John is a 35- year-old male who was referred to a neurologist by his doctor.

About 5 years ago, he

suffered a concussion as a result from a fall from a ladder. John works as a painter. John did not
experience any further neurological problems until about 2 weeks ago when he reported
experiencing a strange sensation, followed by a tonic-clonic seizure lasting around a minute. The
neurologist diagnoses John with epilepsy and initiates treatment with antiepileptic drug therapy.
John is started on a dose of phenytoin PO (oral tablets, 300 mg) daily. After several weeks, John has
another tonic-clonic seizure and phenobarbitone (150 mg PO) is added to the treatment program.
About 4 months after starting the treatment program, John complains to his regular doctor that his
gums seem to be increasing in size and covering more of his teeth. He thinks it might be related to
his medications and makes an appointment to see his neurologist.

1. What factors are known to be related to causing secondary epilepsy? Which factors relate to
John’s case?
The major reasons behind epilepsy are infections of central nervous system (CNS).
CNS prompted by secondary progressive signals of neuronal excitability which cause
development of seizures. There are many factors which promote seizure including
medications, genetic factors, electrolyte abnormalities, sleep state, infections, brain
inflammation, or injury (Huff & Murr, 2020). Moreover, secondary epilepsy happens
at one part of the brain and slowly it develops two sides of the cerebrum.
As such, the individual initially has a central seizure, trailed by a generalized
seizure (Types of Seizures | Epilepsy | CDC, 2020).
The factor which relates to John’s case is his concussion which he experienced
after falling from a ladder. That fall has led injury to his brain which resulted into
epilepsy.

2. ‌Discuss the mechanism of action of phenytoin and phenobarbitone (discuss what happens at
the molecular target level and how this reduces the incidence/frequency of seizures).

Phenytoin is a hydantoin derivative, a first-generation anti-convulsant drug that is effective in

the treatment of generalized tonic-clonic seizures, complex partial seizures, and status
epilepticus without significantly impairing neurological function. 
Phenytoin works by blockade of voltage-dependent membrane sodium channels responsible
for increasing the action potential. Through this action, it obstructs the positive feedback that
sustains high-frequency repetitive firing, thus preventing the spread of the seizure focal point
(Gupta & Tripp, 2020)
How does Phenytoin affect the brain?
Brain cells need to work (fire) at a certain rate to function normally. During a seizure, brain cells
are forced to work much more rapidly than normal. Phenytoin helps prevent brain cells from
working as fast as a seizure requires them to. The cells are prevented from all firing together in an
uncontrolled surge, so seizures can be stopped when they are just beginning.

Usually there is little or no change in the normal functions of brain cells when standard amounts of
phenytoin are taken. (Phenytoin, n.d.)
 Phenobarbital increases the amount of time chloride channels are open, consequently
depressing the central nervous system. This action occurs by acting on GABA-A receptor
subunits. When phenobarbital binds to these receptors, the chloride ion gates open and stay
open, allowing a steady flow of these ions into neuronal cells.[1] This action hyperpolarizes
the cell membrane, increasing the action potential threshold. This increase in action
potential is the reason why this drug is effective in the treatment of seizures. 
(Lewis & Adams, 2021)
The primary action of phenobarbital is to enhance the inhibitory actions of gamma-
aminobutyric acid (GABA) on neurons.
Phenobarbital is useful in controlling focal aware and focal impaired awareness seizures
and generalized tonic-clonic seizures in patients of all ages. It has traditionally been
considered the first choice to treat neonatal seizures (seizures in newborn infants). Most
studies have found that phenobarbital controls these seizures in about one-third of the
infants.
Phenobarbital also has been widely used to prevent recurrent febrile seizures (seizures
accompanying a high fever in infants or young children). Because 2 days or more may be
required to achieve a high enough level of medication in the blood to control seizures,
giving phenobarbital after a fever begins will not be effective. Instead, it must be given
daily. One study found that 4% of children treated with an adequate daily dose had a
repetition of these seizures, compared to 20% of untreated children. Because febrile
seizures usually cause no lasting harm, however, most children should not be given
medication for them.
(phenobarbital and phenytoin completely controlled them in 43% of patients, compared to
48% for Carbamazepine.) 
One-third of those who continued to take phenobarbital for 18 months had complete control
of their partial seizures, compared to nearly two-thirds of those who took carbamazepine.
(Phenobarbital, n.d.)
3. Which medication could be responsible for John’s gums increasing in size? Discuss the
common adverse reactions of John’s medications.
One of the main drugs associated with GO is the antiepileptic
phenytoin, which affects gingival tissues by altering extracellular
matrix metabolism. It is estimated that about 30 to 50% of
patients taking phenytoin develop significant gingival
alterations 
Long-term side effects
Some other side effects only appear after a person has been using phenytoin for a number
of months or years. They are usually, but not always, related to taking high doses. The most
common ones affect appearance:

 overgrowth of the gums

 excessive hair on the face or body
 acne
 coarseness of facial features

Overgrowth of the gums (gingival hyperplasia) is more common in children than in adults.
It can be reduced by vigorous brushing, daily flossing, and regular visits to the dentist, who
may recommend additional treatments. If phenytoin is stopped, the gum problems won’t get
worse, and in some cases will go away within a few months.
(Phenytoin, n.d.)

