Anti-epilepsy Agents

Prajogo Wibowo
Chief of Pharmacologic Department
School of Medicine Hang Tuah University
 Aims
To describe the pathophysiology of epilepsy
To determine the pharmacological agents
used
Mechanism of action
Contra-indications
Adverse effects
Patient management
 Introduction
1 person in 20 will have an epileptic seizure at some
time in their life
Epilepsy is diagnosed on the basis of two or more
epileptic seizures.
Around 450,000 people in the UK have epilepsy (40
million people worldwide)
A seizure is triggered by a sudden interruption in the
brain's highly complex electro-chemical activity

(National Society for Epilepsy UK)

Age/Incidence
 Brain

100 billion neurons

Control centre:
temperature
sensory input
motor control
emotion
thought?
body functions

Taken from OUP Illustration Resource, 2002

 Gross anatomy

Front part of the brain;

involved in planning, organizing, problem solving, selective
attention, personality and a variety of "higher cognitive functions"
including behavior and emotions.
Gross anatomy
The parietal lobes contain the primary
sensory cortex which controls
sensation (touch, pressure).
Gross anatomy
Region in the
back of the
brain which
processes
visual
information.
 Gross anatomy
These lobes allow a person to
distinguish smells and are
believed to be responsible
for short-term memory.
Structure
Action Potential
Synapse Activity
 Seizures are a symptom of an underlying CNS
dysfunction
It is an abnormal, uncontrolled electrical
discharge from neurons
Cell membrane disruptions (permeability)
Altered ion distributions (chemical balance)
Decreased neurotransmitters (Ach and GABA)
Everyone has seizure threshold
 Classification of Seizures
Partial:
Simple partial seizures (no loss of consciousness)
With motor symptoms
With sensory symptoms Dependant on which
area of the brain
With autonomic symptoms
Only involve 1 hemisphere
Complex partial (loss of consciousness)
Simple followed by loss of consciousness
Impaired at the onset
 Unclassified:
Classification not possible to problems with diagnosis
suspected

Generalised (affect whole brain with loss of

consciousness):
Clonic, tonic (1min) or tonic-clonic (2-4min): muscle
spasm (extensors), respiration stops, defecation,
salivation, violent jerks
Myoclonic: seizures of a muscle or group of muscles
Absence: Abrupt loss of awareness of surroundings, little
motor disturbance, mostly children
Atonic: loss of muscle tone/strength
 Pathological Basis
Abnormal electrical discharge in the brain
Coordinated activity among neurons depends on a
controlled balance between excitation and inhibition
Any local imbalance will lead to a seizure
Imbalances occur between glutamate-mediated
excitatory neurotransmission and gamma-
aminobutyric acid (GABA) mediated inhibitory
neurotransmission
Generalised epilepsy is characterised by disruption of
large scale neuro-networks in the higher centres.
 Normal Processes
Depolarising Na+ and Ca++ ionic current shifts are activated
by glutamate receptors
Repolarising K+ currents are mediated by GABA receptors
Hyperpolarisation is mediated by GABAa receptors creating
an influx of Cl- => inhibition of impulse generation.

Any defect causes the neuron to be closer to the all

or none threshold for an AP = HYPEREXCITABLE
STATE.
Leading to instability between excitation and
inhibition => Epilepsy
 Other possible causes

Inherited mutations of proteins involved in the

ion channels

Reduction in the activity of homeostatic

ATPase pumps within neuron cell membranes
 Basis of Pharmacological Rx
Most anti-epileptic agents act either by
blockade of depolarisation channels (Na+ and
Ca++)

OR

Enhancing the activity of GABA

(neurotransmission inhibition)
 5 Categories of Anti-epileptic Drugs
All classifications are based upon chemistry:
Hydantoins
Succinimides
Benzodiazepines
Barbiturates
Miscellaneous
 Hydantoins - Phenytoin (Dilantin)
Use for pts with Tonic-Clonic seizures

Acts to promote intracellular removal of sodium during the

refractory period
Antagonism (blocking) of Na+ channels to reduce
excitability
Antagonism of Ca++ channels
Potentiation (activation) of GABA receptors to promote the
inhibitory role of GABA

