antiseizure drugs 1. introduction globally epilepsy is the third most common neurologic disorder...

Antiseizure Drugs

1

Introduction

Globally epilepsy is the third most common neurologic disorder after cerebrovascular and Alzheimer's disease

Epilepsy affects 0.5-1% of the population

2

Introduction

Epilepsy is a heterogeneous symptom complex—a chronic disorder characterized by recurrent, periodic, and unpredictable seizures originating from several mechanisms that have in common the sudden, excessive, and synchronous discharge of cerebral neurons

The term seizure refers to a transient alteration of behaviour due to the disordered, synchronous, and rhythmic firing of populations of brain neurons

3

Introduction

Often, there is no recognisable cause, although it may develop after brain damage, such as trauma, stroke, infection or tumour growth, or other kinds of neurological disease

In some subgroups, heredity Single gene defects, usually of an autosomal dominant nature involving genes coding voltage-gated ion channels or GABAA receptors has proved to be a predominant factor.

This abnormal electrical activity may result in a variety of events, including loss of consciousness, abnormal movements, atypical or odd behaviour, or distorted perceptions that are of limited duration but recur if untreated

4

Introduction

Seizures are thought to arise from the cerebral cortex, and not from other central nervous system (CNS) structures such as the thalamus, brainstem, or cerebellum

The behavioral manifestations of a seizure are determined by the functions normally served by the cortical site at which the seizure arises

5

Introduction

The clinical classification of epilepsy is done on the basis of the characteristics of the seizure rather than on the cause or underlying pathology

The clinical classification of epilepsy defines two major categories, namely partial and generalised seizures

Either form is classified as simple (if consciousness is not lost) or complex (if consciousness is lost)

6

Partial seziures

Partial seizures are those in which the discharge begins locally and often remains localised

The symptoms of each seizure type depend on the site of neuronal discharge and on the extent to which the electrical activity spreads to other neurons in the brain

The symptoms depend on the brain region or regions involved, and include involuntary muscle contractions, abnormal sensory experiences or autonomic discharge, or effects on mood and behaviour

7

Partial seziures

Partial seizures with no loss of consciousness are classified as simple PS

Partial seizures with an alteration of consciousness are classified as complex PS

Partial seizures may progress, becoming generalized tonic-clonic seizures

8

Partial seziures

1) Simple partial The electrical discharge does not spread,

and the patient is completely aware of the attack and can describe it in detail

Diverse manifestations determined by the region of cortex activated by the seizure (e.g., if motor cortex representing left thumb, clonic jerking of left thumb results; if somatosensory cortex representing left thumb, paresthesia of left thumb results)

Lasting approximating 20-60 seconds9

Partial seziures

2) Complex partial It has a localized onset, but the discharge

becomes more widespread (usually bilateral) and almost always involves the limbic system

Exhibit complex sensory hallucinations, mental distortion, and impaired consciousness lasting 30 seconds to 2 minutes with purposeless movements such as lip smacking or hand wringing (automatism)

10

Partial seziures

2) Complex partial After 30–120 seconds, the patient makes a

gradual recovery to normal consciousness but may feel tired or ill for several hours after the attack

11

Generalized seziures

In contrast to partial seizures, which arise from localized regions of the cerebral cortex, generalized-onset seizures arise from the reciprocal firing of the thalamus and cerebral cortex

Primary generalized seizures may be convulsive or nonconvulsive

The patient usually has an immediate loss of consciousness

12


1) Tonic-clonic: Seizures result in loss of consciousness,

followed by tonic (continuous contraction) and clonic (rapid contraction and relaxation) phases

The seizure may be followed by a period of confusion and exhaustion due to the depletion of glucose and energy stores

13


2) Absence (petit mal): These seizures involve a brief,

abrupt, and self-limiting loss of consciousness

The onset generally occurs in patients at 3 to 5 years of age and lasts until puberty or beyond