4. Why should John be advised to avoid alcohol when taking his medications? Discuss the
mechanism of action of alcohol and how these mechanisms interfere with the actions of Anti-
epileptic drugs

Patients with alcohol withdrawal seizures represent another group of patients who may be
discharged after appropriate treatment and a period of observation. Treatment of alcohol
withdrawal seizures deserves special mention since episodic treatment with lorazepam has shown to
decrease the risk of recurrence (Huff & Murr, 2020).

Phenobarbital can also be used to relieve insomnia and apprehensiveness, although

addiction is a point of concern when using phenobarbital for insomnia. This drug is also
useful for benzodiazepine and alcohol withdrawal treatment due to its anti-seizure
properties and sedative effect. The syndrome resulting from alcohol withdrawal has a better
clinical outcome when treated with benzodiazepines, according to significant evidence-
based studies. (Lewis & Adams, 2021)

Problematic compounds may cause seizures either acutely or on withdrawal:

Their use may reduce effectiveness of antiepileptic drugs, or may simply
promote and enhance chaotic lifestyles. Any or all of these factors may worsen
seizure control or even directly cause seizures. (Leach et al., 2012)

Acute effects.  Acute alcohol ingestion quickly increases glutamate binding to N-

methyl-D-aspartate (NMDA) receptors (Hughes, 2009), and potentiates the γ-
aminobutyric acid (GABA) effects (Hughes, 2009), particularly in receptors with
delta-subunits (Rogawski, 2005). The regional distribution of these subunits
explains why the cerebellum, cortical areas, thalamic relay circuitry, and
brainstem are the main centers that mediate the intoxicating effects of alcohol.

Withdrawal effects.  During acute withdrawal, particularly with disturbed sleep,

the proconvulsant effect may be sufficient to induce seizures in susceptible
patients (Hillbom et al., 2003). Such seizures occur 6–48 h after cessation of
drinking, sometimes with status epilepticus. All age groups are at risk, including
the elderly (Kraemer et al., 1999). Chronic GABA potentiation may change
subunit expression, allowing additional hyperexcitation on alcohol withdrawal
and increasing the seizure risk (Hillbom et al., 2003).
Furthermore, alcohol withdrawal increases the QT interval, maximal at 6–48 h
after stopping, and thereby increases the risk of sudden unexpected death in
epilepsy (SUDEP). In addition, the theoretical risk of kindling may induce seizure
activity by withdrawal via neurologic changes that predispose to seizure
induction by future diminishing stimuli (Pinel, 1980). (Leach et al., 2012)

Effect of alcohol on antiepileptic drugs.  Liver enzyme induction occurs rapidly

with alcohol, reducing the serum level of some AEDs. Although data are more
extensive on the older drugs, there is a clear risk of such effects on some of the
newer drugs undergoing hepatic metabolism. In addition, alcohol may increase
the side effects usually attributed to AEDs.

Types of Seizures | Epilepsy | CDC. (2020, September 30). Www.cdc.gov.

https://www.cdc.gov/epilepsy/about/types-of-
seizures.htm#:~:text=Secondary%20generalized%20seizures%20begin
%20in
(Lü et al., 2016)

Lü, Y., Liu, S., & Yu, W. (2016). The causes of new-onset epilepsy and seizures in
the elderly. Neuropsychiatric Disease and Treatment, 12, 1425.
https://doi.org/10.2147/ndt.s107905
Huff, J. S., & Murr, N. (2020). Seizure. PubMed; StatPearls Publishing.
https://www.ncbi.nlm.nih.gov/books/NBK430765/
Lewis, C. B., & Adams, N. (2021, May 9). Phenobarbital. PubMed; StatPearls
Publishing. https://www.ncbi.nlm.nih.gov/books/NBK532277/
Gupta, M., & Tripp, J. (2020). Phenytoin. PubMed; StatPearls Publishing.
https://www.ncbi.nlm.nih.gov/books/NBK551520/

‌Corrêa, J. D., Queiroz-Junior, C. M., Costa, J. E., Teixeira, A. L., & Silva, T. A. (2011).
Phenytoin-Induced Gingival Overgrowth: A Review of the Molecular,
Immune, and Inflammatory Features. ISRN Dentistry, 2011, 1–8.
https://doi.org/10.5402/2011/497850
Phenytoin. (n.d.). Epilepsy Foundation. Retrieved April 12, 2022, from
https://www.epilepsy.com/medications/phenytoin#:~:text=Phenytoin
%20helps%20prevent%20brain%20cells%20from%20working%20as

‌Phenobarbital. (n.d.). Epilepsy Foundation.

https://www.epilepsy.com/medications/phenobarbital/advanced#:~:text=T
he%20primary%20action%20of%20phenobarbital

‌Leach, J. P., Mohanraj, R., & Borland, W. (2012). Alcohol and drugs in epilepsy:
Pathophysiology, presentation, possibilities, and
prevention. Epilepsia, 53(s4), 48–57. https://doi.org/10.1111/j.1528-
1167.2012.03613.x

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