Medazepam (PIM 460)

<HTML> <HEAD> <META HTTP-EQUIV="Content-Type" CONTENT="text/html; charset=iso-8859-1"> <TITLE>Medazepam (PIM 460)</TITLE> </HEAD> <BODY BGCOLOR="#FFFFFF"> <A HREF="http://www.inchem.org"><IMG SRC="../../inchemhead.jpg" WIDTH="630" HEIGHT="65" BORDER="0" ALT="IPCS INCHEM Home"></A><CENTER><H1>Medazepam</H1></CENTER> <CENTER><TABLE WIDTH=500> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:1. NAME">1. NAME</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:1.1 Substance">1.1 Substance</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:1.2 Group">1.2 Group</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:1.3 Synonyms">1.3 Synonyms</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:1.4 Identification numbers">1.4 Identification numbers</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:1.4.1 CAS number">1.4.1 CAS number</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:1.4.2 Other numbers">1.4.2 Other numbers</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:1.5 Main brand names, main trade names">1.5 Main brand names, main trade names</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:1.6 Main manufacturers, main importers">1.6 Main manufacturers, main importers</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:2. SUMMARY">2. SUMMARY</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:2.1 Main risks and target organs">2.1 Main risks and target organs</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:2.2 Summary of clinical effects">2.2 Summary of clinical effects</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:2.3 Diagnosis">2.3 Diagnosis</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:2.4 First aid measures and management principles">2.4 First aid measures and management principles</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:3. PHYSICO-CHEMICAL PROPERTIES">3. PHYSICO-CHEMICAL PROPERTIES</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:3.1 Origin of the substance">3.1 Origin of the substance</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:3.2 Chemical structure">3.2 Chemical structure</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:3.3 Physical properties">3.3 Physical properties</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:3.3.1 Colour">3.3.1 Colour</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:3.3.2 State/Form">3.3.2 State/Form</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:3.3.3 Description">3.3.3 Description</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:3.4 Other characteristics">3.4 Other characteristics</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:3.4.1 Shelf-life of the substance">3.4.1 Shelf-life of the substance</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:3.4.2 Storage conditions">3.4.2 Storage conditions</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:4. USES">4. USES</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:4.1 Indications">4.1 Indications</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:4.1.1 Indications">4.1.1 Indications</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:4.1.2 Description">4.1.2 Description</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:4.2 Therapeutic dosage">4.2 Therapeutic dosage</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:4.2.1 Adults">4.2.1 Adults</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:4.2.2 Children">4.2.2 Children</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:4.3 Contraindications">4.3 Contraindications</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:5. ROUTES OF EXPOSURE">5. ROUTES OF EXPOSURE</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:5.1 Oral">5.1 Oral</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:5.2 Inhalation">5.2 Inhalation</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:5.3 Dermal">5.3 Dermal</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:5.4 Eye">5.4 Eye</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:5.5 Parenteral">5.5 Parenteral</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:5.6 Other">5.6 Other</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:6. KINETICS">6. KINETICS</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:6.1 Absorption by route of exposure">6.1 Absorption by route of exposure</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:6.2 Distribution by route of exposure">6.2 Distribution by route of exposure</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:6.3 Biological half-life by route of exposure">6.3 Biological half-life by route of exposure</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:6.4 Metabolism">6.4 Metabolism</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:6.5 Elimination and excretion">6.5 Elimination and excretion</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:7. PHARMACOLOGY AND TOXICOLOGY">7. PHARMACOLOGY AND TOXICOLOGY</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:7.1 Mode of action">7.1 Mode of action</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:7.1.1 Toxicodynamics">7.1.1 Toxicodynamics</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:7.1.2 Pharmacodynamics">7.1.2 Pharmacodynamics</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:7.2 Toxicity">7.2 Toxicity</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:7.2.1 Human data">7.2.1 Human data</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:7.2.1.1 Adults">7.2.1.1 Adults</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:7.2.1.2 Children">7.2.1.2 Children</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:7.2.2 Relevant animal data">7.2.2 Relevant animal data</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:7.2.3 Relevant in vitro data">7.2.3 Relevant in vitro data</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:7.3 Carcinogenicity">7.3 Carcinogenicity</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:7.4 Teratogenicity">7.4 Teratogenicity</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:7.5 Mutagenicity">7.5 Mutagenicity</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:7.6 Interactions">7.6 Interactions</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:7.7 Main adverse effects">7.7 Main adverse effects</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS">8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:8.1 Material sampling plan">8.1 Material sampling plan</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:8.1.1 Sampling and specimen collection">8.1.1 Sampling and specimen collection</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.1.1 Toxicological analyses">8.1.1.1 Toxicological analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.1.2 Biomedical analyses">8.1.1.2 Biomedical analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.1.3 Arterial blood gas analysis">8.1.1.3 Arterial blood gas analysis</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.1.4 Haematological analyses">8.1.1.4 Haematological analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.1.5 Other (unspecified) analyses">8.1.1.5 Other (unspecified) analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:8.1.2 Storage of laboratory samples and specimens">8.1.2 Storage of laboratory samples and specimens</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.2.1 Toxicological analyses">8.1.2.1 Toxicological analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.2.2 Biomedical analyses">8.1.2.2 Biomedical analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.2.3 Arterial blood gas analysis">8.1.2.3 Arterial blood gas analysis</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.2.4 Haematological analyses">8.1.2.4 Haematological analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.2.5 Other (unspecified) analyses">8.1.2.5 Other (unspecified) analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:8.1.3 Transport of laboratory samples and specimens">8.1.3 Transport of laboratory samples and specimens</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.3.1 Toxicological analyses">8.1.3.1 Toxicological analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.3.2 Biomedical analyses">8.1.3.2 Biomedical analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.3.3 Arterial blood gas analysis">8.1.3.3 Arterial blood gas analysis</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.3.4 