ANTIEPILEPTIC DRUGS Powerpoint Presentation

ANTIEPILEPTIC DRUGS

Send This

Download

Comment

Favourite

more

Rating :	Rate It:

Notes

Show Notes

Slide 1 :

ANTIEPILEPTIC DRUGS Martha I. Dávila-García, Ph.D. Howard University Department of Pharmacology

Slide 2 :

Epilepsy A group of chronic CNS disorders characterized by recurrent seizures. Seizures are sudden, transitory, and uncontrolled episodes of brain dysfunction resulting from abnormal discharge of neuronal cells with associated motor, sensory or behavioral changes.

Slide 3 :

Epilepsy There are 2.5 million Americans with epilepsy in the US alone. More than 40 forms of epilepsy have been identified. Therapy is symptomatic in that the majority of drugs prevent seizures, but neither effective prophylaxis or cure is available.

Slide 4 :

Causes for Acute Seizures Trauma Encephalitis Drugs Birth trauma Withdrawal from depressants Tumor High fever Hypoglycemia Extreme acidosis Extreme alkalosis Hyponatremia Hypocalcemia Idiopathic

Slide 5 :

Seizures The causes for seizures can be multiple, from infection, to neoplasms, to head injury. In a few subgroups it is an inherited disorder. Febrile seizures or seizures caused by meningitis are treated by antiepileptic drugs, although they are not considered epilepsy (unless they develop into chronic seizures). Seizures may also be caused by acute underlying toxic or metabolic disorders, in which case the therapy should be directed towards the specific abnormality.

Slide 6 :

Neuronal Substrates of Epilepsy The Brain The Synapse The Ion Channels/Receptors

Slide 7 :

Partial (focal) Seizures Simple Partial Seizures Complex Partial Seizures Generalized Seizures Absence Seizures Tonic-Clonic seizures Tonic Seizures Atonic Seizures Clonic and Myoclonic Seizures Infantile Spasms Classification of Seizures

Slide 8 :

Partial (Focal) Seizures Simple Partial Seizures. Complex Partial Seizures.

Slide 9 :

Scheme of Seizure Spread Simple (Focal) Partial Seizures Contralateral spread

Slide 10 :

I. Simple Partial Seizures (Jacksonian) Involves one side of the brain at onset. Focal w/motor, sensory or speech disturbances. Confined to a single limb or muscle group. Seizure-symptoms don’t change during seizure. No alteration of consciousness. EEG: Excessive synchronized discharge by a small group of neurons. Contralateral discharge. Partial (Focal) Seizures

Slide 11 :

Scheme of Seizure Spread Complex Partial Seizures Complex Secondarily Generalized Partial Seizures

Slide 12 :

II. Complex Partial Seizures (Temporal Lobe epilepsy or Psychomotor Seizures) Produces confusion and inappropriate or dazed behavior. Motor activity appears as non-reflex actions. Automatisms (repetitive coordinated movements). Wide variety of clinical manifestations. Consciousness is impaired or lost. EEG: Bizarre generalized EEG activity with evidence of anterior temporal lobe focal abnormalities. Bilateral. Partial (focal) Seizures

Slide 13 :

Generalized Seizures Tonic-Clonic seizures Absence Seizures Atonic Seizures Tonic Seizures Clonic and Myoclonic Seizures Infantile Spasms

Slide 14 :

Neuronal Correlates of Paroxysmal Discharges Generalized Seizures

Slide 15 :

General Seizures (con’t) Generalized Tonic-Clonic Seizures Recruitment of neurons throughout the cerebrum Major convulsions, usually with two phases: 1) Tonic phase 2) Clonic phase convulsions:

Slide 16 :

General Seizures (con’t) Generalized Tonic-Clonic Seizures Tonic phase: - sustained powerful muscle contraction (involving all body musculature) which arrests ventilation. EEG: Rythmic high frequency, high voltage discharges with cortical neurons undergoing sustained depolarization, with protracted trains of action potentials.

Slide 17 :

General Seizures (con’t) Generalized Tonic-Clonic Seizures Clonic phase: - alternating contraction and relaxation, causing a reciprocating movement which could be bilaterally symmetrical or “running” movements. EEG: Characterized by groups of spikes on the EEG and periodic neuronal depolarizations with clusters of action potentials.

