Phenobarbital side effects

Primidone [125-33-7] C22H24N2O2 (39) is an analogue of phenobarbital that is used for the treatment of generalized tonic-clonic seizures. It is metabolized in humans to phenobarbital (6) and phenylethyLmalondiamide [7206-76-0J, C22H24N2O2 (40) and these metaboUtes are probably responsible for its anticonvulsant actions. Primidone has many of the side effect HabiUties seen with phenobarbital. 

Convulsive disorders are still a serious therapeutic problem and new agents are being actively sought. Classical therapy was based upon the barbiturates that are no longer in favor because of their many side effects and their suicide potential. Interestingly, a seemingly minor structural variation of phenobarbital (152, shown as its sodium salt) leads to an anticonvulsant of increased potency and which has less hypnotic activity. In this case, sodium phenobarbital serves as its own base (so the yield is limited to 50%) and reacts readily with... 

The most common side effects are fatigue, drowsiness, and depression. Phenobarbital impairs cognitive performance. In children, hyperactivity can occur. 

Conversely, certain drugs modify the effectiveness or side effects of aspirin. Phenobarbital, occasionally used for seizures, induces liver enzymes that increase the metabolism and excretion of aspirin, (3-adrenoceptorblocking drugs, such as propranolol, and decrease the antiinflammatory effects of aspirin, whereas reserpine decreases its analgesic effects. Antacids decrease the absorption of aspirin. Alcohol consumption in combination with aspirin increases the latter s ulcerogenic effects. 

The first effective treatment of seizure disorders was the serendipitous finding in 1857 that potassium bromide could control seizures in some patients. Even though side effects were troublesome, the bromides were widely used for many years. Phenobarbital was introduced as a treatment for epilepsy in 1912 and was immediately shown to be markedly superior to bromides. While other barbiturates were synthesized and used, none were shown to be superior to phenobarbital, and the latter compound is still used. A chemically related... 

The major untoward effect of phenobarbital and primidone, when used as anticonvulsants, is sedation. Another side effect of considerable importance, particularly in children, is a possible disturbance in cognitive function. Even when the serum concentration is within the therapeutic range, apparently the ability to concentrate and perform simple tasks is decreased. 

Herranz, J.L., Armijo, J.A., and Arteaga, R. (1988) Clinical side effects of phenobarbital, primidone, phenytoin, carbamazepine, and valproate during monotherapy in children. Epilepsia 29 794-804. 

Historically, alcohol has been used as an anxiety-reducing agent, both casually and in professional medical settings. In 1903, barbital was introduced as the first barbiturate to treat anxiety, and phenobarbital followed a few years later. Barbiturates have many side effects and addictive properties, and overdose can lead to coma and death. For these reasons, they are rarely used today, except to treat some forms of epilepsy. This class of drugs was eventually replaced by the benzodiazepines (see Chapter 4). 

Cyclosporin is metabolised by the hepatic cytochrome P-450 enzyme system, and enzyme induction by phenobarbital, phenytoin, carbamazepine, or rifampicin will drastically increase the clearance of cyclosporin. Concurrent administration of these drugs has caused rejection of transplanted organs. Conversely, the use of enzyme inhibitors, such as erythromycin or the azole antifungal agents, e.g. ketoconazole, will increase the blood concentrations of cyclosporin leading to an increased risk of toxic side effects. 

In this condition, ephedrine is used primarily as a chronic medication for mild or only moderately acute cases, especially in children. In severe asthma, the response to ephedrine is usually poor. Compared with epinephrine, ephedrine is less reliable, is slower in action and longer in duration, and probably more often produces undesirable side effects. The average dose is 25 to 50 mg, orally, repeated three or four times a day. Resistance often develops it may often be controlled by discontinuing the drug for a few days. In many patients, ephedrine produces anxiety, nervousness, and insomnia, so a barbiturate is often administered at the same time. Capsules containing either 15 mg of amobarbital, 25 mg of pentobarbital sodium, or 30 mg of phenobarbital in addition to 25 mg of ephedrine sulfate have been used in the past. 

