Tegretol Standard of epilepsy

Hany Magdy

Epilepsy

What is epilepsy? Epilepsy “seizure disorder” is a

syndromic disease characterized by disorder of the brain's electrical system. Abnormal electrical impulses cause brief changes in movement, behaviour, sensation, or awareness. These interruptions, known as seizures, may last from a few seconds to a few minutes. People who have had two or more seizures are considered to have epilepsy.

What is seizure?

Time-limited paroxysmal events that result from abnormal, involuntary, rhythmic neuronal discharges in the brain

Seizures are usually unpredictable and brief ( < 5 minutes) and stop spontaneously

Etiology of epilepsy

Any process that alters the structure or the function of the brain neurons can cause epilepsy

Processes that lead to structural alteration include;

Congenital malformation Degenerative disease Infectious disease Trauma Tumors Vascular process

In majority of patients, the etiology is proposed but not found

Co-Morbidities & Epilepsy

Common co-morbidities include: Cognitive Psychosocial / Psychiatric Behavioural Reproductive (adults) Sleep disturbance

Classification of Seizures

• Traditionally divided into “ grand mal” and “petit mal”

seizures

• ILAE classification of epileptic seizures in 1981 based on

clinical observation and EEG findings

• Seizures were divided into partial and generalized seizures

based on loss of consciousness

• Partial seizures were divided into simple partial and

complex partial based on alteration of consciousness

Observe seizure type

Seizure

Yes

Generalized seizures

No Partial seizures

YesComplex partial

NoSimple partial

Altered consciousness?

Loss of consciousness?

ILAE’s classification of seizureSeiz

ure

Partial

Simple partial

Complex partial

2ry Generalized

Generalized

Absence

Tonic clonic

Myoclonic

Atonic

Tonic

Partial seizures (focal or localized)•In partial seizures just one side of the brain is affected. Simple partial seizures may

cause jerking motions or hallucinations, but the person often remains aware of what is happening.•Simple Partial Seizure•No loss of awareness•With sensory, motor, autonomic, or psychic signs•Complex Partial Seizure•Impaired consciousness. (patient is conscious but unaware of what he’s doing)•Duration (typically 30 seconds to 3 minutes)•Partial Seizure with Secondary Generalization•Begins focally, with or without focal neurological symptoms•Variable symmetry, intensity, and duration of tonic (stiffening) and clonic (jerking) phases•Typical duration 1-3 minutes•Postictal confusion, and somnolence.

Primary generalized seizures

Absence seizures

Brief staring spells (“petit mal”) with impairment of awareness

3-20 seconds Sudden onset and sudden resolution Often provoked by hyperventilation Onset typically between 4 and 14

years of age. Often resolve by 18 years of age. Some children experience up to 100

absence seizures in a day

Myoclonic seizures

Brief, shock-like muscle contractions Typically bilaterally synchronous Impairment of consciousness difficult to

assess (seizures <1 second) May progress into clonic or tonic-clonic

seizure May be associated with a progressive

neurologic deterioration

Tonic seizures

Symmetric, tonic muscle contraction.

Duration - 2-20 seconds

Atonic seizures

Sudden loss of postural muscle tone

When severe often results in falls

When milder produces head nods or jaw drops.

Consciousness usually impaired

Duration - usually seconds, rarely more than 1 minute

Tonic-Clonic Seizures

Associated with loss of consciousness and post-ictal confusion/lethargy

Duration 30-120 seconds

Tonic phase

Stiffening and fall

Often associated with ictal cry

Clonic Phase

Rhythmic extremity jerking

Treatment of epilepsy

First Line Approved Anti-Epileptic Drugs (AEDs)

Second Line (intractable epilepsy) Epilepsy Surgery

Vagus Nerve Stimulation Therapy

Experimental Therapy AEDs

Implanted Devices

Treatment: Medication Most common drugs for epilepsy are

the group called (Anti-epileptics) or (Anti-convulsants).

Most anti-epileptic agents act either by blockade of depolarisation channels (Na+ and Ca++)

OR

Enhancing the activity of GABA (neurotransmission inhibition)

Antiepileptic Drugs (AEDs)

First Generation Second Generation Unconventional

Carbamazepine (Tegretol)

Clonazepam (Klonopin)Clorazepate (Tranxene)Ethosuximide (Zarontin)

PhenobarbitalPhenytoin (Dilantin)Primidone (Mysoline)

Valproic acid (Depakine)

Felbamate (Felbatol)Gabapentin (Neurontin)Lamotrigine (Lamictal)

Levetiracetam (Keppra)

Oxcarbazepine (Trileptal)

Pregabalin (Lyrica) Tiagabine (Gabitril)

Topiramate (Topamax)Zonisamide (Zonegran)

Adrenocorticotropic hormone (ACTH )

Acetazolamide (Diamox)Amantadine (Symmetrel)

BromidesClomiphene (Clomid)Ethotoin (Peganone)

Mephenytoin (Mesantoin)Mephobarbital (Mebaral) Methsuximide (Celontin)Trimethadione (Tridione)

Tegretol (Carbamazepine) (CBZ) Carbamazepine was discovered by chemist Walter

Schindler at J.R. Geigy AG (now part of Novartis) in Basel, Switzerland, in 1953. Schindler then synthesized the drug in 1960, before its anti-epileptic properties had been discovered.