Slide 18 :

Neuronal Correlates of Paroxysmal Discharges

Slide 19 :

II. Absence Seizures (Petite Mal) Brief and abrupt loss of consciousness. Sometimes with no motor manifestations. Usually symmetrical clonic motor activity varying from occasional eyelid flutter to jerking of the entire body. Typical 2.5 – 3.5 Hz spike-and-wave discharge. Usually of short duration (5-10 sec), but may occur dozens of times a day. General Seizures

Slide 20 :

II. Absence Seizures (Petite Mal) (con’t) Often begin during childhood (daydreaming attitude, no participation, lack of concentration). A low threshold Ca2+ current has been found to govern oscillatory responses in thalamic neurons (pacemaker) and it is probably involve in the generation of these types of seizures. EEG: Bilaterally synchronous, high voltage 3-per-second spike-and-wave discharge pattern. spike phase: neurons generate short duration depolarization and a burst of action potentials. No sustained depolarization or repetitive firing. General Seizures

Slide 21 :

Scheme of Seizure Spread Primary Generalized Absence Seizures Thalamocortial relays are believed to act on a hyperexcitable cortex

Slide 22 :

Scheme of Seizure Spread

Slide 23 :

General Seizures (con’t) III. Atonic Seizures (atypical) Loss of postural tone, with sagging of the head or falling. May loose consciousness. IV. Tonic Seizures Opisthotonus, loss of consciousness. Marked autonomic manifestations.

Slide 24 :

General Seizures (con’t) V. Clonic Seizures Rhythmic clonic contractions of all muscles, loss of consciousness, and marked autonomic manifestations. VI. Myoclonic Seizures Isolated clonic jerks associated with brief bursts of multiple spikes in the EEG. VII. Infantile Spasms An epileptic syndrome. Attacks although fragmentary, are often bilateral. Characterized by brief recurrent myoclonic jerks of the body with sudden flexion or extension of the body and limbs.

Slide 25 :

Cellular and Synaptic Mechanisms of Epileptic Seizures (From Brody et al., 1996)

Slide 26 :

Treatment of Epilepsies Goals: Block repetitive neuronal firing. Block synchronization of neuronal discharges. Block propagation of seizure. Minimize side effects with the simplest drug regimen. MONOTHERAPY IS RECOMMENDED IN MOST CASES

Slide 27 :

Treatment of Epilepsies Strategies: Modification of ion conductances. Increase inhibitory (GABAergic) transmission. Decrease excitatory (glutamatergic) activity.

Slide 28 :

Actions of Phenytoin on Na+ Channels Resting State Arrival of Action Potential causes depolarization and channel opens allowing sodium to flow in. Refractory State, Inactivation Na+ Na+ Na+ Sustain channel in this conformation

Slide 29 :

GABAergic SYNAPSE Drugs that Act at the GABAergic Synapse GABA agonists GABA antagonists Barbiturates Benzodiazepines GABA uptake inhibitors

Slide 30 :

GLUTAMATERGIC SYNAPSE Excitatory Synapse. Permeable to Na+, Ca2+ and K+. Magnesium ions block channel in resting state. Glycine (GLY) binding enhances the ability of GLU or NMDA to open the channel. Agonists: NMDA, AMPA, Kianate. Mg++ Na+ AGONISTS GLU Ca2+ K+ GLY

Slide 31 :

Chemical Structure of Antiepileptics X may vary as follows: Barbiturates - C – N - Hydantoins - N – Oxazolidinediones – O – Succinimides – C – Acetylureas - NH2 –* *(N connected to C2) Small changes can alter clinical activity and site of action. e.g. At R1, a phenyl group (phenytoin) confers activity against partial seizures, but an alkyl group (ethosuximide) confers activity against generalized absence seizures.

Slide 32 :

Treatment of Epilepsies Hydantoins: phenytoin Barbiturates: phenobarbital Oxazolidinediones: trimethadione Succinimides: ethosuximide Acetylureas: phenacemide

Slide 33 :

Treatment of Epilepsies Structurally dissimilar: carbamazepine valproic acid BDZs. As are the new compounds: felbamate (Japan) Gabapentin lamotrigine tiagabine topiramate vigabatrin

Slide 34 :

Pharmacokinetic Parameters

Slide 35 :

Effects of three antiepileptic drugs on high frequency discharge of cultured neurons . (From Katzung B.G., 1998) Block of sustained high frequency repetitive firing of action potentials.

