Introduction
INTRODUTION Atropine, a naturally occurring tertiary amine, derives its name from atropos, one of the three fates, who according to Greek mythology, chose how a person die. The atropine, a tropane alkaloid, was first isolated from the Atropa belladonna plant by Mein in 1831 (Weiner, 1985) and also from the Datura stramonium (Jimson weed) or Duboisia myoporoides and other plants of the family Solanaceae (McEvoy, 2002 and Sever and Cekin, 2007). This extracted atropine is a combination of D and L hyoscyamine. Both these isomers may bind to muscarinic receptors (Berghem et. al., 1980) although the pharmacological activity is thought to be due almost entirely to L hyoscyamine (McEvoy, 2002). Atropine is a muscarinic acetylcholine antagonist, reducing cholinergic neurotransmission in both the autonomic and central nervous system (Parrott, 1986). It competitively blocks parasympathetic, postganglionic nerve endings from the action of acetylcholine and other muscarinic agonists. Atropine drugs have little effect at nicotinic receptor sites. Large doses of atropine produce only partial block of autonomic ganglia and have almost no effect at the neuromuscular junction (Joubert and Joubert, 1988).
Introduction 2 Although atropine earlier enjoyed widespread use as a drug with a wide variety of effects in the treatment of peptic ulcer, today it is mostly used in resuscitation, anaesthesia, and ophthalmology, usually as the more soluble sulphate salt. As such, it may also be used to counteract adverse parasympathomimetic effects of pilocarpine, or neostigmine administered in Myasthenia gravis. The role of atropine in the treatment of organophosphate poisoning is essentially unchallenged and act as a specific antidote for the treatment of poisoning with organophosphorus (OPs) insecticides that are a major class of pesticides that elicit acute toxicity by inhibiting acetylcholinesterase (AChE), the enzyme responsible for the degradation of the neurotransmitter acetylcholine in the central and peripheral nervous systems. Acetylcholine accumulation following AChE inhibition increases the stimulation of cholinergic muscarinic and nicotinic receptors on postsynaptic neurons, myocytes and autonomic ganglia end-organs, leading to an acute cholinergic syndrome characterized by involuntary movements, muscle fasciculations, respiratory distress and other signs. Atropine, an anticholinergic drug is used to counteract the cholinergic syndromes produced as result of OPs poisoning. Atropine blocks postsynaptic muscarinic receptors to alleviate clinical signs, SLUDGE (Salivation, Lacrimation, Urination, Diaphoresis, Gastrointestinal
Introduction 3 motility, and Emesis) elicited by acetylcholinesterase inhibition (Lullmann et. al., 1982 and Parrott, 1986). Adverse reactions due to atropine include warm, flushed skin, dry mouth, mydriasis, delirium and hallucinations, urinary retention, ventricular fibrillation, supraventricular or ventricular tachycardia, dizziness, nausea, blurred vision, loss of balance, dilated pupils, photophobia and possibly in the elderly the extreme confusion, and excision (Rodgers and Von Kanel, 1993 and Thomas et. al., 2007). If the dose of atropine is not titrated correctly, it has few serious side effects when used in organophosphate poisoning. Patients, who are hypoxic, however, are at risk of developing ventricular tachycardia or fibrillation if given atropine. It is important, therefore, to correct hypoxia by clearing airways, administering oxygen and, if necessary, mechanically ventilating the patient before giving atropine (Hase et al., 1984; Heath and Meredith, 1992). Small doses of atropine depress sweating and salivary and bronchial secretion. Atropine is particularly useful in relieving bronchoconstriction and salivation induced by anticholinesterases. Doses required to inhibit gastric secretion are invariably accompanied
Introduction 4 by dry mouth and ocular disturbances. At higher doses, the heart rate increases as the effects of vagal stimulation are blocked (Kentala et al., 1990). Atropine shifts the EEG to slow activity, reducing the voltage and frequency of the alpha rhythm. Atropine normalizes increased EEG activity due to isoflurophate (Longo, 1966). The peripheral antimuscarinic effects of atropine may not be the only antidotal property of the drug in organophosphate poisoning. Atropine may also be of value in treating acute dystonic reactions occasionally observed in acute organophosphate poisoning (Joubert et al., 1984; Joubert and Joubert, 1988 and Wedin, 1988). Patients with extrapyramidal signs have been noted to have abnormally low plasma and red blood cell cholinesterase activities, producing an excess of acetylcholine relative to dopamine (Wedin, 1988). However, there is little clinical evidence available on the possible anticonvulsive effects of atropine in man. It has been speculated that the cerebrospinal fluid (CSF) represents a deep compartment with slow drug penetration. Nontheless, atropine penetration is assumed to be greater in to the central nervous system than in to the cerebrospinal fluid (CSF), compatible with the well known central anticholinergic effects of the drug (Kanto and Klotz,