The patient stares and exhibits rapid eye-blinking, which lasts for 3 to 5 seconds

14


3) Myoclonic: These seizures consist of short

episodes of muscle contractions that may reoccur for several minutes without overt signs of neurologic deficit

They generally occur after wakening and exhibit as brief jerks of the limbs

Myoclonic seizures occur at any age but usually begin around puberty or early adulthood

15


4) Atonic seizures: Are those in which the patient

has sudden loss of postural tone. If standing, the patient falls suddenly to the floor and may be injured. If seated, the head and torso may suddenly drop forward

Most often seen in children

16


5) Febrile seizures: Young children may develop

seizures with illness accompanied by high fever

The febrile seizures consist of generalized tonic-clonic convulsions of short duration and do not necessarily lead to a diagnosis of epilepsy

17


6) Status epilepticus: Two or more seizures recur

without recovery of full consciousness between them

These may be partial or primary generalized, convulsive or nonconvulsive

Status epilepticus is life-threatening and requires emergency treatment

18

Pathophysiology

The are multiple mechanism that might contribute to seizures:

1. Alteration in the number, type, and distribution of ion channels in the neuronal membranes

2. Biochemical modifications of receptors

3. Modulation of second messenger systems and gene expression

4. Changes in extracellular ion concentrations

5. Alterations in the neurotransmitters uptake and metabolism in the glial cells

6. Local neurotransmitter imbalance19

Neural mechanisms of epliepsy

The underlying neuronal abnormality in epilepsy is poorly understood

In general, excitation will naturally tend to spread throughout a network of interconnected neurons but is normally prevented from doing so by inhibitory mechanisms

20


The pivotal role of synapses in mediating communication among neurons in the mammalian brain suggested that defective synaptic function might lead to a seizure: a) Reduction of inhibitory synaptic activity

b) Enhancement of excitatory synaptic activity might be expected to trigger a seizure

The neurotransmitters mediating the bulk of synaptic transmission in the mammalian brain are GABA (inhibitory) & glutamate (stimulatory)

21


Neurons from which the epileptic discharge originates display an unusual type of electrical behaviour termed the paroxysmal depolarising shift (PDS), during which the membrane potential suddenly decreases by about 30 mV and remains depolarised for up to a few seconds before returning to normal

This probably results from the abnormally exaggerated and prolonged action of an excitatory transmitter (activation of NMDA receptors)

22


Electrophysiological analyses of individual neurons during a partial seizure demonstrate that the neurons undergo depolarization and fire action potentials at high frequencies

Inhibition of the high-frequency firing is thought to be mediated by reducing the ability of Na+ channels to recover from inactivation

23


Activation of the GABAA receptor inhibits the postsynaptic cell by increasing the inflow of Cl– ions into the cell, which tends to hyperpolarize the neuron

Clinically relevant concentrations of both benzodiazepines and barbiturates enhance GABAA receptor–mediated inhibition through distinct actions on the GABAA receptor

24


In contrast to partial seizures, which arise from localized regions of the cerebral cortex, generalized-onset seizures arise from the reciprocal firing of the thalamus and cerebral cortex

Thalamic neurons is pivotally involved in the generation of the 3-Hz spike-and-wave discharges is a particular type of Ca2+ current, the low threshold ("T-type") current

25


T-type Ca2+ channels are activated at a much more negative membrane potential "low threshold" than most other voltage-gated Ca2+ channels expressed in the brain

T-type currents amplify thalamic membrane potential oscillations and bursts of action potentials in thalamic neurons are mediated by activation of the T-type currents

26

Antiseziure Drugs

Current antiseizure drugs are palliative rather than curative; therapy is symptomatic in that available drugs inhibit seizures, but neither effective prophylaxis nor cure is available

Choice of drug treatment is based on the classification of the seizures being treated, patient specific variables (for example, age, comorbid medical conditions, lifestyle, and other preferences), and characteristics of the drug, including cost and interactions with other medications