Haematological analyses">8.1.3.4 Haematological analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.1.3.5 Other (unspecified) analyses">8.1.3.5 Other (unspecified) analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:8.2 Toxicological Analyses and Their Interpretation">8.2 Toxicological Analyses and Their Interpretation</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:8.2.1 Tests on toxic ingredient(s) of material">8.2.1 Tests on toxic ingredient(s) of material</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.2.1.1 Simple Qualitative Test(s)">8.2.1.1 Simple Qualitative Test(s)</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.2.1.2 Advanced Qualitative Confirmation Test(s)">8.2.1.2 Advanced Qualitative Confirmation Test(s)</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.2.1.3 Simple Quantitative Method(s)">8.2.1.3 Simple Quantitative Method(s)</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.2.1.4 Advanced Quantitative Method(s)">8.2.1.4 Advanced Quantitative Method(s)</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:8.2.2 Tests for biological specimens">8.2.2 Tests for biological specimens</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.2.2.1 Simple Qualitative Test(s)">8.2.2.1 Simple Qualitative Test(s)</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.2.2.2 Advanced Qualitative Confirmation Test(s)">8.2.2.2 Advanced Qualitative Confirmation Test(s)</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.2.2.3 Simple Quantitative Method(s)">8.2.2.3 Simple Quantitative Method(s)</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.2.2.4 Advanced Quantitative Method(s)">8.2.2.4 Advanced Quantitative Method(s)</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.2.2.5 Other Dedicated Method(s)">8.2.2.5 Other Dedicated Method(s)</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:8.2.3 Interpretation of toxicological analyses">8.2.3 Interpretation of toxicological analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:8.3 Biomedical investigations and their interpretation">8.3 Biomedical investigations and their interpretation</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:8.3.1 Biochemical analysis">8.3.1 Biochemical analysis</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.3.1.1 Blood, plasma or serum">8.3.1.1 Blood, plasma or serum</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.3.1.2 Urine">8.3.1.2 Urine</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:8.3.1.3 Other fluids">8.3.1.3 Other fluids</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:8.3.2 Arterial blood gas analyses">8.3.2 Arterial blood gas analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:8.3.3 Haematological analyses">8.3.3 Haematological analyses</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:8.3.4 Interpretation of biomedical investigations">8.3.4 Interpretation of biomedical investigations</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:8.4 Other biomedical (diagnostic) investigations and their interpretation">8.4 Other biomedical (diagnostic) investigations and their interpretation</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:8.5 Overall interpretation of all toxicological analyses and toxicological investigations">8.5 Overall interpretation of all toxicological analyses and toxicological investigations</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:8.6 References">8.6 References</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:9. CLINICAL EFFECTS">9. CLINICAL EFFECTS</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:9.1 Acute poisoning">9.1 Acute poisoning</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.1.1 Ingestion">9.1.1 Ingestion</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.1.2 Inhalation">9.1.2 Inhalation</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.1.3 Skin exposure">9.1.3 Skin exposure</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.1.4 Eye contact">9.1.4 Eye contact</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.1.5 Parenteral exposure">9.1.5 Parenteral exposure</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.1.6 Other">9.1.6 Other</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:9.2 Chronic poisoning">9.2 Chronic poisoning</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.2.1 Ingestion">9.2.1 Ingestion</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.2.2 Inhalation">9.2.2 Inhalation</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.2.3 Skin exposure">9.2.3 Skin exposure</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.2.4 Eye contact">9.2.4 Eye contact</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.2.5 Parenteral exposure">9.2.5 Parenteral exposure</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.2.6 Other">9.2.6 Other</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:9.3 Course, prognosis, cause of death">9.3 Course, prognosis, cause of death</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:9.4 Systematic description of clinical effects">9.4 Systematic description of clinical effects</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.1 Cardiovascular">9.4.1 Cardiovascular</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.2 Respiratory">9.4.2 Respiratory</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.3 Neurological">9.4.3 Neurological</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:9.4.3.1 Central nervous system (CNS)">9.4.3.1 Central nervous system (CNS)</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:9.4.3.2 Peripheral nervous system">9.4.3.2 Peripheral nervous system</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:9.4.3.3 Autonomic nervous system">9.4.3.3 Autonomic nervous system</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:9.4.3.4 Skeletal and smooth muscle">9.4.3.4 Skeletal and smooth muscle</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.4 Gastrointestinal">9.4.4 Gastrointestinal</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.5 Hepatic">9.4.5 Hepatic</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.6 Urinary">9.4.6 Urinary</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:9.4.6.1 Renal">9.4.6.1 Renal</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:9.4.6.2 Other">9.4.6.2 Other</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.7 Endocrine and reproductive systems">9.4.7 Endocrine and reproductive systems</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.8 Dermatological">9.4.8 Dermatological</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.9 Eye, ear, nose, throat: local effects">9.4.9 Eye, ear, nose, throat: local effects</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.10 Haematological">9.4.10 Haematological</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.11 Immunological">9.4.11 Immunological</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.12 Metabolic">9.4.12 Metabolic</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:9.4.12.1 Acid-base disturbances">9.4.12.1 Acid-base disturbances</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:9.4.12.2 Fluid and electrolyte disturbances">9.4.12.2 Fluid and electrolyte disturbances</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>         <A HREF="#DivisionTitle:9.4.12.3 Others">9.4.12.3 Others</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.13 Allergic reactions">9.4.13 Allergic reactions</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.14 Other clinical effects">9.4.14 Other clinical effects</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:9.4.15 Special risks">9.4.15 Special risks</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:9.5 Other">9.5 Other</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:9.6 Summary">9.6 Summary</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:10. MANAGEMENT">10. MANAGEMENT</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:10.1 General principles">10.1 General principles</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:10.2 Life supportive procedures and symptomatic/specific treatment">10.2 Life supportive procedures and symptomatic/specific treatment</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:10.3 Decontamination">10.3 Decontamination</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:10.4 Enhanced