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									             Therapeutic Drug
               Monitoring
             Barbiturates and Benzodiazepines




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   Barbiturates are drugs that act as central nervous
    system depressants, and by virtue of this they produce
    a wide spectrum of effects, from mild sedation to
    anesthesia. They are also effective as anxiolytics,
    hypnotics and as anticonvulsants. They have
    addiction potential, both physical and psychological.
    Barbiturates have now largely been replaced by
    benzodiazepines mainly because benzodiazepines are
    significantly less dangerous in overdose. Barbiturates
    are derivatives of barbituric acid
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     Barbiturates like pentobarbital and phenobarbital were long
      used as anxiolytics and hypnotics. Today benzodiazepines
      have largely supplanted them for these purposes, because
      benzodiazepines have less potential for lethal overdoses
     Barbiturates are classified as ultrashort-, short-, intermediate-,
      and long-acting, depending on how quickly they act and how
      long their effects last. Barbiturates are still widely used in
      surgical anesthesia, especially to induce anesthesia. Ultrashort
      barbiturates such as thiopental (Pentothal) and methohexital
      produce unconsciousness within about a minute of intravenous
      (IV) injection.




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   These drugs are used to prepare patients for
    surgery; other general anesthetics like nitrous
    oxide are then used to keep the patient from
    waking up before the surgery is complete.
    Phenobarbital is used as an anticonvulsant for
    people suffering from seizure disorders.




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   Long-acting barbiturates such as phenobarbital
    (Luminal) is prescribed for two main reasons.
    When taken at bedtime, it helps treat insomnia.
    When taken during the day, it has sedative
    effects that can aid in the treatment of tension
    and anxiety. These same effects have been
    found helpful in the treatment of convulsive
    conditions like epilepsy. Long-acting
    barbiturates take effect within one to two hours
    and last 12 hours or longer.
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                      Barbital
Sedative, Barbiturate
Synonyms. Barb; Barbitalum; Barbitone; Diemalum;
  Diethylmalonylurea; Malonal.

Colourless crystals or white crystalline powder. M.p.
  188° to 192°.
Soluble 1 in about 130 of water, 1 in 13 of boiling
  water, 1 in 14 of ethanol, 1 in 75 of chloroform, and 1
  in 35 of ether; soluble in acetone, ethyl acetate,
  petroleum ether, acetic acid, amyl alcohol, pyridine,
  aniline, and nitrobenzene, and in solutions of alkalis.

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Barbital Sodium
Synonyms. Barbitalum Natricum; Barbitone Sodium;
  Diemalnatrium; Soluble Barbitone.
Proprietary name. Neurinase

A white crystalline powder. A solution in water slowly
  decomposes. M.p. about 190°.
Soluble 1 in 5 of water (1 in 2.5 of boiling water) and 1
  in 400 of ethanol; practically insoluble in chloroform
  and ether.
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Colour Tests.
Koppanyi - violet; Mercurous Nitrate—black.
Koppanyi test involves mixing 3 drops of each of the following
   solutions:
A: Dissolve 0.1 g cobalt acetate tetrahydrate in 100 mL absolute
   methanol and 0.2 mL glacial acetic acid
B: Mix 5 mL isopropylamine with 95 mL methanol

Zwikker Test - violet
Zwikker's reagent (mix 40 mL of a 10% solution of copper
  sulfate with 10 mL of pyridine and add sufficient water to
  produce 100 mL), pink.

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             Disposition in the Body
Readily absorbed after oral administration. It is excreted
  slowly in the urine almost entirely as unchanged
  drug; about 2% of a dose is excreted in 8 h, about
  16% in 32 h, and detectable amounts may still be
  present in the urine after 16 days.
Barbital is a metabolite of metharbital.

Therapeutic concentration
In plasma, usually in the range 5 to 30 mg/L.

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                     Toxicity
The estimated minimum lethal dose is 2 g. Toxic effects
  may be produced with blood concentrations of about
  20 mg/L or more, and concentrations greater than
  90 mg/L may be lethal.

In 6 cases of acute poisoning, the amounts ingested
   ranged from 5 to about 25 g. In 2 cases, death ensued
   after 150 and 160 h when the serum concentrations
   were about 100 and 170 mg/L respectively.

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Half–life
Plasma half–life, about 2 days.

Volume of distribution
About 0.5 L/kg.

Protein binding
In plasma, less than 20%.

Dose
Barbital has been given in a dose of 300 to 600 mg.
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                         Phenobarbital
Hypnotic, Sedative

Synonyms. Fenobarbital; Phenemalum; Phenobarbitalum; Phenobarbitone;
   Phenylethylbarbituric Acid; Phenylethylmalonylurea.

Proprietary names. Aparoxal; Comizial; Edhanol; Fenemal; Fenocriz;
   Gardenal(e); Kaneuron; Luminal(e); Luminaletas; Luminalette;
   Luminaletten; Neurobiol; Phenaemal; Phenaemaletten; Solfoton. It is an
   ingredient of many proprietary preparations

Colourless crystals or a white crystalline powder which may exhibit
   polymorphism. M.p. 174° to 178°.

