DEHY34: Pharmacology for Dental Hygienists
Instructor and Contact: Jim Middleton
Module Eight: ANTICONVULSANT DRUGS & PARKINSON’S DISEASE 
I. Types of convulsive disorders
 --Approximately 1.5 million patients with epilepsy in the US--

   A. Ideopathic--cause unknown; epilepsy
      --most epilepsy classes fall under this category

   B. Symptomatic
      trauma, metabolic disorders, fever, brain tumors
      --metabolic alkalosis, hypokalemia (low potassium), water intoxication, hypoxia, pyridoxine (vitamin B6) deficiency, phenylketonuria, uremia, hypocalcemia (low calcium), hypoglycemia
      --drugs: camphor (used as a form of induced seizure for psychoses, popular in the 1930s along with lobotomies) , picrotoxin, penicillin (over 10 million unit doses), withdrawal from sedative hypnotics, alcohol, anticonvulsants

II. International Classification of Epilepsy
     No more the mere “Grand Mal” and “Petit Mal” classifications for this disease state!
      Adapted from the report from the Commission on Classification and Terminology of the International League Against Epilepsy, 1981 and 1989 (they’re about due to reconvene and create a few dozen more categories–stay tuned!)

 A. Partial Seizures
  1. Simple (no impairment of consciousness)
   a. motor symptoms (formerly “Jacksonian”)
   focal motor symptoms begin in one hand or foot and "march up" the extremity, or spread similarly from a corner of the mouth
   b. sensory (hallucinations of sight, sound, taste); tingling
   c. autonomic
   d. psychic – personality changes

  2. Complex (impaired consciousness)
   a. cognitive impairment, confusion
       attacks of impairment of consciousness with amnesia; sometimes a "deja vu" sensation is felt at the onset of the seizure; often associated with semi purposeful movements of the arms or legs
   b. affective (bizarre behavioral effect)
   c. psychosensory – repetition, purposeless behaviors
   d. compound (tonic, clonic, tonic-clonic)

 B. Partial Seizures, secondarily generalized
  1. unilateral seizures
  2. predominantly unilateral seizures
       a. simple partial evolving to generalized tonic-clonic
       b. complex partial evolving to generalized tonic-clonic
       c. simple evolving to complex, then on to generalized tonic-clonic
 

 C. Generalized seizures (Convulsive or nonconvulsive)
  –widespread involvement of both cerebral hemispheres
  1. tonic-clonic (formerly GRAND MAL)
       a. loss of consciousness
       b. depression of body functions
       c. muscle contractions lasting 1-5 minutes
  2. tonic (sustained contractions of large muscle groups)
  3. clonic (various dysrhythmic contractions in the body)
  4. myoclonic (unaltered consciousness, isolated clonic contractions)
  5. absence (formerly called PETIT MAL) – brief loss of consciousness for a few seconds, no confusion, EEG shows 3/second spike wave patterns; associated with flickering of the eyelids and mild twitching of the mouth; common form of epilepsy in children
  6. atonic (head drop or falling down symptoms)

 D. Localization or focal

 E. Generalized epilepsy–includes but is not limited to
  1. benign neonatal convulsion
  2. childhood absence
  3. West syndrome (infantile spasms)
  4. myoclonic encephalopathy
  5. Lennox-Gastaut syndrome

 F. Special syndromes–febrile seizures

 G. Unclassified–withdrawal of anticonvulsants



  One of our many digressions: A long term prospective study suggests that adults with epilepsy may remain seizure free if their anticonvulsant is withdrawn following at least 2 years of a single therapy regimen.  Approximately one-third of patients relapsed following withdrawal of anticonvulsants.
  Predictors of relapse include:
   1. seizure type (highest relapse with complex partial seizures with secondary generalized types)
   2. number of seizures–highest risk among those with > 100 seizures before controlled
   3. number of drugs for control– highest risk with patients on 2 or more agents
   4. treatment duration– longer duration, higher relapse
   5. EEG classifications– less relapse with fewer EEG abnormalities
   6. specific drug– higher relapse following withdrawal of valproic acid (Depakote, et al)