Can be used in the Rx for neuropathic pain and cardiac

arrhythmias
 Pharmacokinetics:
Slowly absorbed from gut, use a slow IV if rapid
action is required
Avoid IM muscle damage
Eliminated by hepatic biotransformation
Can measure amount of free agent in the saliva
 Cautions: hepatic impairment, pregnancy, breast-feeding;
avoid sudden withdrawal;
Blood or skin disorders
Adverse effects: nausea, vomiting, mental confusion,
dizziness, headache, tremor, transient nervousness,
insomnia occur commonly; rarely dyskinesias, peripheral
neuropathy; ataxia, slurred speech, nystagmus and blurred
vision are signs of overdosage; rashes (discontinue; if mild
re-introduce cautiously but discontinue immediately if
recurrence), gingival hypertrophy and tenderness, coarse
facies, acne and hirsutism, fever and hepatitis; lupus
erythematosus, Stevens-Johnson syndrome, toxic
epidermal necrolysis, polyarteritis nodosa;
lymphadenopathy; rarely haematological effects, including
megaloblastic anaemia (may be treated with folic acid),
leucopenia, thrombocytopenia, agranulocytosis, and
aplastic anaemia; plasma-calcium concentration may be
lowered (rickets and osteomalacia)
Dose:
By mouth, initially 34 mg/kg daily or 150300 mg daily
(as a single dose or in 2 divided doses) increased gradually
as necessary (with plasma-phenytoin concentration
monitoring); usual dose 200500 mg daily (exceptionally,
higher doses may be used); child initially 5 mg/kg daily in
2 divided doses, usual dose range 48 mg/kg daily (max.
300 mg)
Contraindications: increases metabolism of the
contraceptive pill, anti-coagulants, and pethidine
 Succinimides Ethosuximide (Zarontin)
Use for pts with Absence seizures
Acts by antagonising Ca++ channels in the thalamocortical
relay neurons => prevention of synchronised neuronal firing
=> raising AP threshold

Pharmacokinetics:
Almost complete absorption from the gut
Extensive metabolism in the liver with a long half-life (2-
3 days)
Plasma and salivary concentrations correlate well for
monitoring purposes
 Cautions: hepatic and renal impairment; pregnancy and breast-
feeding;
avoid sudden withdrawal
Blood disorders (review)
Adverse effects: gastro-intestinal disturbances, weight loss,
drowsiness, dizziness, ataxia, dyskinesia, hiccup, photophobia,
headache, depression, and mild euphoria. Psychotic states, rashes,
hepatic and renal changes (see Cautions), and haematological
disorders such as agranulocytosis and aplastic anaemia occur rarely
(blood counts required if signs or symptoms of infection); systemic
lupus erythematosus and erythema multiforme (Stevens-Johnson
syndrome) reported; other side-effects reported include gum
hypertrophy, swelling of tongue, irritability, hyperactivity, sleep
disturbances, night terrors, inability to concentrate, aggressiveness,
increased libido, myopia, vaginal bleeding
Dose:
adult and child over 6 years initially, 500 mg daily, increased by
250 mg at intervals of 47 days to usual dose of 11.5 g daily;
occasionally up to 2 g daily may be needed; child up to 6 years
initially 250 mg daily, increased gradually to usual dose of
20 mg/kg daily
Contraindications: may make tonic-clonic seizures worse
 Bensodiazepines Clorazepam (Klonopin),
Diazepam (Valium)
Act by potentiating the actions of GABA causing
neurotransmission inhibition (primarily in the CNS)
Can be used to induce sleep (high dose), anticonvulsant
therapy and reduction in muscle tone.
Pharmacokinetics:
Well absorbed from the gut
Lipid soluble to ensure ready prentration of the blood
brain barrier
Metabolised in the liver to create active agents
(prolonged therapeutic action)
Slow elimination from body
 Clonazepam
Cautions: elderly and debilitated, respiratory disease, spinal or
cerebellar ataxia; history of alcohol or drug abuse, depression or
suicidal ideation; myasthenia gravis; porphyria; hepatic
impairment; renal impairment; pregnancy; breast-feeding
Contra-indications: respiratory depression; acute pulmonary
insufficiency; sleep apnoea syndrome; marked neuromuscular
respiratory weakness including unstable myasthenia gravis
Adverse effects: drowsiness, fatigue, dizziness, muscle
hypotonia, co-ordination disturbances; also poor concentration,
restlessness, confusion, amnesia, dependence, and withdrawal;
salivary or bronchial hypersecretion in infants and small
children; rarely gastro-intestinal symptoms, respiratory
depression, headache, paradoxical effects including aggression
and anxiety, sexual dysfunction, urinary incontinence, urticaria,
pruritus, reversible hair loss, skin pigmentation changes;
dysarthria, and visual disturbances on long-term treatment;
blood disorders reported; overdosage:
Dose:
1 mg (elderly 500 micrograms) initially at night for
4 nights, increased according to response over 24
weeks to usual maintenance dose of 48 mg daily
in 34 divided doses; may be given as a single daily
dose in the evening once maintenance dose
established; max. 20 mg daily; child up to 1 year,
initially 250 micrograms increased as above to
usual maintenance dose of 0.51 mg, 15 years,
initially 250 micrograms increased as above to 1
3 mg, 512 years, initially 500 micrograms
increased as above to 36 mg
Barbiturates Phenobarbital (Luminal)
Used for tonic-clonic seziures.

