Drug Variability and Harmful Effects Flashcards
Variation
* 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.
Pharmacokinetic –
ADME
body on drug
Pharmacogenomics and — Medicine
Personalized
Pharmacodynamic
drug on body
Idiosyncratic –
because of genetic differences or
immunologic response
Implications of Variation
(3)
- Clinical Impact – “response” vs. “toxicity”
- Lack of efficacy
- Side effects and drug toxicity
Side effects and drug toxicity
* Including – side effects
unexpected
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 –
ability to cross into fatty tissue, may increase Volume of Distribution
Lipophilicity – ability to cross into fatty tissue, may increase Volume of Distribution
* Examples:
(diazepam [Valium™], carbamazepine [Tegretol ™], trazodone [Desyrel ™])
Metabolic Pathway –
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 (substitute one nucleotide for another, e.g. C for T)
Genetic polymorphisms
(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)
HLAB*1502 Allele if present (Chinese ancestry)
increases risk of SJS / TEN with carbamazepine (Tegretol™)
Membrane transporters –
P-glycoprotein (delivery and elimination)
Metabolite Activity –
active and inactive metabolites
Elimination –
renal or hepatic
What Contributes to Drug Related
Response Variations
(6)
- Age related changes
- Genetics
- Personalized Medicine
- Immunological
- Concurrent disease
- Drug interactions
Genetics –
influence PK by altering the expression of
proteins involved in drug ADME - “genetic polymorphism”
Concurrent disease – commonly
renal and hepatic
Drug interactions – “think” –
CYP450
Quantitative and
Qualitative 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
genetic
or immunologic differences.
* e.g. Hemolytic anemia secondary to methyldopa and response to antidrug
antibodies that get formed
Qualitative responses can be different in some individuals because of
genetic
or immunologic differences.
* e.g. Hemolytic anemia secondary to methyldopa and response to antidrug
antibodies that get formed
Qualitative responses can be different in some individuals because of
genetic
or immunologic differences.
* e.g. Hemolytic anemia secondary to methyldopa and response to antidrug
antibodies that get formed
Qualitative responses can be different in some individuals because of
genetic
or immunologic differences.
* e.g. Hemolytic anemia secondary to methyldopa and response to antidrug
antibodies that get formed
Quantitative and Qualitative Variation
(4)
- Ethnicity – relates to “race”, variation in population responses
- Age
- Pregnancy
- Disease
Ethnic Variation
African-American
(2)
- 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
Ethnic Variation
Chinese
(2)
- 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
- Absorption –
e.g. 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
* Example: lorazepam (Ativan ™), temazepam (Restoril ™),
and oxazepam (Serax ™) undergo Phase 2 metabolism
Excretion –
less efficient in newborns and over the age of 65
Pregnancy Considerations
(4)
- Reduced maternal plasma albumin
- Increased cardiac output
- Increased renal blood flow and GFR
- Increased transfer of lipophilic drugs
Disease Considerations
(5)
- May result in both pharmacokinetic and
pharmacodynamic variation - Renal function
- Hepatic function
- Gastric stasis
- Pancreatic disease
- Others
Idiosyncratic Reactions
(4)
*Typically harmful
*Do not require large drug doses
*Genetic connection
*Immunological factors
Drug Interactions
(3)
- Dietary considerations
- Cytochrome P450 - Phase 1 Metabolism
- P-glycoproteins
- Dietary considerations
grapefruit juice
inhibits CYP3A4; Vitamin K increases clotting and impacts warfarin (Coumadin ™)
- Beta Blockers –
agents like propranolol (Inderal™) reduce effectiveness of Beta agonists used for asthma treatment (e.g. albuterol [Ventolin™], salmeterol [Serevent™])
- Diuretics –
agents that decrease K+ (e.g. hydrochlorothiazide) predispose to digoxin toxicity
- MAOIs –
inhibit the breakdown of “pressor” agents (e.g. tyramine)
- ASA/Warfarin –
