Lec 25 - Porphyrias/TDM/Toxicology

What are Porphyrias

Group of inherited or acquired disorders resulting from heme synthesis pathway abnormalities (decreased/deficient enzyme)

What are porphyrins

Pigment molecule class with ring of 4 pyrrole units with a central metal atom.

• Precursor for heme

• Synthesized from glycine and succinyl-CoA

What are some porphyrin precusros

Delta aminolevulinic acid (ALA), Porphobilinogen (PBG)

Which enzyme regulates heme synthesis

Amino levulinic acid synthase (ALAS1) in liver - negative feedback

• ALAS2 in BM by iron and EPO

What causes upregulation of ALAS1

• Lipophilic drugs + chemicals

• Glucose def

  • Heme def

What is a trigger of acute porphyria attacks

Uncontrolled ALAS1 regulation

What is an example of an exogenous cause of a porphyra

Lead poisoning

Spectral properties of porphyrins

Absorb EMR, emit fluorescence at 600 nm when exposed to 400 nm UV light (red emission)

Excretion of porphyrias depends on what property of the porphyrin?

Water solubility

Higher solubility porphyrin rings can be collected from where?

Kidney (urine), plasma

Lower solubility porphyrin rings can be collectef from where?

Liver (stool), plasma

What makes a porphyrin ring more solubility

Number of carboxylic acid groups on structure

How are porphyrias classified

Used to be based on location of def (hepatic, erythropoietic). Not based on clinical presentation (acute, chronic)

Acute porphyria

More sudden and severe. Causes abdominal pain, neurologic symptoms, psychiatric disturbances

Chronic porphyria

Gradual, cutaneous. Skin sensitivity and blistering when exposed to sunlight

How is a diagnosis for porphyria made?

Look at initial signs at symptoms of patient, that correspond with screening tests

What is first line of porphyria testing

Urine. Looks for porphyrin precursors (PBG+ALA) and total urine porphyrins

• Cano also HPLC liquid fractionate

Use of fecal porphyra testing

Do total fecal porphyrin, freactionate by HPLC

Use of blood porphyria testing

Total erythrocyte protoporphytin. Can also do fluoerscence scan

Urine porphyria testing sample requirements

• Strore away from light, but can be at room temp for 48H

• Dilute urine inacceptable

  • Collect two samples

What unit is urine porphyrins reported in

umol/mmol creatine

When do first symptoms of acute porphyria develop?

During puberty

Most common acute porphyria

Acute intermittent porphyria (AIP)

Clinical signs of acute porphyria

Non-specific

• GI - abdominal pain, vomit, constipation

• Cardio - increased HR, BP

• Hyponatremia - convulsions

• Neuromuscular - muscle weakness, psychiatric disturbance

Triggers of acute porphyria

• Lipophillic drugs

• Chemicals

• Hormones (esp progesterone)

• Fasting

• Stress

  • infection

How to diagnose acute porphyria

Fist line testing is urine porphobilinogen: collected during attack when symptoms present

• Test first volume morning, needs to be testing within 24H

  • Increased PBG ratio to creatinine quires confirmatiry testing

How do distinguish porphyria?

Analyze urine, fecal, plasma porphyrins

Quantitative methods to meausre porphyrin

• Ion exchange chromatography + Ehrlich

• LC MS

  • Measure absorbance after color chan

    Positive screen samples sent to Ottowa

Gold standard of Porphyrin DI

DNE genetic analysis

False positives and negatives duirng porphyria

• Lead poisononing (increased ALA and An propoporhpyin

• Pregnancy, tyrosenemia (iincreased ALA)

• IDA (increased zin protoporphryin)

• Alcohol, infection, etc. (increased co proporphyrins)

• GI bleed

• Dilute urine

  • Compromised specimen activity

Test results of AIP>

Increased urine PBG//ALA

Increased urine uroporphyrin, coproporphyrin

Fecal results: normal COPRO III/ratio

How to manage porphyria

• Hydration, NaCl infusion for hyponatremia

• Caloric support - IV dextrose 10%

• Heme treatment for attacks (pan hematin)

• Life style changes to avoid triggers

  • Pain

  • Fast HR

Peak Serum concentration

Point of maximum concentration an drug use after injestion

When is peak serum concentration testing used for DM

Drug has narrow range or toxicity

Issue with peak serum concentration

Difficult to control

Trough serum concentration

Minimum serum concentration - theoretically period before next dose

TDM method of analysis

Immunoassays, chromatographic methods

What is the use of toxicology

Enhance patient care by monitoring drug levels and metabolites to prevent toxicity

Is toxicology done stat?

No - patient’s are more treated for supportment of symtpoms

What drugs are quantitative tests of immunoassay

1. Acetominaphin
   Salicylate

2. Ethanol + Alcohol pannel

3. DIgoxin

4. Lithium

5. Iron

6. Osmolality

What kind of testing is often used in toxicology

Immunoassays for screening, GC/MS or LC/MS/MS

Why is toxicology not recommended in emergency symptoms?

Does not impact patient care - only some testing will he done to investigate for supportive therapy

What kind of drugs can toxicology immunoassays wcreen for?

Amphetamines, barbiturates, benzodiazepines, cocaine, fentanyl, marijuana, methadone metabolite, opiates. oxycodone, TCAs

What is harm reduction

Refers to any policy, program, or intervention that seeks to reduce or minimize adverse health and social consequences associated with drug use

Examples of harm reduction

• Pharmacies giving pill calendars

• POCT testing of drugs

• Rapid Confirmatory FTIR spec at festivals