Individual Drug Variation, Drug Interactions, AND Harmful Effects of Drugs Flashcards
Most often ___________ 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
quantitative
How does variation of drug response to the same concentration occur?
- a different drug concentration at sites of drug action
- by different responses to the same drug concentration
Variants exist in the gene that produces aldehyde dehydrogenase 2 enzymes (ALDH2), if two copies are present you will get a __________ response
negative
- Impacts an estimated 5-10% of those who are of Asian descent.
What does idiosyncratic mean?
because of genetic differences or
immunologic response
What are the implications of variation?
- Clinical Impact – “response” vs. “toxicity”
- Lack of efficacy
- Side effects and drug toxicity
What is 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)
What is lipophilicity?
ability to cross into fatty tissue, may increase Volume of Distribution
Examples: (diazepam [Valium], carbamazepine [Tegretol], trazodone [Desyrel])
What is a polymorphism?
alternative sequences at a locus within a DNA strand (alleles) that persist in a population
What is a single nucleotide polymorphism (SNP)?
DNA sequence variations occur when a single nucleotide in the genome sequence is altered
What should you think about for the metabolic pathway and variation?
cytochrome P450
What is the membrane transporter for delivery and elimination that has some variation?
P-glycoprotein
- Biological barrier that extrudes toxins and xenobiotics out of cells playing a roles in both absorption and disposition of medications
- Limits cellular uptake of drugs from blood circulation in the brain and from the intestinal lumen into epithelial cells than on increasing the elimination of medications out of hepatocytes and renal tubules and into the luminal space
HLAB*1502 Allele if present (Chinese ancestry) increases risk of SJS / TEN with ______________
carbamazepine
(Tegretol)
What Contributes to Drug Related
Response Variations?
- 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
Quantitivative variation 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 ___________________ differences
genetic or immunologic
What type of ethnicity associated variation is important to know in African-Americans?
- 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
What type of ethnicity associated variation is important to know in people of Asian decent?
- 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
How does age consideration affect absorption?
hypothermia reduces drug clearance
How does age consideration affect distribution?
reduced total body water, increased lipid distribution with age (increased body fat)
How does age consideration affect Metabolism?
impaired Phase 1 metabolism (e.g. oxidation,
reduction, hydrolysis) = accumulation
How does age consideration affect excretion?
less efficient in newborns and over the age of 65
What should you consider for drug variation and pregnancy considerations?
- Reduced maternal plasma albumin
- Increased cardiac output
- Increased renal blood flow and GFR
- Increased transfer of lipophilic drugs
Lipophilic drugs go to the fetus faster or slower?
faster
What should you consider for drug variation and disease considerations?
- May result in both pharmacokinetic and
pharmacodynamic variation - Renal function*
- Hepatic function*
- Gastric stasis
- Pancreatic disease
- Others
What are the features of idiosyncratic reactions?
- Typically harmful
- Do not require large drug doses
- Genetic connection
- Immunological factors
Are idiosyncractic reactions dose dependent?
NO
What dietary considerations do you need to worry about?
- grapefruit juice inhibits CYP3A4
- Vitamin K increases clotting and impacts warfarin (Coumadin)
What are the pharmacodynamic interactions with beta blockers?
agents like propranolol (Inderal) reduce effectiveness of Beta agonists used for asthma treatment (e.g. albuterol [Ventolin], salmeterol [Serevent])
What are the pharmacodynamic interactions with diuretics?
agents that decrease K+ (e.g. hydrochlorothiazide) predispose to digoxin toxicity
What are the pharmacodynamic interactions with MAOIs?
inhibit the breakdown of “pressor” agents (e.g. tyramine)
What are the pharmacodynamic interactions with ASA/Warfarin?
increased bleeding
What are the pharmacodynamic interactions with NSAIDs?
increase the risk of hypertension by inhibiting prostaglandin
What are the pharmacodynamic interactions with antihistamines, opiates, ETOH?
additive sedative effects
What are the pharmacodynamic interactions with anticonvulsants?
e.g. valproic acid (Depakote) inhibits platelet formation
What are the pharmacodynamic interactions with dopamine blockers?
impacted by dopamine agonists (e.g. levodopa/carbidopa [Sinemet])
What are the pharmacodynamic interactions with anticholinergics?
