Anti-Epileptics (General, Phenytoin and Phenobarbitol)

Question 1

Define a “Seizure?”

Answer 1

A seizure is a paroxysmal (or sudden) event due to abnormal or excessive synchroous neuronal activity in the brain.

Question 2

What is “Epilepsy?”

Answer 2

Recurrent seizures due to some underlying chronic process .

Question 3

What is thought to be the mechanism behind epilepsy?

Answer 3

Disturbances of neuronal excitability, such as direct activation of glutamate or antagonizing the effects of GABA.

Question 4

What part of the brain is it thought that seizures arise from?

Answer 4

Thought to be from the cerebral cortex.

Question 5

Two general concepts of a seizure are:

Answer 5

Partial (focal) seizures. in which the seizure begins focally at a cortical site, and generalized (diffuse) seizures, where the seizures begins in both hemispheres from the outset.

Question 6

How does the Na channel blocker mechanism generally work with anti-epileptics?

Answer 6

It will promote the inactive state of the voltage gated Na channels, thus it will reduce the time of the sustained, repeated firing of the neurons.

Question 7

How does the Glutamate/GABA MOA work in terms of anti-epileptics?

Answer 7

The idea is to diminish glutamate (excitatory) and enhance GABA (inhibitory) synaptic inhibition.

Question 8

How does the T-type Ca channel inhibition work for MOA of anti-epileptics? What kind of seizures are these used for?

Answer 8

It’s used for tx of absence seizures, idea is to shut down the voltage gated Ca 2+ channels so that the T-type Ca currents are shut down

Question 9

Name the 4 drugs that block the voltage gated Na channels?

Answer 9

Phenytoin, Carbamazepine, Lamotrigine, and Valproate.

Question 10

Name the 4 voltage gated Ca channel blockers (pre-synaptic, NOT the T type?)

Answer 10

Ethosuximide, Lamotrigine, Gabapentin and Pregabalin.

Question 11

Name the 12 anti-epileptic drugs?

Answer 11

Benzodiazapine, Carbamazepine, Oxcarbamazepine, Ethosuximide, Felbamate, Gabapentin, Pregabalin, Lamotrigine, Levetiracetam, Phenobarbitol (Primidone), Phenytoin (Phosphenitoin), Topiramate, Valproate (Divalproex).

Question 12

Which are the 2 anti-epileptics that ARE highly protein bound?

Answer 12

Phenytoin and Valproic acid, the rest are NOT highly bound to plasma.

Question 13

What is special about Phenobarbitol administration?

Answer 13

Comes oral, IV and IM, the IV formulation is useful in tx of status epilepticus.

Question 14

How is Phenobarbitol metabolized? Half life?

Answer 14

25% excreted unchanged, but 75% metabolized by 2C9. Long half life (1-5 days in adults, less in infants).

Question 15

How does Primidone compare to Phenobarbitol?

Answer 15

Primidone is oral only, it’s hepatically metabolized to phenobarbitol and PEMA both of which have anti seizure effects. Half life is much shorter (5-16 hrs).

Question 16

What is the MOA of Phenobarbitol?

Answer 16

Basically to hyperpolarize the cell. It does this through potentiating the effects of GABA receptors. Phenobarbitol binds to the allosteric sites of the GABA receptors, and when GABA binds and opens the receptor, Phenobarbital KEEPS THE GABA RECEPTOR OPEN, allowing more Cl- to pour into the channel and inducing hyperpolarization.

Question 17

In order for Phenobarbitol to work, what neurotransmitter is essential to be present?

Answer 17

Phenobarbitol is binds to an allosteric site of the GABA receptor, it REQUIRES GABA to bind to its receptor to open the channel. Phenobarbitol just keeps the channel open longer.

Question 18

What are the 3 uses for Phenobarbitol in terms of Tx?

Answer 18

Used for Partial (focal) seizures, generalized tonic-clonic seizures (esp in children), and alternative tx for status epilepticus.

Question 19

AE’s of phenobarbitol? AE’s of IV phenobarbitol?

Answer 19

HS rxns (rash, hepatotox and bone marrow tox). Sedation (phenobarbitol is used in some sleeping meds), depression, memory loss (cognitive impairment), hyperactivity in kids and pt's in acute pain, agitation and confusion in the elderly.
IV: Respiratory depression ESP when used after BENZO's. Also hypotension.

Question 20

What is the first and second line tx of status epilepticus and what is a potential DDI of these 2 drugs?

Answer 20

Benzo’s are first line, Phenobarbitol (IV) is second line. If PhenoB is administered after Benzo’s this increases the risk of resp depression. Phenytoin is also a first line for status epilepticus.

Question 21

CYP’s and Phenobarbitol?

Answer 21

Metabolized by 2C19, and POTENT CYP INDUCER!

