CNS-For MBBS/BDS theory lecture

2. Seizure:- paroxysmal event due to abnormal
excessive or synchronous neuronal activity in the
brain
A Seizure Latin word meaning "To take
possession of”)
Epilepsy is a disorders of brain function
characterized by paroxysmal cerebral
dysrhythmia.
In this condition a person has recurrent seizures
due to a chronic, underlying process.
Patients who have two or more seizures (within
6-12 month) are considered to have epilepsy

4. History:-
 Hippocrates called “Epilepsy” as ‘Sacred disease’
Christian middle age
(14th century)-epilepsy came
from “demons”
& it was thought to be contagious.

5. Seizures
Focal Generalized
Simple Partial
Complex Partial
Secondarily
Generalized
Absence
Myoclonic
clonic
Tonic
Tonic-Clonic/GTCS
ILAE Classification of Seizures
ILAE – International League Against Epilepsy
Classification based on history ,clinical finding ,EEG recording & imaging studies by ILAE

6. distributed across both cerebral hemispheres.
 They may result from cellular, biochemical or structural
abnormalities that have a more widespread distribution.
Several types of generalized seizures have features that place
them in distinctive categories
1.GTCS:- Generalised tonic-Clonic seizures
also called Grand mal epilepsy
Main seizure type in 10% of all persons
Initial phase of the seizure is usually tonic contraction of muscles
throughout the body

7.  Other feature include-
Tonic phase- Stiff,
crying out, tongue bite,
Apnea- contraction of laryngeal muscle
↑ HR,↓BP,
Salivation,
Clonic Phase-
 Intermittent clonic movement of muscle
 Brief relaxation involves all limbs
 Repetitive bilateral muscle jerking
Recovery:- coma last for 30 min
Post ictal Phase:-
Drowsiness, confusion, headache ,deep sleep

9. Absence seizures (Petit mal):-
No aura, No loss of consciousness
Sudden onset of staring,
Bilateral motor symptoms-rapid blinking of eyelide
Children-more experience
Myoclonic seizures:-
 Single or multiple sudden brief shock like contractions of
skeletal muscles.
 sudden jerking movement observed while falling
asleep

10. -:Focal seizures:-
limited to one cerebral hemisphere (80% pt)
Usually associated with structural abnormalities of the
brain
Accompanied by transient impairment of the patient's
ability to maintain normal contact with the environment
Simple Focal seizures (SFS)/cortical focal epilepsy :-
The manifestations depend on the region of the cortex
involved:-
- no loss of consciousness
- focal motor symptoms (convulsions)
- sensory symptoms ( variety of subjective symptoms)

11. Complex Focal seizures:-
(CFS, Temporal lobe Ep. Psychomotor Ep.)
 Usually originate in the temporal lobe & are accompanied
by partial loss of consciousness
Aura –Amnesia –Abnormal behavior – Automatism

12.  Infancy and childhood
– Prenatal or birth injury
– Inborn error of metabolism
– Congenital malformation
 Childhood and adolescence
– Idiopathic/genetic syndrome
– CNS infection
 Adolescence and young adult
– Head trauma
– Drug intoxication and withdrawal
– Trauma
 Older adult
– Stroke
– Brain tumor
– Acute metabolic disturbances
– Neurodegenerative
Etiology of Seizures and Epilepsy

13. Seizure Precipitants:-
Stimulants/Other Pro-convulsant Intoxication
 I.v. drug use
 Cocaine
 Ephedrine
 Other herbal remedies
 Alcohol withdrawal

14.  Antidepressants:-
Bupropion
Tricyclics
 Neuroleptics:-
Phenothiazines
Clozapine
 Theophylline
 Antimalarials:- chloroquine,mefloquine
 Cardiac anti arrythmics:- lidocaine,disopyramide
 Isoniazid
 Penicillins, fluoroquinolones,metronidazole
 Cyclosporin
 Radiographic contrast
Seizure Precipitants (cont.)

