3. Anticonvulsants(antiepileptic.pptx

Unit Specific Objective Content Hour Teaching learning
activities
Evaluation
A (i) i) To classify anticonvulsants
ii) To discuss the pharmacology of
barbiturate members
iii) To discuss the pharmacology of
barbiturates, hydentoin,
iminostilbin, succinimide, valproate,
benzodiazepins
iv) To discuss pharmacology of helping
drugs in seizure treatment:
lometigrine, gabapentine,
pregabalin, toperamide,
zonisaamide, vigabatrin, Tiagabalin
and lacosamide
a.Barbiturate:Phenobarbitone
b.Deoxybarbiturate:Primidone
c.Hydantoin:Phenytoin,
Fosphenytoin
d.Iminostilbene:Carbamazepine
e.Succinimide:Ethosuximide
f.Aliphatic carboxylic
acid:Valproate sodium, Divalproex
g.Benzodiazepines:Diazepam,
Clonazepam, Clobazepam,
Lorazepam
h.Phenyltriazine:Lamotrigine
i.Cyclic GABA
analogues:Gabaprntin, Pregabalin
j.Newer agents:Topiramate,
Zonisamide, Vigabatrin, Tiagabine,
Lacosamide
3 hr Method:
Interactive lecture
Group discussion
Buzz groups
Problem based learning
Demonstration
Role play
Simulation
Media:
White-board
Power Point Slides
Flip chart
You Tube/ Video
Verbal question asking
MCQ and/or SAQ
Verbal and/or written
Home assignment
Seminar
MANMOHAN MEMORIAL INSTITUTE OF HEALTH SCIENCES
Department of Pharmacy. LESSON PLAN/ Academic year: 2076/77
Daily Lesson Plan No.: Logy -1
Year/Faculty: Pharmacy- First Year Total students: 26 Date:
General Objective: To discuss the pharmacology of Central nervous system depressants (one): Sedative and hypnotics

The ‘anticonvulsants’ are also termed as
‘antiepileptic drugs’ and ‘antiseizure drugs’
that are used invariably in the adequate
and impressive control and management of
CNS disorders essentially characterized by
recurrent transient attacks of disturbed
brain function which ultimately give rise to
motor (convulsive), sensory (seizure), and
psychic sequence of events.
2

The anticonvulsants are a diverse group
of medications used in the treatment
of epileptic seizures.
Anticonvulsants are important drugs,
used in cases of neuropathic pain.
Anticonvulsants are also increasingly
being used in the treatment of bipolar
disorder, since many seem to act as
mood stabilizers.
Anticonvulsants
3

Epilepsy: disorder of brain function characterized by a
periodic and unpredictable occurrence of seizures.
Epilepsy is not a single disease. It is a set of symptoms
that may have different causes in different people.
Seizure: transient alteration of behaviour due to
disordered and rhythmic firing of population of brain
neurons or A seizure is the physical findings or
changes in behavior that occur after an episode of
abnormal electrical activity in the brain.

Convulsion: The major motor manifestations of a
seizure (rhythmic jerking of the limbs).
The term "seizure" is often used interchangeably with
"convulsion." Convulsions occur when a person's
body shakes rapidly and uncontrollably.
Status Epilepticus: characterized by ore than 30
minutes of continuous seizure activity. Two or more
sequential seizures spanning this period without full
recovery between seizures and it is a medical
emergency.

Classification according to mode of action
1. Sodium Channel Blockers: Phenytoin, Carbamazepine, Valproic
Acid, Lamotrigine, Topiramate, Zonisamide and Lidocaine.
2. GABA Enhancer: Barbiturates (Phenobarbital and Pimidone)
Benzodiazepines
(Diazepam, Lorazepam, Clonazepam and Clorazepate), Tiagabine,
Valproic Acid, Topiramate and Zonisamide.
3. Ca2+ Channel Drugs
Ethosuximide, Valproic Acid, Zonisamide, Gabapentin, Pregabalin and
Levetiracetam.
4. N-methyl-D-aspartate( NMDA) glutamate receptor blocker:
Felbamate

1. Carboxamides: Carbamazepine (1963), Oxcarbazepine
(1990) and Eslicarbazepine acetate(2009)
2. Fatty acids: The valproates — valproic acid, sodium
valproate, and divalproex sodium(1967).
3. Fructose derivatives: Topiramate (1995).
4. GABA analogs: Gabapentin (1993).and Pregabalin (2004).
5. Hydantoins: Ethotoin (1957), Phenytoin (1938).
6. Oxazolidinediones: Trimethadione (1946).
7. Succinimides: Ethosuximide (1955),
8. Triazines: Lamotrigine( 1990).
Chemical Classification
8