elimination">10.4 Enhanced elimination</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:10.5 Antidote treatment">10.5 Antidote treatment</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:10.5.1 Adults">10.5.1 Adults</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>      <A HREF="#SubSectionTitle:10.5.2 Children">10.5.2 Children</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:10.6 Management discussion">10.6 Management discussion</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:11. ILLUSTRATIVE CASES">11. ILLUSTRATIVE CASES</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:11.1 Case reports from literature">11.1 Case reports from literature</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:12. Additional information">12. Additional information</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:12.1 Specific preventive measures">12.1 Specific preventive measures</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER>   <A HREF="#SectionTitle:12.2 Other">12.2 Other</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:13. REFERENCES">13. REFERENCES</A></TD></TR> <TR HEIGHT=30><TD ALIGN=LEFT VALIGN=CENTER><A HREF="#PartTitle:14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)">14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)</A></TD></TR> </TABLE></CENTER> <PRE> Medazepam International Programme on Chemical Safety Poisons Information Monograph 460 Pharmaceutical This monograph does not contain all of the sections completed. This mongraph is harmonised with the Group monograph on Benzodiazepines (PIM G008). <A NAME = "PartTitle:1. NAME"></A>1. NAME <A NAME = "SectionTitle:1.1 Substance"></A>1.1 Substance <PIM1.1>Medazepam</PIM1.1> <A NAME = "EndSectionTitle:1.1 Substance"></A><A NAME = "SectionTitle:1.2 Group"></A>1.2 Group ATC classification index <PIM1.2>Psycholeptics</PIM1.2> (N05)/ <PIM1.2>Anxiolytics</PIM1.2> (N05B)/ <PIM1.2>Benzodiazepine derivatives</PIM1.2> (N05BA) <A NAME = "EndSectionTitle:1.2 Group"></A><A NAME = "SectionTitle:1.3 Synonyms"></A>1.3 Synonyms <PIM1.3>Ro-5-4556 (medazepam hydrochloride)</PIM1.3> <A NAME = "EndSectionTitle:1.3 Synonyms"></A><A NAME = "SectionTitle:1.4 Identification numbers"></A>1.4 Identification numbers <A NAME = "SubSectionTitle:1.4.1 CAS number"></A>1.4.1 CAS number <PIM1.4.1><PrimaryCasNo>2898-12-6</PrimaryCasNo></PIM1.4.1> (medazepam) <A NAME = ":1.4.1 CAS number"></A><A NAME = "SubSectionTitle:1.4.2 Other numbers"></A>1.4.2 Other numbers <PIM1.4.2>Medazepam hydrochloride CAS: <SecondaryCasNo>2898-11-5</SecondaryCasNo></PIM1.4.2> <A NAME = ":1.4.2 Other numbers"></A><A NAME = "EndSectionTitle:1.4 Identification numbers"></A><A NAME = "SectionTitle:1.5 Main brand names, main trade names"></A>1.5 Main brand names, main trade names <PIM1.5>Lerisum; Medacepan; Medazepam Capsules BP 1993; Megasedan; Nobrium; Nobrium; Rudotel; Debrum (multi- ingredient preparation); Nobritol (multi-ingredient preparation); Tranquirax (multi-ingredient preparation)</PIM1.5> <A NAME = "EndSectionTitle:1.5 Main brand names, main trade names"></A><A NAME = "SectionTitle:1.6 Main manufacturers, main importers"></A>1.6 Main manufacturers, main importers <A NAME = "EndSectionTitle:1.6 Main manufacturers, main importers"></A><A NAME = "EndPartTitle:1. NAME"></A><A NAME = "PartTitle:2. SUMMARY"></A>2. SUMMARY <A NAME = "SectionTitle:2.1 Main risks and target organs"></A>2.1 Main risks and target organs <PIM2.1>Central nervous system, causing depression of respiration and consciousness.</PIM2.1> <A NAME = "EndSectionTitle:2.1 Main risks and target organs"></A><A NAME = "SectionTitle:2.2 Summary of clinical effects"></A>2.2 Summary of clinical effects <PIM2.2>Central nervous system (CNS) depression and coma, or paradoxical excitation, but deaths are rare when benzodiazepines are taken alone. Deep coma and other manifestations of severe CNS depression are rare. Sedation, somnolence, diplopia, dysarthria, ataxia and intellectual impairment are the most common adverse effects of benzodiazepines. Overdose in adults frequently involves co- ingestion of other CNS depressants, which act synergistically to increase toxicity. Elderly and very young children are more susceptible to the CNS depressant action. Intravenous administration of even therapeutic doses of benzodiazepines may produce apnoea and hypotension.<NL> Dependence may develop with regular use of benzodiazepines, even in therapeutic doses for short periods. If benzodiazepines are discontinued abruptly after regular use, withdrawal symptoms may develop. The amnesia produced by benzodiazepines can have medico-legal consequences.</PIM2.2> <A NAME = "EndSectionTitle:2.2 Summary of clinical effects"></A><A NAME = "SectionTitle:2.3 Diagnosis"></A>2.3 Diagnosis <PIM2.3>The clinical diagnosis is based upon the history of benzodiazepine overdose and the presence of the clinical signs of benzodiazepine intoxication.<NL> Benzodiazepines can be detected or measured in blood and urine using standard analytical methods. This information may confirm the diagnosis but is not useful in the clinical management of the patient.<NL> A clinical response to flumazenil, a specific benzodiazepine antagonist, also confirms the diagnosis of benzodiazepine overdose, but administration of this drug is rarely justified.</PIM2.3> <A NAME = "EndSectionTitle:2.3 Diagnosis"></A><A NAME = "SectionTitle:2.4 First aid measures and management principles"></A>2.4 First aid measures and management principles <PIM2.4>Most benzodiazepine poisonings require only clinical observation and supportive care. It should be remembered that benzodiazepine ingestions by adults commonly involve co- ingestion of other CNS depressants and other drugs. Activated charcoal normally provides adequate gastrointestinal decontamination. Gastric lavage is not routinely indicated. Emesis is contraindicated. The use of flumazenil is reserved for cases with severe respiratory or cardiovascular complications and should not replace the basic management of the airway and respiration. The routine use of flumazenil is contraindicated because of potential complications, including seizures. Renal and extracorporeal methods of enhanced elimination are not effective.</PIM2.4> <A NAME = "EndSectionTitle:2.4 First aid measures and management principles"></A><A NAME = "EndPartTitle:2. SUMMARY"></A><A NAME = "PartTitle:3. PHYSICO-CHEMICAL PROPERTIES"></A>3. PHYSICO-CHEMICAL PROPERTIES <A NAME = "SectionTitle:3.1 Origin of the substance"></A>3.1 Origin of the substance <A NAME = "EndSectionTitle:3.1 Origin of the substance"></A><A NAME = "SectionTitle:3.2 Chemical structure"></A>3.2 Chemical structure <PIM3.2>Chemical Name:<NL> 7-Chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4- - benzodiazepine<NL> <NL> Molecular Formula: C16H15ClN2<NL> <NL> Molecular Weight: 270.8</PIM3.2> <A NAME = "EndSectionTitle:3.2 Chemical structure"></A><A NAME = "SectionTitle:3.3 Physical properties"></A>3.3 Physical properties <A NAME = "SubSectionTitle:3.3.1 Colour"></A>3.3.1 Colour <PIM3.3.1>Yellowish</PIM3.3.1> <A NAME = ":3.3.1 Colour"></A><A NAME = "SubSectionTitle:3.3.2 State/Form"></A>3.3.2 State/Form <PIM3.3.2>Solid-crystals</PIM3.3.2> <A NAME = ":3.3.2 State/Form"></A><A NAME = "SubSectionTitle:3.3.3 Description"></A>3.3.3 Description <PIM3.3.3>Medazepam is odourless or almost odourless. It is practically insoluble in water; freely soluble in alcohol, in chloroform, and in ether (Reynolds, 1996).