Soluble 1 in 1000 of water, 1 in 8 of ethanol, 1 in 40 of chloroform, 1 in 13 of
   ether, and 1 in about 700 of benzene.

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Phenobarbital Sodium
Synonyms. Phenemalnatrium; Phenobarbitone Sodium; Sodium
  Phenylethylbarbiturate; Soluble Phenobarbitone.

Proprietary names. Garnenal(e); Luminal(e).

A white hygroscopic powder, granules, or flakes. M.p. about
  175°.

Soluble 1 in about 1 of water and 1 in about 10 of ethanol;
  practically insoluble in chloroform and ether.

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Colour Tests.
Koppanyi–Zwikker Test—violet; Mercurous Nitrate—black.
Koppanyi test involves mixing two solutions:
A: Dissolve 0.1 g cobalt acetate tetrahydrate in 100 mL absolute
   methanol and 0.2 mL glacial acetic acid
B: Mix 5 mL isopropylamine with 95 mL methanol

Thin–layer Chromatography.
System TD—Rf 47; system TE—Rf 28; system TF—Rf 65;
  system TH—Rf 38; system TAD—Rf 53; system TAE—Rf
  85. (Mercuric chloride–diphenylcarbazone reagent, positive;
  mercurous nitrate spray, black; Zwikker’s reagent, pink.)

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             Disposition in the Body
Readily absorbed after oral administration. During
  chronic dosing, up to about 25% of a dose is excreted
  in the urine in 24 h as unchanged drug and up to
  about 17% as total 4–hydroxyphenobarbital, about
  half of which is the glucuronide conjugate. Urinary
  excretion of unchanged drug is increased when the
  urine is alkaline or when the urinary volume is
  increased; the excretion of conjugated 4–
  hydroxyphenobarbital is reduced in patients with liver
  disease. After a single dose, about 80 to 90% is
  excreted in the urine in 16 days. Phenobarbital
  crosses the placenta and is found in breast milk.

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             Therapeutic concentration
In plasma, usually in the range 2 to 30 mg/L. However, there is
   considerable intersubject variation and there does not appear to
   be any correlation between plasma concentration and clinical
   effect. Concentrations in CSF (cerebrospinal fluid) reach about
   50% of those in plasma.

Following a single oral dose of 100 mg to 6 subjects, peak serum
  concentrations of 2.1 to 3.8 mg/L (mean 2.9) were attained in
  0.5 to 4 h (mean 1.5).

Following daily oral doses of 100 mg to 10 subjects for 15 days,
  serum concentrations of 10.6 to 22.1 mg/L (mean 17) were
  reported 12 h after a dose.

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                     Toxicity
The estimated minimum lethal dose is 1.5 g although
  recovery has occurred after ingestion of as much as
  16 g. Toxic effects have been associated with blood
  concentrations of 4 to 90 mg/L and fatalities with
  concentrations of 4 to 120 mg/L. However, a degree
  of tolerance may develop in chronic dosing.
Blood concentrations ranged from 10 to 300 mg/L
  (mean 86) in 113 fatalities attributed to phenobarbital
  overdose

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In 20 fatalities caused by phenobarbital
  overdose, the following postmortem
  concentrations were reported: blood 15 to
  540 mg/L (mean 113), brain 0 to 833 μg/g
  (mean 135), kidney 17 to 867 μg/g (mean
  152), liver 24 to 1450 μg/g (mean 236), spleen
  0 to 850 μg/g (mean 137).
.

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Bioavailability.: Almost 100%

Half–life.: Plasma half–life, about 90 to 100 h in adults.

Volume of distribution.: About 0.5 L/kg.

Clearance.: Plasma clearance, about 0.06 mL/min/kg.

Protein binding.: In plasma, about 50%.

Dose.: 60 to 180 mg daily.
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                     Butalbital
Sedative
Synonyms. Alisobumalum; Allylbarbituric Acid;
  Itobarbital; Tetrallobarbital.

A white crystalline powder. M.p. 138° to 139°.
Slightly soluble in cold water; soluble in boiling water;
  soluble in acetone, ethanol, chloroform, ether, and
  glacial acetic acid; soluble in aqueous solutions of
  alkali hydroxides and carbonates.

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Colour Tests
Zwikker Test—violet; Vanillin Reagent (Dissolve 2 g
 vanillin in 100 mL concentrated sulfuric acid ) —
 orange/colourless.

Thin–layer Chromatography.
System TB—Rf 01; system TD—Rf 54; system TE—Rf
  44; system TF—Rf 67; system TH—Rf 67; system
  TAD—Rf 57; system TAE—Rf 87. (Mercurous
  nitrate spray, black; acidified potassium
  permanganate solution, yellow–brown.)

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Disposition in the Body.
Absorbed after oral administration. About 5% of a dose is
  excreted in the urine as unchanged drug in 96 h and 20 to 60%
  as 5-(2,3–dihydroxypropyl)-5–isobutylbarbituric acid.

