Porphyria Barbiturates

Neuropsychiatric, neuromuscular, autonomic dysfunction, and intense abdominal pain characterize AIP. In the liver, this enzyme deficiency results in the increased inducibility of abnormal heme intermediates by certain drugs. Drugs and agents known to induce hepatic cytochrome P450 enzymes or to increase hepatic heme mrnover are theoretically capable of precipitating porphyria. Barbiturates, estrogens, alcohol, and heavy metals such as lead have been documented to induce porphyria in genetically susceptible people. ... 

Acute intermittent porphyria is a dominantly inherited partial deficiency of porphobilinogen deaminase, and causes axonal polyneuropathy. Acute intermittent porphyria is caused by partial deficiency of porphobilinogen deaminase, an enzyme required for heme biosynthesis. Patients may present with acute abdominal pain, rapidly progressive sensorimotor axonal polyneuropathy or psychosis, and have elevated concentrations of the heme precursor 8-amino-levulinic acid in their urine. Symptoms may be precipitated by treatment with barbiturates or other drugs and are suppressed by treatment with hematin [59]. 

When used for detoxification, phenobarbital is given in equal doses four times a day. The maximum daily dose of phenobarbital is 600 mg, but much lower doses are usually sufficient. The phenobarbital dose is lowered (i.e., tapered) by about 20% per day. If the patient is too drowsy, then a dose should be skipped. If breakthrough withdrawal symptoms continue to occur, then the pace of the detoxification should be slowed. Before using phenobarbital, liver function tests should be obtained. All barbiturates depend greatly on the liver to be metabolized. Alcoholics with cirrhosis or other forms of liver impairment may have difficulty clearing phenobarbital. Phenobarbital should not be used in patients with poor liver function. In addition, the barbiturates can worsen a medical condition known as porphyria and should be avoided in those with this disorder. Phenobarbital, as noted, is seldom used today for alcohol detoxification. 

Barbiturate sensitivity manifest or latent porphyria marked impairment of liver function severe respiratory disease when dyspnea or obstruction is evident nephritic patients patients with respiratory disease where dyspnea or obstruction is present intra-arterial administration subcutaneous administration previous addiction to the sedative/hypnotic group. 

Barbiturates generally increase the synthesis of porphyrin and intermittent porphyria is therefore an absolute contraindication for their use. 

Most of the adverse reactions associated with the use of the intravenous barbiturates are predictable and therefore can be controlled or avoided. Some reactions, such as hypersensitivity, are entirely unpredictable. Particularly patients with asthma, urticaria, or an-gioedema may acquire allergic hypersensitivity to the barbiturates. Acute intermittent porphyria is an absolute contraindication to the use of barbiturates. 

Contraindications History of manifest or latent porphyria, marked liver dysfunction, marked respiratory disease in which dyspnea or obstruction is evident, and hypersensitivity to secobarbital or barbiturates... 

Barbiturates may precipitate episodes of acute intermittent porphyria (AIP) and their use is contraindicated in patients who are predisposed to this condition. Some animal models indicate that ketamine, etomidate, and the benzodiazepines may be porphyrinogenic and propofol is considered to be the intravenous anaesthetic of choice in AlP-prone patients. 

Barbiturates reduce hepatic blood flow and glomerular filtration rate, but these drugs produce no adverse effects on hepatic or renal function. Barbiturates can exacerbate acute intermittent porphyria by inducing the production of hepatic ct -aminolevulinic acid (ALA) synthase (see Chapter 22). On rare occasions, thiopental has precipitated porphyric crisis when used as an induction agent in susceptible patients. 

Enzyme inducers, such as phenytoin, carbamazepine, and barbiturates, can precipitate attacks in patients with acute intermittent porphyria. 

Precautions As noted previously, barbiturates induce the P-450 system and therefore may decrease the effect of drugs that are metabolized by these hepatic enzymes. Barbiturates increase porphyrin synthesis, and are contraindicated in patients with acute intermittent porphyria. 

Acute hereditary porphyrias are disorders of heme synthesis in which overproduction of heme precursors is often accompanied by severe clinical manifestations. Most of the time these diseases remain clinically latent and only occasionally result in acute abdominal and neuropsychiatric symptoms. Occurrence of the symptoms often follows exposure to drugs, such as barbiturates, sulfonamides, estrogens and some local anesthetics (Blanloeil et al. 1989). 

Excessive production of liver 5-aminolevulinate synthase causes two forms of congenital porphyria. These diseases are characterized by overproduction of porphyrins and excretion of large amounts of 5-aminolevulinate and porphobilinogen. Some ethnic groups have a high incidence of this disease, and in these people, acute attacks are brought on by barbiturates and other compounds that induce synthesis of the enzyme. 

Tuberculous patients lacking in liver N-acetyl transferase who are treated with isoniazid are likely to develop polyneuritis (39). An enzyme abnormality is also responsible for the precipitation of acute intermittent porphyria by the barbiturate drugs (40). Likewise, the rare hereditary resistance to coumarin anticoagulant drugs is thought to be due to an enzyme deficiency (41). 

It is of interest that those who inherited acute intermittent porphyria and variegate porphyria suffered no biological disadvantage from the natural environment and bred as well as the normal population until the introduction of barbiturates and sulphonamides. They are now at serious disadvantage, for many other drugs can precipitate fatal acute attacks. 

The use of thiopental or any other barbiturate is contraindicated in acute intermittent porphyria a progressive neuropathy can occur and can be fatal. 

Hypersensitivity to barbiturates, hepatic dysfunction, porphyria, severe respiratory disease. 

In many types of drug reactions, bullae and vesicles may be found in addition to other manifestations. Bullae are usually noted in erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, fixed eruptions when very intense, urticaria, vasculitis, porphyria cutanea tarda, and phototoxic reactions (from furosemide and nalidixic acid). Tense, thick-walled bullae can be seen in bromoderma and iododerma as well as in barbiturate overdosage. 

The barbiturates induce drug-metabolizing enzymes, including the P450 system, leading to potential drug interactions. They also stimulate heme synthesis and are contraindicated in porphyrias. 

Short-term administration of barbiturates has no clinically significant effect on the hepatic, renal, or endocrine systems. A single induction dose of thiopental does not alter tone of the gravid uterus, but may produce mild transient depression of newborn activity. Drug-induced histamine release is occasionally seen. Barbiturates can induce fatal attacks of porphyria in patients with acute intermittent or variegate porphyria and are contraindicated in such patients. Unlike inhala-tional anesthetics and succinylcholine, barbiturates and all other parenteral anesthetics apparently do not trigger malignant hyperthermia. 

---