III. Considerations
    A. Selection of medication depends on seizure type, or the presence of multiple seizure types
  --therapy falls under the category of "empiric"

    B. Dose depends on
        1. patient size
        2. age
   seizures that develop at an early age have a lower relapse rate after medication is withdrawn than those that appear later in life
        3. physical condition
   pregnancy can result in an increase in seizures in 40% of patients; approximately 5% experience a decrease in seizures during pregnancy
        4. response to medication

    C. Dose is titrated upwards until toxicity seen or the seizure is controlled
  --Approximately 80% of seizures can be controlled with medication
  --Therapy failures are usually the result of
  1. inadequate dosage
  2. frequent changing of drugs without adequate evaluation
  3. poor patient compliance

IV. Drugs/Antiepileptics/Anticonvulsants
    A. Barbiturates
        1. phenobarbital
   a. a long-acting barbiturate
   dose for epilepsy: 60-100mg daily, adults; 3-6mg/kg/day for children
            b. relatively safe, but still a controlled substance (category C-IV)
            c. used alone, or with other antiseizure meds
            d. controls multiple types of seizures
    –partial and generalized tonic-clonic, cortical focal seizures
            e. usually causes drowsiness, however, in children, can cause excitement

       2. mephobarbital (Mebaral) and methabarbital (Gemonil)
          --alternative barbiturates to phenobarbital, not often used

       3. primidone (Mysoline)
           a. metabolized into phenobarbital–requires labwork for both phenobarbital and primidone
           b. side effects more numerous
              --drowsiness
              --n/v, dizziness, diplopia (double vision)
              --nystagmus (involuntary eye movement), anemia
 

      B. Hydantoins: phenytoin (Dilantin), [also,  ethotoin (Peganone), mephenytoin (Mesantoin)]
  1. phenytoin (Dilantin) most popular
             a. gingival hyperplasia with phenytoin (Dilantin)
                    (i) up to 50% of children
                    (ii) may be prevented or reduced with proper oral care instruction
                    (iii) plaque control appears to be essential
                    (iv) surgical intervention sometimes required
                    (v) controversial use of folic acid therapy
                    --while folic acid helps some of the symptoms of gingival hyperplasia, it also works on the liver to increase the metabolism of the phenytoin, a problem on the stabilized patient
                    --another irony here is that long term use of phenytoin can result in folic acid deficiency; folic acid supplements can reduce the effectiveness of phenytoin

   b. primarily for clonic-tonic (formerly Grand Mal) seizures
       –also for psychomotor and status epilepticus (injection)
   c. alone or with other drugs (such as phenobarbital)
   d. no sedation at maintenance doses (100mg q6hrs)
   e. other side effects of phenytoin
        --n/v, peripheral neuropathy, skin eruptions, hepatitis (icterus)
   f. can cause anemia
   g. small but significant increase in fetal malformities and complications (6.4% vs 3.2%)

  3. Drug interactions with phenytoin (Dilantin)
   a. folic acid levels drop
   b. oral contraceptives and pregnancy considerations
  The concurrent use of phenytoin (Dilantin) with oral contraceptives clinically increases the chances of “breakthrough” pregnancies.  Also, phenytoin metabolism is altered during pregnancy, requiring more frequent blood level checks to assure therapeutic levels; in addition, some studies suggest additional VITAMIN K beginning one month prior to and during delivery, and to the infant immediately after birth to reduce the potential for “neonatal coagulation defect” in the newborn.  This is not to suggest that phenytoin be discontinued during pregnancy–the potential for status epilepticus, with its resultant hypoxia to the developing fetus, could be devastating.
   c. lithium toxicity may be increased
   d. meperidine (Demerol) effectiveness may be diminished

