ENGLISH5 QUARTER4 MODULE1 WEEK1-3 How Visual and Multimedia Elements.pptx
Antiepileptic drugs lecture notes for students
1. Antiepileptic drugs
PHL 322: Pharmacology II
Shakir D AlSharari, PhD
Pharmacy College - KSU
Office: 2 B 99
Office Tel: 0114677182
Email: sdalsharari@ksu.edu.sa
2. Seizures
Various forms (depending on the part of the brain
affected)
Result from episodic high-frequency discharge of
a group of neurons (excitotoxicity)
Starting locally
May then spread to other areas of the brain
3.
4. Nature of Epilepsy
• The neurochemical basis of the abnormal
discharge is not well understood. It may be
associated with enhanced excitatory amino
acid transmission, impaired inhibitory
transmission, or abnormal electrical
properties of the affected cells. The
glutamate content in areas surrounding an
epileptic focus is often raised.
5. Nature of epilepsy
Abnormal electrical activity during seizure
can be detected by electroencephalograph
(EEG)
Recording from electrodes distributed over
the surface of the scalp
Can recognize various types of seizures.
6. Symptoms
Range from a brief lapse of attention to a
convulsion (several minutes)
Depends on the function of the region of the
brain that is affected
7. Affected brain regions
Motor cortex (convulsion)
Hypothalamus (peripheral autonomic
discharge)
Reticular formation in the upper brainstem
(loss of consciousness)
9. Causes of epilepsy
No recognizable cause
May develop after brain damage
Trauma, infection or tumor growth
Or other kinds of neurological disease
10. Epileptogenesis
Excitatory transmission is facilitated (e.g. glutamate)
Inhibitory transmission is reduced (e.g. GABA)
Abnormal electrical properties of the affected cells
11.
12. EPILEPSY affects 5–10% of the general population.
It is due to sudden, excessive depolarization of
some or all cerebral neurons. This may be:
• localized (focal or partial seizure);
• spread to cause a secondary generalized seizure;
• may affect all cortical neurons simultaneously
(primary generalized seizure).
13.
14. EEG
Cortex:
F – frontal
O – occipital
T – temporal
Classification of seizures
Rang et al.
Pharmacology
– 5th Ed. (2003)
15. Types of epilepsy
Two major seizure categories:
1. Partial
2. Generalized
Both can be classified as:
Simple (if consciousness is not lost)
Complex (if consciousness is lost)
The type of seizure determines the choice of drug!
16. Partial seizures
Discharge begins locally
(often remain localized)
EEG discharge is
normally confined to one
hemisphere
18. Complex partial seizures
Loss of consciousness
Discharge in the brainstem reticular
formation
Are among the commonest types of
epilepsy
19. Jacksonian epilepsy
In motor cortex
Repetitive jerking of particular muscle group
May spread to involve much of the body
Losses voluntary control of the affected parts
of the body
Does not necessarily loss consciousness
20. Psychomotor epilepsy
In temporal lobe
The attack may consist of movements such as:
Rubbing movements
Dressing or walking or hair-combing
Lasts for a few minutes
Recover with no recollection of the event
The behavior during the seizure can be bizarre
and accompanied by a strong emotional
response
21. Generalized seizures
Involve the whole brain,
including the reticular
system
characterized by immediate
loss of consciousness
Producing abnormal
electrical activity throughout
both hemispheres
23. Tonic-clonic seizures (grand mal)
Tonic phase:
An initial strong
contraction of the whole
musculature, causing a
rigid extensor spasm
Respiration stops,
defecation, micturition,
salivation often occur
Lasts for about 1 minute
Tonic phase (stiffening of the body)
24. Tonic-clonic seizures (grand mal)
Clonic phase:
A series of violent,
synchronous jerks
after the tonic phase
Gradually dies out in
2-4 minutes
Clonic phase (the body jerks)
25. Tonic-clonic seizures (grand mal)
The patient stays
unconscious for a
few more minutes
and then gradually
recovers, feeling ill
and confused
Post-convulsive phase (exhaustion)
26. Absence seizures (petit mal)
Occur in children
Much less dramatic
May occur more frequently (many seizures each
day) than tonic-clonic seizures
27. The patient ceases whatever he was doing
Sometimes stopping speaking in mid-sentence
Stares vacantly for a few seconds, with little or no
motor disturbance.