27

Antiseziure Drugs

The ideal anti-seizure drug would suppress all seizures without causing any unwanted effects

Unfortunately, the drugs used currently not only fail to control seizure activity in some patients (25-35% of patients), but frequently cause unwanted effects that range in severity from minimal impairment of the CNS to death from aplastic anemia or hepatic failure

28

Antiseziure Drugs

An awareness of the antiepileptic drugs available, including their mechanisms of action, pharmacokinetics, potential for drug-drug interactions, and adverse effects, is essential for successful therapy

Measurement of drug concentrations in plasma facilitates optimizing anti-seizure medication, especially when therapy is initiated, after dosage adjustments, in the event of therapeutic failure, when toxic effects appear, or when multiple-drug therapy is instituted

29

Antiseziure Drugs

In newly diagnosed patients, monotherapy is instituted with a single agent until seizures are controlled or toxicity occurs

If seizures are not controlled with the first drug, monotherapy with an alternate antiepileptic drug(s)

However, multiple-drug therapy may be required, especially when two or more types of seizure occur in the same patient

30

1840 1860 1880 1900 1920 1940 1960 1980 20000

5

10

15

20

BromidePhenobarbital

Phenytoin Primidone

Ethosuximide

Sodium Valproate

Benzodiazepines

Carbamazepine

Zonisamide

Felbamate

Gabapentin

Topiramate Fosphenytoin

OxcarbazepineTiagabine

Levetiracetam

RufinamideLacosamideBrivaracetam

Pregabalin

Retigabine

?

Calendar Year

Nu

mb

er

of

Lic

en

sed

An

tiep

ilep

tic D

rug

s

Lamotrigine

20000

5

10

20

Zonisamide

Felbamate

Gabapentin

Topiramate Fosphenytoin

OxcarbazepineTiagabineLevetiracetam

Pregabalin

Calendar Year

Nu

mb

er

of

Lic

en

sed

An

tiep

ilep

tic D

rug

s

Lamotrigine

1990

Antiseziure DrugsMechanism of action

1) Enhancement of inhibitory GABAergic impulses

2) Interference with excitatory glutamate transmission

3) Modification of ionic conductances: Inhibition of sodium channel

function Inhibition of calcium channel

function33

Inhibition of sodium channel function

Agents: phenytoin, carbamazepine, oxcarbazepine, topiramate, valproic acid, zonisamide, and lamotrigine

The sodium channel exists in three main conformations: a resting (R) or activatable state, an open (0) or conducting state, and an inactive (I) or nonactivatable state

The anticonvulsant drugs bind preferentially to the inactive form of the channel reducing the rate of recovery of Na+ channels from inactivation would limit the ability of a neuron to fire at high frequencies

34

A = activation gateI = inactivation gate

Goodman & Gilman’s. 12th ed. 2012

Na+ Na+

CarbamazepinePhenytoin

LamotrigineValproateNa+ Na+

I I

Voltage-gated sodium channel

Open Inactivated

X

Inhibition of sodium channel function

Inhibiting voltage-gated ion channels is a common mechanism of action among anti-seizure drugs with anti–partial-seizure activity

36

Phenytoin

Phenytoin is the oldest nonsedative antiseizure drug

Phenytoin is a valuable agent for the treatment of generalized tonic–clonic seizures and for the treatment of partial seizures with complex symptoms

37

PhenytoinPharmacokinetics

Phenytoin absorption is slow but usually complete, and it occurs primarily in the duodenum

Absorption of phenytoin is highly dependent on the formulation of the dosage form. Particle size and pharmaceutical additives affect both the rate and the extent of absorption

Phenytoin sodium should never be given IM because it can cause tissue damage and necrosis

Fosphenytoin is a prodrug and is rapidly converted to phenytoin in the blood that can be administered IM

