The document discusses anti-convulsant drugs used to treat seizures. It begins by outlining the objectives of discussing pharmacokinetics, side effects, interactions, and nursing considerations for various anti-convulsants. It then defines seizures, epilepsy, and status epilepticus. It classifies seizures as generalized or partial and discusses cellular mechanisms and targets of anti-convulsant drugs including GABA, sodium channels, and calcium channels. The document outlines various classic and newer anti-convulsants, their mechanisms of action, pharmacokinetics, indications, adverse effects and drug interactions.

1. Unit-II-B
Anti-Convulsants or Anti-Epileptic or
Anti-seizures Drugs
By: Muhammad Aurangzeb
Lecturer-INS/KMU

2. Objectives
By the completion of this section the learners will be able to:
• Discuss the pharmacokinetics, side effects and adverse
reactions, therapeutic plasma phenytoin level
• Identify the contraindications and drug interactions.
• Explain the nursing interventions, including client teaching
related to the use of anticonvulsants.
• Calculate the drug dosage accurately for oral and parental
anticonvulsants drug.

3. Anticonvulsants Drugs (ACDs)
• Anticonvulsants or Antiseizure agents (also known
as antiepileptic drugs) are drugs used to manage seizures, the
most prevalent neurological disorder.

4. Basic definitions
• Seizure: the clinical manifestation of an abnormal and
excessive excitation and synchronization of a population of
cortical neurons
• Epilepsy is a collection of different syndromes, all of which is
characterized by sudden discharge of excessive electrical
energy from nerve cells located within the brain.
• Status epilepticus is a state in which seizures rapidly recur
with no recovery between seizures. It is potentially the most
dangerous of seizures.

5. Cellular Mechanisms of Seizure
Generation
• Results from an imbalance between Excitation and inhibition
of Neurons in the part of the brain
• Excitation (too much)
– Ionic—inward Na+, Ca++ currents
– Neurotransmitter—glutamate, aspartate
• Inhibition (too little)
– Ionic—inward CI-, outward K+ currents
– Neurotransmitter—GABA

6. Classification of Seizures
• International Classification of Seizures categorized seizures
based on symptoms and characteristics. The two main
categories include:
Generalized Seizures
• These seizures are characterized by a massive electrical
activity that begins in one area of the brain and rapidly spread
to both hemispheres. It is usually accompanied by loss of
consciousness. It is further classified into sub types:

7. Generalized Seizures Cont.…
Absence seizure
• It is an abrupt and brief (3-5 s) period of loss of consciousness
common in children (starting at age 3) but frequently
disappears by puberty. This seizure does not usually involve
muscle contractions.
Myoclonic seizure
• It is characterized by short, sporadic periods of muscle
contractions that last for several minutes. It is relatively rare.
Atonic seizures:
• Sudden loss of postural tone; most often in children but may
be seen in adults

8. Tonic-clonic seizure
• It involves involuntary muscle contraction (tonic) followed
by relaxation appearing as an aggressive spasm (clonic), loss
of consciousness, and confusion and exhaustion in the early
recovery period.
Generalized Seizures Cont.…

9. Partial (Focal) Seizures
• Originate from one area of the brain, do not spread to
other parts. It can be further classified into three:
Simple Partial Seizure
• Occurs in a single area of brain and may involve a single
muscle movement or sensory alteration.
Complex Partial Seizure
• Occurs by late teenage years and involves a series of
reactions or emotional changes and complex sensory
changes (hallucinations, mental distortion, loss of
consciousness, and loss of social inhibition).
• Motor changes may include involuntary urination,
chewing motions, and diarrhea.

