Drug Variability and Harmful effects Flashcards
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.
-can result from a different drug
concentration at sites of drug action OR by different
responses to the same drug concentration.
Variation
Different response
to the same concentration
Variation:
Phase ___ metabolism decreases with age:
Reduction, Oxidation and hydrolysis
Phase 1 metabolism
Phase ____ metabolism does not decrease with age
Phase 2 metabolism
Implications of \_\_\_\_\_\_\_\_ • Clinical Impact – “response” vs. “toxicity” • Lack of efficacy • Side effects and drug toxicity • Including unexpected side effects
Variation
– 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)
Half-life
– ability to cross into fatty tissue, may increase Volume of Distribution
• Examples: (diazepam [Valium™], carbamazepine [Tegretol ™], trazodone [Desyrel ™])
Lipophilicity
– alternative sequences at a locus within a DNA strand (alleles) that persist in a population
Polymorphisms
– DNA sequence variations occur when a single nucleotide in the genome
sequence is altered (substitute one nucleotide for another, e.g. C for T)
Single nucleotide polymorphisms (SNPs)
(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)
Genetic polymorphisms
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).
Quantitative variation
• In african americans, Hydralazine and Nitrates offer better or worse mortality
benefit in heart failure vs. Caucasian
Better mortailty benefit
• In african americans ACE inhibitors (enalapril [Vasotec ™ ])do or do not work
as well because of lower renin concentrations
Do not
• Chinese do or Don’t metabolize alcohol as well, results in
increase plasma concentration of acetaldehyde
Don’t
• Chinese display Increased or decreased sensitivity to the beta-blocker
propranolol (Inderal ™) even though metabolized
faster
Increased
Is excretion more or less efficient in newborns and over age of 65?
Less efficient
Age ____ total body water and _____ lipid distribution with age
Decreased body water; increased lipid distribution
Pregnancy considerations
______ maternal plasma albumin
• Reduced
Pregnancy considerations
_____ cardiac output
• Increased
Pregnancy considerations
______ renal blood flow and GFR
• Increased
Pregnancy considerations
_______ transfer of lipophilic drugs
• Increased
___ drugs are slow to get to fetus
Hydrophilic drugs
____ drugs are quickly gotten to fetus despite slow clearance
Lipophilic
\_\_\_\_\_ Reactions •Typically harmful •Do not require large drug doses •Genetic connection •Immunological factors
Idiosyncratic
– agents like propranolol (Inderal™) reduce effectiveness of Beta agonists used for asthma treatment (e.g. albuterol [Ventolin™], salmeterol [Serevent™])
Beta Blockers
– agents that decrease K+ (e.g. hydrochlorothiazide) predispose to digoxin toxicity
Diuretics
– inhibit the breakdown of “pressor” agents (e.g. tyramine)
MAOIs
– increased bleeding
ASA/Warfarin
– increase the risk of hypertension by inhibiting prostaglandin
NSAIDs
– additive sedative effects
Antihistamines, Opiates, ETOH
– e.g. valproic acid (Depakote ™) inhibits platelet formation
Anticonvulsants
– impacted by dopamine agonists (e.g. levodopa/carbidopa [Sinemet™])
Dopamine Blockers
– Cogentin may decrease the effectiveness of AChE Inhibitors (e.g. donepezil [Aricept ™])
Anticholinergics
GI absorption ____ by meds that inhibit gastric emptying
e.g. atropine, anticholinergics, opiates
slowed
GI absorption ______ by meds that increase gastric
emptying (e.g. metoclopramide [Reglan™])
increased
- Competition for protein binding sites
- Alterations in “free” drug concentrations
- Impact secondarily on elimination
Distribution
- Tubular secretion
* Altered urine flow and urine pH
Excretion
- Use of multiple medications by a patient
* ≥ 5 medications
Polypharmacy
• Result from main pharmacological action and can reasonably be expected • Often addressed with dose reduction • Usually reversible • Some events more discrete
Adverse effects
Adverse effects • Can be \_\_\_\_\_ when dose is excessive • Aspirin and tinnitus • Clozapine (Clozaril ™ ) and seizures • Bupropion (Wellbutrin ™) and seizures
predictable
Adverse effects
______ idiosyncratic reactions
• Penicillin and anaphylaxis
• Clozapine and aplastic anemia
Unpredictable
• Animal testing
• Doses significantly above therapeutic range
• Identify organ toxicity
• “acceptable” toxicity differences dependent upon
targeted disease state
Drug toxicity testing
•__________ Interactions
Lipid peroxidation – peroxidation of unsaturated lipids, hydroperoxides
(ROOH) are formed and break down lipid membranes
Reactive oxygen species – formation of hydrogen peroxide and are
excitotoxic, cytotoxic, and neurodegenerative
Depletion of glutathione – disrupts normal cellular defense
Modification of sulfhydryl groups – result in cell death from acute calcium
overload and activation of degrading enzymes
Non-Covalent
What are the 4 non covalent interactions that induce cell damage via toxins?
Lipid peroxidation
ROS
Depletion of glutathione
Modification of sulfhydryl groups
What are the 2 covalent interactions that cause cell damage?
Hepatotoxicity
Nephrotoxicity
_______ Interactions – targets DNA, proteins,
peptides, lipids, and carbohydrates
Hepatotoxicity
Nephrotoxicity
Covalent
– results from covalent modification of
DNA
Mutagenesis
– sequence codes for proteins that
regulate cell growth
Alteration of DNA
– chemical substances that cause
cancer
Carcinogens
– result is gross structural
malformations during fetal development and is
different than other forms of fetal damage (e.g.
growth retardation)
Teratogenesis
What are the 3 mechanisms of teratogenicity?
Blastocyte formation – cell division occurring
Organogenesis – structural formation
Histogenesis and maturation of function – nutrient supply
( known teratogens)
– sedative/hypnotic – shortened long bone development
Thalidomide
( known teratogens)
– tretinoin and isotretinoin: facial issues
Vitamin A Derivatives
( known teratogens)
– cyclophosphamide causing neural tube defects
• Alkylating agents and antimetabolites
- May be immediate or delayed following exposure
- Dose doesn’t matter
- Not related to primary drug MOA
- Incidence < 25%
- Skin reactions most common
Allergic reactions
Are most meds immunogenic on their own and low or high molecular weight?
No immunogenic on own; low molecular weight
_______ – release of histamine and leukotrienes (sudden onset)
• Penicillins
• Adrenocorticotropin
• Heparin
Anaphylactic shock
What drug causes hemolytic anemia as a hematological rxn?
Sulfonamides
Which 3 drugs cause agranulocytosis as a hematological rxn?
Clozapine
Sulfonamides
Thiazide diuretics
____ drugs cause thrombocytopenia as a hematological rxn?
Valproic acid
• Swelling of mouth, face, neck, or tongue • Red skin, rash, hives • Difficulty breathing • Wheezing • Rapid Pulse - Wheel and flare
Anaphylaxis
