DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1862 type (ATSDR, 2007b; Levin et al., 2008). Blood lead levels in the
general population have steadily decreased since the 1970s. Between
1976 and 2002, mean blood levels in children 1-5 years of age
dropped from 15-1.9 μg/dL. The Centers for Disease Control and
Prevention (CDC) recommends screening of children at 6 months
of age and the use of aggressive lead abatement for children with
blood lead levels >10 μg/dL.
Occupational exposure to lead also has decreased markedly
because of protective regulations. Occupational exposure generally
is through inhalation of lead containing dust and lead fumes.
Workers in lead smelters and in storage battery factories are at the
greatest risk for lead exposure because fumes are generated and dust
containing lead oxide is deposited in their environment. Other workers
at risk for lead exposure are those associated with steel welding
or cutting, construction, rubber and plastic industries, printing, firing
ranges, radiator repair shops, and any industry where lead is
flame soldered (ATSDR, 2007b).
SECTION IX
SPECIAL SYSTEMS PHARMACOLOGY
Chemistry and Mode of Action. Lead exists in its metallic form and as
divalent or tetravalent cations. Divalent lead is the primary environmental
form; inorganic tetravalent lead compounds are not naturally
found. Organo-lead complexes primarily occur with tetravalent lead
and include the gasoline additive tetraethyl lead.
Lead toxicity results from molecular mimicry of other divalent
metals (Garza et al., 2006). Lead takes the place of zinc or calcium
in a number of important proteins. Because of its size and
electron affinity, lead alters protein structure and can inappropriately
activate or inhibit protein function. Specific molecular targets
for lead are discussed below.
Absorption, Distribution, and Excretion. Lead exposure occurs
through ingestion or inhalation. GI absorption of lead varies considerably
with age and diet. Children absorb a much higher percentage
of ingested lead (~40% on average) than adults (<20%).
Absorption of ingested lead is drastically increased by fasting.
Dietary calcium or iron deficiencies increase lead absorption, suggesting
that lead is absorbed through divalent metal transporters.
The absorption of inhaled lead generally is much more efficient
(~90%), particularly with smaller particles. Tetraethyl lead is readily
absorbed through the skin, but this is not a route of exposure for
inorganic lead.
About 99% of lead in the bloodstream binds to hemoglobin.
Lead initially distributes in the soft tissues, particularly in the tubular
epithelium of the kidney and the liver. Over time, lead is redistributed
and deposited in bone, teeth, and hair. About 95% of the adult
body burden of lead is found in bone. Growing bones will accumulate
higher levels of lead and can form lead lines visible by radiography.
Bone lead is very slowly reabsorbed into the bloodstream, except
when calcium levels are depleted, such as during pregnancy. Small
quantities of lead accumulate in the brain, mostly in gray matter and
the basal ganglia. Lead readily crosses the placenta.
Lead is excreted by humans primarily in the urine, although
there also is some biliary excretion. The concentration of lead in
urine is directly proportional to its concentration in plasma, but
because most lead is in erythrocytes, only a small quantity of total
lead is removed by filtration. Lead is excreted in milk and sweat and
deposited in hair and nails. The serum t 1/2
of lead is 1-2 months, with
a steady state achieved in ~6 months. Lead accumulates in bone,
where its t 1/2
is estimated at 20-30 years.
Health Effects. Although the effects of high-dose lead
poisoning have been known for >2000 years, the
insidious toxicities of chronic low-dose lead poisoning
(blood lead <20 μg/dL) have only recently been discovered.
Although lead is a nonspecific toxicant, the
most sensitive systems are the nervous, hematological,
cardiovascular, and renal systems (Figure 67–4).
Uncovering the effects of low-level lead exposure on
complex health outcomes, such as neurobehavioral
function and blood pressure, has been the subject of
extensive research.
Neurotoxic Effects. The biggest concerns with low-level
lead exposure are cognitive delays and behavior
changes in children (ATSDR, 2007b; Bellinger and
Bellinger, 2006). The developing nervous system is
very sensitive to the toxic effects of lead.
Lead interferes with the pruning of synapses, neuronal
migration, and the interactions between neurons
and glial cells. Together, these alterations in brain
development result in decreased IQ, poor performance
on exams, and behavioral problems such as distractibility,
Succinyl CoA + Glycine
δ-Aminolevulinate (δ-ALA)
Porphobilinogen
Uroporphyrinogen III
Coproporphyrinogen III
Protoporphyrin IX
Heme
δ-aminolevulinate synthase
δ-aminolevulinate dehydratase
porphobilinogen deaminase
uroporphyrinogen III cosynthase
uroporphyrinogen decarboxylase
coproporphyrinogen oxidase
ferrochelatase + Fe 2+
Action produced by lead:
Inhibition
Postulated inhibition
Figure 67–4. Heme biosynthesis and actions of lead. Lead interferes
with the biosynthesis of heme at several enzymatic steps.
Steps that definitely are inhibited by lead are indicated by red
blocks. Steps at which lead is thought to act but where evidence
is inconclusive are indicated by pink blocks.