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A.
Case study A week later, she presented with the same symptoms; however, her symptoms were far more severe, and she was in hypertensive crisis. The doctor on duty decided to investigate possible allergic reactions. WHAT SHOULD BE CONSIDERED
AT THIS STAGE? a. In an interview about
her food and beverage intake, it was found that she had been consuming
at least 4 cups of coffee and Coca Cola daily over the exam period.
She would treat herself to a piece of chocolate every second day. When
she thought about the previous episode, she recalled that she had eaten
out the night before with friends and had enjoyed a gourmet pizza with
camembert, salami and avocado. She had eaten half the pizza and kept
the rest for the following day. She had forgotten to store the pizza
in the refridgerator but still ate it for lunch the next day. She had
presented to the trauma unit that afternoon. On the day of the second
episode, she had eaten nothing similar to what she had eaten the previous
time. After her exam, she had met friends at a local pub. She had drunk
a pint of the draft that was on tap. She drank the beer on an empty
stomach and then ate Russian hot dogs on the way home. That night she
went to the trauma unit. DISCUSSION The psychological evaluation revealed that she had in fact diagnosed herself with depression and was taking an antidepressant medication. Due to her profession, she had been ashamed to mention the fact. The medication was a monoamine oxidase inhibitor. She had been unaware of the potentially devastating interaction with foods containing high levels of tyramine. The consumption of aged cheese, cured meat, improperly stored food, and tap beer, in combination with incorrect administration of the antidepressant medication, a monoamine oxidase inhibitor (MAOI), had led to excessive tyramine levels and associated symptoms, including the hypertensive crisis. WHAT CAN BE DONE?
Vasoactive amines constitute the largest class of substances responsible for pharmacologic reactions to food. These substances include dopamine, histamine, norepinephrine, phenylethylamine, serotonin, tryptamine and tyramine. Of these substances, dopamine, histamine, phenylethylamine, serotonin and tyramine may be present in appreciable amounts in foods and are responsible for producing the majority of clinically apparent pharmacologic effects. Adverse reactions to tyramine, probably due to low levels of the enzyme monoamine oxidase required to break it down, may present in 3 different forms, namely 1) tyramine sensitivity, 2) migraine and/or chronic urticaria, and 3) food-drug interaction with monoamine oxidase inhibitors (MAOIs). In this review, only tyramine sensitivity due to food-drug interaction with MAOIs will be discussed. Monoamine oxidase inhibitor (MAOI) medications are an important class of drugs, which have been used since the 1950s for the treatment of a variety of psychiatric disorders, including depression with either melancholic or atypical features, dysthymia, psychotic depression, bipolar major depression, mixed anxiety and depression, and refractory depression.1,2,3 They have also been used successfully as effective and relatively safe options in the treatment of depression in the elderly, and of panic disorder and phobias.1,2 There is, however, concern over using these drugs, due to the serious, even fatal, interaction observed between the drugs and foods containing tyramine. This interaction can lead to hypertensive crisis, with symptoms such as severe headache, nausea, neck stiffness, palpitations, diaphoresis, and confusion, and may even cause stroke and death.1,3 Although these agents tend to be infrequently used because of concerns over safety, the American Psychiatric Association and the British Association for Psychopharmacology have recently reversed their opinions regarding MAOIs and in their practice guidelines have recommended their use, with appropriate dietary restrictions, for patients with major depressive disorder with atypical features and for some patients for whom other antidepressant medication is ineffective.2,4,5 a. What
is tyramine, and where is it found? Although dietary tyramine does not cause detectable clinical effects in the majority of individuals, it is thought to play a role in migraine headaches and symptoms of hypersensitivity in some individuals. Urticaria and other symptoms are similar to those in histamine sensitivity. Dietary tyramine can cause hypertensive crisis in patients receiving concurrent treatment with MAOIs.6 Tyramine is also present in a number of foods, particularly in aged cheeses (especially in Camembert and Cheddar). High levels of tyramine are found in some fermented foods as a result of microbial fermentation or bacterial decarboxylation of tyrosine. These foods include wine (especially red and Chianti), beer and other fermented beverages, vinegars, pickles, relishes, pickled herring, fermented bean curd, fermented soya bean and soya sauces, miso soup and yeast extract (Marmite, Vegemite). Tryramine occurs naturally in some foods, especially raspberries, bananas, avocadoes, figs, red plums, eggplant (aubergine), tomatoes and chicken liver.6,7 b. What
