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1.ProstigminProstigmin (neostigmine bromide), an anticholinesterase agent, is availablefor oral administration in 15 mg tablets. Each tablet also contains gelatin,lactose, corn starch, stearic acid, sugar andtalc.

Chemically, neostigmine bromide is (m-hydroxyphenyl) trimethylammoniumbromide dimethylcarbamate. It is a white, crystalline, bitter powder, soluble1:1 in water, with a molecular weight of 303.20 and the following structuralformula:

Get emergency medical help if you have any of these signs of an allergicreaction: hives; difficulty breathing; swelling of your face, lips, tongue, orthroat.

Call your doctor at once if you have any of these serious side effects:

severe diarrhea; seizure (convulsions); feeling light-headed, fainting; vision problems; orfast, slow, or uneven heartbeats.

Neostigmine is used to improve muscle strength in patients with a certainmuscle disease (myasthenia gravis). It works by preventing the breakdown ofa certain natural substance (acetylcholine) in your body. Acetylcholine isneeded for normal muscle function.

How to use Prostigmin OralTake thismedicationby mouth with or without food as directed by your doctor.

Taking this medication with food or milk may help to decrease side effects.Dosage is based on your medical condition and response to therapy. Talkwith your doctor about how you respond to the medication and about whenyou feel the most tired or weak so that your doctor can make the properdosage changes.Do not increase your dose or take this medication more often than prescribed.Doing so may increase the risk of serious side effects.

Synthesis

Neostigmine was first synthesized by Aeschlimann and Reinert in

1931.[1]Neostigmine is made by first reacting 3-dimethylaminophenol with N-dimethylcarbamoyl chloride, which forms a dimethylcarbamate. Next,that product is alkylated using dimethylsulfate, which formsneostigmine.[2]

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Pharmacology

By interfering with the breakdown ofacetylcholine, neostigmine

indirectlystimulatesbothnicotinicandmuscarinic receptors. Unlikephysostigmine, neostigmine has a quaternary nitrogen; hence, it is more
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polar and does not enter the CNS. Its effect on skeletal muscle isgreater than that of physostigmine, and it can stimulate contractilitybefore it paralyzes. Neostigmine has moderate duration of action,usually two to four hours.[3] Neostigmine binds to the anionic site ofcholinesterase. The drug blocks the active site of acetylcholinesteraseso the enzyme can no longer break down the acetylcholine moleculesbefore they reach the postsynaptic membrane receptors. This allows forthe threshold to be reached so a new impulse can be triggered in thenext neuron. In myasthenia gravis there are too few acetylcholinereceptors so with the acetylcholinesterase blocked, acetylcholine canbind to the few receptors and trigger a muscular contraction.

[edit]

Clinical uses

It is used to improve muscle tone in people withmyasthenia gravisandroutinely, inanesthesiaat the end of an operation, to reverse the effectsof non-depolarizingmuscle relaxantssuch asrocuroniumandvecuronium, usually in a dose of 25 to 50 mcg per kilogram.

It can also be used forurinary retentionresulting fromgeneralanesthesiaand to treatcurariformdrug toxicity.

Another indication for use is theOgilvie syndromewhich is apseudoobstruction of the colon in critically ill patients.

Historically, it has been used as a test for early pregnancy. In a non-pregnant female whose menstrual period is delayed, administration ofneostigmine can provoke menstrual bleeding. Modern tests which relyon detectinghCGin urine have rendered this application obsolete.

Though one of only two treatments available for myasthenia gravis thisdrug is no longer available to anyone using theMedicare Part Dprogram.

[edit]

Side effects

Neostigmine can induce generic ocular side effects including:headache, brow pain, blurred vision, phacodonesis, pericornealinjection, congestive iritis, various allergic reactions, and rarely, retinaldetachment.[4]

Neostigmine will cause slowing of the heart rate (bradycardia), for thisreason it is usually given along with aparasympatholyticdrug such asatropineorglycopyrrolate.

Gastrointestial symptoms occur earliest after ingestion and includeanorexia, nausea and vomiting, abdominal cramps and diarrhea.[5]

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Spectral data

Neostigmine shows notable UV/VIS absorption at 261nm, 267nm, and225nm.[6]

Neostigmine's 1H NMR Spectroscopy reveals shifts at: 7.8, 7.7, 7.4, 7.4,3.8, and 3.1 parts per million. The higher shifts are due to the aromatichydrogens. The lower shifts at 3.8ppm and 3.1ppm are due to theelectronic withdrawing nature of the tertiary and quarterary nitrogen,respectively.[7]

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Chemistry

Neostigmine, N,N,N-trimethyl-meta-(dimethylcarbomoyloxy)-

phenylammonium methylsulfonate, which can be viewed as a simplifiedanalog of physostigmine, is made by reacting 3-dimethylaminophenolwith N-dimethylcarbamoyl chloride, which forms the dimethylcarbamate,and its subsequent alkylation usingdimethylsulfateforming the desiredcompound.