The patient is unaware of his surrounding
Recovers with no after-effects
Absence seizures (petit mal)
30. Thalamic neurons activity depends on the
calcium channels that they express
Treated by blocking calcium channels
Absence seizures (petit mal)
31. Lennox-Gastaut Syndrome
(LGS: Lennox Syndrome)
Severe kind of epilepsy
Occurs in children
Causes excitotoxic neurodegeneration
Associated with progressive mental
retardation
32. Antiepileptic drugs
Effective in controlling seizures in about 70%
of patients
Their use is often limited by side-effects
33. Treatment
• Monotherapy with anticonvulsant
– Increase dose gradually until seizures are controlled
or adverse effects become unacceptable.
– Multiple-drug therapy may be required.
• Achieve steady-state kinetics
• Monitor plasma drug levels
• Avoid sudden withdrawal
36. MECHANISM OF ACTION OF ANTIEPILEPTIC DRUGS
Antiepileptics inhibit the neuronal discharge or its spread in one or
more of the following ways:
(1) Enhancing GABA synaptic transmission: barbiturates, benzo-
diazepines, gabapentin, levetiracetam, tiagabine, vigabatrin, topira-
mate, valproate; the result is increased permeability to chloride ion,
which reduces neuronal excitability. Valproate and topiramate block
GABA transaminase and tiagabine blocks reuptake of GABA.
(2) Reducing cell membrane permeability to voltage-dependent
sodium channels: carbamazepine, lamotrigine, oxcarbazepine,
phenytoin, topiramate, valproate.
(3) Reducing cell membrane permeability to calcium T-channels:
valproate, ethosuximide; the result is diminishing of the generation
of action potential.
(4) Inhibiting excitory neurotransmitter glutamate: lamotrigine.
37. Treatment of Seizures
Strategies:
• Modification of ion conductances.
• Increase inhibitory (GABAergic) transmission.
• Decrease excitatory (glutamatergic) activity.
38. Antiepileptic drugs
Three main mechanisms:
1.Enhancement of GABA action
2.Inhibition of sodium channel function
3.Inhibition of calcium channel function
Other mechanisms include:
Inhibition of glutamate release
Block of glutamate receptors
40. I. Na+ Channel Inhibitors
blocks voltage-gated sodium channels by selectively
binding to the channel in the inactive state and slowing its
rate of recovery
Antiseizure drugs, enhanced Na+ channel inactivation
Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)
42. Na+ Channel Inhibitors
1. Phenytoin (Dilantin, Phenytek):
• Oldest nonsedative antiepileptic drug.
• Narrow therapeutic window (~ 40-100 μmol/l)
• Well absorbed.
– Indications:
• First choice for partial and generalized tonic-clonic seizures
• Some efficacy in clonic, myoclonic, atonic,
• No effect on infantile spasms or absence seizures
– Drug Interactions:
• Decreases blood levels of many medications
• Increases blood levels of phenobarbital & warfarin
43. Na+ Channel Inhibitors
Phenytoin (Dilantin, Phenytek):
– Adverse Effects:
• Hirsutism & coarsening of facial features
• Acne
• Gingival hyperplasia (20-40%)
• Megaloplastic anemia. (corrected by folic acid)
• Decreased serum concentrations of folic acid,
thyroxine, and vitamin K with long-term use.
• “Fetal hydantoin syndrome”: teratogenic
• includes growth retardation, microencephaly, and craniofacial
abnormalities (e.g., cleft palate) and is possibly due to an epoxide
metabolite of phenytoin.
44. Phenytoin Induced Gingival Hyperplasia
17 year old boy treated with
300mg/day phenytoin for 2
years (unsupervised)
Partial recovery at 3 months
after discontinuation
45. • Fosphenytoin is a prodrug
• rapidly converted to phenytoin in the blood, providing
high levels of phenytoin within minutes.
• Fosphenytoin may also be administered intramuscularly
(IM).
• Phenytoin sodium should never be given IM because it
can cause tissue damage and necrosis.
• Fosphenytoin is the drug of choice and standard of care
for IV and IM administration.
• Due to sound-alike and look-alike names, there is a risk
for medication error to occur.
– The trade name of fosphenytoin is Cerebyx®
– Celebrex®, the cyclooxygenase-2 inhibitor
– Celexa®, the antidepressant.
46. Na+ Channel Inhibitors
2. Carbamzepine (Tegretol, Carbatrol):
• Derived from Tricyclic, antidepressant (bipolar)
– Indications:
• First choice for complex partial and generalized
tonic-clonic seizures.
