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Isoniazid associated pn
1.
2. Introduction
• INH, a synthetic hydrazide derivative of
isonicotinic acid, was introduced in 1952 for
the treatment of TB
• INH typically causes a sensory-predominant
PN with prominent tingling and paresthesiae
• In isolated cases sensory symptoms have
progressed rapidly with the development of
ataxia and weakness
3. • Although these findings typically reverse
within a few weeks of drug withdrawal, the
longer the symptoms are present without
intervention the longer they may take to
regress
4. Pharmacology and genetics
• INH is rapidly absorbed after oral
administration with peak plasma levels
occurring within 1–2 h, and it readily crosses
cell membranes
• INH is metabolised and inactivated in the liver
by an acetylation process that is under the
genetic control of a polymorphic arylamine N-
acetyltransferase type 2 (NAT2) locus
5. • Several combinations of slow acetylator alleles
may give rise to the slow acetylation
phenotype.
• Correlative studies between NAT2 genotypes
and INH pharmacokinetics have shown that
INH plasma concentrations are higher (up to
six-fold at short intervals) in those subjects
homozygous for low-activity alleles
6. • The rate of acetylation is therefore a critical
determinant of both therapeutic efficacy and toxicity,
with slow acetylators being more susceptible to toxicity
but also more likely to benefit
• In most European Caucasian populations, the
proportions of slow and fast acetylators are equal,
whereas in Alaskan Inuits the majority (95%) are fast
acetylators, Saudi Arabians are generally slow
acetylators (95%),and indigenous Africans have
approximately 59% fast and 41% slow acetylators.
7. Risk factors
• The risk of PN is related to the dose of INH used.
• 2–12% of patients treated with low or standard
dosages of 3–5 mg/kg/ day compared to 44% of
those receiving 16–24 mg/kg/day develop PN
symptoms
• PN among TB-HIV co-infected subjects receiving
standard doses of INH appears to be four-fold
higher than among those without concomitant
HIV infection on similar dose
9. Time of onset
• The time from drug initiation to onset of
neuropathic symptoms also appears to correlate
with the dose of INH: higher doses (>10
mg/kg/day) are likely to cause symptoms within
3–5 weeks, whereas symptoms associated with
doses of 3–5 mg/kg/day appeared to be delayed
for 16 weeks, with or without HIV co-infection.
• Children do not appear as susceptible to this
complication as adults, tolerating doses of up to
10 mg/kg for longer periods of time without
developing PN
10. Pyridoxine and the mechanism of INH-
associated PN Pyridoxine metabolism
• Humans cannot synthesise pyridoxine (vitamin
B6), and must therefore obtain this micronutrient
from exogenous sources via intestinal absorption
• Vitamin B6 naturally appears in three forms:
pyridoxine, pyridoxal and pyridoxamine.
• They are enzymatically interconvertible, and are
all phosphorylated to pyridoxal-5-phosphate
(PLP) via a phosphokinase (pyridoxal kinase)
dependent on adenosine triphosphate, which is
abundant in all tissues
11. • PLP and pyridoxal are the main circulating
forms, but they require dephosphorylation for
tissue uptake from the circulation.
• Plasma PLP levels are reduced in celiac
disease, infl ammatory bowel disease,
rheumatoid arthritis, renal disease and
patients on anti-tuberculosis treatment that
includes INH
12. The mechanism of INH-induced
pyridoxine defi ciency
• Sixty years ago, it was recognized that INH neuropathy was
related to a deficiency in biologically active pyridoxine.
• The excretion of urinary pyridoxine doubled during INH
treatment, which suggested that INH combines with
pyridoxine to form a hydrazone that is excreted in the
urine.
• Although the capacity of pyridoxine to form true
hydrazones with INH is still being debated, it is accepted
that INH forms a complex with pyridoxine, resulting in
increased pyridoxine excretion
• inhibitory effect of INH on pyridoxine dependent enzyme
systems
13. • The most widely supported view holds that INH
combines with PLP via the Schiff base
condensation between the aldehyde group of PLP
and the free amine group of INH to form
pyridoxal isonicotinoyl hydrazone
• This irreversible reaction prevents the utilisation
of pyridoxal by nerve tissue
• INH inhibits phosphorylation of pyridoxine by
inhibiting the enzyme pyridoxal kinase, thereby
reducing PLP production
14. • PLP represents an essential enzyme for energy production
supplying metabolites to the Krebs tricarboxylic cycle.
• Function and activity of nervous tissue depend almost
exclusively upon energy derived from oxidative metabolism
of glucose.
• When energy supplies fail, dysfunction and permanent
structural damage rapidly follow principally that of an
axonopathy with Wallerian degeneration and regeneration
of both myelinated and unmyelinated fibres
• The exact mechanism whereby pyridoxine defi ciency
causes PN is, however, unclear
15. Prevention of INH-associated PN
• There remains tremendous variability in the
recommendations regarding pyridoxine
prophylaxis and therapy in the context of INH
treatment
• South African guidelines, in particular, do not
recommend prophylaxis without evidence of
risk factors
16.
17. Pyridoxine toxicity
• Vitamins of the B family are water-soluble, and
excessive intake is generally innocuous as they
are eliminated in the urine
• Despite historic hyper vigilance towards B6
toxicity and differences among supplementation
guidelines, there is no evidence to suggest a risk
of toxicity with recommended dosages for INH
induced PN.
• Safe levels of daily intake are approximately 100
times the RDA