DESCRIPTION: Prostigmin (neostigmine bromide), an anticholinesteraseagent, is available for oral administration in 15 mg tablets. Each tablet alsocontains gelatin, lactose, corn starch, stearic acid, sugar and talc.Chemically, neostigmine bromide is (m-hydroxyphenyl) trimethylammoniumbromide dimethylcarbamate. It is a white, crystalline, bitter powder, soluble1:1 in water, with a molecular weight of 303.20 and the following structuralformula:CLINICAL PHARMACOLOGY: Neostigmine inhibits the hydrolysis ofacetylcholine by competing with acetylcholine for attachment toacetylcholinesterase at sites of cholinergic transmission. It enhances

cholinergic action by facilitating the transmission of impulses acrossneuromuscular junctions. It also has a direct cholinomimetic effect on skeletalmuscle and possibly on autonomic ganglion cells and neurons of the centralnervous system. Neostigmine undergoes hydrolysis by cholinesterase and isalso metabolized by microsomal enzymes in the liver. Protein binding tohuman serum albumin ranges from 15 to 25 percent.Neostigmine bromide is poorly absorbed from the gastrointestinal tractfollowing oral administration. As arule, 15 mg of neostigmine bromide orally isequivalent to 0.5 mg of neostigmine methylsulfate parenterally, due to poorabsorption of the tablet from the intestinal tract. In a study in fastingmyasthenic patients, the extent of absorption was estimated to be 1 to 2

percent of the ingested 30 mg single oral dose. Peak concentrations inplasma occurred 1 to 2 hours following drug ingestion, with considerable
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individual variations. The half-life ranged from 42 to 60 minutes with a meanhalf-life of 52 minutes.INDICATIONS AND USAGE: Prostigmin is indicated for the symptomatictreatment of myasthenia gravis. Its greatest usefulness is in prolongedtherapy where no difficulty in swallowing is present. In acute myasthenic crisis

where difficulty in breathing and swallowing is present, the parenteral form(neostigmine methylsulfate) should be used. The patient can be transferred tothe oral form as soon as it can be tolerated.CONTRAINDICATIONS: Prostigmin is contraindicated in patients with knownhypersensitivity to the drug. Because of the presence of the bromide ion, itshould not be used in patients with a previous history of reaction to bromides.It is contraindicated in patients with peritonitis or mechanical obstruction of theintestinal or urinary tract.WARNINGS: Prostigmin should be used with caution in patients withepilepsy, bronchial asthma, bradycardia, recent coronary occlusion,vagotonia, hyperthyroidism, cardiac arrhythmias or peptic ulcer. As a rule, 15

mg of neostigmine bromide orally is equivalent to 0.5 mg of neostigminemethylsulfate parenterally, due to poor absorption of the tablet from theintestinal tract. Large doses should be avoided in situations where there mightbe an increased absorption rate from the intestinal tract. It should be usedwith caution when co- administered with anticholinergic drugs, in order toavoid reduction of intestinal motility.PRECAUTIONS: General:It is important to differentiate between myastheniccrisis and cholinergic crisis caused by overdosage of Prostigmin. Bothconditions result in extreme muscle weakness butrequire radically different treatment. (See OVERDOSAGE section.)Drug Interactions:Certain antibiotics, especially neomycin, streptomycin andkanamycin, have a mild but definite nondepolarizing blocking action whichmay accentuate neuromuscular block. These antibiotics should be used in themyasthenic patient only where definitely indicated, and then carefuladjustment should be made of adjunctive anticholinesterase dosage.Local and some general anesthetics, antiarrhythmic agents and other drugsthat interfere with neuromuscular transmission should be used cautiously, if atall, in patients with myasthenia gravis; the dose of Prostigmin may have to beincreased accordingly.Carcinogenesis, Mutagenesis and Impairment of Fertility:There have been nostudies with Prostigmin which would permit an evaluation of its carcinogenic

or mutagenic potential. Studies on the effect of Prostigmin on fertility andreproduction have not been performed.Pregnancy:Teratogenic Effects: Pregnancy Category C. There are noadequate or well-controlled studies of Prostigmin in either laboratory animalsor in pregnant women. It is not known whether Prostigmin can cause fetalharm when administered to a pregnant woman or can affect reproductivecapacity. Prostigmin should be given to a pregnant woman only if clearlyneeded.Nonteratogenic Effects: Anticholinesterase drugs may cause uterine irritabilityand induce premature labor when given intravenously to pregnant womennear term.

Nursing Mothers:It is not known whether Prostigmin is excreted in humanmilk. Because many drugs are excreted in human milk and because of the


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potential for serious adverse reactions from Prostigmin in nursing infants, adecision should be made whether to discontinue nursing or to discontinue thedrug, taking into account the importance of the drug to the mother.Pediatric Use:Safety and effectiveness in children have not been established.ADVERSE REACTIONS: Side effects are generally due to an exaggeration of

pharmacological effects of which salivation and fasciculation are the mostcommon. Bowel cramps and diarrhea may also occur.The following additional adverse reactions have been reported following theuse of either neostigmine bromide or neostigmine methylsulfate:Allergic:Allergic reactions and anaphylaxis.Neurologic: Dizziness, convulsions, loss of consciousness, drowsiness,headache, dysarthria, miosis and visual changes.Cardiovascular:Cardiac arrhythmias (including bradycardia, tachycardia,A-V block and nodal rhythm) and nonspecific EKG changes have beenreported, as well as cardiac arrest, syncope and hypotension. These havebeen predominantly noted following the use of the injectable form of

Prostigmin.Respiratory:Increased oral, pharyngeal and brochial secretions, anddyspnea. Respiratory depression, respiratory arrest and bronchospasm havebeen reported following the use of the injectable form of Prostigmin.Dermatologic:Rash and urticaria. Gastrointestinal:Nausea, emesis,flatulence andincreased peristalsis.Genitourinary:Urinary frequency. Musculoskeletal:Muscle cramps andspasms, arthralgia.Miscellaneous:Diaphoresis, flushing and weakness.OVERDOSAGE: Overdosage of Prostigmin can cause cholinergic crisis,which is characterized by increasing muscle weakness, and throughinvolvement of the muscles of respiration, may result in death. Myastheniccrisis, due to an increase in the severity of the disease, is also accompaniedby extreme muscle weakness andmay be difficult to distinguish from cholinergic crisis on a symptomatic basis.However, such differentiation is extremely important because increases in thedose of Prostigmin or other drugs in this class, in the presence of cholinergiccrisis or of a refractory or insensitive state, could have grave consequences.The two types of crises may be differentiated by the use of Tensilon(edrophonium chloride) as well as by clinical judgment.

