ALUMINUM HYDROXIDE

김윤영

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

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

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.

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

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-)).

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

유통중인 ALUMINUM HYDROXIDE

가스민에프정 Aluminum hydroxide gel 450mg

뉴란타 Aluminum hydroxide gel 250g Chlorhexidine acetate 0.003g +Magnesium hydroxide 400mg

다겔정 (건조수산화알루미늄겔)

Aluminum hydoxide gel 300mg

메빌정 Aluminum hydoxide gel 250mg

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.

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)

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.

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.

Magnitude of teratogenic risk to child born after exposure during gestation

: UNDETERMINED

Quality and quantity of data on which risk estimated is based

: LIMITED

TERATOGENICITY

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)

ALUMINUM

not occur free in its metallic form in nature

it exists naturally combined with fluorine, silicon, oxygen and

other substances in the earth's crust

(Bingham et al, 2001; HSDB , 2001; Lewis, 1997)

It often occurs as an oxide and combined with silica (Budavari, 1996)

Soy-based infant formulas may contain a mean aluminum

content of 1,478 mcg/L

should probably not be used in infants with renal impairment

or in low-birth-weight infants (Committee on 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)

ALUMINUM SALT % ELEMENTAL ALUMINUM

Aluminum hydroxide 34.58

Aluminum oxide 52.91

Aluminum phosphate 22.12

Bismuth aluminate 20.97

Dihydroxy aluminum carbonate 18.74

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).

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.

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

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.

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).

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

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

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.

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.

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.

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.

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

Control

Age, gravity

Co-exposure to other madicine

Other relevant co-exposures

Alcohol, cigarette smoking, X-ray

Outcome

Spontaneous abortion

Live births

Gestational age at delivery(weeks)

Birth weight(g)

Low birth weight (>2500g)

Preterm births(<37weeks)

Major malformations

Minor malformations

Chromosomal abnormalities

Major malformation :abnormality of structure, function, metabolism present at birth that may result in physical, mental, social disabilities or death

Minor malformation : defects with limited medical, mental, or social malformation

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

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)

감사합니다.

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.