TUGAS

FARMAKOLOGI SUKSINILKOLIN DAN FARMAKOLOGI

ATRACURIUM

Oleh

Ayu Ika Gustati Nurrahmah, S.Ked

70 2010 019

Pembimbing

dr. Achmad Marwan, Sp.An, M.Kes

BAGIAN ILMU ANESTESI DAN REANIMASIRUMAH SAKIT UMUM DAERAH PALEMBANG BARI

FAKULTAS KEDOKTERAN UNIVERSITAS MUHAMMADIYAH PALEMBANG2015

DEPOLARIZING NEUROMUSCULAR-BLOCKING DRUGS

SuccinylcholineThe only depolarizing neuromuscular-blocking drug in clinical use is SCh. SCh rapidly produces intense paralysis(30 to 60 s) and has a short duration of action(3 to5 minutes).These characteristics make Scha useful drug for providing skeletal muscle relaxation to facilitate the intubation of the trachea. SCh has several associated adverse effects that can limit or even contraindicate its use.

Dose The traditional intravenous dose of SCh to facilitate tracheal intubation is 1mg/kg. Conceptually, it is anticipated that administration of 1mg/kg IV to a preoxygenated patient would be associated with the return of spontaneous breathing before arterial hypoxemia became significant. Considering the variability inresponse to SCh among patients,it is concluded that no single perfect intubating dose of SCh exists.

Mechanismof Action SCh attaches to one or both of the α-subunits of nAChRs and mimics the action of acetylcholine (partial agonist), thus depolarizing the post junctional membrane. Compared with acetylcholine, the hydrolysis of SCh is slow, resulting insustained depolarization (opening) ofthe receptor ion channels. Neuromuscular blockade develops because a depolarized post junctional membrane can not respond to subsequent release of acetylcholine (depolarizing neuromuscular blockade). Depolarizing neuromuscular blockade is also referred to as phase I blockade. A single large intravenous dose of SCh (>2mg/kg), repeated doses, or a prolonged continuous infusion of SCh may result in post junctional membranes that do not respond normally to acetylcholine even when the post junctional membranes have become repolarized (desensitization neuromuscular blockade). The mechanism for the development of desensitization neuromuscular blockade is unknown and, for this reason, designation as phase II blockade, which does not imply a mechanism, is the preferred terminology.

Characteristics of Phase I Blockade 1. Decreased contraction in response to single twitch2. Decreased amplitude but sustained response to continuous stimulation 3. Train-of-four ratio>0.7 4. Absence of post tetanic facilitation 5. Augmentation of neuromuscular blockad eafter administration of anticholinesterase

drugs.

Characteristics of Phase II Blockade Electrically evoked mechanical responses, using a peripheral nerve stimulator, are characteristic of phase II blockade and resemble those considered typical of the neuromuscular blockade produced by nondepolarizing neuromuscular-blocking drugs. When neuromuscular blockade is predominantly phase I, administering an anticholinesterase drug will enhance existing neuromuscular blockade. Conversely, an anticholinesterase drug will antagonize a predominant phase II blockade. If a small dose of edrophonium (0.1 to0.2mg/kg IV) improves neuromuscular transmission, it is likely that an additional dose of anticholinesterase drug will antagonize, rather than enhance, the neuromuscular blockade produced by SCh.

Duration of Action The brief duration of action of SCh (3 to5minutes) is principally due to its hydrolysis by plasma cholinesterase (pseudocholinesterase) enzyme. Plasma cholinesterase has an enormous capacity to hydrolyze SC hat a rapid rate so that only a small fraction of the original intravenous dose of drug actually reaches the NMJ. Because plasma cholinesterase is not present in significant amounts at the NMJ, the neuromuscular blockade produced by SCh is terminated by its diffusion away from the NMJ and into extracellular fluid. Therefore, plasma cholinesterase influences the duration of action of SCh by controlling the amount of neuromuscular-blocking drug that is hydrolyzed before reaching the NMJ.

Plasma Cholinesterase Activity Decreases in the hepatic production of plasma cholinesterase, drug-induced decreases in plasma cholinesterase activity, or the genetically determined presence of atypical plasma cholinesterase result in the slowed to absent hydrolysis of SCh and a corresponding prolongation of the neuromuscular blockade produced by the drug. Liver disease must be severe before decreases in plasma cholinesterase production sufficient to prolong SCh-induced neuromuscular blockade occur.

Atypical Plasma Cholinesterase The presence of atypical plasma cholinesterase is often recognized only after another wise healthy patient experiences prolonged neuromuscular blockade (1 to3hours) after a conventional dose of SCh. A single cholinesterasegene is present, and nucleotide alteration sin this geneare responsible for the numerous variants in the enzyme. Among these veral genetically determined variants of plasma cholinesterase, the dibucainerelated variants seem to be the most important. Dibucaine, a local anesthetic with a namide linkage, inhibits the activity of normal plasma cholinesterase enzyme by approximately 80% compared with only approximately 20% inhibition of the activity of atypical enzyme. A dibucaine number of 80, which reflects the 80% inhibition of enzyme activity, confirms the presence of normal plasma cholinesterase enzyme, where as approximately 1 inevery 3,200 patients is homozygous for an atypical plasma cholinesterase enzyme variant and has a dibucaine number of 20. In these patients, neuromuscular blockade after the administration of SCh, 1mg/kg IV, may persist for 3 hours or longer. Approximately 1 in every 480 patients is heterozygous for the atypical plasma cholinesterase enzyme that results in a dibucaine number of 40 to 60.T hese heterozygous patients may manifest a modestly prolonged duration of neuromuscular blockade (up to 30 minutes) after the administration of SCh. It is important to recognize that the dibucaine number reflects the quality of cholinesterase enzyme (ability to hydrolyze SCh) and not the quantity of the enzyme that is circulating in the plasma. For example, decreases in the plasma cholinesteras eactivity due to liver disease or anticholinesterase drugs are associated with normal (near 80) dibucaine numbers.