38


The pharmacokinetic characteristics of phenytoin are influenced markedly by its binding to serum proteins, by the nonlinearity of its elimination kinetics, and by its metabolism by CYPs

Phenytoin is extensively bound (about 90%) to serum proteins, mainly albumin

The majority (95%) of phenytoin is metabolized principally in the hepatic endoplasmic reticulum by CYP2C9/10 and to a lesser extent CYP2C19

39


The elimination of phenytoin is dose-dependent:

At very low blood levels, phenytoin metabolism follows first-order kinetics

As blood levels rise within the therapeutic range, the maximum capacity of the liver to metabolize phenytoin is approached

Further increases in dosage, though relatively small, may produce very large changes in phenytoin concentrations, the half-life of the drug increases markedly, & steady state is not achieved

40

A) Nonlinear Pharmacokinetics:

(Michaelis-Menten type)Clearance decreases as dose increases

PHT

C) Nonlinear pharmacokinetics:

Clearance increases with dose

CBZ

A) Nonlinear

B) Linear

C) Nonlinear

Ave

. Ser

um C

onc.

(m

g/L)

Daily Dose (mg/kg/day)

Cloyd and Birnbaum, 1995

Elderly (aged 65-79 years)1

Nonelderly (aged 19-64 years)2

Km=5.8 mg/LVmax=5.5 mg/kg/day

Vmax=8.45 mg/kg/day

Km=6.25 mg/L

1. Bauer LA, Blouin RA. Clin Pharmacol Ther. 1982;31:301-304. 2. Cloyd J, et al. Presented at: 10th Epilepsy International Symposium; 1978; Vancouver, British Columbia.

864200

10

20

30

40

50

60

Daily Dose (mg/kg) as PHT Acid

Ph

enyt

oin

Co

nce

ntr

atio

n (

mg

/L)

PhenytoinDrug interactions

Drug interactions involving phenytoin are primarily related to protein binding or to metabolism

Highly bound drugs, such as salicylates, valproate, phenylbutazone and sulfonamides, can competitively displace phenytoin from its binding site

The protein binding of phenytoin is decreased in the presence of renal disease, neonate, in patients with hypoalbuminemia

43


PTN induces microsomal enzymes responsible for metabolism of a number of drugs (e.g. oral anticoagulants)

Treatment with phenytoin can enhance the metabolism of oral contraceptives and lead to unplanned pregnancy

The metabolism of phenytoin itself can be either enhanced or competitively inhibited by various drug metabolized by CYP2C9 or CYP2C10

44


Carbamazepine, which may enhance the metabolism of phenytoin, causes a well-documented decrease in phenytoin concentration

Interaction between phenytoin and phenobarbital is variable

45

PhenytoinAdverse effects

Dose-depedent: usually result from overdosage Characterized by nystagmus, ataxia, vertigo, and

diplopia (cerebellovestibular dysfunction)

Higher doses lead to altered levels of consciousness and cognitive

Gingival hyperplasia occurs in about 20% of all patients during chronic therapy and is probably the most common manifestation of phenytoin toxicity in children and young adolescents

46

47

Figure 1. A 17-year-old boy had generalized tonic–clonic seizures for four years. When the seizures began, a computed tomographic scan of his brain and an electroencephalogram were normal. Treatment with 300 mg of phenytoin per day was subsequently begun and continued unsupervised for a period of two years. Examination revealed coarsening of facial features and severe gingival hyperplasia (Panel A), brisk deep-tendon reflexes, and cerebellar ataxia. Withdrawal of phenytoin was followed by marked regression of the gingival hyperplasia within three months (Panel B); however, ataxia persisted.

http://content.nejm.org/cgi/content/full/342/5/325


Dose-depedent: Endocrine side effects: Inhibition of release of anti-diuretic hormone (ADH)

in patients with inappropriate ADH secretion

Hyperglycemia and glycosuria due to inhibition of insulin secretion

Osteomalacia, with hypocalcemia and elevated alkaline phosphatase activity, due to both altered metabolism of vitamin D and the attendant inhibition of intestinal absorption of Ca2+

