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antiepileptic drugs "lecture 1&2" (AEDs according to…
antiepileptic drugs "lecture 1&2"
:star:TYPES OF SEIZURES
{according to the source of it within the brain}
:check: PARTIAL (focal) :
it occur in specific part ( lobe) in the brain
simple partial
conscious
complex partial
unconscious
:check:GENERALIZED
[ involved the entire brain ]
Atonic seizures
it is a sudden decrease in muscle tone
[ head drop ]
Myoclonic seizures
1- convulsive type
2- no loss of consciousness
3- it is in general an uncontrolled movement
4-involve the entire body
Absence seizures (Petit mal)
1- nonconvulsive type
3-consciousness:
brief, abrupt loss
2- the patient is disconnected for a few seconds from the surrounding.
4- Person can be altered during the seizure
5- Minor muscular twitching restricted to eyelids (eyelid
flutter) and face
[ staring & blinking without falling ]
6-it occur mostly in children and it may develop into generalized tonic/clonic as they grow
Status epilepticus
single prolonged seizure lasting more than 5 minutes
[ life threatening condition]
Generalized Tonic-Clonic seizures (Grand mal)
1- convulsive type.
2- start with the tonic phase --> muscle contraction
stiffness
3- then the clonic phase --> alternating contraction & relaxation
decreased muscle tone
4- finally the patient passes into sleep
:star:epilepsy in general
it is produced by a sudden changes in the electrical function of the brain
while seizures are sudden and uncontrolled episodes of brain dysfunction resulting from abnormal discharge of neuronal cells(excessive abnormal neuronal activity) with
associated motor, sensory or behavioural change.
the medication can only prevent seizures or delay it but it can't cure epilepsy.
the main test that is used to detect any abnormalities in the brain is the
Electroencephalography
it refer to the measurement of the electrical activity produced by the brain, and it records the brain’s spontaneous electrical activity in the time-domain as recorded from multiple electrodes
placed on the scalp
:star: seizures control
how do seizures happen?
resulted from the following
Membrane depolarization, ion channel disturbances
Increased excitatory (Glutamate) input
Decreased inhibitory (GABA) input
how to control it? ( it work by 3 mechanisms )
1-
BLOCKING
Ion Channels
by limiting firing of neurons by slowing rate of recovery in Na channels
2- enhance GABAergic Synapse activity
inhibition
3- limit activation of Ca ++ channels
:star: The structure of the
ideal
AED
1- don't cause sedation or other undesired CNS toxicity
2- well tolerated
3- highly effective against various types of seizures
4-Have a rapid onset of action when given IV especially for control of status epilepticus
5-Have a long duration of action when given orally
6- devoid of undesirable side effects on vital organs
and functions
AEDs according to chemical structures are classified into 6 groups:
Hydantoins
work on sodium channels
:check:
Phenytoin
:
1- used for the complex partial & tonic-clonic seizures. BUT not for
absence seizures
2- bind to and stabilize the inactivated state of sodium channels.
slow firing
3- bind to plasma protein.
