MED 7721: CLINICAL NEUROLOGY

PHARMACOTHERAPY OF CNS
INFECTIONS AND EPILEPSY II
ELEUS HILGREJA J. FAJARDO, M.D., MHA
FPPS, FPPSAP
2. GABA A RECEPTOR ANTAGONISTS:

CLONAZEPAM:
1. First benzodiazepines to be used for epilepsy
2. It is used in the treatment of myoclonus, especially in
patients with concomitant anxiety disorder
3. It has higher affinity for the GABA-A receptor site than
diazepam and binds to GABA-A receptors that do not bind
with other benzodiazepines
4. It may also have some action on sodium-channel
conductance
 CLONAZEPAM. . . .
5. Its oral bioavailability is 80% with half-life of 1-4 hours but
maybe delayed to 8 hour
6. It is highly lipid soluble and can cross the BBB rapidly
7. It is acetylated in the liver and its metabolism is dependent on
the genetic acetylator function
8. Its elimination half-life ranges from 20 – 80 hours and only
0.5% is eliminated in the kidneys
9. Withdrawal from clonazepam can induce status epilepticus
10. It can be given through IV or rectally
11. Its major adverse effect is sedation, even in low doses
 CLONAZEPAM. . . . .
12. Children tolerate this medication than adults, that is why
they are more often used by pediatricians
13. It is abailable in 0.5, 1 & 2 mg tablets and as an IV solution
14. Usual starting dose: 0.25 – 4 mg OD or BID, but slow
titration is mandatory

 PHENOBARBITAL:
1. Most common prescribed antiseizure drug
2. It is a very potent anticonvulsant with broad spectrum of
action
3. However, its use is limited because of its adverse effects
 PHENOBARBITAL . . . .
4. It is a free acid and insoluble in water
5. It has a direct action on GABA-A receptors by binding to the
barbiturate binding site that prolongs the duration of chloride
channel opening
6. It also reduces sodium and potassium conductance and
calcium influx
7. It depresses glutamate excitability
8. Ethanol increases the rate of phenobarbital absorption
9. Mainly absorbed in the S.I.
10. Plasma protein binding is 40 – 60%
11. A change in pH causes a shift of the drug between
compartments, therefore acidosis increase levels in tissue
compartment
 PHENOBARBITAL. . . . .
12. After IV administration, phenobarbital is quickly distributed
to highly vascular organs, except the BRAIN. Thereafter, it is
distributed evenly and 6-12 minutes after administration,
13. It penetrates the brain much faster during status epilepticus
because of increased blood flow and acidosis
14. It has a very long elimination half-life especially in infants
15. It is metabolized in the liver to p-hydroxy phenobarbital
which is excreted as a glucuronide conjugate
 PHENOBARBITAL . . . .
16. It has extensive resorption, which is enhanced by acidification
of the urine
17. Its metabolism is inhibited by phenytoin, valproate,
dextropropoxyphene
18. Rifampin decreases its level
19. It increases metabolism of estrogen, steroids, warfarin,
carbamazepine, diazepam, clonazepam and valproate
20. Its effect is unpredictable
21. It is effective in a wide variety of seizures and is currently the
cheaper AEDs
22. It is still the first-line drug for treatment of status epilepticus
 PHENOBARBITAL . . . . .
23. Its most important adverse effects are cognitive and behavior
alteration
24. Long term use maybe associated with coarsening of facial
features, osteomalacia and Dupuytren contractures
25. Preparation: Tablet form in 15, 30, 50, 60 and 100 mg; elixirs
at 15 mg/ml and injections in 200 mg/ml
26. Usual starting dose is 30 – 60 mg OD, but can be titrated up
to 240 mg/day
 3. ANTISEIZURE DRUGS WITH POTENTIAL GABA
MECHANISM OF ACTION

