Transcript Therapeutics Week 1

Chapter 16:
Anticonvulsants
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
Chapter 16 Outline

Anticonvulsants


Epilepsy
• Generalized seizures
• Partial (focal) seizures
Drug therapy of patients with epilepsy
• General adverse reactions to anticonvulsant agents
• Carbamazepine
• Valproate
• Phenobarbital
• Phenytoin
• Miscellaneous anticonvulsant agents
• New anticonvulsant agents
cont’d…
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
2
Chapter 16 Outline


Dental treatment of the patient with epilepsy
Nonseizure uses of anticonvulsants
• Neurologic pain
• Psychiatric use
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
3
Epilepsy


Haveles (pp. 213-214)
A group of disorders involving a chronic
stereotyped recurrent attack of involuntary
behavior or experience or changes in
neurologic function caused by electrical
activity in the brain that can be recorded via
an electroencephalogram (EEG)

Can be localized or generalized
cont’d…
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
4
Epilepsy

Each episode is termed a seizure


The seizure can be accompanied by motor activity such
as convulsions or by other neurologic changes
Seizure disorders are estimated to affect
approximately 1% of the population


Many etiologies: infection, trauma, toxicity to
exogenous agents, genetic or birth influences,
circulatory disturbances, metabolic or nutritional
alterations, neoplasms, hereditary factors, fevers, and
degenerative diseases
Most patients have idiopathic epilepsy; the cause is
unknown
cont’d…
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
5
Epilepsy


Haveles (pp. 213-214) (Fig. 16-1; Box 16-1)
The International Classification of Epileptic
Seizures divides seizures into two major
groups and a miscellaneous group

The two major groups are partial and generalized
seizures
• Partial seizures are divided into simple and complex
attacks
• The most common generalized seizures are tonic-clonic
and absence seizures
cont’d…
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
6
Generalized Seizures


Consciousness is lost in both absence and
tonic-clonic seizures


Haveles (p. 213)
Little movement occurs in absence seizures;
major movement of large muscle groups occurs in
tonic-clonic seizures
The patient may experience an aura before
the onset of the seizure

May be characterized by numbness, nausea, or
unusual sensitivity to light, odor, or sound
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
7
Absence Seizures (Petit Mal)


Haveles (p. 214)
Symptoms of absence seizures include a
brief loss of consciousness with characteristic
EEG waves and little movement

Absence seizures usually begin during childhood
and disappear during middle age
 The patient is usually unaware that these seizures
are occurring, and body tone is not lost
 No aura or postictal state occurs
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
8
Tonic-Clonic Seizures


Haveles (p. 214)
Generalized tonic-clonic seizures include
longer periods of loss of consciousness and
major motor activity of the large muscles of
the body

The seizure begins by the body becoming rigid
and the patient falling to the floor
 Tonic rigidity is followed by clonic jerking of the
face, limbs, and body
 Finally, the patient becomes limp and comatose
 Consciousness gradually returns with postictal
confusion, headache, and drowsiness
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
9
Status Epilepticus


Haveles (p. 214)
Status epilepticus seizures are continuous tonicclonic seizures that last longer than 30 minutes
or recur before the end of the postictal period of
the previous seizure



Status epilepticus seizures represent an emergency
situation
Rapid therapy is required, especially if the seizure
activity has produced hypoxia
Parenteral benzodiazepines, such as diazepam, are
the drugs of choice to control this type of seizure
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
10
Partial (Focal) Epilepsies


Haveles (pp. 213-214)
Partial epilepsies involve activation of only
part of the brain, and the location of the
activity determines the clinical manifestations

The attack is called an elementary (simple) partial
attack when consciousness is not impaired
 The attack is termed a complex partial attack
when consciousness is impaired
• Complex seizures are also called psychomotor or
temporal-lobe seizures
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
11
Drug Therapy of Patients with
Epilepsy


Haveles (p. 215) (Fig. 16-2; Box 16-2)
Drug therapy has variable efficacy, from
complete control of all seizures to reducing
the frequency of seizures

Anticonvulsant agents may be used singly or in
combination
 These agents are central nervous system (CNS)
depressants that attempt to prevent epileptic
seizures without causing excessive drowsiness
 These agents prevent the spread of abnormal
electric discharges in the brain
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
12
General Adverse Reactions to
Anticonvulsant Agents