Slide 36 :

PHENYTOIN (Dilantin) Oldest nonsedative antiepileptic drug. Fosphenytoin, a more soluble prodrug is used for parenteral use. “Fetal hydantoin syndrome” It alters Na+, Ca2+ and K+ conductances. Inhibits high frequency repetitive firing. Alters membrane potentials. Alters a.a. concentration. Alters NTs (NE, ACh, GABA) Toxicity: Ataxia and nystagmus. Cognitive impairment. Hirsutism Gingival hyperplasia. Coarsening of facial features. Dose-dependent zero order kinetics. Exacerbates absence seizures.

Slide 37 :

CARBAMAZEPINE (Tegretol) Tricyclic, antidepressant (bipolar) 3-D conformation similar to phenytoin. Mechanism of action, similar to phenytoin. Inhibits high frequency repetitive firing. Decreases synaptic activity presynaptically. Binds to adenosine receptors (?). Inh. uptake and release of NE, but not GABA. Potentiates postsynaptic effects of GABA. Metabolite is active. Toxicity: Autoinduction of metabolism. Nausea and visual disturbances. Granulocyte supression. Aplastic anemia. Exacerbates absence seizures.

Slide 38 :

OXCARBAZEPINE (Trileptal) Closely related to carbamazepine. With improved toxicity profile. Less potent than carbamazepine. Active metabolite. Mechanism of action, similar to carbamazepine It alters Na+ conductance and inhibits high frequency repetitive firing. Toxicity: Hyponatremia Less hypersensitivity and induction of hepatic enzymes than with carb.

Slide 39 :

PHENOBARBITAL (Luminal) Except for the bromides, it is the oldest antiepileptic drug. Although considered one of the safest drugs, it has sedative effects. Many consider them the drugs of choice for seizures only in infants. Acid-base balance important. Useful for partial, generalized tonic-clonic seizures, and febrile seizures Prolongs opening of Cl- channels. Blocks excitatory GLU (AMPA) responses. Blocks Ca2+ currents (L,N). Inhibits high frequency, repetitive firing of neurons only at high concentrations. . Toxicity: Sedation. Cognitive impairment. Behavioral changes. Induction of liver enzymes. May worsen absence and atonic seizures.

Slide 40 :

PRIMIDONE (Mysolin) Metabolized to phenobarbital and phenylethylmalonamide (PEMA), both active metabolites. Effective against partial and generalized tonic-clonic seizures. Absorbed completely, low binding to plasma proteins. Should be started slowly to avoid sedation and GI problems. Its mechanism of action may be closer to phenytoin than the barbiturates. Toxicity: Same as phenobarbital Sedation occurs early. Gastrointestinal complaints.

Slide 41 :

VALPROATE (VALPROIC ACID) Fully ionized at body pH, thus active form is valproate ion. One of a series of carboxylic acids with antiepileptic activity. Its amides and esters are also active. Mechanism of action, similar to phenytoin. ? levels of GABA in brain. May facilitate Glutamic acid decarboxylase (GAD). Inhibits GAT-1. ? [aspartate]Brain? May increase membrane potassium conductance. Toxicity: Elevated liver enzymes including own. Nausea and vomiting. Abdominal pain and heartburn. Tremor, hair loss, Weight gain. Idiosyncratic hepatotoxicity. Negative interactions with other antiepileptics. Teratogen: spina bifida

Slide 42 :

ETHOSUXIMIDE (Zarontin) Drug of choice for absence seizures. High efficacy and safety. VD = TBW. Not plasma protein or fat binding Mechanism of action involves reducing low-threshold Ca2+ channel current (T-type channel) in thalamus. At high concentrations: Inhibits Na+/K+ ATPase. Depresses cerebral metabolic rate. Inhibits GABA aminotransferase. Phensuximide = less effective Methsuximide = more toxic Toxicity: Gastric distress, including, pain, nausea and vomiting Lethargy and fatigue Headache Hiccups Euphoria Skin rashes Lupus erythematosus (?)

