PHARM > drug variability and harmful > Flashcards

drug variability and harmful Flashcards

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
Q

Antihistamines, Opiates, ETOH pharmycodynamic effect

A

additive sedative effects

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26
Q

Anticonvulsants pharmycodynamic effects

A

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

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27
Q

Dopamine Blockers pharmycodynamic interactions

A

impacted by dopamine agonists (e.g. levodopa/carbidopa)

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28
Q

Anticholinergics pharmycodynamic effect (cogentin effect?)

A

– Cogentin may decrease the effectiveness of AChE Inhibitors (e.g. donepezil, ALZ tx )

29
Q

Pharmacokinetic
Interactions

A
  • Absorption
  • Distribution
  • Metabolism
  • Excretion
30
Q

Absorption
* GI absorption slowed by meds that? examples?
* GI absorption increased by meds that? examples?

A
  • GI absorption slowed by meds that inhibit gastric emptying
    (atropine, anticholinergics, opiates)
  • GI absorption increased by meds that increase gastric emptying (metoclopramide (reglan))
31
Q

absorption interations within the gut?

examples?

A
  • 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
Q

important Li drug rxns to know

A
33
Q

distribution interactions
Competition for?
* Alterations in?
* Impact secondarily on?

A

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
Q

Metabolism interactions

examples?

A
  • Enzyme induction (phenytoin, carbamazepine,
    rifampin, theophylline)
  • Enzyme inhibition (allopurinol, ciprofloxacin,
    paroxetine, fluoxetine, cimetidine)
35
Q

Excretion interactions

A
  • Tubular secretion alterations
  • Altered urine flow and urine pH
36
Q
  • What is polypharmacy?
A
  • Use of multiple medications by a patient
  • ≥ 5 medications
37
Q

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

A
  • 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
Q

Adverse Effects: Independent of Main
pharmacological Action
* Can be?

ASA. clozapine, buproion, PCN?

A
  • 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
Q

phenytoin oral adverse effect?

A

ging hyper

40
Q

Drug Toxicity Testing procedure?
* tests on?
* Doses?
* Identify?
* “acceptable” toxicity?

A
  • Animal testing
  • Doses significantly above therapeutic range
  • Identify organ toxicity
  • “acceptable” toxicity differences dependent upon
    targeted disease state (more severe dx=more acceptable)
41
Q

Toxin Induced Cell Damage Drug Metabolites forms?

A

covalent and non-covalent interactions

42
Q
  • Non-Covalent Interactions of toxin induced cell damage via metabolites examples
A

Lipid peroxidation
Reactive oxygen species
Depletion of glutathione
modification of sulfahydral groups

43
Q

lipid peroxidation toxin induced cell damage

A

a non-covalent toxin induced cell damage
– peroxidation of unsaturated lipids, hydroperoxides
(ROOH) are formed and break down lipid membranes

44
Q

ROS as toxin induced cell damage

A

as a non-covalent toxin induced cell
– formation of hydrogen peroxide and are excitotoxic, cytotoxic, and neurodegenerative

45
Q

Depletion of glutathione toxin induced cell damage

A

non-covalent toxin induced cell damage
disrupts normal cellular defense

46
Q

Modification of sulfhydryl groups toxin induced cell damage

A

non-covalent toxin induced cell damage
result in cell death from acute calcium overload and activation of degrading enzymes

47
Q

Toxin Induced Cell Damage Drug Metabolites Covalent Interactions

A

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

48
Q

Mutagenesis and Carcinogenicity
* Mutagenesis def
* how many mutations needed?
* Carcinogens def

A
  • 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
Q

Mutagenesis and
Teratogenicity

A
  • Teratogenesis – result is gross structural malformations during fetal development and is different than other forms of fetal damage (e.g. growth retardation)
50
Q

teratogenesis potential stages to occur in:

A

Blastocyte formation – cell division occurring, days 0-16
Organogenesis – structural formation, 17-60
Histogenesis and maturation of function – nutrient supply’ 60-term

51
Q

Known Teratogens (classes and drug names?)

A
  • 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
Q

Allergic Reactions
* timing?
* Dose?
* Not related to?
* Incidence%
* reactions most common?

A
  • May be immediate or delayed following exposure
  • Dose doesn’t matter
  • Not related to primary drug MOA
  • Incidence < 25%
  • Skin reactions most common
53
Q

common allergic responses

A

anaphylaxis and hematological rxns

54
Q
  • Anaphylactic shock

release of, onset, common drugs

A

– release of histamine and leukotrienes (sudden onset)
* Penicillins
* Adrenocorticotropin
* Heparin

55
Q
  • Hematological reactions
  • Sulfonamides?
  • Clozapine?
  • Sulfonamides?
  • Thiazide diuretics ?
  • Valproic Acid?
A

affect hematologic balance
* Sulfonamides – hemolytic anemia
* Clozapine - agranulocytosis
* Sulfonamides - agranulocytosis
* Thiazide diuretics - agranulocytosis
* Valproic Acid - thrombocytopenia

56
Q

CNS signs anaphylaxis

A

anx
lightheadedness
LOC
confusion
headache

57
Q

CV anaphylaxis signs

A

low bp
brady/tachycardia

58
Q

anaphylaxis at skin

A

flushing
hives
itching

59
Q

GI signs anaphylaxis

A

diarrhea
vomiting
cramping

60
Q

res signs anaphylaxis

A

cough
dysphagia
hoarseness
SOB
wheezing
runny nose

61
Q

swelling with anaphylaxis

A

swelling of lips, tongue and/or throat

62
Q

Anaphylaxis simple signs

A
  • Swelling of mouth, face, neck, or tongue
  • Red skin, rash, hives
  • Difficulty breathing
  • Wheezing
  • Rapid Pulse
63
Q

PCN allergic rxn presentation

A

commonly rash

64
Q

what other common Abx can cause rash/allergic rxn

A

amoxicillin

65
Q

phase 1 and 2 with age

A

phase 1 will be decreased and phase 2 will be unaffected

66
Q

what allele can cause SJS/TEN with carbamazepine? ethnicity?

A

HLAB 1502, chinese ancestry

67
Q

GFR with age

A

decreases

68
Q

why can there be ethic differences

A

genetic polymorphisms

PHARM (15 decks)

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