Act by increasing the duration of Cl- ion channel

opening by activating neuronal GABAa receptors
Causing hyperpolarisation of the AP, making it less
likely to fire again
Essentially, acts like GABA and can even potentiate
the effects of GABA when present.
 Pharmacokinetics:
Almost complete absorption
Elimination is by heptic and renal (25% excreted
unchanged)
Biotransformed in the liver into 2 active
metabolites
Plasma concentrations relate poorly to seizure
control, use only for monitoring of patient
compliance.
 Adverse effects:
CNS effects (sedation and fatigue)
Restlessness/Hyperactivity
Folate deficiency
Tolerance
Dependence with physical withdrawal reactions
Adverse drug-drug reactions (contraception and
warfarin).

Contraindications: Do not use with patients with

respiratory depression, children or elderly.
NOTE: low therapeutic index means more toxic and
overdose can have serious consequences
 Miscellaneous Agents Carbamazepine
(Tegretol)
Used in most epilepsy types.
MoA not fully understood but believed to be
related to:
Antagonist action of Na+ channels to inhibit
repetitive neuronal firing
Decreasing the production (or release) of
glutamate (excitatory chemical)
Can also be used in the Rx of neuropathic pain
 Pharmacokinetics:
Slow and incomplete absorption
Metabolised in the liver creates an expoxide
metabolite that can have a weak therapeutic effect
Relatively long half-life (1-2 days)
Potency decreases overtime therefore need to increase
dose to ensure adequate control of seizures
Plasma and salivary concentrations correlate well to
clinical effectiveness
 Adverse effects:
Nausea & vomiting (especially early Rx), constipation,
diarrhoea and anorexia
Skin irritation
CNS toxcity dizzy, drowsy, confusion
Bone marrow depression (rare)
Drug-drug reactions (contraception, warfarin)

Contraindications: see drug-drug reactions.

 Sodium Valproate
Use in all forms of epilepsy, as it suppresses the initial
seizure discharge and its spread.
Clinical actions are:
Antagonism of Na+ and Ca++ channels
Potentiation of GABA
Attenuation of Glutamate
Can be fast acting due to Na+ MoA, although the full Rx
effect usually takes weeks.
 Pharmacokinetics:
Well absorbed from gut (should be taken with food to
counteract gastric irritation)
Extensively metabolised in the liver
Rapidly transported across the blood brain barrier
Monitor plasma concentration for patient compliance
only
 Adverse effects:
GI upset (Nausea, vomiting, anorexia, abdominal pain
and diarrhoea)
Weight gain (appetite stimulation)
Transient hair loss
Tremor
Coma (rare)
Thrombocyptopenia (platelets)
Oedema
Severe hepatotoxicity (liver damage)