Cogentin may decrease the effectiveness of AChE Inhibitors (e.g. donepezil [Aricept])
What are the pharmacokinetic interactions?
Absorption
Distribution
Metabolism
Excretion
GI absorption slowed by meds that inhibit…
gastric emptying
atropine, anticholinergics, opiates
GI absorption increased by meds that increase…
gastric emptying
metoclopramide [Reglan]
What enzymes increase metabolism?
phenytoin, carbamazepine,
rifampin, theophylline
What enzymes decrease metabolism?
allopurinol, ciprofloxacin,
paroxetine, fluoxetine, cimetidine
What is polypharmacy?
- Use of multiple medications by a patient
- ≥5 medications
What adverse effects can occur through pharmacological action that are expected?
not an allergy/not a problem
- Result from main pharmacological action and can reasonably be expected
- Often addressed with dose reduction
- Usually reversible
- Some events more discrete
What types of adverse effects can be predictable when dose is excessive?
- Aspirin and tinnitus
- Clozapine (Clozaril) and seizures
- Bupropion (Wellbutrin) and seizures
What types of adverse effects are unpredictable idiosyncratic reactions?
- Penicillin and anaphylaxis
- Clozapine and aplastic anemia
How do they test drug toxicity?
- Animal testing
- Doses significantly above therapeutic
range - Identify organ toxicity
- “acceptable” toxicity differences dependent upon targeted disease state
What are examples of non-covalent interactions?
- Lipid peroxidation
- Reactive oxygen species
- Depletion of glutathione (disrupts normal cellular defense)
- Modification of sulfhydryl groups
What do covalent interactions do?
targets DNA, proteins, peptides, lipids, and carbohydrates
Hepatotoxicity
Nephrotoxicity
What is mutagenesis?
results from covalent modification of DNA
How many mutations are required for malignancy?
more than one
proto-oncogenes or tumor suppressor genes
What are carcinogens?
chemical substances that cause cancer
What is teratogenesis?
result is gross structural malformations during fetal development and is different than other forms of fetal damage (e.g. growth retardation)
What is the mechanism of teratogenesis?
- Blastocyte formation – cell division occurring
- Organogenesis – structural formation
- Histogenesis and maturation of function – nutrient supply
What are known teratogens?
- Thalidomide – sedative/hypnotic – shortened long bone development
- Cytotoxic Medications
— Alkylating agents and antimetabolites – cyclophosphamide
— Folate antagonists – valproic acid (Depakote) - Vitamin A Derivatives – tretinoin and isotretinoin
- Antiepileptics
— Phenytoin (Dilantin), valproic acid (Depkaote), carbamazepine (Tegretol), lamotrigine (Lamictal) - Anticoagulants
— Warfarin (Coumadin)
What are the features of allergic reactions?
- May be immediate or delayed following exposure
- Dose doesn’t matter
- Not related to primary drug MOA
- Incidence < 25%
- Skin reactions most common
What is anaphylactic shock?
release of histamine and leukotrienes (sudden onset)
Penicillins, Adrenocorticotropin, Heparin
What are the signs of anaphylaxis?
- low blood pressure
- fast/slow heart rate
- flushing
- hives, itchiness
- vomiting, diarrhea, cramping
- cough
- shortness of breath, wheezing
- runny nose
- swelling of lips, tongue, throat
- anxiety
- lightheadedness
- loss of consciousness
What are examples of hematological reactions?
- Sulfonamides – hemolytic anemia
- Clozapine - agranulocytosis
- Sulfonamides - agranulocytosis
- Thiazide diuretics - agranulocytosis
- Valproic Acid - thrombocytopenia
What are the main signs of anaphylaxis?
- Swelling of mouth, face, neck, or tongue
- Red skin, rash, hives
- Difficulty breathing
- Wheezing
- Rapid Pulse