  4. Dosages and dosage forms for phenytoin
           note: toxicity is seen with blood levels over 20mcg/ml; lethal oral doses are 2-5gm; there is no known antidote, and treatment is supportive
   a. capsules: 30mg and 100mg– brand name exhibits a sustained-release effect
           Doses are individualized; goal is to maintain serum levels between 10-20mcg/ml; 100mg tid is common, daily doses in excess of 600mg/day are sometimes necessary.  ONLY THE “EXTENDED RELEASE” DILANTIN-BRAND CAPSULES ARE RECOMMENDED FOR ONCE-DAILY DOSING.
   b. chewable tablets: 50mg   (Nice smell, terrible taste)
   c. liquid: 30mg/ml (pediatric suspension) or 125mg/ml (Dilantin -125), shake well, do not refrigerate
   d. injection: 50mg/ml
           Administration of IV phenytoin (Dilantin) is at best tricky.  It is incompatible with all IV solutions, especially D5W.  The use of NS (normal saline) will still result in a cloudy solution, but this is the best IV line to use.  Whenever possible, inject phenytoin (Dilantin) slowly and directly into a large vein through a large gauge needle or IV catheter.
           Do not exceed an IV infusion rate of 50mg/min in adults, or 1-3mg/kg/minute in neonates.  Monitor ECG and blood pressure while administering. During STATUS EPILEPTICUS, the IV route is preferred due to erratic absorption following an IM injection.
           For STATUS EPILEPTICUS: administer IV of 10-15mg/kg SLOWLY, following with 100mg IV or po q6-8 hours thereafter.
           As a result, Cerebyx is now becoming the preferred IV hydantoin...

    C. Oxazolidones: trimethadione (Tridione), paramethadione (Paradione)
        1. primarily absence seizures
        2. side effects of therapy are severe
   --alopecia, ataxia, photophobia, bone marrow depression, kidney damage
   --birth defects possible

    D. Succinimides: phensuximide (Milontin), ethosuximide (Zarontin)
        1. absence seizure therapy
        2. less toxic than oxazolidones

    E. Valproic acid (Depakene, Depakote) introduced 1978
          1. organic solvent accidently found to have antiseizure activity
          2. for all seizure types, especially in simple or complex absence type; often in combination
          3. may inhibit platelets (spontaneous bleeding)
               may cause hepatotoxicity and pancreatitis
           Fatal hepatic failure, especially among children (<2yrs) on multiple antiseizures medications; of note since some physicians will use valproic acid to prevent recurrent febrile seizures in children
          4. no reported gingival hyperplasia


        Another digression: Lennox-Gastaut Syndrome

Lennox-Gastaut syndrome (LGS) is one of the more severe and difficult to control forms of epilepsy. It usually develops between one and eight years of age and is characterized by several seizure types in addition to developmental delay. It is estimated that LGS occurs in between 3 to 11 per cent of  childhood epilepsies and affects slightly more males than  females. The average age of onset is three years.

A child may experience all or some of several types of seizure. With LGS the most common seizure types are tonic, atonic and atypical absence seizures. There may be periods of both frequent and less frequent seizure activity.

Most children with LGS show some degree of impaired intellectual ability. Approximately two thirds of children with LGS show signs of intellectual disability either before or at the time of diagnosis. Other children tend to show such behaviour within a couple of years of the onset of the seizures. This may take the form of developmental goals not being reached or declining school results.

Some possible causes of intellectual impairment include: The underlying condition (if found) that causes the seizures; the sedatory effects of anti-epileptic drugs; and the abnormal electrical activity in the brain in uncontrolled seizures.

LGS often follows Infantile Spasms (West Syndrome) which are sudden spasms where typically the arms stretch out, and the head may nod forward and the eyes look upwards, lasting for less than a few  seconds. These usually start at between three and eight months and can evolve into the mixed seizure pattern, which typifies LGS, at two to three years. LGS may also be caused by the effects of other rare childhood diseases.