Slide 43 :

CLONAZEPAM (Klonopin) A benzodiazepine. Long acting drug with efficacy for absence seizures. One of the most potent antiepileptic agents known. Also effective in some cases of myoclonic seizures. Has been tried in infantile spasms. Doses should start small. Increases the frequency of Cl- channel opening. Toxicity: Sedation is prominent.

Slide 44 :

VIGABATRIN (?-vinyl-GABA) Absorption is rapid, bioavailability is ~ 60%, T 1/2 6-8 hrs, eliminated by the kidneys. Use for partial seizures and West’s syndrome. Contraindicated if preexisting mental illness is present. Irreversible inhibitor of GABA-aminotransferase (enzyme responsible for metabolism of GABA) => Increases inhibitory effects of GABA. S(+) enantiomer is active. Toxicity: Drowsiness Dizziness Weight gain Agitation Confusion Psychosis

Slide 45 :

LAMOTRIGINE (Lamictal) Presently use as add-on therapy with valproic acid (v.a. conc. are be reduced). Almost completely absorbed T1/2 = 24 hrs Low plasma protein binding Suppresses sustained rapid firing of neurons and produces a voltage and use-dependent inactivation of sodium channels, thus its efficacy in partial seizures. Also effective in myoclonic and generalized seizures in childhood and absence attacks. Toxicity: Dizziness Headache Diplopia Nausea Somnolence Rash

Slide 46 :

FELBAMATE (Felbatrol) Effective against partial seizures but has severe side effects. Because of its severe side effects, it has been relegated to a third-line drug used only for refractory cases. Toxicity: Aplastic anemia Severe hepatitis

Slide 47 :

TOPIRAMATE Rapidly absorbed, bioav. is > 80%, has no active metabolites, excreted in urine.T1/2 = 20-30 hrs Blocks repetitive firing of cultured neurons, thus its mechanism may involve blocking of voltage-dependent sodium channels Potentiates inhibitory effects of GABA (acting at a site different from BDZs and BARBs). Depresses excitatory action of kainate on AMPA receptors. Teratogenic in animal models. Toxicity: Somnolence Fatigue Dizziness Cognitive slowing Paresthesias Nervousness Confusion Urolithiasis

Slide 48 :

TIAGABINE (Gabatril) Derivative of nipecotic acid. 100% bioavailable, highly protein bound. T1/2 = 5 -8 hrs Effective against partial and generalized tonic-clonic seizures. GABA uptake inhibitor GAT-1. Potentiates inhibitory effects of GABA (acting at a site different from BDZs and BARBs). Depresses excitatory action of kainate on AMPA receptors. Teratogenic in animal models. Toxicity: Dizziness Nervousness Tremor Difficulty concentrating Depression Asthenia Emotional lability Psychosis Skin rash

Slide 49 :

ZONISAMIDE Sulfonamide derivative. Marketed in Japan. Good bioavailability, low pb. T1/2 = 1 - 3 days Effective against partial and generalized tonic-clonic seizures. Mechanism of action involves voltage and use-dependent inactivation of sodium channels (?). May also involve Ca2+ channels. Toxicity: Drowsiness Cognitive impairment High incidence of renal stones (?).

Slide 50 :

GABAPENTIN (Neurontin) Used as an adjunct in partial and generalized tonic-clonic seizures. Does not induce liver enzymes. not bound to plasma proteins. drug-drug interactions are negligible. Low potency. An a.a.. Analog of GABA that does not act on GABA receptors, it may however alter its metabolism, non-synaptic release and transport. Toxicity: Somnolence. Dizziness. Ataxia. Headache. Tremor.

Slide 51 :

Status Epilepticus Status epilepticus exists when seizures recur within a short period of time , such that baseline consciousness is not regained between the seizures. They last for at least 30 minutes. Can lead to systemic hypoxia, acidemia, hyperpyrexia, cardiovascular collapse, and renal shutdown. The most common, generalized tonic-clonic status epilepticus is life-threatening and must be treated immediately with concomitant cardiovascular, respiratory and metabolic management.