10. Partial (Focal) Seizures
Secondarily Generalized Seizures
• Begins focally, with or without focal neurological symptoms
• Variable symmetry, intensity, and duration of tonic (stiffening)
and clonic (jerking) phases
• Typical duration up to 1-2 minutes
• Postictal confusion, somnolence, with or without transient
focal deficit

12. Anticonvulsants Drugs
• Drugs which decreases the frequency and/or severity of
seizures
• Goal—maximize quality of life by minimizing seizures and
adverse drug effects

13. Classification of ACDs
Classical
• Phenytoin
• Phenobarbital
• Primidone
• Carbamazepine
• Ethosuximide
• Valproate (valproic acid)
Newer
• Lamotrigine
• Felbamate
• Topiramate
• Gabapentin
• Tiagabine
• Vigabatrin
• Oxycarbazepine
• Levetiracetam
• Fosphenytoin
In general, the newer ACDs have less CNS sedating effects than the
classical ACDs

14. Mechanism Of Action Of Anticonvulsants Drugs
Three main mechanisms:
• Enhancement of GABA action
• Inhibition of sodium channel function
• Inhibition of calcium channel function.
Other mechanisms include:
• Inhibition of glutamate release and
• Block of glutamate receptors.

15. Targets for Anticonvulsants Drugs
• Increase inhibitory neurotransmitter system— GABA
• Decrease excitatory neurotransmitter system— glutamate
• Block voltage-gated inward positive currents— Na+ or Ca++
• Increase outward positive current—K+
• Many AEDs are pleiotropic—act via multiple mechanisms

16. Excitatory Neurotransmitter-Glutamate and its
receptors
• The brain’s major excitatory neurotransmitter
• There are three types of Glutamate receptors i.e. NMDA
receptors, AMPA receptors, and kainate receptors
• The NMDA receptor when activated by glutamate and glycine
allows positively charged ions to flow through the cell
membrane.
• The AMPA receptor (AMPA-R) is coupled to ion channels that
modulate cell excitability by gating the flow of calcium and
sodium ions into the cell
• In addition to NMDA and AMPA receptors, kainate (KA)
receptors have been found to play roles in synaptic
transmission

17. Glutamate Receptors as ACDs Targets
• NMDA receptor sites as targets
– Ketamine, phencyclidine, dizocilpine block channel and
have anticonvulsant properties but also dissociative
and/or hallucinogenic properties; open channel blockers.
– Felbamate antagonizes strychnine-insensitive glycine site
on NMDA complex
• AMPA receptor sites as targets
– Topiramate antagonizes AMPA site

18. Inhibitory neurotransmitter-GABA
• Major inhibitory neurotransmitter in the CNS
• Two types of receptors
– GABAA—post-synaptic, specific recognition sites, linked to
CI- channel
– GABAB —presynaptic autoreceptors, mediated by K+
currents

19. GABAA Receptor

20. ACDs That Act Primarily on GABA
• Benzodiazepines (diazapam, clonazapam)
– Increase frequency of GABA-mediated chloride channel
openings
• Barbiturates (phenobarbital, primidone)
– Prolong GABA-mediated chloride channel openings
– Some blockade of voltage-dependent sodium channels

21. AEDs That Act Primarily on GABA
Gabapentin
• May modulate amino acid transport into brain
• May interfere with GABA re-uptake
Tiagabine
• Interferes with GABA re-uptake
Vigabatrin (not currently available in US)
• Elevates GABA levels by irreversibly inhibiting its main
catabolic enzyme, GABA- transaminase

22. Na+ Channels as ACD Targets
• Neurons fire at high frequencies during seizures
• Action potential generation is dependent on Na+ channels
• Na+ channel blockers reduce high frequency firing without
affecting physiological firing

23. AEDs That Act Primarily on Na+ Channels
Phenytoin, Carbamazepine
• Block voltage-dependent sodium channels at high firing
frequencies—use dependent
Oxcarbazepine
• Blocks voltage-dependent sodium channels at high firing
frequencies
• Also effects K+ channels
Zonisamide
• Blocks voltage-dependent sodium channels and T-type
calcium channels

24. Ca2+ Channels as Targets
• Absence seizures are caused by oscillations between
thalamus and cortex that are generated in thalamus by T-type
(transient) Ca2+ currents
• Ethosuximide is a specific blocker of T-type currents and is
highly effective in treating absence seizures

25. What about K+ channels?
• K+ channels have important inhibitory control over neuronal
firing in CNS—repolarize membrane to end action potentials
• K+ channel agonists would decrease hyperexcitability in brain
• So far, the only ACD with known actions on K+ channels is
valproate (Epival)
• Retiagabine is a novel ACD in clinical trials that acts on a
specific type of voltage-dependent K+ channel

26. Pleiotropic ACDs
Felbamate
• Blocks voltage-dependent sodium channels at high firing
frequencies
• May control NMDA receptor
Lamotrigine
• Blocks voltage-dependent sodium channels at high firing
frequencies
• May interfere with pathologic glutamate release
• Inhibit Ca++ channels?