Contraindications: People with liver damage or a

history hepatic dysfunction
 Vigabatrin
Only used in conjunction with other agents when pt
becomes resistant (due to tolerance) or poorly tolerates
Effective in partial epilepsy but with restricted used due to
severe adverse effects (vision)
MoA: completely different to other agents as it is a
structural analogue of GABA that the enzyme that normally
inactivates GABA will degrade instead of GABA.
More GABA available to inhibit neuron transmission
Pharmacokinetics:
Rapidly absorbed from the gut
Unchanged by renal processes
Intermediate half-life (hrs)
Blood concentrations are of no value.
 Adverse effects:
Sedation, fatigue, dizziness, nervousness, irritability,
depression, impaired concentration. tremor (CNS
effects)
Psychotic reactions (check pt history)
Visual defects after prolonged use
Weight gain and oedema
 Lamotrigine (Lamictal)
Used for partial seizures in adults only
Acts by the inhibition (antagonism) of neuronal Na+
channels but is highly selective (onlu neurons that
synthesise glutamate and aspartate)
Additionally, decrease glutamate release
Pharmacokinetics: well absorbed, extensively
metabolised in the liver and has a long half-life.
 Adverse effects:
Fever, influenza-like symptoms
Skin irritation
GI disturbances (vomiting, diarrhoea)
CNS effects (drowsiness, headache, dizziness,
double vision)

Contraindications: Pts with hepatic

impairment
 Gabapentin (Neuronitin)
Used for partial seizures in adults
Designed to be a structural analogue of GABA
but it does not mimic GABA in the brain.
Acts via:
Increased synthesis and release of GABA
Decrease degradation of GABA
Inhibition of Ca++ channels
 Pharmacokinetics:
Incompletely absorbed in the gut
Excreted unchanged via kidney processes
Short half-life
Adverse effects:
CNS effects (dizzy, drowsy, fatigue, headache, double
visions)
Nausea and vomiting
Contraindication: be careful with sudden
withdrawal in the elderly due to kidney effects and
alterations in acid-base balance.
Anti-Parkinson Drugs
 Aims

To review pathogenesis of Parkinson's

To review clinical presentation

To identify treatment drugs

 Prevalence
1.5 million in USA and 120,000 in the UK accounts for
about 10% of all acute hospital admissions
Effects 2 in 1,000 people; aged 80+ incidence is 1 in 50.
Mainly affects adults in later life
Slightly more common in men, Afro-Caribbean's and people
from the Indian subcontinent
Affects the quality of life of about 500,000 (family, carers
etc)
 Causes
Unclear, but is a number of factors:
Environmental toxins
Free Radicals there is a increase in post-mortem brain
sections
Aging age related decline in dopamine production
Genetic possible, no single gene identified
 Parkinsons Disease
A degenerative and progressive disorder
Associated with neurological consequences of
decreased dopamine levels produced by the basal
ganglia (substantia nigra)
Dopamine is a neurotransmitter found in the neural
synapses in the brain
Normally, neurones from the SN supply dopamine to
the corpus striatum (controls unconscious muscle
control)
Initiates movement, speech and self-expression
 Balance, posture, muscle tone and involuntary
movement depends on the roles of dopamine
(inhibitory) and acetylcholine (Ach: excitatory)
If dopamine missing, Ach produces more of an effect
on muscles

Basis to exploit by drugs:

Restore dopamine function
Inhibit Ach within corpus striatum
Consequences of dopamine reductions
Tremors hands and head develop involuntary
movements when at rest; pin-rolling sign (finger and
thumb)
Muscle rigidity arthritis-like stiffness, difficulty in
bending or moving limbs; poker face
Brandykinesia problems chewing, swallowing or
speaking; difficulty in initiating movements and
controlling fine movements; walking becomes
difficult (shuffle feet)
Postural instability humped over appearance,
prone to falls
 Additional symptomology
Anxiety
Depression
Sleep disturbance
Dementia
Disturbance of ANS (difficulty in urinating)
 Clinical Presentation
Altered body image Excessive sweating (impaired
(depression) thermoregulation)
Poor balance Festinating gait
Bradykinesia (slow movement) Hullucinations (visual)
Bradyphrenia (slowness of Postural hypotension
thought) Restless leg syndrome (leg
Constipation aches, tingle, or burn)
Dribbling/drooling Rigidity
Dyskinesias (involuntary Sleep disturbance
movements) Slurring/slowing of speech
Dysphagia (difficulty swallowing Tremor
Dystonia (pain spasms)

