Uploaded by i.e.m.de.jong

Summary hepatotoxicity TCP

advertisement
Monoamine oxidase (MAO) is a flavoprotein present in mitochondrial membranes and
catalyzes the oxidative deamination of several neurotransmitters (noradrenaline, dopamine,
serotonine) to aldehydes. Other enzymes convert the aldehyde to an alcohol or carboxylic
acid. MAO catabolizes an excess of the neurotransmitter. The antidepressant action of MAOinhibitors lies in interfering in this process and prolonging the action of the
neurotransmitters.
MAO-inhibitors are a heterogeneous group of drugs that can be subdivided into a hydrazinederivates such as iproniazid, phenelzine, and pheniprazine and non-hydrazine-based
therapeutics such as isocarboxazid and tranylcypromine (TCP) (Table 1). These drugs were
the first clinically useful antidepressant drugs and had therefore an important impact on the
development of modern biological psychiatry. After 1970, MAO-inhibitors were tarnished
because they interact with many drugs and food-derived amines and exert therefore
notorious side effects such as hepatic necrosis and hypertensive crises. However, new
insights brought selective MAO inhibitors, such as TCP, with lesser side effects back on the
market, albeit under strict medical supervision of a psychiatrist.
Specifically, TCP is a mechanism-based (or suicide) inhibitor that first interacts reversibly
with the enzyme to form a non-covalent complex. Thereafter, the irreversible reaction takes
place to form a covalently-bound enzyme-inhibitor adduct: 𝐸 + 𝐼 ⇌ 𝐸𝐼 ⟶ 𝐸𝐼 ∗
This irreversible binding can manifest for 14 days.
Tranylcypromine inhibits CYP2A6, CYP2C9, CYP2C19, and CYP2E1.
Maximum plasma levels are reached after 0.5-3.5 hours. Primary liver biotransformation
products are p-hydroxytranycypromine and n-acetyltranylcypromine.
Whereas all metabolites are eliminated within 24 hours after the latest dose, it takes 3-5
days to fully recover the activity of the enzyme MAO because of the irreversible MAOinhibition. Metabolites are eliminated via bile and mainly via the kidneys. Only 4% of its dose
is unchanged eliminated via urine as tranylcypromine.
*Each of the drugs which has caused jaundice is a derivative of hydrazine, itself a potent
hepatotoxic agent in laboratory animals (Yard and McKennis 1955)
*TCP has been regarded as a much safer drug than iproniazid, as it is not cumulative.
*TCP rarely causes jaundice. There have been 2 cases of hepatocellular damage due to this
drug, one reported (Bandt 1964). See also table 2. Toloxatone is also a non-hydrazine
monamine oxidase inhibitor. It also has led to at least two cases of hepatocellular injury.
Both were fatal.
More information TCP: what are the common side-effects? --> Mild gastro-intestinal
problems.
Prof Gouw (hepatopathologist UMCG) has another book where tranylcypromine is
mentioned: MacSween’s Pathology of the liver. She will look into it tomorrow..
Substance
N-isoNicotinoyl-Nisopropylhydrazine
a-methylphenethylhydrazine
Official name
Iproniazid
Proprietary name
Marsilid
Pheniprazine
N-(2-Benzylcarbamlethyl)-Nisonicotinylhydrazine
Phenethylhydrazine
Nialamine
Cavodil
Catron
Niamid
Phenelzine
Nardil
Isocarboxazid
Tersavid
Marplan
1-benzyl-2-pivaloylhydrazine
3-N-Benzylhydrazinecarbonyl-5methylisoxazole
Trans (±)-2Phenylcyclopropylamine
Table 1. MAO-inhibiting drugs
Tranylcypromine
Parnate
Parstellazine
Features of TCP-induced hepatotoxicity
Clinical symptoms such as jaundice, malaise, anorexia, and
nausea after 1-4 months
Serum aminotransferase elevations are hepatocellular
Mechanism of aminotransferase elevations unknown,
possibly cause is production of a toxic intermediate
metabolism. The hepatotoxicity seems to be based on
idiosyncrasy.
