Big Wordy Boring Text Outline Version
Contact: Jim Middleton, Pharmacist and Instructor

At the completion of this section, the participant should be able  to:
 1. Describe the various types of sedatives available to treat the anxious patient
 2. Identify those barbiturates that are useful for treating anxiety, and differentiate them from those that are used for IV anesthesia
 3. Understand the chronic effects of the use of some tranquilizers and how those effects can have an impact on dental care
 4. Identify members of the class of drugs known as the benzodiazepines
 5.  Identify the IV varieties of benzodiazepines
 6. Identify the IV treatment for benzodiazepine overdosage
 7. Identify a natural product used to treat insomnia.
 8. Discuss the difference the presence of a generic medication has on the purchase price of its brand name equivalent.
 9. Understand the side effects of serotonin reuptake inhibitors and how they may have interactions with other drugs

Consider this case study.  Why would someone on a major tranquilizer (Thorazine, for example) for six months have red areas under her (or his) partial denture?

I. Anxiety and the effect on pain

    A. Recall discussion of psychogenic pain
        1. some people actually fear dentists
        2. some people actually fear dental hygienists

    B. Allay fears
        1. method #1:
            a. explain procedure
            b. instill confidence in yourself and in your patient
        2. method #2:          Drug 'em

II. Categories of sedatives, hypnotics, and tranquilizers
     1. sedative-hypnotics ($810 million spent annually on prescription drugs for insomnia)
     2. minor tranquilizers
     3. sedative-antihistamines
     4. nitrous oxide--to be discussed in a future lecture

     A. Warnings with these agents
         1. drowsiness, sedation, CNS depression
         2. EtOH (alcohol) effect enhancement
         3. avoid using heavy machinery--get a ride
         4. allergies/prior response experience

     B. Disadvantages of these agents
         1. patient-to-patient variation
             --lack of a consistent response
         2. patient compliance
             --forgetfulness; children dislike liquid chloral hydrate (ptui!)

  3. lipid solubility
            --long-term dosing
   --the drug accumulates in the body

III. Barbiturates
     A. Activity
         1. can cause anything from light sedation to coma and death, depending on dose given
         2. low doses, decrease anxiety
         3. high doses, for sleep "HYPNOTICS"

 THE OFFICIAL LIST: Barbiturates

    CLASSIFICATION AND NAME                            SEDATIVE DOSE                                 HYPNOTIC DOSE
    Long Acting
         Phenobarbital                                                           15-30mg 2-4x/day                                      100-200mg

    Intermediate Acting
         Amobarbital (Amytal)                                               30-50mg 2-3x/day                                      100-200mg
         Pentobarbital (Nembutal)                                          30mg 2-4x/day                                           100mg, 1hr preop
         Secobarbital (Seconal)                                              30-50mg 2-4x/day                                      100-200mg,
                                                                                                                                                                  30 mins preop

    Ultra-short Acting--for IV anesthesia only!
         Methohexital (Brevital)
         Thiopental (Pentothal)
                      --the good, old fashioned “truth serum”

 B. Recall lipid solubility
  1. meninges: sheath of lipid surrounding the brain and central nervous system
  2. the more lipid soluble, the more rapidly the agent crosses this barrier
  3. HOWEVER, how does this affect metabolism?
  4. AND is the brain the sole lipid source in the body?

     C. Pharmacology
         1. CNS effects
             a. inhibition of Recticulo Activating System (RAS)
             b. initially, an inhibition of inhibition
                i. the gregarious drunk syndrome
                ii. can actually increase pain sensations and delirium
                iii. not a therapeutic effect
                iv. not seen with long-term dosing

         2. ANTICONVULSANT use of barbiturates
               --phenobarbital and epilepsy

         3. DIMINISHED GI TONE AND MOTILITY with barbiturates
   --Donnatal (combination product--contains phenobarbital and belladonna alkaloids, ie atropine–recall the anticholinergic activity of atropine and how this might be useful for a “nervous stomach”) used for spastic gut; before the advent of H-2 antihistamines (ie cimetidine [Tagamet], ranitidine [Zantac], et al), Donnatal was the drug of choice for ulcer conditions and “nervous stomachs”)

  4. Barbiturates as a drug class have metabolism in LIVER, with HEPATIC ENZYME INDUCTION!
   -seen especially with phenobarbital

 D. Administration of Barbiturates
          1. IV (intravenous)--ultrashort acting agents/GENERAL ANESTHESIA
          2. po (oral) --for long acting agents/better blood levels
               --IM, IV possible here for immediate effects
                --SQ: ouch!

