LEARNING DRUG INTERACTIONS Flashcards
Multiple agonists at the same receptor causing additive effect
morphine & oxycodone at mu opioid receptor. both taken together, cause additive effect with increased side effects (excessive sedation & higher degree of respiratory depression & death
antagonist interacting with agonist drug
naloxone (mu opioid receptor antagonist) and morphine. naloxone binds to mu receptors, blocks morphine binding. reverses analgesia & respiratory depression
additive effect from agonists binding to different receptors (2 examples)
- benzodiazepines & opioids
both cause sedation & resp depression
BZD will enhance GABA activity which then binds to the GABA receptor, causing anxiolytic, hypnotic, anticonvulsant, and muscle relaxant effects (including relaxing the diaphragm, which suppresses respiration. this along with opioids can cause fatal resp depression - warfarin and aspirin
warfarin causes anticoagulation through inhibition of vitamin K dependent clotting factors. Aspirin blocks the effects of platelets. Although they work through different mechanisms, both can cause increased bleeding, and when used together the risk is greater
synergism
when the effect from two drugs taken in combination is greater than the effect from simply adding the two individual effects together.
oxycodone & acetaminophen
oxycodone – analgesia - mu-receptor agonist. Acetaminophen is thought to provide some of the analgesic effect by inhibiting prostaglandin synthesis in the central nervous system. both different moa, but taken together produces more analgesia than with individual drug
pharmacokinetic parameters
- Absorption (with oral drugs, typically occurring in the small intestine)
- Distribution (through the blood and dispersed throughout the tissues)
- Metabolism (including enzymatic reactions)
- Excretion (to remove the drug or end products (metabolites) from the body
PK DI
A Drug Reduces the Absorption of Another Drug
- chelation - drug binding to charged ions of other drugs, forming a complex. this cannot dissolve in gut fluid and will be excreted. tetracyclines/fqs with calcium/magnesium
- sticky drugs - bisphosphonates. can only be taken with water and not it food
- gut ph - antacids decrease the absorption of some antivirals and antifungals. The interaction can result in untreated/ resistant infections.
PK DI
Inducers and Inhibitors Alter the Metabolism of Other (Substrate) Drugs
inhibition - 1. ritonavir and darunavir are used concurrently; ritonavir inhibits the metabolism of darunavir, which provides a higher level of darunavir, and increased efficacy in treating HIV.
2. quinolones and macrolides inhibit warfarin metabolism (which increases the INR). warf dose is decreased
induction - rifampin induces warfarin metabolism (which decreases the INR). warf dose is increased
PK DI
A Drug Decreases or Increases the Excretion of Another Drug
- probenecid & penicillin - probenecid blocks the renal excretion of penicillin. High penicillin levels are needed to cross the blood-brain barrier (BBB) and provide effective treatment of neurosyphilis. Probenecid is given with penicillin to increase the penicillin serum level, resulting in more penicillin moving across the BBB.
- salicylate poisoning & sodium bicarbonate - salicylate (e.g., aspirin) overdose results in toxicity. Sodium bicarbonate given IV alkalinizes the urine, which causes the salicylates to become ionized making it more hydrophilic (less lipophilic) and stay in the watery urine. Less will be reabsorbed through the renal tubules (i.e., across a lipid membrane) and move back into the blood. Compounds that stay in the urine will be renally excreted.
Drug metabolism sites
Primary sites for drug metabolism include the liver and the gut, due to high levels of metabolic enzymes in these areas
phases of metabolism
drugs that are excreted unchanged
phase 1 - chemical reactions that change the parent molecule into a metabolite. oxidation, reduction, hydrolysis. phase I reactions usually inactivate the compound.
phase 2 - mainly conjugation reactions. n these reactions, an enzyme binds the compound to another substance (e.g., glucuronide, glutathione or sulfate) to increase water solubility and facilitate elimination
A small number of drugs are renally excreted without any transformation reactions, including the water-soluble drug penicillin G, and lithium
first pass metabolism
First-pass metabolism refers to the changes made to a drug in Phase I and Phase II reactions prior to the drug reaching the systemic (blood) circulation. This reduces bioavailability of the drug, and results in the inactivation of some fraction of -75% of oral drug
CYP Enzymes and Polymorphism
The changes are due to a single nucleotide polymorphism (SNP) in the DNA that codes for the enzyme. A SNP can cause the enzyme production in an individual to increase or decrease, which will increase or decrease the rate of drug metabolism and, consequently, the serum level of the substrate drug.
enzyme inducers (PSPORCS)
Inducers increase enzyme production or enzyme activity, which increases the rate of drug metabolism decreasing the serum level of substrates. Phenytoin Smoking Phenobarbital Oxcarbazepine (and eslicarbazepine) Rifampin (and rifabutin, rifapentine) Carbamazepine (and is an auto-inducer) St. John's wort Possible Actions: increase dose of substrate (unless a prodrug), use alternate agent to avoid combination
enzyme inhibitors (G PACMAN)
Inhibitors result in less functional enzymes, which decreases the rate of drug metabolism increasing substrate in serum drug level
Grapefruit
Pis - Protease Inhibitors (don’t miss ritonavir) but check all Pis since many are potent inhibitors
Azole antifungals (fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole and isavuconazonium)
C - cyclosporine, cimetidine, cobicistat
Macrolides (clarithromycin and erythromycin, but not azithromycin) Amiodarone (and dronedarone)
Non-DHP CCBs (diltiazem and verapamil)
Possible Actions: Decrease dose of substrate (unless a prodrug), use alternate agent to avoid combination
inhibition vs induction (lag time)
Inhibition of an enzyme is fast; effects are seen within a few days and will end quickly when the inhibitor is discontinued.
Induction most often requires additional enzyme production, which takes time. The full effect on drug levels due to enzyme induction may not be seen for up to 4 weeks. When the inducer is stopped it could take 2-4 weeks for the induction to disappear completely; the excess enzymes will degrade based on their half-lives.