Transient serum aminotransferase elevations in a
proportion of patients; usually mild, asymptomatic, selflimiting and does not require dose modification.
Rare cases of acute, clinically apparent liver injury
These cases described have resembled those caused by
other MAO inhibitors
Patients that developed hepatotoxicity are likely to have
cross sensitivity with other MAO inhibitors
Table 2. Features of TCP-induced hepatotoxicity. TCP: tranylcypromine; MAO: monoamine oxidase
Case reports (only 1 case described with TCP!)
Tranylcypromine (1964)
To a 49-years old woman with involutional depression was tranylcypromine 20mg daily
prescribed. 6 weeks after onset of treatment she complained of weaknesss and malaise.
Subsequently, dosage tranylcypromine was increased to 30mg daily. One week later:
nausea, diarrhea, and anorexia. Also, dark urine, light stools, jaundice, and epigastric pain
relieved by vomiting. She had no history of alcohol abuse and she used no other
medications. The liver was palpable 4 cm below the costal margin of the right side and was
tender. The spleen was not palpable. There was no lymphadenopathy. Serological test for
syphilis was negative. After 7 weeks first laboratory tests were performed as shown in table
3. The pathologist examined the liver biopsy taken and concluded that the observed changes
were consistent with regressing viral hepatitis.
In this case the clinicians and the patient agreed on giving a challenge dose: 24 hours after
the first dose, liver enzymes elevated until 540 units and nausea and vomiting recurred. 2
months after tranylcypromine was stopped, liver function tests were normal and no liverrelated symptoms were present.
Time After
Starting
Time After
Stopping
AST
(U/L)
Alk P (U/L)
Bilirubin
(mg/dL)
Other
Tranylcypromine taken for 7 weeks
670
26.5
14.9
410
5.0
340
3.2
36
6.5
0.9
Tranylcypromine restarted for 2 days
10 weeks (0)
21 days
19
0.6
Rechallenge
22 (0) days
540
1.1
23 (1) day
420
24 (2) days
200
0.5
25 (3) days
67
27 (4) days
31
0.4
Normal Values
<35
<13
<1.2
Table 3. Liver enzymes indicating hepatocellular and cholestatic damage. AST: aspartate
7 weeks
8 weeks
9 weeks
10 weeks
0
5 days
10 days
17 days
aminotransferase; Alk P: alkaline phosphatase
Iproniazid/pheniprazine (1960)
Patient: 52-year old woman with cardiac ischemic pain
Medication: iproniazid
Time interval: After 4 weeks
Symptoms: malaise, dizziness, vomiting, and jaundice
After 2 years, anticoagulant therapy was supplemented by pheniprazine 6 mg daily
Time interval: After 7 months
Symptoms: anorexia, malaise, jaundice, continuous upper abdominal pain, intense palmar
erythema, liver edge was 3 cm below right costal margin and tender.
Lab: bilirubin 12 mg/100ml, AP 36 units
Decision: stop both ipronaizid and pheniprazine
Patient died 2 months later due to a cardiac infarction.
Pheniprazine/nialamide (1959)
Patient: 60-year old woman with anxiety and loss of confidence
Medication: pheniprazine 6 mg daily
Time interval: After 3 months
Symptoms: hematemesis
After a few months pheniprazine was discontinued and restarted again because of depressive
symptoms.
Time interval: After 1 month
Symptoms: malaise, anorexia, and jaundice. Liver 2 cm below costal margin.
Lab: Bilirubin 3.3 mg/100 ml
Biopsy: Patchy necrosis and infiltration of portal tracts by neutrophils, lymphocytes, and
fibroblasts, and many contained fat-droplets.
Gastroscopy: Single varix on the anterior wall of the oesophagus
Decision: stop pheniprazine
After 6 weeks, nialamide 25 mg was prescribed because of recurrence of depressive
symptoms.
