Module 37

Question 1

What factor appears to be responsible for the ability of halothane to induce hepatitis? Is the mechanism described in the UofT pharmacology textbook (page 579) correct, which involves reduction of halothane to a free radical? How does this hypothesis fit with the relative risk of specific agents for the induction of hepatitis?

Answer 1

There are multiple lines of evidence to indicate that the mechanism of halothane-induced liver injury involves oxidation to a very reactive trifluoroacetyl chloride (shown below) leading to covalent binding and an immune response against trifluoroacetylated proteins.
- Isoflurane and desflurane can produce a similar reactive metabolite, but the rates of reactive metabolite formation with these agents are much less than for halothane, and they are much safer. The reductive pathway is minor except under hypoxic conditions, and it does not lead to significant covalent binding to proteins (Free radicals react with unsaturated fatty acids.) It is strange that this mistake would be made because the free radical hypothesis is very old.

Question 2

What is malignant hyperthermia? What would make you suspect that someone is susceptible to malignant hyperthermia, and how would you test for it? What anesthetics can be used safely in patients who are susceptible to malignant hyperthermia? What is the animal analog? If a patient has had a previous exposure to one of these agents without developing malignant hyperthermia does it mean that it is safe to use such agents in subsequent procedures? Is it safe for a susceptible patient to drink coffee?

Answer 2

• Malignant hyperthermia is a life-threatening condition triggered by volatile anesthetics and depolarizing neuromuscular blocking agents such as succinylcholine. These agents cause opening of the ryanodine receptor with a marked increase in intracellular calcium in muscles leading to muscle contraction and rhabdomyolysis. It is an autosomal dominant disorder.
  
  • The best diagnostic procedure is to treat a muscle biopsy specimen with caffeine or halothane and observe the amount of contraction. Although the test involves the use of caffeine, the amount of caffeine in coffee is not sufficient to trigger the reaction in patients.
  • Genetic testing is less invasive, but not all of the mutations leading to the syndrome are known; therefore, genetic testing could be falsely negative. A family history is often, but not always present. There was a similar reaction in pigs called porcine stress syndrome in which stress caused muscle contraction, and the meat became watery and basically unfit to eat; therefore, breeding programs got rid of this gene variant in pigs.
    A patient can be exposed to one of the triggering agents without developing the syndrome only to have it occur later. At one time other agents such as local anesthetics were thought to be dangerous in these patients, but they are not, and other anesthetics such as propofol are safe, as are the non-depolarizing neuromuscular blocking agents such as atracurium. It is a medical emergency treated with dantrolene.

Question 3

Why are paralyzing agents used during surgery?

Answer 3

• It is important that muscles not contract during surgery such as when they are being cut. High levels of anesthesia prevent muscle contraction, but that results in a prolonged recovery time. If paralyzing agents are combined with lower doses of anesthesia, it results in similar effects, but faster recovery times, which decreases the complication rate.

Question 4

Ketamine is often used for acute sedation such as in the ER, but it can cause hallucinations and delirium. Which drug of abuse is related to ketamine?

Answer 4

Phencyclidine (angel dust)

Question 5

Describe the pharmaceutical properties of propofol. In what population is its use not recommended?

Answer 5

• Propofol is very lipophilic and administered as an emulsion. The emulsion is white, and the effects of propofol are said to be pleasant, which led to referring to propofol as mother’s milk. Because it is an emulsion, the transfer of drug across the blood brain barrier is complex. The drug is short acting because of redistribution to body fat; however, if it is administered for a long period of time, it builds up in fat and the “wash out” period can be very long, especially in obese patients.
  
  • It is not generally recommended for young children because it can rarely cause a life-threatening reaction consisting of metabolic acidosis, liver enlargement, and rhabdomyolysis, and this is more common in young children.