</PIM3.3.3> <A NAME = ":3.3.3 Description"></A><A NAME = "EndSectionTitle:3.3 Physical properties"></A><A NAME = "SectionTitle:3.4 Other characteristics"></A>3.4 Other characteristics <A NAME = "SubSectionTitle:3.4.1 Shelf-life of the substance"></A>3.4.1 Shelf-life of the substance <A NAME = ":3.4.1 Shelf-life of the substance"></A><A NAME = "SubSectionTitle:3.4.2 Storage conditions"></A>3.4.2 Storage conditions <A NAME = ":3.4.2 Storage conditions"></A><A NAME = "EndSectionTitle:3.4 Other characteristics"></A><A NAME = "EndPartTitle:3. PHYSICO-CHEMICAL PROPERTIES"></A><A NAME = "PartTitle:4. USES"></A>4. USES <A NAME = "SectionTitle:4.1 Indications"></A>4.1 Indications <A NAME = "SubSectionTitle:4.1.1 Indications"></A>4.1.1 Indications <A NAME = ":4.1.1 Indications"></A><A NAME = "SubSectionTitle:4.1.2 Description"></A>4.1.2 Description <A NAME = ":4.1.2 Description"></A><A NAME = "EndSectionTitle:4.1 Indications"></A><A NAME = "SectionTitle:4.2 Therapeutic dosage"></A>4.2 Therapeutic dosage <A NAME = "SubSectionTitle:4.2.1 Adults"></A>4.2.1 Adults <A NAME = ":4.2.1 Adults"></A><A NAME = "SubSectionTitle:4.2.2 Children"></A>4.2.2 Children <A NAME = ":4.2.2 Children"></A><A NAME = "EndSectionTitle:4.2 Therapeutic dosage"></A><A NAME = "SectionTitle:4.3 Contraindications"></A>4.3 Contraindications <A NAME = "EndSectionTitle:4.3 Contraindications"></A><A NAME = "EndPartTitle:4. USES"></A><A NAME = "PartTitle:5. ROUTES OF EXPOSURE"></A>5. ROUTES OF EXPOSURE <A NAME = "SectionTitle:5.1 Oral"></A>5.1 Oral <A NAME = "EndSectionTitle:5.1 Oral"></A><A NAME = "SectionTitle:5.2 Inhalation"></A>5.2 Inhalation <A NAME = "EndSectionTitle:5.2 Inhalation"></A><A NAME = "SectionTitle:5.3 Dermal"></A>5.3 Dermal <A NAME = "EndSectionTitle:5.3 Dermal"></A><A NAME = "SectionTitle:5.4 Eye"></A>5.4 Eye <A NAME = "EndSectionTitle:5.4 Eye"></A><A NAME = "SectionTitle:5.5 Parenteral"></A>5.5 Parenteral <A NAME = "EndSectionTitle:5.5 Parenteral"></A><A NAME = "SectionTitle:5.6 Other"></A>5.6 Other <A NAME = "EndSectionTitle:5.6 Other"></A><A NAME = "EndPartTitle:5. ROUTES OF EXPOSURE"></A><A NAME = "PartTitle:6. KINETICS"></A>6. KINETICS <A NAME = "SectionTitle:6.1 Absorption by route of exposure"></A>6.1 Absorption by route of exposure <A NAME = "EndSectionTitle:6.1 Absorption by route of exposure"></A><A NAME = "SectionTitle:6.2 Distribution by route of exposure"></A>6.2 Distribution by route of exposure <A NAME = "EndSectionTitle:6.2 Distribution by route of exposure"></A><A NAME = "SectionTitle:6.3 Biological half-life by route of exposure"></A>6.3 Biological half-life by route of exposure <A NAME = "EndSectionTitle:6.3 Biological half-life by route of exposure"></A><A NAME = "SectionTitle:6.4 Metabolism"></A>6.4 Metabolism <A NAME = "EndSectionTitle:6.4 Metabolism"></A><A NAME = "SectionTitle:6.5 Elimination and excretion"></A>6.5 Elimination and excretion <A NAME = "EndSectionTitle:6.5 Elimination and excretion"></A><A NAME = "EndPartTitle:6. KINETICS"></A><A NAME = "PartTitle:7. PHARMACOLOGY AND TOXICOLOGY"></A>7. PHARMACOLOGY AND TOXICOLOGY <A NAME = "SectionTitle:7.1 Mode of action"></A>7.1 Mode of action <A NAME = "SubSectionTitle:7.1.1 Toxicodynamics"></A>7.1.1 Toxicodynamics <A NAME = ":7.1.1 Toxicodynamics"></A><A NAME = "SubSectionTitle:7.1.2 Pharmacodynamics"></A>7.1.2 Pharmacodynamics <A NAME = ":7.1.2 Pharmacodynamics"></A><A NAME = "EndSectionTitle:7.1 Mode of action"></A><A NAME = "SectionTitle:7.2 Toxicity"></A>7.2 Toxicity <A NAME = "SubSectionTitle:7.2.1 Human data"></A>7.2.1 Human data <A NAME = "DivisionTitle:7.2.1.1 Adults"></A>7.2.1.1 Adults <A NAME = "EndDivisionTitle:7.2.1.1 Adults"></A><A NAME = "DivisionTitle:7.2.1.2 Children"></A>7.2.1.2 Children <A NAME = "EndDivisionTitle:7.2.1.2 Children"></A><A NAME = ":7.2.1 Human data"></A><A NAME = "SubSectionTitle:7.2.2 Relevant animal data"></A>7.2.2 Relevant animal data <A NAME = ":7.2.2 Relevant animal data"></A><A NAME = "SubSectionTitle:7.2.3 Relevant in vitro data"></A>7.2.3 Relevant in vitro data <A NAME = ":7.2.3 Relevant in vitro data"></A><A NAME = "EndSectionTitle:7.2 Toxicity"></A><A NAME = "SectionTitle:7.3 Carcinogenicity"></A>7.3 Carcinogenicity <A NAME = "EndSectionTitle:7.3 Carcinogenicity"></A><A NAME = "SectionTitle:7.4 Teratogenicity"></A>7.4 Teratogenicity <A NAME = "EndSectionTitle:7.4 Teratogenicity"></A><A NAME = "SectionTitle:7.5 Mutagenicity"></A>7.5 Mutagenicity <A NAME = "EndSectionTitle:7.5 Mutagenicity"></A><A NAME = "SectionTitle:7.6 Interactions"></A>7.6 Interactions <A NAME = "EndSectionTitle:7.6 Interactions"></A><A NAME = "SectionTitle:7.7 Main adverse effects"></A>7.7 Main adverse effects <A NAME = "EndSectionTitle:7.7 Main adverse effects"></A><A NAME = "EndPartTitle:7. PHARMACOLOGY AND TOXICOLOGY"></A><A NAME = "PartTitle:8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS"></A>8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS <A NAME = "SectionTitle:8.1 Material sampling plan"></A>8.1 Material sampling plan <A NAME = "SubSectionTitle:8.1.1 Sampling and specimen collection"></A>8.1.1 Sampling and specimen collection <A NAME = "DivisionTitle:8.1.1.1 Toxicological analyses"></A>8.1.1.1 Toxicological analyses <A NAME = "EndDivisionTitle:8.1.1.1 Toxicological analyses"></A><A NAME = "DivisionTitle:8.1.1.2 Biomedical analyses"></A>8.1.1.2 Biomedical analyses <A NAME = "EndDivisionTitle:8.1.1.2 Biomedical analyses"></A><A NAME = "DivisionTitle:8.1.1.3 Arterial blood gas analysis"></A>8.1.1.3 Arterial blood gas analysis <A NAME = "EndDivisionTitle:8.1.1.3 Arterial blood gas analysis"></A><A NAME = "DivisionTitle:8.1.1.4 Haematological analyses"></A>8.1.1.4 Haematological analyses <A NAME = "EndDivisionTitle:8.1.1.4 Haematological analyses"></A><A NAME = "DivisionTitle:8.1.1.5 Other (unspecified) analyses"></A>8.1.1.5 Other (unspecified) analyses <A NAME = "EndDivisionTitle:8.1.1.5 Other (unspecified) analyses"></A><A NAME = ":8.1.1 Sampling and specimen collection"></A><A NAME = "SubSectionTitle:8.1.2 Storage of laboratory samples and specimens"></A>8.1.2 Storage of laboratory samples and specimens <A NAME = "DivisionTitle:8.1.2.1 Toxicological analyses"></A>8.1.2.1 Toxicological analyses <A NAME = "EndDivisionTitle:8.1.2.1 Toxicological analyses"></A><A NAME = "DivisionTitle:8.1.2.2 Biomedical analyses"></A>8.1.2.2 Biomedical analyses <A NAME = "EndDivisionTitle:8.1.2.2 Biomedical analyses"></A><A NAME = "DivisionTitle:8.1.2.3 Arterial blood gas analysis"></A>8.1.2.3 Arterial blood gas analysis <A NAME = "EndDivisionTitle:8.1.2.3 Arterial blood gas analysis"></A><A NAME = "DivisionTitle:8.1.2.4 Haematological analyses"></A>8.1.2.4 Haematological analyses <A NAME = "EndDivisionTitle:8.1.2.4 Haematological analyses"></A><A NAME = "DivisionTitle:8.1.2.5 Other (unspecified) analyses"></A>8.1.2.5 Other (unspecified) analyses <A NAME = "EndDivisionTitle:8.1.2.5 Other (unspecified) analyses"></A><A NAME = ":8.1.2 Storage of laboratory samples and specimens"></A><A NAME = "SubSectionTitle:8.1.3 Transport of laboratory samples and specimens"></A>8.1.3 Transport of laboratory samples and specimens <A NAME = "DivisionTitle:8.1.3.1 Toxicological analyses"></A>8.1.3.1 Toxicological analyses <A NAME = "EndDivisionTitle:8.1.3.1 Toxicological analyses"></A><A NAME = "DivisionTitle:8.1.3.2 Biomedical analyses"></A>8.1.3.2 Biomedical analyses <A NAME = "EndDivisionTitle:8.1.3.2 Biomedical analyses"></A><A NAME = "DivisionTitle:8.1.3.3 Arterial blood gas analysis"></A>8.1.3.3 Arterial blood gas analysis <A NAME = "EndDivisionTitle:8.1.3.3 Arterial blood gas analysis"></A><A NAME = "DivisionTitle:8.1.3.4 Haematological analyses"></A>8.1.3.4 Haematological analyses <A NAME = "EndDivisionTitle:8.1.3.4 Haematological analyses"></A><A NAME = "DivisionTitle:8.1.3.5 Other (unspecified) analyses"></A>8.1.3.5 Other (unspecified) analyses <A NAME = "EndDivisionTitle:8.1.3.5 Other (unspecified) analyses"></A><A NAME = ":8.1.3 Transport of laboratory samples and specimens"></A><A NAME = "EndSectionTitle:8.1 Material sampling plan"></A><A NAME = "SectionTitle:8.2 Toxicological Analyses and Their Interpretation"></A>8.2 Toxicological Analyses and Their Interpretation <A NAME = "SubSectionTitle:8.2.1 Tests on toxic ingredient(s) of material"></A>8.2.1 Tests on toxic ingredient(s) of material <A NAME = "DivisionTitle:8.2.1.1 Simple Qualitative Test(s)"></A>8.2.1.1 Simple Qualitative Test(s) <A NAME = "EndDivisionTitle:8.2.1.1 Simple Qualitative Test(s)"></A><A NAME = "DivisionTitle:8.2.1.2 Advanced Qualitative Confirmation Test(s)"></A>8.2.1.2 Advanced Qualitative Confirmation Test(s) <A NAME = "EndDivisionTitle:8.2.1.2 Advanced Qualitative Confirmation Test(s)"></A><A NAME = "DivisionTitle:8.2.1.3 Simple Quantitative Method(s)"></A>8.2.1.3 Simple Quantitative Method(s) <A NAME = "EndDivisionTitle:8.2.1.3 Simple Quantitative Method(s)"></A><A NAME = "DivisionTitle:8.2.1.4 Advanced Quantitative Method(s)"></A>8.2.1.4 Advanced Quantitative Method(s) <A NAME = "EndDivisionTitle:8.2.1.4 Advanced Quantitative Method(s)"></A><A NAME = ":8.2.1 Tests on toxic ingredient(s) of material"></A><A NAME = "SubSectionTitle:8.2.2 Tests for biological specimens"></A>8.2.2 Tests for biological specimens <A NAME = "DivisionTitle:8.2.2.1 Simple Qualitative Test(s)"></A>8.2.2.1 Simple