How are the Minimum Effective Dose for Therapeutic Response and Minimum Effective Dose for Adverse Response calculated?
Quantal Dose Response Curves are calculated for both the therapeutic and "lethal" (now commonly non-lethal adverse effects), and the 50% (midpoints) of each are then compared. Some are calculated to so the 99th%ile of therapeutic vs the 1st%ile of adverse effects, a much tighter range.
What does the "therapeutic index" measure and what is the standard safety margin?
The ED50 vs LD50 of the drug. The standard safety margin is the difference between the dose that is effective in 99% of the population and the dose that is toxic in 1%.
How can the standard safety margin be a better measure of a drug than the therapeutic index?
The SSM looks at the extremes of the population. Therapeutic index can mask potential toxic effects because it onlt shows the difference between the 50% points.
Which figures are calculated into the therapeutic window?
Commonly ED99 and LD1
What are the three types of adverse drug reactions?
Side effects - effects that occur within the therapeutic window due to drug actions on non-target systems. Extension effects - effects that occur above the therapeutic window on the target organs. Toxic effects - effects that occur at toxic concentrations of the drug.
What are two classes of unpredictable adverse reactions?
Idiosyncratic reactions - genetically determined abnormal response to drug -> unpredictable, from altered drug metabolism or unusual receptor affinity. Drug allergies - immunologic, unpredictable and dose independent (Penicillin-induced anaphylactic shock)
What do pharmacokinetic DDIs do?
Pharmacokinetic DDIs change the plasma level of the drug. They can result in elevated Cp and cause toxicity via decreased drug elimination/protein displacement. They can also result in decreased Cp leading to subtherapeutic levels via increased drug elimination/decreased drug absorption.
What is the "perfect storm" of DDIs that cause harm?
A DDI does not commonly cause problems in a patient. Usually there must be a "triple hit" of DDI, affecting a drug with a narrow therapeutic window, in a patient with significant comorbidities that are affected as well.
What do pharmacodynamic DDIs do?
Pharmacodynamic DDIs affect the drug's action at the target. Results in pharmacologic enhancement or antagonism of a drugs action via the same target, or the physiologic enhancement or antagonism of a drug's action via a separate effector system. Has NO EFFECT on the plasma concentration.
What are four categories of patients at high risk for DDIs?
The elderly - commonly taking many drugs, may have diminished metabolic pathways. Patients with renal/hepatic disease. Patients with multiple prescribing physicians. Patients in high risk clinical situations - acute illness, unstable disease, or dependent on the drug treatment.
What effect do gastric motility and stomach chemistry have on drug absorption?
Decreases in motility result in lower peak Cp, slower drug passage to larger absorptive areas, possible decreased absorptive rate. NO change in extent of absorption. Changes in pH and/or formation of insoluble complexes may result in reduced bioavailability.
What effect does cardiac output have on drug clearance?
Decreased cardiac output -> decreased blood flow to liver -> decreased hepatic clearance -> increased plasma levels/duration.
What are four types of pharmacodynamic interactions?
Antagonistic effects - two drugs with opposite effects; Synergistic or additive effects - two drugs with similar effects; Synergistic or additive SIDE EFFECTS (safe dose ethanol + safe dose benzo = lethal CNS depression; Indirect Pharmacodynamic Effect - Pharmacologic effect of one drug indirectly affects 2nd drug (diuretic caused hypokalemia enhances toxic effects of digoxin)