15.  Excitation (too much) :-
– Ionic—inward Na+, Ca++ currents
– Neurotransmitter—glutamate, aspartate
 Inhibition (too little):-
– Ionic—inward CI-, outward K+ currents
– Neurotransmitter—GABA
Cellular Mechanisms of Seizure Generation

16. Antiepileptic Drug
 Drug ↓ frequency/severity of seizures
 Treats symptom of seizures,
underlying epileptic condition
 Goal—maximize quality of life by minimizing seizures and
adverse drug effects

17. Clinical Classification of Antiepileptic Drugs
Seizure type Preferred drugs Alternative
drugs
GTCS Carbamazepine
Sodium valproate
Phenytoin
Phenobarbitone
Lamotrigine
Topiramate
Primidone
Simple focal
seizure
Carbamazepine
Phenytoin
Sod.valproate
Gabapentin,Lamotrigine,T
opiramate,Tiagabine
Zonisamide
Complex focal seizure Carbamazepine
Phenytoin
Sod.valproate
Gabapentin,Lamotrigine,Topi
ramate,Tiagabine
Zonisamide
Absence seizure Sod.valproate
Ethosuximide
Clonazepam
Lamotrigine
Myoclonic seizure Sodium valproate Clonazepam
Lamotrigine
Topiramate

18. Chemical Classification:-
1. Hydantoins: Phenytoin,fosphenytoin
2.Barbiturates: Phenobarbitone, Mephobarbitone
3. Iminostilbenes: Carbamazepine,oxcarbazepine
4. Succinimides: Ethosuximide
5. BZDs: Clonazepam,Diazepam,lorazepam,Clobazam,
5. Aliphatic carboxylic acid derivative: Valproic acid
6. Deoxybarbiturates: Primidone
8. Phenyltriazine:- Lamotrigine, Gabapentin, Vigabatrin
9.Cyclic GABA analogue:- Gabapentin, pregabalin
Newer drugs:-
Topiramate,Zonisamide,Levetiracetam,Tiagabine,Lacosami
de

19. Mechanism of action of different anti-epileptics
Prolongation of
Na+ channel
inactivation
Phenytoin
Carbamazepine
Valproate
Lamotrigine
Topiramate
Zonisamide
Lacosamide
Rufinamide
Facilitation of
GABA mediated
Cl- channel
Opening
Barbiturate
Benzodiazepine
Vigabatin
Gabapentin
Tigabine
Inhibition of T-
type Ca++
channel
Ethosuximide
Trimethadione
Valproate
Decrease of
Excitatory
Neurotransmitt
er
Lamotrigine
Felbamate
Topiramate
Hormone
ACTH
Others
oLevetiracetam
oPregabalin
oMgS04
oAcetazolamide
oKetogenic diet
oVagal nerve
stimulation

20. 1840 1860 1880 1900 1920 1940 1960 1980 2000
0
5
10
15
20
Bromide
Phenobarbital
Phenytoin Primidone
Ethosuximide
Sodium valproate
Benzodiazepines
Carbamazepine
Vigabatrin
Zonisamide
Lamotrigine
Felbamate
Gabapentin
Topiramate Fosphenytoin
Oxcarbazepine
Tiagabine
Levetiracetam
More
Year
AEDs
Antiepileptic drug development

21. • Hydantoin derivative
• One of the most commonly used drug
• Does not produce significant Drowsiness
• Effective against all types of Partial and Tonic clonic
seizures but not absence seizures
Mechanism:-
Phenytoin
Inhibit the generation of repetitive action potentials
Phenytoin
Bind to voltage dependent Na+ channels
(Prolongs the inactivated state) and prevent
further entry of Na+ ions into the neuron.
(Stabilize neuronal membrane )
Therefore, prevent /reduce the
spread of seizure discharges

22. Other mechanism :-
• At high conc. Phenytoin
- reduce Ca2+ influx(during depolarization) into the neurons
Suppresses repetitive firing of neurons & NT
- Reduces glutamate levels
- increases GABA responses
• Pharmacokinetics:-
• Absorption- slowly after oral administration
• Highly bound to plasma proteins
• Metabolism- by Hydroxylation(CYP2C9,CYP2C19)
and glucuronide conjugation, Repeated doses cause
enzyme induction

