PHARMACOLOGY: DEFINITION: CHRONIC BRONCHITIS: CLINICAL USE:

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1 1 PHARMACOLOGY: HSCH2CH(NHCOCH3)COOH Crystals with a melting point of C; used as a mucolytic drug. DEFINITION: Acetylcysteine, also known as N- acetylcysteine (abbreviated NAC), is a pharmacological agent used mainly as a mucolytic and in the management of Paracetamol overdose. NAC (N-Acetyl-Cysteine) is a precursor of glutathione in the body. This valuable glutathione precursor boosts cellular antioxidant protection. This sulfur-containing compound, derived from the amino acid cysteine, can serve as a nutritional substrate for synthesis of intercellular glutathione, an important antioxidant. Unlike cysteine, NAC is virtually nontoxic and is the preferred nutrient for enhancing glutathione levels inside cells. Take with multi-vitamins and minerals for maximum benefit. CLINICAL USE: Evidence suggests that regular use of N-acetyl-cysteine (NAC) is helpful for individuals with chronic bronchitis, a condition commonly associated with smoking and emphysema. NAC is a natural expectorant which help thin mucus and loosen phlegm and bronchial secretions. also be helpful in a life-threatening condition called acute respiratory distress syndrome. Very preliminary evidence indicates that NAC may help prevent colon cancer and slow the progression of Alzheimer's disease. NAC is often used by people with HIV in hopes of enhancing immune function. CHRONIC BRONCHITIS: Individuals who have smoked cigarettes for many years eventually develop deterioration in their lungs leading to various symptoms, including chronic production of thick mucus. This socalled chronic bronchitis tends to flare up periodically into severe acute attacks possibly requiring hospitalization. Regular use of NAC may diminish the number of these attacks. A review and meta-analysis selected eight doubleblind placebo-controlled trials of NAC for chronic bronchitis. 1-9 The results of these studies, involving a total of about 1,400 individuals, suggest that NAC taken daily at a dose of 400 to 1,200 mg can reduce the number of acute attacks of severe bronchitis. Mixed evidence suggests that NAC may be helpful for people who take the drug nitroglycerin for angina. NAC may

2 2 CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD): A chronic lung disease, such as asthma or emphysema, in which breathing becomes slowed or forced. CAUSES: The main risk factor in the development of COPD is smoking. Approximately 15% of all chronic smokers will develop the disease. In susceptible people, this causes chronic inflammation of the bronchi and eventual airway obstruction. Other etiologies include: Alpha 1-antitrypsin deficiency (augmented by smoking) Byssinosis Idiopathic disease COPD can also be caused by prolonged exposure to certain dusty environments. For example, many people develop COPD after working in the coal mining industry and being exposed to high levels of respirable coal dust. Among people over 70 who have never smoked, women make up 85 percent of those with COPD. This appears to be tied to decreases in estrogen as women age. Female mice that had their ovaries removed to deprive them of estrogen lost 45 percent of their working alveoli from their lungs. Upon receiving estrogen, the mice recovered full lung function. Two proteins that are activated by estrogen play distinct roles in breathing. One protein builds new alveoli, the other stimulates the alveoli to expel carbon dioxide. Loss of estrogen hampered both functions in the test mice. (Massaro & Massaro, 2004). ANGINA PECTORIS: One 4-month double-blind placebocontrolled study of 200 individuals with heart disease found that the combination of nitroglycerin and NAC significantly reduced the incidence of heart attacks and other severe heart problems.10 NAC alone and nitroglycerin alone were not as effective. The only problem was that the combination of nitroglycerin and NAC caused severe headaches in many participants. MUCOLYTIC THERAPY: MUCOLYTIC AGENT: A mucolytic agent is any agent which dissolves thick mucus to help relieve respiratory difficulties. (Hydrolyzing glycosaminoglycans: tending to break down/lower the viscosity of mucincontaining body secretions/components).

3 3 Cysteine, which is available as the over-the-counter supplement N- acetylcysteine (NAC), is known to assist in processing acetaldehyde, best taken while already drinking and/or before going to bed. N-acetylcysteine (NAC) is known to assist in processing acetaldehyde in the body and therefore can help to relieve hangover symptoms. Acetylcysteine taken together with vitamin C and B1 can be used to prevent and relieve symptoms of Veisalgia. The claimed mechanism is through scavenging of acetaldehyde, a toxic intermediate in the metabolism of ethanol. N.B. Egg yolk is also rich in cysteine, and it is notable that many hangover folk remedies or morningafter breakfasts incorporate eggs. COLON CANCER PREVENTION: A preliminary double-blind placebocontrolled study of NAC enrolled 62 individuals, each of whom had had a polyp removed from the colon.the abnormal growth of polyps is closely associated with the development of colon cancer. In this study, the potential anticancer benefits of NAC treatment were evaluated by taking a biopsy of the rectum. Individuals taking NAC at 800 mg daily for 12 weeks showed more normal cells in the biopsy of the tissue as compared to those in the placebo group. An antioxidant drug that may keep cancer cells from developing or reduce the risk of growth of existing cancer. HIV: Early human trials, including a double-blind study of 45 people, suggest that NAC may increase levels of CD4+ cells (a type of immune cell) in healthy people and slow CD4+ cell decline in people with HIV. It has been proposed as a supplement for patients with AIDS, who generally have decreased glutathione levels. However, it does not appear to be effective in restoring glutathione levels (Witschi et al., 1995). NEPHROPROTECTIVE AGENT: Radiocontrast agents (Contrast agents): They are compounds used to improve the visibility of internal bodily structures in an X-ray image. Some recent studies suggest that Oral N-acetylcysteine protects the kidney from the toxic effects of the contrast agent (Gleeson & Bulugahapitiya 2004). This effect is, in any case, not overwhelming. Some researchers (e.g. Hoffmann et al 2004) even claim that the effect is due to interference with the creatinine laboratory test itself. This is supported by a lack of

