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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 REANIMASI


RUMAH SAKIT UMUM DAERAH PALEMBANG BARI
FAKULTAS KEDOKTERAN UNIVERSITAS MUHAMMADIYAH
PALEMBANG
2015

DEPOLARIZING NEUROMUSCULAR-BLOCKING DRUGS


Succinylcholine
The 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 -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.
2.
3.
4.
5.

Decreased contraction in response to single twitch


Decreased amplitude but sustained response to continuous stimulation
Train-of-four ratio>0.7
Absence of post tetanic facilitation
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 SChinduced 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. Myoglobinuria
5. 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.
2.
3.
4.
5.
6.

Decreased twitch response to a single stimulus


Unsustained response (fade) during continuous stimulation
Train-of-four ratio <0,7
Post-tetanic potentiation
Potentiation of other nondepolarizing neuromuscular-blocking drugs
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 atracuriuminduced 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 0.3g/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

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