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Carisoprodol Intoxication: a Comprehensive Review Zulkifli Amin, Steven Zulkifly, Stephen Diah Iskandar

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Carisoprodol Intoxication: a Comprehensive Review Zulkifli Amin, Steven Zulkifly, Stephen Diah Iskandar Crit Care Shock (2019) 22:197-203 Carisoprodol intoxication: a comprehensive review Zulkifli Amin, Steven Zulkifly, Stephen Diah Iskandar Abstract only a few case reports about carisoprodol in- Carisoprodol has been widely used as a muscle toxication and no guideline has been published. relaxant agent. In Indonesia, carisoprodol is This article aims to provide an overview about well-known as carnophene/zenith. Many re- carisoprodol intoxication, starting from the tailers sell this drug illegally, especially to sex mechanism of action to its management. In the workers to make them feel more relaxed. Due to body, carisoprodol is metabolized to meproba- high incidence of carisoprodol abuse, Drug mate by CYP2C19 liver enzyme. Diagnosis of Enforcement Administration (DEA) categorized carisoprodol intoxication is challenging because it into Schedule IV. Knowledge about pharma- carisoprodol and meprobamate have opposite cokinetic and pharmacodynamic of carisopro- effect. Gastric lavage, administration of flu- dol are essential to be understood for proper mazenil and bemegride may be effective for diagnosis and management. Until now, there are acute intoxication case. Key words: Carisoprodol, meprobamate, intoxication. Introduction 160 mg paracetamol and 32 mg caffeine. Based on Carisoprodol (N-isopropyl-2-methyl-2-propyl-1,3- Indonesia’s Drug Specialite Information (DSI/ propanediol dicarbamate, N isopropyl meproba- ISO), carnophene is indicated to relieve low back mate) was developed by Dr. Frank M. Berger as a pain, muscle spasm, tension type headache, dys- muscle relaxant agent. Carisoprodol was syn- mennorhea, and chronic arthritis. (4) In Sulawesi, thesized to create a better muscle relaxing carnophene is widely used by sex worker to make property, safer, and less abuse potential than me- them feel less ashamed, more relaxed and probamate. (1) Decades after carisoprodol inven- confident to face their customer. (5) tion, several researches reported that carisoprodol The incidence of carisoprodol abuse have been was converted to meprobamate in human body by reported worldwide, therefore Drug Enforcement liver. (2,3) Administration (DEA) classified carisoprodol in In Indonesia, carisoprodol is known as carnophene Schedule IV list as a drug can lead to physical and (zenith), which contained 200 mg carisoprodol, p s yschological dependance. (6) In Norway, cariso- . prodol is one of the most abused drugs and causes fatality. (7-9) In Indonesia, many retailers sell carisoprodol illegally with average cost of cariso- From Division of Respirology and Critical Illness, Department prodol is IDR 40,000 - 100,000 (US$3 - US$7.5) of Internal Medicine, Faculty of Medicine Universitas for 10 pills. Many cases of carisoprodol intoxi- Indonesia, Cipto Mangunkusumo National General Hospital, cation are found in Indonesia, but not recorded Jakarta, Indonesia (Zulkifli Amin, Steven Zulkifly, Stephen properly. (4,5) Diah Iskandar). Knowledge about pharmacokinetic and pharma- codynamic of carisoprodol are essential for proper Address for correspondence: diagnosis and treatment. Until now, there is no Zulkifli Amin Division of Respirology and Critical Illness, Department of guideline about carisoprodol intoxication have Internal Medicine, Faculty of Medicine Universitas Indonesia, been published, only several case reports discuss Cipto Mangunkusumo National General Hospital, Jakarta, about this issue. The current review was conducted Indonesia to explore studies about carisoprodol intoxication Jalan Salemba Raya No. 6, Central Jakarta, Jakarta 10430 Email: [email protected] and its management. Crit Care Shock 2019 Vol. 22 No. 4 197 Pharmacokinetic of carisoprodol than 1% is excreted unchanged and 4.7% excreted Absorption as meprobamate over 24 hours after administration Two studies tried to determine pharmacokinetic of 350 mg carisoprodol tablet. (18) properties of carisoprodol, using liquid chromatog- raphy-mass spectrometry (LC-MS) method. Simon Mechanism of carisoprodol intoxication et al measured plasma level of carisoprodol and After carisoprodol is metabolized by enzyme meprobamate over 48 hours after administration of CYP2C19 in liver, it undergoes biotransformation 250 and 350 mg carisoprodol, while the study con- to three metabolic products, such as hydroxy cari- ducted by Bramness et al measured plasma level of soprodol, hydroxy meprobamate, and meproba- carisoprodol and meprobamate for 11 hours and 45 mate. In human, the main metabolic product is me- minutes after administration of 700 mg cari- probamate. Meprobamate acts similar with benzo- soprodol. (10,11) The comparison of pharmacoki- diazepine