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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