Phenobarbital is the oldest antiepileptic drug in common use and has a solid efficiency record for the control of seizure. However, due to some side effects (hypertension, depression, dizziness, rash, memory lapses) and drug interactions (primarily other anticonvulsants), phenobarbital is now generally used as a second-line treatment. 

Iivanainen M, Savolainen H. Side effects of phenobarbital and phenytoin during long-term treatment of epilepsy. Acta Neurol Scand Suppl 1983 97 49-67. 

Central nervous system depressants include the barbiturates, such as phenobarbital, and the antianxiety drugs, including diazepam (VaUum), chlordiazepoxide Odbrium), oxazepam (Serax), flurazepam hydrochloride (Dalmane), and lorazepam (Ativan). The benzodiazepines, including diazepam, occasionally cause mydriasis, presumably because of their anticholinergic side effects. 

With chronic exposure, side effects may include rash, thrombocytopenia, leukopenia, and a lupus-like disorder. Chronic therapy is likely to result in tolerance, and withdrawal symptoms if primidone therapy is abruptly stopped. Doses in excess of 1500 mg (twice the maximum recommended daily dose) should be considered toxic. Less common side effects are hypotension, hypothermia, and dermal bullae. Encephalopathy has been observed in an epileptic patient with high plasma levels and poor renal function. With plasma concentrations exceeding 80pgml primidone may precipitate and cause crystalluria. Plasma levels >10 rgpml are associated with toxic effects. The therapeutic range is reportedly 5-10pgml , but clinical effects correlate more closely with phenobarbital blood levels. 

The optimally effective therapeutic concentration of phenobarbital is between 15 and 40p.g/mL. The predominant side effect observed in adults at blood concentrations greater than 40[Xg/mL is sedation, although tolerance to this effect develops with chronic therapy. 

All narcotics are expected to have this problem. The most common side effects demonstrated with narcotics include decreased gastrointestinal motility and risk of hypotension. Lorazepam is the preferred sedative agent in the absence of pain owing to its fast onset of action, its lack of hemodynamic toxicities, and its low risk of metabolite accumulation in comparison with diazepam. Midazolam continuous infusion is a reasonable altemative, although more costly and requiring additional fluid, which may be detrimental in a patient predisposed to PDA. Muscle paralysis has been used to reduce ventilator fighting and the consequent comphcations. However, its role in RDS has diminished owing to adverse effects (e.g., edema and hypoventilation). If paralysis is induced, assessment of sedation and seizures is confounded. Consequently, concurrent phenobarbital serum concentrations of 40 mg/L are recommended. Independent of... 

The traditional treatment of tonic-clonic seizures is phenytoin or phenobarbital however, the use of carbamazepine and valproic acid is increasing because these AEDs have a lower incidence of side effects and equal efficacy. Valproic acid generally is considered the drug of first choice for atonic seizures and for juvenile myoclonic epilepsy. Lamotrigine and perhaps topiramate and zonisamide may be alternative agents for these seizure types. 

I Adverse Effects. CNS side effects are the primary factors limiting the use of phenobarbital. Tolerance usually develops to initial complaints of fatigue, drowsiness, sedation, and depression. In children, paradoxically, the primary side effect is hyperactivity. Phenobarbital impairs higher cortical function and depresses cognitive performance. Phenobarbital also may cause porphyria and rash, including serious rashes such as Stevens-Johnson (see Table 54-6). 

It is clear that the cheapest drugs in epilepsy (e.g., phenobarbital) are not the best because of the number of side effects. Eurther drug therapy that would control seizures, decrease side effects, improve the quality of life, and reduce the use of other health care resources would be cost-effective. Because epilepsy treatment continues to be... 

When drug-induced megaloblastic anemia is related to chemotherapy, no real therapeutic option is available, and the anemia becomes an accepted side effect of therapy. If drug-induced megaloblastic anemia results from cotrimoxazole, a trial course of folinic acid, 5 to 10 mg up to four times a day, may correct the anemia. Folic acid supplementation of 1 mg every day often corrects the drug-induced megaloblastic anemia produced by either phenytoin or phenobarbital, but some clinicians suggest that supplementation of folic acid may decrease the effectiveness of the antiepileptic medications. ... 

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