is monoamine oxidase? Individuals with rare deletions in their MAO-A gene have increased urinary levels of serotonin, epinephrine and norepinephrine, while MAO-B-deficient subjects have increased phenylethylamine levels. The MAO-A-deficient individuals, clinically observed, seem to have impaired impulse control and a propensity to stress-induced aggression. MAO-B-deficient individuals do not seem to have clinically apparent disturbances in their behaviour. Reasons for the clinical differences are still unclear, although raised serotonin levels in the MAO-A-deficient individuals may have a disruptive effect on the developing brain.6 c. Sensitivity
to tyramine People taking MAOIs, such as certain antidepressants (tranylcypromine, phenelzine and moclobemide), and some drugs for the treatment of Parkinson’s disease (selegiline and eldepryl), are especially at risk for tyramine toxicity and hypertensive crisis.7,8 The “cheese effect” was first identified in 1963 and refers to a sudden rise in blood pressure in patients taking MAOIs and exposed to the amine tyramine. Manifestations of hypertensive crisis include severe headache, nausea, neck stiffness, palpitations, diaphoresis, confusion, stroke and even death. Most reported fatal and non-fatal reactions have been associated with cheese ingestion.1,8 Severe hypertensive episodes can be averted in individuals taking MAOIs by avoiding food rich in tyramine. Treatment includes administration of the alpha-adrenergic antagonist phentolamine, which is given until blood pressure stabilises.6 The fear of dietary
hypertensive events in patients treated with traditional MAOIs has also
led clinical researchers to study the effectiveness of newer agents
with selective properties for MAO-A or MAO-B inhibition in humans. Selegiline,
an MAOI with superior antidepressant efficacy, has now been developed
into a selegiline transdermal system (STS) with unique pharmacokinetic
and pharmacodynamic properties, which allow inhibition of central nervous
system MAO-A and MAO-B enzymes while substantially avoiding inhibition
of intestinal and liver MAO-A enzyme. This novel transdermal system
provides targeted MAO inhibition without clinically significant increases
in sensitivity to dietary tyramine, therefore eliminating the need for
concurrent tyramine dietary restrictions.2 A variety of factors may affect the rate and extent of tyramine absorption, including variation between foods in the same category, and the ingestion of food of a kind that may affect both drug absorption and reduce the average peak increase in blood pressure due to tyramine.10 The freshness of food has been identified as a factor in the amount of tyramine present; i.e., the longer a food is stored, the greater the tyramine content. Improperly stored or spoiled food can create an environment where tyramine concentrations increase. These foods either have free tyrosine, or during storage tyrosine is liberated; then the tyrosine is converted to tyramine by microorganisms with decarboxylase enzymes. This phenomenon has been noted in meat, specifically chicken liver and air-dried sausages, and in tap beer and cheese. Of interest is the fact that in certain foods considered to have relatively high levels of naturally occurring tyramine, improper or prolonged storage did not increase the tyramine content to unsafe levels. Although conditions of growth were present in these foods, it is thought that either tyrosine was not liberated or was liberated in only small quantities, or decarboxylation activity was lacking.10 It is also important to note that improper fermentation or storage of some foods results in an increase not only of tyramine but also of other amines such as histamine and putrescine. As these are also metabolised by monoamine oxidase, it may be that individuals can be affected even by a product containing lower levels of tyramine. Severe tyramine restriction has caused much controversy over the years; it is not entirely clear which foods should be allowed on an MAOI diet.3 Many MAOI diets are considered to be excessively restrictive and founded on poor scientific evidence.1,9,11 Overly restrictive diets may in fact inhibit physicians from recommending MAOIs, a potentially useful treatment option; may lead to excessive limitations on lifestyle for patients; and may paradoxically increase risk of hypertensive crisis by increasing non-compliance with the diet.1,2,9,11 It has therefore been suggested that dietary prohibitions need not be so restrictive and should be limited to foods with the highest risk of inducing a hypertensive reaction.1,8,9,11 Current recommendations for the MAOI diet represent an attempt