Qualitative Test(s) <A NAME = "EndDivisionTitle:8.2.2.1 Simple Qualitative Test(s)"></A><A NAME = "DivisionTitle:8.2.2.2 Advanced Qualitative Confirmation Test(s)"></A>8.2.2.2 Advanced Qualitative Confirmation Test(s) <A NAME = "EndDivisionTitle:8.2.2.2 Advanced Qualitative Confirmation Test(s)"></A><A NAME = "DivisionTitle:8.2.2.3 Simple Quantitative Method(s)"></A>8.2.2.3 Simple Quantitative Method(s) <A NAME = "EndDivisionTitle:8.2.2.3 Simple Quantitative Method(s)"></A><A NAME = "DivisionTitle:8.2.2.4 Advanced Quantitative Method(s)"></A>8.2.2.4 Advanced Quantitative Method(s) <A NAME = "EndDivisionTitle:8.2.2.4 Advanced Quantitative Method(s)"></A><A NAME = "DivisionTitle:8.2.2.5 Other Dedicated Method(s)"></A>8.2.2.5 Other Dedicated Method(s) <A NAME = "EndDivisionTitle:8.2.2.5 Other Dedicated Method(s)"></A><A NAME = ":8.2.2 Tests for biological specimens"></A><A NAME = "SubSectionTitle:8.2.3 Interpretation of toxicological analyses"></A>8.2.3 Interpretation of toxicological analyses <A NAME = ":8.2.3 Interpretation of toxicological analyses"></A><A NAME = "EndSectionTitle:8.2 Toxicological Analyses and Their Interpretation"></A><A NAME = "SectionTitle:8.3 Biomedical investigations and their interpretation"></A>8.3 Biomedical investigations and their interpretation <A NAME = "SubSectionTitle:8.3.1 Biochemical analysis"></A>8.3.1 Biochemical analysis <A NAME = "DivisionTitle:8.3.1.1 Blood, plasma or serum"></A>8.3.1.1 Blood, plasma or serum <PIM8.3.1.1>"Basic analyses"<NL> "Dedicated analyses"<NL> "Optional analyses"</PIM8.3.1.1> <A NAME = "EndDivisionTitle:8.3.1.1 Blood, plasma or serum"></A><A NAME = "DivisionTitle:8.3.1.2 Urine"></A>8.3.1.2 Urine <PIM8.3.1.2>"Basic analyses"<NL> "Dedicated analyses"<NL> "Optional analyses"</PIM8.3.1.2> <A NAME = "EndDivisionTitle:8.3.1.2 Urine"></A><A NAME = "DivisionTitle:8.3.1.3 Other fluids"></A>8.3.1.3 Other fluids <A NAME = "EndDivisionTitle:8.3.1.3 Other fluids"></A><A NAME = ":8.3.1 Biochemical analysis"></A><A NAME = "SubSectionTitle:8.3.2 Arterial blood gas analyses"></A>8.3.2 Arterial blood gas analyses <A NAME = ":8.3.2 Arterial blood gas analyses"></A><A NAME = "SubSectionTitle:8.3.3 Haematological analyses"></A>8.3.3 Haematological analyses <PIM8.3.3>"Basic analyses"<NL> "Dedicated analyses"<NL> "Optional analyses"</PIM8.3.3> <A NAME = ":8.3.3 Haematological analyses"></A><A NAME = "SubSectionTitle:8.3.4 Interpretation of biomedical investigations"></A>8.3.4 Interpretation of biomedical investigations <A NAME = ":8.3.4 Interpretation of biomedical investigations"></A><A NAME = "EndSectionTitle:8.3 Biomedical investigations and their interpretation"></A><A NAME = "SectionTitle:8.4 Other biomedical (diagnostic) investigations and their interpretation"></A>8.4 Other biomedical (diagnostic) investigations and their interpretation <A NAME = "EndSectionTitle:8.4 Other biomedical (diagnostic) investigations and their interpretation"></A><A NAME = "SectionTitle:8.5 Overall interpretation of all toxicological analyses and toxicological investigations"></A>8.5 Overall interpretation of all toxicological analyses and toxicological investigations <PIM8.5>Sample collection<NL> For toxicological analyses: whole blood 10 mL; urine 25 mL and gastric contents 25 mL.<NL> <NL> Biomedical analysis<NL> Blood gases, serum electrolytes, blood glucose and hepatic enzymes when necessary in severe cases.<NL> <NL> Toxicological analysis<NL> Qualitative testing for benzodiazepines is helpful to confirm their presence, but quantitative levels are not clinically useful. More advanced analyses are not necessary for the treatment of the poisoned patient due the lack of correlation between blood concentrations and clinical severity (Jatlow et al., 1979; MacCormick et al., 1985; Minder, 1989).<NL> <NL> TLC and EMIT: These provide data on the presence of benzodiazepines, their metabolites and possible associations with other drugs.<NL> <NL> GC or HPLC: These permit identification and quantification of the benzodiazepine which caused the poisoning and its metabolites in blood and urine.</PIM8.5> <A NAME = "EndSectionTitle:8.5 Overall interpretation of all toxicological analyses and toxicological investigations"></A><A NAME = "SectionTitle:8.6 References"></A>8.6 References <A NAME = "EndSectionTitle:8.6 References"></A><A NAME = "EndPartTitle:8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS"></A><A NAME = "PartTitle:9. CLINICAL EFFECTS"></A>9. CLINICAL EFFECTS <A NAME = "SectionTitle:9.1 Acute poisoning"></A>9.1 Acute poisoning <A NAME = "SubSectionTitle:9.1.1 Ingestion"></A>9.1.1 Ingestion <PIM9.1.1>The onset of impairment of consciousness is relatively rapid in benzodiazepine poisoning. Onset is more rapid following larger doses and with agents of shorter duration of action. The most common and initial symptom is somnolence. This may progress to coma Grade I or Grade II (see below) following very large ingestions.<NL> <NL> Reed Classification of Coma (Reed et al., 1952)<NL> <NL> Coma Grade I: Depressed level of consciousness, response to painful stimuli<NL> Deep tendon reflexes and vital signs intact<NL> <NL> Coma Grade II: Depressed level of consciousness, no response to painful stimuli<NL> Deep tendon reflexes and vital signs intact<NL> <NL> Coma Grade III: Depressed level of consciousness, no response to painful stimuli<NL> Deep tendon reflexes absent. Vital signs intact<NL> <NL> Coma Grade IV: Coma grade III plus respiratory and circulatory collapse</PIM9.1.1> <A NAME = ":9.1.1 Ingestion"></A><A NAME = "SubSectionTitle:9.1.2 Inhalation"></A>9.1.2 Inhalation <PIM9.1.2>Not relevant.</PIM9.1.2> <A NAME = ":9.1.2 Inhalation"></A><A NAME = "SubSectionTitle:9.1.3 Skin exposure"></A>9.1.3 Skin exposure <PIM9.1.3>No data.</PIM9.1.3> <A NAME = ":9.1.3 Skin exposure"></A><A NAME = "SubSectionTitle:9.1.4 Eye contact"></A>9.1.4 Eye contact <PIM9.1.4>No data.</PIM9.1.4> <A NAME = ":9.1.4 Eye contact"></A><A NAME = "SubSectionTitle:9.1.5 Parenteral exposure"></A>9.1.5 Parenteral exposure <PIM9.1.5>Overdose by the intravenous route results in symptoms similar to those associated with ingestion, but they appear immediately after the infusion, and the progression of central nervous system (CNS) depression is more rapid. Acute intentional poisoning by this route is uncommon and most cases are iatrogenic. Rapid intravenous infusion may cause hypotension, respiratory depression and apnoea.</PIM9.1.5> <A NAME = ":9.1.5 Parenteral exposure"></A><A NAME = "SubSectionTitle:9.1.6 Other"></A>9.1.6 Other <A NAME = ":9.1.6 Other"></A><A NAME = "EndSectionTitle:9.1 Acute poisoning"></A><A NAME = "SectionTitle:9.2 Chronic poisoning"></A>9.2 Chronic poisoning <A NAME = "SubSectionTitle:9.2.1 Ingestion"></A>9.2.1 Ingestion <PIM9.2.1>Toxic effects associated with chronic exposure are secondary to the presence of the drug and metabolites and include depressed mental status, ataxia, vertigo, dizziness, fatigue, impaired motor co-ordination, confusion, disorientation and anterograde amnesia. Paradoxical effects of psychomotor excitation, delirium and aggressiveness also occur. These chronic effects are more common in the elderly, children and patients with renal or hepatic disease.<NL> <NL> Administration of therapeutic doses of benzodiazepines for 6 weeks or longer can result in physical dependence, characterized by a withdrawal syndrome when the drug is discontinued. With larger doses, the physical dependence develops more rapidly.</PIM9.2.1> <A NAME = ":9.2.1 Ingestion"></A><A NAME = "SubSectionTitle:9.2.2 Inhalation"></A>9.2.2 Inhalation <PIM9.2.2>No data.</PIM9.2.2> <A NAME = ":9.2.2 Inhalation"></A><A NAME = "SubSectionTitle:9.2.3 Skin exposure"></A>9.2.3 Skin exposure <PIM9.2.3>No data.</PIM9.2.3> <A NAME = ":9.2.3 Skin exposure"></A><A NAME = "SubSectionTitle:9.2.4 Eye contact"></A>9.2.4 Eye contact <PIM9.2.4>No data.</PIM9.2.4> <A NAME = ":9.2.4 Eye contact"></A><A NAME = "SubSectionTitle:9.2.5 Parenteral exposure"></A>9.2.5 Parenteral exposure <PIM9.2.5>The chronic parenteral administration of benzodiazepines may produce thrombophlebitis and tissue irritation, in addition to the usual symptoms (Greenblat & Koch-Weser, 1973).</PIM9.2.5> <A NAME = ":9.2.5 Parenteral exposure"></A><A NAME = "SubSectionTitle:9.2.6 Other"></A>9.2.6 Other <PIM9.2.6>No data.