Module 36

Question 1

What are some factors that can precipitate seizures?

Answer 1

• Almost any stress can decrease the seizure threshold. The most common example is febrile seizures in children, which do not indicate that the child will develop a permanent seizure disorder.
  
  • Metabolic disturbances are frequent causes, and they include hypoglycemia in patients taking insulin, hyponatremia, and alcohol withdrawal. In the case of alcohol, alcohol actually increases the seizure threshold, but on withdrawal, the threshold is markedly decreased, and this can result in a seizure.
  • There are many drugs that decrease the seizure threshold, and these drugs should be avoided in patients with a seizure disorder.
    ○ These drugs include many antipsychotics and antidepressants.
    ○ Maprotiline and clomipramine, among the antidepressants, and chlorpromazine and clozapine, among the antipsychotic medications, appear to be the worst offenders.
    ○ In contrast, fluoxetine, paroxetine, sertraline, venlafaxine, and trazodone appear to be relatively safe antidepressants, and haloperidol, pimozide, and risperidone appear to be relatively safe antipsychotic agents with respect to decreasing the seizure threshold.

Question 2

Antipyretics decrease the risk of febrile seizures.

Answer 2

antipyretics do not appear to decrease the risk of febrile seizures. Therefore, the only reason to treat fevers in children is to make them more comfortable. However, there is a worry that decreasing fever decreases the immune response and clearance of viruses.

Question 3

What factors need to be considered when a woman with a seizure disorder becomes pregnant?

Answer 3

• As with other drug therapy during pregnancy it is a delicate balance. Several anticonvulsants are associated with an increased risk of birth defects. However, uncontrolled seizures pose an even greater threat to the fetus.
  It appears that the use of combination therapy is associated with a greater risk than single agents. Of the older anticonvulsants, carbamazepine appears to be safer than phenytoin or valproic acid. The metabolism and protein binding of anticonvulsants can change during therapy; therefore, careful drug monitoring is warranted.

Question 4

Describe the aromatic anticonvulsant hypersensitivity syndrome. If a patient on an “aromatic” anticonvulsant develops a rash, what are the options?

Answer 4

• the aromatic anticonvulsant hypersensitivity syndrome is associated with the use of aromatic anticonvulsants, especially phenytoin, phenobarbital, and carbamazepine, and to a lesser degree lamotrigine. It can be life-threatening. It overlaps with DRESS (drug reaction with eosinophilia and systemic symptoms).
  
  • If a patient is started on an aromatic anticonvulsant and develops a rash, it may be the beginning of the hypersensitivity syndrome. On the other hand, in most cases it is will be a mild rash that resolves even if the drug is continued, and there are risks to stopping anticonvulsants. One very important sign is fever; if the patient develops a fever it is the sign of a more severe reaction with the release of cytokines, and in such cases it is mandatory that the drug be stopped immediately.
  • There is a relatively high degree of cross sensitivity (more than 50%) to other aromatic anticonvulsants. I call it cross sensitivity because if it were cross reactivity, the reaction should occur rapidly when starting the drug just as it would if the patient were rechallenged with the original offending drug. However, in most cases the time to onset of a reaction to the alternate aromatic anticonvulsant is delayed.

Question 5

The UofT textbook states that rashes occur with lamotrigine more commonly if the patient is also taking valproic acid. What is the likely explanation for this interaction.

Answer 5

• The major mode of lamotrigine clearance is glucuronidation, and valproic acid inhibits the glucuronidation of lamotrigine and increases lamotrigine blood levels.

Question 6

What is the interaction between valproate and carbapenems?

Answer 6

• Carbapenems decrease the blood levels of valproate and can lead to loss of seizure control. The mechanism is not totally clear.

Question 7

Describe the liver toxicity associated with valproic acid, and what appears to be the mechanism of this idiosyncratic drug reaction.

Answer 7

• The characteristics of valproate-induced liver injury are different from the idiosyncratic liver injury caused by most other drugs. Specifically, although it can occur in adults, the risk is much higher in infants below the age of 2. In addition, it often displays characteristics similar to Reye’s syndrome with hyperammonemia and microvesicular steatosis, evidence of mitochondrial dysfunction. This is probably because it is a carboxylic acid that is branched at the beta position, which is where fatty acids are oxidized during their metabolism in mitochondria. Therefore, it inhibits beta-oxidation of fatty acids.
  
  • A significant risk factor is a genetic mutation in mitochondrial DNA polymerase, and this may be a required genetic test before prescribing the drug in the future. Even though valproate-induced liver injury clearly involves mitochondrial injury, it still may have an immune component.

Question 8

Why don’t the anticonvulsive effects of vigabatrin correlate with its blood levels?

Answer 8

• Vigabatrin works by inhibition of GABA transaminase thereby increasing the levels of GABA (gamma-aminobutyric acid), which is an inhibitory neurotransmitter. A transaminase converts an amino group into a carbonyl group. If the amino group of vigabatrin were replaced with a carbonyl group it would be an acrolein analog. Of course acrolein is the classic reactive Michael acceptor that you should remember from PHM144. The carbonyl group is not actually formed, it is an iminium ion intermediate that actually covalently binds to the enzyme, but the principle is the same, and in the process of the reaction, vigabatrin becomes an electrophile that irreversibly binds to the GABA transaminase.
  
  • Because it covalently binds to the enzyme, the inhibition is irreversible. Therefore, the time to recovery of enzyme activity is based on the half-life of the enzyme, not the half-life of the drug. In other words the drug can have an effect that outlives the presence of the drug.

Question 9

Why can a patient’s steady state total valproic acid level remain unchanged despite and increase in dose from 1250 mg QHS to 1500 QHS?

Answer 9

• Valproic acid exhibits nonlinear kinetics, but it is the opposite of phenytoin. Valproic acid is highly protein bound, but it requires high doses to be effective, and protein binding becomes saturated. When the protein binding is saturated, additional drug increases the free concentration that is available for clearance. This increases clearance and flattens the dose – concentration relationship