Side Effect Of Succinylcholine

1. Cardiac dysrhythmias(sinus bradycardia reflects actions of SCh at muscarinic cholinergic receptors, where it mimics actions of acetylcholine)

2. Hyperkalemia (occurs in patients with clinically unrecognized skeletal muscle dystrophy, unhealed third-degree burns, denervation leading to skeletal muscle atrophy; occurs within 96 hours of denervation and persists for an indefinite period)

3. Myalgia (prominentin muscles of neck, back and abdomen,may mimic sore throat) 4. Myoglobinuria5. Increased intragastric pressure 6. Increased intraocular pressure(transient)7. Increased intracranial pressure(not a consistent observation) 8. Sustained skeletal muscle contractions(especially in children)

NON DEPOLARIZING NEUROMUSCULAR BLOCKADE

Characteristics of Nondepolarizing Neuromuscular Blockade 1. Decreased twitch response to a single stimulus 2. Unsustained response (fade) during continuous stimulation 3. Train-of-four ratio <0,74. Post-tetanic potentiation5. Potentiation of other nondepolarizing neuromuscular-blocking drugs 6. Antagonismof neuromuscular blockade after administration of anticholinesterase

drugs 7. Absence of fasciculations

Atracurium Atracuriumis abisquaternary benzylisoquinolinium nondepolarizing neuromuscular-blocking drug (mixture of tengeometric isomers) with an ED95 of 0.2mg/kg that produces an onset in 3 to5minutes and a duration of neuromuscular blockade lasting 20 to 35 minutes.

Clearance Atracurium undergoes spontaneous non enzymatic degradation at normal body temperature and pH by a base catalyzed reaction termed Hofmann elimination. A second and simultaneously occurring route of metabolism is hydrolysis by non specific plasma esterases. Hofmann elimination represents a chemical mechanism of elimination, where as ester hydrolysisis a biologic mechanism. These two routes of metabolism are independent of hepatic and renal function as well as plasma cholinesterase activity (duration of atracurium-induced neuromuscular blockade is similar in normal patients and those with absent or impaired renal or hepatic function or those with atypical plasma cholinesterase). The absence of prolonged neuromuscular blockade after the administration of atracurium to patients with atypical cholinesterase emphasizes the dependence of atracurium's ester hydrolysis on non specific plasma esterases that are unrelated to plasma cholinesterase. Hofmann elimination and ester hydrolysis also account for the lack of cumulative drug effects with repeated doses or continuous infusions of atracurium. Overall, ester hydrolysis accounts for an estimated two-thirds of degraded atracurium, where as Hofmann elimination provides a “safety net,”especially in patients with impaired hepatic and/or renal function.

Laudanosine Laudanosine is the major metabolite of both pathways of metabolism of atracurium. Laudanosine depends on the liver for clearance, with approximately 70% excreted in the bile and there mainder in urine. Despite increases in plasma laudanosine concentrations during each stage of liver transplantation in patients receiving atracurium, these levels are considered to be far below clinically significant concentrations. Although in active at the NMJ (in contrast to metabolites of many other non depolarizing neuromuscular-blocking drugs), animal studies have shown laudanosine to be a CNS stimulant, to increase the MAC of volatile anesthetics, and to cause peripheral vasodilation. In patients receiving a full paralyzing dose of atracurium (0.5mg/kg IV), the resulting peak plasma concentrations of laudanosine are approximately 0.3µg/mL, which is approximately 20 times less than the plasma concentrations producing cardiovascular effects in animals. Laudanosine resulting from the metabolism of atracurium probably will not produce seizure activity in anesthetized patients, because skeletal muscle paralysis from atracurium would prevent movement.

Acid-Base Changes Despite pH-dependent Hofmann elimination (accelerated by alkalosis and slowed by acidosis), it is unlikely that the range of pH changes encountered clinically is sufficiently great to alter the rate of Hofmann elimination and, thus, the duration of atracurium induced neuromuscular blockade.

Cumulative Effects Consistency of onset to recovery intervals after repeated supplemental doses of atracurium is characteristic of this drug and reflects the absence of significant cumulative drug effect.

Cardiovascular Effects Systemic blood pressure and heart rate changes do not accompany the rapid intravenous administration of atracurium in doses u pto2 × ED95 with background anesthetics including nitrous oxide, fentanyl, and isoflurane. Facial and truncal flushing in some patients suggests a release of histamine as the mechanism for the circulatory changes accompanying the rapid administration of high doses (3 × ED95 ) of atracurium. It is estimated that the plasma histamine concentration must double before cardiovascular changes manifest clinically.

Pediatric Patients Effective doses of atracurium are similar in adults and children (2 to 16 years old), when differences in extracellular fluid volume are minimized by calculating the dose on a mg/m2 rather than a mg/kg basis.

Elderly Patients Increasing age has no effect on the continuous rate of atracurium infusion necessary to maintain a constant degree of neuromuscular blockade. This most likely reflects the independence of clearance mechanisms (Hofmann elimination and ester hydrolysis )from age-related effects on renal and hepatic function.

Sumber :Pharmacology And Physiology In Anesthetic Practice, Robert K. Stoelting