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 sedativehypnotics. 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. 2. 3. 4.

5. 6.

Benzodiazepines Barbiturates Non-benzo benzos (Zaleplon, zopidem) Melatonin receptor agonist (Ramelteon) Buspirone 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 channelopening 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.
3.

Inhibition of sodium channel function

-phenytoin, carbamazepine, valproic acid, lamotrigine

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 drugscarbamazepine, valproic acid, and the benzodiazepinesare 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 80100% 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 longacting. 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 TonicClonic Seizures The classic major drugs for partial and generalized tonicclonic seizures are phenytoin (and congeners), carbamazepine, valproate, and the barbiturates. However, the availability of newer drugslamotrigine, 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 noncompliance)

Therapeutic choices (adapted from Dr.

M.Sadler, Division of Neurology, Dalhousie University)
Seizure type Tonic-clonic 1st choice carbamazepine phenytoin valproic acid ethosuximide valproic acid alternative or add-on clobazam lamotrigine topiramate clobazam lamotrigine topiramate clobazam lamotrigine valproic acid phenobarbital

Absence

Partial (simple or complex)

carbamazepine phenytoin

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 5-10 min history, physical examination, intubation?, ECG start 2 large bore IV saline, dextrose, thiamine, lorazepam or diazapam IV Phenytoin or phenobarbital IV

10-30 min

30-60 min If seizures persist after phenytoin, use phenobarbital or vice versa. Admit to CCU, get EEG, consider thiopental, propofol