48


Idiosyncratic reactions (Hypersensitivity reactions): seen shortly after therapy has begun: rash in 2-5% of patients and occasionally more serious skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis

Systemic lupus erythematosus and potentially fatal hepatic necrosis have been reported rarely

49

PhenytoinTeratogenicity Phenytoin has been implicated

in a specific syndrome called fetal hydantoin syndrome

The symptoms of this disorder may include abnormalities of the skull and facial features, growth deficiencies, underdeveloped nails of the fingers and toes, and/or mild developmental delays

50

Carbamazepine It is one of the most widely used antiepileptic drugs, is

chemically derived from the tricyclic antidepressant drugs

The mechanism of action of carbamazepine appears to be similar to that of phenytoin

Clinical Uses

1) DOC for partial seizures, also used for generalized tonic-clonic seizures

2) Peripheral neuropathy, e.g. trigeminal neuralgia

3) In some patients with mania (bipolar disorder)

51

CarbamazepinePharmacokinetics

Carbamazepine is absorbed slowly and erratically after oral administration

The drug has a notable ability to induce microsomal enzymes. Typically, the half-life of 36 hours observed in subjects after an initial single dose decreases to as little as 8–12 hours in subjects receiving continuous therapy

Considerable dosage adjustments are thus to be expected during the first weeks of therapy

Carbamazepine-10,11-epoxide is a pharmacologically active metabolite with significant anticonvulsant effects of its own

52

CarbamazepineDrug interactions

Phenobarbital, phenytoin, and valproate may increase the metabolism of carbamazepine by inducing CYP3A4

Carbamazepine may enhance the metabolism of phenytoin

Concurrent administration of carbamazepine may lower concentrations of valproate, lamotrigine, tiagabine, and topiramate

The metabolism of carbamazepine may be inhibited by propoxyphene, erythromycin, cimetidine, fluoxetine, and isoniazid

53

CarbamazepineSide effects

1) Dose-dependent

Diplopia and ataxia: most common

Mild gastrointestinal upsets, unsteadiness, and, at much higher doses, drowsiness

Hyponatremia and water intoxication

54

CarbamazepineSide effects

2) Dose-independent

The most common idiosyncratic reaction is an erythematous skin rash

Transient, mild leukopenia occurs in ~10% of patients during initiation of therapy and usually resolves within the first 4 months of continued treatment

Idiosyncratic blood dyscrasias, including fatal cases of aplastic anemia and agranulocytosis

Transient elevation of hepatic transaminases in plasma in 5-10% of patients

55

Oxcarbazepine

It is a keto analog of carbamazepine Oxcarbazepine is a prodrug that is almost

immediately converted to its main active metabolite, a 10-monohydroxy derivative

Its mechanism of action is similar to that of carbamazepine

Oxcarbazepine is less potent than carbamazepine: clinical doses of oxcarbazepine may need to be 50% higher than those of carbamazepine to obtain equivalent seizure control

56

Oxcarbazepine

Oxcarbazepine is a less potent enzyme inducer than carbamazepine

Oxcarbazepine does not induce the hepatic enzymes involved in its own degradation

Most adverse effects that occur with oxcarbazepine are similar in character to reactions reported with carbamazepine

Hyponatremia may occur more commonly with oxcarbazepine than with carbamazepine

57

Lamotrigine

Lamotrigine, like phenytoin, suppresses sustained rapid firing of neurons and produces a voltage- and use-dependent blockade of Na+ channels

Lamotrigine also inhibits voltage-gated Ca2+ channels, particularly the N- and P/Q-type channels, which would account for its efficacy in primary generalized seizures in childhood, including absence attacks