Treatment of the two conditions differs radically. Whereas the presence ofmyasthenic crisisrequires more intensive anticholinesterase therapy,cholinergic crisiscalls for the prompt withdrawal of all drugs of this type. Theimmediate use of atropine in cholinergic crisis is also recommended.Atropine may also be used to abolish or minimize gastrointestinal side effectsor other muscarinic reactions; but such use, by masking signs of overdosage,can lead to inadvertent induction of cholinergic crisis.The LD50 of neostigmine methylsulfate in mice is 0.30.02 mg/kgintravenously, 0.540.03 mg/kg subcutaneously, and 0.3950.025

mg/kg intramuscularly; in rats the LD50 is 0.3150.019 mg/kgintravenously, 0.4450.032 mg/kg subcutaneously, and 0.4230.032 mg/kg

intramuscularly.DOSAGE AND ADMINISTRATION: The onset of action of Prostigmin given


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orally is slower than when given parenterally, but the duration of action islonger and the intensity of action more uniform. Dosage requirements foroptimal results vary from 15 mg to 375 mg per day. In some instances it maybe necessary to exceed these dosages, but the possibility of cholinergic crisismust be recognized. The average dose is 10 tablets (150 mg) administered

over a 24-hour period. The interval between doses is of paramountimportance. The dosage schedule should be adjusted for each patient andchanged as the need arises. Frequently, therapy is required day and night.Larger portions of the total daily dose may be given at times when the patientis more prone to fatigue (afternoon, mealtimes, etc.). The patient should beencouraged to keep a daily record of his or her condition to assist thephysician in determining an optimal therapeutic regimen.HOW SUPPLIED: Scored, white tablets containing 15 mg neostigminebromide bottles of 100 (NDC 0187- 3100-10). Imprint on tablets: (front)PROSTIGMIN 15; (back) ICN.Valeant Pharmaceuticals North America One Enterprise Aliso Viejo, CA

92656 USA (949) 461-6000 Rev. 08/06

ehidineFrom Wikipedia, the free encyclopedia


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Jump to: navigation, searchPethidine

Systematic (IUPAC) nameEthyl 1-methyl-4-phenylpiperidine-4-

carboxylateClinical data

Pregnancy cat. Category C (USA)Legal status Controlled (S8)(AU)

Schedule I(CA) ? (UK) ?(US)Schedule II

Dependenceliability

Moderate - High

Routes oral, intranasal, rectalPharmacokinetic data

Bioavailability 5060%Metabolism LiverHalf-life 35 hoursExcretion Renal

IdentifiersCAS number 57-42-1

ATC code N02AB02PubChem CID 4058DrugBank DB00454ChemSpider 3918

UNII 9E338QE28F

KEGG D08343

ChEMBL CHEMBL607

Chemical dataFormula C15H21NO2

Mol. mass 247.33g/molSMILES eMolecules&

PubChemInChI[show]
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(what is this?) (verify)

Pethidine(INN) or meperidine hydrochloride(USAN) (commonlyreferred to as Demerol[1] but also referred to as: isonipecaine; lidol;pethanol; piridosal; Algil; Alodan; Centralgin; Dispadol; Dolantin; Mialgin

(in Indonesia); Petidin Dolargan (in Poland);[2] Dolestine; Dolosal;Dolsin; Mefedina) is a fast-actingopioidanalgesicdrug.

Pethidine was the first synthetic opioid synthesized in 1932 as apotential anti-spasmodic agent by the chemist Otto Eislib. Its analgesicproperties were first recognized by Otto Schaumann working forIGFarben, Germany.[3]

Pethidine is indicated for the treatment of moderate to severepain, andis delivered as ahydrochloridesalt in tablets, as a syrup, or byintramuscular,subcutaneousorintravenous injection. For much of the20th century, pethidine was the opioid of choice for many physicians; in1983 60% of doctors prescribed it for acute pain and 22% for chronicsevere pain.[4]

Compared tomorphine, pethidine was supposed to be safer and carryless risk of addiction, and to be superior in treating the pain associatedwithbiliary spasmorrenal colicdue to its putative antispasmodiceffects. In fact, pethidine is no more effective than morphine at treatingbiliary or renal pain, and its low potency, short duration of action, andunique toxicity (i.e., seizures, delirium, other neuropsychological effects)relative to other available opioid analgesics have seen it fall out of favor

in recent years for all but a very few, very specific indications.[5] Severalcountries, including Australia, have put strict limits on its use.[6]Nevertheless, some physicians continue to use it as a first line strongopioid.