          3. suicide/abuse potential: yep! and all are controlled substances (some with controls as strict as those for morphine)

      E. Side Effects/Toxicity
          1. sedation, possible allergies

          2. intentional overdosage
              a. respiratory depression
              b. cardiovascular depression
              c. renal shutdown
              --treat with IV sodium bicarbonate (changes the pH of the urine to a more alkaline environment  to enhance excretion) and osmotic diuretics (mannitol)

          3. addiction possible (again, controlled substances)

                --consider effects of alcohol, other sedative-hypnotics, narcotics
              b. ENZYME INDUCTION!!!!
   –barbiturates stimulate metabolic enzymes that can also reduce the effectiveness of these drugs:
                 i. anticoagulants--warfarin (Coumadin)
                ii. phenytoin (Dilantin)--another drug to treat epilepsy
                iii. tricyclic antidepressants (TCAs)--amitriptylene (Elavil)

   c. barbiturates reduce the effectiveness of these drugs as well:
    i. acetaminophen
    ii. birth control pills
    iii. estrogens
    iv. steroids
    v. beta-blockers

           5. CONTRAINDICATION--PORPHYRIA, a condition with elevated levels of porphyrin (a constituent of hemoglobin)  --barbiturates stimulate porphyrin production

     A. Chloral hydrate, very old drug, from early 19th century
        1. "Noctec" (trade name); the TRADITIONAL "Mickey Finn"
         2. primarily for children (comes in liquid and suppository forms), the elderly, or the debilitated

    A. Three groups now
         1. the BENZODIAZEPINES
            a. chlordiazepoxide (Librium) –1955 by Roche
            b. diazepam (Valium) –1963 also by Roche
            c. eleventy zillion others (see chart)
            d. the Improved Mickey Finn for the Millenium

          2. the PROPANEDIOLS ( primarily, meprobamate with the trade names "Equanil" "Miltown", or in combination with aspirin to yield “Equagesic”)

          3. and! since November, 1986:  "THE AZASPIRODECANEDIONES"

        1. Advantages over phenobarbital
            a. fewer CNS side effects at therapeutic doses
            b. less mental/physical impairment
            c. less potential for successful suicide
            d. causes muscle relaxation

I. For Anxiety
         Agent                           Equivalent Dose                   Drug Cost (7 days at 3 times daily dosing)
     alprazolam (Xanax)              0.5mg                                          $11.97
     alprazolam (generic)                                                                  $0.61
                        Note: brand Xanax cost $2.95 (1990) for the same quantity
                             before the generic was available
     chlorazepate (Tranxene)        7.5mg                                            $24.36
     chlorazepate (generic)                                                                  $0.60
                         Note: brand Tranxene cost $3.57 (1991) before the generic
                                                             was available
     chlordiazepoxide (Librium)     10mg                                            $0.52 (generic cost)
     diazepam (Valium)                  5mg                                            $0.70 (generic cost)
                                             brand Valium 5mg costs $11.81/21 tablets
     halazepam (Paxipam)              40mg                                            $2.97
     lorazepam (Ativan)                  1mg                                                $17.34
     lorazepam (generic)                                                                      $0.77
     oxazepam (Serax)                      15mg                                        $23.07
     oxazepam (generic)                                                                          $1.67
     prazepam (Verstran/Centrax)         10mg                                        $4.00

II. For Sedation (cost figures from bedtime dosage for 7 days)
     Agent                                       Equivalent Dose                          Drug Cost (7 days' therapy)
     flurazepam (Dalmane)                  15mg                                          $4.13
     flurazepam (generic)                                                                       $ 0.37
     temazepam (Restoril)                      15mg                                       $4.10
     temazepam (generic)                                                                       $0.20
     triazolam (Halcion)                          0.25mg                                    $4.45
     triazolam (generic)                                                                          $2.03
 triazolam (Halcion) has also been implicated in causing
 erratic, violent behaviors in some very highly publicized cases
     quazepam (Doral)                          7.5mg                                        $3.95

