Anti Seizure Drugs 07

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DRUGS THAT ACT ON THE

CNSH.A. ROBERTSON, Ph.D.

PROFESSOR OF PHARMACOLOGY AND MEDICINE(NEUROLOGY)

Telephone 494-3430

Email: [email protected]


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Sedative-Hypnotic Drugs, Chapter 22

OBJECTIVES

1. Identify the major chemical classes of sedative-

hypnotics.2. Describe the pharmacodynamics of benzodiazepines

and barbiturates, including their mechanisms of action.

3. Compare the pharmacokinetics of commonly used

benzodiazepines and barbiturates and discuss how

differences among them affect clinical use.

4. Describe the clinical uses and the adverse effects of

sedative-hypnotics.


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1. Benzodiazepines2. Barbiturates

3. Non-benzo benzos(Zaleplon, zopidem)

4. Melatonin receptor

agonist (Ramelteon)

5. Buspirone

6. Others(antpsychotics,antidepressants)


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Neuropharmacology of the benzodiazepines

GABA (gamma-aminobutyric acid) is the major inhibitory neurotransmitter in

the central nervous system. Benzodiazepines increase the efficiency of

GABAergic synaptic inhibition. The benzodiazepines do not substitute for

GABA but appear to enhance GABA's effects allosterically without directly

activating GABAA receptors or opening the associated chloride channels.

Increased chloride ion conductance >>> increase in the frequency of channel-

opening events.

Barbiturates also facilitate the actions of GABA at multiple sites in the central

nervous system. In contrast to benzodiazepines they increase the duration of the

GABA-gated chloride channel openings. At high concentrations, the barbiturates

may also be GABA-mimetic, directly activating chloride channels. These effects

involve a binding site or sites distinct from the benzodiazepine binding sites.

their more pronounced central depressant effects. They have a low margin of

safety compared with benzodiazepines and the newer hypnotics. Serious suicide

potential (Marilyn Monroe, etc, etc.)


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Endogenous ligands for the BZ receptor

The physiologic significance of endogenous modulators of the functions of

GABA in the central nervous system remains unclear.

Benzodiazepine Binding Site Ligands

Three types of ligand-benzodiazepine receptor interactions have been reported:

(1) Agonists facilitate GABA actions, and this occurs at multiple BZ binding

sites in the case of the benzodiazepines. As noted above, the nonbenzodiazepines

zolpidem, zaleplon, and eszopiclone are selective agonists at the BZ sites that

contain an 1 subunit.

(2) Antagonists are typified by the synthetic benzodiazepine derivative

flumazenil, which blocks the actions of benzodiazepines, eszopiclone, zaleplon,

and zolpidem

(3) Inverse agonists act as negative allosteric modulators of GABA-receptor

function. Their interaction with BZ sites on the GABAA receptor can produce

anxiety and seizures, an action that has been demonstrated for several

compounds, especially the -carbolines, eg, n-butyl--carboline-3-carboxylate

(-CCB). In addition to their direct actions, these molecules can block the effects

of benzodiazepines.


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Antiseizure Drugs, Chapter 24

OBJECTIVES

2. Identify the mechanisms of antiseizure drug action.

3. Describe the main pharmacokinetic features and adverse effects

of major antiseizure drugs.

4. Identify new antiseizure drugs and their important

characteristics.

5. Describe the factors that must be considered in designing a

dosage regimen for an anti-seizure drug.


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Drug Development for EpilepsyIt was once assumed that a single drug could be developed for the treatment of all forms of epilepsy, but causes of

epilepsy are extremely diverse, encompassing genetic and developmental defects and infective, traumatic,

neoplastic, and degenerative disease processes.

Some specificity according to seizure type, most clearly seen with generalized seizures of the absence type.Respond to ethosuximide and valproate but can be exacerbated by phenytoin and carbamazepine.

Drugs acting selectively on absence seizures identified by animal screens, using either threshold pentylenetetrazol

clonic seizures in mice or rats or mutant mice showing absence-like episodes (lethargic, star-gazer, or tottering

mutants).

In contrast, the maximal electroshock (MES) test, with suppression of the tonic extensor phase, identifies drugs

such as phenytoin, carbamazepine, and lamotrigine that are active against generalized tonic-clonic seizures and

complex partial seizures.Use of the maximal electroshock test as the major initial screen for new drugs has probably led to the identification

of drugs with a common mechanism of action involving prolonged inactivation of the voltage-sensitive sodium

channel.

Limbic seizures induced in rats by the process of electrical kindling (involving repeated episodes of focal electrical

stimulation) probably provide a better screen for predicting efficacy in complex partial seizures.


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Antiseizure drugsMechanisms of action

1. Enhancement of GABA actions

-increase GABA actions at receptor (benzodiazepines,phenobarbital)

-vigabatrin inhibits GABA transaminase

-tiagabin blocks GABA uptake

2. Inhibition of sodium channel function

-phenytoin, carbamazepine, valproic acid, lamotrigine

3. Inhibition of Calcium T-type channels (ethosuximide)


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Basic Pharmacology of Antiseizure Drugs: Chemistry

Until 1990, ~ 16 antiseizure drugs available, and 13of them can be classified into five very similarchemical groups: barbiturates, hydantoins,oxazolidinediones, succinimides, and acetylureas.These groups have in common a similar heterocyclicring structure with a variety of substituents.

The remaining drugs

carbamazepine, valproicacid, and the benzodiazepinesare structurallydissimilar, as are the newer compounds marketedsince 1990, ie, felbamate, gabapentin, lamotrigine,levetiracetam, oxcarbazepine, pregabalin, tiagabine,topiramate, vigabatrin, and zonisamide.