1. Primary Medications for the Treatment of
Seizures
Carbamazepine, Clonazepam, Diazepam,
Ethosuxamide, Phenytoin.
2. Alternate Medications for Seazures
Phenobarbital, Primidone.
3. Adjunct Medications for Seizures
Lamotrigine, Gabapentine, Oxcarbazepine,
Topiramide, Valproic Acid, Zonisamide.
Anticonvulsants
9

Antiepileptic Drugs: [3 Hrs]
a.Barbiturate:Phenobarbitone
b.Deoxybarbiturate:Primidone
c.Hydantoin:Phenytoin, Fosphenytoin
d.Iminostilbene:Carbamazepine
e.Succinimide:Ethosuximide
f.Aliphatic carboxylic acid:Valproate sodium, Divalproex
g.Benzodiazepines:Diazepam, Clonazepam, Clobazepam, Lorazepam
h.Phenyltriazine:Lamotrigine
i.Cyclic GABA analogues:Gabaprntin, Pregabalin
j.Newer agents:Topiramate, Zonisamide, Vigabatrin, Tiagabine, Lacosamide

Phenobarbitone: PK
Phenobarbital has an oral bioavailability of about 90%. Peak plasma
concentrations (Cmax) are reached 8 to 12 hours after oral administration. It
is one of the longest-acting barbiturates.
Half-life of 2 to 7days and has very low protein binding (20 to 45%).
Phenobarbital is metabolized by the liver, mainly through hydroxylation and
glucuronidation, and induces many isozymes of the cytochrome P450
system. CYP 450 is specifically induced by Phenobarbital. Excretion is
primarily renal..

Phenobarbitone: Mechanism of Action
Phenobarbitone mainly acts on the site of GABA –
Benzodiazepine (BZD) receptor Cl- (chloride ion)
channel complex. It prolongs the duration of
GABA induced chloride channel opening and
produces hyperpolarization and decreases firing
rate of neurons.
13

Phenobarbitone: Mechanism of Action…..
Phenobarbitone also has GABA mimetic action. At high
concentrations Phenobarbitone directly increases chloride ion
conductance and decreases transmission of calcium ion (Ca2+ )
dependent neurotransmitters.
Phenobarbitone also inhibits excitatory glutamate
neurotransmitters. At high concentration it also inhibits sodium
ion channel and potassium ion channel. Phenobarbitone is used
as an antiepileptic to control partial and generalized tonic-clonic
seizures.
14

Phenobarbitone: Dose for Daytime Sedation: 30 to 120 mg orally, IM, or IV in 2 or 3
divided doses
Maximum dose: 200 mg during a 24-hour period
Preoperative Sedation: Parenteral: 100 to 200 mg IM 60 to 90 minutes before surgery
For insomenia, Oral: 60 to 100 mg orally once a day
-Maximum dose: 200 mg during a 24-hour period
Acute Convulsions Parenteral: 20 to 200 mg IM or IV every 6 hours as necessary
Anticonvulsant: Oral: 60 to 200 mg orally per day
Anticonvulsant:Febril seizure, Oral: -Initial dose: 15 to 20 mg/kg orally
-Recommended dose: 3 to 6 mg/kg orally
Status epilepticus: Parenteral: Initial dose: 15 to 20 mg/kg IV over 10 to 15 minutes

Phenobarbitone: ADRs
Common ADRs include:
Aggression,Dizziness, Drowsiness, Excitation, Fatigue,
Headache, Irritability, Loss of appetite, Loss of balance or
coordination,Loss of control of bodily movements,Numbness
and tingling,Problems with memory or
concentration,Repetitive, uncontrolled eye movements,
Respiratory depression,Restlessness,Slurred or slow speech
and Spinning sensation (vertigo)

Phenobarbitone: ADRs.....
Phenobarbital is a cytochrome P450 hepatic enzyme inducer. It binds
transcription factor receptors that activate cytochrome P450 transcription,
thereby increasing its amount and thus its activity. Due to this higher
amount of CYP450, drugs that are metabolized by the CYP450 enzyme
system will have decreased effectiveness. This is because the increased
CYP450 activity increases the clearance of the drug, reducing the amount of
time they have to work.
Caution is to be used with children. Among anti-convulsant drugs,
behavioural disturbances occur most frequently with clonazepam and
phenobarbital.

Deoxybarbiturate:Primidone: PK
converted to phenobarbital and phenylethylmalonamide
(PEMA),the phenobarbital, in turn, is metabolized to p-
hydroxyphenobarbital. The rate of primidone metabolism
was greatly accelerated by phenobarbital , moderately
accelerated by primidone and reduced by PEMA.
It is well absorbed after oral administration, with about
25% of the drug bound to plasma proteins. Half-life of
primidone is 3–12 hours, that of PEMA 29–36 hours.