Introduction 5 1988). For many years, the central anticholinergic effects of the Belladonna alkaloids in reducing tremor were the mainstay of therapy for Parkinson's disease. The normal pupillary response to light or upon convergence may be completely abolished. These ocular effects may be seen after oral, systemic, or local administration of the drug (Weiner, 1985). The selection of liver to asses the impact of atropine is based on the fact that it is a versatile and metabolically complex organ in the body which reveals response against various xenobiotic substances and is actively involved in metabolism and independently engaged in many other biochemical functions. Liver is the key organ and also a place for the metabolism of carbohydrates, lipids and proteins as well as for other plant chemicals. Liver perform so many functions such as formation and secretion of bile, synthesis of certain blood coagulation factors, synthesis of protein detoxication of foreign chemicals, protection from various infections, storage of necessary biochemical substances like glycogen and lipid, and blood formation (in embryo).liver is the index of health of an animal (Plaa, 1986). The integrated pharmacokinetic and phamacodynamic study of atropine in healthy humans shows that intravenous injection, 57% of the dose is found in the urine as
Introduction 6 unchanged atropine and 29% as tropine (Hinderling et. al., 1985). Since the renal plasma clearance was found to approach the renal plasma flow, tubular excretion may occur. Thus both liver and renal disease can expected to influence the kinetics of atropine (Vander Meer et. al., 1986). Liver is also vulnerable to damage induced by huge variety of drug and chemicals (Udem e.t al., 2010). It is therefore, necessary to evaluate the adverse effect of atropine on liver of rats. Albino rat, Rattus norvegicus has been selected in the present investigation because of their easy maintenance in laboratory conditions. Being homoeothermic animal these show system similarity with other higher mammals and the results can more closely be applied on human beings. The species has provided valuable information in the field of the cure of diseases, working of brain and effect of xenobiotics in the mammalian body (Bernett, 1963). Pesticides such as organophosphates are very widely used to control pests to increase crop production. The indiscriminate use of these pesticides also causes harm to nontarget organisms such as wild life and human beings. Organophosphates (OPs) are used as insecticides and cause mortality. A regional two-year study found that the rate of organophosphate usage in suicides was 5.18% (Al et al., 2010). It was
Introduction 7 determined that insecticides caused 7% of fatal suicides (Canturk et. al., 2010). OPs inhibit acetylcholinesterase (AChE) and produce irreversible effects via accumulation of acetylcholine (ACh) at synapses (Goel and Aggarwar, 2007). Atropine is a very useful drug against organophosphate poisoning and has been used for emergency treatment and in experimental studies to counteract the effects of excess ACh (Gokel et. al., 2002 and Gulalp et. al., 2007). Previous studies found that large doses of atropine are key in treating toxic and lethal doses of OP intoxication with parathion, mentioned in WHO: Class 1A (WHO, 2001; Gokel et. al., 2002 and Gulalp et. al., 2007). However, basic and systemic analysis related to the negative effects of atropine in different doses on liver (healthy tissue) histopathology and biochemistry in albino rats without OP poisoning has not clearly been demonstrated. Therefore it is aimed to find out the effect of atropine on liver histopathology and biochemistry of Rattus norvegicus, which will be helpful for the safe use of the drug. The toxicological manifestations of any plant derivative in animals also depend on the period of exposure. It is therefore, this experimental study has also designed to demonstrate the side effects of atropine after acute and sub-chronic intramuscular administration in albino rats.