Module 3 Flashcards
Overdoses with tricyclic antidepressants are very difficult to treat and often lead to fatal arrhythmias. There is a paper that reports that hemoperfusion was a useful therapy for tricyclic antidepressant overdoses because it removed over 90% of the drug in one pass through the hemoperfusion cartridge. A representative tricyclic antidepressant is desipramine, which has a half life of about 48 hours, a volume of distribution of 40 L/kg, and protein binding is 82%. This represents an important advancement in the treatment of tricyclic antidepressant overdoses.
No, Even though most of the drug was removed from the blood, with a Vd of 40 L/kg there is very little drug in the blood. Specifically, the blood volume is about 5 L, and for a 70 kg person, the total volume of distribution is 2800 L (40 X 70), so only 5/2800 or 0.18% is in the blood. The hepatic clearance is actually quite high and much higher than the clearance that could be achieved by hemoperfusion. The only reason that the half-life is long is the high Vd. Therefore, hemoperfusion would not have a significant effect of tricyclic antidepressant clearance and has significant side-effect
A child who is being treated with digoxin develops a cardiac arrhythmia. A digoxin level is drawn, and the result that comes back is 6 ng/ml (which is well above the toxic range). Digoxin can cause a variety of cardiac arrhythmias. This high blood level means that the child’s arrhythmia is due to digoxin
- No; In general it is always important to know when the blood was drawn relative to when the drug was administered in order to interpret the results. In the case of digoxin, it very slowly redistributes to the sites in the heart where it affects ion channels and so it is important to wait at least 4 hours after drug administration before measuring drug levels. At early time points the blood levels can be very high but do not cause any cardiotoxicity.
A patient had a seizure disorder and had been on phenytoin for several years. Her phenytoin had always been in the therapeutic range, and she had never had signs of significant toxicity. She then developed glomerulonephritis and renal failure. She developed nystagmus and other symptoms of phenytoin toxicity, but her phenytoin blood level was not significantly different than it had been previous to her renal failure. This occurred because
- The renal failure affected phenytoin protein binding.
When blood levels of a drug are measured, in general it is the total level that is determined. But phenytoin is highly protein bound, and it is the free level that is pharmacologically important. In this patient the renal failure led to an increase in the concentration of various anions in the blood, which competed with phenytoin for protein binding and the free concentration and toxicity increased even though the total did not.
Propranolol is a ß-blocker with a half-life of about 4 hours. The usual therapeutic dose is about 40 mg. The effect of a 0.1 mg dose of propranolol given orally is essentially zero, but given IV, the same dose leads to significant ß-blockade in the heart. This ß-blockade only lasts for a few minutes, but it can be used to test the safety of propranolol in a specific patient. This is because
Propranolol has a large first pass clearance when given orally
The blood level of propranolol, and therefore the level in the heart, is much higher when it is given iv, but it rapidly decreases as the drug redistributes out of the blood
Charcoal is commonly used to treat drug overdoses by binding drug in the intestine and preventing absorption. Is it possible for charcoal to decrease blood levels of a drug even after the drug has been absorbed?
Yes, there is an equilibrium between the blood and intestinal contents; therefore, charcoal in the gut can “pull” the drug out of the body
Liver failure leads to a buildup of toxic metabolites, some of which decrease brain function. This is referred to as hepatic encephalopathy. One of those toxic metabolites is ammonia. Lactulose is metabolized to lactic acid by gut bacteria, and it is often used to treat hepatic encephalopathy. Its likely mechanism of action is
- The lactic acid acidifies the gut and leads to ion trapping of the ammonia.
- lactulose is a laxative and decreases the amount of toxic metabolites formed and retained in the gut
The Breathalyzer test measures the amount of alcohol in the breath as a measure of the amount of alcohol in the blood. Is this valid?
- This is valid because the large surface of the lung which produces a very rapid equilibrium between the blood alcohol and alcohol in the breath. A major determinant of the vapor pressure of alcohol is temperature. A rapid rate of respiration can falsely decrease the breath alcohol level.
- Although temperature is an important determinant of alcohol vapor pressure, body and lung temperature are usually quite constant, and the police are trained to make sure the subject does not hyperventilate.
if the mouthwash contains alcohol it can falsely produce a increase level of alcohol if it contains alcohol
- Although temperature is an important determinant of alcohol vapor pressure, body and lung temperature are usually quite constant, and the police are trained to make sure the subject does not hyperventilate.
Most drugs are not evenly distributed in the body. This has significant effects on the efficacy and adverse reactions caused by drugs. Efflux transporters obviously play a major role in the blood/brain barrier. In contrast, many drugs are concentrated in the liver. A good example is the statins. How do interindividual differences in statin distribution affect their pharmacology?
Pts with OATP1B1 are at an increased risk of serious statin myopathy. OATP1B1 is a hepatic uptake transporter, and this variant results in a decrease in hepatic uptake of statins and an increase in blood levels of statins. This decreased hepatic uptake of statins presumably also decreases their efficacy given that cholesterol synthesis occurs in the liver.
