Porphyria Everything you need to know ....well almost!

Cerys Lockett UKPMIS, WMIC, Cardiff Definition of Porphyria

Porphyrias are a group of inherited metabolic disorders of the haem pathway, caused by a deficiency of one of the eight involved, leading to accumulation of neurotoxic or phototoxic haem precursors. The conditions are characterised by acute neurovisceral crises, skin lesions or both. Haem biosynthesis pathway

Ref: http://www.stepwards.com/wp- content/uploads/2015/12/porphyria-9-638.jpg Types of porphyria

ACUTE PORPHYRIAS NON-ACUTE PORPHYRIAS AIP = Acute intermittent PCT = porphyria cutanea porphyria tarda VP = EPP = erythropoietic HCP = Hereditary protoporphyria coproporphyria CEP = congenital ALAD-deficiency porphyria = 5-aminolevulinic acid dehydratase deficiency porphyria There are many types of porphyria. What type of porphyria does your patient have?

Mechanism of an acute attack

• Acute porphyrias (AIP, VP and HCP) are conditions that can present with acute porphyria attacks.

• Due to the genetic defect there is a deficiency in one of the enzymes so patients have a rate limiting step in the biosynthetic pathway during periods of increased requirements of hepatic haem biosynthesis.

• Although haem is produced, it is at the expense of excessive production of neurotoxic precursors, , 5-aminolevulinic acid (ALA) and porphobilinogens (PBGs).

• The consequence of which is the range of symptoms

• Many things can increase requirements of hepatic haem biosynthesis including reproductive hormones, fasting, stress, infection or certain porphyrinogenic drugs or . Symptoms of acute attacks

• Gastro-intestinal: • Severe incl. , , • Cardiovascular: • , , arrhythmias • Peripheral motor neuropathy: • muscle weakness, loss of sensation, progressing to flaccid , respiratory insufficiency • Psychiatric: • Agitation, insomnia, , delirium, disorientation, • Central : • Hyponatraemia, convulsions • that turns orange / red / purple on exposure to visible light. • Can be fatal Acute porphyria attacks can be life threatening and severely disabling

• Early symptoms of an acute attack are: • acute severe abdo pain, • nausea, vomiting, • constipation, • peripheral motor neuropathy, • paraesthesia

Acute Porphyria Attack Management • Contact National Acute Porphyria Service (NAPS) for clinical support / advice • Supportive treatments e.g. haem arginate • BIPNET acute attack management guidelines • UKPMIS for drug safety advice and guidance How to assess risk of an attack Precipitating Factors Risk Factors • Excessive alcohol • Women > men • Fasting / starvation • AIP > VP > HCP • Stress • Susceptible age • Infection • Previously suffered • Porphyrinogenic drugs – acute attacks (esp drug- prescribed and illicit induced) • Hormone fluctuations • Recent / current porphyria attack

All factors are cumulative How do drugs become involved? • Induction of the haem synthetic pathway • Induce ALA synthase-1 • Induction of P450 enzymes

• Female Sex Hormones • Mechanism unclear, but known to be porphyrinogenic

• Adverse drug reactions • e.g. nausea and vomiting ADRs may induce sufficient physiological disturbance to trigger an acute attack Porphyrinogenic Fasting / drugs Starvation Infection

Hormonal fluctuations Risk of Susceptible age Acute Attack

Excessive alcohol Female > Male

Porphyria Stress history

Precipitating factors are cumulative “Is this drug safe to use in my patient who has porphyria?” • Obtain patient details, porphyria type and history, indication of drug, etc. • Consider all precipitating factors • UKPMIS safe list • BNF unsafe list • NAPOS / French / American safe lists • If any doubt, conflicting information, or enter the ‘grey area’ contact UKPMIS to discuss

N.B. Porphyrinogenic drugs only affect acute porphyria patients. Acute Porphyria Drug Safety Enquiries Process

Obtain patient details: Porphyria type & status / Indication for the drug in question

Is medication on the UKPMIS safe list? N.B. check group names.

NO YES = OK to USE

On BNF unsafe list? N.B. Check group names

NO YES = AVOID

Safety information available? NO Benefit > Risk e.g. NAPOS, French or American lists

YES YES = Seek specialist NO = AVOID advice from UKPMIS

Confident that medication is safe to use? Benefit > Risk

NO YES = OK to USE UKPMIS Safe List BNF Unsafe List Your new BFFs….

UKPMIS safe list BNF unsafe list UKPMIS Any questions...... ?

[email protected] UKPMIS, WMIC, Cardiff 02920 742251 / 02920 743877 Useful resources 1 • National Acute Porphyria Service (NAPS) – 029 20747747 and ask for NAPS. Available 24hr / day, 7 days / week • UK Porphyria MI Service (UKPMIS) – 029 20742251 or via [email protected] • UKPMIS Safe List: http://www.wmic.wales.nhs.uk/pdfs/porphyria/2016PorphyriaSafeList. pdf • BNF Unsafe List: accessed via BNF and search for ‘unsafe’ • Welsh MI Centre (WMIC): http://www.wmic.wales.nhs.uk/porphyria_info.php • Multiple UKMi Q+A around the topic of acute and non-acute porphyrias available via https://www.sps.nhs.uk • Scandinavian drug lists via NAPOS: http://www.drugs-porphyria.org/ • French lists: http://www.porphyrie.net/porphyries-et-medicaments/ • American lists: http://www.porphyriafoundation.com/drug-database Useful resources 2

• British and Irish Porphyria Network (BIPNET) - Guidelines on managing an acute porphyria attack: Ann Clin Biochem May 2013; Vol 50; No 3: pp. 217 – 223. Accessed via: http://acb.sagepub.com/content/50/3/217.full.pdf+html • Lockett C, Badminton M. Safe Prescribing in the autosomal dominant acute porphyrias: a practical approach: Part I. Adverse Drug Reaction Bulletin August 2015; No 293: pp. 1131 – 1134 • Lockett C, Badminton M. Safe Prescribing in the autosomal dominant acute porphyrias: a practical approach: Part II. Adverse Drug Reaction Bulletin October 2015; No 294: pp. 1135 – 1138 • Puy H, Gouya L, Deybach J-C. Porphyrias. 2010; Vol 375: pp. 924 – 937 • Harper P, Sardh E. Management of acute intermittent porphyria. Expert Opinion on Orphan Drugs 2014; Vol 2 (4): pp. 349 - 368 • European Porphyria Network (EPNET): http://porphyria.eu/