1. ALUMINUM HYDROXIDE
김윤영

2. ALUMINUM HYDROXIDE IN PEPTIC ULCER DISEASE
 MECHANISM
 Aluminum hydroxide : direct cytoprotective effect
 The exact mechanism of action is UNCLEAR.
 The drug binds to and forms an adherent complex with protein
in the ulcer base, thus inhibiting further acid-pepsin digestion.
 It also forms complexes with pepsin and stimulates endogenous
prostaglandin synthesis in the mucosa
 Help to relieve the symptoms of heartburn or dyspepsia

3. ALUMINUM HYDROXIDE IN PEPTIC ULCER DISEASE
 EFFICACY : healing rate for duodenal ulcer
 Sucralfate 75% at 4 wks, 90-95% at 8 wks
 Ranitidine 85% at 4 wks, 90-95% at 8 wks
 The agent can also prevent ulcer recurrence when given 1 gm BID
 Single doses usually provide 200-1200 mg of aluminum hydroxide
 The amount of aluminum hydroxide in various antacid preparations
varies greatly, and doses as high as 12,000 mg/d may be taken in
extreme cases.
 orally as an antacid
 Combination with magnesium hydroxide, magnesium carbonate,
calcium carbonate, and/or simethicone.
 Commonly cause constipation

4. ALUM IRRIGATION THERAPY OF BLADDER HEMORRHAGE
 Common causes of intravesical (bladder) hemorrhage : bladder or
prostate cancer, radiation cystitis, cyclophosphamide-induced
cystitis, and intravesical Bacillus Calmette-Guerin (BCG)
immunotherapy of transitional cell carcinoma
 Intravesical alum
 Tissue contraction and blanching, which produces tamponade of
bleeding vessels.
 Hardening of the cement substance of capillary endothelium,
which inhibits transcapillary movement of plasma protein and
reduces local edema, inflammation and exudation.
 Alum is minimally absorbed.
 More serious side effects such as encephalopathy may result
when an instillation rate of 3 grams or more per hour is employed
in renally-impaired patients.

5. ALUMINUM HYDROXIDE
 Al(OH)3, ATH, Hydrate of alumina
 Insoluble forms of aluminum
Properties
Molecular formula Al(OH)3
Molar mass 78.00 g/mol
Appearance White amorphous powder
Density 2.42 g/cm³, solid
Melting point 300 °C, 573 K, 572 °F
solubility in water 0.0001 g/100 mL (20 °C)
Solubility soluble in acids, alkalis, HCl, H2SO4
Acidity(pKa) >7

6. CHEMISTRY
 Amphoteric
 It dissolves in acid, forming Al(H2O)63+
(hexaaquaaluminium(3+)) or its hydrolysis
products.
 It also dissolves in strong alkali, forming Al(OH)4-
(tetrahydroxidoaluminate(1-)).

7. USE
 Antacids, antiperspirants, dentifrices
 Included as an adjuvant in some vaccines (e.g. anthrax
vaccine)
 Stimulates the immune system by inducing the
release of uric acid, an immunological danger signal.
 In a mouse model of allergen sensitization during
pregnancy
 Aluminum hydroxide is also widely used in the chemical,
pharmaceutical, fabric, paper, glass, pottery, and
printing industries.
: Fire retardant, polyesters, acrylics,
ethylene vinyl acetate, epoxies, PVC, rubber

8. 유통중인 ALUMINUM HYDROXIDE
가스민에프정 Aluminum hydroxide gel
450mg
뉴란타 Aluminum hydroxide gel 250g
Chlorhexidine acetate 0.003g
+Magnesium hydroxide
400mg
다겔정 Aluminum hydoxide gel
300mg
(건조수산화알루미늄겔)
메빌정 Aluminum hydoxide gel
250mg

9. ADVERSE EFFECTS
 Adverse effects in humans resulting from the use of aluminium
hydroxide adjuvants have not been proven, although it has been
a subject of controversy.
 Brain lesions found in Alzheimer's disease sometimes contain
more aluminium compared to normal tissue.
 It is not thought that aluminium causes Alzheimer's, but rather that
once the disease develops, aluminium may be involved in its
progression.
 Multiple epidemiological studies have found no connection
between exposure to aluminium and neurological disorders.
 In 2007, tests in mice of the anthrax vaccine using aluminium
hydroxide adjuvant were reported as resulting in adverse
neuropathy symptoms.

