Definition
Porphyrias are a group of inherited or acquired disorders of certain enzymes in the heme biosynthetic pathway (also called porphyrin pathway). They are broadly classified as hepatic porphyrias or erythropoietic porphyrias, based on the site of the overproduction and mainly accumulation of the porphyrins (or their chemical precursors). They manifest with either skin problems or with neurological complications (or occasionally both).
The term derives from the Greek πορφύρα, porphura, meaning purple pigment. The name is likely to have been a reference to the purple discolouration of some body fluids in patients during an attack.Although original descriptions are attributed to Hippocrates, the disease was first explained biochemically by Felix Hoppe-Seyler in 1874,and acute porphyrias were described by the Dutch physician B.J. Stokvis in 1889
What are porphyrins?
A porphyrin is a heterocyclic macrocycle
derived from four pyrrole-like subunits interconnected via
their α"C"atoms via methine bridges(=CH-).The macrocycle,therefore,
is a highl conjugated system,and is consequently deeply coloured.
The macrocycle has 22 pi e-.The parent porphyrin is porphine,
and substituted porphines are called porphyrins.
Many porphyrins occur in nature
in green leaves and red blood cells,and in
bio-inspired synthetic catalysts and device.
Types of porphyrias
Old and New Classifications
In the past, the porphyrias were divided into groups based on the site of the porphyrin production :
hepatic or erythropoietic
Category related to organ in which accumulation of porphyrins and their precursors appears.
Other clinicians classified them by whether there were effects on the person's skin or not
(cutaneous porphyria).
Today, the porphyrias are usually divided into
acute or non-acute types
Acute porphyrias produce attacks of pain and neurological effects which are severe and appear rapidly. Acute types include acute intermittent porphyria, ALAD-deficiency porphyria, variegate porphyria, and hereditary coproporphyria. The non-acute types are porphyria cutanea tarda, and hepatoerythopoietic and congenital erythropoietic porphyrias.
Epidemiology,How common is porphyria?
The incidence varies considerably throughout the world and is probably between 0.5 and 10 cases per 100,000 population. Porphyria cutanea tarda is the commonest form in Europe, North America and probably worldwide. ALAD is very rare. Inheritance is mostly dominant with limited penetrance.
The exact prevalence of this condition is unknown, but probably ranges from 1 in 500 to 50,000 people worldwide. Overall, porphyria cutanea tarda is the most common type of the disease, affecting 1 to 2 in 100,000 people. For some forms of porphyria, the incidence is uncertain because many people with a gene mutation never experience signs or symptoms.
The diagnosis of porphyria can be done after an careful clinical exam and a scrupulous valutation of laboratory exams which have to include the qualitative and quantitative determination of porphyrines and their precursiors in blood, urines and feces. Porphyrines are increased in the bone marrow, in erythrocites, in plasma in urines and feces with a characteristic pattern, usually with higher levels respect those observed in other porphyries. Uroporphyrin I and coproporphyrineare the prevalent porphyrines in urines, in plasma and in erytrocites, whereas coproporphyrin I prevales in feces. Sometimes erythrocits contain big quantity of protoporphyrin I, as in other homozygote porphyries. A demonstration of the deficit of uroporphyrinogen enzyme’s activity confirm the diagnosis. ALA and PBG are not augmented.
Clinical evideces : THE ACUTE ATTACK
People with AIP HC or VP are always at risk of an acute attack of porphyria. This may be very dangerous, and they should read this section carefully and make sure they understand how they can prevent such an attack. Those with PCT, EPP and CP are not at risk, and this section does not apply to them.
WHAT IS AN ACUTE ATTACK?
The acute attack takes place when the levels of the porphyrin precursors become very much raised for one or other reason. One can think of this as an overloading of the body with porphyrins and their precursors. During such an attack, the affected person may experience abdominal pain, cramps, constipation, nausea or vomiting. They may also show marked anxiety or disturbed behaviour. Such attacks can be bad enough to require admission to hospital, and the most severe cases may go on to weakness and paralysis. People have even died of such an attack. Fortunately, a fatal outcome has become rare as modern hospitals now have the facilities to treat such complications. This emphasises the need for people experiencing an acute attack to be admitted to an experienced hospital. It is more common nowadays for people with AIP or VP to develop milder forms of the acute attack with not much more than a feeling of being unwell, some pain in the stomach and, perhaps, nausea. If you are experiencing such problems, it is important that you immediately stop any medication you may be taking and consult your doctor. Yet everyone has some of these symptoms at one time or another and you cannot blame everything on your porphyria!