23. • Exhibits dose dependent elimination through saliva
Phenytoin
At low doses, follow first order kinetics
As the plasma conc. increases
Elimination processes get saturated
Kinetics changes to zero order
(Saturation kinetics)
• Plasma conc. Should be monitored in neonates and in pt
suffering with uremia, liver disease ,hypoprotenaemia
• On I.M. administration-get ppt in muscle cause pain
• Upon I.V. administration-thrombophlebitis

24. A/Es:-
It has narrow therapeutic range(10-20µg/ml)
Acute toxicity:- at plasma conc. beyond 20µg/ml
Manifested by –nystagmus,ataxia,CNS depression,lethergy &
blurred vision
In high dose/I.V.-inj. Cardiovascular collapse, coma
Chronic toxicity:-
• Hypertrophy and Hyperplasia of gum-inhibit collagenase
• Hirsuitism- in female due to ↑ androgens secretion
• Hypersensitivity reactions:-rashes including Stevens-
Johnson syndrome and TEN
• Megaloblastic anemia-
↑demand of Folic acid

25. GUM HYPERTROPHY

26. • Hypoprothrombinemia-Vit-K deficiency
Haemorrhage in the new born of the mother who received
phenytoin during pregnancy –
Treatment:- vit K supplements as prophylaxis should be
given in these mother
• Osteomalacia- Vit-D deficiency due to ↑metabolism of
calciferol
• Hyperglycemia-due to inhibition of insulin secretion
• It also decrease ADH release-polyuria
• Phenytoin in pregnancy- ↑ risk of congenital malformation-
Fetal hydantoin syndrome- presented as cleft palate,cleft lip
& congenital heart disease –these are associated with
formation of toxic epoxide metabolite & also with impaired
DNA synthesis due to folate deficiency

27. cleft palate, cleft lip

28. • Purple glove syndrome:- progressive edema,
discoloration & pain in limb after I.V. pheytoin
extravasation rarely can leads to limb amputation
• Liphodenopathy- pseudolymphoma(resemble
lymphoma but remission occurs automatically after
stoppage of drug)
• CNS effect:- Like virtigo,nausea, Tremors & confusion
• Phenytoin should not be discontinue suddenly-
withdrawal seizures

29. Drug Interaction:-
OC pills,Theophylline, levodopa
Corticosteroid, Doxycycline,Rifampicin
Vit.D,Vit-K, Enzyme Inducer
Disulfiram,Cimetidine,Isoniazide,
Chloramphenicol ↓Metabolism of
Phenytoin
Carbamazepine & Phenytoin /Phenobarbitone - ↑ each other
metabolism
Sodium Valproate Phenytoin – Inhibit Metabolism of
Phenytoin
Phenytoin
Phenytoin

30. Therapeutic Uses
Epileptic uses:-
Effective drugs for all focal seizures(simple & complex)
First choice of seizure prophylaxis in head injury
First choice for Tonic-clonic seizure
Status epilepticus
Non-Epileptics:-
Trigeminal neuralgia
To treat ventricular arrhythmias due to digitalis toxicity
To enhance wound healing
Phenytoin ↑platelet derived growth factors-B & its mRNA from
macrophages enhance wound healing, promote local
angiogenesis

31. -:Contraindication:-
 Bradyarrhythmias
 Pregnancy & lactation
 Absence seizure & Myoclonic seizures

32. Fosphenytoin
 Water soluble Prodrug of phenytoin (Diphosphate -ester)
Active metabolite is phenytoin
 It is available for IM & IV administration
 Antiepileptic effect=phenytoin
Advantages:-
 Less irritating to vein
 Less cardiotoxic
 Safer & better tolerated-infuse 3 times faster than I.V.
phenytoin
Disadvantage:- Expensive