Seizures may be triggered by illness, particularly the high body temperatures from fevers. Diarrhea and vomiting affect the drug absorption in the body, and thus may affect seizure activity.

 Approximately 50% of LGS patients experience Status epilepticus. Convulsive status may ultimately lead to brain damage and death unless stopped quickly, usually with the administration of rectal (‘rectoclysis’) diazepam (Valium).  Generally, LGS is permanent and two-thirds of patients are likely to be resistant to conventional therapy. Approximately 80% continue with seizures in their adult life.



Additional Indications for Valproic Acid
    a. migraine therapy (250mg or more daily)
    b. bipolar (or manic-depressive) illnesses and panic attacks: 750mg daily in divided doses, increased to desired clinical effect
  6. other precautions with valproic acid
   a. GI distress, even with the “enteric coated” versions (the “kote” of Depa”kote”); take with food
   b. thrombocytopenia and bleeding
   c. hyperammonenmia – requires liver monitoring
  7. Dosage for epilepsy
   a. 15mg/kg/day with a max of 60mg/kg/day
   b. available in “sprinkles,” liquid, regular and enteric coated tablets

V. Other agents
 A. FELBATOL (Felbamate)
  1. 1993 introduction
  2. for those who don't respond to other therapies (approximately 30% of epileptics have some resistance to currently available therapies)
  3. also for the 50,000 children with Lennox-Gastaut syndrome, also unresponsive to current treatment modalities
  4. expected to be an "add on" treatment, especially with partial seizures or partial seizures that become generalized
  5. 21 cases of aplastic anemia reported
  6. dose begins at 1200mg/day, in 3-4 divided doses

  DRUG INTERACTIONS with felbatol:
  --increases the blood levels of phenytoin (Dilantin) and valproic acid (Depakote/Depakene) in patients on multiple therapies
  --currently under restricted use--seemed to cause catastrophic drop in white blood count, requiring weekly blood work--available, but not for everyone with seizures!

  B. NEURONTIN (gabapentin)
  1. Primary use in epilepsy
   a. Neurontin was approved in December 1993 as an anticonvulsant, chemically unrelated to any other anticonvulsant marketed.  It is only approved in the US for the treatment of patients with seizure disorders.
   b. During initial clinical trials, 2074 patients were studied(for anticonvulsant activity)

  2. Other uses
   a. migraine
   b. bipolar disorder management
   As of journal searches through 1997, there are no systematic studies that establish the safety or efficacy of Neurontin as a treatment for people with mood disorders (bipolar, unipolar, et al).  Such studies are in the planning stages, however.

  3. Actions on the body
  Unknown!  It is structurally related to GABA (gamma amino butyric acid), but does not interact with GABA receptors.

  4. Indications “Official” –for “add on” treatment of incompletely responsive epilepsy

  5. The “Unofficial Indications”
   a. Neurontin has been successful in controlling the mixed bipolar states in patients not adequately controlled by Tegretol (carbamazepine) and Depakote (valproic acid); it also seems to have a greater antianxiety and antiagitation potency than either Tegretol or Depakote.  It has been effective in about 2/3 of patients with bipolar mood disorders that have not responded to lithium or other mood stablilizers.

   b. Other conditions may be responsive, but presently it is being used in psychiatric circles for those patients who have had unsuccessful treatment with other standard therapies.

  6. Dosage
   a. For epilepsy “add on” therapy: 900-1800mg/day, in divided doses

   b. For bipolar disorder, 300mg/day initiation, usually at bedtime, with dose increases every 3 to 5 days; the standard dosage range has been 600-4800mg/day for this therapy; up to 1 month may elapse before the drug seems to “kick in”

  7. Side effect profile
   The side effects most often associated with discontinuation of gabapentin are sleepiness (1.2%), unsteadiness (0.8%), fatigue (0.6%), nausea and/or vomiting (0.6%), and dizziness (0.6%).

   Psychiatric side effects at doses used to treat bipolar disorders are depersonalization, induction of mania, agitation, paranoia, and changes in libido.