Lamotrigine also decreases the synaptic release of glutamate

58

Lamotrigine

Clinical Uses

a) Partial seizures, absence and myoclonic seizures in children, and for seizure control in the Lennox-Gastaut syndrome

b) Lamotrigine is also effective for bipolar disorder

59

Lamotrigine

Lamotrigine is almost completely absorbed The drug has linear kinetics and is

metabolized primarily by glucuronidation to the 2-N-glucuronide, which is excreted in the urine

Lamotrigine has a half-life of approximately 24 hours

Administration of phenytoin, carbamazepine, or phenobarbital reduces the t1/2 and plasma concentrations of lamotrigine

Valproate causes a twofold increase in the drug's half-life

60

Lamotrigine

The most common adverse effects are dizziness, ataxia, blurred or double vision, nausea, vomiting, and rash when lamotrigine was added to another anti-seizure drug

A few cases of Stevens-Johnson syndrome and disseminated intravascular coagulation have been reported

The incidence of serious rash in pediatric patients is higher than in the adult population

61

Topirmate

Topiramate main mechanism of action nis likely to involve blocking of voltage-gated Na+ channels

It also acts on high-voltage activated (L-type) Ca2+ channels

It potentiates the inhibitory effect of GABA, acting at a site different from the benzodiazepine or barbiturate sites

Topiramate also depresses the excitatory action of kainate on glutamate receptors

62

Topirmate

Clinical uses:

1) Partial and generalized tonic-clonic seizures

2) Lennox-Gastaut syndrome

3) Infantile spasms

4) Absence seizures

5) Treatment of migraine headaches

63

Topirmate

Topiramate is well tolerated The most common adverse effects are

somnolence, fatigue, weight loss, and nervousness

It can precipitate renal calculi, which is most likely due to inhibition of carbonic anhydrase

Topiramate has been associated with cognitive impairment and patients may complain about a change in the taste of carbonated beverages

64

Zonisamide

Zonisamide primary site of action appears to be the Na+ channel

it also acts on T-type voltage-gated Ca2+ channels

It is effective against partial and generalized tonic-clonic seizures and may also be useful against infantile spasms and certain myoclonias

Adverse effects: drowsiness, cognitive impairment, and potentially serious skin rashes

Zonisamide does not interact with other antiseizure drugs

65

Anti-seizure drug-induced reduction of current through T-type Ca2+ channels Agents: valporate and ethusximide

They reduce the flow of Ca2+ through T-type Ca2+ channels thus reducing the pacemaker current that underlies the thalamic rhythm in spikes and waves seen in generalized absence seizures

66

Ca+2 Ca+2Valproate Ethusuximide

Ca+2

I

X

Goodman & Gilman’s. 12th ed. 2012

Ethosumximide

It reduces low threshold Ca2+ currents (T-type currents) in thalamic neurons

Ethosuximide has a very narrow spectrum of clinical activity & is particularly effective against absence seizures

Administration of ethosuximide with valproic acid results in a decrease in ethosuximide clearance and higher steady-state concentrations owing to inhibition of metabolism

68

Ethosumximide

The most common dose-related side effects are GIT complaints (nausea, vomiting, and anorexia) and CNS effects (drowsiness, lethargy, euphoria, dizziness, headache, and hiccough)

69

Valproic Acid & Sodium Valproate Mechanism of action

1) Like phenytoin and carbamazepine, it prolongs the recovery of voltage-activated Na+ channels from inactivation

2) It increases the levels of GABA in the brain: it stimulates the activity of the GABA synthetic enzyme, glutamic acid decarboxylase, and inhibit GABA degradative enzymes, GABA transaminase and succinic semialdehyde dehydrogenase

3) Blockade of NMDA receptor-mediated excitation

4) Reductions of T-type Ca2+ currents in the thalamus

70

Valproic Acid & Sodium Valproate

Clinical uses

1) Valproate is a broad-spectrum anti-seizure drug effective in the treatment of absence, myoclonic, partial, and tonic-clonic seizures