Slide 52 :

DIAZEPAM (Valium) AND LORAZEPAM (Ativan) Benzodiazepines. Will also be discussed with Sedative hypnotics. Given I.V. Lorazepam may be longer acting. 1° for treating status epilepticus Have muscle relaxant activity. Allosteric modulators of GABA receptors. Potentiates GABA function, by increasing the frequency of channel opening. Toxicity Sedation Children may manifest a paradoxical hyperactivity. Tolerance

Slide 53 :

Treatment of Status Epilepticus in Adults Initial Diazepam, i.v. 5-10 mg (1-2 mg/min) repeat dose (5-10 mg) every 20-30 min. Lorazepam, i.v. 2-6 mg (1 mg/min) repeat dose (2-6 mg) every 20-30 min. Follow-up Phenytoin, i.v. 15-20 mg/Kg (30-50 mg/min). repeat dose (100-150 mg) every 30 min. Phenobarbital, i.v. 10-20 mg/Kg (25-30mg/min). repeat dose (120-240 mg) every 20 min.

Slide 54 :

Treatment of Epilepsies PARTIAL SEIZURES ( Simple and Complex, including secondarily generalized) Drugs of choice: carbamazepine phenytoin valproate Alternatives: Gabapentin phenobarbital topiramate lamotrigine primidone tiagabine levetiracetam zonisamide

Slide 55 :

Infantile spasms Infantile spasms are an epileptic syndrome and not a seizure type. The attacks although sometimes fragmentary are most often bilateral and are included, for pragmatic purposes with the generalized seizures Characterized by recurrent myoclonic jerks with sudden flexion or extension of the body and limbs; the form of infantile spasms are, however, quite heterogeneous. 90% have their first attack before the age of 1 year. Most patients are mentally retarded, presumably from the same cause of the spasms. The cause is unknown. Infections, kernicterus, tuberous sclerosis and hypoglycemia have all been implicated.

Slide 56 :

Treatment of Epilepsies PRIMARY GENERALIZED TONIC-CLONIC SEIZURES (Grand Mal) Drugs of choice: Carbamazepine Phenytoin Valproate* Alternatives: Lamotrigine Phenobarbital Topiramate Primidone *Not approved except if absence seizure is involved

Slide 57 :

Treatment of Epilepsies GENERAL ABSENCE (Petite Mal) Drugs of choice: Ethosuximide Trimethadione Valproate* Alternatives: Lamotrigine Clonazepam Topiramate (?) * First choice if primary generalized tonic-clonic seizure is also present.

Slide 58 :

Treatment of Epilepsies ATYPICAL ABSENCE, MYOCLONIC, ATONIC* Drugs of choice: Valproate Lamotrigine Alternatives: Topiramate Clonazepam Falbamate * Often refractory to medications.

Slide 59 :

Treatment of Epilepsies INFANTILE SPASMS Drugs of choice: Corticotropin or Corticosteroids Zonisamide Alternatives: Clonazepam Vigabatrin Phenobarbital

Slide 60 :

ANTIEPILEPTIC DRUG INTERACTIONS With other antiepileptic Drugs: - Carbamazepine with phenytoin Increased metabolism of carbamazepine phenobarbital Increased metabolism of epoxide. - Phenytoin with primidone Increased conversion to phenobarbital. - Valproic acid with clonazepam May precipitate nonconvulsive status epilepticus phenobarbital Decrease metabolism, increase toxicity. phenytoin Displacement from binding, increase toxicity.

Slide 61 :

ANTIEPILEPTIC DRUG INTERACTIONS With other drugs: antibiotics ? phenytoin, phenobarb, carb. anticoagulants phenytoin and phenobarb? met. cimetidine displaces pheny, v.a. and BDZs isoniazid ? toxicity of phenytoin oral contraceptives antiepileptics ? metabolism. salicylates displaces phenytoin and v.a. theophyline carb and phenytoin may? effect.

drbahrami2003 on Mar 09, 2012 Says :

primary generalized epilepsy

Post a comment

Post Comment on Twitter Post Comment on SlideWorld

Comments:

Subscribe to follow-up comments

Adverse Drug Reactio...

Error in Patient Car...

GLORIA Module 11 Dru...

Developing new drugs...

Drug Treatment of Ps...

The role of psychotr...

Free Powerpoint Templates

	SlidesOnline 4 Years ago. Category: General

Tags:	other

9534 Views, 0 favourite
Febrile seizures or seizures caused by meningitis are treated by antiepileptic drugs, although they more Febrile seizures or seizures caused by meningitis are treated by antiepileptic drugs, although they are not considered epilepsy (unless they develop into ... less