   Alcohol may increase the severity of any of these side effects.

  8.  Drug interactions –
  It is recommended that antacids containing aluminum or magnesium not be given within 2 hours of administering a dose of Neurontin

  In addition, there is a slight increase in Neurontin levels when a patient is taking Tagamet (cimetidine), regardless of dose.  While this is not considered clinically significant, there are other H2 antagonists on the market (Pepcid, Axid, Zantac) that can be given without this interaction.

  Neurontin does not cause interactions with Dilantin (phenytoin), phenobarbital, Tegretol (carbamazepine), or Depakote (valproic acid) (these chemical names are driving the spell-check on this computer crazy, by the way)

  9. Labs and overdosage
   --Blood levels for monitoring therapy are considered unnecessary
   However, before Neurontin is used for psychiatric purposes, the patient should have a thorough medical evaluation, including blood and urine tests, to rule out any medical condition, such as a thyroid disorder, that may exacerbate or cause a mood disorder.
   -- Up to 49gm (that’s 122 ½  400mg capsules) were taken in an overdose attempt; patient recovered with “supportive therapy”


 OTHER DRUGS FOR EPILEPSY
 C. Other New Drugs for epilepsy
  1. lamotrigine (Lamictal, December 1994)
    --works on sodium channels to "stabilize neural membranes"
       a. adjunctive therapy for partial seizures in adults; may be useful for generalized tonic-clonic, absence, atypical absence, and myoclonic seizures (unlabeled uses)
       b. 10% of patients develop a rash (0.3% of patients during initial tests had to be hospitalized)
       c. coadministration of valproic acid (Depakote) has even made this rash life-threatening (ie toxic epidermal necrolysis, angioedema); the drug binds to melanin
       d. 20 sudden, unexplained deaths during premarketing development among 4700 patients
       e. usual dose is 300-500mg daily, in divided doses

  2. Topiramade (Topamax)
   a. new since 1997
   b. appears to block spread of seizure activity rather than increase seizure thresholds
   c. effective in treating simple and comples partial and generalized tonic-clonic seizures;  used only as adjunct, add-on therapy
   d. optimal dose approximately 400mg/day; begin with 25mg daily dose and increase by 25mg increments

  3. Fosphenytoin (Cerebyx)
   a. controversial sound-alike name
   b. indicated for short-term control of generalized convulsive status epileptics and prevention and treatment of seizures occurring during surgery when other means of phenytoin administration are unavailable
   c. available in 10ml vials of 750mg
   d. administration with IV infusion loading dose of 15-20mg/kg, then 100-150mg/min
   e. can also be used as substitute for oral phenytoin (Dilantin) if given by IM injection
   f. not be evaluated for use over 5 days

  4. Levetiracetam (Keppra)
   a. The effectiveness of Keppra as adjunctive therapy in the treatment of partial seizures in adults was demonstrated in three multi-centre, randomized, double-blind, placebo-controlled clinical studies. 904 patients from Europe and the USA, who had experienced refractory partial seizures with or without secondary generalization for at least one to two years and had taken one or two standard anti-epileptic agents, participated in the studies.
   b. Pooled results from these trials showed that 28 percent (at a dose of 1000mg/day) to 41 percent (at a dose of 3000mg/day) of patients responded to Keppra (where response is defined as a 50 percent reduction in rate of seizures).
   c. At a dose of 3000mg/day, 8 percent of patients became entirely seizure free.
   d. in keeping with the usual usage of antiseizure medications, levetiracetam has been actually used more for its potential benefit in migraine than in epilepsy at this point

  5. tiagabine (Gabitril) – add-on therapy
   a. for patients 12 years and older
   b. a GABA uptake inhibitor:  inhibits the uptake of GABA after a nerve impulse has been transferred across the synapse from one neuron to another; the GABA released at the nerve ending into the synapse space is not reabsorbed, thus preserving the inhibitory effect. This action prevents the abnormally high stimulation that is characteristic of epilepsy.