poor water soluble
4- by the aromatic hydroxylation --> metabolite
SIDE EFFECTS
1- Teratogenic “fetal hydantoin
syndrome”
2-Coarsening of facial features
3-
Drug interactions
: increase
(phenobarbital,
carbamazepine, lamotrigine,
valproate) rate of
metabolism; competition for
protein binding sites
4- Phenytoin toxicity increases
in the elderly
:check: Fosphenytoin (Cerebyx®) :
PRODRUG
1- become Phenytoin by the remove of phosphate groups by
phosphatase enzyme
2- Completely converted to phenytoin after IM or IV dosing
3- used in status epilepticus as it is soluble and convert to phenytoin after IM or IV dosing -->
rapid onset
4- Lower doses with elderly
Barbiturates
work on GABA synapse
:check: Phenobarbital
1- The oldest antiepileptic drug and one of the safest drugs,
despite its sedative effects
2- used for treating seizures in children
3- Useful for partial, generalized tonic-clonic seizures
4- GABA enhancement by prolongs opening of Cl channels
5- half life 2-6 days
6- Metabolized into inactive metabolite only at high concentrations
side effects
Enzyme inducing drugs of CYO3A4, increase metabolism
of carbamazepine, lamotrigine, valproate
drowsiness, cognitive impairment,
behavioural changes, worsen absence and atonic seizures
:check: Primidone (2-deoxy derivative)
1- Metabolized to phenobarbital
(active metabolite)
2- Effective against
partial and
generalized tonic-clonic
seizures
3- low binding to plasma protein --> absorbed completely
4- Should be started slowly to avoid sedation and GI problems
5- Mechanism of action closer to
phenytoin
than barbiturates
Oxazolidine-2,4-diones
:check: Trimethadione
1- The oldest AEDs for treatment of
absence
seizures
2- Metabolized to dimethadione
(active metabolite)
vary toxic compound
Succinimides
:check: Ethosuximide (Zarontin)
1- for
absence seizures
2- High efficacy and safety
3- no plasma protein binding
work by reducing Ca2+ channels activity
SIDE EFFECTS:
GI problems
Carboxylic acids
:check: Valproic acid (Depakote®)
1-
Blocks Na+ and Ca2+ channels and Increases GABA synthesis
2-Used in
multiple seizure
types, Mood stabilizer primarily in the treatment of
bipolar disorder (mood disorder)
main metabolite:
Amides, esters are also active
SIDE EFFECT:
1- weight gain
2- hepatotoxicity
3- Drug interactions with other AEDs:
inhibits phenobarbital and phenytoin metabolism
:check:Carbamazepine ( Tegretol )
1- one of the safest AEDs
2-Initial or adjunct therapy for
complex, partial, grand mal and mixed seizures AND bipolar disorders
3- NOT for
absence or myoclonic
seizures (makes them worse)
SIDE EFFECTS:
1- Auto-induction CYP450 (Induces its own metabolism)
2-gastric upset (take it after meals), dizziness, blurred vision, cardiac disturbances
3-Hematological toxicity (aplastic anemia)
4- Drug interaction similar to phenytoin
mechanism similar to
phenytoin
the main metabolite:
aromatic hydroxylation, epoxide
epoxide
is more active and toxic
Caution with people with cardiac arrhythmia or history with hematologic reaction
7- Benzodiazepines
DIAZEPAM
1- number1 for treating status
epilepticus ( one daily use)
2- work on
GABA
by increasing the frequency of channel opening
Side effects:
sedation and tolerance
OTHERS:
:check:Lamotrigine (Lamictal®)
Inhibits excitatory amino acid release (glutamate & aspartate ) by blockade of Na+ channels.
SIDE EFFECTS:
drowsiness, blurred vision, ataxia, headache,
main metabolite:
:check:Felbamate (Felbatol®)
1- dicarbamate
2- work by
Block NMDA receptors, so inhibit glutamate
transmission
3- Effective against
partial seizures
but has severe side
effects
it is
not first line of treatment
--> cause haematological and hepatic toxicities
:check: Topiramate (Topamax®)
1- it is a sulfamate-substituted monosaccharide derived from fructose
2- one of the safest AEDs, used alone for
partial and generalized tonic-clonic, and absence seizures
work by
Blocks sodium channels (membrane stabilization) and also potentiates the inhibitory effect of GABA.
:check: gapapentin (Neuronten®)
does not work on GABA receptors
work on
inhibiting Ca 2+ channels
used for
treatment of partial and mixed seizure disorders+ relieving neuropathic pain
Not metabolized and excreted
unchanged in urine
:check:Pregabalin
1- Anticonvulsant drug used for
neuropathic pain
and as
an adjunct therapy for
partial seizures
2- work by
Inhibiting voltage-gated calcium channels in the CNS and inhibiting the release of several neurotransmitters
3-Excreted unchanged in urine (90%)
the main metabolite: N-methylated derivatives
