NCM 235

Drugs Acting on the

central and
peripheral nervous
system
 NCM 235

Drugs for Seizures

• Epilepsy may be defined as any disorder
characterized by recurrent seizures
• The characteristic event is the seizure,
which is often associated with convulsion,
but may occur in many other forms
• Seizure is a disturbance of electrical
activity in the brain that may affect
consciousness, motor activity, and
sensation
• Seizure is caused by an abnormal high-
frequency discharge of a group of neurons,
starting locally and spreading to a varying
extent to affect other parts of the brain.
• Convulsions refer to involuntary, violent
spasms of the large skeletal muscles of the
face, neck, arms, and legs.
• The term seizure and convulsion are not
synonymous. Although other types of
seizures do involve convulsions, other
seizures do not.
• Thus it may be stated that all convulsions
are seizures, but not all seizures are
convulsions.
• A seizure is considered a symptom of an
underlying disorder, rather than a disease in
itself
Causes of Seizures:
• Infectious diseases such as meningitis and
encephalitis
• Physical trauma like direct blows to the
skull which may increase intracranial
pressure
• Metabolic disorders such as changes in
fluids and electrolytes (e.g., hypoglycemia,
hyponatremia)
Causes of Seizures:
• Vascular diseases such those caused by
respiratory hypoxia and carbon
monoxide poisoning
• Most frequent cause of a seizure is the
failure to take medication to control
previously diagnosed seizure activity.
 Nature of Epilepsy

• Seizures may be partial or generalized

depending on the location and spread of
the abnormal neuronal discharge.
• The attack may involve mainly motor,
sensory or behavioral phenomena.
 Types of Epilepsy
Partial seizures
• The discharge begins locally, and often
remains localized. Produce relatively simple
symptoms without loss of consciousness.
Generalized seizures
• Involve the whole brain, including the reticular
system, thus producing abnormal electrical
activity throughout both hemispheres.
Immediate loss of consciousness.
Classification of Seizures
• Simple partial seizures, which occur in a single area of the
brain and may involve a single muscle movement or
sensory alteration
• Complex partial seizures, which involve a series of
reactions or emotional changes and complex sensory
changes such as hallucinations, mental distortion,
changes in personality, loss of consciousness, and loss of
social inhibitions. Motor changes may include involuntary
urination, chewing motions, diarrhea, and so on. The
onset of complex partial seizures usually occurs by the
late teens.
Two common forms of generalised
epilepsy:
• Tonic-clonic fit (grand mal) and the
absence seizure (petit mal)
• Status epilepticus is a life- threatening
condition in which seizure activity is
uninterrupted.
 Mechanism of Action

Anti-seizure drugs act by

• Blocking the Na+ channel
• Blocking the Ca++ channel
• Blocking the excitatory
neurotransmitters and ↑ the activity of
inhibitory neurotransmitter (GABA)
 Antiseizure Drugs
A. Barbiturates
 Phenobarbital – all forms of epilepsy, status
epilepticus, severe recurrent seizures
B. Benzodiazepines
 clonazepam – petit mal
 lorazepate – focal seizures
 diazepam – all forms of epilepsy, status
epilepticus, recurrent seizures, tetanus
C.Hydantoins
phenytoin – grand mal and
psychomotor seizures
D.Succinimides
ethosuximide – petit mal seizures
C. Other Drugs
 valproic acid – petit mal seizures in
adults and children
 carbamazepine – grand mal, mixed,
psychomotor seizures
 topiramate – adjunctive therapy for
partial-onset seizures in adults and
children
The main drugs in current use are:
Primary:
• phenytoin, carbamazepine, valproate
and ethosuximide
Secondary:
• phenobarbitone: highly sedative
• clonazepam
• diazepam used in treating status
epilepticus
 Phenytoin

Mechanism of Action:
Acts by stabilizing membranes
1. Blocking voltage-dependence Na+ channel
2. Blocking voltage-dependence Ca2+ channel
3. Inhibiting calcium-induced secretory processes,
including release of hormones and neurotransmitters
4. Inhibiting post tetanic potentiation (PTP)
Pharmacokinetics:

• Phenytoin is a weak acid, its intestinal

absorption is variable and plasma
concentration can vary widely therefore
monitoring is needed
• Metabolized by the microsomal system and
is excreted first in the bile and then in the
urine.
 Treatment and Uses
• Treatment of grand mal epilepsy and
tonic-clonic seizure disorders, but not in
absence seizures
• Treatment on peripheral neuralgia - an
abnormal condition characterized by
severe stabbing pain
• Antiarrhythmias
 Other Adverse Effects
• Ataxia
• Diplopia
• Blood dyscrasias
• Hirsutism
• Increased collagen proliferation
• Fetal malformations: fetal hydantion
syndrome
Gingival hyperplasia
Drug interactions:
• increased plasma concentrations of
phenytoin can occur by concurrent
administration of chloramphenicol,
isoniazid, cimetidine, dicumarol.
 Carbamazepine

• Derivative of tricyclic antidepressants

• Similar profile to that of phenytoin, but
with fewer unwanted effects
• Effective in most forms of epilepsy
(except absence seizures); particularly
effective in psychomotor epilepsy; also
useful in trigeminal neuralgia and mania.
 Valproate

• Very effective against absence seizure

• Mechanism: facilitate glutamic acid
decarboxylase; inhibit GABA-transaminase;
enhance synaptic responses
• Unwanted effects: anorexia, nausea,
teratogenicity, liver damage (rare but
serious)
 Ethusuximide

• The main drug used to treat absence

seizures, may exacerbate other forms
• Acts by blocking T-type Ca2+-channels
• Relatively few unwanted effects, mainly
nausea and anorexia sometimes mental
disturbances
 Benzodiazepines

• Diazepam: preferred drugs for status

epilepticus
• Nitrazepam: petit mal, especially myoclonic
seizures and infantile spasms
• Clonazepam: one of the most effective in
some cases of myoclonic seizures. Used in
petit mal and status epilepticus
 Barbiturates

• phenobarbital (Luminal) is useful in the

treatment of generalized tonic-clonic
seizures and status epilepticus
• Adverse effects: sedation, depression, drug
interaction.
 Clinical Uses of Antiepileptic Drugs
Tonic-clonic (grand mal) seizures:
• carbamazepine is preferred because of low
incidence of side-effects
• phenytoin and valproate may be prescribed
• Use of single drug is preferred when possible,
because of risk of pharmacokinetic interactions.
Partial (focal) seizures: carbamazepine, valproate;
clonazepam or phenytoin are alternatives.
Absence seizures (petit mal): ethosuximide or
valproate
• Valproate is used when absence seizures
coexist with tonic-clonic seizures, since most
drugs used for tonic-clonic seizures may
worsen absence seizures
Myoclonic seizures: valproate or clonazepam.
Status epilepticus: must be treated as an
emergency, with diazepam intravenously