     3. As you can see, this is a very popular group of "anxiolytics"
         a. decrease anxiety
         b. decrease aggressive behavior
            --again, however, consider inhibitory inhibition
         c. muscle relaxant
         d. anticonvulsant (DTs--or "delerium tremens" from withdrawal symptoms, status epilepticus in epilepsy)
    once only chlordiazepoxide (Librium) was given for this, but nearly any injectable benzodiazepine has shown effectiveness
          e. exert their effect by facilitating the effects of ? (gamma) -amino-butyric acid (GABA)
    GABA is a major inhibitory transmitter in the Central Nervous System
    benzodiazepines act as AGONISTS to GABA receptors
       f. in dentistry,
        --benzodiazepines have caused both xerostomia and increased salivation
        –swollen tongue
        –bitter or metallic taste in the mouth

     4. Diazepam (Valium) vs chlordiazepoxide (Librium)
         a. very similar drugs, pharmacologically speaking
         b. on a mg-per-mg basis, diazepam is more potent
            --5mg of diazepam (Valium) is equivalent to 10mg chlordiazepoxide (Librium)

     5. Diazepam (Valium)--additional indications
         a. night terrors; insomnia secondary to anxiety
         b. the dental regimen in some ol' textbook

    5mg at bedtime (HS), 5mg in am of procedure, and l0mg, 2hrs prior to visit

     6. Amnesia is possible with almost all benzodiazepines
       --most pronounced with lorazepam (Ativan) and midazolam (Versed) (to be covered; read on)

     7. Chlordiazepoxide (Librium)
       --has the specific indication for DTs, but other IV benzodiazepines, such as diazepam (Valium) or lorazepam (Ativan), are just as effective, and do not have as long of a half life in the body (of particular concern with older patients)

     8. Contraindicated with pregnancy
   a. Benzodiazepines have been implicated in an increased risk of congenital malformations if taken during the first trimester by the mother.
   b. Cleft lip and palate, microencephaly, and GI and cardiovascular abnormalities have been reported.
   c. near-term administration has resulted in “floppy infant syndrome” (hypoactivity, hypotonia, apnea, and feeding problems)

     9. Something (relatively) new:
   MIDAZOLAM (Versed)
          a. a new benzodiazepine
          b. mainly for IV use, although 1999 saw the introduction of a liquid form for pediatric oral dosing
          c. indicated for preoperative sedation
          d. main advantage: WATER SOLUBILITY
           --diazepam (Valium) is not--burns on injection, frequently precipitates in IV fluids
              --midazolam (Versed) can be mixed with other preop medications and can be administered through IV fluids
          e. amnesia possible through and after procedure
          f. can cause ideosyncratic hicchoughing (consider the limitations for outpatient eye surgery)

 FLUMAZENIL (Mazicon from Roche labs)
 a. a new, specific ANTAGONIST for benzodiazepine sedation
 b. 0.2mg dose, IV, over 15 seconds will reverse the effects of (only) benzodiazepine sedation; requires redosing every 20 minutes
 c. released to the market in January, 1992
 d. rather expensive

 11. A Frightening Benzodiazepine: flunitrazepam (Rohypnol)
  a. associated with “date rape”
  b. a benzodiazepine with approximately ten-times the potency of diazepam (Valium)
  c. The tablets manufactured in Mexico (the source for most of the U.S. supply) are round, white and slightly smaller than an aspirin. The manufacturer's (Roche)  marking are similar to those found on other pills, including Rivotril and Valium.
  --Rohypnol cannot be prescribed or sold legally in Canada, however, it can be brought into the country in limited amounts if prescribed by a foreign physician. It cannot be prescribed, sold, or legally imported into the U.S. (importation banned in March 1996)
  --In March 1995, this drug became the first benzodiazepine to be moved to Schedule III (most benzodiazepines are Schedule IV) by the World Health Organization, requiring more thorough record keeping on its distribution.
  The first reports of Rohypnol abuse in the U.S. were in 1993 in southern Florida (Proceedings of the Community Epidemiology Workgroup, National Institute on Drug Abuse, June 1993); since then cases have been reported to the Drug Enforcement Agency (DEA) in 32 states and Puerto Rico.
  *Anecdotal reports indicate Rohypnol use is growing among high school students in the South, where it is seen as a cheap high - $.50 to $3.00 a pill. Because it is sold in a bubble pack, it can be mistaken for a legal (safe) substance. Continued use can result in addiction.
  *Adverse effects can include loss of memory, impaired judgement, dizziness, and prolonged periods of blackout. Although a sedative, Rohypnol can induce aggressive behaviour.
  *This drug has been associated with date rape. Several arrests have been made in cases where it has allegedly been added to a woman's drink without here knowledge, for the purpose of reducing resistance. It is odourless, colourless and tasteless when added to either alcoholic or non-alcoholic beverages. AND CAUSES RETROGRADE AMNESIA!
  *Use is also reported by poly-drug users, among whom Rohypnol is a secondary drug.

