UNIVERSITAS SRIWIJAYAFAKULTAS KEDOKTERAN

UNIT PENDIDIKAN KEDOKTERAN (UPK)Zono F. Gedung I Kompus Unsri lndrcloyo Ol Sumotero Selolon, lndonesio Te1p. 07i I - 580061

otou / or JI. dr. Muh. Ali Kornptek RSUP Polembong 30126, lndonesio, Telp.0Zl 1 -352342, Fox 0Tll -373438'

-' SKENARIO BLOK 12

SKENARIO B

Tn. Aceng, umur 35 tahun akan menjalani herniotomi dekstra. Spesialis Anastesi (SpAn) berencanamemberikan anestesi umum berupa inhalasi halothone. sebelumnya, telah dilakukan konsultasi

dengan bagian penyakit Dalam yang menyatakan tidak ditemukan adanya kelainan jantung danparu.Keesokan harinya, setelah pemberian succinylchollne intravena dilakukan intubasi dilanjutkandengan pemberian inhalasi halothane. Pada saat pembedahan berlangsung, 1'n Aceng mengalami

kekakuan pada otot, suhu tubuh meningkat sarnpai40oC dan tekanan darah rnenjadi 170/90 mmHgdan denyut jantung 120 kali/menit. Dokter spB dan Dokter spAn menduga terjadinya suatuMalignant hYPerthermia'

Hasil Labratorium darah cito:Base deficit >8 mEq/1, pH 20,000/L units' cola-colored

urine, excess myoglobin in urine or serum, plasma lK+] >6 mEq/L

Jelaskan apa yang terjadi pada Tn. Aceng daiam tinjauan farmakologi sehubungan dengan obat-obat yang diberikan I

Learning objective1". Mahasiswa mampu menjelaskan tentang Hernia inguinalis dextra2. Mahasiswa dapat menjelaskan mekanisme kerja, penggunaan klinis serta efek samping

succinylcholine3. Mahasiswa dapat menjelaskan mekanisme kerja, penggunaan klinis serta efek samping

halothane4, Mahasiswa dapat menjelaskan interaksi succinylcholine dengan halothane5. Mahasiswa dapat menjelaskan patofisiologi terjadinya Malignant hypertermia (MH)6. Mahasiswa dapat menjelaskan pada tingkat genetik gen yang berhubungan dengan terjadi

MH

Klarifikasi istilah1. Herniotomi dekstra2, lnhalasi3. Halothane4. Succinylcholine5. lntubasi6. Kekakuan Pada otot7. Malignant hYPerthermia

ldentifikasi masalahl-. Tn, Aceng, umur 35 tahun akan menjalani herniotomi dekstra2. Setelah pemberian succinylcholine intravena dilakukan intubasi dilanjutkan dengan

pem berian inhalasi halothane3. Pada saat pembedahan berlangsung,

meningkat samPai 40oC dan tekanankali/menit.

4. Dokter SpB dan Dokter SpAn menduga

Tn Aceng mengalami kekakuan pada otot, suhu tubuhdarah menjadi 17019A mmHg dan denyut jantung 120

terjadinya suatu Malignant hyperthermia

Analisis masalah1. a. Bagaimanakah mekanisme kerja succinylcholine?

. Succinylcholin (SC) merupakan obat yang secara struktural analog dengan asetilkolindan bekerja sebagai agonis reseptor nikotinik motor end-plate pada neuromuscularjunction. iebagaimana asetilkolin, SC dapat menyebabkan stimulasi dan depolarisasipersisten sel otot.

b. Apa indikasi pemberian succinylcholine?, Untuk mendapatkan efek relaksasi otot yang sempurna tanpa perlu memberikan dosis

obat anestesi Yang tinggi.. Karena efek SC ying cepat dan masa kerja yang pendek, digunakan untuk

endotrachea selama induksi anestesi

'SCdigunakanpadapengobatansyokelectroconvulsivec. Apa adverse effect pemberian succinylcholine?

' HYPerthermia'Pada anestesi halothane, pemberian SC akan menyebabkan malignant hyperthermia(MH) pada orang dengan polimorfisme gen tertentu

' ApneaApnea dihubungkangenetik atau adanYadiafragma.

2. a. Bagaimanakah mekanisme kerja halothane?b. Apa indikasi pemberian halothane?