 D. other agents used in seizure
           1 diazepam (Valium), lorazepam (Ativan); for status epilepticus, IV
    diazepam rectal gel being now made available for refractory seizures (Diastat)
  2. carbamazepine (Tegretol) and acetazolamide (Diamox); for trigeminal neuralgia (tic  doloreux)
             --numbness reported in head and neck region (consider locale of trigeminal neuralgia, however)
  3. another benzodiazepine: clonazepam (Klonopin)
   Used as adjunct treatements for epilepsy of many types; in addition, used in some forms of Parkinsonian dysarthria, acute manic episodes, multifocal tic disorders, neuralgias, and in adjunct treatment of schizophrenia

 E. Barbiturates, carbamazepine (Tegretol), phenytoin (Dilantin), and primidone (Mysoline) can decrease the effectiveness of oral contraceptives
   some success in use of the alternative Depo Provera injection for contraception

 F. isoniazid (INH) may cause phenytoin toxicity when the two are given together (INH is used for tuberculosis treatment)


 PARKINSONISM

Parkinsonism, degenerative brain disorder first described by the English surgeon James Parkinson in 1817. Causes can include head injury, encephalitis, syphilis, carbon monoxide poisoning, MPTP (a synthetic narcotic), and cerebral arteriosclerosis. When there is no apparent cause, the condition is called Parkinson's disease. The disorder is also termed paralysis agitans, or shaking palsy. (infoplease.com)

I. Drugs for Parkinsonism
 A. Parkinsonism is a non-heriditary, progressive neurologic disorder of the extrapyramidal system (EPS) characterized by
  1. difficulty in moving
  2. tremors, rigidity
  3. "tongue darting" and "pill rolling" reflexes

 B. Why?
  1. Theory time: thought to be caused by a deficiency of dopamine in the striatum, a part of the CNS's basal ganglia.  With the lack of dopamine, the neurons in the striatum fire, releasing acetylcholine.  A sympathetic/parasympathetic battle wages, and lo, there are the tremors.

  2. Treatment strategies
   a. introduce dopamine to the area, or--
   b. use anticholinergic-type drugs to slow the firing of the neurons

 C. Problems with these theories
  1. dopamine cannot cross the blood-brain barrier (BBB)
  2. however, an altered version of this drug, L-DOPA, can.
   L-DOPA crosses the BBB, gets converted to dopamine by a an enzyme called "aromatic amino acid decarboxylase," and then does its work!
  3. BUT! And there's always a BUT!
   Only about 5% of L-DOPA crosses the BBB.  That leaves 95% of the drug floating around in the bloodstream which can ALSO be converted to dopamine by the same enzyme found in the CNS.  We have already learned about what dopamine does in and to the general system in our discussion of cardiac emergencies.
  4. What's a pharmacologist to do?  We've got to make a buck on this idea somehow...
   L-DOPA is combined with a drug that inhibits that enzyme: carbidopa.  Carbidopa doesn't readily cross the BBB, so it keeps the effects of free floating dopamine in the periphery to a minimum.
   This combination of L-dopa and carbidopa is known as SINEMET.
  5. Sinemet works well, but since everyone is different, it doesn't always work perfectly...
   Side effects include
    n/v
    postural hypotension
    abnormal involuntary movements
    various psychiatric disorders (elements of schizophrenia and mania)

 C1. The levodopa agents
  1. levodopa (Larodopa)
   a. Indicated for ideopathic, postencephalitic and symptomatic Parkinsonism; for Parkinsonism secondary to physical injury to the CNS or from carbon monoxide poisoning or manganese intoxication; unofficial use: to relieve pain from herpes zoster (shingles) and restless leg syndrome
   b. not with MAOI therapy; may activate malignant melanoma; caution with wide angle glaucoma
   c. dose is 0.5-1.0grams daily, in divided doses, given with food