increased bleeding
- NSAIDs –
increase the risk of hypertension by inhibiting prostaglandin
- Antihistamines, Opiates, ETOH –
additive sedative effects
- Anticonvulsants –
e.g. valproic acid (Depakote ™) inhibits platelet formation
- Dopamine Blockers –
impacted by dopamine agonists (e.g. levodopa/carbidopa [Sinemet™])
- Anticholinergics –
Cogentin may decrease the effectiveness of AChE Inhibitors (e.g. donepezil [Aricept ™])
Pharmacokinetic
Interactions
(4)
- Absorption
- Distribution
- Metabolism
- Excretion
Absorption
* GI absorption slowed by meds that
* GI absorption increased by meds that
* Interactions within the gut
inhibit gastric emptying (e.g. atropine, anticholinergics, opiates)
increase gastric emptying (e.g. metoclopramide [Reglan™])
(e.g. calcium and iron bind with
tetracycline; cholestyramine binds digoxin and warfarin;
reasons to separate doses of Maalox, Mylanta, and
Metamucil from orally administered medications)
Distribution
* Competition for
* Alterations in
* Impact secondarily on
protein binding sites
“free” drug concentrations
elimination
Metabolism
* Enzyme (2)
- Enzyme induction (phenytoin, carbamazepine,
rifampin, theophylline) - Enzyme inhibition (allopurinol, ciprofloxacin,
paroxetine, fluoxetine, cimetidine)
Excretion
(2)
- Tubular secretion
- Altered urine flow and urine pH
What is polypharmacy?
(2)
- Use of multiple medications by a patient
- ≥ 5 medications
Adverse Effects:
Pharmacological Action
* Result from –
* Often addressed with –
* Usually –
* Some events more –
main pharmacological action and can
reasonably be expected
dose reduction
reversible
discrete
Adverse Effects:
Independent of Main
Pharmacological Action
* Can be predictable when dose is excessive
(3)
- Aspirin and tinnitus
- Clozapine (Clozaril ™ ) and seizures
- Bupropion (Wellbutrin ™) and seizures
Adverse Effects:
Independent of Main
Pharmacological Action
* Unpredictable idiosyncratic reactions
(2)
- Penicillin and anaphylaxis
- Clozapine and aplastic anemia
Drug Toxicity Testing
(4)
- Animal testing
- Doses significantly above therapeutic range
- Identify organ toxicity
- “acceptable” toxicity differences dependent upon
targeted disease state
Toxin Induced Cell Damage
Drug Metabolites
* Non-Covalent Interactions
(4)
Lipid peroxidation
Reactive oxygen species
Depletion of glutathione
Modification of sulfhydryl groups
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
Covalent Interactions –
(3)
targets DNA, proteins,
peptides, lipids, and carbohydrates
Hepatotoxicity
Nephrotoxicity
- 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
Teratogenesis –
result is gross structural
malformations during fetal development and is
different than other forms of fetal damage (e.g.
growth retardation)
Mutagenesis and
Teratogenicity
Mechanism
(3)
Blastocyte formation – cell division occurring
Organogenesis – structural formation
Histogenesis and maturation of function – nutrient supply
Known Teratogens
(5)
- Thalidomide –
- Cytotoxic Medications
- Vitamin A Derivatives –
- Antiepileptics
- Anticoagulants
- Thalidomide –
sedative/hypnotic – shortened long bone development
- Cytotoxic Medications
(2)
- 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™)
Allergic Reactions
(5)
- May be immediate or delayed following exposure
- Dose doesn’t matter
- Not related to primary drug MOA
- Incidence < 25%
- Skin reactions most common
Allergic Responses
(2)
Anaphylactic shock
Hematological reactions
Anaphylactic shock –
release of histamine and leukotrienes (sudden onset)
Anaphylactic shock – ex (3)
- Penicillins
- Adrenocorticotropin
- Heparin
Hematological reactions
(5)
- Sulfonamides – hemolytic anemia
- Clozapine - agranulocytosis
- Sulfonamides - agranulocytosis
- Thiazide diuretics - agranulocytosis
- Valproic Acid - thrombocytopenia
anaphylaxis
a serious allergic rxn and should be treated as a medical emergency
it can occur within minutes of exposure or take serveral hours
Anaphylaxis
signs (5)
- Swelling of mouth, face, neck,
or tongue - Red skin, rash, hives
- Difficulty breathing
- Wheezing
- Rapid Pulse
