drug variability and harmful Flashcards
Variation
* Most often qualitative or quantitative? drug produces?
* Variation can result from?
- 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.
variations and concentrations
people may respond differently to the same concentrations
forms of Individual Variation
- Pharmacokinetic – ADME- Pharmacogenomics and Personalized Medicine
- Pharmacodynamic
- Idiosyncratic – because of genetic differences or
immunologic response
Implications of Variation
- Clinical Impact – “response” vs. “toxicity”
- Lack of efficacy
- Side effects and drug toxicity: Including unexpected side effects
Half-life
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)
Lipophilicity
examples of very lipophilic drugs?
Lipophilicity – ability to cross into fatty tissue, may increase Volume of Distribution
* Examples: (diazepam, carbamazepine, trazodone)
how can there be metabolic variations?
– 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)
Metabolite Activity
active and inactive metabolites
elimination variabilty?
renal/hepatic
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
Quantitative and Qualitative Variation
* Results when?
* Qualitative responses can be different in individuals why?
* factors?
- 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
what sedatives can be given to older individuals safely and why?
LOT
loreazepam, oxazepam, temazepam
DO NOT ACCUMULATE, will undergo phase 2 not phase 1 which is decreased
African-American variations
* Hydralazine and Nitrates?
* ACE inhibitors (enalapril [Vasotec ™ ]?
- 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
Chinese variations
* alc?
* Increased sensitivity to?
- 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
Age Considerations of pharmokenetic variations
- 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
Pregnancy physio Considerations and their implications
- 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
Disease Considerations of variations
* May result in what variations?
* Renal?
* Hepatic ?
* Gastric?
* Pancreatic?
* Others:
- May result in both pharmacokinetic and pharmacodynamic variation
- Renal function: elim
- Hepatic function: metab
- Gastric stasis: slows absorbtion
- Pancreatic disease: decreased Absorb
- Others: MG
Idiosyncratic Reactions
*Typically harmful= fatal
*Do not require large drug doses
*usual causes: Genetic connection and Immunological factors
Drug Interactions
dietary with warfarin?
often affected systems/proteins?
- Dietary considerations: grapefruit juice inhibits CYP3A4; Vitamin K increases clotting and impacts warfarin (Coumadin ™)
- Cytochrome P450 - Phase 1 Metabolism
- P-glycoproteins
- Non-specific Beta Blockers pharmycodynamic interactions
agents like propranolol reduce effectiveness of Beta agonists used for asthma treatment (e.g. albuterol, salmeterol)
non-specific blockers
diuretics pharmycodynmaic interactions
agents that decrease K+ (e.g. hydrochlorothiazide) predispose to digoxin toxicity
MAOIs pharmycodynamic interaction
inhibit the breakdown of “pressor” agents (e.g. tyramine) cause HTN
ASA/warfarin pharmycodynamic interaction
increase bleeding
NSAIDS pharmycodynamic interaction
increase HTN risk with inhbition of PG production
Antihistamines, Opiates, ETOH pharmycodynamic effect
additive sedative effects
Anticonvulsants pharmycodynamic effects
e.g. valproic acid (Depakote ™) inhibits platelet formation
Dopamine Blockers pharmycodynamic interactions
impacted by dopamine agonists (e.g. levodopa/carbidopa)
Anticholinergics pharmycodynamic effect (cogentin effect?)
– Cogentin may decrease the effectiveness of AChE Inhibitors (e.g. donepezil, ALZ tx )
Pharmacokinetic
Interactions
- Absorption
- Distribution
- Metabolism
- Excretion
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))
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
important Li drug rxns to know
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
Metabolism interactions
examples?
- Enzyme induction (phenytoin, carbamazepine,
rifampin, theophylline) - Enzyme inhibition (allopurinol, ciprofloxacin,
paroxetine, fluoxetine, cimetidine)
Excretion interactions
- Tubular secretion alterations
- Altered urine flow and urine pH
- What is polypharmacy?
- Use of multiple medications by a patient
- ≥ 5 medications
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
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
phenytoin oral adverse effect?
ging hyper
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)
Toxin Induced Cell Damage Drug Metabolites forms?
covalent and non-covalent interactions
- Non-Covalent Interactions of toxin induced cell damage via metabolites examples
Lipid peroxidation
Reactive oxygen species
Depletion of glutathione
modification of sulfahydral groups
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
ROS as toxin induced cell damage
as a non-covalent toxin induced cell
– formation of hydrogen peroxide and are excitotoxic, cytotoxic, and neurodegenerative
Depletion of glutathione toxin induced cell damage
non-covalent toxin induced cell damage
disrupts normal cellular defense
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
Toxin Induced Cell Damage Drug Metabolites Covalent Interactions
– targets DNA, proteins, peptides, lipids, and carbohydrates:
Hepatotoxicity
Nephrotoxicity
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
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)
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
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
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
common allergic responses
anaphylaxis and hematological rxns
- Anaphylactic shock
release of, onset, common drugs
– release of histamine and leukotrienes (sudden onset)
* Penicillins
* Adrenocorticotropin
* Heparin
- 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
CNS signs anaphylaxis
anx
lightheadedness
LOC
confusion
headache
CV anaphylaxis signs
low bp
brady/tachycardia
anaphylaxis at skin
flushing
hives
itching
GI signs anaphylaxis
diarrhea
vomiting
cramping
res signs anaphylaxis
cough
dysphagia
hoarseness
SOB
wheezing
runny nose
swelling with anaphylaxis
swelling of lips, tongue and/or throat
Anaphylaxis simple signs
- Swelling of mouth, face, neck, or tongue
- Red skin, rash, hives
- Difficulty breathing
- Wheezing
- Rapid Pulse
PCN allergic rxn presentation
commonly rash
what other common Abx can cause rash/allergic rxn
amoxicillin
phase 1 and 2 with age
phase 1 will be decreased and phase 2 will be unaffected
what allele can cause SJS/TEN with carbamazepine? ethnicity?
HLAB 1502, chinese ancestry
GFR with age
decreases
why can there be ethic differences
genetic polymorphisms