33. • Chemically related to TCA
• MOA:- Same as phenytoin but claim to cause less cognitive
impairment
Pharmacokinetics:-
 Unstable substance (protect from hot/humid condition)
 High lipid solubility-enters brain rapidly
 Therapeutic blood level:-4-12µg/ml
 Induces its own hepatic metabolism(auto induction)
USES:- 1.All focal seizures
2.Tonic-clonic seizures(not effective for absence & myoclonic
seizures)
3.DOC- trigeminal neuralgia
4. Occasionally used in manic depressive pt.
Carbamazepine

34. Adverse effect:-
1.Hepatotoxicity –
2.GIT-stomach irritation, nausea,Vomiting
3.Chronic administration-dose related vertigo, ataxia,
blurred vision ,consciousness alterations, respiratory
depression
4.Toxic doses-breakthrough seizures
5.Water retention & hyponatremia can occur In the elderly
because it enhances ADH action
6.Rare idiosyncreatic aplastic anemia, agranulocytosis &
thrombocytopenia-all pt should have CBC monthly for 3-
4 months
7.Dangerous skin reaction-

35. Drug Interaction:-
OC pills, lamotrigine,
Topiramate, valproate
Enzyme
Inducer
Phenobarbitone,phenytoin
Chloramphenicol ↑Metabolism of
CBZ
 INZ, erythromycin inhibit the metabolism of
carbamazepine
Oxcarbazepine:- (Analogue) more expensive, similar mechanism
of action
Advantages over CBZ:-
1.No auto-induction
2.Less drug interaction
Carbamazepine
Carbamazepine

36. Benzodiazepines Barbiturate
Safest & all most free from
Severe side effects of all
Antiepileptic
Chronic treatment:-
Clonazepam,
Clobazam,
Clorazepate
In status epilepticus:-
Diazepam ,Lorazepam
(DOC)
Very potent anticonvulsant
Significant ADR
Chronic treatment:-
Used as 2nd line drugs
Phenobarbitone DOC:-
•In Pregnancy
• Recurrent febrile
seizures in children

37. Tiagabine:-
 Reversibly inhibits GABA reuptake Transporter-1 (GAT-
1)
 Second line adjunctive
therapy in refractory
partial or secondarily
generalized seizures
 Can worsen absence
epilepsy

38. Vigabatrin:-
Uses:-
 Infantile spasms
 Refractory Complex
Partial seizure
Adverse Effects:-
 Visual toxicity due to
retinal atrophy and
Neuropsychiatric
Symptoms
3-6 days Resynthesize

39. -:Valproate:-
Broad spectrum anti-epileptics
Mechanism:-
 Blockade of sodium channel
 ↑GABA activity by inhibiting GABA transminases
 Inhibition of T-type Ca++ channel
 ↓ release of glutamate in brain
Therapeutic Uses:- Epileptic uses:-
 All types of Generalized & focal seizures
 DOC in idiopathic generalized epilepsy
 DOC myoclonic seizures
 DOC in absence seizures in (adult)-children ethosuximide is DOC
because of hepatotoxic potential of valproate
 DOC in tonic-clonic seizure

40.  DOC atonic seizure
 First line drug in photosensitive epilepsy
Non-Epileptic uses:-
 DOC in bipolar disorder with rapid cyclers
 Prophylaxis of migraine
Pharmacokinetics:-
 Absorption:- Orally rapid
 Plasma protein binding:- Highly (conc. Dependent & nonlinear)
 Metabolism:- liver
 Therapeutic blood levels- 50-150mg/ml
Adverse Effects:-
Idiosyncratic,genetically determined hepatic toxicity
Nausea & vomiting

41. • ↑ appetite leading to weight gain
• Rash
• Alopecia
• Thrombocytopenia
• Endocrine effect- insulin resistance, anovulatory cycles,
amenorrhea, polycystic ovary syndrome
• Bone marrow suppression- rare
• Fatal acute pancreatitis
• Teratogenic effects especially neural tube defects
Gabapentin:- ↑GABA level(brain) ↓Glutamate level (brain)
Only modest efficacy in partial & secondary generalized
tonic-clonic seizures
 Has analgesic properties