Ref: Noble C (2000) Parkinsons Disease the challenge. Nursing Standard, 15 (12), 43-51
 Treatment (early stage)
Clinical judgements based upon level of disability,
age, cognitive status, concurrent medial problems
Initial pharmacological therapies are titrated to
determine optimal dose per person
Agent used: Levodopa
Social support and health education vital
Referrals to other professional groups
 Treatment (maintenance stage)
Speech therapist is prophylactic and deals with
swallowing problems (recommend exercises etc)
Impaired thermoregulation use beta-blockers
Disturbance in sleep can be side effects of
medication; change time of intake or use a controlled
release drug delivery system
Continued health education and liaison with other
professionals
 Treatment (complex stage)
Function has deteriorates to such a level a
combination of drugs are prescribed
Dyskinesias and Dystonia can be associated with
long-term Levodopa use and it can be difficult to
manage these effects co-agent is co-beneldopa
Restless-leg dopamine agonists
Anxiety relaxation, distraction, CBT
Depression alterations in dose of anti-parkinsons
drugs
 Cognitive problems referral to clinical
psychologist and prescription of anti-dementia
agents
Hallucinations - ? anti-psychotics

Essentially, a multidimensional approach to

pharmacological treatment combined with a
multidisciplinary approach
 Medication Rational
Replace depleted levels of dopamine
Stimulate the nerve receptors enabling
neurotransmission
Increase the effect of dopamine on nerve receptors
(agonist)
Counteract the imbalance of Ach and Dopamine
 The Drugs:
Dopaminergic drugs (improving dopamine
functioning)
Levodopa
Dopamine receptor agonists
Amantadine
Selective monoamine oxidase B inhibitors
Catechol-O-methyltransferase inhibitors
Antimuscarinic drugs (Ach inhibitors)
 Levodopa (or Levodopamine)
Can not administer dopamine directly, as it does not
cross the blood brain barrier
A natural amino acid that the brain converts into
dopamine (replacement therapy) used since the
1960s
To make it slow release, combined with benserazide
(an enzyme inhibitor) to create co-beneldopa or co-
careldopa (Sinemet)
Dose = 50, 100 or 200mg (12.5, 25 or 50mg)
Sumber: Adams et al (2006). Pharmacology for Nurses
A Pathophysiologic Approach. Prentice Hall Publishers
 Pharmacokinetics:
Absorbed by the small intestine by an active
transport system
Decarboxylation occurs in peripheral tissues (gut
wall, liver and kidney
decrease amount available for distribution 1% of an
oral dose
Extracerebral dopamine amounts causing unwanted
effects (benserazide)
Short half-life
 Cautions: pulmonary disease, peptic ulceration, cardiovascular
disease, diabetes mellitus, osteomalacia, open-angle glaucoma,
history of skin melanoma (risk of activation), psychiatric illness (avoid
if severe); warn patients about excessive drowsiness; in prolonged
therapy, psychiatric, hepatic, haematological, renal, and
cardiovascular surveillance is advisable; warn patients to resume
normal activities gradually; avoid abrupt withdrawal;
Contra-indications: closed-angle glaucoma; pregnancy breast-
feeding
Adverse effects: anorexia, nausea and vomiting, insomnia, agitation,
postural hypotension (rarely labile hypertension), dizziness,
tachycardia, arrhythmias, reddish discoloration of urine and other
body fluids, rarely hypersensitivity; abnormal involuntary movements
and psychiatric symptoms which include hypomania and psychosis
may be dose-limiting; depression, drowsiness, headache, flushing,
sweating, gastro-intestinal bleeding, peripheral neuropathy, taste
disturbance, pruritus, rash, and liver enzyme changes also reported;
syndrome resembling neuroleptic malignant syndrome reported on
withdrawal
Dose:
Initially 125500 mg daily in divided doses after meals, increased according to
response (but rarely used alone, see notes above)
 WHAT DRUGS INTERACT WITH LEVODOPA?

