The Effect of Pancuronium Bromide as a Muscle Relaxant Alone or Combination with Diazepam in Sheep

The effect of pancuronium bromide (0.025 mg/kg. B.W.) alone or combined with diazepam (1mg/Kg. I.V) were evaluated in six adult ewes. Pancuronium bromide alone exhibited a muscle relaxants effect, but without analgesia. All baseline measurements were taken before the administration the anesthetic agent and were repeated at 5,10,15,20 and 25 min. intervals after induction an aesthesia alone or combination with diazepam . it was found that heart rate decreased at 5 min.,but respiratory rate did change at 5-25 min. and it was significantly at 15,20 and 25 min. Pancuronium bromide – diazepam combination is responsible for declined respiratory rate and decumbency position in early stage. Pancuronium bromide – diazepam induce effective and safe an aesthesia for periods 45 minutes, due to competitive diazepam as a sedative effect of muscle relaxation. Adequate strength and duration of analgesia due to prevent impulse transmission histamine and ensured rapid and safe recovery. INTRODUCTION Pancuronium bromide, an amino steroid free from any hormonal action, abis – quaternary ammonium steroids, is a non – depolarizing neuromuscular blocking agent that competes with acetylcholine for cholinoceptive sites at the post junctional membrane and therapy blocks competitively the transmitter action of acetylcholine resulting in muscle paralysis (1). Clinical studies have been shown that pancuronium is approximately fives times as potent as d – tubocurarine as a competitive neuromuscular blocker. Pancuronium causes moderate increase in heart rate with an attendant increase in cardiac output and blood pressure there does not cause measurable effect on systemic vascular resistance. Pancuronium bromide causes little or no histamine release and no ganglionic blockade, and therefore anesthetic does not cause hypotension or Bronchospasm. Despite its steroid structure, the drug exhibits no hormonal activity. Cholinesterase inhibitors such as pyridostigmine and neostigmine reverse the action of pancuronium (2). Plasma concentrations of pancuronium bromide appear to decline in a triphasic manner. In patients with normal renal and hepatic function the half – life in the terminal phase is about 2 hours. Since a large fraction of pancuronium bromide is excreted in the urine the duration of neuromuscular blockade is prolonged in patients with renal failure and the dose should be reduced. In patients with impaired hepatic function, prolonged and elimination half – lives result in a higher initial does to be given and longer duration of action respectively (3). Since the introduction of pancuronium, many new neuromuscular blocking (NMB) agents have been brought into anesthesia practice. The large molecular size and the quaternary ammonium structure of these compounds are unique among anesthesia – related drugs. For practical purpose, understanding their structure – activity relationship (SAR) is a rational way to understand their actions and metabolism (4). Bas.J.Vet.Res.,Vol.7,No.1,2008 65 Neuromuscular blocking agents interact with many different drugs inducting general anesthesia and other NMB themselves. At a molecular level of the acetylcholine receptor, other drugs interact with NMB by direct competition at the binding sites for acetylcholine (Ach), allosterie modulation of the receptor, or direct interference with ion flux through the central ion channel of the receptor. In addition, some drugs interact with NMB an a pharmacokinetic level by interfering with their distribution and elimination (4.5). Ach is a flexible molecule capable of adopting several conformations without significant energy penalty. This allows it to be physiologically multifunctional. Its symmetrical conformers can flip easily. The structure of Ach, CH3–CO–O–(CH2)2 – N + (CH3)3, although simple, has several important functional features, namely the methonium head cantered on the positively charged quaternary N atom, the alcohol O atom that forms the ester (–O–), and the acetyl group with the carbonyl O atom (–CO–) (5). The skeletal muscle endplate Ach receptor (Ach R) is generally modeled after the electric nicotinic AchR as a pentameric structure of 2, or subunits in a rosette around a sodium – potassium ionic channel. Each receptor has two Ach receptive sites, one on each  subunit in a packet near where the  subunit interfaces with its neighbor  or  subunit (6). Various cholinergic receptors and cholinesterase have different conformational requirements or preferences of their agonists (or substrates in the case of cholinesterase) and antagonists of the cholinergic compounds. Amino steroids as a pancuronium bromide are among the amino steroid NMB agents. The steroid nucleus provides a rigid bulky of the two Ach moieties of pancuronium, with both functional groups pointing up. The amino steroids several structure activity relationship (SAR) and conformation activity relationship (CAR), and the structure of the pancuronium bromide as the following (4) The aim of this study was to evaluate the effects of Pancuronium Bromide as a Muscle Relaxant Alone or Combination with Diazepam on heart , respiratory rate and induction of anesthesia stage of ewes . Intravenous anesthetics have a lower muscle – relaxing effect than volatile anesthetics. The reversal of neuromuscular blockade, as currently done with inhibition of the enzyme acetylchdine esterase as neostigmine has important limitations (6,7,8):  The mechanism of reversal is indirect such as administration of the acetylcholine esterase inhibitor; enzymatic degradation of acetylcholine in the synaptic cleft is reduced thereby increasing the numbers of Ach molecules compacting for the binding sites with the NMB.  The efficacy is limited and residual block occurs because reversal is dependent on the increase of Ach concentration and the decrease of the concentration of the NMB according to its inherent rate of elimination.  Reversal is inadequate or impossible against profound block because of the competitive nature of the interaction between Ach and NMB .  True rescue reversal in a (cannot ventilate – cannot intubate) situation does not exist.  The effect of Ach esterase inhibitors is not selective, but also potientitates neurotransmission at muscarinic Ach receptors leading to bradycardia, hypotension, bronchoconstriction, nausea and diarrhea. Therefore, in clinical practice, Ach esterase inhibitors are combined with atropine or glycopyrrolate to antagonize the muscarinic effect of the Ach (3,4). Depolarizing agent, which act peripherally at the neuromuscular junctions? Anticholinesterases such as pyridostigmine and edrophonium are antagonistic to the non – depolarizing agent. The agents are used as adjuncts to general anesthetics were profound muscle, relaxation is desired. Because these agents produce motor paralysis only and don’t produce either sedation or analgesia, their use for euthanasia is unacceptable as it results in a unnecessarily stressful death due to as asphyxia (9). Bas.J.Vet.Res.,Vol.7,No.1,2008 66 The use of muscle relaxant drugs in conjunction with a general anesthetic agent to induce complete skeletal muscle relaxation gives rise to difficulty in evaluating the depth of anesthesia. The use of NMB agents is not acceptable because more effective and human drugs are available for this purpose (10). MATERIALS AND METHODS Six adult ewes Awassi breed, ranging in weight between 40-50 kg, and 3-4 years old , experimental animals were divided into two main groups . in group one treated included three ewes each ewe was given (0.025-mg/kg B.W) intravenously of pancuronium 1 bromide, and group two gives (0.025 mg/kg B.W.) of pancuronium bromide with (1 mg/kg W.B.) of Diazepam 2 intravenously. In alone and combination group, as the anesthesia started the animals were laid on lateral recumbency and observed until recovery and spontaneous standing. Data were analyzed by using student’s t test. And one way analysis of variance, to a certain the statistical difference at P < 0.05.(11).