10. TERATOGENICITY
 The frequency of malformations was not increased among the
offspring of pregnant rats or mice given 192-768 mg/kg/d or 66.5-
300 mg/kg/d of aluminum hydroxide
 Respectively Decreased fetal weight and increased frequencies
of skeletal variations were seen among the offspring of pregnant
rats given 384 mg/kg/d of aluminum hydroxide and also citric acid,
which promotes absorption of aluminum, but maternal toxicity
was evident under these conditions.
(Gomez et al., 1991)
 Similarly, decreased fetal weight was seen along with evidence of
maternal toxicity when pregnant mice were treated with 166
mg/kg/d of aluminum hydroxide and also with lactic acid, which
increases the solubility of the aluminum.
(Colomina et al., 1992)

11. TERATOGENICITY
 The coadministration of citrate with aluminum hydroxide, to
promote the absorption of aluminum, did not increase the
incidence of malformations among exposed rats, but it did
increase the incidence of developmental variations and
fetotoxicity.
 As was suggested by the data in this report, other animal studies
indicate that parenterally administered aluminum from various
aluminum salts can cross the placenta and accumulate in fetal
tissues. These exposures have been associated with an increase
in fetal death and reabsorptions in rats, as well as abnormal skeletal
growth, and impaired learning, memory, and neuromotor
development in treated offspring.


12. TERATOGENICITY
 In a case report from 1998, the mother of a 9-year-old girl with
profound mental retardation, multifocal seizures, spastic tetraplegia,
growth retardation, and spasticity (cerebral cortical atrophy and
neurological dysfunction) was found to have used an average of
15,000 mg of aluminum hydroxide per day throughout pregnancy,
implicating aluminum intoxication as a possible cause of the
neurological dysfunction in the child.
(Gilbert-Barness et al., 1998)
 In a review of mice, rat, and rabbit studies, Borak and Wise
question whether dietary aluminum exposure will lead to significant
accumulation in pregnant animals or their fetuses.
 It is important to note that in most studies, adverse developmental
effects of aluminum have not been associated with orally
administered aluminum.

13. TERATOGENICITY
 Magnitude of teratogenic risk to child born
after exposure during gestation
: UNDETERMINED
 Quality and quantity of data on which risk
estimated is based
: LIMITED

14. ALUMINUM
 Ubiquitous distribution
 The most abundant metal in the earth's crust
(Baselt, 2000; Lewis, 1997)
 Sources of exposure are constant through dust
particles and ingestion of food and water.
 Aluminum has one naturally occurring isotope: Al(27).
In addition, ten radioactive isotopes are known
(Budavari, 1996)
 Absorption of aluminum through the skin is insignificant.
An average adult is estimated to absorb 15 mcg (0.3 to
0.5 %) of the 5 mg/day that is taken in from the
environment
(Committee on Nutrition, 1986)

15. ALUMINUM
 not occur free in its metallic form in nature
 it exists naturally SALT
ALUMINUM combined with fluorine, silicon, ALUMINUM
% ELEMENTAL oxygen and
other substances in the earth's crust
(Bingham et al, 2001; HSDB , 2001; Lewis, 1997)
Aluminum hydroxide 34.58
 It often occurs as an oxide and combined with silica (Budavari,
Aluminum oxide 52.91
1996)
Soy-based infant formulas may contain a mean22.12
 Aluminum phosphate aluminum
content of 1,478 mcg/L
Bismuth aluminate 20.97
 should probably not be used in infants with renal impairment
Dihydroxy aluminum carbonate (Committee on 18.74
or in low-birth-weight infants Nutrition, 1986).
 aluminum content was lowest in breast milk (23.4 +/- 9.6 mcg/L)
 cows milk was 70 mcg/L
 reconstituted infant formulas was 226 mcg/L, with wide
variation (302 to 1,149 mcg/L) in aluminum content
(Fernandez-Lorenzo et al, 1999 Spain)

16. ALUMINUM-DIETARY SOURCES
 present in most foods and is used in food packaging
 intake may range from 4 to 80 mg/day (Baselt, 2000).
 found in a number of commercial teas.
: One study found between 555 and 1,009 mcg Al per gram (dry weight)
the absorption of aluminum from tea may be very low.