and barbiturate by modulating the func- netics properties is given in Table 1. Another tion of γ aminobutyric acid A (GABAA) receptor. study found that rapid gastrointestinal absorption (19) GABAA receptor is an ionotropic receptor of carisoprodol resulted in peak plasma concentra- that directly connected with Cl-channel, thus the tion of 4-7 mg/l, which were achieved within 2-4 activation of this receptor causes the increase of hours and onset of action within 30 minutes after chloride ion conductance and hyperpolarization of ingestion. (12) Carisoprodol has a pKa of 4.2, post-synaptic cells. (20) The impact of hyperpolar- which facilitate it to be highly absorbed in stomach ization of the cells is inhibition of intraneuronal and small intestine. (13) transmission of descending reticular formation and spinal cord, which explained the sedative-hypnosis Distribution effect of carisoprodol. (21) Among other receptors, Carisoprodol is rapidly distributed to central nerv- GABAA receptors are the major fast synaptic inhi- ous system. Protein binding of carisoprodol and bition receptor in central nervous system. (20) meprobamate are approximately 60% and 25%, Meanwhile, four cases of carisoprodol intoxication respectively. (13) There is no report of volume of showed similar manifestations to serotonin syn- distribution (Vd) for carisoprodol in human until drome, including hypertension, tachycardia, now. Based on animal study by US National Toxi- choreiform movements, shivering and tremor. (22) cology program, estimated Vd of carisoprodol is These findings showed that carisoprodol had dif- 0.72 l/kg in rats and 0.65 l/kg in mice. An analysis ferent mechanisms beside interaction with using two-compartment pharmacokinetic model GABAA receptor. It hypothesized that cari- described that estimated Vd for carisoprodol in soprodol had direct effect to central nervous sys- human is 0.93-1.3 l/kg, while for meprobamate is tem without conversion to meprobamate. However, 1.4-1.6 l/kg. (14) the mechanism of this effect was still unclear. GABAA receptors are the major fast synaptic inhi- Metabolism bition receptor in central nervous system. GABAA Carisoprodol is metabolized in liver by enzyme receptor is member of cys loop ligand gated ion CYP2C19, produces its primary metabolite, me- channels, including six α subunits, three β subu- probamate. Carisoprodol is also metabolized to nits, three γ subunits, three ρ subunits, as well as hydroxy carisoprodol in much lesser extent by un- one ϵ, δ, θ, and π subunit. (20) known enzyme. Both meprobamate and hydroxy Many studies tried to solve the question why cari- carisoprodol are metabolized to hydroxy mepro- soprodol had different effect than its metabolite, bamate, then partially conjugated. (15) The rela- meprobamate. Gonzales et al found that cari- tionship between variation in CYP2C19 activity soprodol directly activate human α1β2γ2 GABAA and metabolism of carisoprodol has been proven to receptor. However, this potentiation of GABA- be correlated with mephenytoin hydroxylation pol- gated currents was only occurred at micromolar ymorphism (using probe drug S-mephenytoin). (3) concentration. On the contrary, high concentration Many drugs may interact with CYP2C19 and in- of carisoprodol (millimole concentration) produced hibit the metabolism of carisoprodol. Fluoxetine, GABA inhibition, followed by rebound currents fluvoxamine, omeprazole, and oral contraceptive after termination of the drug. (23) This phenome- drugs have been shown to reduce the metabolism non could be explained by dose-dependent channel of S-mephenytoin. (11,15-17) block of GABAA receptor that limits the maxi- mum total current conducted, as found in other Excretion study with barbiturate compounds. (24,25) Even, Carisoprodol is primarily excreted in urine. Less in the absence of GABA neurotransmitter, micro- . 198 Crit Care Shock 2019 Vol. 22 No. 4 molar concentration of carisoprodol causes rapid festations will be initiated with acute carisoprodol and reversible inward currents that can be blocked intoxication syndrome then followed by meproba- by picrotoxin, a non-competitive channel blocker mate intoxication. However, none of the case re- for GABAA receptor. These inward currents are ported these clinical manifestations. (19,29) significantly higher than inward currents produced Acute carisoprodol intoxication causes decreases by meprobamate. (23) level of consciousness to coma or semi-coma. This Study in multiple combination of GABAA recep- high concentration of carisoprodol in serum (>25 tors found that meprobamate also had direct-gating µg/ml) also causes sign and symptoms of serotonin and allosteric effect in α1-6β2γ2 GABAA receptor, and anticholinergic syndrome that overlap each with the largest effect in combination of α5 subu- other. The clinical manifestations including nys- nit. (26) However, carisoprodol is more potent and
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