Therapeutic concentration.
In plasma, usually in the range 1 to 10 mg/L.

A small group of healthy volunteers was administered 100 mg
  butalbital orally. Peak blood concentrations reached 2.1 mg/L
  and fell to 1.5 mg/L after 24 h.

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Toxicity
Plasma concentrations of 10 to 25 mg/L are usually associated
   with toxic effects.

The following concentrations were reported in one fatality
  attributed to butalbital overdose: blood 26 mg/L, liver 50 μg/g.

Half–life
Derived from urinary excretion data, about 30 to 40 h.

Dose: 150 to 400 mg daily as a sedative.

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                      Hexobarbital
Sedative

Synonyms. Ciclobarbital; Enhexymalum; Enimal;
  Hexobarbitalum; Hexobarbitone; Methexenyl; Methyl–
  cyclohexenylmethyl–barbitursäure; Methylhexabarbital.
Proprietary names. Noctivane; Sombulex.

Colourless crystals or a white crystalline powder. M.p. 145° to
  147°.

Practically insoluble in water; soluble 1 in 45 of ethanol, 1 in 4 of
   chloroform, and 1 in 80 of ether; soluble in acetone, benzene,
   and methanol.
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             Hexobarbital Sodium

Synonyms. Enhexymalnatrium; Hexenalum; Sodium
  Hexobarbitone; Soluble Hexobarbital.

Proprietary names. Evipan-Natrium; Noctivane Sodium.

A white, very hygroscopic powder.

Very soluble in water; freely soluble in ethanol, acetone, and
  methanol; practically insoluble in chloroform, ether, and
  benzene. A solution in water slowly decomposes

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Colour Tests
Koppanyi–Zwikker Test—violet; Mercurous Nitrate—black;
  Vanillin Reagent—brown/violet.

Dille-Koppanyi Reagent, Modified
Solution A: Dissolve 0.1 g of cobalt (II) acetate dihydrate in 100
  mL of methanol. Add 0.2 mL of glacial acetic acid and mix.
Solution B: Add 5 mL of isopropylamine to 95 mL of methanol.

Procedure: Add 2 volumes of solution A to the drug, followed
  by 1 volume of solution B.

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Thin–layer Chromatography.
System TD—Rf 65; system TE—Rf 53; system
  TF—Rf 65; system TH—Rf 85; system
  TAD—Rf 69; system TAE—Rf 85. (Mercuric
  chloride–diphenylcarbazone reagent, positive;
  mercurous nitrate spray, black; acidified
  potassium permanganate solution, yellow–
  brown on violet.)

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             Disposition in the Body
Readily absorbed after oral administration. The
 sodium salt has a very short duration of action
 and is usually administered intravenously.
 Hexobarbital is inactivated in the liver by N-
 demethylation and oxidation. About 32% of a
 dose is excreted in the urine in 24 h as 3′-
 oxohexobarbital, 5% as 3′-
 hydroxyhexobarbital, and 18% as 1,5–
 dimethylbarbituric acid; less than 1% of a dose
 is excreted unchanged in the urine in 24 h.
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Therapeutic concentration
In plasma, usually in the range 1 to 5 mg/L.
Following a single oral dose of 500 mg to 6 subjects,
   peak plasma concentrations of 4.9 to 10.9 mg/L
   (mean 7) were attained in about 1 h.

Toxicity
The estimated minimum lethal dose is 2 g. Plasma
  concentrations greater than about 8 mg/L may
  produce toxic effects.
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Half–life.
Plasma half–life, 3 to 7 h.

Volume of distribution.
About 1 L/kg.

Clearance.
Plasma clearance, about 3.5 mL/min/kg.

Protein binding.
In plasma, 42 to 52%.
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                     Pentobarbital
Hypnotic, Barbiturate

Synonyms. Aethaminalum; Mebubarbital; Mebumal;
  Pentobarbitalum; Pentobarbitone.

Colorless crystals or a white crystalline powder. M.p. 129° to
  130° (from alcohol). A polymorphic form may occur, with an
  m.p. of about 115°; it gradually reverts to the more stable form
  on heating at about 110°.

Very slightly soluble in water; soluble 1 in 4.5 of ethanol, 1 in 4
  of chloroform, and 1 in 10 of ether; very soluble in acetone
  and methanol.

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Pentobarbital Sodium
Synonyms. Ethaminal Sodium; Mebumalnatrium; Pentobarbitone
  Sodium; Soluble Pentobarbitone.
Proprietary names. Nembutal; Nova Rectal; Pentone; Petab.

A white, hygroscopic, crystalline powder or granules.
   Decomposes at about 127°.
Freely soluble in water and ethanol; practically insoluble in
   benzene and ether. A solution in water slowly decomposes.


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Colour Tests
Koppanyi–Zwikker Test—violet; Mercurous Nitrate—
 black; Vanillin Reagent—brown–red/violet.