</PIM9.2.6> <A NAME = ":9.2.6 Other"></A><A NAME = "EndSectionTitle:9.2 Chronic poisoning"></A><A NAME = "SectionTitle:9.3 Course, prognosis, cause of death"></A>9.3 Course, prognosis, cause of death <PIM9.3>Benzodiazepines are relatively safe drugs even in overdose. The clinical course is determined by the progression of the neurological symptoms. Deep coma or other manifestations of severe central nervous system (CNS) depression are rare with benzodiazepines alone. Concomitant ingestion of other CNS depressants may result in a more severe CNS depression of longer duration.<NL> <NL> The therapeutic index of the benzodiazepines is high and the mortality rate associated with poisoning due to benzodiazepines alone is very low. Complications in severe poisoning include respiratory depression and aspiration pneumonia. Death is due to respiratory arrest.</PIM9.3> <A NAME = "EndSectionTitle:9.3 Course, prognosis, cause of death"></A><A NAME = "SectionTitle:9.4 Systematic description of clinical effects"></A>9.4 Systematic description of clinical effects <A NAME = "SubSectionTitle:9.4.1 Cardiovascular"></A>9.4.1 Cardiovascular <PIM9.4.1>Hypotension, bradycardia and tachycardia have been reported with overdose (Greenblatt et al., 1977; Meredith & Vale 1985). Hypotension is more frequent when benzodiazepines are ingested in association with other drugs (Hojer et al., 1989). Rapid intravenous injection is also associated with hypotension.</PIM9.4.1> <A NAME = ":9.4.1 Cardiovascular"></A><A NAME = "SubSectionTitle:9.4.2 Respiratory"></A>9.4.2 Respiratory <PIM9.4.2>Respiratory depression may occur in benzodiazepine overdose and the severity depends on dose ingested, amount absorbed, type of benzodiazepine and co-ingestants. Respiratory depression requiring ventilatory support has occurred in benzodiazepine overdoses (Sullivan, 1989; Hojer et al.,1989). The dose-response for respiratory depression varies between individuals. Respiratory depression or respiratory arrest may rarely occur with therapeutic doses. Benzodiazepines may affect the control of ventilation during sleep and may worsen sleep apnoea or other sleep-related breathing disorders, especially in patients with chronic obstructive pulmonary disease or cardiac failure (Guilleminault, 1990).</PIM9.4.2> <A NAME = ":9.4.2 Respiratory"></A><A NAME = "SubSectionTitle:9.4.3 Neurological"></A>9.4.3 Neurological <A NAME = "DivisionTitle:9.4.3.1 Central nervous system (CNS)"></A>9.4.3.1 Central nervous system (CNS) <PIM9.4.3.1>CNS depression is less marked than that produced by other CNS depressant agents (Meredith & Vale, 1985). Even in large overdoses, benzodiazepines usually produce only mild symptoms and this distinguishes them from other sedative-hypnotic agents. Sedation, somnolence, weakness, diplopia, dysarthria, ataxia and intellectual impairment are the most common neurological effects. The clinical effects of severe poisoning are sleepiness, ataxia and coma Grade I to Grade II (Reed). The presence of more severe coma suggests the possibility of co-ingested drugs. Certain of the newer short-acting benzodiazepines (temazepam, alprazolam and triazolam) have been associated with several fatalities and it is possible that they may have greater acute toxicity (Forrest et al., 1986). The elderly and very young children are more susceptible to the CNS depressant action of benzodiazepines.<NL> The benzodiazepines may cause paradoxical CNS effects, including excitement, delirium and hallucinations. Triazolam has been reported to produce delirium, toxic psychosis, memory impairment and transient global amnesia (Shader & Dimascio, 1970; Bixler et al, 1991). Flurazepam has been associated with nightmares and hallucinations.<NL> There are a few reports of extrapyramidal symptoms and dyskinesias in patients taking benzodiazepines (Kaplan & Murkafsky, 1978; Sandyk, 1986).<NL> The muscle relaxation caused by benzodiazepines is of CNS origin and manifests as dysarthria, incoordination and difficulty standing and walking.</PIM9.4.3.1> <A NAME = "EndDivisionTitle:9.4.3.1 Central nervous system (CNS)"></A><A NAME = "DivisionTitle:9.4.3.2 Peripheral nervous system"></A>9.4.3.2 Peripheral nervous system <A NAME = "EndDivisionTitle:9.4.3.2 Peripheral nervous system"></A><A NAME = "DivisionTitle:9.4.3.3 Autonomic nervous system"></A>9.4.3.3 Autonomic nervous system <A NAME = "EndDivisionTitle:9.4.3.3 Autonomic nervous system"></A><A NAME = "DivisionTitle:9.4.3.4 Skeletal and smooth muscle"></A>9.4.3.4 Skeletal and smooth muscle <A NAME = "EndDivisionTitle:9.4.3.4 Skeletal and smooth muscle"></A><A NAME = ":9.4.3 Neurological"></A><A NAME = "SubSectionTitle:9.4.4 Gastrointestinal"></A>9.4.4 Gastrointestinal <PIM9.4.4>Oral benzodiazepine poisoning will produce minimal effects on the gastrointestinal tract (GI) tract but can occasionally cause nausea or vomiting (Shader & Dimascio, 1970).</PIM9.4.4> <A NAME = ":9.4.4 Gastrointestinal"></A><A NAME = "SubSectionTitle:9.4.5 Hepatic"></A>9.4.5 Hepatic <PIM9.4.5>A case of cholestatic jaundice due focal hepatic necrosis was associated with the administration of diazepam (Tedesco & Mills, 1982).</PIM9.4.5> <A NAME = ":9.4.5 Hepatic"></A><A NAME = "SubSectionTitle:9.4.6 Urinary"></A>9.4.6 Urinary <A NAME = "DivisionTitle:9.4.6.1 Renal"></A>9.4.6.1 Renal <PIM9.4.6.1>Vesical hypotonia and urinary retention has been reported in association with diazepam poisoning (Chadduck et al., 1973).</PIM9.4.6.1> <A NAME = "EndDivisionTitle:9.4.6.1 Renal"></A><A NAME = "DivisionTitle:9.4.6.2 Other"></A>9.4.6.2 Other <A NAME = "EndDivisionTitle:9.4.6.2 Other"></A><A NAME = ":9.4.6 Urinary"></A><A NAME = "SubSectionTitle:9.4.7 Endocrine and reproductive systems"></A>9.4.7 Endocrine and reproductive systems <PIM9.4.7>Galactorrhoea with normal serum prolactin concentrations has been noted in 4 women taking benzodiazepines (Kleinberg et al., 1977). Gynaecomastia has been reported in men taking high doses of diazepam (Moerck & Majelung, 1979). Raised serum concentrations of oestrodiol were observed in men taking diazepam 10 to 20 mg daily for 2 weeks (Arguelles & Rosner, 1975).</PIM9.4.7> <A NAME = ":9.4.7 Endocrine and reproductive systems"></A><A NAME = "SubSectionTitle:9.4.8 Dermatological"></A>9.4.8 Dermatological <PIM9.4.8>Bullae have been reported following overdose with nitrazepam and oxazepam (Ridley, 1971; Moshkowitz et al., 1990).<NL> Allergic skin reactions were attributed to diazepam at a rate of 0.4 per 1000 patients (Brigby, 1986).</PIM9.4.8> <A NAME = ":9.4.8 Dermatological"></A><A NAME = "SubSectionTitle:9.4.9 Eye, ear, nose, throat: local effects"></A>9.4.9 Eye, ear, nose, throat: local effects <PIM9.4.9>Brown opacification of the lens occurred in 2 patients who used diazepam for several years (Pau Braune, 1985).</PIM9.4.9> <A NAME = ":9.4.9 Eye, ear, nose, throat: local effects"></A><A NAME = "SubSectionTitle:9.4.10 Haematological"></A>9.4.10 Haematological <PIM9.4.10>No data.</PIM9.4.10> <A NAME = ":9.4.10 Haematological"></A><A NAME = "SubSectionTitle:9.4.11 Immunological"></A>9.4.11 Immunological <PIM9.4.11>Allergic reaction as above (see 9.4.8).</PIM9.4.11> <A NAME = ":9.4.11 Immunological"></A><A NAME = "SubSectionTitle:9.4.12 Metabolic"></A>9.4.12 Metabolic <A NAME = "DivisionTitle:9.4.12.1 Acid-base disturbances"></A>9.4.12.1 Acid-base disturbances <PIM9.4.12.1>No direct disturbances have been described.</PIM9.4.12.1> <A NAME = "EndDivisionTitle:9.4.12.1 Acid-base disturbances"></A><A NAME = "DivisionTitle:9.4.12.2 Fluid and electrolyte disturbances"></A>9.4.12.2 Fluid and electrolyte disturbances <PIM9.4.12.2>No direct disturbances have been described.</PIM9.4.12.2> <A NAME = "EndDivisionTitle:9.4.12.2 Fluid and electrolyte disturbances"></A><A NAME = "DivisionTitle:9.4.12.3 Others"></A>9.4.12.3 Others <A NAME = "EndDivisionTitle:9.4.12.3 Others"></A><A NAME = ":9.4.12 Metabolic"></A><A NAME = "SubSectionTitle:9.4.13 Allergic reactions"></A>9.4.13 Allergic reactions <PIM9.4.13>Hypersensitivity reactions including anaphylaxis are very rare (Brigby, 1986). Reactions have been attributed to the vehicle used for some parenteral diazepam formulations (Huttel et al., 1980). There is also a report of a type I hypersensitivity reaction to a lipid emulsion of diazepam (Deardon, 1987).</PIM9.4.13> <A NAME = ":9.4.13 Allergic reactions"></A><A NAME = "SubSectionTitle:9.4.14 Other clinical effects"></A>9.4.14 Other clinical effects <PIM9.4.14>Hypothermia was reported in 15% of cases in one series. (Martin, 1985; Hojer et al., 1989).