Contents [hide] 1 Pharmacodynamics/mechanism of action 2 Interactions 3 Adverse effects 4 Hazardous use, harmful use,

dependence, and diversion

4.1 Trends 5 Notes 6 References 7 References

[edit]

Pharmacodynamics/mechanism of action

Main article:OpioidLike morphine, pethidine exerts its analgesic effects by acting as an

agonist at themu opioid receptor.[7]

It also has akappa opioid receptoraction, which is of unknown clinical significance. It has structural
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similarities toatropineand othertropane alkaloidsand may have someof their effects and side effects.[1]In addition to these opioidergic andanticholinergiceffects, it haslocal anestheticactivity related to itsinteractions withsodium ion channels.

Pethidine's apparentin vitroefficacy as an "antispasmodic" is due to itslocal anesthetic effects. It does not have antispasmodic effectsinvivo.[8] Pethidine also has stimulant effects mediated by its inhibition ofthedopaminetransporter (DAT)andnorepinephrinetransporter (NAT).Because of its DAT inhibitory action, pethidine will substitute for cocainein animals trained to discriminate cocaine from saline.[9]

Severalanalogues of pethidinehave been synthesized that are potentinhibitors of the reuptake of themonoamine neurotransmittersdopamine andnorepinephrinevia DAT and NET.[10][11] It has also beenassociated with cases ofserotonin syndrome, suggesting some

interaction withserotonergic neurons, but the relationship has not beendefinitively demonstrated.[6][12][9][11] It is more lipid-soluble thanmorphine, resulting in a faster onset of action. Its duration of clinicaleffect is 120150 minutes although it is typically administered in 4-6hour intervals. Pethidine has been shown to be less effective thanmorphine,diamorphineorhydromorphoneat easing severe pain, orpain associated with movement or coughing.[12][9][11] It is also used forthe treatment ofpostanesthetic shivering.

Like other opioid drugs, pethidine has the potential to causephysical

dependenceoraddiction. Pethidine may be more likely to be abusedthan other prescription opioids, perhaps because of its rapid onset ofaction.[13] When compared withoxycodone,hydromorphone, andplacebo, pethidine was consistently associated with more euphoria,difficulty concentrating, confusion, and impaired psychomotor andcognitive performance when administered to healthy volunteers.[14] Theespecially severe side effects unique to pethidine among opioids serotonin syndrome, seizures, delirium, dysphoria, tremor areprimarily or entirely due to the action of its metabolite,norpethidine.[12][15]); accumulating with regular administration, or in

renal failure. Norpethidine is toxic and has convulsant andhallucinogenic effects. The toxic effects mediated by the metabolitescannot be countered with opioidreceptor antagonistssuch asnaloxoneornaltrexoneand are probably primarily due to norpethidine'santicholinergicactivity probably due to its structural similarity toatropinethough its pharmacology has not been thoroughly explored. Theneurotoxicity of pethidine's metabolites is a unique feature of pethidinecompared to other opioids. Pethidine's metabolites are furtherconjugated withglucuronic acidand excreted into the urine.
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[edit]

Interactions

Pethidine has serious interactions that can be dangerous withMAOIs(e.g., furazolidone, isocarboxazid, moclobemide, phenelzine,procarbazine, selegiline, tranylcypromine). Such patients may sufferagitation, delirium, headache, convulsions, and/orhyperthermia. Fatalinteractions have been reported including the death ofLibby Zion.[16] Itis thought to be caused by an increase in cerebral serotoninconcentrations. It is possible that pethidine can also interact with anumber of other medications, including muscle relaxants, someantidepressants,benzodiazepines, andalcohol.

Pethidine is also relatively contraindicated for use when a patient issuffering fromliver, orkidneydisease, has a history of seizures orepilepsy, has an enlargedprostateor urinary retention problems, or

suffers fromhypothyroidism,asthma, orAddison's disease.[edit]

Adverse effects

The adverse effects of pethidine administration are primarily those ofthe opioids as a class: nausea, vomiting, sedation, dizziness,diaphoresis, urinary retention and constipation. Unlike other opioids, itdoes not causemiosis. Overdosage can cause muscle flaccidity,respiratory depression,obtundedness, cold and clammy skin,

hypotension and coma. A narcotic antagonist such as naloxone isindicated to reverse respiratory depression. Serotonin syndrome hasoccurred in patients receiving concurrent antidepressant therapy withselective serotonin reuptake inhibitorsormonoamine oxidase inhibitors.Convulsive seizures sometimes observed in patients receivingparenteral pethidine on a chronic basis have been attributed toaccumumulation in plasma of the metabolite norpethidine(normeperidine). Fatalities have occurred following either oral orintravenous pethidine overdosage.[17][18]

[edit]

Hazardous use, harmful use, dependence, and
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diversion

[edit]

Trends

In data from the U.S.Drug Abuse Warning Network, mentions ofhazardous or harmful use of pethidine declined between 1997 and2002, in contrast to increases forfentanyl,hydromorphone,morphine,andoxycodone.[19] The number of dosage units of pethidine that werereported lost or stolen in the U.S. increased 16.2% between 2000 and2003, from 32,447 to 37,687.[20]

[edit]

Notes

This article uses the terms "hazardous use", "harmful use", and"dependence" in accordance with Lexicon of alcohol and drug termspublished by theWorld Health Organization(WHO) in 1994.[21] In WHOusage, the first two terms replace the term "abuse" and the third termreplaces the term "addiction".[21]http://pubs.acs.org/doi/suppl/10.1021/jm0401614/suppl_file/jm0401614_s.pdf