42. Ethosuximide
 Block T-type Ca++ channels
 First choice in Absence seizure –children (below 3yr.)
 Not use in other seizures
 T1/2-60 hrs
 No drug interaction
 Sedation common side effects
 Characterized side effects- hemeralopia (Photophobia)
 Therapeutic Blood level-40-100 µg/ml

43. Very effective ,broad spectrum & well tolerated
DOC-focal seizure in elderly
Less incidence of congenital malformation(preferred
during pregnancy)
Use in manic depressive psychosis
Side effect-rash (rarely cause SJ-syndrome)
Zonisamide
• T-type Ca++ channel blocked also process weak CA-inhibiting
property
• Neuroprotective action
• Juveniles myoclonic epilepsy
• Main side effects- sedation, metabolic acidosis, renal stone
Lamotrigine

44. Glutamate Receptor blockers
Felbamate:-
o potent ,very effective against all seizures
o Blocks NMDA receptors & voltage gated Ca++ channels
o No effects on GABA receptors
o Has neuroprotective effect on hypoxic-ischemic injuries
uses:- secondary generalized seizure
Topiramate
Very potent, chemical relatives of fructose has several
action
Blocked of glutamate receptors
Blocked of voltage gated Na+ channels
↑ GABA activity at GABAA receptors

45. • Therapeutic uses:-
 Partial onset & secondarily generalized tonic clonic
seizures
 Primary GTCS
SE:- nausea, appetite subpression –weight loss
Renal stone-due to CA-Inhibition.
RX- drink plenty of fluids
Others:-
 ACTH:- acts by modulating GABA receptors (open Cl-
channels )
 Levetiracetam- inhibit Ca++ release
 Pregabalin- GABA analogue.(anticonvulsant+ analgesic
+anxiolytics)

46.  Acetazolamide:- CA-I (use:- epileptic women who
experience seizures exacerbation at the time of menses)
 MgS04- DOC in controlling Seizure in eclampsia
 Newer drugs:-
Retigabine:- (K+ channel facilitator )
Partial onset seizures in adult

47. Status Epilepticus
• Continuous repetitive, discrete seizures with impaired
consciousness without recovery
• Medical emergency & should be treated immediately with
i.v. route- to prevent permanent brain damage
• Last for more than 30min
• Hypoglycemia & hypocalcemia-in children
Treatment:- (General supportive measures)
1. Hospitalized the pt
2. Maintain airway, fluid & electrolyte balance
3. Administer oxygen
4. Hypoglycemia-iv 50ml of 50% dextrose
 Apart from General measure drugs are used one by one till the
convulsions are controlled
Status Epilepticus

48. Slow I.V.-Lorazepam-4mg (0.1mg/Kg ) at a rate of 2mg/min-
(repeat if no response after 10 min)
Or
Slow i.v. diazepam-10mg at a rate of 2mg/min- (repeat if no response after 10 min)
Watch for hypotension & respiratory depressant
Seizure Continue
If Seizure Stop No further treatment
Fosphenytoin 20mg/kg I.V. at 150 mg/min in normal saline
if not available
Phenytoin 20mg/Kg IV.slow infusion in normal saline
Monitor cardiac
rhythm & BP
Seizure Continue
If Seizure Stop No further treatment
Phenobarbitone 10-15mg/Kg IV. At a rate of 60mg/min Watch for respiratory
depressant
Seizure Continue Admit to ICU
IV anesthesia with propofol /midazolam/Phenobarbitone- prevent acidosis & rhabdomyosis

49. 1.Classify anti-epileptic drugs. Discuss the mechanism of action, uses
and adverse effects of phenytoin (2019) 10M
2.Discuss the treatment of Status Epilepticus (5M) 2018,2016,2011
3.Describe briefly the therapeutic uses and adverse effect of
Phenytoin (4M) 2014
4.Discuss the Pharmacotherapy of following disease condition-
Grand mal epilepsy (3M)