김윤영 Aluminum hydroxide
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 heartburnor 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 transcapillarymovement 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
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
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 aluminiumcompared 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 variationswere 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.
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
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/daythat 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, 1999Spain)
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).
ALUMINUM • Aluminum is renallyexcreted • 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 osteomalaciawas 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 osteodystrophyand a type of microcytic anemiaas 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 osteomalaciathat 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
Major malformation :abnormality of structure, function, metabolism present at birth that may result in physical, mental, social disabilities or death • 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 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
TREATMENT OVERVIEW • CHELATION - Aluminum intoxication may be treated with the chelating agent deferoxaminewith 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.