A. VALPROATE:
 Drug of choice for primary generalized epilepsies
 Has also been used for partial seizures
 Its antiepileptic property was discovered by accident
when it was used as a solvent for the experimental
screening of new AEDs
 MOA is not certain but it was noted to enhance GABA
function, although it was observed only in high
concentration
 Its structure is similar to endogenous fatty acids
 It is slightly soluble in water but highly soluble in organic
solvents
 Peak plasma level after oral administration is reached in
minutes – 2 hours
 It is 85-95% bound to plasma protein but its ability to bind to
plasma decreases at higher doses in pregnant women, in
renal and hepatic diseases
 It reaches the brain by an active transport process that is
saturable
 It is metabolized in the liver by beta-oxidation followed by
glucuronidation
 Less than 4% is excreted in the urine
A. VALPROATE . . . . .
 Some metabolites are responsible for adverse effects, especially
the 4 –ene metabolite, which cause hepatic toxicity
 It is a potent AED, effective against a wide range of seizure
types
 It is the drug of choice in idiopathic generalized epilepsy
 It is the drug of choice for juvenile myoclonic epilepsy and
other types of myoclonus
 It is also the 1st line drug in photosensitive epilepsy and Lennox
Gastaut syndrome
A. VALPROATE . . . .
 It is available as 125, 250 & 500 mg delayed-release
tablets; 125 and 250 mg sprinkle capsules; 500 mg
extended-release tablets; 250 mg/5 ml syrup and parental
preparation for IV injection
 The usual starting dose is 250 mg/day with a maintenance
dose of 500 – 1500 mg/day given TID
 Usual dose in children is 20 mg/kg/day and maintenance
dose is 40 mg/kg/day
 IV valproate is administered as a 60-minute infusion, with
a rate that does not exceed 20 mg/min
 Data shows that children exposed to the drug during
pregnancy has decreased IQs at age of 6 as compared to
other AEDs
A. VALPROATE . . . . .
 It has adverse endocrine effects, including insulin
resistance and change in sex hormone levels, causing
anovulatory cycles, amenorrhea and polycystic ovary
syndrome
 Bone marrow suppression with neutropenia and allergic
rashes maybe present, but very rare
 Acute pancreatitis is rare, but potentially fatal but can be
reversed with withdrawal of the drug
 The most serious idiosyncratic adverse effect is
hepatotoxicity, especially in children < 2 years of age and
in those taking multiple AEDs
 STATUS EPILEPTICUS
A neurological emergency requiring immediate evaluation and
management to prevent significant morbidity or mortality
DEFINITION:
 Previously, was defined as a seizure with a duration equal to or
greater than 30 minutes or a series of seizures in which the patient
does not regain normal mental status between seizures.

 In 2012, the Neurocritical Care Society guidelines revised the

definition to a “seizure with 5 minutes or more of continuous
clinical and/or electrographic seizure activity or recurrent seizure
activity without recovery between seizures.”
 TREATMENT OF STATUS EPILEPTICUS
1. The condition should be addressed quickly and in an organized
manner, with simultaneous assessment/management of airway,
breathing and circulation, while administering AED treatment
2. The primary goal of management is to definitely abort seizure
activity as rapidly as possible, while supporting the patient’s
cardiovascular and respiratory status
A. Position the head to maintain open airway
B. Provide dupplemental oxygen
C. Initiate monitoring of the heart rate, respiratory rate, blood
pressure and oxygen saturation
D. Obtain vascular access
E. Check a bedside blood glucose and treat hypoglycemia if
present. If thiamine deficiency is a possibility, administer
thiamine before dextrose
F. Benzodiazepines are the antiepileptic drug of choice for
emergent control
F.1. Lorazepam is preferred because of its rapid onset of action
Dose: 0.1 mg/kg IV, not to exceed 2 mg/minute
F.2. If Lorazepam is not available, Diazepam, at 0.15 mg/kg IV
up to a maximum of 5 mg per minute
A repeat dose maybe administered after 3-5 minutes if
seizures do not resolve after the first dose
The drug can be administered via IM, rectal, nasal or buccal
route if vascular access is not available
F.3. Antiepileptic drugs should be administered together with
benzodiazepines . Choices include:
• Fosphenytoin at 20 mg/kg
• Phenytoin equivalents (PE) up to 100 – 150 PE/min
• Phenytoin at 20 mg/kg up to 25 – 50 mg/min
• Valproic acid at 30 mg/kg up to 10 mg/kg/minute
F.4. If the second dose of benzodiazepines does not abort
seizures, then treat as refractory status epilepticus
• Should be treated with a continuous infusion of an
antiepilecptic drug from the following choices:
• IV infusion of midazolam, pentobarbital, thiopental or
propofol
 References:
1. Katzung, Textbook of Pharmacology, 13th Ed

2. https://www.ncbi.nlm.nih.gov/books/NBK430686/#:
~:text=History%20and%20Physical,
activity%20without%20recovery%20between%20seiz
ures.

3. https://emedicine.medscape.com/article/1164462-
treatment#d11