WHAT MAY BRING ON AN ACUTE ATTACK?
Acute attacks may follow the use of many drugs. Porphyric people are unable to handle these drugs in the normal way and their bodies respond to them by overproducing porphyrins. This is the commonest cause of the acute attack. However, attacks can also be precipitated by alcohol, by an infection and even by dieting. Smoking has been shown to worsen attacks.
What can I do to avoid developing an acute attack?:
You must understand that there are many medicines that can aggravate your porphyria, possibly resulting in an acute attack. Therefore, you must never take any medicine or remedy without checking that it is safe for porphyrics. This includes drugs given to you by a doctor, pharmacist or dentist, as well as those you can buy without prescription. Always consult our list (which you will find in this booklet) before you take the medicine given to you. Note that this includes tonics, herbal remedies and even the contraceptive pill, which has been a major factor in the development of acute attacks.
If you ever need an operation, you must tell the surgeon and anaesthetist that you have porphyria, as some anaesthetic drugs in common use are very dangerous for porphyrics. Safer alternatives can be used. It is desirable to wear a Medic-Alert disc or carry a similar form of identification, so that doctors will know you have porphyria in the event of an accident.
Finally, it is wise to eat regular meals and not to go without food for long periods, or to embark on 'crash' diets. Other than this, there is no special diet that needs to be followed. If you wish to lose weight, discuss your diet with your doctor beforehand. It is also best to avoid alcoholic drinks and to stop (or never start) smoking.
MANAGEMENT OF ACUTE ATTACK
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SPECIFIC THERAPY OF ACUTE ATTACK
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Prevention and therapy
Patients, who have experienced a clinical attack of porphyria, should be carefully counselled concerning the avoidance of precipitating factors. They should be encouraged to maintain a regular diet and to abstain completely from alcohol and to stop smoking. In addition, they should be warned about the dangers of certain drugs and given a Reference Booklet, showing which drugs are safe and which are unsafe to take (see Tables 1 and 2). It is also important to ensure that the patient's General Practitioner is fully informed about the disease and given advice about management. Patients should be reminded to tell any Medical Attendant that they suffer from porphyria. As an added precaution, they should wear a bracelet or necklace, indicating that they have porphyria, to prevent the administration of dangerous drugs or anaesthetics if an accident or other emergency.
Analgesic and Anti-hypertensive
Effects of selected antihypertensives and analgesics on hepatic porphyrin accumulation: Implications for clinical porphyria :
When patients with acute porphyrias are treated with antihypertensives and analgesics, they could be placed at increased risk of developing porphyric attacks, since little is known about the potential for many of these drugs to induce these attacks. We used primary chick embryo liver cells, which maintain intact heme synthesis and regulation, to study the effects of antihypertensives and analgesics on porphyrin accumulation. Cells were treated with desferrioxamine to block heme synthesis partially, simulating conditions encountered in porphyric patients. Typically, cells were treated for 20 hr with the test drugs (3.16 to 1000 μM), along with desferrioxamine. Porphyrins were measured spectrofluorometrically, as uro-, copro,- and protoporphyrin. The evaluated drugs included six antihypertensives (two calcium channel blockers, an angiotensin receptor antagonist, and three inhibitors of angiotensin converting enzyme) and eight analgesics. Of the calcium channel blockers tested, nifedipine greatly increased porphyrin accumulation, whereas diltiazem caused only a slight increase. Losartan (an angiotensin receptor antagonist), captopril, or lisinopril (two angiotensin converting enzyme inhibitors) produced only small increases in porphyrin accumulation. In contrast, enalapril (another angiotensin converting enzyme inhibitor) substantially increased porphyrin accumulation when given in high concentrations. Among the analgesics tested, fentanyl and tramadol produced the highest porphyrin accumulations. Nalbuphine, hydrocodone, oxycodone, and dezocine were moderately or weakly porphyrogenic, whereas buprenorphine and morphine did not increase porphyrin accumulation. These studies suggest that patients with acute porphyrias may be at greater risk for developing porphyric attacks when treated with nifedipine (compared with diltiazem), enalapril (compared with captopril or lisinopril), and tramadol (compared with the other analgesics).
