Module 4 Flashcards
A drug interaction has been reported between omeprazole and clopidogel in which omeprazole decreases the antiplatelet effects of clopidogel. Both are metabolized by CYP 2C19. The mechanism for this interaction is
Clopidogel is prodrug and must be bioactivated by CYP 2C19. Omeprazole is a competitive inhibitor of CYP 2C19 and so it is safer to use a different proton pump inhibitor in combination with clopidogel.
During the process of development of a new drug it is important to determine what metabolites are formed. In some cases one of the metabolites is found to be a glutathione conjugate
This is seen as a warning sign because glutathione conjugates are formed from chemically reactive metabolites, which may cause adverse reactions, especially immune-mediated idiosyncratic drug reaction
A 10-year-old asthmatic girl had been taking theophylline for several years without difficulty. She developed a viral infection with fever and worsening of her asthma. Her physician was concerned that she might develop a secondary bacterial infection, and he started her on erythromycin. Two days later she had a seizure and was found to have toxic levels of theophylline even though she had not changed her dose. What caused the increase in her theophylline levels?
Fevers are caused by cytokines such as IL-6, IFN-gamma, and IL-1. These cytokines also inhibit the synthesis of many proteins including cytochromes P450 and transporters. Therefore, infections associated with a fever can represent a risk of impaired drug metabolism.
○ Clearance of theophylline was inhibited by erythromycin
○ Although mild viral infections are not associated with decreased drug clearance, fever is a sign that there is a significant immune response with the production of cytokines that are likely to lead to impaired drug metabolism.
Propranolol is a competitive inhibitor of the ß-adrenergic receptor. It is metabolized by the polymorphic debrisoquine P-450 (CYP-2D6), yet slow metabolizers of debrisoquine have the same pharmacological response to propranolol as rapid metabolizers. This is because:
○ Propranolol is a competitive inhibitor of ß-receptors, and at a therapeutic dose the receptor is almost completely occupied so even if there were an increase in the propranolol concentration there would be little change in the pharmacological effect
○ Although propranolol is metabolized by CYP 2D6, this is only one of the enzymes involved in the metabolism of propranolol, and in fact the product is a minor metabolite of propranolol so that the concentration of propranolol is not changed significantly
○ The metabolite of propranolol formed by CYP 2D6 may also be a ß-adrenergic inhibitor
○ all of the answers are correct. Hopefully they are clear and you should be familiar with the dose response curve for a competitive inhibitor in which at some concentration the receptor is saturated and increasing the concentration will not lead to a greater effect
A new drug for the treatment of viral hepatitis was found to be associated with a high incidence of minor liver injury, and the fear was that if the drug were developed further there would be more severe cases including cases of liver failure. However, when it was combined with ritonavir, which is a very potent P450 inhibitor, the dose could be decreased markedly and none of the patients had evidence of liver injury. This is likely because:
○ Ritonavir inhibited the formation of a reactive metabolite, which was a major metabolic pathway and responsible for the liver injury
The total exposure to the parent drug is the same with the combination of lower dose and inhibition of metabolism but formation of the reactive metabolite is less. Ritonavir is sometimes used at subtherapeutic doses to decrease the clearance of other HIV drugs, and by inhibiting clearance, the blood level of the other HIV drug is more constant
A patient had an idiopathic seizure and was started on phenytoin at a dose of 300 mg/day. After 6 days he had another seizure and a blood level at that time was 10 µg/ml. The dose was increased to 400 mg/day and 3 days later the patient developed symptoms of toxicity. A blood level at that time was 30 µg/ml. How could a 33% increase in the dose lead to a 200% increase in the blood level?
○ Phenytoin exhibits saturation kinetics.
○ because phenytoin exhibits saturation kinetics, a small increase in dose can lead to a large increase in concentration.
At high drug concentrations, the maximal rate of metabolism is reached and cannot be exceeded. Under these conditions, a constant amount of drug is eliminated per unit time no matter how much drug is in the body. Zero order kinetics then apply rather than the usual first order kinetics where a constant proportion of the drug in the body is eliminated per unit time. Some examples of drugs which exhibit non-linear kinetic behaviour are phenytoin, ethanol, salicylate and, in some individuals, theophylline
What dosage change should be made in the treatment of an obese patient with a lipophilic drug that distributes to fat?
Use a loading dose if necessary to achieve a rapid therapeutic effect but keep the daily dose the same
Obesity would lead to an increase in Vd, but an increase in Vd does not decrease clearance, and therefore it does not lead to a decrease in the steady state concentration. It only increases the time required to reach steady state
If you add a drug that decreases the serum protein binding of another drug, how will this affect the free drug concentration and clearance of the drug whose protein binding was decreased?
○ In most cases it will not have much of an effect on the free concentration because the increase in free fraction will increase the clearance, and that decreases the blood level and compensates for the increase in free fraction
○ For a high clearance drug, the clearance is proportional to total concentration, not free concentration.
○ Decreasing protein binding leads to larger variations in the free concentration, or put another way, protein binding acts as a buffer of the free concentration
Dr. Bob Smith discovered the genetic polymorphism in the metabolism of debrisoquine, a drug used to lower blood pressure in hypertensive patients. They were doing a study with the drug, and after he took one dose himself, he developed postural hypotension and passed out. He found that the half-life of the drug was much longer in him than in most individuals and eventually it was determined to be a genetically polymorphic trait. The half-life in normal individuals is about 12 hours. The fact that the drug was metabolized more slowly in Dr. Smith leading to a long half-life should not, in itself, lead to a significantly higher peak level of the drug. Why did Dr. Smith pass out?
○ The postural hypotension was related to the Cmax, not the total exposure. The higher Cmax is due to a decreased first pass metabolism
A decrease in clearance usually leads to an increase in half-life and area under the curve, but not a significant increase in Cmax. The most likely reason for the postural hypotension is a decrease in first pass clearance leading to an increase in Cmax. The relatively long half-life suggests a low clearance, which would also correlate with low first-pass metabolism, but the long half-life in this case is due to a large Vd
There are many drugs whose blood concentration decreases after about a week of treatment. What is the most common mechanism for this effect
○ Auto-induction of metabolic enzymes, especially P450
○ Tolerance is a vague term and can have many mechanisms. In this case the explanation is auto-induction of enzymes such as P450. Drugs, especially lipophylic drugs, often induce the production of more metabolic enzyme in an attempt to get rid of the drug. This process takes several days and up to a week for maximal induction. Therefore, unless a drug has a very long half-life, and it takes as long to reach steady state as it does to induce enzymes such as P450, there is often a noticeable decrease in blood concentration after a week of therapy
How can heart failure affect drug clearance, and what kind of drug is affected the most
○ Heart failure leads to decreased liver perfusion, and for high clearance drugs, the rate of clearance is a function of liver perfusion – the rate at which the drug is delivered to the liver - not the free concentration of the drug
○ The clearance of a high clearance drug is dependent on blood flow, and therefore the decrease in blood flow associated with heart failure can lead to a decrease in clearance. But in general this is only significant with a high clearance drug
Most drug clearance is either renal or hepatic. How are large molecules usually cleared?
○ by metabolism and by transport into bile and elimination in the feces
Although there are exceptions based on being very good substrates for an efflux transporter, the renal clearance of large molecules in the kidney is usually low. Therefore, the drug has to be metabolized to be cleared. In addition, large molecules are often good substrates for eflux transporters in the liver that pump drugs into bile. The drug can then be reabsorbed in the intestine, but in some cases excretion of unchanged drug in the feces is significant