Haveles (pp. 215-217)
Anticonvulsants have a narrow therapeutic index
Most anticonvulsants stimulate liver microsomal
enzymes that metabolize themselves, other
anticonvulsants, and other drugs that the patient
may be taking
The metabolism of anticonvulsants can saturate
the liver microsomal enzymes

At some point, when the enzymes become saturated,
the metabolism converts to zero-order kinetics, and
the drug level can increase abruptly
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
13
Central Nervous System
Depression


Haveles (pp. 215-216)
Depressed CNS function is a common side
effect of the anticonvulsant agents


Tolerance often develops to these effects,
whereas the anticonvulsant effect persists
Behavior alterations are reported to include both
hyperactivity and sedation
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
14
Gastrointestinal Distress


Haveles (p. 216)
Gastrointestinal (GI) distress, including
anorexia, nausea, and vomiting, can occur
with most anticonvulsants

Effects can be minimized by taking the drug with
food
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
15
Drug Interactions


The most important drug interaction involves
stimulation of the hepatic microsomal
enzymes


Haveles (pp. 216-217)
Inducing these enzymes results in a reduction in
the blood level of the affected drugs
Drug interactions with anticonvulsants are
more significant than with other drug groups
because of their narrow therapeutic indexes
cont’d…
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
16
Drug Interactions


Idiosyncratic reactions




Several interactions have been implicated in production
of fetal anomalies
Associated with alteration in growth
Withdrawal


Dermatologic side effects: rash, Stevens-Johnson
syndrome, exfoliative dermatitis, and erythema
multiforme
Drug-induced systemic lupus erythematosus and
hematologic effects have been reported
Teratogenicity/growth


Haveles (p. 217)
Abrupt withdrawal can precipitate seizures
Other interactions

Suppression of antidiuretic hormone
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
17
Carbamazepine


Haveles (pp. 217-218 )
Related to tricyclic antidepressants

Used in the treatment of trigeminal neuralgia; also
indicated in treatment of bipolar depression
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
18
Pharmacologic Effects of
Carbamazepine


An anticonvulsant, anticholinergic,
antidepressant, sedative, and muscle
relaxant
Blocks sodium channels, which blocks the
propagation of nerve impulses
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
19
Adverse Reactions of
Carbamazepine


CNS effects


Can produce dizziness, vertigo, drowsiness, fatigue,
ataxia, confusion, headache, nystagmus, and visual
(diplopia) and speech disturbances
GI effects


Haveles (p. 217)
Side effects include nausea, vomiting, and gastric
distress
Hematologic effects

Fatal blood dyscrasias have been reported
cont’d…
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
20
Adverse Reactions of
Carbamazepine


Dermatologic effects


Rashes, urticaria, photosensitivity reactions, and
altered skin pigmentation can occur
Oral effects


Haveles (p. 217)
Dry mouth, glossitis, and stomatitis can sometimes
be seen in patients taking carbamazepine
Other effects


Cardiovascular side effects include congestive heart
failure and alterations in blood pressure
Abnormal liver function tests and cholestatic
jaundice have been reported
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
21
Drug Interactions of
Carbamazepine


Haveles (pp. 217-218) (Box 16-3)
Carbamazepine can induce liver microsomal
enzymes


It can decrease the effect of doxycycline, warfarin,
theophylline, and oral contraceptives
Effects may be increased by erythromycin,
isoniazid, propoxyphene, and calcium channel
blockers
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
22
Valproate


Haveles (p. 218)
Valproates are a group of anticonvulsants that
are not structurally related to any other
agents

The mechanism of action may be its effect on
sodium and potassium channels, a reduction in
aspartate levels, or an increase in the inhibitory
neurotransmitter γ-aminobutyric acid (GABA)
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
23
Adverse Reactions of Valproate






Haveles (p. 218)
GI effects: the most frequent side effects are
indigestion, nausea, and vomiting
CNS effects: sedation and drowsiness have
been reported
Hepatotoxicity: the idiosyncratic toxicity of
valproate
Bleeding: bleeding time may be prolonged
Teratogenicity: may increase birth defects
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
24
Drug Interactions of Valproate


Haveles (p. 218) (Box 16-4)
Other drugs that are CNS depressants can
have an additive CNS depressant effect when
used with valproate

Valproate inhibits the metabolism of phenobarbital,
producing excessive sedation
 It also has been associated with drug interactions
with phenytoin, resulting in decreased valproate
action and increased phenytoin action
 It can affect bleeding
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
25
Phenobarbital


Haveles (p. 218)
The most common barbiturate used in
treatment of epilepsy



Used to treat tonic-clonic and partial seizures
Sedation is the most common side effect
Skin reactions occur in 1% to 3% of patients
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
26
Phenytoin


