lecture 19 Flashcards
Give an example of DDI that result in inhibition of drug metabolism
Give 3 example of cyp3A4 inhibitors
Terfenadine toxicity, in the presence of erythromycin
ketoconzaole, erythromycin, grapefruit juice
A patient who was taking cyclosporine immunosupressant agent had acutre heart transplant rejection. It is shown that he had decreased level cyclosporine concentrations. What can be the reason? (consider PK DDI and drug transporter)
The patient can be taking St John’s wort, which induce cyp3A4 activity as well as MDR P-GP activity, This speed up drug mtabolism, leading to insufficient drug dosage
Give two example of DDI that causes induction of drug metabolism
eg: Antibiotics (rifampin) and antiseizure medicine (carbamazepine) induces CYP3A4, causing decrease level of estrogen and progestins, leading to failure of oral contraceptives
eg: phenytoin induces CYP2C9/10, reducing anticoagulant effect of warfarin
How do morphine, codeine and fentanyl cause a greater effect in PD DDI?
All 3 drugs are agonists that bind and activate mu opiod receptors
How does alteration of pH affect excretion? Give example
Changing pH can make drug more ionized, which facilitae drug elimination, as charged drug won’t be reabsorped
Eg: Aspirin is an acidic drug. When there is aspirin OD, baking soda is blous injected, increasing the pH of the urine. More basic urine will make the acidic drug charged, decreasing absorption and increasing elimination, protect brain from drug
How does fruit juice affect druh absorption? Give an example
Fruit juice can inhibit some OATPs uptake transporter, decreasing the absorption of drug
eg: fruit juice inhibit OATPs activity, decreasing the absorption of antihistamine fexofenadine allegra, which is a substrate of OATP1A2
How does pharmacodynamic drug interaction occur? Give an example using kidney damage
Occur when there’s a combination of drug products containing the same ingredients, or when two or more drugs produce the same toxicities
Eg: Drug A and B both cause light damage to kiney. It is safe to take them on their own, but when combined, severe damage will occur
What are the three classification of drug interactions?
Unintentional VS intentional
Direct VS indirect
Pharmacokinetic VS pharmacodynamic
What are the three PD DDI that cause a greater effect of the drugs? What are they? Give example
1: Duplications: When taking different products containing the same drug, eg: Both tylenol and Neocitran contain acetaminophen, so when taken together, a very high dose of acetaminophen will be taken
2: Additive effects: 1+1=2, two different drugs having the same effect (mechanism of action), eg: both propranolol and timolol bind to beta-adrenergic receptor
3: Synergistic effects: Supra additive, 1+1>2, both drug have similar effect on body eg: ethanol and diazepam are both sedating (CNS depressant)
What are the three ways to decrease drug effects? (in term of drug receptor mechanism)
1: Competitive antagonism :A combination of agonist drug and an antagonist drug ( or partial / inverse agonist) compete for the same receptor
2: Negative allosteric modulation (non-competeive antagonism), when a drug bind to a receptor and cause a conformational change that hinder a different drug from binding at the different site on the same receptor
3: Two or more drug produce opposing clinical effects by different mechanism
What are the three ways to increase drug effects? (in term of drug receptor mechanism)
1: The SAME recptos are activated by 2 or more drugs binding to the SAME site
2: Positive allosteirc modulation (potentiation), where one drug bind to a recptor, causing conformational change that faciliate another drug to bind on a different site on the same recptor
3: Two or more drugs produce the same clincial effect in different mechanism
What is chelation?
The molecules of a chelating agent can form tight bonds with a metal ion, forming a metal complexes, which decrease distribution
eg: ;ead is chelated by EDTA, iron is chelated by deferoxamine
What is complexation? Give an example
The therapeutic agent in drug ibind to something that prevent them from being absorped
eg: some antibiotics form complexes with metals in some antacid drug, so they will pass through GI tract without absorption
What is direct VS indirect drug interaction?
Direct: 2 drugs compete for the same protein, eg: 2 drugs fight for cyp3A4 metabolism
Indirect: Drug cause an adverse effect that need to be counter by another drug, eg: drug A cause vomit, so take drug B to counter it
What is dissolution? Give an example
The therapeutic agent in drug is dissolved in material that cannot be absorped
Eg: When fat soluble vitamins is taken with mineral oil, it is dissolved in these oil, and these oil cannot be absorped by human body, so absorption of the vitamins will be reduced
What is ion exchange binding? What will happen to the drug in the body? What is the consequence? Give an example
Drugs with opposite charge (+/-) are attracted to each other, and cant be absrobed when paired
The drugs will be stuck to the delivery system, reducing the drug availability for absorption, as not all drug can enter body system
eg: diazepam and tacrolimus stick to PVC tubing
What is the effect of taking digoxin and Propafenone together? Specify the mechanism of action
Digoxin is absorped into bloodstream by transporter. P-GP is a MDR1 efflux transpoter that pump digoxin out, reducing the absorption
When the two drugs are taken together, propafenone inhibit the P-Glycoprotein activity, which decrease efflux, and increase digoxin absorption into the bloodstream. This increases the digoxin level, which is dangerous, as digoxin has low TI
What is the effect of taking loperamide and quinidine together? Specify mechanism and location
loperamide is a substrate of P-GP, which efflux the drug out of the brain and neurons, so it cannot pass the BBB and bind to opioid receptor, so you won’t get high from it
When taken with quinidine, it inhibit MDR1 P-GP activity, blocking the BBB, so loperamide will pass and enter the brain, binding to opioid receptor, and making you high
What is the effect of taking acidic drug and drug that raise pH together? What about basic drug?
Acidic drug: When pH is raised above the pKa, most drug will be deprotonated and charged, causing reduce in absorption
Bacic drug: When pH in above pKa, most drug will be unprotonated and uncharged, causing increase in absorption
What is the largest population of people who use 3 or more prescriptional drug?
People who are 65 years old or older, so elderly
What is the PD DDI that causes lesser drug effects? Give example
Antagonistic effect: Drug compete in recpetor binding
eg: Fentanyl (agonist) and Naloxone (antagonist) compete binding to opiod receptor, leading to less opioid effect
What is the relationship between GI motility and PK DDI? Give examples of increase and decrease GI motility, and the consequence
Drug that speed up/slow down GI motility can affect the rate or extent of absorption of other drug
eg: cathartics (laxatives0 increase GI motility, which increase the rate of absorption of other drug, but decrease the extent of absorption
Tmax maybe be shorten, leading to quicker onsent of action
eg: Opiods decrease GI motility (cause constipation), decreasing the rate of gastric emptying rate, and the rate of absorption of other drug. But it increase the extent of absorption, as there are more contact with epithelial GI
Tmax is increased, Cmax is decreased, leading to delay onset of action
What is the relationship between PK DDI and drug metabolism? Give two example
Drug can affect the bacterial activity in GI, or enzyme actitivity, leading to affect in biotransformation of other drug
eg: Antibiotics can kill helpful bacteria in the gut, reducing bacterial metabolism of other drug such as digoxin
eg: Drug can induce/ inhibit drug metabolizing enzyme, modifying the first pass effect of other drug
What is the relationship between PK DDI and gastric pH? give example
Some drug can alter the pH in sotmach, affecting the absorption of other drug
Antacids, H2 recpetor antagonist, and proton pump inhibitors can raise the pH in stomach