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Pharmacokinetics

The antiseizure drugs exhibit many similar pharmacokinetic properties because most havebeen selected for oral activity and all must enter the central nervous system. Although manyof these compounds are only slightly soluble, absorption is usually good, with 80100% ofthe dose reaching the circulation. Most antiseizure drugs are not highly bound to plasmaproteins.

Antiseizure drugs are cleared chiefly by hepatic mechanisms and liver. Plasma clearance isrelatively slow; many anticonvulsants are therefore considered to be medium- to long-acting. Some have half-lives longer than 12 hours. Many of the older antiseizure drugs arepotent inducers of hepatic microsomal enzyme activity.


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Drugs Used in Partial Seizures & Generalized Tonic-

Clonic Seizures

The classic major drugs for partial and generalized tonic-clonic seizures are phenytoin (and congeners),

carbamazepine, valproate, and the barbiturates.

However, the availability of newer drugslamotrigine,

levetiracetam, gabapentin, oxcarbazepine, pregabalin,

topiramate, vigabatrin, and zonisamide is altering clinical

practice in countries where these compounds areavailable.


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Phenytoin

Phenytoin is the oldest (1938) nonsedative antiseizuredrug (diphenylhydantoin old name).

Alters Na channel, prolongs opening time


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Phenytoin: Toxicity

Dose-related adverse effects caused by phenytoin are unfortunately similar to other antiseizuredrugs in this group, making differentiation difficult in patients receiving multiple drugs.

Nystagmus occurs early, as does loss of smooth extraocular pursuit movements, but neither is an

indication for decreasing the dose.

Diplopia and ataxia are the most common dose-related adverse effects requiring dosage adjustment;

sedation usually occurs only at considerably higher levels.

Gingival hyperplasia and hirsutism occur to some degree in most patients; the latter can beespecially unpleasant in women.

Long-term use is associated in some patients with coarsening of facial features and with mild

peripheral neuropathy, usually manifested by diminished deep tendon reflexes in the lower

extremities.

Long-term use may also result in abnormalities of vitamin D metabolism, leading to osteomalacia.


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Phenytoin

Drug Interactions &Interference withLaboratory Tests

Induction of dugmetabolizing

enzymes


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Carbamazepine

Closely related to imipramine antidepressants, carbamazepine is a tricyclic compoundeffective in treatment of bipolar depression.

Initially marketed for the treatment of trigeminal neuralgia but has proved useful for

epilepsy as well.

Clinical Use

long been considered a drug of choice for both partial seizures and generalized tonic-clonic seizures,some of the newer antiseizure drugs are beginning to displace it from this role.

Toxicity

most common adverse effects of carbamazepine are diplopia and ataxia.

Considerable concern exists regarding the occurrence of idiosyncratic blood dyscrasias with

carbamazepine, including fatal cases of aplastic anemia and agranulocytosis.


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Adjuncts in the treatment of Partial Seizures

Felbamate blocks glycine activation of NMDA

receptors and inhibit initiation of seizures Gabapentin despite the fact that Gabapentin has a

similar structural relationship to GABA, it does not acton the GABA receptor. Gabapentin may alter GABAmetabolism or alter reuptake by presynaptic GABAtransporters.

Lamotrigine blocks voltage-sensitive NA channelsand has another mechanism of action (inhibits therelease of excitatory amino acids such as

glutamate?) Topiramate - blocks voltage-sensitive NA channels,

augments GABA activation of GABAA receptor,blocks kainate and AMPA glutamate receptors


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Drugs for GeneralizedAbsence, Myoclonic or Atonic

Seizures

Ethosuximide blocks T-type Ca

channels in thalamic neurons

Valproate -Na channels

Lamotrigine -Na channels


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Management of Seizure Disorders

Start therapy with low dose of single drug

Increase dose to attain serum concentration

If single drug is not effective, a second drugmay be added or substituted

Discontinue drug use slowly

Monitor serum levels to ensure adequate

dosage (toxicity, therapeutic failure or non-compliance)


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Therapeutic choices (adapted from Dr.M.Sadler, Division of Neurology, Dalhousie University)

Seizure type 1st choice alternative or add-on

Tonic-clonic carbamazepine clobazam

phenytoin lamotrigine

valproic acid topiramate

Absence ethosuximide clobazam

valproic acid lamotrigine

topiramate

Partial (simple carbamazepine clobazam

or complex) phenytoin lamotrigine

valproic acid

phenobarbital


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Summary

Partial and generalized seizures

Three mechanisms of antiepileptic drug

action

Drugs of choice

Many antiepileptic interact with other

medications and produce CNS and GIside effects


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Antiseizure drugsUse of antiseizure drugs in other non-seizure conditions

Carbamazepinemania, trigeminal neuralgia (possibly behavioural disturbances in dementia)

Gabapentin

neuropathic pain (possibly mania)

Lamotrigine

(possibly mania, migraine, schizophrenia, first effective use in treatment-resistantschizophrenia by Dr. Serdar Dursun, Psychiatry, Dalhousie Univ.)

Phenytoin

(possibly neuropathic pain, trigeminal neuralgia)

Valproic acid

Mania, migraine (possibly behavioural disturbances in dementia)


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Antiseizure drugsOther drugs used in management of epilepsy

Benzodiazepines

Status epilepticus

0-5 min history, physical examination, intubation?, ECG

5-10 min start 2 large bore IV saline, dextrose, thiamine,lorazepam or diazapam IV

10-30 min Phenytoin or phenobarbital IV

30-60 min If seizures persist after phenytoin, use phenobarbital orvice versa. Admit to CCU, get EEG, consider thiopental, propofol

Anti Seizure Drugs 07

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