DRUGS THAT ACT ON THE

CNS
H.A. ROBERTSON, Ph.D.
PROFESSOR OF PHARMACOLOGY AND MEDICINE
(NEUROLOGY)
Telephone 494-3430
Email: Harold.Robertson@dal.ca
 Sedative-Hypnotic Drugs, Chapter 22

OBJECTIVES

1. Identify the major chemical classes of sedative-

hypnotics.
2. Describe the pharmacodynamics of benzodiazepines
and barbiturates, including their mechanisms of action.
3. Compare the pharmacokinetics of commonly used
benzodiazepines and barbiturates and discuss how
differences among them affect clinical use.
4. Describe the clinical uses and the adverse effects of
sedative-hypnotics.
1. Benzodiazepines
2. Barbiturates
3. Non-benzo benzos
(Zaleplon, zopidem)
4. Melatonin receptor
agonist (Ramelteon)
5. Buspirone
6. Others
(antpsychotics,
antidepressants)
 Neuropharmacology of the
benzodiazepines
GABA (gamma-aminobutyric acid) is the major inhibitory neurotransmitter in
the central nervous system. Benzodiazepines increase the efficiency of
GABAergic synaptic inhibition. The benzodiazepines do not substitute for
GABA but appear to enhance GABA's effects allosterically without directly
activating GABAA receptors or opening the associated chloride channels.
Increased chloride ion conductance >>> increase in the frequency of channel-
opening events.

Barbiturates also facilitate the actions of GABA at multiple sites in the central
nervous system. In contrast to benzodiazepines they increase the duration of the
GABA-gated chloride channel openings. At high concentrations, the barbiturates
may also be GABA-mimetic, directly activating chloride channels. These effects
involve a binding site or sites distinct from the benzodiazepine binding sites.
their more pronounced central depressant effects. They have a low margin of
safety compared with benzodiazepines and the newer hypnotics. Serious suicide
potential (Marilyn Monroe, etc, etc.)
Endogenous ligands for the BZ receptor
The physiologic significance of endogenous modulators of the functions of
GABA in the central nervous system remains unclear.
Benzodiazepine Binding Site Ligands
Three types of ligand-benzodiazepine receptor interactions have been reported:
(1) Agonists facilitate GABA actions, and this occurs at multiple BZ binding
sites in the case of the benzodiazepines. As noted above, the
nonbenzodiazepines zolpidem, zaleplon, and eszopiclone are selective agonists
at the BZ sites that contain an 1 subunit.
(2) Antagonists are typified by the synthetic benzodiazepine derivative
flumazenil, which blocks the actions of benzodiazepines, eszopiclone, zaleplon,
and zolpidem
(3) Inverse agonists act as negative allosteric modulators of GABA-receptor
function. Their interaction with BZ sites on the GABAA receptor can produce
anxiety and seizures, an action that has been demonstrated for several
compounds, especially the -carbolines, eg, n-butyl--carboline-3-carboxylate
(-CCB). In addition to their direct actions, these molecules can block the
effects of benzodiazepines.
 Antiseizure Drugs, Chapter 24
OBJECTIVES

2. Identify the mechanisms of antiseizure drug action.

3. Describe the main pharmacokinetic features and adverse effects
of major antiseizure drugs.
4. Identify new antiseizure drugs and their important
characteristics.
5. Describe the factors that must be considered in designing a
dosage regimen for an anti-seizure drug.
 Drug Development for Epilepsy
•It was once assumed that a single drug could be developed for the treatment of all forms of epilepsy, but causes of
epilepsy are extremely diverse, encompassing genetic and developmental defects and infective, traumatic,
neoplastic, and degenerative disease processes.
•Some specificity according to seizure type, most clearly seen with generalized seizures of the absence type.
•Respond to ethosuximide and valproate but can be exacerbated by phenytoin and carbamazepine.
•Drugs acting selectively on absence seizures identified by animal screens, using either threshold pentylenetetrazol
clonic seizures in mice or rats or mutant mice showing absence-like episodes (lethargic, star-gazer, or tottering
mutants).
•In contrast, the maximal electroshock (MES) test, with suppression of the tonic extensor phase, identifies drugs
such as phenytoin, carbamazepine, and lamotrigine that are active against generalized tonic-clonic seizures and
complex partial seizures.
•Use of the maximal electroshock test as the major initial screen for new drugs has probably led to the
identification of drugs with a common mechanism of action involving prolonged inactivation of the voltage-
sensitive sodium channel.
•Limbic seizures induced in rats by the process of electrical kindling (involving repeated episodes of focal
electrical stimulation) probably provide a better screen for predicting efficacy in complex partial seizures.
 Antiseizure drugs
Mechanisms of action

1. Enhancement of GABA actions

-increase GABA actions at receptor (benzodiazepines,
phenobarbital)
-vigabatrin inhibits GABA transaminase
-tiagabin blocks GABA uptake
2. Inhibition of sodium channel function
-phenytoin, carbamazepine, valproic acid, lamotrigine
3. Inhibition of Calcium T-type channels (ethosuximide)
Basic Pharmacology of Antiseizure Drugs: Chemistry

•Until 1990, ~ 16 antiseizure drugs available, and 13

of them can be classified into five very similar
chemical groups: barbiturates, hydantoins,
oxazolidinediones, succinimides, and acetylureas.
These groups have in common a similar heterocyclic
ring structure with a variety of substituents.
•The remaining drugs—carbamazepine, valproic
acid, and the benzodiazepines—are structurally
dissimilar, as are the newer compounds marketed
since 1990, ie, felbamate, gabapentin, lamotrigine,
levetiracetam, oxcarbazepine, pregabalin, tiagabine,
topiramate, vigabatrin, and zonisamide.
 Pharmacokinetics
The antiseizure drugs exhibit many similar pharmacokinetic properties because most have been
selected for oral activity and all must enter the central nervous system. Although many of these
compounds are only slightly soluble, absorption is usually good, with 80–100% of the dose reaching
the circulation. Most antiseizure drugs are not highly bound to plasma proteins.

