HYDANTOINS

HYDANTOINS ARE USED FOR

partial and generalised tonic clonic seizures

PHENYTOIN IS A

diphenyl hydantoin

CHARACTERISTICS OF PHENYTOIN

non sedative

does not cause generalised depression of the CNS

MOA OF PHENYTOIN

Binds to Na+ channels and prolongs its inactivated state.

Alters

1. Na+ ,K+ ,Ca2+ conductance

2. Membrane potential

3. Concentration of amino acids

4. Concentration of neurotransmitters Ach , GABA

Blocks post tetanic potentiation in spinal cord preparation

Blocks sustained high frequency repetitive firing of action potential

EFFECTS OF PHENYTOIN IN HIGH CONCENTRATIONS

high concentration blocks the release of NE and 5HT

promotes uptake of dopamine

inhibits MAO (monoamino oxidase) activity

stabilises membranes by binding to membrane lipids

may cause excitation of some cerebral neurons

inhibit CA2+ influx across membranes

INDICATIONS OF PHENYTOIN

partial seizures

generalised tonic clonic seizures

arrhythmias

PK OF PHENYTOIN

ad - orally - almost completely absorbed
     - IM - unpredictable absorption , drug precipitation in muscles  NOT RECOMMENDED
fosphenytoin- IV ,IM it is more water soluble and well absorbed following IM
Dis - high ppb 
       csf conc proportionate to plasma conc of free drug
metabolism- in the liver by CYP450 - hydroxylation and conjugation with glucuronic acid
elimination is dose dependent - 
    low plasma conc - 1st order kinetics  t1/2= 24 hrs    5-7 days to reach steady levels
    high plasma conc- 0 order kinetics     t1/2 =20-30hrs  4-6 weeks to reach steady levels
excretion- through bile and urine

FOSPHENYTOIN IS A

more soluble phosphate ester

a prodrug of phenytoin

PK OF FOSPHENYTOIN

IV, IM

slow iv infusion - prevents arrhythmias ,coma

more water soluble that phenytoin

90% bound to albumin

accumulates in the brain, liver, muscle , fat

csf conc= plasma conc of the free drug

Metabolised in the liver by CYP450 ~ hydroxylation and conjugation with glucuronic acid

it is converted to phenytoin by phosphatases in the liver and RBCs

t1/2 = 8-15min

excreted through bile mainly and urine

DOES PHENYTOIN UNDERGO FIRST ORDER OR ZERO ORDER KINETICS

undergoes both first and zero order kinetics

first order kinetics occurs in low plasma concentrations t1/2= 24hrs

zero order kinetics occurs in high therapeutic plasma concentrations t1/2= 20-30 hrs

This is known as saturation kinetics

ADRS OF PHENYTOIN

Nystagmus

IM administration = tissue damage

Rapid IV administration ~ fosphenytoin = arrhythmias and hypotension

Phlebitis

Diplopia and ataxia

gingival hypeprplasia

Hirsutism

Coarsening of facial feature

Mild peripheral neuropathy

Osteomalacia in chronic use due to abnormal vitamin D metabolism

Idiosyncrasy - rash and lymphadenopathy

Haematologic - agranulocytosis with fever and rash

Megaloblastic anaemia - altered folate metabolism

DRUG INTERACTIONS

drugs that increase levels of phenytoin - by inhibiting cyp enzymes

• azoles

• macrolides

• cimetidine

• valproic acid

drugs that decrease  levels of phenytoin - inducing cyp enzymes

• rifampin

• carbamazepine

• phenobarbital

• theophylline

phenytoin as an inducer of cyp450 enzymes enhances metabolism of 

• oral contraceptives

• warfarin

• corticosteroids

• anti fungals

PPB - Phenybutazone and sulfonamides

intereferes with thyroid test as it has affinity to thyroid binding globulin (TBG)

CONGENER OF PHENYTOIN

mephenytoin

ethotoin

phenacemide

What is the value of congeners in the care of epilepsy

1. improves tolerability
2. broader administration options
3. reduced toxicity
4. alternative for pts with hypersensitivity

Hydantoins is contraindicated in

those known to be hypersensitive to the drugs
pregnancy - teratogenic 
lactation