. Haiothane digunakan sebagai anestesi umum berupa anestesia inhalasi

c, Apa kontraindikasi pemberian halothane?. Anak-anak usia < 18 tahun. Riwayat jaundice atau demam setelah mendapatkan halothane sebelumnya . ).PasiendenganprmiMalignanthyperthermia.[

d. Apakah adverse effect Pe@' HePatotoksisitas' Peningkatan tekanan. Menurunkan kontraktilitas uterus

3. Bagaimana interaksi succinylcholine dangan halothane?. Dapat saling berinteraksi r"n.ny.brukan MH pada individu yang mengalami mutasi pada

gen rYanodine4. Bagaimana patofisiologi terjadinya Malignant hyperthermia?

, Adanya mutasi gen penyandi ryanodine akan menyebabkan pelepasan kalsium denganjumlah tidak terkendali. Hal ini akan mengakibatkan terjadinya kontraksi otot dalamwaktu yang lama. Bila kontraksi berlangsung lama maka sel-sel otot akan mati danmelepaskan isi selnya termasuk berbagai molekul, protein, enzim yang dapat dideteksidalam darah (potassium, myoglobin, creatinine phosphokinase)' PenlnRkatan fadar zat-zat ini dalani i-a rah ddfi'heni ngkatnya frfr6nyebabkan kerusakan organ

dengan adanya defisiensi cholinesterasesuatu bentuk enzim yang atipik yang

plasma yang bersifatmenyebabkan Paralisis

seperti ginjal dan jantung'5. Bagaimana pengaruh genetik terhadap terjadinya Malignant hyperthermia?

. MH terjadi prO. inOiuiau yang mengalami mutasi pada gen reseptor ryanodine yangmengaturpelepasankalsiumpadaototyansterletakpadakromosom19.

6.Obatapayangdapatdiberikanuntukmengatasigejalayangterjadi?. Dantrolene

.v--'\7. Bagaimanb caE mencegah terjadinya Malignant hyperthermia?

. Genetic screening

HypothesisTn Aceng, 35 tahun mengalami Malignant hyperthermia yang diinduksi oleh irrteraksi succinylcholin

dengan halothane "'- 'e' ...----=-t

Sintesis. Neuromuscular blocking agents are classified as either depolarizing or non-depolarizing and are

used mostly as adjuncts with general anesthetics to block motor endplate activity of ACh at theneu romuscula r junction.

. Succinylcholine is the prototype for depolarizing agents and used for brief paralysis for surgeryand for intubation.

. Tubocurarine, the prototype, and other nondepolarizing agents (e.9., cisatracurium,vecuronium, rocuronium) are used for longer term paralysis for surgery.

. Succinylcholine is the only depolarizing neuromuscular agent in wide clinical use. lt is used forthe rapid induction of a brief flaccid paralysis.

. lt works as an agonist of the nicotinic receptor at the motor endplate of the neuromuscular'li-ction. This caises;Tei"sistent stimulation and depolarization of the muscle, preventing

stimulation of contraction by ACh'. lt has a rapid onset and short duration of action because it is quickly hydrolyzed by plasma

and liver cholinesterase.. Malignant hyperthermia, a rare but significant cause of anesthetic morbidity and mortality,

is an inherited autosomal dominant disorder that results in tachycardia, muscle rigidity, and highbody temperatures in response to the use of certain inhaled anesthetics in combination withmuscle relaxants, usually succinylcholine.

, lt is caused by a release of calcium ions from the sarcoplasmic reticulum in muscle cells.. Dantrolene interferes with this release and is therefore the treatment of choice for

thiffindition.r ln addition to malignant hyperthermia, succinylcholine administration may result in

hyperkalemia, particularly in patients with burn and trauma, which could result in cardiac arrest,Myalgia is also commonly reported.

. Numerous drug interactions between neuromuscular blocking agents and other drugs have beenreported that lead to increased neuromuscular blockade, particularly with certain antibioticsand inhaled anesthetics.

. StructureThe neuromuscular blocking agents resemble ACh (succinylcholine contains two linked Achmolecules) and contain one or two quaternary nitrogens that limit entry into the CNS.

' Mechanism of Action. After a single dose, succinylcholine occupies the nicotinic receptor to produce a

persistent endplate depolarization (phase I block) that results in flaccid paralysisbecause the muscles become unresponsive to endogenously released ACh. Theinitial depolarization is accompanied by muscle fasciculations, Continued exPosure of

.'lendplates to succinylcholine results in their repolarization. However, through an unclear'fmechanism, they become relatively insensitive to subsequent depolarization (to- Icalled desensitization, or phase ll block). t

r Nondepolarizing blocking agents act as reversible competitive antagonists that block the \action of ACh at nicotinic cholinoreceptors in muscle endplates and autonomic ganglia'Cholinesterase inhibitors ie.g., neostigmine, pyridostigmine) can effectively 'antagonize and reverse the neuromuscular blocking action of non depolarizing agentsand succinylcholine during phase ll. However, they will augment the action ofsuccinylcholine during Phase l.