Thin–layer Chromatography
System TD—Rf 55; system TE—Rf 45; system TF—Rf
  66; system TH—Rf 76; system TAD—Rf 59; system
  TAE—Rf 90. (Mercuric chloride–diphenylcarbazone
  reagent, positive; mercurous nitrate spray, black;
  Zwikker’s reagent, pink.)

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             Disposition in the Body
More than 90% of the sodium salt is absorbed
 after oral administration. About 80% of a dose
 is excreted in the urine in 5 days, with about
 7% as (+)-3′-hydroxypentobarbital, 30% as the
 (−)-3′-hydroxy isomer, up to 13% as the N-
 hydroxy metabolite, 7 to 14% as the 3′-oxo
 metabolite, and about 10 to 15% as the 3′-
 carboxy derivative. About 1% of a dose is
 excreted in the urine unchanged.
11/22/2011                                    39
Therapeutic concentration
In plasma, usually in the range 1 to 10 mg/L.

Following a single oral dose of 50 mg to 5 fasting
  subjects, peak plasma concentrations of 0.62 to
  0.88 mg/L (mean 0.73) were attained in 1 h.

After an IV injection of 100 mg to 7 subjects, mean
  plasma concentrations of 3 mg/L were reported in
  6 min
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                    Toxicity
The estimated minimum lethal dose is 1 g. Toxic effects
  are usually associated with blood concentrations
  greater than about 8 mg/L and concentrations of
  12 mg/L or more may produce coma. Fatalities have
  been associated with plasma concentrations of 8 to
  73 mg/L.

In 55 fatalities, the following postmortem
   concentrations were reported: blood 5 to 169 mg/L
   (mean 30), liver 23 to 550 μg/g (mean 130).

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Half–life
Plasma half–life, about 15 to 50 h (mean 27).

Volume of distribution
About 0.7 to 1 L/kg.

Clearance
Plasma clearance, about 0.3 to 0.5 mL/min/kg.

Protein binding
In plasma, about 60 to 70%.
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             Diazepines




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                        Diazepam
Tranquilliser : Reduce stress and tension without reducing
  mental clarity (sedative)

Proprietary names. Antenex; Anxicalm; Apozepam; Dialar;
  Diapam; Diazemuls; Diazep; Ducene; Faustan; Gewacalm;
  Hexalid; Lamra; Medipam; Novazam; Novodipam; Pro-Pam;
  Psychopax; Rimapam; Serenack; Stesolid; Tensium;
  Tranquase; Umbrium; Valaxona; Valclair; Valiquid; Valium;
  Vivol.

A white or yellow crystalline powder. M.p. 131° to 135°.
Slightly soluble in water; soluble 1 in 25 of ethanol, 1 in 2 of
   chloroform, and 1 in 39 of ether.

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Color Test.
Formaldehyde–Sulfuric Acid—orange.

Thin–layer Chromatography.
System TA—Rf 75; system TB—Rf 27; system TC—
  Rf 73; system TD—Rf 58; system TE—Rf 76;
  system TF—Rf 49; system TL—Rf 59; system
  TAD—Rf 72; system TAE—Rf 82; system TAF—Rf
  85; system TAJ—Rf 67; system TAK—Rf 48;
  system TAL—Rf 96. (Dragendorff spray, positive;
  FPN reagent, yellow; acidified iodoplatinate solution,
  positive; Marquis reagent, yellow.)
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             Disposition in the Body
Rapidly and completely absorbed after oral administration, with peak plasma
  levels occurring within about 30 to 90 min. The main metabolic reactions
  are N-demethylation, 3–hydroxylation, and glucuronic acid conjugation.
  The major active metabolite is desmethyldiazepam [nordazepam] which
  accumulates during chronic dosing; other metabolites include oxazepam
  and temazepam, both of which are active.
Only small traces of unchanged diazepam are excreted in the urine and the
  relative amounts of metabolites are variable and appear to be dose–
  dependent. About 70% of a dose is excreted in the urine, mainly as
  oxazepam glucuronide and conjugated desmethyldiazepam, together with
  smaller amounts of conjugated temazepam. About 10% of the dose may be
  eliminated in the faeces. Diazepam and its metabolites cross the blood–
  brain barrier and the placenta; they are also found in breast milk




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Therapeutic concentration
In plasma, usually in the range 0.1 to 1.0 mg/L. After
   discontinuation of chronic therapy, concentrations of
   desmethyldiazepam may be substantially higher than
   diazepam and both unchanged drug and metabolite
   are still detectable 7 days after cessation of dosing.

Following a single oral dose of 10 mg to 4 subjects,
  peak blood concentrations of 0.14 to 0.19 mg/L
  (mean 0.15) were attained in 1 to 1.5 h; average peak
  concentrations of 0.03 mg/L of desmethyldiazepam
  were attained after 24 h
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After chronic daily oral dosing of 5 mg twice
  daily to 15 subjects, steady–state plasma
  concentrations were: diazepam 0.09 to
  0.37 mg/L (mean 0.23), desmethyldiazepam
  0.13 to 0.46 mg/L (mean 0.29), oxazepam
  0.01 to 0.03 mg/L (mean 0.02), temazepam
  0.01 to 0.05 mg/L (mean 0.03).