The first QSAR focused on exploring how changing the nature of thearomatic substituents alters monoamine reuptake inhibitoraffinities.[22][23]

Pethidine

Nitrile Precursors Pethidine/Analogs Ki & IC50, M

Ar [3H]Pax [3H]CFT [3H]DopPh ? 0.413 ? 17.8 ? 12.6

p-F 10.1 0.308 45% 10.7 8% 47%
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p-Cl 5.11 0.277 22.0 4.10 36% 26.9

p-I 0.430 0.0211 8.34 3.25 36.7 11.1p-Me 13.7 1.61 41.8 12.4 22% 76.2

m,p-Cl2 0.805 0.0187 2.67 0.125 11.1 1.40

-Naph 0.125 0.0072 2.36 1.14 21.8 11.6Mean SEMof 3 experiments in triplicate. % inhibition @100MParticular emphasis needs to be placed on the D/S of the p-iodo and-Naph analogs.

p-I , D/S = 155 BN, D/S = 158In behavioral activity studies, none of the compounds would substitutefor cocaine in mice, and they were also inactive as LMA stimulants.

This is in direct contrast to the methylphenidate analogs which moreconvincingly displayed cocaine-like traits.

The aryl moiety can be modified depending on whether DAT affinity isactually desirable or SERT affinity is wanted.

(J. Rhoden et, al.)[24]

Meperidinewas initially found to be selective for the SERT over theDAT.

All the further analogs in the second QSAR study are based around the

m,p-Cl2 phenyl substitution pattern.m,p-Cl2 Meperidine esters

RCFTnM

ParanM

Ratio

Et 125 18.7 6.7Me 383 15.4 25n-Pr

449 16.4 27

i-Pr 271 43.3 6.3n-Bu 864 16.0 54

n-Pen

283 44.3 6.4

The N-demethyl metabolite of meperidine is toxic and accumulatesupon repeat dosing.

Also, the ester in meperidine is readily hydrolyzed.

The above picture is of "UCB" a SRI/NK1antagonist currently underdevelopment byAstra Zeneca.[25]

[edit]
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PETHIDINE INJECTION INTRAMED

25 mg/mL


50 mg/mL


100 mg/2 mL

SCHEDULING STATUS:

S7

PROPRIETARY NAME

(and dosage form):

PETHIDINE INJECTION INTRAMED 25 mg/mL

PETHIDINE INJECTION INTRAMED 50 mg/mL

PETHIDINE INJECTION INTRAMED 100 mg/2 mL

COMPOSITION:1 mL Ampoules containing 25 mg Pethidine Hydrochloride.

1 mL Ampoules containing 50 mg Pethidine Hydrochloride.

2 mL Ampoules containing 100 mg Pethidine Hydrochloride.

PHARMACOLOGICAL CLASSIFICATION:

A 2.9 Other Analgesics

PHARMACOLOGICAL ACTION:

Pethidine has an analgesic potency approximately equal to one-fifth that of

morphine. Pethidine binds to the opioid receptors in the central nervous systemand exerts its main pharmacological action on the central nervous system and

the neural elements of the bowel.

INDICATIONS:

Pethidine is indicated for the relief of pain. It is particularly useful for the relief

of post-operative pain. It may be used in obstetric practice to relieve labour

pain.

CONTRA-INDICATIONS:

Pethidine is contra-indicated in respiratory depression, obstructive pulmonarydisease, hepatic insufficiency and pain following cholecystectomy and for the


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relief of pain associated with renal colic. Increased intracranial pressure is also

a contra-indication. It must not be administered to patients receiving

phenothiazines or meprobamates. Pethidine should not be given to patients who

are being treated with monoamine oxidase inhibitors, or within 2 weeks of thediscontinuation of such treatment.

WARNING:

Dependence can occur.

DOSAGE AND DIRECTIONS FOR USE:

Children: 1 to 1,5 mg per kg body-mass given intramuscular or subcutaneous,

but not exceeding the adult dose.

Adults: 50 to 100 mg S.C., I.M. or in reduced doses I.V. repeated every 3 to

4 hours if required but not exceeding maximum of 150 mg as a single dose.

Obstetric Analgesia: 50 mg to 100 mg I.M./S.C. as soon as contractions occur

at regular intervals. This dose may be repeated after 1 to 3 hours if necessary.

SIDE EFFECTS AND SPECIAL PRECAUTIONS:

It may give rise to dry mouth, dizziness, perspiration, vomiting, constipation,

urinary retention, dysphoria and nausea. Monoamine oxidase inhibitorspotentiate the action of pethidine and this may have severe consequences, such

as collapse of or severe respiratory depression. Local reactions often follow

injections of pethidine; general hypersensitivity reactions occur. Intravenous

injection may produce vasodilation and hypotension. Pethidine should be given

with caution to elderly patients and to patients with supraventriculartachycardia. If given in conjunction with meprobamate or phenothiazines

hypotension may develop. Pethidine must be regarded as a drug of addiction. It

may prolong labour and cause respiratory depression in the newborn.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF

ITS TREATMENT:

Overdosage with pethidine causes muscular twitching, tremors, hyperactive

reflexes, dilated pupils and convulsions followed by respiratory depression,

hypotension with circulatory failure and deepening coma. Death may occur

from respiratory failure.Treatment of Toxic Effects:The stomach should be emptied by aspiration and lavage if oral ingestionoccurs. The antidote is naloxone hydrochloride 400 to 2000 g given

subcutaneously, intramuscularly or intravenously, repeated at intervals of 2 to

3 minutes if necessary. In children a dose of 5 to 10 g/kg body-mass may be

given, similarly repealed at intervals of 2 to 3 minutes. Further treatment issupportive and symptomatic. The circulation should be maintained with

infusions of dextrose injection and suitable electrolyte solutions. Assisted

respiration may be necessary.