Deoxybarbiturate:Primidone: MOA
Primidone's metabolites, phenobarbital and
phenylethylmalonamide (PEMA), are active
anticonvulsants.
Primidone does not directly interact with GABA-A receptors
or chloride channels but phenobarbital does.
Primidone alters transmembrane sodium and calcium
channel transport, reducing the frequency of nerve firing,
which may be responsible for the primidone’s effect on
convulsions and essential tremor.

Deoxybarbiturate:Primidone: Dose
Titration to maintenance dose
Days 1 to 3: Take 100-125 mg PO hs
Days 4 to 6: Take 100-125 mg PO bid
Days 7 to 9: Take 100-125 mg PO tid
Days >10: Take 250 mg PO tid
Maintenance dosing
Standard dosing: 250 mg PO tid-qid
Maximum dosing: 500 mg PO qid (do not exceed)

Deoxybarbiturate:Primidone: ADRs
Common: Ataxia, Vertigo,
Occasional:
Nausea, Vomiting or Anorexia
Fatigue or drowsiness
Hyperirritability or other emotional disturbance
Sexual Impotence
Diplopia or Nystagmus
Morbilliform skin rash

Which of the following is an adjunct medications for seizures?
A. Carbamazepine
B. Phenytoin
C. Valproic acid
D. Gabapentine

Phenytoin: MOA
Phenytoin is believed to protect against seizures
by causing voltage-dependent block of voltage
gated sodium channels. This blocks sustained high
frequency repetitive firing of action potentials.
This is accomplished by reducing the amplitude of
sodium-dependent action potentials through
enhancing steady state inactivation.
Sodium channels exist in three main
conformations: the resting state, the open state,
and the inactive state.

Phenytoin: Properties
White, odourless powder. Melts at
about 295°. Practically insoluble in
water; soluble in hot alcohol; slightly
soluble in cold alcohol, in chloroform,
and in ether.

Fosphenytoin: MOA
Fosphenytoin is rapidly metabolized to
phenytoin.
Fosphenytoin: Properties
Fosphenytoin Sodium: White to pale
yellow solid. Freely soluble in water

Carbamazepine: MOA
Carbamazepine is a sodium channel blocker. It binds
preferentially to voltage-gated sodium channels in
their inactive conformation, which prevents repetitive
and sustained firing of an action potential.
Carbamazepine has effects on serotonin systems but
the relevance to its antiseizure effects is uncertain.
There is evidence that it is a serotonin releasing
agent and possibly even a serotonin reuptake
inhibitor.

White to yellowish-white crystalline
powder Almost odourless, carbamazepine
can either have no taste or be slightly
bitter.
It is practically Insoluble in water and ether but
soluble in acetone, alcohol, carbon tetrachloride,
chloroform, dimethylformamide dioxane, and
propylene glycol
Melting point: 190 to 193°C.
Carbamazepine: Properties
31

Valproic acid: MOA
Valproate is known to inhibit succinic semi-
aldehyde dehydrogenase. This inhibition results
in an increase in succinic semi-aldehyde which
acts as an inhibitor of GABA transaminase
ultimately reducing GABA metabolism and
increasing GABAergic neurotransmission. As
GABA is an inhibitory neurotransmitter, this
increase results in increased inhibitory activity.

Valproic acid: Properties
Colorless to pale yellow, slightly viscous,
clear liquid, having a characteristic odor.
Refractive index: about 1.423 at 20°.
Slightly soluble in water; freely soluble in
1 N sodium hydroxide, in methanol, in
alcohol, in acetone, in chloroform, in
benzene, in ether, and in n-heptane;
slightly soluble in 0.1 N hydrochloric acid.

Divalproex Sodium
Valproate sodium is a mixture
of valproic acid and its sodium salt in
a 1:1 molar ratio.
is a stable coordination compound
comprised of sodium valproate and
valproic acid with anticonvulsant and
antiepileptic activities. Divalproex
dissociates to the valproate ion in the
gastrointestinal tract.

Trimethadione: MOA
It reduce T-type calcium currents in thalamic neurons,
including thalamic relay neurons. It does so via the
inhibition of voltage dependent T-type calcium
channels.
This raises the threshold for repetitive activity in the
thalamus, and inhibits corticothalamic transmission.
Thus, the abnormal thalamocortical rhythmicity.