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Toxicity
Toxic effects may be produced by blood concentrations
  greater than 1.5 mg/L; fatalities caused by diazepam
  alone are rare, but may occur at blood concentrations
  greater than 5 mg/L.

In a review of 914 drug–related deaths in which
   diazepam was involved it was found to be the sole
   cause of death in only 2 cases; postmortem
   concentrations of diazepam in the 2 cases were: blood
   5 and 19 mg/L, liver 13 mg/kg in the first case.

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Half–life
Plasma half–life, diazepam 20 to 40 h,
  desmethyldiazepam about 40 to 100 h but there is
  considerable intersubject variation. The plasma half–
  life appears to be increased in elderly subjects and
  neonates, and in subjects with liver disease; sex
  differences have also been suggested.

Volume of distribution
Diazepam and desmethyldiazepam 0.5 to 2.5 L/kg,
  increased in elderly subjects.

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Clearance
Plasma clearance, diazepam about 0.3 to
  0.5 mL/min/kg, desmethyldiazepam about 0.1
  to 0.3 mL/min/kg.

Protein binding
In plasma, diazepam 98 to 99%,
  desmethyldiazepam about 97%.
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                          Nordazepam
Tranquilliser

Synonyms. A-101; Demethyldiazepam; Desmethyldiazepam; N-
   Desmethyldiazepam; Nordiazepam.

Proprietary names. Calmday; Madar; Nordaz; Sopax; Stilny; Tranxilium N;
   Vegesan.

A white or pale yellow crystalline powder. M.p. 216° to 217° (crystals from
   acetone).

Practically insoluble in water; slightly soluble in ethanol and chloroform .



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Colour Test.
Formaldehyde–Sulfuric Acid—orange.

Thin–layer Chromatography.
System TA—Rf 62; system TB—Rf 03; system TC—
  Rf 55; system TD—Rf 34; system TE—Rf 67;
  system TF—Rf 45; system TL—Rf 60; system
  TAD—Rf 57; system TAE—Rf 82; system TAF—Rf
  83; system TAJ—Rf 53; system TAK—Rf 60;
  system TAL—Rf 92. (Dragendorff spray, positive;
  acidified iodoplatinate solution, positive).

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Disposition in the Body.
Absorbed after oral administration, maximum blood
  concentrations being attained in 2 to 4 h. It is metabolised to
  oxazepam and then to oxazepam glucuronide.

Nordazepam is a metabolite of several benzodiazepines including
  medazepam, and prazepam.

Therapeutic concentration
Following a single oral dose of 10 mg to 2 subjects, a mean peak
  plasma concentration of 0.17 mg/L was reported

11/22/2011                                                          57
Following daily oral doses of 20 to 30 mg to 9 subjects
  for 10 days, plasma concentrations of 0.63 to
  1.84 mg/L (mean 1.1) were reported 10 h after a
  dose.

Bioavailability. : About 50%.

Protein binding.: In plasma, about 97%.

Dose.: Nordazepam has been given in doses of 15 mg
 daily.
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Half–life.
The plasma half–life is very variable and values ranging from 25
  to over 200 h have been reported. Mean values that have been
  reported are usually in the range 40 to 100 h in normal
  subjects. The plasma half–life is prolonged in elderly subjects
  and in subjects with liver disease.

Volume of distribution.: 0.5 to 2.5 L/kg

Clearance.: Plasma clearance, about 0.1 to 0.3 mL/min/kg.



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                            Oxazepam
Tranquilliser

Proprietary names. Adumbran; Alepam; Alopam; Anxiolit; Azutranquil;
   Benzotran; Isodin; Mirfudorm; Murelax; Opamox; Oxabenz; Oxahexal;
   Oxaline; Oxamin; Oxanid; Oxapax; Oxepam; Noctazepam; Praxiten;
   Sigacalm; Serax; Serenal; Serenid-D; Serepax; Seresta; Serpax; Sobril;
   Tranquo; Uskan.

A white to pale yellow crystalline powder. M.p. 205° to 206° (crystals from
   alcohol).

Practically insoluble in water; soluble 1 in 220 of ethanol 1 in 270 of
   chloroform, and 1 in 2200 of ether; soluble in dioxan




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Colour Test.
Formaldehyde–Sulfuric Acid—orange.

Thin–layer Chromatography.
System TA—Rf 56; system TB—Rf 00; system TC—Rf 40;
  system TD—Rf 22; system TE—Rf 45; system TF—Rf 35;
  system TL—Rf 51; system TAD—Rf 42; system TAE—Rf
  82; system TAF—Rf 91; system TAJ—Rf 47; system TAK—
  Rf 47; system TAL—Rf 89.
(Acidified iodoplatinate solution, positive; acidified potassium
  permanganate solution, positive(.