27. Pleiotropic AEDs
Topiramate
• Blocks voltage-dependent sodium channels at high firing
frequencies
• Increases frequency at which GABA opens Cl- channels
(different site than benzodiazepines)
• Antagonizes glutamate action at AMPA/kainate receptor
subtype?
Valproate
• May enhance GABA transmission
• Blocks voltage-dependent sodium channels
• May also augment K+ channels
• T-type Ca2+ currents

28. Classic AEDs

29. Phenytoin
• First line drug for partial seizures
• MOA: Inhibits Na+ channels—use dependent
• Prodrug fosphenytoin for IM or IV administration. Highly
bound to plasma proteins.
• The t1/2 - 12-24 hours progressively ↑es upto 60 hr when
plasma concentration rises above 10 ug/ml as metabolizing
enzymes get saturated.
• Therapeutic plasma level is between 10 and 20 µg/mL.
• Some adverse effects of phenytoin are related to specific
serum levels. Nystagmus is frequently observed at levels
greater than 20 µg/mL.

30. Indications of phenytoin
• Generalized tonic-clonic, simple and complex partial seizures.
• It is ineffective in absence seizures.
• Dose: 100 mg BD, maximum 400 mg/day; Children 5-8
mg/kg/day,
• Status epilepticus: occasionally used by slow i.v. injection.
• Trigeminal neuralgia - second choice drug to carbamazepine.

31. Adverse effects of Phenytoin
• Adverse effects: CNS sedation (drowsiness, ataxia, confusion,
insomnia, nystagmus, etc.), gum hyperplasia, hirsutism
• Interactions: carbamazepine, phenobarbital will decrease
plasma levels; alcohol, diazepam, methylphenidate will
increase.
• Stimulates cytochrome P-450, so can increase metabolism of
some drugs.

32. Carbamazepine
• First line drug for partial seizures
• MOA: Inhibits Na+ channels—use dependent
• Half-life: 6-12 hours
• Adverse effects: CNS sedation. Agranulocytosis and aplastic
anemia in elderly patients, rare but very serious adverse
effect. A mild, transient leukopenia (decrease in white cell
count) occurs in about 10% of patients, but usually
disappears in first 4 months of treatment. Can exacerbate
some generalized seizures.
• Drug interactions: Stimulates the metabolism of other drugs
by inducing microsomal enzymes, stimulates its own
metabolism. This may require an increase in dose of this and
other drugs patient is taking.

33. Phenobarbital
• Partial seizures, effective in neonates
• Second-line drug in adults due to more severe CNS sedation
• Allosteric modulator of GABAA receptor (increase open time)
• Absorption: rapid
• Half-life: 53-118 hours (long)
• Adverse effects: CNS sedation but may produce excitement in
some patients. Skin rashes if allergic. Tolerance and physical
dependence possible.
• Interactions: severe CNS depression when combined with
alcohol or benzodiazapines. Stimulates cytochrome P-450
•

34. Primidone
• Partial seizures
• Mechanism—see phenobarbital
• Absorption: Individual variability in rates. Not highly bound to
plasma proteins.
• Metabolism: Converted to phenobarbital and phenylethyl
malonamide, 40% excreted unchanged.
• Half-life: variable, 5-15 hours.
• Adverse effects: CNS sedative
• Drug interactions: enhances CNS depressants, drug
metabolism, phenytoin increases conversion to PB

35. Benzodiazepines (Diazepam and
clonazepam)
• Status epilepticus (IV)
• Allosteric modulator of GABAA receptors—increases
frequency
• Absorption:Rapid onset. Diazepam—rectal formulation for
treatment of SE
• Half-life: 20-40 hours (long)
• Adverse effects: CNS sedative, tolerance, dependence.
Paradoxical hyperexcitability in children
• Drug interactions: can enhance the action of other CNS
depressants