Trimethadione: Properties
Colorless, granular crystals; odour,
slightly camphoraceous. Soluble in
water; freely soluble in ethanol (~750
g/l) TS and ether R.
Melting point: 45-46°C

Ethosuximide: MOA
It block of T-type calcium channels, and may include
effects of the drug on other classes of ion channel.
A particularity of this type of channels is an opening
at quite negative potentials and a voltage-dependent
inactivation. T-type channels serve pacemaking
functions in central neurons s and support calcium
signalling in secretory cells and vascular smooth
muscle. They may also be involved in the modulation
of firing patterns of neurons.

Ethosuximide: Properties
White to off-white, crystalline powder or waxy solid,
having a characteristic odour. Freely soluble in water
and in chloroform; very soluble in alcohol and in
ether; very slightly soluble in solvent hexane.

Diazepam: Pharmacokinetics -1
Diazepam can be administered orally, intravenously,
intramuscularly, or as a suppository.
Oral: it is rapidly absorbed and has a fast onset of action.
IV: The onset of action is 1–5 minutes for IV
administration and IM: 15–30 minutes for IM
administration.
The duration of diazepam's peak pharmacological effects
is 15 minutes to 1 hour for both routes of
administration.
PPL are achieved 30 minutes to 2 hours after oral
administration. When diazepam is administered as an
intramuscular injection, absorption is slow, erratic and
incomplete.
41

Diazepam is highly lipid-soluble, and is
widely distributed throughout the body. It
easily crosses both the blood-brain barrier
and the placenta, and is excreted into
breast milk.
Diazepam is redistributed into muscle and
adipose tissue. Continual daily doses of
diazepam will quickly build up to a high
concentration in the body (mainly in
adipose tissue), which will be far in excess
of the actual dose for any given day.
42

Diazepam has a half-life of 20–50 hours, and
desmethyldiazepam has a half-life of 30–200 hours and
is considered to be a long acting benzodiazepine.
Most of the drug is metabolised; very little diazepam is
excreted unchanged.
In humans, the protein binding of diazepam is around
98.5%.
The elimination half life of diazepam and also the active
metabolite desmethyldiazepam increases significantly in
the elderly which may result in prolonged action as well
as accumulation of the drug during repeated
administration.
43

Pharmacists have to know;
Diazepam can absorb into plastic, and,
therefore, diazepam solution is not
stored in plastic bottles or syringes, etc.
It can absorb into plastic bags and tubing used for
intravenous infusions. Absorption appears to be
dependent on several factors such as temperature,
concentration, flow rates, and tube length.
Diazepam should not be administered if a
precipitate has formed and will not
dissolve.
44

Clinical use of Diazepam
1.Treatment of anxiety, panic attacks, and
states of agitation, status epilepticus.
2.Treatment of vertigo associated with
Meniere's Disease(is a disorder of the inner
ear).
3.Treatment of the symptoms of alcohol and
opiate withdrawal, Short-term treatment of
insomnia, Treatment of tetanus, together
with other measures of intensive-
treatment.
45

Clinical use of Diazepam ...............
4. Initial management of mania,
together with first line drugs like
lithium, valproate, lamotrigine and
antipsychotics, Adjunctive treatment
of painful muscle conditions.
Adjunctive treatment of spastic
muscular paresis caused by cerebral or
spinal cord conditions such as stroke,
multiple sclerosis, spinal cord injury
(long-term treatment is coupled with
other rehabilitative measures.
46

Clinical use of Diazepam ........
5. Palliative treatment of stiff person
syndrome (rare neurologic disorder
of unknown etiology).
6.Pre-/postoperative sedation,
anxiolysis and/or amnesia (e.g.
before endoscopic or surgical
procedures).
47

Clinical use of Diazepam ................
7.Treatment of over dosage with
hallucinogens or CNS stimulants.
8.Adjunctive treatment of drug-
induced seizures, resulting from
exposure to poisons
organophosphate, lindane,
chloroquine, physostigmine, or
pyrethroids.
48

Clinical use of Diazepam ................
9. Emergency treatment of eclampsia, along
with IV magnesium sulfate.
10.Prophylactic treatment of oxygen toxicity
during hyperbaric oxygen therapy.
11.Used in the treatment for irritable bowel
syndrome.
12.Used to treat pain resulting from muscle
spasms caused by various spastic
dystonias, including blepharospasm
(forcible closure of the eyelids) and
spasmodic dysphonia.
49

Adverse Effects -1: Diazepam
Most common include:
Somnolence, Suppression of REM sleep,
Impaired motor function (Impaired
coordination, Impaired balance,
dizziness and nausea), Depression,
Impaired learning, Anterograde
amnesia (especially pronounced in
higher doses), Cognitive deficits and
reflex tachycardia.
50

Adverse Effects -2
impair learning and memory
impair the ability to drive vehicles or operate machinery.
Tolerance to the sedative effects, but not to the
anxiolytic and myorelaxant effects.
Diazepam in doses of 5 mg or more causes significant
deterioration in alertness performance combined with
increased feelings of sleepiness.
51

