DRUG TOXICITY x_x Flashcards
Adverse drug reaction
harm directly caused by the drug at normal doses
adverse drug event
harm associated with a drug or the use of a drug
medications error
inappropriate use of a drug that may or may not result in harm
Toxicity is rare (~1 in 20,000 pts) so to detect more than
60,000 pts must be exposed after the drug is marketed
Most new drug exposure have only ~
3000 short term patient exposures
ADRs increase exponentially with
four or more prescriptions
misconception about ADRs and reporting
all serious ADRs are documented by the time a drug is marketed
difficult to determine if a drug or another clinical cause is responsible
ADRs should be reported only if absolutely certain
Non deleterious effects
side effects
Deleterious effects
toxic effects
- pharmcological
- pathological
- genotoxic
drug interactions are
preventable
Types of antagonism
functional
chemical
dispositional
receptor
mechanism of chemical interactions: Pharmacokinetics
biotransformation
distribution
absorption
excretion
Mechanism of Pharmacodynamics
Receptor
non receptor
Clinical trials Phase I
first in human, after animal studies 10-100 subjects usually healthy volunteers, sometimes pts with advanced rare disease Open label looking at safety and tolerability Months to 1 yr US 10 million success rate: 50%
Clinical trials: Phase II
first in patient 50-500 subjects patient-subjects receiving experimental drug randomized and controlled (can be placebo controlled) may be blinded Looking at Efficacy and dose ranging 1-2 years US 20 million Success rate: 30%
Clinical trials: Phase III
Multi site trial
few hundred to few thousand participants
patient-subjects receiving experimental drug
randomized and controlled (can be placebo controlled) or uncontrolled
may be blinded
Confirm efficacy in larger population
3-5 years
US 50-100 million
success rate: 25-50%
Clinical Trials: Phase IV
Post marketing surveillance
many thousands of participants
patients in treatment with approved drug
Open label
Adverse events, compliance, drug-drug interaction
ADR risk factors
age multiple medications multiple co-morbid conditions inappropriate medication prescribing, use, or monitoring end-organ dysfunction altered physiology Prior history of ADRs extent (dose) and duration of exposure genetic predisposition
Limitations of ADR detection in Clinical trials
exposure limited to few individuals so rare and unusual ADRs not detected (1 in 10000)
3000 pts at risk are needed to detect ADR with incidence of 1/1000 with 95% certainty
exposure is often short term
external validity - excludes kids, elderly, women of child bearing age,
Examples of medications where ADR is seen much much later
DES - (1940-50s) given to pregnant moms to maintain pregnancy, later on female offspring would develop rare cervical cancer
Vioxx and heart attacks
Some drugs that manifest symptoms more than 4-6 hrs after oral overdose
Acetaminophen aspirin Illicit drugs in rubber or plastic packages Monoamine oxidase inhibitors Thyroid hormones Valproic acid Warfarin like anticoagulants Sulfonylureas sustained release formulation drugs
What age group shows the highest opioid analgesic poisoning death rates?
45-54 yrs (most) 35-44 yrs 25-34 55-64 15-24 65 and over
Some scenarios for therapeutic errors
inadvertently took/given medication twice wrong medication taken/given incorrect dose confused units of measure iatrogenic error drug interaction more than 1 product containing the same ingredient 10 fold dosing error exposure through breast milk
Types of allergic reactions
Type I - immediate, anaphylatic (IgE) - penicillins
Type II - cytotoxic antibody (IgG, IgM) - methyldopa or hemolytic anemia
Type III - serum sickness (IgG, IgM) - procainamide induced lupus
Type IV - delayed hypersensitivity (T cell) - contact dermatitis (could take weeks to show up)