to balance realistic compliance concerns with quality of life and safety. Gardner et al. propose a much-simplified MAOI diet with a solid scientific and clinical basis, which is above all practical and user-friendly.1 The guidelines are based on critical reviews of the literature and careful analyses of the tyramine content of various foods, but individualised counseling is still essential.1,3,8,9,11 The single most important considerations in avoiding the “cheese effect” are “Buy fresh, cook fresh, and eat fresh.” Freshness of food is paramount, especially in meat, poultry, and fish, and in related items such as pâté, gravy and soup stock.1,3 Very aged and overripe cheeses, hard cheeses, and those with fermentation holes (all of these types being easily recognised by their strong smell or their very salty and biting taste) should be avoided, as they are most commonly associated with hypertensive crisis. Moderate portions (<100 g) of pasteurised, fresh cheese may be consumed. The cheese should not be stored in the refrigerator for longer than 2 or 3 weeks. During maturation of cheese, continuous protein breakdown occurs, and therefore the amount of tyrosine rises steadily. Cheeses produced from non-pasteurised milk contain contaminant bacteria able to decarboxylate tyrosine time-dependently into tyramine.1,8,9,10,11,12 In addition to aged cheeses, foods that should be avoided include aged and cured meats, all soybean products (especially soya sauce and tofu), sauerkraut and all tap beers. Fava or broad bean pods, banana peels and yeast extract spreads (e.g., Vegemite and Marmite) should also be excluded.1,3,8,9,11 Mixed foods raise a further set of issues. Most pizzas from large chain commercial outlets are considered safe; however, caution should be exercised with pizzas from smaller outlets, or gourmet pizzas known to contain aged cheeses.9,13 No case reports or laboratory analyses of ambiguous foods such as avocados, raspberries, chocolate, banana pulp and peanuts are compelling, and restriction of these foods is considered unnecessary at present. Both red and white wine (with the possible exception of Chianti) are considered safe when consumed in moderate amounts (1-2 glasses per day). Regarding beer, patients are advised to limit their selection to bottled and canned beer from major domestic breweries (whether alcohol-containing or de-alcoholised) and to consume only moderate quantities (not more than 2 bottles or cans per day).1 As a general rule, MAOIs should be taken at the end of a meal in order to avoid tyramine absorption occurring at a time when the drug has reached its peak concentration at the intestinal enzyme.12 Dietary modifications
should begin as soon as a medication is started and continue for 2-3
weeks after the medication has been discontinued. Initially, the patient’s
current dietary practices and knowledge of food and nutrient guidelines
should be assessed. Patients must be made fully aware of the importance
of following the dietary guidelines and not “cheating,”
and continued review of compliance is especially important. Consistency
in information communicated to patients from the numerous possible sources
(family doctors, psychiatrists, pharmacists, dietitians, nurses and
drug companies) is essential. Individual dietary teaching and monitoring
provide an excellent mechanism to reduce MAOI risk and increase the
comfort of psychiatrists in prescribing this important class of antidepressants.1,3,11 Relative restrictions of foods and beverages with MAOI use 1
C. Comments by our editors
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1.
True or false: Monoamine oxidase inhibitor (MAOI) medications are frequently
used for treatment of depression. 2. True or false:
High levels of tyramine in the body have a predominantly vasodilating
effect, resulting in migraine headaches, palpitations and hypertensive
crisis in sensitive individuals. 3. Examples of two
aged cheeses are: 4. Tyramine can
be metabolised by the following enzyme/s: 5. True or false:
The “cheese effect” refers to a sudden rise in blood pressure
in patients who are taking MAOIs and are exposed to the amine tyramine. 6. Which treatment
provides targeted MAO inhibition without clinically significant increases
in sensitivity to dietary tyramine, eliminating the need for tyramine
dietary restrictions? 7. Choose the correct
answer: Improperly stored or spoiled food can create an environment
where tyramine concentrations increase because: 8. True or false:
Avocados, raspberries, chocolate, banana pulp and peanuts should not
be restricted from the MAOI diet. 9. When in relation
to meals should MAOIs be taken? 10. True or false:
Tap, bottled and canned beer should be consumed in moderate amounts
on the MAOI diet. Cut and paste
the section below into an e-mail message HPCSA number: DT Please make an “X” in the appropriate block for each question
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