Adverse effects:
As a result of the amount of peripheral dopamine
levels
Nausea, vomiting
Postural hypotension
As a result of the amount of CNS dopamine levels
Dyskinetic involuntary movements (face & neck)
Hallucinations and confusion
 Dopamine receptor agonists
Apopmorphine (APO-go):
SC administration
Rescue therapy rapid onset with a short
duration of action (~50mins)
Bromocriptine (Parlodel); Pergolide (Celance);
Ropinirole (Requip)
Direct agonists of dopamine receptors in the
brain
?longer lasting therapeutic effects that Levodopa
 Start a pt on this alone, then combine with
levodopa to smooth out control when PD is
getting progressive (especially young)
Pharmacokinetics:
Incompletely abosrbed need extensive first-pass
metabolism (biotransformed in liver)
Pergolide & Ropinirole have higher bioavailability
(distribution)
Short to medium half life (Potency)
 Adverse effects:
Use gradual dose titration
N + V (particularly Apomorphine)
Dyskinesia
Hallucinations and confusion
Peripheral vasospasm (Raynaunds)
Respiratory depression (Apomorphine
 Amantadine (Symmetrel)
Originally an antiviral drug, now used as conjucntive
therapy for dyskinesis effects produced by Levodopa
MoA:
stimulates/promotes the release of dopamine stored in the
synaptic terminals
Reduces reuptake of released dopamine by pre-synaptic neuron
Pharmacokinetics:
Well absorbed, long half-life, excreted unchanged by the kidney
Adverse effects:
Not many
Ankle oedema, postural hypotension, nervousness, insomnia,
hallucinations (high dose)
 Other Disease Modifying Drugs
Selective monoamine oxidase B inhibitors (selegiline
Trade name Eldepryl/Zelapar):
MoA: prolongs the effects of levodopa as MAO-B degrades
dopamine
Pharmacokinetics: completely absorption, short half-life
Adverse effects: N, V, Dia, Constipation; dry mouth, sore
throat; transient dizziness; insomnia, confusion and
hallucinations
Early stage prescribed on it is own to delay need for
levodopa and there is good evidence for its slowing down
of PD progression
 Catechol-O-methltransferase inhibitors - COMT
(entacapone, Trade name Comtess)
MoA: inhibits the breakdown of levodopa
Pharmacokinetics: variability of absorption, extensive first-
pass metabolism, short half-life
Adverse effects: dyskinesias, hallucinations; N, V, Dia and
abdominal pain
New combination Levodopa/carbidopa/entacapone
(Stalevo) as 1 tablet (50, 100, 150mg)
 Antimuscarinic/Anticholinergic Drugs:
Trihexyphenidyl (Broflex, Artane, Agitane); Benztropine
(Cogentin); Orphanadrine (Disipal); Procycline (Kemadrin,
Arpicolin)
Less common drugs but they affect Ach based interactions
MoA: blocking cholingeric (Ach) receptors to restore
balance
Pharmacokinetics: fairly well absorbed, extensive hepatic
metabolism, intermediate to long half-lifes
Adverse effects: dry mouth and confusion
Disease Modifying Drugs Overview
 Symptom Management Drugs

PD is multidimensional, therefore there are a

number of clinical presentations that require
supplementary agents
Drug-Drug reactions is the problem
Major area is depression
 Antidepressants
Amitriptyline (Tryptizol), imipramine (Tofranil),
Nortriptyline (Allegron), Iofepramine (Gamanil)
MoA: block re-uptake of noradrenaline and serotonin
=> Sedative actions, can help with drooling and loss
of appetite
Adverse effects: sleepiness, dry mouth, increased
hunger, cardiac arrhythmias and changes in BP
Can interfere with the effects of levodopa!
 Other Drugs to Avoid

Generic Name Brand Name Prescribed for

Prochlorperazine Stemetil N +V, Dizziness
Prephenazine Triptafen Depression
Flupentixol Fluanxol/Depixol Confusion,
Hallucinations
Chlorpromazine Largactil
Pimozide Orap
Sulpiride Dolmatil