36. Valproate (Valproic Acid)
• Partial seizures, first-line drug for generalized seizures.
• Enhances GABA transmission, blocks Na+ channels, activates
K+ channels
• Absorption: 90% bound to plasma proteins
• Half-life: 6-16 hours
• Adverse effects: CNS depressant (esp. w/ phenobarbital),
anorexia, nausea, vomiting, hair loss, weight gain, elevation of
liver enzymes. Hepatoxicity is rare but severe, greatest risk in
<2 year old. May cause birth defects.
• Drug interactions: May potentiate CNS depressants, displaces
phenytoin from plasma proteins, inhibits metabolism of
phenobarbital, phenytoin, carbamazepine (P450 inhibitor).

37. Ethosuximide
• Absence seizures
• Blocks T-type Ca++ currents in thalamus
• Half-life: long—40 hours
• Adverse effects: gastric distress—pain, nausea, vomiting. Less
CNS effects that other AEDs, transient fatigue, dizziness,
headache
• Drug interactions: administration with valproate results in
inhibition of its metabolism

38. Newer Drugs

39. Oxcarbazepine
• Approved for add-on therapy, monotherapy in partial
seizures that are refractory to other AEDs
• Activity-dependent blockade of Na+ channels, may also
augment K+ channels
• Half-life: 1-2 hours, but converted to 10- hydroxycarbazepine
8-12 hours
• Adverse effects: similar to carbamazepine (CNS sedative) but
may be less toxic.
• Drug interactions: less induction of liver enzymes, but can
stimulate CYP3A and inhibit CYP2C19

40. Gabapentin
• Add-on therapy for partial seizures, evidence that it is also
effective as monotherapy in newly diagnosed epilepsies
(partial)
• MOA: May interfere with GABA uptake
• Absorption: Non-linear. Saturable (amino acid transport
system), no protein binding.
• Metabolism: none, eliminated by renal excretion
• Half-life: 5-9 hours, administered 2-3 times daily
• Adverse effects: less CNS sedative effects than classic AEDs
• Drug interactions: none known

41. Lamotrigine
• Add-on therapy, monotherapy for refractory partial seizures.
Also effective in Lennox Gastaut Syndrome and newly
diagnosed epilepsy. Effective against generalized seizures.
• Use-dependent inhibition of Na+ channels, glutamate
release, may inhibit Ca++ channels
• Half-life—24 hours
• Adverse effects: less CNS sedative effects than classic AEDs,
dermatitis potentially life-threatening in 1-2% of pediatric
patients.
• Drug interactions: levels increased by valproate, decreased by
carbamazepine, PB, phenytoin

42. Felbamate
• Third-line drug for refractory partial seizures
• Frequency-dependent inhibition of Na+ channels, modulation
of NMDA receptor
• Adverse effects: aplastic anemia and severe hepatitis restricts
its use (black box)
• Drug interactions: increases plasma phenytoin and valproate,
decreases carbamazapine. Stimulates CYP3A and inhibits
CYP2C19

43. Levetiracetam
• Add-on therapy for partial seizures
• Binds to synaptic vesicle protein SV2A, may regulate
neurotransmitter release
• Half-life: 6-8 hours (short)
• Adverse effects: CNS depresssion
• Drug interactions: minimal

44. Tiagabine
• Add-on therapy for partial seizures
• Interferes with GABA reuptake by depressing GABA
transporter GAT-1 which removes synaptically released GABA
• Half-life: 5-8 hours (short)
• Adverse effects: CNS sedative
• Drug interactions: minimal
• Uses – add on therapy of partial seizures with or without
secondary generalization.