  12. Similar subject, gamma-hydroxybutyrate (GHB) – usually obtained from cleaning solvents and degreasers, when ingested, GHB is produced in the body.
  Other street names: GHB, "G" (most common), Gamma-OH, Liquid E, Fantasy, Georgia Home Boy, Grievous Bodily Harm, Liquid X, Liquid Ecstasy (is not ecstasy), Scoop, Water, Everclear, Great Hormones at Bedtime, GBH, Soap, Easy Lay, Salty Water, G-Riffick, Cherry Meth, and Organic Quaalude, Jib.
  Clear liquid, distinct taste.  Also used in “date rape”

  12. Drug Interactions with benzodiazepines
   a. enhanced CNS sedation with other sedatives
   b. smoking and tobacco use reduces the effectiveness of benzodiazepines
   c. enzyme inhibitors such as cimetidine (Tagamet) can elevate levels of benzodiazepines in the blood
   d. may reduce the effectiveness of larodopa, used for Parkinsonism

  1. meprobamate  (Equanil or Miltown alone, or "Equagesic" when combined with aspirin)  is the only agent of interest here
        2. muscle relaxant, anti-anxiety
        3. can cause exitement in children
        4. a wide therapeutic index
        5. usual dose is 400mg, up to four times daily
       6. can cause ataxia (ataxia means:    –difficulty walking–   ), and drowsiness
        7. also contraindicated with porphyria


 THE   A Z A P I R O D E C A N E D I O N E S ! !

        1. only one agent so far:
            Buspirone (BuSpar)
        2. chemically distinct from benzodiazepines
        3. advantages
            a. no more drowsiness than placebo
            b. no impairment of motor skills
            c. no apparent potentiation of alcohol effects
            d. no apparent abuse liability
   e. no withdrawal syndromes reported, even with abrupt discontinuation of therapy
  (update: after years on the market, it still appears that buspirone is very safe)
        5. No effects on
            a. muscle relaxation
            b. epilepsy
            c. drug-withdrawal convulsions
        6. currently, not a controlled substance
        7. currently, not all that popular as compared to the benzodiazepines; it takes about 1 week to “kick in”

    E. Sedative-Antihistamines
        1. hydroxyzine (Atarax, Vistaril)
        2. promethazine (Phenergan)
  3. sedative, reduces anxiety, treats n/v (nausea and vomiting), adjunct with meperidine, morphine in preops
        4. a side note on diphenhydramine (Benadryl)
   Diphenhydramine, although not considered a sedative, is the antihistamine that has the greatest degree of sedation as a side effect.  It is becoming increasingly popular in nursing homes as an alternative to the benzodiazepine sleeping aids because it has relatively few other side effects (and it has the nice touch of clearing up the patient's sinuses).  However, it has one class of patient who would not benefit from its use as a nighttime sedative--psychotic patients; it seems that this antihistamine can induce a mild form of psychosis in these patients.  This was discovered in a prison psychiatric hospital where the patients were given diphenhydramine as a more "cost effective" sedative than the benzodiazepines...

 F. Natural products
  1. Valerian root (Valeriana officinalis)
  --a pungent plant that had been used for many years to treat epilepsy, nervousness, anxiety, and sleeplessness in the pre-phenobarbital days
  --available alone in capsules, or mixed with skullcap and hops as a sleep aid; usual dose 1-2 capsules 30 minutes before bedtime
  --effective, and better yet, non-addictive (but, oh what a smell!)