Fentanyl and similar (alfentanyl, remifentanyl, sufentanyl)
It’s an opioid analgesic used for chronical pain as in neoplasia and as analgesic in general anhestesia. It's 80 times more powerful than morphine. It has a very low half life.
It is administered by cutaneous band-aid. The band-aid is fully effective only with an 24-hours application. The dosage must be calculated in relationship with previous administration of opioids and tolerance.
Every administration of opioid must be stopped 12 hours before band-aid application.
The hangin up of the treatment must be graduated, because it’s not known at what dosage the analgesic can lead up to dependence. The dosages must be reduced for children, old people and patients with renal and hepatic failure.
Most common unwanted effects :
1. the worst unwanted effect is respiratory depression
2. sleepiness, confusion, hallucinations, headache
3. sickness, vomit, constipation
4. xerostomia
5. perspiration, itch
6. hypersensitivity
7. tolerance, dependence, drug withdrawal.
It has a specific antagonist: naloxone
Tramadol
It’s an opioid analgesic. It’s used for acute and chronical pain of different kind and cause as pain caused by neoplasia or by surgery.
It must be administered in relationship with medical judgement, with pain intensity and with patient’s sensitivity.
The unwanted effects are similar to the fentanyl.
It can causes tolerance, dependence, drug withdrawal too.
Nifedipine
Nifedipine is used to treat hypertension (high blood pressure) and angina (chest pain). Angina occurs when the heart muscle does not receive enough oxygen. Nifedipine can also be used to treat Raynaud's phenomenon, a condition caused by bad circulation (lack of blood) to the hands and feet. Nifedipine works by relaxing and opening up the blood vessels. This allows blood to circulate more freely around the body, lowering blood pressure, increasing the flow of blood to the extremities and improving the efficiency of the heart.
Local Anesthesia
Bupivacaine
It is recommended to people who’s suffering from porphyria. This local anaesthetic is long acting, which may be a draw-back, but it is a drug with only positive results for use in the acute porphyrias.
Active principle: bupivacaine chlorhydrate.
Category: local anesthetics
Use: it’s useful for every kind of peripheral anesthesia. It’s useful for every general surgery, orthopaedics, ophtalmology, dentistry, obstetrics and gynaecology, dermatology. It can be used alone or in narcosi.
The bupivacaine it’s usually used in small dosage, despect on the indications.
Unwanted effects :
1. tossic reactions
2. allergic reactions. in people with hypersensibility.
3. central nervous stimulation with exciting, trembling, vertigo, fever, paroxism, due to a wrong dosage of bupivacaine.
4. In the cardiovascular system we can observe modification in conduction capacity, and depression of heart conduction.
5. decrease of blood pressure for vessels dilation.
Articaine
Is a relatively new local anaesthetic and still untried in acute porphyria, but from a theoretical standpoint seems to be well suited for use in these conditions.
Active principle: articaine with epinephrine. Es. cartidont ( curaden healtcare)
Category: local anesthetic for dentistry use.
Use: it’s useful to extraction of single tooth or many teeth, to preparation of cavity and monconi. It can be used for every type of local anesthesia.
Controindications :
1. case of hypersensibility
2. pregnancy
3. not for endovenous use
4. heart disease
5. high blood pressure
6. ischemic disease
7. hyperthyroidism
8. nefropatie
9. glaucoma.
Unwanted effects :
1. toxic reactions
2. allergic reactions, also in absence of hypersensibility
3. nervous stimulation (with exciting, trembling, vertigo)
4. effects on cardiac-circulatory system due to a wrong dosage of epinephrine: ( anxiety, perspiration, heart trouble, high blood pressure, headache, photophobia, vomit, retrosternal pain)
The other local anaesthetic
Are unsafe to use dependent on the dose administered. Anaesthesia of the skin and mucous membranes can probably be made by any local anaesthetic available, provided that large areas are not covered.
They are:
• lidocaine (medium safety)
• mepivacaine
• ropivacaine
• levobupivacaine
• prilocaine
.
Case reports