Time interval: 3 weeks
Symptoms: nausea, anorexia, jaundice, the liver was 3 cm below costal margin palpable.
Decision: continuation of nialamide
After 3 weeks the liver diminished in size, liver-function tests returned to normal and jaundice
subsided.
Pheniprazine (1960)
Patient: 27-year old man with depression
Medication: Pheniprazine 18 mg daily
Time interval: after 2 months
Symptoms: Upper abdominal discomfort, anorexia, and jaundice
Decision: stop pheniprazine
Jaundice progressively deepened, anorexia persisted.
Lab: bilirubin 40 mg/100ml, AP 26 units
Biopsy: necrosis of liver cells, with loss of lobular structure and invasion by inflammatory
cells.
Decision: prednisone was started
A day thereafter, the patient collapsed and died.
Phenelzine (1960)
Patient: 56-year old woman
Medication: phenelzine 30 mg daily
Time interval: 5 months
Symptoms: pruritis, pain behind the eyes, anorexia and jaundice
Lab: Bilirubin 2.8 mg/100ml, AP 31 units
Biopsy: patchy necrosis of parenchymal cells, with variation in nuclear size of the intact cells.
The portal tracts and the necrotic areas were infiltrated by lymphocytes.
Decision: Stop phenelzine
2 weeks later, the jaundice had subsided an liver function tests had returned to normal.
1. Bandt C, Hofbauer FW. Liver injury associated with tranylcypromine therapy. JAMA
1964 188: 752-3.
2. Holdswoth CD, Atkinson M, Goldie W. Hepatitis caused by the newer amine-oxidaseinhibiting drugs. Lancet 1961; 2: 621-23.
3. Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on
the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 493-8.
4. Baker GB, Coutts RT, McKenna KF, et al. Insights into the mechanisms of action of the
MAO inhibitors phenelzine and tranylcypromine: a review. J Psychiatry Neurosci
1992;17:206-14
5. Prokai-Tatrai K, Pop E, Anderson W, et al. Redox derivatives of tranylcypromine:
syntheses, properties, and monoamine oxidase inhibitor activity of some chemical
delivery systems. J Pham Sci 1991;80:255-61
6. Fowler CJ, Mantle TJ, Tipton KF. The nature of the inhibition of rat liver monoamine
oxidase types A and B by the acetylenic inhibitors clorgyline, I-deprenyl and
pargyline. Biochem Pharmacol. 1982;31:3555-61
7. Li AP, Lu C, Brent JA, et al. Cyropreserved hyman hepatocytes: characterization of
drug-metabolizing enzyme activities and applications in higher throughput screening
assays for hepatotoxicity, emtabolic stability, and drug-drug interaction potential.
Chem Biol Interact. 1999;121:17-35
8. Yard and McKennis. Effect of structure of the ability of hydrazino compounds to
produce fatty livers. J Pharmacol Exp Ther. 1955;114:391-7
9. https://livertox.nih.gov/Tranylcypromine.htm
10. https://pubchem.ncbi.nlm.nih.gov/compound/tranylcypromine#section=Substancesby-Category
Questions:
- Altitude of ALT/AST elevations: diagnostic discriminative?
 international expert group proposed following thresholds for diagnosis of DILI
(drug-induced liver injury) (1):
o ALT >5xULN (upper limit of normal)
o ALP>2x ULN
- Our casus has also elevated AP, GGT and LDH: what is the significance of this?
o In book of prof Gouw: TCP causes combined cholestatic and
hepatocellular injury.. In Zimmerman: only hepatocellular.
- Maybe pre-existing NASH, with an exacerbation due to medication?
- How long was our patient taking statins also known to increase liver enzymes..
1. Kullak-Ublick GA, Andrade RJ, Merz M, et al. Drug-induced liver injury: recent advances in
diagnosis and risk assessment. Gut 2017;66:1154-1164
Download
Random flashcards
fff

2 Cards Rick Jimenez

Create flashcards