AdministrationThe neuromuscular blocking agents are highly polar and therefore must be administeredparenterally. Most nondepolarizing agents are eliminated through the kidney'Succinylcholine is etiminated by the hydrolytic action of plasma butyrylcholinesterase( pseudocholinesterase).

PharmacokineticsNeuromuscular blocking agents are highly ionized and therefore have limited volume ofdistribution and limited access to the CNS.

I

Maligna nt Hyperthermia

E(,

I>What

Malignant hyperthermia is a disorder of skeletal muscle and is characterized by prolonged musclecontraction and increased body temperature after being exposed to certain kinds of anesthesia ormuscle relaxants. lt is inherited in an autosomal dominant manner. Although this condition can be life-threatening, it can be treated if the symptoms are recognized early and therapy is promptly initiatecl.

Who

The incidence of malignant hyperthermia has been reported from 1 in 5,000 to L in 10,000 children and1 in 50,000 to f. in 100,000 adults who undergo anesthesia. There is a male predominance with a maleto female ratio of 2 to 1. lt is considered to be a rare condition.

Signs and Symptoms

People with malignant hyperthermia have no symptoms until they are exposed to halogenatedanesthetics or depolarizing muscle relaxants, the most frequent triggers of a crisis. Examples oftriggeringanestheticsincludehalothane,isoflurane,enriu,lneSuccinylcholine is an example of a depolarizing muscle relaxant. Other triggers include exercise in hotconditions, seizure medication, alcohol use and infections. Most people present with symptoms durine /an operation while under anesthesia. Symptoms include a sudden increase in heart rate, sudden /increase in body temperature and prolonged muscle contraction. Symptoms may even present 2 % |hours after initial exposure to the anesthesia or in the recovery room. While in recovery, the patient/begins to have a gradual increase in temperature that is unexplained accompanied by muscle pain and{cramping. Other patients may also experience hemolysis which is the rupture of red blood cells. Somepeople who have had previous exposure to the anesthestic without incidence can later developmalignant hyperthermia with subsequent exposure. Some early symptoms that may arise while underanesthesia include: rigidity of the masseter muscle found in the face, blood that is acidic due to troubledbreathing, low oxygenation, increased output of carbon dioxide from the lungs, elevated muscle proteinlevels in the blood (myoglobin or reatine phosphokinase) or urine (myoglobin) due to musclebreakdown and heart rhythm abnormalities.

Possible Causes

Most patients with malignant hyperthermia have point mutations in the ryanodine receptor gene onchromosome 19. This gene is involved in the regulation of calcium release in the muscle. The mutatedreceptor allows calcium to be released from the muscle cells at an uncontrolled rate. This causes themuscles to contract for a prolonged period of time. When the muscle contracts for such a long time, themuscle cells begin to die and they release their contents which include various molecules, proteins andenzymes that can be detected in the blood (i.e. potassium, myoglobin, creatinine phosphokinase).lncreased levels of these substances in the blood and the elevated body temperature are verydangerous, potentially leading to damage of organs like the kidney and the heart. Although themutation in the ryanodine receptor gene on chromosome 19 is most common, others with malignanthyperthermia have mutations in genes on other chromosomes (chromosomes 1,7,3,5,17l'. The roleand function of these genes that lead to rnalignant hyperthermia have yet to be determined.

Diagnosis

There are no specific findings to diagnose malignant hyperthermia. The diagnosis is through the clinicalsymptoms and certain laboratory findings such as an increased blood concentration of potassium,creatinine phosphokinase, and aldolase. Muscle biopsy will show a variety of muscle cell abnormalitiesto

lyg4hologist confirm the diagnosis.

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Treatment

During a crisis the offending anesthestic is discontinued and the drug dantrolene is used to reverse the

effects of muscre rigidity. oxygenation and cooring measures are initiated, as well as corrections of the

other blood abnormalities. People with a family history of malignant hyperthermia or othercomplications due to anesthesia should consider being screened for their risk of malignanthyperthermia. The test involves taking a muscle sample and exposing it to caffeine

and halothane' The

amount of contraction is measured and compared to normal samples in order to assess whether an

abnormal reaction occurred. since this test is invasive, alternative tests are under investigation but most

are not used as screening tools'

Prognosis

The rerease of muscre celr contents and the increased body temperature during marignant hyperthermia

crisiscancausemultipleorganstofail,includingtheheartwhichcanleadtodeath'However'ifthesymptomsarerecognizedearly,theycanbetreatedwithminimalresidualeffects'otherfamilymembers should ue icreened to assess their own risk of malignant

hyperthermia'

/./.