Anti-convulsants and its side affect and mechanism of action

It is best care of epilepsy patients

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

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

12. Classification of A C Ds 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 s e dating effects than the classical ACDs

13. 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.

14. 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

15. 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

16. 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

17. 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

18. GABA A Receptor

19. 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

20. 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

21. 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

22. 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

23. Ca 2+ Channels as Targets Absence seizures are caused by oscillations between thalamus and cortex that are generated in thalamus by T-type (transient) Ca 2+ currents Ethosuximide is a specific blocker of T-type currents and is highly effective in treating absence seizures

24. 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

25. 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 ?

26. 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

27. Classic AEDs

28. 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 .

29. 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.

30. 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.

31. 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.

32. 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 •

33. 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

34. 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

35. 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).

36. 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

37. Newer Drugs

38. 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

39. 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

40. 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

41. 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

42. 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

43. 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.

44. 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

45. 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

46. 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

47. 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

48. 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)

49. 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.

50. 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.

51. 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

52. 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

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

54. 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

55. 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.