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 HEM-ORRHAGE

Common causes of intravesical (bladder) hemorrhage : bladder or prostate cancer, radiation cystitis, cyclophosphamide-induced cysti-tis, and intravesical Bacillus Calmette-Guerin (BCG) immunother-apy 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 re-duces 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 for-mula

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 wa-ter 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)6

3+ (hexaaquaa-luminium(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 re-

lease 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 250gChlorhexidine acetate 0.003g+Magnesium hydrox-ide 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 pro-gression.

Multiple epidemiological studies have found no connection be-tween exposure to aluminium and neurological disorders.

In 2007, tests in mice of the anthrax vaccine using aluminium hy-droxide 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 in-creases the solubility of the aluminum.

(Colomina et al., 1992)

TERATOGENICITY

The coadministration of citrate with aluminum hydroxide, to pro-mote the absorption of aluminum, did not increase the incidence of malformations among exposed rats, but it did increase the inci-dence 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 skele-tal growth, and impaired learning, memory, and neuromotor devel-opment in treated offspring.

TERATOGENICITY In a case report from 1998, the mother of a 9-year-old girl

with profound mental retardation, multifocal seizures, spas-tic tetraplegia, growth retardation, and spasticity (cerebral cortical atrophy and neurological dysfunction) was found to have used an average of 15,000 mg of aluminum hy-droxide per day throughout pregnancy, implicating aluminum intoxication as a possible cause of the neuro-logical 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 admin-istered 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 par-enteral nutrition with aluminum-contaminated solu-tions (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 alu-

minum toxicity, either from aluminum in the dialysate or other exogenous sources, especially aluminum-containing phosphate binders and antacids. Signs and symptoms may include de-mentia, memory loss, aphasia, ataxia, seizures, altered EEG and osteomalacia.

Chronic exposure to aluminum dust may cause dyspnea, cough, pulmonary fibrosis, pneumothorax, pneumoconiosis, encephalopa-thy, weakness, incoordination and epileptiform seizures.

HEENT: Eye: innocuous Aluminum salts : may cause eye irritation. mucous mem-

branes, conjunctivitis, dermatoses, and eczema. CARDIOVASCULAR

Cardiac hypertrophy may occur in chronic hemodialysis pa-tients with aluminum accumulation.

RESPIRATORY Pulmonary fibrosis, asthma, COPD, chronic interstitial pneumo-

nia, 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, sub-

sternal pain, weakness and fatigue; spontaneous pneumoth-orax is a frequent complication.

Autopsy findings include emphysema and interstitial pul-monary 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 alu-minum 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 constipa-

tion.

HEPATIC Linked to liver disorder. Aluminum-induced osteomalacia was reported in pa-

tients with liver failure who were taking aluminum con-taining antacids.

GENITOURINARY The dialysis encephalopathy syndrome in patients with

renal failure. Renal failure patients may also develop renal os-

teodystrophy and a type of microcytic anemia as ef-fects of aluminum toxicity.

HEMATOLOGIC Microcytic anemia may present as an effect of aluminum

toxicity.

DERMATOLOGIC Dermatitis, irritation, delayed hypersensitivity, telangiec-

tases 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, frac-tures and crippling deformities. Aluminum may contrib-ute 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 malforma-tions. Other toxicity of aluminum may occur if a sufficient amount is absorbed.

Study design

Case : 임신중 (1st trimester) aluminum hydroxide 에 노출된 산모 271 대상 Estimate the gestational age at expose Estimate the time and dose of exposure to

aluminum hydroxide demographic information, medical, obstet-

ric history, details of any concomitant ex-posure

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 be-

tween 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 deferoxam-ine with symptomatic relief of dialysis en-cephalopathy and osteomalacia and alu-minum-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 tis-sues.