</PIM9.4.14> <A NAME = ":9.4.14 Other clinical effects"></A><A NAME = "SubSectionTitle:9.4.15 Special risks"></A>9.4.15 Special risks <PIM9.4.15>Pregnancy<NL> Passage of benzodiazepines across the placenta depends on the degree of protein binding in mother and fetus, which is influenced by factors such as stage of pregnancy and plasma concentrations of free fatty acids in mother and fetus (Lee et al., 1982). Adverse effects may persist in the neonate for several days after birth because of immature drug metabolising enzymes. Competition between diazepam and bilirubin for protein binding sites could result in hyperbilirubinemia in the neonate (Notarianni, 1990).<NL> The abuse of benzodiazepines by pregnant women can cause withdrawal syndrome in the neonate. The administration of benzodiazepines during childbirth can produce hypotonia, hyporeflexia, hypothermia and respiratory depression in the newborn.<NL> Benzodiazepines have been used in pregnant patients and early reports associated diazepam and chlordiazepoxide with some fetal malformations, but these were not supported by later studies (Laegreid et al., 1987; McElhatton, 1994).<NL> <NL> Breast feeding<NL> Benzodiazepines are excreted in breast milk in significant amounts and may result in lethargy and poor feeding in neonates. Benzodiazepines should be avoided in nursing mothers (Brodie, 1981; Reynolds, 1996).</PIM9.4.15> <A NAME = ":9.4.15 Special risks"></A><A NAME = "EndSectionTitle:9.4 Systematic description of clinical effects"></A><A NAME = "SectionTitle:9.5 Other"></A>9.5 Other <PIM9.5>Dependence and withdrawal<NL> Benzodiazepines have a significant potential for abuse and can cause physical and psychological dependence. Abrupt cessation after prolonged use causes a withdrawal syndrome (Ashton, 1989). The mechanism of dependence is probably related to functional deficiency of GABA activity.<NL> Withdrawal symptoms include anxiety, insomnia, headache, dizziness, tinnitus, anorexia, vomiting, nausea, tremor, weakness, perspiration, irritability, hypersensitivity to visual and auditory stimuli, palpitations, tachycardia and postural hypotension. In severe and rare cases of withdrawal from high doses, patients may develop affective disorders or motor dysfunction: seizures, psychosis, agitation, confusion, and hallucinations (Einarson, 1981; Hindmarch et al, 1990; Reynolds, 1996).<NL> The time of onset of the withdrawal syndrome depends on the half-life of the drug and its active metabolites; the symptoms occur earlier and may be more severe with short- acting benzodiazepines. Others risk factors for withdrawal syndrome include prolonged use of the drug, higher dosage and abrupt cessation of the drug.<NL> <NL> Abuse<NL> Benzodiazepines, particularly temazepam, have been abused both orally and intravenously (Stark et al., 1987; Woods, 1987; Funderburk et al, 1988)<NL> <NL> Criminal uses<NL> The amnesic effects of benzodiazepines have been used for criminal purposes with medicolegal consequences (Ferner, 1996).</PIM9.5> <A NAME = "EndSectionTitle:9.5 Other"></A><A NAME = "SectionTitle:9.6 Summary"></A>9.6 Summary <A NAME = "EndSectionTitle:9.6 Summary"></A><A NAME = "EndPartTitle:9. CLINICAL EFFECTS"></A><A NAME = "PartTitle:10. MANAGEMENT"></A>10. MANAGEMENT <A NAME = "SectionTitle:10.1 General principles"></A>10.1 General principles <PIM10.1>Most benzodiazepine poisonings require only clinical observation and supportive care. It should be remembered that benzodiazepine ingestions by adults commonly include other drugs and other CNS depressants. Activated charcoal normally provides adequate gastrointestinal decontamination. Gastric lavage is not routinely indicated. Emesis is contraindicated. The use of flumazenil is reserved for cases with severe respiratory or cardiovascular complications and should not replace the basic management of the airway and respiration. Renal and extracorporeal elimination methods are not effective.</PIM10.1> <A NAME = "EndSectionTitle:10.1 General principles"></A><A NAME = "SectionTitle:10.2 Life supportive procedures and symptomatic/specific treatment"></A>10.2 Life supportive procedures and symptomatic/specific treatment <PIM10.2>The patient should be evaluated to determine adequacy of airway, breathing and circulation. Continue clinical observation until evidence of toxicity has resolved. Intravenous access should be available for administration of fluid. Endotracheal intubation, assisted ventilation and supplemental oxygen may be required on rare occasions, more commonly when benzodiazepines are ingested in large amounts or with other CNS depressants.</PIM10.2> <A NAME = "EndSectionTitle:10.2 Life supportive procedures and symptomatic/specific treatment"></A><A NAME = "SectionTitle:10.3 Decontamination"></A>10.3 Decontamination <PIM10.3>Gastric lavage is not routinely indicated following benzodiazepine overdose. Emesis is contraindicated because of the potential for CNS depression. Activated charcoal can be given orally.</PIM10.3> <A NAME = "EndSectionTitle:10.3 Decontamination"></A><A NAME = "SectionTitle:10.4 Enhanced elimination"></A>10.4 Enhanced elimination <PIM10.4>Methods of enhancing elimination are not indicated.</PIM10.4> <A NAME = "EndSectionTitle:10.4 Enhanced elimination"></A><A NAME = "SectionTitle:10.5 Antidote treatment"></A>10.5 Antidote treatment <A NAME = "SubSectionTitle:10.5.1 Adults"></A>10.5.1 Adults <PIM10.5.1>Flumazenil, a specific benzodiazepine antagonist at central GABA-ergic receptors is available. Although it effectively reverses the CNS effects of benzodiazepine overdose, its use in clinical practice is rarely indicated.<NL> Use of Flumazenil is specifically contraindicated when there is history of co-ingestion of tricyclic antidepressants or other drugs capable of producing seizures (including aminophylline and cocaine), benzodiazepine dependence, or in patients taking benzodiazepines as an anticonvulsant agent. In such situations, administration of Flumazenil may precipitate seizures (Lopez, 1990; Mordel et al., 1992).<NL> Adverse effects associated with Flumazenil include hypertension, tachycardia, anxiety, nausea, vomiting and benzodiazepine withdrawal syndrome.<NL> The initial intravenous dose of 0.3 to 1.0 mg may be followed by further doses if necessary. The absence of clinical response to 2 mg of flumazenil within 5 to 10 minutes indicates that benzodiazepine poisoning is not the major cause of CNS depression or coma.<NL> The patient regains consciousness within 15 to 30 seconds after injection of flumazenil, but since it is metabolised more rapidly than the benzodiazepines, recurrence of toxicity and CNS depression can occur and the patient should be carefully monitored after initial response to flumazenil therapy. If toxicity recurs, further bolus doses may be administered or an infusion commenced at a dose of 0.3 to 1.0 mg/hour (Meredith et al., 1993).</PIM10.5.1> <A NAME = ":10.5.1 Adults"></A><A NAME = "SubSectionTitle:10.5.2 Children"></A>10.5.2 Children <PIM10.5.2>The initial intravenous dose of 0.1 mg should be repeated each minute until the child is awake. Continuous intravenous infusion should be administered at a rate of 0.1 to 0.2 mg/hour (Meredith et al., 1993).</PIM10.5.2> <A NAME = ":10.5.2 Children"></A><A NAME = "EndSectionTitle:10.5 Antidote treatment"></A><A NAME = "SectionTitle:10.6 Management discussion"></A>10.6 Management discussion <PIM10.6>Most benzodiazepine poisonings require only clinical observation and supportive care. Flumazenil is the specific antagonist of the effects of benzodiazepines, but the routine use for the treatment of benzodiazepine overdosage is not recommended. The use of Flumazenil should only be considered where severe CNS depression is observed. This situation rarely occurs, except in cases of mixed ingestion. The administration of flumazenil may improve respiratory and cardiovascular function enough to decrease the need for intubation and mechanical ventilation, but should never replace basic management principles.<NL> Flumazenil is an imidazobenzodiazepine and has been shown to reverse the sedative, anti-convulsant and muscle-relaxant effects of benzodiazepines. In controlled clinical trials, flumazenil significantly antagonizes benzodiazepine-induced coma arising from anaesthesia or acute overdose. However, the use of flumazenil has not been shown to reduce mortality or sequelae in such cases.