 The main dietary source of aluminum is food additives.
 Food preparation and storage, including soft drink
packaging in aluminum cans, contributes little aluminum to
the diet. Preparation of acidic foods in aluminum cookware
can increase their aluminum content (Muller et al, 1993).

17. ALUMINUM
 WITH POISONING/EXPOSURE
 Acute aluminum toxicity is unlikely.
 Most cases of aluminum toxicity in humans are in one of two
categories:
 Patients with chronic renal failure
 People exposed to aluminum in the workplace
 Soluble forms of aluminum
 Aluminum chloride AlCl(3+), aluminum fluoride AlF(3), aluminum
sulfate (Al(SO4)3), aluminum citrate (AlC(6)H(8)O(7))
 Greater potential for toxicity than , due to their greater absorption
 Insoluble forms (such as aluminum hydroxide (AlOH(3)).
 Insoluble forms of aluminum are poorly absorbed from the
gastrointestinal tract.

18.  Aluminum accumulation may occur in individuals with normal renal
function and who receive chronic parenteral nutrition with
aluminum-contaminated solutions (Klein, 1995).
ADDITIVES & SOLUTIONS MEAN ALUMINUM
CONTENT (mcg/L)
Albumin 5% 486
Albumin 25% 1161-1647
Ca gluconate 10% 270-5056
Heparin 1000 units/Ml 684
Potassium phosphate 1890-16,598
Sodium phosphate 54-5994

19. ALUMINUM
 Aluminum is renally excreted
 Patients with renal failure are prone to aluminum toxicity,
either from aluminum in the dialysate or other exogenous
sources, especially aluminum-containing phosphate binders
and antacids. Signs and symptoms may include dementia,
memory loss, aphasia, ataxia, seizures, altered EEG and
osteomalacia.
 Chronic exposure to aluminum dust may cause dyspnea,
cough, pulmonary fibrosis, pneumothorax, pneumoconiosis,
encephalopathy, weakness, incoordination and epileptiform
seizures.

20.  HEENT:
 Eye: innocuous
 Aluminum salts : may cause eye irritation. mucous membranes, conjunctivitis,
dermatoses, and eczema.
 CARDIOVASCULAR
 Cardiac hypertrophy may occur in chronic hemodialysis patients with
aluminum accumulation.
 RESPIRATORY
 Pulmonary fibrosis, asthma, COPD, chronic interstitial pneumonia, sarcoid-
like lung granulomatosis, dyspnea, cough and pneumothorax may occur after
chronic inhalation.
 SHAVER'S DISEASE –
 This illness is caused by industrial exposure to aluminum fumes or dust
 Respiratory distress and fibrosis with large blebs.
 Symptoms include productive coughing and wheezing, substernal pain,
weakness and fatigue; spontaneous pneumothorax is a frequent
complication.
 Autopsy findings include emphysema and interstitial pulmonary fibrosis.
Silicon is often inhaled with the aluminum, and the function of each of
these elements is as yet unclear
(Bingham et al, 2001; Hammond & Beliles, 1980; Harbison, 1998).

21.  NEUROLOGIC
 Dialysis encephalopathy syndrome (DES)
 The most widely recognized and probably the most severe
manifestation of aluminum toxicity.
 DES usually requires serum aluminum levels above 100 mcg/L.
 DES was originally secondary to high levels of aluminum in
dialysate, mainly in dialysis therapy using softened or untreated
water.
 Reduction in the aluminum content to 0.4 micromol/L (10 mcg/L) or
less resulted in prevention.
 Moreover, the switch to aluminum-free phosphate binders (such as
calcium carbonate) to treat patients with chronic renal failure has
also decreased their per oral aluminum exposure
 Clinical features of 'dialysis dementia
 Memory loss, include speech and language impairment
 epileptic seizures (focal or grand mal), motor disturbance ,
dementia