IDENTIFICATION:


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Clear solution in clear glass ampoules.

PRESENTATION:

Boxes of 1 mL Ampoules in 10s and 100s 25 mg/mLBoxes of 1 mL Ampoules in 10s and 100s 50 mg/mL

Boxes of 2 mL Ampoules in 10s and 100s 100 mg/2 mL

STORAGE INSTRUCTIONS:

Store below 25C. Protect from light.

Keep out of the reach of children.

REGISTRATION NUMBER:

25 mg/1 mL

=B/2.9/92

850 mg/1 mL

=B/2.9/92

5100 mg/2 mL

=B/2.9/16

30

NAME AND BUSINESS ADDRESS OF APPLICANT:

Pharmac

are

Limited

7

Fairclough Road

PORT

ELIZAB

ETH

6001

Marketed by:

Intramed,

Division of

Pharmacare

6 Gibaud RoadPORT

ELIZABETH

6001

pethidine

> Indication &Dosage> Overdosage

> SpecialPrecautions

>Adverse DrugReactions> Drug Interactions

> Food Interaction> Pregnancy Category(US FDA)

> Storage> Mechanism of Action> MIMS Class

>ATC Classification

Related Information

See related pethidine information

Abbreviation Index
http://www.mims.com/resources/drugs/common/Abbreviation-Index.pdfhttp://www.mims.com/resources/drugs/common/Abbreviation-Index.pdfhttp://www.mims.com/resources/drugs/common/Abbreviation-Index.pdf


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Indication & Dosage OralModerate to severe acutepainAdult:As hydrochloride: 50-150 mg every 4Child:As hydrochloride: Children 2 mth to 12yr: 0.5-2 mg/kg; 12-18 yr: 50-100 mg. Repeat

dose every 4-6 hr if necessary.Elderly:As hydrochloride: 50 mg every 4 hr.Renal impairment:Dose reductions may benecessary.Hepatic impairment:Dose reductions may bnecessary.ParenteralModerate to severe acute painAdult:As hydrochloride: 25-100 mg IM/SC inor 25-50 mg by slow IV inj repeated after 4 hrChild:As hydrochloride: SC/IM: Children 2 m

to 12 yr: 0.5-2 mg/kg; 12-18 yr: 25-100 mg.Repeat dose every 4-6 hr if needed. IV inj:Neonates and children 12 yr: 0.5-1 mg/kg IVinj every 10-12 hr if needed in those up to 2and every 4-6 hr if needed in older children. 118 yr: 25-50 mg every 4-6 hr if needed. IV injand continuous IV infusion: Children 1 mth to18 yr: Initially, 1 mg/kg by IV inj as a loadingdose, then 100-400 mcg/kg/hr continuous IVinfusion adjusted according to response.Elderly:25 mg every 4 hr.Renal impairment:Dose reductions may benecessary.Hepatic impairment:Dose reductions may bnecessary.ParenteralObstetric analgesiaAdult:As hydrochloride: 50-100 mg by IM/Sinj as soon as contractions occur at regularintervals; repeat after 1-3 hr if needed. Max:400 mg in 24 hr.

Renal impairment:Dose reductions may benecessary.Hepatic impairment:Dose reductions may bnecessary.ParenteralPreoperative medicationAdult:As hydrochloride: 25-100 mg IM/SCgiven 1 hr before surgery.Child:As hydrochloride: 0.5-2 mg/kg IM/SCgiven 1 hr before surgery.Renal impairment:Dose reductions may be

necessary.Hepatic impairment:Dose reductions may b
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necessary.ParenteralPostoperative painAdult:As hydrochloride: 25-100 mg IM/SC inevery 2-3 hr if necessary.

Renal impairment:Dose reductions may benecessary.Hepatic impairment:Dose reductions may bnecessary.ParenteralAdjunct to nitrous oxide-oxygenanaesthesiaAdult:As hydrochloride: 10-25 mg by slow Iinj.Renal impairment:Dose reductions may benecessary.

Hepatic impairment:Dose reductions may bnecessary.

Reconstitution:IV infusion: Dilute with gluco5% or sodium chloride 0.9% to requiredvolume. IV inj: Dilute with water for inj to aconcentration of 5-10 mg/ml.Incompatibility:Incompatible with allopurinoamphotericin B cholesteryl sulfate complex,cefepime, cefoperazone, doxorubicin liposomidarubicin, imipenem/cilastatin, minocycline.not admix with aminophylline, amobarbital,floxacillin, furosemide, heparin, morphine,phenobarbital, phenytoin, thiopental,pentobarbital.

Overdosage Symptoms: CNS/respiratory depression,mydriasis, bradycardia, pulmonary oedema,chronic tremor, CNS excitability, seizures.Treatment: Symptomatic. Naloxone can beused to reverse opioid effects. Do not usenaloxone for pethidine-induced seizures.

