Quiz feedback: Anticonvulsants/Seasonal allergic rhinitis

All anticonvulsant medications are associated with adverse effects. Typically these effects are dose related and adverse effects may be minimised by:

• Choosing a slow release formulation when practical to avoid rapid rises in serum concentration
• Starting with a low dose and slowly increasing at one or two week intervals
• Using monotherapy if possible

With a rapid release formulation high peak drug concentrations are achieved quickly and as a result some dose related adverse effects may be more troublesome. These effects may be minimised by choosing a slow release formulation when practical to avoid rapid rises in serum concentration.

Monotherapy is recommended when possible. Initial monotherapy results in 50-70% of patients being seizure free. The traditional approach has been to try up to two or three single anticonvulsants, before embarking on polytherapy.

If more than one drug is used there is the possibility of additive adverse effects such as sedation and confusion. Some combinations may increase the risk of more serious adverse effects such as liver toxicity, and the possibility of clinically significant drug interactions is also increased. Newer generation antiepileptics in combination can be associated with less toxicity and improved seizure control.

Most anticonvulsants exhibit linear pharmacokinetics where the dose of the anticonvulsant is directly proportional to the plasma concentration and choosing the optimal dose relies primarily on a careful assessment of the patient’s clinical state; the persistence of seizures or signs of toxicity.

Examples of anticonvulsants with linear pharmacokinetics include sodium valproate, carbamazepine, lamotrigine and topiramate. Routine therapeutic drug monitoring (measuring the plasma drug concentration) is not required with these anticonvulsants but can aid dosing decisions especially in the following situations;

• When pharmacokinetics alter (and consequently, dose requirement), e.g. in children, in older people, in pregnancy, in people with co-morbidities or when a drug interaction is suspected
• If seizures persist despite an apparently adequate dosage
• To gauge compliance – erratic dosing or poor compliance may result in lower than expected drug concentrations
• If toxicity is suspected or when it is difficult to assess this clinically, e.g. in children or people with mental disability

In contrast, phenytoin exhibits non-linear pharmacokinetics as its metabolism becomes saturated at plasma concentrations associated with therapeutic use. Small increases in phenytoin dose can lead to toxicity. Increments should be made cautiously, e.g. a dose increase of 30 mg, and after each dose increase, both the clinical effect and plasma concentration monitored. Therapeutic drug monitoring is useful after a dose increase of phenytoin as the effect on the drug concentration is more difficult to predict than with other anticonvulsants. Interpretation of drug concentrations should be made in conjunction with symptom control and the patient’s clinical state.

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Interpreting serum phenytoin levels

In some situations extra care needs to be taken in interpreting the serum phenytoin level against the usual therapeutic range. Phenytoin has a high degree of serum protein binding but it is the unbound drug that produces the clinical effects. Normally the ratio of unbound to bound phenytoin is fairly constant and the measure of total serum concentration is proportional to the amount of active drug available. This changes when there is hypoalbuminaemia, renal failure and interactions with other highly protein-bound drugs (e.g. sodium valproate) that alter the protein binding of phenytoin. In these situations the therapeutic range of phenytoin will be much less and care needs to be taken that changes are not based on the therapeutic range alone. For example, if phenytoin's unbound fraction doubles from 10% to 20%, the therapeutic range based on total phenytoin concentration should be halved. If dose adjustments are made according to the usual therapeutic range, toxicity may result.

An anticonvulsant choice made in adolescence is often life long. It can be difficult to change anticonvulsants once someone is seizure free and driving. Therefore, women need to start treatment with an anticonvulsant that appears to be the most suitable for their seizure type and syndrome, has a low teratogenic risk and preferably does not interact with the combined oral contraceptive. Other considerations are changes to physical appearance e.g. coarsening of the features, hirsutism and gum hypertrophy with phenytoin and increased appetite, weight gain and increased risk of polycystic ovarian syndrome with sodium valproate.

Although most pregnancies in women with epilepsy are without complications, and the majority of infants are delivered healthy, the use of the majority of anticonvulsant medications increases the risk of teratogenicity. The risk of a major congenital malformation in the general population is about 2 – 3 % compared to 4 – 7% in women taking anticonvulsant medicines. The risk is higher for the older anticonvulsant medicines (especially sodium valproate), with combination therapy and when anticonvulsants are taken at higher doses.

The safest and most appropriate anticonvulsant regimens for women of child bearing potential are monotherapy with carbamazepine or lamotrigine at doses under 200 mg/day.

Phenytoin, carbamazepine, phenobarbitone, primidone and to a lesser extent topiramate and lamotrigine, induce and increase the production of hepatic enzymes. This can result in clinically significant drug interactions by increasing the metabolism of some co-administered drugs, reducing their effectiveness at standard doses. One of the co-administered drugs affected this way is the combined oral contraceptive (COC).

It is recommended that women taking enzyme inducing anticonvulsants who would like to use the COC as contraception, be prescribed a COC containing at least 50 μg of oestrogen. If there are indications that the oestrogen dose is inadequate, such as mid cycle bleeding, the oestrogen dose can be increased by taking two 30 μg pills per day (and in some cases up to two 50 μg pills per day).

If emergency contraception is required for women taking enzyme inducing anticonvulsants, it is usually recommended that twice the normal dose of the progesterone-only emergency contraceptive pill should be taken. An alternative is to insert an IUCD within five days of the unprotected intercourse.

As many anticonvulsants are associated with an increased risk of neural tube defects and it is recommended that all women of child bearing potential who are on anticonvulsants take folic acid 5 mg/day.

Most women taking anticonvulsants can breast feed safely as the amounts excreted in to breast milk are very small.