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             Disposition in the Body
Readily absorbed after oral administration. It crosses the
  placenta and is found in breast milk. About 70 to 80%
  of a single dose is excreted in the urine in 72 h almost
  entirely as oxazepam glucuronide, with only traces of
  unchanged oxazepam and other minor metabolites.
  Up to 10% of a dose is eliminated in the faeces,
  mostly as unchanged drug.

Oxazepam is a metabolite of several benzodiazepines
 including nordazepam, diazepam ,ketazolam ,
 medazepam ,prazepam, and temazepam
11/22/2011                                              63
Therapeutic concentration.
In plasma, usually in the range 0.5 to 2 mg/L.

A single oral dose of 45 mg administered to 8 subjects, produced
  serum concentrations of 0.88 to 1.44 mg/L (mean 1.1) of
  oxazepam in about 2 h, and concentrations of 0.7 to 1.4 mg/L
  (mean 0.9) of oxazepam glucuronide in 2 to 4 h. Daily oral
  doses of 10 mg every 6 h administered to 6 subjects, produced
  serum concentrations of 0.14 to 0.56 mg/L (mean 0.3) of
  oxazepam 2 h after a dose, and concentrations of 0.22 to
  0.40 mg/L (mean 0.3) of oxazepam glucuronide 4 h after a
  dose

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Toxicity.
Blood concentrations greater than 2 mg/L may produce toxic
  effects.

Half–life.: Plasma half–life, 4 to 15 h (mean 8).

Volume of distribution.: 0.5 to 2 L/kg.

Clearance.: Plasma clearance, about 1 to 2 mL/min/kg.

Protein binding.: In plasma, about 95%.

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                          Temazepam
Hypnotic

Synonyms. ER-115; 3-Hydroxydiazepam; K-3917; N-Methyloxazepam;
   Oxydiazepam; Ro–5–5345; Temazepamum; Wy–3917.

Proprietary names. Euhypnos; Euipnos; Gelthix; Levanxene; Levanxol;
   Maeva; Nocturne; Normison; Nortem; Perdorm; Planum; Remestan;
   Restoril; Somapam; Temaze; Temtabs; Tenox.

A white to almost white crystalline powder. M.p. 156° to 159°.

Very slightly soluble in water; soluble 1 in 10 of ethanol and 1 in 10 of
   chloroform; freely soluble in dichloromethane.



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Colour Test.
Formaldehyde–Sulfuric Acid—orange.

Thin–layer Chromatography.
System TA—Rf 53; system TB—Rf 08; system TC—Rf 59;
  system TD—Rf 51; system TE—Rf 62; system TF—Rf 47;
  system TL—Rf 53; system TAD—Rf 65; system TAE—Rf
  82; system TAF—Rf 82; system TAJ—Rf 65; system TAK—
  Rf 54; system TAL—Rf 92. (Dragendorff spray, positive;
  acidified iodoplatinate solution, positive; acidified potassium
  permanganate solution, positive (.


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             Disposition in the Body
Rapidly absorbed after oral administration. The exact
  rate of absorption is determined by the formulation of
  the drug administered. Metabolised principally by
  glucuronic acid conjugation; demethylation to
  oxazepam occurs to a small extent. About 80% of a
  dose is excreted in the urine, mostly as the inactive
  glucuronide conjugates; less than 2% of a dose is
  excreted as unchanged drug. About 12% of a dose is
  eliminated in the faeces. Small amounts of the
  demethylated derivative, oxazepam, and its
  conjugated form have also been detected. Temazepam
  can be found in breast milk and cerebrospinal fluid

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Temazepam is a metabolite of several benzodiazepines,
  including diazepam, ketazolam and medazepam.

Therapeutic concentration.
The therapeutic serum concentration is 0.3 to 0.9 mg/L.

Dose.: For insomnia, 10 to 20 mg at night; exceptional
 circumstances, 30 to 40 mg.

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Toxicity.: Toxic effects may be produced by serum
  concentrations greater than 1.0 mg/L.

Half–life.: Plasma half–life, about 8 to 15 h; there is
  considerable inter–subject variation, and sex differences have
  been reported.

Volume of distribution.: About 1 L/kg.

Clearance.: Plasma clearance, about 1 to 2 mL/min/kg.

Protein binding.: In plasma, about 96%.

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                   Medazepam
Tranquilliser

Proprietary names. Nobrium; Rudotel.
7-Chloro–2,3–dihydro–1–methyl–5–phenyl–1H-1,4–
  benzodiazepine

A white to greenish–yellow crystalline powder. M.p.
  95° to 97° (crystals from ether and petroleum ether).

Practically insoluble in water; soluble 1 in 8 of ethanol,
  1 in 1 of chloroform, and 1 in 5 of ether.
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Colour Tests.
Formaldehyde–Sulfuric Acid—orange (add water).
  Cold nitric acid—red colour.