Special Precautions May impair ability to drive or operatemachinery. Hypovolaemia, CV disease; adreinsufficiency; biliary tract disorder; CNSdepression or coma; history of drug abuse oracute alcoholism; head injury, intracraniallesions, elevated intracranial pressure; hepatior renal impairment; morbidly obese; prostatihyperplasia; toxic psychoses; pre-existingrespiratory compromise (hypoxia and/orhypercapnia), COPD or other obstructiveairway disease; sickle-cell disease;

supraventricular tachycardia; thyroiddysfunction. Elderly and debilitated patients.
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Withdraw gradually. Pregnancy (avoidprolonged use or high doses at term) andlactation.

Adverse Drug Reactions Hypotension; fatigue, drowsiness, dizziness,nervousness, headache, restlessness, malais

confusion, depression, hallucinations, tremormuscle twitches, increased intracranialpressure, seizure, serotonin syndrome; rash,urticaria; nausea, vomiting, constipation,anorexia, stomach cramps, xerostomia, biliarspasm, paralytic ileus, sphincter of Oddi spasureteral spasms, decreased urination; pain atinj site; weakness; dyspnoea; histaminerelease, physical and psychologicaldependence.

Drug Interactions Increased pethidine metabolite levels withaciclovir,cimetidine,ritonavir. Reducedanalgesic effects withphenytoin, barbituratesAdditive sedative and/or respiratory depressieffects withalcohol, barbiturates,benzodiazepines, phenothiazines, TCAs, othCNS depressants.Potentially Fatal: Increased risk of serotoninsyndrome with MAOIs (not be givenconcurrently or within 14 days of theirdiscontinuation), serotonin agonists, serotoni

reuptake inhibitors,sibutramine, TCAs.Click to view more pethidine Drug Interaction

Food Interaction Increased CNS depression with valerian, StJohn's wort, kava kava, gotu kola.

Pregnancy Category (US FDA)Storage Oral: Protect from light. Parenteral: Store at

room temperature. Do not freeze and protectfrom light.

Mechanism of Action Pethidine is a phenylpiperidine derivative opianalgesic. It acts mainly as mu-receptoragonist. Like most, opioid analgesics, it mimi

endogenous opioids by activating opioidreceptors in the central and peripheral nervousystem. It reduces the release ofneurotransmitter substances and also reducethe activity of postsynaptic neurons in the spicord thus preventing transmission of painimpulse.Absorption:Absorbed from the GI tract; only50% reaches the circulation due to 1st-passeffect. Peak plasma concentrations after 1-2(oral). Variable absorption (IM).

Distribution: Crosses the placenta; entersbreast milk; appears in CSF. Protein-binding:
http://www.mims.com/USA/interaction/Search/pethidine%7Ccimetidinehttp://www.mims.com/USA/interaction/Search/pethidine%7Ccimetidinehttp://www.mims.com/USA/interaction/Search/pethidine%7Ccimetidinehttp://www.mims.com/USA/interaction/Search/pethidine%7Critonavirhttp://www.mims.com/USA/interaction/Search/pethidine%7Critonavirhttp://www.mims.com/USA/interaction/Search/pethidine%7Critonavirhttp://www.mims.com/USA/interaction/Search/pethidine%7Cphenytoinhttp://www.mims.com/USA/interaction/Search/pethidine%7Cphenytoinhttp://www.mims.com/USA/interaction/Search/pethidine%7Cphenytoinhttp://www.mims.com/USA/interaction/Search/pethidine%7Calcoholhttp://www.mims.com/USA/interaction/Search/pethidine%7Calcoholhttp://www.mims.com/USA/interaction/Search/pethidine%7Calcoholhttp://www.mims.com/USA/interaction/Search/pethidine%7Csibutraminehttp://www.mims.com/USA/interaction/Search/pethidine%7Csibutraminehttp://www.mims.com/USA/interaction/Search/pethidine%7Csibutraminehttp://www.mims.com/USA/interaction/Search/pethidinehttp://www.mims.com/USA/Viewer/Html/PregDef.htmhttp://www.mims.com/USA/Viewer/Html/PregDef.htmhttp://www.mims.com/USA/drug/info/pethidine/?type=brief&mtype=generic#Storagehttp://www.mims.com/USA/drug/info/pethidine/?type=brief&mtype=generic#Storagehttp://www.mims.com/USA/drug/info/pethidine/?type=brief&mtype=generic#Actionshttp://www.mims.com/USA/drug/info/pethidine/?type=brief&mtype=generic#Actionshttp://www.mims.com/USA/drug/info/pethidine/?type=brief&mtype=generic#Actionshttp://www.mims.com/USA/drug/info/pethidine/?type=brief&mtype=generic#Storagehttp://www.mims.com/USA/Viewer/Html/PregDef.htmhttp://www.mims.com/USA/interaction/Search/pethidinehttp://www.mims.com/USA/interaction/Search/pethidine%7Csibutraminehttp://www.mims.com/USA/interaction/Search/pethidine%7Calcoholhttp://www.mims.com/USA/interaction/Search/pethidine%7Cphenytoinhttp://www.mims.com/USA/interaction/Search/pethidine%7Critonavirhttp://www.mims.com/USA/interaction/Search/pethidine%7Ccimetidine


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60-80%.Metabolism: Extensively hepatic via hydrolyto pethidinic acid and norpethidinic acid anddemethylation to norpethidine.Excretion: Via urine (small amounts as

unchanged drug); elimination half-life: 3-5 hr(unchanged drug), 20 hr (norpethidine).

MIMS Class Analgesics (Opioid)

ATC Classification N02AB02 - Pethidine ; Belongs to the class ophenylpiperidine derivative opioids. Used torelieve pain.