<NL> The administration of flumazenil is more effective in reversing the effects of benzodiazepines when they are the only drugs producing CNS toxicity. Flumazenil does not reverse the CNS depressant effects of non-benzodiazepine drugs, including alcohol. The diagnostic use of flumazenil in patients presenting with coma of unknown origin can be justified by its high therapeutic index and the fact that this may limit the use of other diagnostic procedures (CT scan, lumbar puncture, etc).<NL> Flumazenil is a relatively expensive drug and this may also influence its use, especially in areas with limited resources.</PIM10.6> <A NAME = "EndSectionTitle:10.6 Management discussion"></A><A NAME = "EndPartTitle:10. MANAGEMENT"></A><A NAME = "PartTitle:11. ILLUSTRATIVE CASES"></A>11. ILLUSTRATIVE CASES <A NAME = "SectionTitle:11.1 Case reports from literature"></A>11.1 Case reports from literature <A NAME = "EndSectionTitle:11.1 Case reports from literature"></A><A NAME = "EndPartTitle:11. ILLUSTRATIVE CASES"></A><A NAME = "PartTitle:12. Additional information"></A>12. Additional information <A NAME = "SectionTitle:12.1 Specific preventive measures"></A>12.1 Specific preventive measures <A NAME = "EndSectionTitle:12.1 Specific preventive measures"></A><A NAME = "SectionTitle:12.2 Other"></A>12.2 Other <A NAME = "EndSectionTitle:12.2 Other"></A><A NAME = "EndPartTitle:12. Additional information"></A><A NAME = "PartTitle:13. REFERENCES"></A>13. REFERENCES <PIM13.>Arguelles AE, & Rosner J. (1975) Diazepam and plasma testosterone levels. Lancet, ii: 607.<NL> <NL> Ashton CH (1989) Drug-induced stupor and coma: some physical signs and their pharmacological basis. Adverse drug React Acute Poisoning Rev, 8: 1-59.<NL> <NL> Bixler EO, Kales A, Manfredi RL, Vgontzas AN, Tyson KL, & Kales JD (1991) Next-day memory impairment with triazolam use. Lancet, 337: 827-831.<NL> <NL> Brigby M. (1986) Drug induced cutaneous reactions. JAMA, 256: 3358-63.<NL> <NL> Brodie RR, Chasseaud LF & Taylor T (1981) Concentrations of N- descyclopropylmethyl-prazepam in whole-blood, plasma and milk after administration of prazepam to humans. Biopharm Drug Dispos, 2: 59-68.<NL> <NL> Chadduck WM, Loar CR & Denton IC. (1973) Vesical hypotonicity with diazepam. J Urol, 109: 1005-1007.<NL> <NL> Deardon DJ. (1987) Acute hypersensivity to IV Diazulmuls. Br J Anaesth, 59: 391.<NL> <NL> Einarson TR (1981) Oxazepam withdrawal convulsions. Drug Intell Clin Pharm, 15: 487.<NL> <NL> Ellenhorn, M. (1996) Medical Toxicology. 2nd Ed., Elsevier.<NL> <NL> Ferner RE (1996) Forensic Pharmacology, 1st Ed. Oxford University Press, Oxford.<NL> <NL> Forrest ARW, Marsh I, Bradshaw C & Braich SK (1986) Fatal temazepam overdoses (letter). Lancet, 2: 226.<NL> <NL> Funderburk FR, Griffiths RR, McLeod DR, Bigelow GE, Mackenzie A, Liebson IA & Newmeth-Coslett R (1988) Relative abuse liability of lorazepam and diazepam: an evaluation in "recreational" drug users. Drug Alcohol Depend, 22: 215-222.<NL> <NL> Greenblatt DJ, Allen MD, Noel BJ et al (1977) Acute overdose with benzodiazepine derivatives. Clin Pharm Ther, 21: 497-513.<NL> <NL> Guilleminault C. (1990) Benzodiazepines, bresthing and sleep. Am J Med, 88 (suppl 3A): 25S - 28S.<NL> <NL> Hindmarch I, Beaumont G, Brandon S, & Leonard, B. (1990) Benzodiazepines Current Concepts, John Wiley & Sons Ltd, UK.<NL> <NL> Hojer J, Baehrendtz S & Gustafsson L. (1989) Benzodiazepine poisoning: experience of 702 admissions to an intensive care unit during a 14-year period. J Intern Med, 226: 117-122.<NL> <NL> Huttel MS, Schou Olesen A & Stofferson E (1980) Complement- mediated reactions to diazepam with Cremophor as solvent. Br J Anaesth, 52: 77-9.<NL> <NL> Hyams SW & Keroub C (1977) Glaucoma due to diazepam. Am J Psychiatry, 134: 477-479.<NL> <NL> Kaplan SR, & Murkofsky C (1978) Oral-buccal dyskinesic synptoms associated with low dose benzodiazepine treatment. Am J Psychiatry, 135: 1558-1559.<NL> <NL> Kleinberg DL, Noel GL & Frantz AG (1977) Galactorrhea a study of 235 cases. N Eng J Med 296: 589-600.<NL> <NL> Laegreid L, Olegard R, & Wahlstrom J (1987) Abnormalities in children exposed to benzodiazepines in utero. Lancet, 1: 108-109.<NL> <NL> Lee JN, Chen SS, Richens A, Menabawey m & Chard T (1982) Serum protein binding of diazepam in maternal and foetal serum during pregnancy. Br J Clin Pharmacol, 14: 551-4.<NL> <NL> Lopez A & Rebollo J (1990) Benzodiazepine withdrawal syndrome after a benzodiazepine antagonist. Crit Care Med, 18:1480-1481.<NL> <NL> Martin SM (1985) The effect of diazepam on body temperature change in humans during cold exposure. J Clin Pharmacol, 25: 611-613.<NL> <NL> McCormick SR, Nielsen J & Jatlow PI (1985) Alprazolam overdose: clinical findings and serum concentrations in two cases. J Clin Psychiatr, 46:247-248.<NL> <NL> McElhatton PR. (1994) The effects of benzodiazepines use during pregnancy and lactation. Reprod Toxicol, 8: 461-75.<NL> <NL> Meredith TJ, Jacobsen D, Haines JA, Berger JC (1993) IPCS/CEC Evaluation of Antidotes Series, Vol1, Naloxone, flumazenil and dantrolene as antidotes, 1st ed. Cambridge University Press, Cambridge.<NL> <NL> Meredith TJ, & Vale JA (1985) Poisoning due to psychotropic agents. Adverse Drug React Acute Poison Rev, 4: 83-122.<NL> <NL> Minder EI (1989) Toxicity in a case of acute and massive overdose of chlordiazepoxide and its correlation to blood concentration. Clin Toxicol, 27: 117-127.<NL> <NL> Moerck HJ, Majelung G (1979) Gynaecomastia and diazepam abuse.Lancet, i: 1344-5.<NL> <NL> Mordel A, Winkler E, Almog S, Tirosh M & Ezra D (1992) Seizures after flumazenil administration in a case of combined benzodiazepine and tricyclic antidepressant overdose. Crit Care Med, 12: 1733-1734.<NL> <NL> Notarianni LJ. (1990) Plasma protein binding of drugs in pregnancy and neonates. Clin Pharnacokinet, 18: 20-36.<NL> <NL> Pau Braune H (1985) [Eyes effect of diazepam.] Klin Monatsbl Augenheilkd, 187: 219-20 (in German).<NL> <NL> Reed C E, Driggs M F, & Foote CC (1952) Acute barbiturate intoxication. A study of 300 cases based on a physiologic system of classification of the severity of intoxication. Ann Intern Med, 37: 390-396.<NL> <NL> Reynolds J (1996) Martindale, The Extra Pharmacopeia. 30th ed. The Pharmaceutical Press, London, 699-744.<NL> <NL> Ridley CM (1971) Bullous lesions in nitrazepan overdosage. Br Med J, 3: 28-29.<NL> <NL> Sandyk R (1986) Orofacial diskynesias associated with lorazepam therapy. Clin Pharm, 5: 419-21.<NL> <NL> Shader RI & Dimascio A (1970) Psychotropic drug side effects, 1st ed. Willians & Wilkins, Baltimore.<NL> <NL> Stark C, Sykes R & Mullin P (1987) Temazepam abuse (letter). Lancet, 2:802-803.<NL> <NL> Sullivan RJ Jr (1989) Respiratory depression requiring ventilatory support following 0.5 mg of Triazolam. J Am Geriatr, Soc 37: 450-452.<NL> <NL> Tedesco FJ, & Mills LR. (1982) Diazepam hepatites. Dig Dis Sci 27: 470-2.</PIM13.> </S><A NAME = "EndPartTitle:13. REFERENCES"></A><A NAME = "PartTitle:14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)"></A>14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) <PIM14.>Author: Dr Ligia Fruchtengarten<NL> Poison Control Centre of Sao Paulo - Brazil<NL> Hospital Municipal Dr Arthur Ribeiro de Saboya - Coperpas 12<NL> FAX / Phone: 55 11 2755311<NL> E-mail: lfruchtengarten@originet.com.br<NL> <NL> Mailing Address: Hospital Municipal Dr Arthur Ribeiro de Saboya - Coperpas 12<NL> Centro de Controle de Intoxica鏾es de Sao Paulo<NL> Av Francisco de Paula Quintanilha Ribeiro, 860<NL> 04330 - 020 Sao Paulo - SP - Brazil.<NL> <NL> Date: July 1997<NL> <NL> Peer Review: INTOX 10 Meeting, Rio de Janeiro, Brazil, September 1997.<NL> R. Ferner, L. Murray (Chairperson), M-O. Rambourg, A. Nantel, N. Ben Salah, M. Mathieu- Nolf, A. Borges.<NL> <NL> Review 1998: Lindsay Murray<NL> Queen Elizabeth II Medical Centre<NL> Perth, Western Australia.<NL> <NL> Editor: Dr M.Ruse, April 1998</PIM14.> <A NAME = "EndPartTitle:14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)"></A> </PRE> <script src="/scripts/google_analytics.js" type="text/javascript"></script> </BODY> <PRE> </PRE> <PRE> See Also: <A HREF="../../eintro/eintro/abreviat.htm">Toxicological Abbreviations</A> </PRE> </HTML>

CINXE.COM

Medazepam (PIM 460)