Alcohol is a CNS depressant and can lower seizure threshold. In some people a small amount of alcohol may trigger a seizure, but the majority of people with epilepsy can safely consume a small amount of alcohol.

Limited alcohol intake has been shown not to alter serum concentrations of anticonvulsants, nor to increase the frequency of seizures. A suggested safe upper level of alcohol intake is one to two drinks per occasion, totalling no more than three to six drinks per week.

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Anticonvulsants can confound interpretation of liver function tests

Enzyme inducing anticonvulsants such as phenytoin and carbamazepine can increase GGT concentrations. Most anticonvulsants can cause asymptomatic increases in serum transaminases. This can confound interpretation of liver function tests with respect to the effects of alcohol intake.

Allergic rhinitis is characterised by sneezing (especially paroxysmal – short, frequent attacks), congestion, watery anterior rhinorrhoea, itchy nose, eyes and throat, sinus pressure, facial pain and decreased sense of smell or taste.

Symptoms not usually associated with allergic rhinitis include: unilateral symptoms, nasal obstruction without other symptoms, mucopurulent rhinorrhoea, posterior rhinorrhoea with thick mucuous, recurrent epistaxis.

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Diagnosing allergic rhinitis in children

It is sometimes difficult to diagnose allergic rhinitis in children as they are unable to articulate some of the symptoms. Signs in children which may indicate allergic rhinitis include tiredness, daytime sleepiness, sniffing, blinking, rubbing of the eyes, speech problems, snoring and dark circles under the eyes (shiners).

Allergic rhinitis is significantly associated with asthma. Allergic rhinitis occurs in 75–80% of patients with asthma and conversely, 20–30% of patients with known allergic rhinitis are subsequently found to have asthma. Family history of atopy is also a known risk factor for seasonal allergic rhinitis.

Many people have both seasonal and perennial allergic rhinitis and are allergic to both indoor and outdoor allergens. Their symptoms are perennial, with seasonal exacerbations.

Skin prick testing is not essential for diagnosis but may be considered, if the diagnosis is in doubt, if the patient wishes to determine possible sensitivity to a specific allergen or when expensive avoidance measures or immunotherapy are being contemplated. A positive reaction to an extract does not necessarily mean that this allergen causes the patients symptoms, but it provides supportive evidence as part of an overall exposure history.

Towards the end of pollen season, symptoms may worsen. This is known as allergen priming where after repeated exposure to pollen, the amount of allergen required to induce a response decreases.

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The united airways disease concept

It has been hypothesised that allergic rhinitis and asthma are two manifestations of the same underlying disease and that an integrated management approach will improve the control of both conditions. Both genetic and environmental factors are recognised as contributing to the development of an allergic airway syndrome. It has been demonstrated that impaired nasal function affects the lower airways of patients with asthma. It is thought that a systemic pathway exists between the upper and lower airways, involving blood and bone marrow.

For more see: Braunstahl G. United airways concept. The Proceedings of the American Thoracic Society 2009;6:652-4.

Intranasal antihistamines may be used as first-line treatment for people with mild symptoms who wish to gain immediate relief. They have a rapid onset of action so may be used on an “as needed” basis. They are not as effective for the treatment of symptoms related to the eye and throat.

Oral antihistamines may provide equal relief from symptoms, but they are associated with more adverse effects. They may be used if a nasal spray formulation is not acceptable, or if targeted relief from eye symptoms is required (as they are more effective than intranasal antihistamines for this symptom).

Note that sedating antihistamines are contraindicated for the treatment of allergic rhinitis in children.

Intranasal corticosteroids are very effective for the treatment of allergic rhinitis but as maximum effect may take up to two weeks to achieve, they are recommended for people with more severe symptoms, who wish to use preventative measures throughout the pollen season.

Oral corticosteroids are not generally recommended except in cases of severe or intractable nasal symptoms or nasal polyps.

Intranasal corticosteroids are recommended first-line for people with moderate to severe symptoms of seasonal allergic rhinitis. Corticosteroid nasal sprays are considered to be the most effective medicine class for controlling the four main symptoms of hay fever – sneezing, itching, rhinorrhoea and nasal blockage. The onset of action can be up to 12 hours and maximum efficacy can take up to two weeks to achieve. Treatment may be started prior to the anticipated beginning of the pollen season and be continued throughout.

Intranasal and oral antihistamines may be used for rapid relief of mild symptoms. If moderate to severe symptoms remain uncontrolled despite maximum dosage of an intranasal antihistamine, the addition of an oral antihistamine may be considered, especially for breakthrough symptoms.

Oral corticosteroids are not generally recommended except in cases of severe or intractable nasal symptoms or nasal polyps.

Intranasal decongestants should only be used short-term (less than ten days) and intermittently because of the risk of rhinitis medicamentosa (rebound nasal congestion).

Oral corticosteroids should not be used throughout the pollen season. A short course of oral corticosteroids (e.g. five to seven days), may be considered for very severe or intractable nasal symptoms or nasal polyps.

Parenteral corticosteroid injections are not recommended due to the risk of long-term corticosteroid adverse effects and the availability of more effective treatments.

Intranasal anticholinergics, e.g. ipatropium bromide, can be effective in reducing rhinorrhoea, although have no effect on other nasal symptoms. They can be used as an “add-on” treatment to intranasal corticosteroids and antihistamines if required for symptom control.

Intranasal sodium cromoglycate has limited effectiveness for the treatment of seasonal allergic rhinitis, although it is a safe treatment to use in young children and during pregnancy. For most people, intranasal sodium cromoglycate is less effective than intranasal corticosteroids.