4 4 correlation between creatinine levels and cystatin C levels. Some studies show that prior administration of acetylcysteine markedly decreases (90%) radiocontrast nephropathy (Tepel et al 2000), while others appear to cast doubt on its efficacy (Hoffman et al., 2004; Miner et al., 2004) Nevertheless, acetylcysteine continues to be commonly used in individuals with renal impairment to prevent the precipitation of acute renal failure. PARACETAMOL OVERDOSE: MECHANISM OF TOXICITY: Paracetamol is one of the most commonly available medications. An overdose of paracetamol or acetaminophen as it is otherwise called can have deleterious side effects due to its narrow therapeutic index. The toxicity of paracetamol is related to its metabolism. In therapeutic doses, 60-90% of the drug is metabolized by conjugation to form paracetamol glucuronide and sulphate; 5-10% is oxidized by mixed function oxidase enzymes to form the toxic and highly reactive N-acetyl-pbenzoquinoneimine which is immediately conjugated with glutathione and subsequently excreted as cysteine and mercapturate conjugates. Only 1-4% of a therapeutic dose of paracetamol is excreted unchanged in the urine. When a person takes an overdose, larger amounts of the drug are metabolized by oxidation as saturation of the conjugation pathway occurs rapidly due to the large amount of the drug being metabolized. As a result the liver stores of glutathione become depleted and unable to deactivate the toxic metabolite N-acetyl-pbenzoquinoneimine, which acts as a potent oxidizing agent that depletes cellular glutathione and inactivating key enzyme sulfhydryl groups. Paracetamol is also known to induce renal damage through N-acetyl-pbenzoquinoneimine. ACETYLCYSTEINE: Intravenous acetylcysteine is indicated for the treatment of Paracetamol (acetaminophen) overdose. Oral acetylcysteine for this indication is uncommon as it is poorly tolerated owing to the high doses required (due to poor oral bioavailability), unpleasant taste/odor and adverse drug reactions (particularly nausea and vomiting). Acetylcysteine reduce paracetamol toxicity by supplying sulfhydryl groups (mainly in the form of glutathione, of which it is a precursor to react with the toxic NAPQI metabolite so that it does not damage cells and can be safely excreted. It acts to augment glutathione reserves (depleted by toxic Paracetamol metabolites) in the body and, together with glutathione to directly bind to toxic metabolites. These actions serve to protect hepatocytes in the liver from toxicity due to paracetamol overdose. If the patient presents less than 8 hours after paracetamol overdose, then acetylcysteine significantly reduces the risk of serious hepatotoxicity. If Acetylcysteine is started more than 8 hours after ingestion, there is a

5 5 sharp decline in its effectiveness because the cascade of toxic events in the liver has already begun and the risk of acute hepatic necrosis and death increases dramatically. Although Acetylcysteine is most effective if given early, it still has beneficial effects if given as late as 48 hours after ingestion. In clinical practice, if the patient presents more than 8 hours after the paracetamol overdose, then activated charcoal is probably not useful, and Acetylcysteine is started immediately. In earlier presentations the doctor can give charcoal as soon as the patient arrives, start giving Acetylcysteine, and wait for the paracetamol level from the laboratory. INSULIN RESISTANCE SYNDROME: The most common type of insulin resistance is associated with metabolic syndrome. This was first described in the 1930's by H.P. (Harry) Himsworth (University College Hospital Medical School, London). He described results of experiments in an article in 1936, entitled, "Diabetes Mellitus: Its differentiation into insulin sensitive and insulin insensitive types." He found that those with diabetes can be differentiated into two types: those in whom injected insulin produces an immediate suppression of hyperglycemia; and those in whom the insulin has little or no effect. Hyperglycemia itself can lead to insulin resistance, but N- acetylcysteine and taurine can prevent this effect. HEPATORENAL SYNDROME: A complex of syndromes due to hepatic and renal failure, including hyperpyrexia, oliguria, and coma. Also known as Hyde's syndrome. Other agents used in treatment include Pentoxifylline, Acetylcysteine and Misoprostol. It is also used post-operatively, as a diagnostic aid, and in tracheotomy care. It is considered ineffective in cystic fibrosis (Rossi, 2006). Oral acetylcysteine may also be used as a mucolytic in less serious cases. Solution for inhalation inhaled for mucolytic therapy or ingested for Nephroprotective effect. Intravenous injection treatment of paracetamol overdose. Oral solution (Acetylcysteine sachets SEDICO) & other various indications. The IV injection and inhalation preparations are generally prescription only, while oral solution is available over the counter in many countries.