MophineFrom Wikipedia, the free encyclopedia

Jump to: navigation, searchThis article is about the drug. For other meanings, seeMorphine(disambiguation)."Morphia" redirects here. For other uses, seeMorphia (disambiguation).Not to be confused withMorphinae,Morphea, orMorpholine.

Morphine
http://www.mims.com/USA/Browse/Classification/http://www.mims.com/USA/Browse/Classification/http://www.mims.com/USA/drug/search/Analgesics%20(Opioid)http://www.mims.com/USA/drug/search/Analgesics%20(Opioid)http://en.wikipedia.org/wiki/Morphine_(disambiguation)http://en.wikipedia.org/wiki/Morphine_(disambiguation)http://en.wikipedia.org/wiki/Morphine_(disambiguation)http://en.wikipedia.org/wiki/Morphine_(disambiguation)http://en.wikipedia.org/wiki/Morphia_(disambiguation)http://en.wikipedia.org/wiki/Morphia_(disambiguation)http://en.wikipedia.org/wiki/Morphia_(disambiguation)http://en.wikipedia.org/wiki/Morphinaehttp://en.wikipedia.org/wiki/Morphinaehttp://en.wikipedia.org/wiki/Morphinaehttp://en.wikipedia.org/wiki/Morpheahttp://en.wikipedia.org/wiki/Morpheahttp://en.wikipedia.org/wiki/Morpheahttp://en.wikipedia.org/wiki/Morpholinehttp://en.wikipedia.org/wiki/Morpholinehttp://en.wikipedia.org/wiki/Morpholinehttp://en.wikipedia.org/wiki/File:Morphin_-_Morphine.svghttp://en.wikipedia.org/wiki/Morpholinehttp://en.wikipedia.org/wiki/Morpheahttp://en.wikipedia.org/wiki/Morphinaehttp://en.wikipedia.org/wiki/Morphia_(disambiguation)http://en.wikipedia.org/wiki/Morphine_(disambiguation)http://en.wikipedia.org/wiki/Morphine_(disambiguation)http://www.mims.com/USA/drug/search/Analgesics%20(Opioid)http://www.mims.com/USA/Browse/Classification/


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Systematic (IUPAC) name

(5,6)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol

Clinical dataTrade names Mscontin, OramorphAHFS/Drugs.com monographPregnancy cat. C (AU) C (US)

Legal status Controlled (S8)(AU)Schedule I(CA)Schedule II(US)

Dependenceliability

High

Routes Inhalation(smoking),insufflation(snorting),oral,rectal,subcutaneous(S.C),intramuscular(I.M),intravenous(I.V), andintrathecal(I.T)

Pharmacokinetic dataBioavailability 20-40% (oral), 36-71%

(rectally),[1] 100%(IV/IM)

Protein binding 3040%Metabolism Hepatic90%Half-life 23 hExcretion Renal 90%, biliary 10%

IdentifiersCAS number 57-27-2

64-31-3 (neutral

sulfate),52-26-6 (hydrochloride)ATC code N02AA01
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PubChem CID 5288826IUPHAR ligand 1627DrugBank DB00295ChemSpider 4450907

UNII 76I7G6D29C

KEGG D08233

ChEBI CHEBI:17303

ChEMBL CHEMBL70

Chemical dataFormula C17H19NO3

Mol. mass 285.34SMILES eMolecules&

PubChemInChI[show]

Physical dataSolubilityinwater HCl & sulf.: 60 mg/mL

(20 C)(what is this?) (verify)

Morphine(INN) ( /mfin/;MS Contin, MSIR, Avinza, Kadian,Oramorph, Roxanol, Kapanol) is apotentopiateanalgesicdrugthat isused to relieve severe pain. It was first isolated in 1804 byFriedrichSertrner, first distributed by him in 1817, and first commercially sold byMerckin 1827, which at the time was a single small chemists' shop. Itwas more widely used after the invention of thehypodermic needlein1857. It took its name from the Greek god of dreamsMorpheus(Greek:).[2]

Morphine is the most abundantalkaloidfound inopium, the dried sap(latex) derived from shallowly slicing the unripe seedpods of the opium,or common and/or edible, poppy,Papaver somniferum. Morphine wasthe firstactive principlepurified from a plant source and is one of atleast 50 alkaloids of several different types present in opium,poppystraw concentrate, and other poppy derivatives. Morphine is generally 8to 14 percent of the dry weight of opium,[3] although specially bredcultivarsreach 26 percent or produce little morphine at all, under 1percent, perhaps down to 0.04 percent. The latter varieties, includingthe 'Przemko' and 'Norman' cultivars of the opium poppy, are used toproduce two other alkaloids,thebaineandoripavine, which are used inthe manufacture of semi-synthetic and synthetic opioids likeoxycodoneandetorphineand some other types of drugs.P. bracteatumdoes notcontain morphine or codeine, or other narcoticphenanthrene-type,alkaloids. This species is rather a source ofthebaine.[4] Occurrence ofmorphine in otherpapaveralesandpapaveraceae, as well as in somespecies ofhopsandmulberrytrees has not been confirmed. Morphineis produced most predominantly early in the life cycle of the plant. Pastthe optimum point for extraction, various processes in the plant producecodeine,thebaine, and in some cases negligible amounts ofhydromorphone,dihydromorphine,dihydrocodeine, tetrahydrothebaine,
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