  2. levodopa and carbidopa combination (Sinemet)
   a. combinations are 10/100, 25/100, and 25/250
    First number “10" “25" represents carbidopa
    Second number “100" “250" represents levodopa
   b. sustained release product: SINEMET CR 50/200

 D. Other agents for Parkinsonism
  1. Amantidine (Symmetrel), 100mg capsules, 100mg bid to tid dosing
   a. also works on the dopamine theory
   b. stimulates the release of dopamine and delays its uptake and metabolism
   c. also has an antiviral action; has been used to reduce duration of viral infections
   d. not considered as effective as L-dopa/carbidopa, but is more effective than anticholinergic agents

  2. Bromocriptine (Parlodel)
   a. stimulates dopamine release; 2.5-5mg tablets, doses up to 40mg daily
   b. used to inhibit prolactin relase (stop post partum production of breast milk)

  3. The anticholinergic drugs
   –often used to treat patients on drug therapy that can cause extrapyramidal symptoms (ie haloperidol [Haldol] or the phenothiazines [ie chlorpromazine {Thorazine}])
   --often used in conjunction with L-dopa/carbidopa
   --useful with patients having minimal symptoms
   a. benztropine (Cogentin)
    1-2mg daily
    Also in injection form
   b. trihexphenidyl (Artane)
    1-2mg daily, increased to 10mg daily
    Available in sustained release capsules
   c. biperiden (Akineton)
    2mg, tid to qid
   SIDE EFFECTS--. xerostomia, xeropthalmia, urinary retention; care with glaucoma and prostatic hypertrophy

  4. Selegiline (Eldepryl), 5mg tablets; 10mg daily, in divided doses
  –adjunct therapy with Sinemet
  –BIG DRUG INTERACTION with fluoxetine (Prozac)-- death from dopamine! At least 5 weeks must pass between use of these two drugs– and meperidine (Demerol) toxicity seen

  5. Pergolide (Permax)
  –another adjunct with Sinemet
  –orthostatic and sustained hypotension possible
  –dose range of 0.25mg to 1.0mg; individualized

New (and destined to be infrequently used) Agent for Parkinson’s disease
 E. tolcapone (Tasmar) tablets, 100 or 200mg strengths
  1. indicated only for adjunct therapy with levodopa and carbidopa
  2. AS OF NOVEMBER 1998, TOLCAPONE (TASMAR) IS NOT TO BE USED BY PATIENTS UNTIL THERE HAS BEEN A COMPLETE DISCUSSION OF THE RISKS AND THE PATIENT HAS PROVIDED WRITTEN INFORMED CONSENT.
  3. This has been to the development of severe, potentially life-threatening cases of severe heptocellular injury, including three deaths from acute fulminant liver failure that have been associated with use of tolcapone (Tasmar)
  4. Patients who elect to maintain therapy with tolcapone (Tasmar) must be monitored for liver function every 2 weeks for the first year of therapy, then every 4 weeks for the next 6 months, and then every 8 weeks thereafter.  If the dose is increased to 200mg tid, liver enzyme monitoring should take place before increasing the dose.
  5. The original intent was to increase levels of levodopa and sustain them for greater effect.
  6. Other adverse effects noted were diarrhea, hallucinations, and hematuria.



So far in our discussions, we have identified the following as causing gingival hyperplasia:
1. calcium channel blockers (especially verapamil)
2. phenytoin (Dilantin)
Let us add to that list
3. CYCLOSPORINS
The rationale: cyclosporin therapy may cause an increase in connective tissue, which may account for its propensity for gingival enlargement.  It appears to occur only when the threshold blood cyclosporin levels have been exceeded,  progresses only during the first 12 months of therapy, and may be clinically reversible upon cessation or interruption of cyclosporin therapy.