Question 22

What is the difference between Phenytoin and Fosphenytoin?

Answer 22

Fosphenitoin is formulated so that it can be administered in a soluble form IV, once in the blood it turns into phenytoin. Phenytoin also can be IV but very prone to precipitate out, hence Fosphenytoin. Also, IM variant of Phenytoin (not recommended, unpredictable absorption). Fosphenytoin is $$$$$ so IV Phenytoin still used in hospital.

Question 23

What is the kinetics of phenytoin and what are 2 other drugs that share this kinetics? What is special about this kind of kinetics? How is half life determined for this kind of kinetics?

Answer 23

Phenytoin display 0 order kinetics, alcohol and asprin also demonstrate this. Zero order kinetics means it is non-linear, that once the enzymes that metabolize the drug is saturated, the level of the drug in the body will spike dramatically because until the enzyme finishes the metabolism one molecule it won’t move onto the next. Half life therefore is determined by the conc in the plasma.

Question 24

What is special to note about Phenytoin in terms of Bioavailability and distribution?

Answer 24

Wide range of bioavailibility 20-90%, highly plasma bound so patient’s albumin levels become important, as well as hyperbilirubenimia (will decrease available albumin).

Question 25

Metabolism of Phenytoin?

Answer 25

2C9 and 2C19 (major), 3A4 minor. This is also a strong INDUCER of 2B6, 2C and 3A family.

Question 26

How is phenytoin generally administered?

Answer 26

IV or oral loading doses (regardless of liver failure, loading dose is determined by Vd not clearance), must monitor blood for conc to determine half life. Steady state is dependent on clearance. Renal failure pt’s need lower dose due to hypoalbuminemia.

Question 27

What is the MOA of Phenytoin?

Answer 27

Na channels have 2 gates. When depolarized both gates open to trigger an AP down the cell, and soon after the bottom gate closes (the top remains open) so that the AP has time to propogate – this is called the refractory or inactive Na channel. The top gate then closes and repolarization is complete, so next cycle of depol both gates open again and cycle continues. Phenytoin will bind to the Na channels in its refractory/inactive state, prolonging the inactive state and preventing the continual firing of seizures.

Question 28

What is necessary for Phenytoin to work?

Answer 28

They need the Na channels to be active, so it is both voltage dependent and use dependent. This is advantageous because now Phenytoin will only bind to the Na channels that are firing, not the ones that are quiet.

Question 29

How does Phenytoin related to glutamate and GABA?

Answer 29

Probably has some effect in decreasing glutamate release and increasing GABA. This is a minor MOA.

Question 30

Tx uses of Phenytoin?

Answer 30

Partial and complex (focal and diffuse), generalized tonic-clonic, status epilepticus (BUT slow IV infusions due to 0 order kinetics so slow onset).

Question 31

Besides seizures when can Phenytoin be used?

Answer 31

Can be used for ventricular arrythmias caused by digitalis tox.

Question 32

What kind of patients are especially prone to the rare but fatal HS tox of phenytoin? What are these tox?

Answer 32

Skin rash, SJS, TEN, hepatotox, agranulocytosis, Asian patients with HLA B*1502 are more prone to these effects.

Question 33

What are IV related AE’s of phenytoin?

Answer 33

Hypotension, Bradycardia –> Dysrythmias, Extravasation (this drug has pH of 12 so extremely damaging in that case), purple glove syndrome (hand turns purple due to vascular issues).

Question 34

Cosmetic AE’s of Phenytoin?

Answer 34

Gingival hyperplasia, hirsuitism, coarsening of facial features.

Question 35

Dose related AE’s of phenytoin?

Answer 35

DIPLOPIA should alert physicians of AE, also nausea, nystagmus, dizziness, cognitive impairment, ataxia/tremors/movement disorders, sedation at high doses, suicidal ideations (this is common in all anti-epileptics).

Question 36

Delayed AE’s of Phenytoin?

Answer 36

Peripheral neuropathy, atrophy of cerebellum.

Question 37

Endocrine AE’s of phenytoin?

Answer 37

Vit D deficiency (osteomyalgia can result), folic acid def (megaloblastic anemia can result).

Question 38

Preggo and Phenytoin?

Answer 38

Cat D, mothers need to be given folic acid (the entire time) and vit K (last month) during preggo.

Question 39

Why can Phenytoin show decreased T4 levels?

Answer 39

Phenytoin binds to TBG which can present as a false decreased T4 levels.

Question 40

DDI’s of phenytoin?

Answer 40

Phenytoin is metabolized by 2C9 and 19 and 3A4 so anything that messes with that. Phenytoin also induces 2B6, 3A and 2C family so other drugs that uses those CYPs are messed with. Anything that binds to albumin like sulfonamides will increase blood levels of phenytoin.