Thin–layer Chromatography.
System TA—Rf 67; system TB—Rf 41; system TC—
  Rf 74; system TD—Rf 54; system TE—Rf 78;
  system TF—Rf 40; system TL—Rf 62; system
  TAD—Rf 73; system TAE—Rf 79; system TAF—Rf
  83; system TAJ—Rf 70; system TAK—Rf 12;
  system TAL—Rf 95. (Acidified iodoplatinate
  solution, positive.)
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             Disposition in the Body
Readily absorbed after oral administration. The active
  metabolites desmethyldiazepam )nordazepam) and
  diazepam may be detected in the blood shortly after
  dosing; desmethyldiazepam accumulates during
  chronic treatment. Desmethylmedazepam has also
  been detected in plasma. A total of up to about 75%
  of a dose is excreted in the urine and about 20% is
  eliminated in the faeces. The major urinary
  metabolite is oxazepam glucuronide, 2 to 3% of a
  dose being excreted in this form in 72 h; other urinary
  metabolites include desmethyldiazepam and
  temazepam

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Therapeutic concentration
Following single oral doses of 10 mg given to 4
  subjects, peak plasma concentrations of 0.14 to
  0.26 g/L (mean 0.21) of medazepam were attained in
  about 1 h

Doses of 10 to 50 mg given daily to 20 subjects,
 resulted in the following steady–state plasma
 concentrations: medazepam 0.01 to 0.16 mg/L (mean
 0.06), diazepam 0 to 0.12 mg/L (mean 0.03),
 desmethyldiazepam 0.2 to 1.7 mg/L

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Half–life.
Plasma half–life, medazepam 1 to 2 h,
  desmethyldiazepam about 40 to 100 h, but there is
  considerable intersubject variation

Protein binding.: In plasma, almost completely bound.

Dose.
Usually 10 to 20 mg daily, but doses of up to 60 mg
  daily have been given
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                  Analgesics
   Pain relief drugs are of variable types and
    potencies. They are administered according to
    the severity of the pain. The usual drug for
    mild pains is undoubtedly paracetamol, while
    the most potent is an opioid like morphine.
   Tramal or tramadol is administered to
    overcome moderate to severe pains.


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                                                                     Morphine
                            Pain Ladder
                                                              Oxycodone or
                                                              Oxymorphone

                                                      Hydrocodone or combo


                                              Tylenol #3 + NSAID


                                     Tylenol #3 or Tramadol


                            NSAID + Acetaminophen


                     NSAIDs


             Acetaminophen or nonacetylated salicylates
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Nonpharmacologic Approaches
       Modified WHO Analgesic
               Ladder
                               Invasive treatments       Pain
Proposed 4th Step          Opioid Delivery               Severity

                       Pain persisting or increasing

                                  Step 3
                    Opioid for moderate to severe pain     8 -10
                          ±Nonopioid ±Adjuvant
                        Pain persisting or increasing
                                 Step 2
                    Opioid for mild to moderate pain
The WHO                 ±Nonopioid ± Adjuvant                4-7
                      Pain persisting or increasing
 Ladder                          Step 1
                               ±Nonopioid
                               ± Adjuvant                       1-3
                                 Pain
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                        Tramadol
Narcotic Analgesic
(1R,2R)-rel–2-[(Dimethylamino)methyl]-1-(3–
  methoxyphenyl)cyclo- hexanol

Tramadol Hydrochloride
Synonyms. CG-315; CG-315E; U-26225A.
Proprietary names. Dromadol; Tramake; Tramal; Ultram;
  Zamadol; Zydol.

A white, bitter, odourless crystalline powder. M.p. 180° to 181°.
Readily soluble in water and ethanol.


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Tramadol is a centrally acting, synthetic analgesic of the
  aminocyclohexanol group, which has opioid-like
  effects. It has been in clinical use in Europe since the
  late 1970s. Its mode of action is not completely
  understood but it appears to have a dual mechanism
  of action, which involves inhibition of re-uptake of
  serotonin (5-HT) and/or noradrenaline as well as
  weak affinity for opioid (mu) receptors. Since
  tramadol does not affect prostaglandin synthesis, it
  does not have antipyretic or anti-inflammatory
  effects.
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                   Tramadol (Ultram)

            Short acting & ER (Extended Release)
            FDA approved for moderate to severe
             chronic pain in adults requiring around-the-
             clock treatment
            Do not use in:
              Severe renal impairment (Stage 4 or 5)

              Severe liver impairment

              Patients under age 18
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              Tramadol (Ultram)
     Adverse Events (Dose related) :
       Dizziness

       Nausea

       Constipation

       Headache

       Fatigue

       Dry mouth

      Do not exceed 300 mg per day
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Tramadol is an opioid - which is a synthetic product that
  has psychoactive effects through its actions on Opiate
  receptors in the brain. However, the chemical
  structure of Tramadol is significantly different from
  the structure of free Morphine which is what Opiate
  drug tests are designed to screen for. Consequently, it
  is highly unlikely that Tramadol can cross-react with
  Opiate drug screening immunoassays - whether
  laboratory based or an on-site test.

