1. Antiseizure drugs: partial and generalized tonic-clonic seizures
Domina Petric, MD

2. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Phenytoin I.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

3. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Phenytoin
Phenytoin is the oldest nonsedative antiseizure drug.
Phenytoin is a diphenyl-substituted hydantoin.
It has much lower sedative properties than compounds with alkyl substituents at the 5 position.
A more suluble prodrug of phenytoin is fosphenytoin.
Fosphenytoin is available for parenteral use.
This phosphate ester compound is rapidly converted to phenytoin in the plasma.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

4. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Mechanism of action
Phenytoin alters:
Na+, K+, and Ca2+ conductance
membrane potentials
concentrations of amino acids
concentrations of the neurotransmitters norepinephrine, acetylcholine and γ-aminobutyric acid (GABA)
Katzung, Masters, Trevor. Basic and clinical pharmacology.

5. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Mechanism of action
Phenytoin blocks sustained high-frequency repetitive firing of action potentials.
Phenytoin also blocks the persistent Na+ current.
This drug paradoxically causes excitation in some cerebral neurons.
Phenytoin decreases the synaptic release of glutamate and enhances the release of GABA.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

6. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Mechanism of action
At therapeutic concentrations, the major action of phenytoin is to block Na+ channels and inhibit the generation of rapidly repetitive action potentials.
Presynaptic actions of glutamate and GABA release probably arise from actions other than those on voltage-gated Na+ channels.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

7. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Clinical use
PARTIAL SEIZURES
GENERALIZED TONIC-CLONIC SEIZURES (both primary and secondary)
Katzung, Masters, Trevor. Basic and clinical pharmacology.

8. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Pharmacokinetics
Absorption of phenytoin sodium from the GI tract is nearly complete in most patients.
Absorption after im. injection is unpredictable.
Fosphenytoin is well absorbed after im. administration.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

9. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Pharmacokinetics
Phenytoin is highly bound to plasma proteins.
In uremia and hypoalbuminemia the percentage of the drug that is bound decreases and total plasma level too.
Drug concentration in cerebrospinal fluid is proportionate to the free plasma level.
Phenytoin accumulates in brain, liver, muscle and fat.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

10. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Pharmacokinetics
Phenytoin is metabolized to inactive metabolites that are excreted in the urine.
Only a very small proportion of the dose is excreted unchanged.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

11. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Pharmacokinetics
The elimination of phenytoin is dose-dependent.
At very low blood levels, phenytoin metabolism follows first-order kinetics.
As blood levels rise within the therapeutic range, the maximum capacity of the liver to metabolize phenytoin is approached.
Further increases in dosage may produce very large changes in the drug concentration.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

12. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Pharmacokinetics
The half-life varies from 12 to 36 hours.
Average is 24 hours for most patients in the low to mid therapeutic range.
Higher the concentration, longer the half-life.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

13. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Therapeutic levels
The therapeutic plasma level of phenytoin for most patients is between 10 and 20 mcg/mL.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

14. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Dosage
A loading dose can be given either orally or intravenously (fosphenytoin).
Start oral dose is 300 mg/day.
If seizures continue, higher doses are usually necessary: dose increment is by mg in adults.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

15. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Dosage
A common clinical error is to increase the dosage directly from 300 mg/day to 400 mg/day because of toxicity!
Start dose for children is mg/kg/day.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

16. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Drug interactions
Related to protein binding and metabolism.
Phenytoin is 90% bound to plasma proteins.
Other highly bound drugs (phenylbutazone, sulfonamides) can displace phenytoin from its binding site.
Such displacement may cause a transient increase in free drug.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

17. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Drug interactions
A decrease in protein binding (hypoalbuminemia) results in decrease in the total plasma concentrations of drug, but not the free concentration.
The protein binding of phenytoin is decreased in the presence of renal disease.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

18. Interference with laboratory tests
Phenytoin has an affinity for thyroid-binding globulin.
The most reliable screening test of thyroid function in patients taking phenytoin is measurement of thyroid-stimulating hormone (TSH).
Katzung, Masters, Trevor. Basic and clinical pharmacology.

19. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Toxicity
Nystagmus and loss of smooth extraocular pursuit movements occur early.
Diplopia and ataxia are the most common dose-related adverse effects requiring dosage adjustment.
Sedation usually occcurs only at higher levels.
Gingival hyperplasia, hirsutism.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

20. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Toxicity
Long-term use is associated in some patients with:
coarsening of facial features
mild peripheral neuropathy: diminished deep tendon reflexes in lower extremities
abnormalities of vitamin D metabolism, osteomalacia
low folate levels and megaloblastic anemia
Katzung, Masters, Trevor. Basic and clinical pharmacology.

21. Idiosyncratic reactions
Relatively rare.
Skin rash, fever, severe and exfoliative skin lesions (rarely).
Lymphadenopathy.
Agranulocytosis rarely.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

22. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Carbamazepine
II.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

23. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Carbamazepine
Carbamazepine is a tricyclic compound effective in treatment of bipolar depression.
Ureide moiety (-N-CO-NH2) in the heterocyclic ring is present in most antiseizure drugs, also in carbamazepine.
Spatial conformation is similar to that of phenytoin.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

24. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Mechanism of action
Carbamazepine shows activity against maximal electroshock seizures.
It blocks Na+ channels at therapeutic concentrations.
It also acts presynaptically to decrease synaptic transmission.
Potentiation of a voltage-gated K+ current has been also described.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

25. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Clinical uses
Carbamazepine is not sedative in its usual therapeutic range.
Indications:
partial seizures
generalized tonic-clonic seizures
trigeminal neuralgia
mania in some patients with bipolar disorder
Katzung, Masters, Trevor. Basic and clinical pharmacology.

26. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Pharmacokinetics
Peak levels after almost complete absorption in most of the patients are usually achieved 6-8 hours after administration.
Slowing absorption by giving the drug after meal helps the patient tolerate larger total daily doses.
Distribution is slow.
Volume of distribution is 1 L/kg.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

27. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Pharmacokinetics
The drug is approximately 70% bound to plasma proteins.
Carbamazepine has a very low systemic clearance of approximately 1 L/kg/day at the start therapy.
The drug has a notable ability to induce microsomal enzymes.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

28. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Pharmacokinetics
One of the metabolites, carbamazepine-10,11-epoxide, has been shown to have anticonvulsant activity.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

29. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Dosage
Carbamazepine is available only in oral form.
Dose for children: mg/kg/day.
Dose for adults: 1 g, up to 2 g/day.
Higher dosage: multiple divided daily doses.
Extended release preparations: twice-daily dosing.
Therapeutic level just before the morning dose (trough level): 4-8 mcg/mL.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

30. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Drug interactions
Related to the drug´s enzyme-inducing properties.
The increased metabolic capacity of the hepatic enzymes may cause a reduction in steady-state carbamazepine concentrations and an increased rate of metabolism for some drugs:
primidone, phenytoin, ethosuximide, valproic acid, clonazepam.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

31. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Drug interactions
Valproic acid bay inhibit carbamazepine clearance and increase steady-state carbamazepine blood levels.
Phenytoin and phenobarbital may decrease steady-state concentrations of carbamazepine through enyzme induction.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

32. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Toxicity
The most common dose-related adverse effects are diplopia and ataxia.
Diplopia often occurs first and may last less than an hour during a particular time of day.
Rearrangement of the divided daily dose can remedy diplopia.
Other dose-related complaints are mild GI upsets, unsteadiness and drowsiness (higher doses).
Katzung, Masters, Trevor. Basic and clinical pharmacology.

33. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Toxicity
Hyponatremia and water intoxication have occasionally occurred and may be dose related.
Idiosyncratic blood dyscrasias include fatal cases of aplastic anemia and agranulocytosis, mostly in elderly patients with trigeminal neuralgia and within the first 4 months of treatment.
The mild and persistent leukopenia is not necessarily an indication to stop treatment.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

34. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Toxicity
The most common idiosyncratic reaction is an erythematous skin rash.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

35. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Phenobarbital
III.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

36. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Phenobarbital
Phenobarbital is one of the four derivatives of barbituric acid clinically useful as antiseizure drugs together with mephobarbital, metharbital and primidone.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

37. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Mechanism of action
Phenobarbital may selectively suppress abnormal neurons, inhibiting the spread and suppressing firing from the foci.
Phenobarbital suppresses high-frequency repetitive firing in neurons in culture through an action on Na+ conductance at high concentrations.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

38. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Mechanism of action
Also at high concentrations, barbiturates block some Ca2+ currents (L-type and N-type).
Phenobarbital binds to an allosteric regulatory site on the GABAA receptor.
It enhances the GABA receptor-mediated current by prolonging the openings of the Cl- channels.
Phenobarbital can also decrease excitatory responses.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

39. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Mechanism of action
Both the enhancement of GABA-mediated inhibition and the reduction of glutamate-mediated excitation are seen with therapeutically relevant concentrations of phenobarbital.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

40. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Clinical uses
Partial seizures and generalized tonic-clonic seizures.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

41. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Primidone
IV.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

42. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Primidone
Primidone is 2-desoxyphenobarbital.
Primidone is metabolized to phenobarbital and phenylethylmalonamide (PEMA): all three compouns are active anticonvulsants.
Indications: partial seizures and generalized tonic-clonic seizures.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

43. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Pharmacokinetics
Primidone is completely absorbed, usually reaching peak concentrations about 3 hours after oral administration.
It is generally distributed in total body water.
Volume of distribution is 0,6 L/kg.
It is not highly bound to plasma proteins.
70% circulates as unbound drug.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

44. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Pharmacokinetics
It is metabolized by oxidation to phenobarbital.
Both primidone and phenobarbital undergo subsequent conjugation and excretion.
Primidone has a larger clearance than most other antiseizure drugs: 2 L/kg/day.
Half-life is 6-8 hours.
During chronic therapy, phenobarbital levels derived from primidone are usually two to three times higher than primidone levels.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

45. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Dosage
Primidone is most efficacious with plasma levels in the range of 8-12 mcg/mL.
Dosage: mg/kg/day.
Primidone has to be started at low doses with gradual increment over days to a few weeks to avoid prominent sedation and GI complaints.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

46. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Toxicity
The dose-related adverse effects are similar to phenobarbital.
Drowsiness occurs early in treatment and may be prominent if the initial dose is too large.
Gradual increments are indicated when starting the drug both in children and adults.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

47. Gabapentin, pregabalinV.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

48. Gabapentin, pregabalin
Gabapentin is an amino acid, an analog of GABA.
It is effective against partial seizures.
Pregabalin is also GABA analog, closely related to gabapentin.
Pregabalin has been approved for both antiseizure activity and for its analgesic properties.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

49. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Mechanism of action
Gabapentin and pregabalin do not act directly on GABA receptors.
They may modify the synaptic or nonsynaptic release of GABA.
Gabapentin is transported into the brain by the L-amino acid transporter.
Gabapentin and pregabalin bind avidly to the α2δ subunit of voltage-gated Ca2+ channels.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

50. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Clinical use
Gabapentin is effective as an adjunct against partial seizures and generalized tonic-clonic seizures in dose up to 2400 mg/day.
Gabapentin is also used for the treatment of neuropathic pain.
It is indicated for postherpetic neuralgia in adults at doses of 1800 mg and above.
Side effects: somnolence, dizziness, ataxia, headache and tremor.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

51. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Clinical use
Pregabalin is approved for the adjunctive treatment of partial seizures, with or without secondary generalization.
Dosage ranges from 150 to 600 mg/day, usually in two or three divided doses.
Pregabalin is approved for use in neuropathic pain, including painful diabetic peripheral neuropathy and postherpetic neuralgia.
It is also approved for fibromyalgia and generalized anxiety disorder.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

52. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Other
VI.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

53. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Other
mephenytoin
ethotoin
phenacemide
oxcarbazepine
eslicarbazine
felbamate
lacosamide
lamotrigine
levetiracetam
retigabine
rufinamide
stiripentol
tiagabine
topiramate
vigabatrin
zonisamide
Katzung, Masters, Trevor. Basic and clinical pharmacology.

54. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Literature
Katzung, Masters, Trevor. Basic and clinical pharmacology.
Katzung, Masters, Trevor. Basic and clinical pharmacology.