Drug Interactions -1
If diazepam is to be administered concomitantly with
other drugs, attention should be paid to the possible
pharmacological interactions. Particular care should be
taken with drugs that enhance the effects of diazepam,
such as
• Barbiturates,
• Phenothiazines,
• Narcotics and
• Antidepressants.
Agents which have an effect on hepatic cytochrome P450
pathways or conjugation can alter the rate of diazepam
metabolism. These interactions would be expected to
be most significant with long-term diazepam therapy,
and their clinical significance is variable.
52

Drug Interactions - 2
Diazepam increases the central
depressive effects of
• alcohol, other hypnotics/sedatives,
• narcotics, and other muscle relaxants.
• The euphoriant effects of opioids may
be increased, leading to increased risk
of psychological dependence.
53

Drug Interactions - 3
Cimetidine, omeprazole, ketoconazole, itraconazole,
disulfiram, fluvoxamine, isoniazid, erythromycin,
probenecid, propranolol, imipramine, ciprofloxacin,
fluoxetine and valproic acid prolong the action of
diazepam by inhibiting its elimination.
Oral contraceptives ("the pill") significantly decrease the
elimination of desmethyldiazepam, a major metabolite
of diazepam.
Rifampin, phenytoin, carbamazepine and phenobarbital
increase the metabolism of diazepam, thus decreasing
drug levels and effects.
54

Contraindications of Diazepam
Use of Diazepam should be avoided, or carefully
monitored, in individuals with the following conditions:
⮚Myasthenia gravis,
⮚Acute narrow-angle glaucoma,
⮚Severe liver deficiencies (e.g., cirrhosis),
⮚Severe sleep apnea,
⮚Pre-existing respiratory depression,
⮚Acute pulmonary insufficiency,
⮚Chronic psychosis, Borderline personality disorder (may
induce suicidality and dyscontrol).
55

Pregnancy
If taken in the third trimester, causes a definite risk of a
severe benzodiazepine withdrawal syndrome in the
neonate with symptoms including hypotonia, and
reluctance to suck, to apnoeic spells, cyanosis, and
impaired metabolic responses to cold stress.
Floppy infant syndrome and sedation in the newborn may
also occur. Symptoms of floppy infant syndrome and
the neonatal benzodiazepine withdrawal syndrome
have been reported to persist from hours to months
after birth.
56

Clonazepam: Properties
Clonazepam is classified as a high potency
benzodiazepine and is sometimes used as a
second-line treatment of epilepsy.
Clonazepam, like other benzodiazepines,
while being a first-line treatment for acute
seizures, is not suitable for the long-term
treatment of seizures due to the
development of tolerance to the
anticonvulsant effects
58

Clonazepam: Pharmacokinetics
Complete absorption
Bioavailability about 90%.
PPL within 1 to 4 hours after oral administration.
PPB approximately 85%
Clonazepam is highly metabolized, with less than 2%
unchanged clonazepam being excreted in the urine.
Biotransformation occurs mainly by reduction of the 7-
nitro group to the 4-amino derivative. This derivative
can be acetylated, hydroxylated and glucuronidated.
59

But !
The anticonvulsant properties of
diazepam and other
benzodiazepines may be in part or
entirely due to binding to voltage-
dependent sodium channels rather
than benzodiazepine receptors.
60

Clonazepam: ADRs
1. CNS: depression, Drowsiness, Ataxia (these may diminish with time)
2. Behavior problems have been noted. amnesia, hallucinations, hysteria,
increased libido, insomnia, psychosis .
3. Neurologic: Abnormal eye movements, aphonia, choreiform movements,
coma, diplopia, dysarthria, dysdiadochokinesis, ''glassy-eyed'' appearance,
headache, hemiparesis, hypotonia, nystagmus, respiratory depression,
slurred speech, tremor, vertigo .
4. Respiratory: Chest congestion, rhinorrhea, shortness of breath,
hypersecretion in upper respiratory passages
5. Cardiovascular: Palpitations
6. Dermatologic: Hair loss, hirsutism, skin rash, ankle and facial edema
7. Gastrointestinal: Anorexia, coated tongue, constipation, diarrhea, dry
mouth, gastritis, increased appetite, nausea, sore gums
8. Genitourinary: Dysuria, enuresis, nocturia, urinary retention
9. Musculoskeletal: Muscle weakness, pains
61

Clonazepam: Anticonvulsant MOA
Clonazepam enhances the activity of the inhibitory
neurotransmitter GABA in the central nervous system to give
its anticonvulsant, skeletal muscle relaxant,
and anxiolytic effects. It acts by binding to the
benzodiazepine site of the GABA receptors, which enhances
the electric effect of GABA binding on neurons, resulting in
an increased influx of chloride ions into the neurons. This
further results in an inhibition of synaptic transmission
across the CNS.