– Contraindications:
• May exacerbate absence or myoclonic seizures.
• Blood disorders
• Liver disorders
47. Na+ Channel Inhibitors
Carbamazepine (Tegretol, Carbatrol):
– Drug Interactions: A powerful inducer of hepatic microsomal
enzymes
• CBZ metabolism is affected by many drugs, and CBZ affects
the metabolism of many drugs. oral contraceptives, warfarin,
corticosteroids, etc.
– Determination of plasma levels and clearance may be
necessary for optimum therapy.
• Adverse Effects:
– Common: Diplopia and ataxia (most common), gastrointestinal
disturbances; sedation at high doses
– Occasional: Retention of water and hyponatremia; rash,
agitation in children
– Rare: Idiosyncratic blood dyscrasias and severe rashes
48. Na+ Channel Inhibitors
3. Oxcarbazepine (Trileptal):
– FDA approved in 2000 for partial seizures
• Complex partial seizures
• Primary & secondarily generalized tonic-clonic
seizures
– Is a prodrug whose actions are similar to those of
carbamazepine; it has a short half-life of 1—2 hour.
– Its activity is due to a 10-hydroxy metabolite with a
half-life of 10 hours.
– Fewer adverse effects than CBZ, phenytoin
49. Na+ Channel Inhibitors
4. Valproic Acid (Valproate; Depakene, Depakote):
– Other Mechanisms of Action:
1) Some inhibition of T-type Ca2+ channels.
2) Increases GABA production and decreases GABA
metabolism. (Inhibition of GABA transaminase )
– Indications:
• Simple or complex partial, & primary generalized tonic-clonic
• Also used for absence, myoclonic, and atonic seizures.
• Highly effective for photosensitive epilepsy and juvenile
myoclonic epilepsy.
• Low toxicity and lack of sedative action
– Contraindications:
• Liver disease
50. Na+ Channel Inhibitors
4. Valproic Acid (Valproate; Depakene, Depakote):
– Drug Interactions:
• Affects metabolism of many drugs through liver
enzyme inhibition
51. Na+ Channel Inhibitors
4. Valproic Acid (Valproate; Depakene, Depakote):
– Adverse Effects:
• Weight gain (30-50%)
• Dose-related tremor
• Transient hair loss
• Polycystic ovary syndrome (PCOS) and menstrual
disturbances
• Bone loss
• Ankle swelling
• The most serious side-effect is hepatotoxicity
• An increase in serum glutamic oxaloacetic
transaminase (sign of liver damage)
52. Na+ Channel Inhibitors
5. Lamotrigine (Lamictal):
– Other Mechanism of Action:
• May inhibit synaptic release of glutamate.
– Indications:
• Adjunct therapy (ages 2 & up):
– Simple & complex partial seizures
– Generalized seizures of Lennox-Gastaut Syndrome
• Monotherapy (adults):
– Simple & complex partial seizures
– Contraindications:
• May make myoclonic seizures worse.
54. Na+ Channel Inhibitors
6. Topiramate (Topamax):
– Other Mechanism of Action:
• Enhances post-synaptic GABAA receptor currents.
• Kainate receptor antagonist (blocks a certain type of
glutamate channel)
– Indications:
• Adjunct therapy for partial and primary generalized
• seizures in adults and children over 2.
• Decreases tonic and atonic seizures in children with Lennox-
Gastaut syndrome.
– Contraindications:
• History of kidney stones, teratogenic
56. Na+ Channel Inhibitors
7. Zonisamide (Zonegran):
• is a sulfonamide derivative that has a broad spectrum
of action
– Other Mechanism of Action:
• Inhibits T-type Ca2+ currents.
• Binds to GABA receptors.
• Facilitates dopaminergic and serotonergic
neurotransmission.
57. Na+ Channel Inhibitors
7. Zonisamide (Zonegran):
– Indications:
• Approved for adjunct treatment of partial seizures
in adults.
• Appears to have a broad spectrum:
– Myoclonic seizures
– Infantile spasms
– Generalized & atypical absence seizures
– Lennox-Gastaut Syndrome
– Drug Interactions:
• Phenytoin and carbamazepine decrease its half-life by half.
58. Na+ Channel Inhibitors
7. Zonisamide (Zonegran):
– Adverse Effects:
• Weight loss
• Abnormal thinking
• Nervousness
• Agitation/irritability
• Usually well tolerated