2) Intravenous formulations are occasionally used to treat status epilepticus

3) Management of bipolar disorder

4) Migraine prophylaxis

71


Valproate is well absorbed after an oral dose, with bioavailability greater than 80%

Food may delay absorption, and decreased toxicity may result if the drug is given after meals

Valproic acid is 90% bound to plasma The vast majority of valproate (95%)

undergoes hepatic metabolism, with < 5% excreted unchanged in urine

Its hepatic metabolism occurs mainly by UGT enzymes (20%) and β-oxidation

72

Valproic Acid & Sodium Valproate1) Dose-dependent

GIT: nausea, vomiting, abdominal pain, and heartburn

Sedation if valproate is added to phenobarbital

Weight gain Increased appetite Hair loss

73


2) Idiosyncratic

Thrombocytopenia Acute pancreatitis Hyperammonemia Elevation of hepatic

transaminases in plasma is observed in up to 40% of patients and often occurs asymptomatically during the first several months of therapy

74


2) Idiosyncratic

Hepatotoxicity: Risk is greatest for patients under 2 years

of age and for those taking multiple medications

Most fatalities have occurred within 4 months after initiation of therapy

Careful monitoring of liver function is recommended when starting the drug

Hepatotoxicity is reversible in some cases if the drug is withdrawn

75

Valproic Acid & Sodium ValproateTeratogenicity Valproic acid use during pregnancy can produce

teratogenic effects :

Neural tube defects: spina bifida

Cardiovascular, orofacial, and digital abnormalities

76

Valproic Acid & Sodium ValproateD/D interactions Valproate displaces phenytoin

from plasma proteins Valproate inhibits the metabolism

of several drugs that are substrates for CYP2C9, including phenytoin and phenobarbital, and UGT , including the metabolism of lamotrigine and lorazepam

78

Enhancement of inhibitory GABAergic impulses

1) Several antiepileptic drugs (e.g. phenobarbital and benzodiazepines) enhance the activation of GABAA receptors, thus facilitating the GABA-mediated opening of chloride channels

2) Enhancement of the action of GABA as an inhibitory transmitter by:

a) Inhibiting the enzyme GABA transaminase, which is responsible for inactivating GABA: vigabatrin

b) Inhibiting GABA uptake: tiagabine

79

Na

+

Ca 2+GABA

metabolites

Succinic Semialdehyde

GA

BA

-TSS

D

Vigabatrin

Valproate

Cl-GABA recognition site

BarbituratesBenzodiazepine

GAT-1

Tiagabine

Phenobarbital

It has relatively low toxicity, is inexpensive, and is still one of the more effective and widely used drugs

Phenobarbital, exert maximal anti-seizure action at doses below those required for hypnosis, which determines their clinical utility as anti-seizure agents

81

Phenobarbital

Mechanism of Action

1) Phenobarbital increased the GABAA receptor–mediated current by increasing the duration of bursts of GABAA receptor–mediated currents

2) At higher concentrations: blocks some Ca2+ currents (L-type & N-type), suppresses high-frequency repetitive firing in neurons through an action on Na+ conductance, and decrease glutamate release

82

PhenobarbitalPharmacokinetics

Oral absorption of phenobarbital is complete but somewhat slow

Up to 25% of a dose is eliminated by pH-dependent renal excretion of the unchanged drug; the remainder is inactivated by hepatic microsomal enzymes, principally CYP2C9

83

PhenobarbitalAnti-seizure properties

It is often tried for virtually every seizure type, especially when attacks are difficult to control

It is useful in the treatment of partial seizures and generalized tonic-clonic seizures

84

PhenobarbitalD/D interactions

Interactions between phenobarbital and other drugs usually involve induction of the hepatic CYPs by phenobarbital

The interaction between phenytoin and phenobarbital is variable

Concentrations of phenobarbital in plasma may be elevated by as much as 40% during concurrent administration of valproic acid