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             Disposition in the Body
Tramadol is rapidly and almost completely absorbed
  after oral or parenteral administration. The presence
  of food does not significantly affect the rate or extent
  of absorption. As the drug is administered as the
  racemate, both the (−) and (+) drug and metabolites
  are detected in circulation. Peak serum concentrations
  are achieved in about 2 h. Tramadol is extensively
  metabolised. The main metabolic reactions are N- and
  O--demethylation and conjugation with glucuronic
  acid and sulfate

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The major metabolites formed are O-
  monodesmethyltramadol, N,O-didesmethyltramadol
  and their conjugates, and N-monodesmethyltramadol.
  O-Monodesmethyltramadol is an active metabolite
  and has a greater analgesic activity than the parent
  drug. The extent of metabolism is reduced in patients
  with hepatic impairment. About 90% of an oral dose
  is excreted in the urine in 3 days, about 30% of the
  dose as unchanged drug and the rest as metabolites.



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The remainder of the dose is eliminated in the
 faeces. The rate and extent of excretion is
 reduced in patients with renal impairment. The
 drug is widely distributed throughout the body
 and crosses the placenta; it has also been
 detected in breast milk. Steady-state
 concentrations of both the drug and main
 metabolite are achieved within 2 days of
 multiple dosing.
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             Therapeutic concentration
The therapeutic tramadol blood concentration is
  100 to 800 μg/L.
12 male and female healthy subjects (mean age
  30.1 years; range 21 to 41 years) were fasted
  overnight for 12 h and orally administered
  with a single 50 mg dose of tramadol
  hydrochloride. The mean peak serum
  concentration was 136 μg/L observed at a
  median of 1.1 h (minimum 0.74 h and
  maximum 1.5 h).
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12 healthy males received a single 50 mg dose of
  tramadol hydrochloride either as an
  intramuscular injection or as a 30 min
  intravenous infusion, after an overnight fast
  (with a 1 week washout period between doses).
  After intramuscular injection, a mean peak
  serum tramadol concentration of 0.166 mg/L
  was reached after 0.75 h and after intravenous
  infusion, a peak of 0.293 mg/L was reached at
  0.5 h
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92 patients who were intravenously administered with a
  maximum dose of 200 mg (+)-tramadol, (−)-tramadol
  or racemic tramadol and 20 mg doses of each were
  also administered, as requested, for 24 h. Drug and
  metabolite serum concentrations were measured
  before each additional dose. The mean tramadol
  concentration was 470 μg/L for (+)-drug, 590 μg/L
  for the racemate and 771 μg/L for the (−)-drug. The
  mean O-desmethyltramadol concentration was 57, 84
  and 96 μg/L for the three drug types, respectively



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                        Toxicity
The toxic tramadol blood concentration is 1.0 mg/L; lethal,
  2.0 mg/L.
A 26–year–old male nurse returned home from work after a night
  shift and went to bed to sleep. Later that evening he was found
  dead face down on his bed. A bottle of tramadol was found in
  his pocket. The peripheral blood tramadol concentration was
  9.6 mg/L, which is approximately 30 times the observed
  therapeutic concentration range (0.1 to 0.3 mg/L). The heart
  blood concentration was 13.1 mg/L; urine, 46.0 mg/L; bile,
  46.1 mg/L; liver, 6.2 μg/g and kidney, 3.1 μg/g. There was
  also a trace of the drug detected in the gastric contents. No
  other drugs or alcohol were detected

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A 30–year–old woman was found dead at her home
  after ingestion of unknown amounts of alprazolam,
  tramadol and alcohol (empty packages of each found
  at the scene). She had a history of depression.
  Toxicological analysis showed concentrations of
  tramadol in her peripheral blood at 38.3 mg/L
  (approx 100 times the therapeutic concentration).
  Tramadol was also detected at concentrations of
  44.0 mg/L, 27.6 μg/g and 130 mg total in the bile,
  liver and gastric contents, respectively

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Analysis of 12 blood samples from tramadol–
 related death and 4 from non–fatal tramadol
 intoxications revealed concentrations ranging
 from 0.03 to 22.59 mg/L for tramadol, 0.02 to
 1.84 mg/L for O-desmethyltramadol and 0.01
 to 2.08 mg/L for N-desmethyltramadol. 3 of
 the fatalities were attributable to morphine and
 6 were multiple drug overdoses


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Bioavailability.
About 75%.

Half–life.
Plasma half–life, tramadol about 6 h (increases
  to 7 h with multiple dosing), O-
  monodesmethyltramadol, about 9 h.

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Volume of distribution.
About 3 L/kg; slightly higher in females compared with
  males (2.9 L/kg versus 2.6 L/kg).

Clearance.
Plasma clearance, about 6 mL/min/kg; slightly higher in
  males compared with females (6.4 mL/min/kg versus
  5.7 mL/min/kg).

Protein binding.
In plasma, 20%.
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