  2. Kava kava (Piper methysticum)
  –muscle relaxant, originally from the Polynesian islands
  –communal bowl dosing, prepared by children and women with strong jaws
  –specific mechanism of action is unknown, but appears to contain some chemical constituents similar to nutmeg
  –horrified missionaries to the region tried to suppress its use, substituting the more Christian brews (namely, beer)
  –improperly marketed as a “natural Valium”

 G. New prescription products for sedation
  1. Zolpidem (Ambien, Searle labs)
   --in 5 and 10mg strengths
   --represents a departure from benzodiazepines or barbiturates; in Europe, it is not considered a controlled substance.  The FDA, however, could not bring itself to allow a sleep aid on the market without giving it some controlled substance status.
   --usual dose is one tablet, to be repeated 3 hours later if necessary

  2. Zaleplon (Sonata)
   –5 or 10mg dose
   –some discussion on whether it is significantly more effective than placebo

 A. The Selective Serotonin Reuptake Inhibitors (SSRIs)

Serotonin, a neurotransmitter in the central nervous system, has been theorized to be deficient in patients suffering from depression.  Two mechanisms have been proposed to alter serotonin levels: (1) increasing the sensitivity of the serotonin receptor sites [this is how antidepressants such as amitriptyline — Elavil — are proposed to exert their effect] and (2) increasing the effective concentrations of serotonin by inhibiting the nerve’s ability to reabsorb (ie, “inhibiting” the “reuptake”) serotonin once it has been released.  This latter action is how SSRIs exert their effect. (Clinical Pharmacy 11:930, November 1992)

 B. The Specific Agents
  1. Sertraline (Zoloft), 25mg, 50mg, 100mg
  2. Paroxetine (Paxil) 10mg, 20mg
  3. Fluoxetine (Prozac) 10mg, 20mg, 40mg
  4. Fluvoxamine (Luvox) 50mg, 100mg
  5.  Citalopram hydrobromide (Celexa) 20mg, 40mg

 A. Actions
        1. mental and physical slowing
        2. indifference to incoming stimuli
        3. emotional quieting
 these three actions make up the "neuroleptic syndrome"

    B. The major class here:  PHENOTHIAZINES
 Chlorpromazine (Thorazine)
 Promazine (Sparine)
 Thioridazine (Mellaril)
 Fluphenazine (Prolixin)
 Trifluoperazine (Stelazine)
 Prochlorperazine (Compazine)
    C. Chlorpromazine (Thorazine)
        1. antiemetic activity (not suited for motion sickness, however)
        2. postural (or orthostatic) hypotension
        3. simulates the extrapyramidal system (EPS)
            --symptoms of Parkinsonism can develop: "pill rolling" and darting tongue
        4. decrease threshold for convulsions
        5. LEUKOPENIA (low white count) to agranulocytosis to infection (sore throat is the first symptom)
        6. xerostomia (anticholinergic effects)
            --opening for monilial infection (aka "thrush")
            --edentulous ridges; reddened or with white spots
            --treat monilial infections with nystatin
        7. also affects thermoregulatory mechanism (can reduce body temperature, although this is not used therapeutically)

A whole bunch of Antipsychotic Drugs, listed by appropriate chemical categories
(informational purposes only)

Chlorpromazine (Thorazine)
Promazine (Sparine)
Triflupromazine (Vesprin)

Thioridazine (Mellaril)
Mesoridazine (Serentil)

Acetophenazine (Tindal)
Perphenazine (Trilafon)
Prochlorperazine (Compazine)
Fluphenazine (Prolixin/Permitil)
Trifluoperazine (Stelazine)

Chlorprothixine (Taractan)
Thiothixine (Navane)

Haloperidol (Haldol)

Molindone (Moban)

Loxapine (Loxatane)

Clozapine (Clozaril)

Pimozide (Orap)

And, of course,
Lithium (Eskalith)

Review questions

1. What is the cause of death from overdose of a barbiturate?
2. What drug used for epilepsy is also responsible for enzyme induction?
3. What are the advantages of Versed (midazolam) over Valium (diazepam) injection?
4. What was the “traditional Mickey finn”? What is the “NEW” “Mickey Finn”?  Why is the “new” Mickey Finn more dangerous?
5. Which antianxiety agent is in the class of azapirodecanediones?
6. What is the name of an herbal sleep aid?  What is it’s greatest distinction?
7. What is the most sedative of all antihistamines?
8. What is an oral complication of long-term therapy with a phenothiazine such as chlorpromazine (Thorazine)?
9. What is ataxia?
10. What is the ultrashort acting barbiturate also known as “truth serum”?

End of Module Five
Local and General Anesthesia
Jim Middleton, Pharmacist and Instructor
KCC Pharmacology for Dental Hygienists