85

PhenobarbitalD/D interactions

Phenobarbital induces uridine diphosphate-glucuronosyltransferase (UGT) enzymes as well as the CYP2C and CYP3A subfamilies

Drugs metabolized by these enzymes can be more rapidly degraded when co-administered with phenobarbital; importantly, oral contraceptives are metabolized by CYP3A4

86

Primidone

A prodrug converted to phenobarbital & phenylethylmalonamide (PEMA): all three compounds are active anticonvulsants

It is effective against partial seizures and more generalized tonic-clonic seizures

The dose-related adverse effects of primidone are similar to those of its metabolite, phenobarbital, except that drowsiness occurs early in treatment and may be prominent if the initial dose is too large

87

Benzodiazepines

At therapeutically relevant concentrations, benzodiazepines act at subsets of GABAA receptors and increase the frequency, but not duration, of openings at GABA-activated Cl– channels

At higher concentrations, diazepam and many other benzodiazepines can reduce sustained high-frequency firing of neurons, similar to the effects of phenytoin, carbamazepine, and valproate

88

Benzodiazepines

Diazepam given intravenously or rectally is highly effective for stopping continuous seizure activity, especially generalized tonic-clonic status epilepticus. However, its short duration of action is a disadvantage

Lorazepam is longer acting than diazepam in the treatment of status epilepticus and is sometime preferred

89

Benzodiazepines

Clonazepam is useful in the therapy of absence seizures as well as myoclonic seizures in children. However, tolerance to its anti-seizure effects usually develops after 1-6 months of administration

90

Other antiepileptic

drugs

Levetiracetam

Levetiracetam modifies the synaptic release of glutamate and GABA through an action on synaptic vesicle protein (SV2A)

It neither induces nor is a high-affinity substrate for CYP isoforms or glucuronidation enzymes and thus is devoid of known interactions with other antiseizure drugs, oral contraceptives, or anticoagulants

92

Levetiracetam

It is approved for adjunct therapy of partial seizures in adults and children for primary generalized tonic-clonic seizures and for the myoclonic seizures of juvenile myoclonic epilepsy

Side effects most often reported include dizziness, sleep disturbances, headache, and weakness

93

Gabapentin

Gabapentin is an an analog of GABA, that is effective against partial seizures

It dose not act directly on GABA receptors It modifies the synaptic or nonsynaptic

release of GABA: an increase in brain GABA concentration is observed in

Gabapentin binds avidly to the α 2 δ subunit of voltage-gated N-type Ca 2+ channels: decrease Ca 2+ entry, with causes a predominant decreasethe synaptic release of glutamate

94

Gabapentin

Gabapentin is not metabolized and does not induce hepatic enzymes

Absorption is nonlinear and dose-dependent at very high doses

The drug is not bound to plasma proteins

Drug-drug interactions are negligible Elimination is via renal mechanisms The half-life is relatively short (5-8 hrs)

95

Gabapentin

Clinical uses:

1) effective as an adjunct against partial seizures and generalized tonic-clonic seizures

2) Treatment of neuropathic pain and postherpetic neuralgia

ADRs: somnolence, dizziness, ataxia, headache, and tremor

96

Felbamate

It produces a use-dependent block of the NMDA receptor, with selectivity for the NR1-2B subtype

It also produces a barbiturate-like potentiation of GABAA receptor responses

it is effective in some patients with partial seizures and it is effective in patients with Lennox-Gastaut syndrome

However, it causes aplastic anemia and severe hepatitis at unexpectedly high rates and therefore has been relegated to the status of a third-line drug for refractory cases

97

antiseizure drugs 1. introduction globally epilepsy is the third most common neurologic disorder...

Documents

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complex pspartial seizures

unpredictable seizures

autonomic discharge

loss of consciousness

alteration of consciousness

seizure type

region of cortex