Lorazepam: MOA
Lorazepam is thought to have high affinity
for GABA receptors, which may also explain its
marked amnesic effects. Its main
pharmacological effects are the enhancement of
the effects of the neurotransmitter GABA at the
GABAA receptor.
It enhances the effects of GABA at the
GABAA receptor via increasing the frequency of
opening of the chloride ion channel on the
GABAA receptors; which results in the
therapeutic actions of benzodiazepines.
Thus, as other benzodiazepines it enhances the
effects of the neurotransmitter GABA.
64

Lorazepam: Use
It is indicated for the management of:
• Anxiety disorders or for the short-term relief of the
symptoms of anxiety or anxiety associated with
depressive symptoms.
• Anxiety or tension associated with the stress of
everyday life usually does not require treatment with
an anxiolytic.
• The effectiveness of lorazepam in long-term use, that
is, more than 4 months, has not been assessed by
systematic clinical studies.
• Management of Insomnia
• The physician should periodically reassess the
usefulness of the drug for the individual patient.
65

Lorazepam: ADRs
Confusion, depressed mood, thoughts of suicide or
hurting them self; hyperactivity, agitation,
hallucinations; or feeling light-headed, fainting.
Less serious side effects may include:
drowsiness, dizziness, tiredness; blurred
vision; sleep problems.
66

Lorazepam injectable solution is
administered either by deep intramuscular
injection Intramuscular injection
Intramuscular injection is the injection of a
substance directly into a muscle.
In medicine, it is one of several alternative
methods for the administration of
medications .
It is used for particular forms of medication
that are administered in small amounts or
by intravenous therapy.
67

Lorazepam
The injectable solution comes in 1 mL
ampoules containing 2 mg or 4 mg
lorazepam. The solvents used are
polyethylene glycol 400 Polyethylene
glycol.
68

Lorazepam
As a preservative, the injectable solution contains benzyl
alcohol. Toxicity from propylene glycol as a solvent has
been reported in the case of a patient receiving a
continuous lorazepam infusion. Intravenous injections
should be given slowly and patients closely monitored
for side effects, such as respiratory depression,
hypotension, or loss of airway control.
69

Primidone: MOA
It is believed to work via interactions with
voltage-gated sodium channels which
inhibit high-frequency repetitive firing of
action potentials.
The major metabolite, phenobarbital, is
also a potent anticonvulsant in its own
right and likely contributes to primidone's
effects in many forms of epilepsy

Primidone: Properties
White, crystalline powder. Is odourless and has
a slightly bitter taste. Very slightly soluble in
water and in most organic solvents; slightly
soluble in alcohol.

Gabapentin: MOA
It inhabit the voltage-dependent calcium
channels which is responsible for
anticonvulsant action.
it does not bind to the GABA receptors, does not
convert into GABA or another GABA receptor agonist
in vivo, and does not modulate GABA transport or
metabolism.

Gabapentin: Properties
White to off-white, crystalline solid. Freely
soluble in water and in alkaline and acidic
solutions.

Pregabalin: MOA
It inhabit the voltage-dependent calcium channels which is
responsible for anticonvulsant action.
In addition: It increase the GABA concentration as following:
Pregabalin has been found to produce a dose-dependent
increase in the brain expression of L-glutamic acid
decarboxylase (GAD), the enzyme responsible
for synthesizing GABA, and hence may have some
indirect GABAergic effects by increasing GABA levels in the
brain.

Pregabalin: Properties
It is a white to off-white, highly crystalline, non-
hygroscopic and water soluble (freely soluble
below pH 3.7) powder. It contains one chiral
centre, but is synthesised as the single
enantiomer S.

Newer agents: Topiramate: PK
Topiramate is quickly absorbed after oral use. It has a half
life of 21 hours and a steady state of the drug is reached in
4 days in patients with normal renal function. Most of the
drug (70%) is excreted in the urine unchanged. The
remainder is extensively metabolized
by hydroxylation, hydrolysis, and glucuronidation.
Six metabolites have been identified in humans, none of
which constitutes more than 5% of an administered dose.

Newer agents: Topiramate
MOA
It actions on voltage-dependent sodium channels, GABA receptors, and
glutamate receptors.
Topiramate stimulates GABA-A receptor activity at brain non-benzodiazepine
receptor sites and reduces glutamate activity at both AMPA and kainate
receptors. Normally, GABA-A receptors are inhibitory and glutaminergic
receptors are stimulatory for neuronal activity.1 By increasing GABA activity
and inhibiting glutamate activity, topiramate blocks neuronal excitability,
preventing seizures and migraines.