“NATURAL PRODUCTS” AND THE CNS

 A. St. John’s Wort (Hypericum perforatum)
  1. A lot of recent publicity
   --mild to moderate depression and SAD; flowering tops used
  2. Patients switching therapy and starting use without physician input
  3. Suggested mechanisms of action (active principles are hypericin and pseudohypericin)
   a. MAO inhibition far less potent than Nardil
   b. reduce the availability of serotonin receptors, resulting in impaired uptake of serotonin by neurons
  4. Other promoted uses
   a. antiviral (Herpes simplex I and II, Influenza A and B, Epstein Barr)
   b. topical for treatments of burns and wounds

  5. Clinical studies
   a. 20 clinical studies as of 1996, major news reports are from about a dozen double blind studies
   b. Hamilton Depression Scale
    70% reduction with St. John’s Wort
    45% with placebo group
    8 week trial
   c. comparison of extract, 300mg tid with maprotiline (Ludiomil) 75mg daily and imipramine (Tofranil) 25mg tid
    219 patients diagnosed with major depression in total studies
    HAMD improved by 56% with herb vs 45% for imipramine
    ADRs reported in 12% of herb vs 16% with imipramine

   d. SAD combined with bright light therapy (3000 lux) vs dim light therapy (300 lux)

  6. Doses
   based on hypericin content
   --extracts containing 0.2% hypericin would require a 500mg dose daily (usually administered in 2 divided doses); most studies have used 0.3% concentration with a daily dose of 300mg,  three times daily...it also takes up to 3 weeks for full benefits to be seen

  7. Side effects/contraindications
   a. ADRs reported have included emotional vulnerability, fatigue, pruritis, and weight increase
   b. due to MAO inhibition, avoidance of tyramine containing foods, alcohol, amphetamines, and OTC cold and flu remedies
   c. photosensitivity (this is based on an Australian study where sheep, grazing in fields containing St. John’s Wort, developed photosensitivity)
   d. German commission E Monograph has no contraindications; however, not a good choice among pregnant and lactating women

 B. Lithium and herbal interactions--“Natural diuretics” can lead to increased lithium levels
  birch leaf
  dandelion
  juniper

 C. Kava Kava (Piper methysticum)
  –a native plant of the Polynesian island cultures, with intriguing rituals
  –becoming an alternative in Australia to “cocktail parties”
  –promoted for muscle relaxant and peace-promoting properties, a “natural Valium”
  What to look for: 100mg capsules of a standardized product of 70% kavalactones; this is to be taken three times daily

  Cautions: do not drive or operate machinery while taking kava kava, not for use in pregnancy or during bouts of depression



QUESTIONS FOR REVIEW:

KCC Dental Hygiene Students: to send your homework, highlight the questions below, go to "edit," click on "copy," then click onto my email address below...when the email appears, go to "edit" in the email menu, click on "paste," and the questions will appear as the body of the email.  Answer the questions and then press "send." Your homework will be reviewed and returned via email within 72 hours.  Or just do it all on paper and bring your work to the next class session.

1 What effect does phenobarbital have on its own metabolism?  Are other drugs affected?
2. Which drug for epilepsy is metabolized into phenobarbital?
3. What is the effect of phenytoin (Dilantin) on a patient’s gums?
4. What is the effect of phenytoin (Dilantin) on a patient’s folic acid levels?
5. What is the effect of oral antiseizure medications on oral contraceptives?
6. List three uses for valproic acid (Depakene/Depakote)
7. What organ should be monitored when a patient is using valproic acid?
8. What is the advantage of gabapentin (Neurontin) over valproic acid?
9.  Name the injectable alternative to phenytoin (Dilantin).
10. Which drug for Parkinson’s disease is also used as an oral antiviral agent?
11. What are side effects of the use of anticholinergic agents in the treatment of Parkinson’s disease?
12. What is the proper dose for St. John’s Wort?  What are appropriate indications for its use?  What care should be given in “self administration?”
13. What is the greatest side effect of concern with kava kava?

End of Module Eight
Epilepsy and Parkinsonism
January 2002
Instructor and Contact: Jim Middleton