Drug Interactions

• what are the factors affecting drug interaction?

  age, genetics, underlying health conditions
• what happens if you take Warfarin with vitK? why?

  Warfarin (anticoagulant) can prolong the blood clotting time by competitively inhibiting the effects of Vitamin K. If the intake of Vitamin K is increased, the effects of Warfarin is opposed, leading to unexpected blood coagulation. • So, we either increase dose of Warfarin, or avoid high intake of Vitamin K. (Antagonistic (opposing) interaction)
• what will happen if you take Methotrexate with Co-trimoxazole?

  ncreased folic acid antagonism: Methotrexate + Co-trimoxazole will lead to bone marrow megaloblastosis ( Synergistic interactions)
• what will happens if you take 2 or more of these drugs together Aminoglycosides, Ciclosporin, Cisplatin? why?

  Giving two nephrotoxic drugs (Aminoglycosides, Ciclosporin, Cisplatin) will lead to increased nephrotoxicity. ( Synergistic interactions)
• what will happen if you take ACEI's with potassium supplements? why?

  ACEI's is a Potassium sparing drug, with potassium supplements it will lead to increased risk of high potassium that can lead to Hyperkalemia, thus to heart attack or even death (Synergistic interaction)
• what is a Antagonistic interaction?

  when two chemicals (or drugs) cancel each other out
• what is a Synergistic (additive) interaction?

  when the sum of the effect is more than the two individual chemical effects combined.
• since oral contraceptives go through the entero-hepatic process, what will happen if the gut flora was diminished after taking antibiotics?

  the oral contraceptive drug will be not recycled and is eliminated from the body more quickly. This may explain the failure of oral contraceptives that can be brought about by the simultaneous use of antibiotics, e.g. Penicillins or Tetracyclines.
• what is the impact of the entero-hepatic process on the drug?

  This entero-hepatic process prolongs the stay of the drug (e.g. oral contraceptives) within the body
• what happens to drugs during biliary excretion?

  A number of drugs is excreted in the bile, either unchanged or conjugated. Some of the conjugates are metabolized to the parent drug by the gut flora and are then reabsorbed (Entero-hepatic circulation).
• is Interactions during Excretion significant clinically? why or why not?

  Clinically not significant since most drugs are metabolized and reabsorption occurs with metabolites that are already pharmacologically inactive. Only few drugs are excreted unchanged in kidney.
• what is an example of a drug that decreases tubular secretion of another drug?

  Probenecid decreases tubular secretion of Methotrexate (disadvantage: increased toxicity), and Penicillin G (advantage: prolonged duration of action).
• what will happen to the excretion of acids and bases after taking a drug that increases pH of urine?

  Any drug that increases pH of urine will facilitate excretion of acids, whereas bases will be facilitated in their reabsorption.
• what can alter the excretion of drugs/

  Renal tubular cells additionally possess active and passive transport systems for the re-absorption of drugs. Interference with drugs by a renal tubular fluid pH or active transport system can alter the excretion of drugs.
• where are most drugs excreted?

  Most drugs are excreted either in bile or urine.
• how can drugs compensate the inhibited pathway?

  Some drugs are metabolized by more than one CYP450 isoenzyme, so they may be able to pick up more metabolism to compensate the inhibited pathway.
• how long does it take for Enzyme inhibition to happen?

  it happens within 2-3 days, resulting in rapid development of toxicity
• true or false: Enzyme inhibition is more common than enzyme induction.

  true
• what is the impact of Ritonavir on metabolism of drugs? how?

  Ritonavir inhibits the metabolism of Sildenafil by CYP3A4 resulting in marked increase in plasma level of even a single dose of sildenafil.
• what is the impact of Cimetidine (ciprofloxacin, ofloxacin, enoxacin, histamine H2 -receptor antagonist and Fluorquinolones (antibiotics) on metabolism?

  inhibit the metabolism of many drugs metabolized through oxidative reactions, e.g. Warfarin.
• how is Enzyme induction interactions accomidaetd?

  It may be possible to accommodate the interaction simply by raising the dosage of the drug affected, but this requires good monitoring. However, the raised drug dosage may be an overdose when the drug metabolism has returned to normal.
• how long do Enzyme induction interactions take?

  Enzyme induction interactions are delayed in onset and slow to resolve, and it may take days or even 2-3 weeks to develop fully, and may persist for similar length of time when the enzyme inducer is stopped
• are Phenytoin and Phenobarbital enzyme inducers or inhibitors? how?


  Phenytoin and Phenobarbital are enzyme inducers, and both increase metabolism of: ▪ Warfarin ▪ Digitoxin ▪ Oral contraceptive ▪ T3 and T4

  
• which family of enzymes is the mainly involved in oxidative metabolism?

  P-450 family (~ 30 isoenzymes) is mainly involved in oxidative metabolism , and especially CYP-4503A4 is metabolizing ~ 36% of all drugs metabolized through oxidation
• what are the factors that impact PPB?

  Vd and clearance
• what are the drugs that have a low extraction ratio?

  Sulfonylurea Warfarin Phenytoin
• other than low Vd, what is another factor that impacts the competition between drugs?

  Another important factor is clearance. Drugs with low excretion ratio, go out slowly, so possibility is high for another drug to come and find the first one and compete with it on PPB.
• what are the drugs that have low Vd?

  Sulfonylurea, Warfarin, Phenytoin
• what type of drugs are impacted by competitions regarding plasma protein binding? g

  drugs with low volume distribution (Vd) (means mainly present in blood) will be affected
• what is the impact of a drug A that competes with drug B causing the drug B to reduce its plasma protein binding?

  A drug that reduces the plasma protein binding of drug B from 99% to 95% would increase the unbound concentration of free drug B from 1% to 5% (a five-fold increase).
• what type of drugs remain free and pharmacologically active?

  Only unbound drugs remain free and pharmacologically active, while those bound form a circulating but pharmacologically inactive reservoir
• what is the most important thing when it comes to distribution?

  Plasma Protein Binding
• Tetracyclines and Quinolones can form a chelate complex which is poorly absorbed. how can we avoid this?

  Dose spacing... (dont take antibiotics and milk in the same time)
• what are the molecules that can form a chelate complex? how?

  Tetracyclines and Quinolones can form a chelate complex with divalent and trivalent metallic ions, such as Ca2+ , Al3+ , and Fe2+that are poorly absorbed and have lower antibacterial activity.
• Increases of pH values (more alkaline) due to Proton Pump Inhibitors (PPI's) or H2 antagonists can markedly reduce the absorption of some drug. what is the drug that will have a lower absorption due to Histamine H2 antagonists?

  Histamine H2 antagonists decrease absorption of Fosamprenavir
• Increases of pH values (more alkaline) due to Proton Pump Inhibitors (PPI's) or H2 antagonists can markedly reduce the absorption of some drug. what is the drug that will have a lower absorption due to PPI's?

  Atazanavir
• what does the passage of drugs through biological membranes depends on?

  being noionized, and this again depends on pKa of the drug, its lipid-solubility, and pH of contents of the gut.
• in which type of drugs is the rate of absorption important?

  , drugs taken as single dose (hypnotics or analgesics). in this case we have to avoid such interactions affecting rate of absorption, since failure in that might result in failure to achieve adequate therapeutic effect.
• is the extent of warfarin absorption important?

  yes
• does it matter if the rate of absorption of warfarin was impacted by another drug? why or why not?


  no, because Warfarin is given for long term (multiple dosing) so every day one tablet which is only maintenance dose. so if rate is affected there is no problem, since after 1 or 2 hours the therapeutic dose will be achieved.