Antiseizure drugs are cleared chiefly by hepatic mechanisms and liver. Plasma clearance is relatively
slow; many anticonvulsants are therefore considered to be medium- to long-acting. Some have half-
lives longer than 12 hours. Many of the older antiseizure drugs are potent inducers of hepatic
microsomal enzyme activity.
 Drugs Used in Partial Seizures & Generalized Tonic-
Clonic Seizures

The classic major drugs for partial and generalized tonic-

clonic seizures are phenytoin (and congeners),
carbamazepine, valproate, and the barbiturates.

However, the availability of newer drugs—lamotrigine,

levetiracetam, gabapentin, oxcarbazepine, pregabalin,
topiramate, vigabatrin, and zonisamide is altering clinical
practice in countries where these compounds are
available.
 Phenytoin
Phenytoin is the oldest (1938) nonsedative antiseizure
drug (diphenylhydantoin old name).
Alters Na channel, prolongs opening time
 Phenytoin: Toxicity
•Dose-related adverse effects caused by phenytoin are unfortunately similar to other antiseizure drugs
in this group, making differentiation difficult in patients receiving multiple drugs.
•Nystagmus occurs early, as does loss of smooth extraocular pursuit movements, but neither is an
indication for decreasing the dose.
•Diplopia and ataxia are the most common dose-related adverse effects requiring dosage adjustment;
sedation usually occurs only at considerably higher levels.
•Gingival hyperplasia and hirsutism occur to some degree in most patients; the latter can be
especially unpleasant in women.
•Long-term use is associated in some patients with coarsening of facial features and with mild
peripheral neuropathy, usually manifested by diminished deep tendon reflexes in the lower
extremities.
•Long-term use may also result in abnormalities of vitamin D metabolism, leading to osteomalacia.
Phenytoin

Drug Interactions &

Interference with
Laboratory Tests

Induction of dug
metabolizing
enzymes
 Carbamazepine
•Closely related to imipramine antidepressants, carbamazepine is a tricyclic compound
effective in treatment of bipolar depression.
•Initially marketed for the treatment of trigeminal neuralgia but has proved useful for
epilepsy as well.
Clinical Use
long been considered a drug of choice for both partial seizures and generalized tonic-clonic seizures,
some of the newer antiseizure drugs are beginning to displace it from this role.
Toxicity
most common adverse effects of carbamazepine are diplopia and ataxia.
Considerable concern exists regarding the occurrence of idiosyncratic blood dyscrasias with
carbamazepine, including fatal cases of aplastic anemia and agranulocytosis.
Adjuncts in the treatment of Partial Seizures
• Felbamate – blocks glycine activation of NMDA
receptors and inhibit initiation of seizures
• Gabapentin – despite the fact that Gabapentin has a
similar structural relationship to GABA, it does not act
on the GABA receptor. Gabapentin may alter GABA
metabolism or alter reuptake by presynaptic GABA
transporters.
• Lamotrigine – blocks voltage-sensitive NA channels
and has another mechanism of action (inhibits the
release of excitatory amino acids such as glutamate?)
• Topiramate - blocks voltage-sensitive NA channels,
augments GABA activation of GABAA receptor, blocks
kainate and AMPA glutamate receptors
 Drugs for Generalized
Absence, Myoclonic or Atonic
Seizures
• Ethosuximide – blocks T-type Ca
channels in thalamic neurons
• Valproate -Na channels
• Lamotrigine -Na channels
 Management of Seizure Disorders

• Start therapy with low dose of single drug

• Increase dose to attain serum concentration
• If single drug is not effective, a second drug
may be added or substituted
• Discontinue drug use slowly
• Monitor serum levels to ensure adequate
dosage (toxicity, therapeutic failure or non-
compliance)
 Therapeutic choices (adapted from Dr.
M.Sadler, Division of Neurology, Dalhousie University)
Seizure type 1st choice alternative or add-on
Tonic-clonic carbamazepine clobazam
phenytoin lamotrigine
valproic acid topiramate

Absence ethosuximide clobazam

valproic acid lamotrigine
topiramate

Partial (simple carbamazepine clobazam

or complex) phenytoin lamotrigine
valproic acid
phenobarbital
 Summary
• Partial and generalized seizures
• Three mechanisms of antiepileptic drug
action
• Drugs of choice
• Many antiepileptic interact with other
medications and produce CNS and GI
side effects
 Antiseizure drugs
Use of antiseizure drugs in other non-seizure conditions
Carbamazepine
mania, trigeminal neuralgia (possibly behavioural disturbances in dementia)
Gabapentin
neuropathic pain (possibly mania)
Lamotrigine
(possibly mania, migraine, schizophrenia, first effective use in treatment-resistant
schizophrenia by Dr. Serdar Dursun, Psychiatry, Dalhousie Univ.)
Phenytoin
(possibly neuropathic pain, trigeminal neuralgia)
Valproic acid
Mania, migraine (possibly behavioural disturbances in dementia)
 Antiseizure drugs
Other drugs used in management of epilepsy
Benzodiazepines

Status epilepticus

0-5 min history, physical examination, intubation?, ECG

5-10 min start 2 large bore IV saline, dextrose, thiamine,

lorazepam or diazapam IV

10-30 min Phenytoin or phenobarbital IV

30-60 min If seizures persist after phenytoin, use phenobarbital or vice

versa. Admit to CCU, get EEG, consider thiopental, propofol