22.  NEUROLOGIC
 linked to the histopathology of Alzheimer disease.
 Alzheimer disease : illness with deterioration of mental functions
related to memory, judgment and abstract thinking, plus
personality/behavior changes.
 The distinctive pathohistological features : neurofibrillary tangles,
senile plaques and amyloid deposits. According to some sources,
aluminum is linked to these senile plaques and amyloid deposits.
 Increased concentrations of aluminum have been found in the
brain tissue of patients with Alzheimer disease.
 It is still unclear whether aluminum is involved etiologically in this
disease or exists merely as a marker of some other
pathophysiologic process.
 Occupational exposure to aluminum has been associated with
cognitive deficits and delayed reaction times

23.  GASTROINTESTINAL
 Chronic aluminum hydroxide use may cause constipation.
 HEPATIC
 Linked to liver disorder.
 Aluminum-induced osteomalacia was reported in patients with liver
failure who were taking aluminum containing antacids.
 GENITOURINARY
 The dialysis encephalopathy syndrome in patients with renal failure.
 Renal failure patients may also develop renal osteodystrophy and a
type of microcytic anemia as effects of aluminum toxicity.
 HEMATOLOGIC
 Microcytic anemia may present as an effect of aluminum toxicity.

24.  DERMATOLOGIC
 Dermatitis, irritation, delayed hypersensitivity, telangiectases and
granulomas may occur from dermal contact with aluminum.
 MUSCULOSKELETAL
 Aluminum-related bone disease is a progressive form of
osteomalacia that can lead to severe bone pain, fractures and
crippling deformities. Aluminum may contribute to dialysis-
associated arthropathy.
 ENDOCRINE
 May decrease parathyroid hormone secretion.

25. RANGE OF TOXICITY
 TLV (Al metal/Al oxides) - 10 mg/m.
 Reported oral animal LD50 values
 0.1 g/kg for aluminum fluoride
 1 to 4 g/kg for aluminum chloride
 6 g/kg for aluminum sulfate.
 LABORATORY/MONITORING
 The most common method used for measuring aluminum in
serum, water and dialysate is graphite furnace atomic absorption.

26. ALUMINUM HYDROXIDE
 Quick take: Based on experimental animal studies,
aluminum hydroxide is not expected to increase the risk
of congenital malformations. Other toxicity of aluminum
may occur if a sufficient amount is absorbed.

27. Study design
 Case : 임신중(1st trimester) aluminum hydroxide
에 노출된 산모 271대상
 Estimate the gestational age at expose
 Estimate the time and dose of exposure to aluminum
hydroxide
 demographic information, medical, obstetric history,
details of any concomitant exposure
 Co-exposure to other medication
 Other relevant co-exposure

28.  Control
 Age, gravity
 Co-exposure to other madicine
 Other relevant co-exposures
 Alcohol, cigarette smoking, X-ray

29. Major malformation
 Outcome :abnormality of structure,
function, metabolism present at
 Spontaneous abortion birth that may result in physical,
mental, social disabilities or death
 Live births
 Gestational age at delivery(weeks)
 Birth weight(g)
 Low birth weight (>2500g)
 Preterm births(<37weeks) Minor malformation
: defects with limited medical,
 Major malformations mental, or social malformation
 Minor malformations
 Chromosomal abnormalities

30.  Data analysis
 Continuous variables were compared between
groups by Student t test.
 Categorical variables including rate of minor and
major malformation, were compared between
groups by means of a Fisher;s exact test
 Value of p <0.05 : statistically significant

31. Age(years) (mean±SD) 30.0±3.6
Gravity (n) (mean±SD) 2.0±1.3
Exposure to Aluminum hydroxide(median range)
gestational age at expose(weeks)
Dose(mg/day)
Duration of exposure(day)
Co-exposure to other medication (n)

32.  감사합니다.

34. TREATMENT OVERVIEW
 CHELATION - Aluminum intoxication may be
treated with the chelating agent deferoxamine
with symptomatic relief of dialysis
encephalopathy and osteomalacia and
aluminum-induced anemia.
 ENHANCED ELIMINATION - Hemodialysis,
hemofiltration, and peritoneal dialysis will
reduce SERUM aluminum. This may not effect
the total body burden of aluminum unless
aluminum has been mobilized from the tissues.