Newer agents: Topiramate: Use
Topiramate is indicated for the following conditions:
1)Monotherapy for partial onset or primary generalized tonic-clonic
seizures for patients 2 years of age and above
2)Adjunctive therapy for partial onset seizures or primary generalized
tonic-clonic seizures for both adult and pediatric patients above 2 years
old
3)Adjunctive therapy for seizures associated with Lennox-Gastaut
syndrome (type of epilepsy) in patients above 2 years of age
4)Prophylaxis of migraine in children 12 years of age and older and
adults.

Lennox-Gastaut syndrome (LGS) is a type of epilepsy.
Patients with LGS experience many different types of
seizures including: Tonic - stiffening of the body.
Atonic - temporary loss of muscle tone and
consciousness, causing the patient to fall. Atypical
absence - staring episodes

Topiramate: Dosage
• For seizures (taken with other medicines):Adults—At first, 25 to 50 mg once
a day. Your, the dose is usually not more than 100 mg per day (upto 400 mg
in western countries).
• Children—
• Children 2 years of age and older—Dose is based on body weight and
must be determined by your doctor.
Newer agents: Topiramate: ADRs
Very common (>10% incidence) adverse effects include:
Dizziness, Weight loss, Paraesthesia– e.g., pins and needles, Somnolence,
Nausea, Diarrhea, Fatigue, Nasopharyngitis and Depression.

Newer agents: Topiramate: Drug interaction
• As topiramate inhibits carbonic anhydrase, use with other inhibitors of
carbonic anhydrase (e.g. acetazolamide) increases the risk of kidney
stones.
• Enzyme inducers (e.g. carbamazepine) can increase the elimination of
topiramate, possibly necessitating dose escalations of topiramate.
• Topiramate may increase the plasma-levels of phenytoin.
• Alcohol may cause increased sedation or drowsiness, and increase the risk
of having a seizure.

Newer agents: Zonisamide: PK
•Absorption
•Variable, yet relatively rapid rate of absorption with a time
to peak concentration of 2.8-3.9 hours. Bioavailability is
close to 100% and food has no effect on the bioavailability
of zonisamide but may affect the rate of absorption.
•Metabolism
•Zonisamide is metabolized to 2-(sulphamoylacetyl)-phenol
via reductive cleavage of the 1,2-benzisoxazole ring.

Newer agents: Zonisamide: MOA
It blocks sodium and T-type calcium channels, which leads
to the suppression of neuronal hyper synchronization (that
is, seizure-form activity).
It is also known to be a weak carbonic anhydrase inhibitor
(similarly to the anticonvulsant topiramate). It is also
known to
modulate GABAergic and glutamatergic neurotransmission.

Newer agents: Zonisamide: Use
Epilepsy
Parkinson's disease
In Japan, zonisamide has been used as an adjunct to
levodopa treatment since 2009 for the control of motor
symptoms of PD.
Obesity
Migraine
Bipolar depression (off label)

The motor symptoms of Parkinson's include:
• Tremor.
• Rigidity.
• Slowness of movement.
• Falls and dizziness.
• Freezing.
• Muscle cramps and dystonia.
PD patient describe it as feeling like their feet are 'glued'
to the ground. If patient experience freezing he/she may
suddenly not be able to move forward for several
seconds or minutes.

Newer agents: Zonisamide: Dosage
The initial dose of should be 100 mg daily. After two
weeks, the dose may be increased to 200 mg/day for at
least two weeks.
Zonisamide: ADRs
•Very common (>10% incidence) adverse effects include:
•Anorexia, Somnolence, Dizziness, Agitation, Irritability,
Confusion, Depression, Diplopia and Memory
impairment.

Newer agents: Zonisamide: Interactions
Zonisamide may interact with other carbonic
anhydrase inhibitors to increase the potential for
metabolic acidosis.
Additionally, the metabolism of zonisamide is
inhibited
by ketoconazole, ciclosporin, miconazole, fluconazole
and carbamazepine.

Newer agents: Vigabatrin: PK
Absorption following oral administration is essentially complete.7 The
Tmax is approximately 2.5 hours in infants (5m - 2y) and 1 hour in all other
age groups. Half life 5.7 hrs.
Vigabatrin does not bind to plasma proteins. Vigabatrin is not metabolized
to any significant extent. Approximately 95% of the drug is eliminated in
the urine within 72 hours of administration, of which ~80% is unchanged
parent drug.