Carbamazepine was first marketed as a drug to treat trigeminal neuralgia (formerly known as tic douloureux) in 1962. It has been used as an anticonvulsant and antiepileptic in the UK since 1965, and has been approved in the U.S. since 1974.

It was first used to control mania at 1971.

Indications It’s used primarily in the treatment of epilepsy and bipolar disorder, as well as

trigeminal neuralgia.

It is also used off-label for a variety of indications, including Attention-deficit hyperactivity disorder (ADHD),

Schizophrenia, phantom limb syndrome,

Complex regional pain syndrome,

Paroxysmal extreme pain disorder,

Neuromyotonia,

intermittent explosive disorder,

borderline personality disorder,

post-traumatic stress disorder.

PharmacokineticsBioavailability 80 % (CR tab is less by 15% than other forms)

Protein binding 76 %

MetabolismHepatic by CYP3A4 to active epoxide from (10,11 epoxide)

Half-life (25-65) hours

Excretion72 % in urine (2-3) % unchanged 28 % in feces

Therapeutic range (17-50) ngm/ml

Saliva conc.(Compared with plasma conc.)

(20-30) %

Breast milk conc.(Compared with plasma conc.)

(25-60) %

Placental barriers Cross

PPCReached after

Syrup 2 hours

Conv. tab 12 hours

CR tab 24 hours (CR is less by 25% than conv. tabs).

T1/2

Single dose 36 hours

Multiple doses 16-24 hours

Tegretol precautionsDo not start taking Tegretol without telling your doctor if you are pregnant or planning to become pregnant. Seizure control is very important during pregnancy. The benefit of preventing seizures may outweigh any risks posed by taking Tegretol, do not stop taking it without your doctor's adviceDO NOT take Tegretol if you have:• a history of boneif you are allergic to

carbamazepine or an antidepressant such as imipramine marrow suppression

• (Tofranil).

Tegretol in Novartis sales (2007)

Name Indication(s)Sales

(US$millions)

Diovan Hypertension 5000

Gleevec Chronic myelogenous leukemia 3100

Zometa Cancer complications 1300Sandostatin Acromegaly 1000

Sandimmune and Neoral Organ transplantation 944Femara Breast cancer 937Lotrel Hypertension 748

Voltaren anti-inflammatory 747Trileptal Epilepsy 692

Lescol hypercholesterolemia 665Exelon Alzheimer's disease 632Comtan Parkinson's disease 420

Tegretol Epilepsy 413Lucentis Age-related macular degener

ation393

Ritalin AD/HD 375Exjade Iron chelator 357

Tobramycin Cystic fibrosis 273

Tegretol

13th

Trileptal

9th

Mechanism of action The mechanism of action of carbamazepine and

its derivatives is relatively well understood. Carbamazepine stabilizes the inactivated state of Voltage-gated sodium channels, making fewer of these channels available to subsequently open. This leaves the affected cells less excitable until the drug dissociates. Carbamazepine has also been shown to potentiate GABA receptors made up of alpha1, beta2, gamma2 subunits

Tegretol interactions

• Kwan and Brodie. NEJM 2000; 342: 314-319.• Mohanraj and Brodie. Epil Behav 2005; 6: 382-387

Tegretol provides excellent sensory symptomes relief in diabetic neuropathy patients

Patients with diabetic neuropathy after six weeks of treatment of CBZ with daily dose of 600mg.

An update on the pharmacological management of post-herpetic neuralgia and painful diabetic neuropathy . CNS drugs. 2008;22(5) :417-42

Carbamazepine and phenytoin. Comparison of cognitive side-effects in epileptic patients during monotherapy and withdrawal.

We compared the cognitive effects of carbamazepine and phenytoin with neuropsychological tests exploring intelligence, vigilance, attention, memory, and visuomotor performances in 25 epileptics (13 receiving carbamazepine and 12 receiving phenytoin) and 26 matched normal controls. Patients were seizure free for at least two years and taking prolonged monotherapy. We also evaluated the effects of drug withdrawal by retesting patients three months after reduction at half drug dose and three months and one year after complete withdrawal. Our findings suggest that phenytoin affects the cognitive functions more than carbamazepine does, although the negative effects of both drugs are reversible by complete therapy withdrawal.

Arch Neurol. 1988 Aug;45(8):892-4.

http://www.ncbi.nlm.nih.gov/pubmed/3395263

Forms & Concentrations

References

1. www.Wikipedia.com

2. www.Drugs.com

3. www.Rxlist.com

4. http://www.ncbi.nlm.nih.gov/pubmed

5. Other presentations by some neurologists.

6. Recreation of some data.

Thank You