Lecture 33: Drug Interactions Flashcards
Why is it important to understand how drugs interact with each other?
Drug A may influence the effectiveness of Drug B by altering its “availability” (pharmacokinetic considerations), or by altering its interaction with its receptor (pharmacodynamic considerations)
drug interactions should be considered in ways that they may lead to a loss or enhancement of drug action, or enhanced drug toxicity/adverse effects
every drug will have interactions of some sort - we will use examples to illustrate some common ways that drugs can interact, and how to find this information
What is a product monograph?
drug interactions are usually listed in “product monographs” issued by the manufacturers
information in the product monograph should inform physicians about contraindicated conditions or potential drug interactions
What happens to drug interactions when a drug has a small therapeutic window?
drugs with a narrow therapeutic index are most susceptible to issues with drug interactions
if the TI is narrow: small changes in our responsiveness to a drug can lead to toxic outcomes, small changes in availability of a drug can lead to significant changes in outcome (either too much drug leading to a toxic effect, or too little drug leading to a loss of therapeutic effect)
What is an antagonistic interaction?
in this situation, Drug A may act as an antagonist at a receptor for Drug B - this will reduce the effectiveness of Drug B
example is the effect of Vitamin K rich foods on Warfarin
Warfarin is administered as an anti-coagulant in patients with blood clot issues (pulmonary embolism, deep vein thrombosis, etc.)
What is the interaction between Warfarin and Vitamin K?
Warfarin is an inhibitor of Vitamin K epoxide reductase - this enzyme recycles oxidized Vitamin K (KO in the figure) to reduced Vitamin K (KH2)
this is important for the production of active clotting factors (by inhibiting this enzyme, warfarin reduces the level of many clotting factors)
the balance of clotting factors is very important (too much leads to formation of clots, too little can lead to severe unstoppable bleeding)
foods that are rich in Vitamin K will weaken the effectiveness of Warfarin
Vitamin K will compensate for occupancy of the enzyme (Vit K epoxide reductase) and also provide a new source of reduced Vitamin K for generation of active clotting factors
other scenarios that diminish Vitamin K (e.g. certain antibiotics may inhibit Vitamin K production in the gut) can lead to stronger Warfarin effectiveness
What is synergism or addictive drug interactions?
in this scenario, multiple agonists/modulators may act on the same receptor, leading to excessive activation
“synergism” usually refers to effects that are greater than the individual effects of two drugs
“additive” usually refers to effects that are roughly the sum of the individual effects of two drugs
a good example of excessive receptor activation arising from drugs acting on the same receptor arises from the use of benzodiazepines, alcohol, barbiturates, and other modulators of GABAA receptors
What are examples of synergism or additive drug interactions?
multiple drugs act on the GABAA receptor (chloride channel) and can enhance its activity
benzodiazepines (e.g. Xanax, Valium): positive allosteric modulators of GABAA
barbiturates: PAMs or agonists of GABAA
alcohol: PAM of GABAA
zolpidem (e.g. Ambien): PAM or GABAA
combination of multiple drugs at low concentrations can significantly enhance GABA-mediated activation of these receptors, leading to sedation, unconsciousness, etc.
What are indirect drug interactions?
in this scenario, the effects of multiple drugs might influence the same signaling pathway, but not necessarily the same receptor
a classic example is serotonin syndrome, arising from combinations of drugs that lead to overabundance of 5-HT/serotonin in the CNS, and overstimulation of 5-HT receptors (especially 5-HT2a and 1A)
serotonin syndrome is characterized by high body temperature, agitation, sweating, dilated pupils, muscle twitching, elevated blood pressure (many other symptoms)
How are monoamine oxidase inhibitors involved in serotonin syndrome?
prevent breakdown of 5-HT/serotonin by MAO-A (mitochondrial membrane protein), lead to increased cellular levels of 5-HT
many of these act irreversibly, so they can have very long lasting effects that will increase susceptibility to serotonin syndrome when taking some of these other drugs
How are tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors involved in serotonin syndrome?
prevent reuptake of 5-HT from the synaptic cleft, prolonging the lifetime of 5-HT in the synapse
How are various opioids involved in serotonin syndrome?
metabolites may have direct serotonergic effects or interfere with serotonin reuptake
How is St. John’s wort involved in serotonin syndrome?
likely acts as a serotonin reuptake inhibitor
How are recreational drugs (MDMA, methamphetamine) involved in serotonin syndrome?
promote serotonin release (often causing “uptake” transporters/pumps to operate in reverse)
How are precursors of serotonin (5-HTP, L-trytophan) involved in serotonin syndrome?
used as anti-depressants
How do pharmokinetic interactions later drug availability?
drugs that alter gut motility, pH (e.g. antacids), can alter the absorption of a drug
drugs that alter local blood flow can alter absorption of a drug (co-administration of lidocaine with epinephrine for local vasoconstriction)