45. Zonisamide
• Add-on therapy for partial and generalized seizures
• Blocks Na+ channels and T-type Ca++ channels
• Half-life: 1-3 days (long)
• Adverse effects: CNS sedative
• Drug interactions: minimal

46. Topimerate
• Add-on for refractory partial or generalized seizures. Effective
as monotherapy for partial or generalized seizures, Lennox-
Gastaut syndrome.
• Use-dependent blockade of Na+ channels, increases
frequency of GABAA channel openings, may interfere with
glutamate binding to AMPA/KA receptor
• Half-life: 20-30 hours (long)
• Adverse effects: CNS sedative
• Drug interactions: Stimulates CYP3A and inhibits CYP2C19,
can lessen effectiveness of birth control pills

47. Vigabatrin
• Add-on therapy for partial seizures, monotherapy for infantile
spasms. (Not available in US).
• Blocks GABA metabolism through actions on GABA-
transaminase
• Half-life: 6-8 hours, but pharmacodynamic activity is
prolonged and not well-coordinated with plasma half-life.
• Adverse effects: CNS sedative, ophthalmologic abnormalities
• Drug interactions: minimal

48. Treatment of Epilepsy
• First consideration is efficacy in stopping seizures
• Because many AEDs have overlapping, pleiotropic actions,
the most appropriate drug can often be chosen to reduce
side effects. Newer drugs tend to have less CNS depressant
effects.
• Potential of long-term side effects, pharmokinetics, and cost
are other considerations

49. Partial Onset Seizures
• With secondary generalization
– First-line drugs are carbamazepine and phenytoin (equally
effective)
– Valproate, phenobarbital, and primidone are also usually
effective
• Without generalization
– Phenytoin and carbamazepine may be slightly more
effective
• Phenytoin and carbamazepine can be used together (but
both are enzyme inducers)

50. Partial Onset Seizures—New Drugs
• Adjunctive (add-on) therapy where monotherapy does not
completely stop seizures—newer drugs felbamate,
gabapentin, lamotrigine, levetiracetam, oxcarbazepine,
tiagabine, topiramate, and zonisamide
• Lamotrigine, oxcarbazepine, felbamate approved for
monotherapy where phenytoin and carbamazepine have
failed.

51. Generalized Onset Seizures
• Tonic-clonic, myoclonic, and absence seizures— first line drug
is usually valproate
• Phenytoin and carbamazepine are effective on tonic-clonic
seizures but not other types of generalized seizures
• Valproate and ethoxysuximide are equally effective in
children with absence seizures, but only valproate protects
against the tonic-clonic seizures that sometimes develop.
Rare risk of hepatoxicity with valproate—should not be used
in children under 2.

52. Generalized Onset Seizures
• Clonazepam, phenobarbital, or primidone can be useful
against generalized seizures, but may have greater sedative
effects than other AEDs
• Tolerance develops to clonazepam, so that it may lose its
effectiveness after ~6 months
• Lamotrigine, topiramate, and zonisamide are effective against
tonic-clonic, absence, and tonic seizures

53. Status Epilepticus
• More than 30 minutes of continuous seizure activity
• Two or more sequential seizures spanning this period without
full recovery between seizures
• Medical emergency

54. Status Epilepticus
• Treatment
– Diazepam, lorazapam IV (fast, short acting)
– Followed by phenytoin, fosphenytoin, or phenobarbital
(longer acting) when control is established

56. Nursing role in ACDs
• Assess for mentioned contraindications and cautions (e.g.
drug allergy, diabetes, hepatorenal dysfunction,
arrhythmias, hypotension, etc.) to prevent untoward
complications.
• Discontinue the drug at any sign of hypersensitivity reaction
• Provide safety measures (e.g. adequate lighting, raised side
rails, etc.) to prevent injuries.
• Educate client on drug therapy to promote understanding and
compliance.
• Monitor patient response to therapy (decrease in incidence or
absence of seizures).
• Monitor for adverse effects

57. References
• Lippincott's illustrated pharmacology 6th edition page 157-168
• Essentials of Medical Pharmacology 7th edition by KD tripathi
• Karch, A. M., & Karch. (2011). Focus on nursing pharmacology. Wolters Kluwer
Health/Lippincott Williams & Wilkins. [Link]
• Katzung, B. G. (2017). Basic and clinical pharmacology. McGraw-Hill Education.
• Lehne, R. A., Moore, L. A., Crosby, L. J., & Hamilton, D. B. (2004). Pharmacology for
nursing care.
• Smeltzer, S. C., & Bare, B. G. (1992). Brunner & Suddarth’s textbook of medical-
surgical nursing. Philadelphia: JB Lippincott.