Newer agents: Vigabatrin: MOA
Vigabatrin is an irreversible GABA transaminase inhibitor.
So, Vigabatrin increases concentrations of GABA in the
central nervous system by irreversibly inhibiting the
enzymes responsible for its metabolism to succinic
semialdehyde: gamma-aminobutyric acid transaminase
(GABA-T).
Inhibition of GABA-AT results in increased levels of GABA in
the brain. Vigabatrin is a racemic compound, and its [S]-
enantiomer is pharmacologically active.

Newer agents: Vigabatrin: Dosage
Refractory Complex Partial Seizures. Adults (Patients 17 Years of Age and
Older)
Treatment should be initiated at 1000 mg/day (500 mg twice daily). Total
daily dose may be increased in 500 mg increments at weekly intervals
depending on response.
Newer agents: Vigabatrin: ADRs
Sleepiness (12.5%), headache (3.8%), dizziness (3.8%), nervousness
(2.7%), depression (2.5%), memory disturbances (2.3%), diplopia (2.2%),
aggression (2.0%), ataxia (1.9%), vertigo (1.9%), hyperactivity (1.8%), vision
loss (1.6 confusion (1.4%), insomnia (1.3%), impaired concentration
(1.2%), personality issues (1.1%). Out of 299 children, 33 (11%) became
hyperactive.

Newer agents: Vigabatrin: Drug Interaction
Concurrent use of chloroquine,
hydroxychloroquine, phenothiazines including
thioridazine), orlistat increased retinotoxicity.
All CNS depressants may increase the diziness and
drowsiness.

Newer agents: Tiagabine: PK
Tiagabine is nearly completely absorbed (>95%). Bioavailability: 90%. PPL=
45 minutes.
PB= 90 %. Half life = 7-9 hours.
Approximately 2% of an oral dose of tiagabine is excreted unchanged, with
25% and 63% of the remaining dose excreted into the urine and feces,
respectively, primarily as metabolites.

Newer agents: Tiagabine: MOA
Tiagabine increases the level of γ-aminobutyric
acid (GABA), the major inhibitory neurotransmitter in
the central nervous system, by blocking the GABA
transporter 1 (GAT-1), and hence is classified as a GABA
reuptake inhibitor (GRI).

Newer agents: Tiagabine: Dosage and ADRs
4 mg to 8 mg daily according to response.
ADRs: Dizziness and adverse effects such
as confusion, aphasia (difficulty speaking clearly)/stuttering,
and paresthesia (a tingling sensation in the body's extremities,
particularly the hands and fingers) may occur at higher dosages
of the drug (e.g., over 8 mg/day).

Newer agents: Tiagabine: Interactions
With Zolpidem & Diphenhydramine :
dizziness, drowsiness, confusion, and
difficulty concentrating.

Newer agents: Lacosamide: PK
Lacosamide has a negligible first pass effect with bioavailability of
about 100%. The maximum Lacosamide plasma concentrations
occur about 1-4 hours.
Primary compounds excreted were unchanged lacosamide
(approximately 40% of the dose), its O-desmethyl metabolite
(approximately 30%), and a structurally unknown polar fraction
(~20%). The plasma exposure of the major human metabolite, O-
desmethyl-lacosamide, is approximately 10% of that of
lacosamide. This metabolite has no known pharmacological
activity.

Newer agents: Lacosamide: MOA
Lacosamide enhances the slow inactivation of voltage-gated sodium
channels without affecting the fast inactivation of voltage-gated
sodium channels. This inactivation prevents the channel from
opening, helping end the action potential. Many antiepileptic drugs,
like carbamazepine or lamotrigine, slow the recovery from
inactivation and hence reduce the ability of neurons to fire action
potentials.
inhibition of sodium channels is responsible for analgesia.

Newer agents: Lacosamide: Uses, Dosage & ADRs
As with other anti-epileptic drugs (AEDs), lacosamide may
have a variety of off-label uses, including for pain
management and treatment of mental health disorders.
ADRs
dizziness, ataxia, diplopia, nystagmus, nausea, vertigo and
drowsiness. These adverse reactions were observed in at
least 10% of patients. Less common side-effects
include tremors, blurred vision, vomiting and headache.

Newer agents: Lacosamide: Interactions
Use with caution when administered concomitantly with
medications that affect cardiac conduction, including sodium
channel blockers, beta-blockers, calcium channel blockers,
potassium channel blockers, and medications that prolong the
PR interval; obtain an ECG before beginning therapy, and after
titrating to steady-state maintenance dose, in such patients;
closely monitor if intravenous route used to administer
medication.

Clinical significance of PR-interval
A long PR interval (of over 200 ms) indicates a slowing of
conduction between the atria and ventricles, usually due
to slow conduction through the atrioventricular node (AV
node). This is known as first degree heart block.

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