Haveles (pp. 218-220)
Used to treat both tonic-clonic and partial
seizures with complex symptoms


Has been used to treat trigeminal neuralgia
Also has quinidine-like antiarrhythmic properties
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
27
Adverse Reactions of Phenytoin


GI effects


Reactions are not uncommon
CNS effects


Haveles (p. 219)
Mental confusion, nystagmus, ataxia, slurred speech,
blurred vision, diplopia, amblyopia, dizziness, and
insomnia
Dermatologic effects


Skin reactions range from rash to exfoliative dermatitis,
lupus erythematosus, or Stevens-Johnson syndrome
Some patients have hypertrichosis on the trunk and
face
cont’d…
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
28
Adverse Reactions of Phenytoin


Vitamin deficiency



Haveles (p. 219) (Fig. 6-3)
Deficiency may involve vitamin D and folate
Osteomalacia may result from interference with
vitamin D metabolism
Teratogenicity/growth


Maternal ingestion of phenytoin is associated with
fetal hydantoin syndrome
Includes craniofacial anomalies, microcephaly, nail
or digit hypoplasia, limb defects, growth deficiency,
and mental retardation
cont’d…
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
29
Adverse Reactions of Phenytoin


Gingival enlargement


Haveles (pp. 219-220)
Occurs in approximately 50% of all chronic users
Symptoms

Often begin as a painless enlargement of the gingival
margin
 With time, the interproximal papillae become involved
and finally coalesce to cover even the occlusal
surfaces of the teeth
 The better the patient’s oral hygiene is, the less likely
the lesions are to occur or the less severe they will be
cont’d…
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
30
Adverse Reactions of Phenytoin


Etiology


Haveles (p. 220) (Box 16-5)
The cause of phenytoin gingival enlargement is
unknown
Management: some possible alternatives
include the following:





Choose another antiepileptic drug
Discontinue phenytoin
Improve oral hygiene
Consider gingivectomy
Consider other drugs
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
31
Miscellaneous Anticonvulsant
Agents


Haveles (p. 220)
Ethosuximide

The drug of choice for the treatment of absence
seizures
 Its mechanism of action may involve inhibiting the Ttype calcium channels
 GI adverse effects: anorexia, gastric upset, cramps,
pain, diarrhea, and nausea and vomiting
 CNS adverse effects: drowsiness, hyperactivity,
headache, and hiccups
cont’d…
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
32
Miscellaneous Anticonvulsant
Agents



Haveles (p. 220)
Benzodiazepines
Clonazepam is used as an adjunct to treat
absence seizures not responsive to
ethosuximide

Drowsiness and ataxia occur often
 Behavioral disturbances and adverse neurologic
effects can occur
 Other side effects reported relate to the GI tract and
to the dermatologic and hematologic systems
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
33
New Anticonvulsant Agents


Haveles (p. 220) (Table 16-2)
Felbamate



A newer anticonvulsant that has been associated
with serious toxicities
Aplastic anemia and acute hepatic failure have
been reported
This agent should be reserved for use only if the
seizures are refractory to other anticonvulsant
agents
cont’d…
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
34
New Anticonvulsant Agents


Haveles (p. 221) (Table 16-2)
Gabapentin

Effective as an adjunct against partial and
generalized tonic-clonic seizures
 Its mechanism of action is unknown
 CNS effects: somnolence, dizziness, tremor, and
ataxia
 Gastric complaints: dyspepsia, nausea, and
vomiting
 One major advantage over the other
anticonvulsants is that it is not metabolized
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
35
Dental Treatment of the Patient
with Epilepsy


Haveles (p. 221)
The dental team should not treat a patient who
has a history of seizure disorders without
reviewing the management of the patient with
epilepsy, including the procedures for handling a
patient experiencing tonic-clonic seizures

Management should include moving the patient to the
floor if possible, tilting the patient’s head to one side
to prevent aspiration, and removing objects from the
patient’s mouth before the seizure to prevent
fractured teeth
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
36
Nonseizure Uses of
Anticonvulsants


Neurologic Pain


Haveles (p. 221)
Several anticonvulsants are used to manage
chronic pain syndromes
Psychiatric Use


Carbamazepine, valproic acid, clonazepam, and
gabapentin have been used in the treatment of
certain mental disorders
They can be used to “level out” (stabilize) the
mood in patients with bipolar disorder
Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.
37