Drugs Affecting the Nervous System

By Dr.Sreerangarajan. M.D.

Nervous system
Basic unit of the nervous system = neuron Sensory Associative Motor Parts of the neuron Cell body Dendrite Axon

Nervous system Two parts of the nervous system CNS (central): brain and spinal cord PNS (peripheral): cranial nerves, spinal nerves, autonomicnervous system

CNS Drugs
Anticonvulsants: help prevent seizures by suppressing the spread of abnormal electric impulses from the seizure focus to other areas of the cerebral cortex All anticonvulsants are CNS depressants and may cause ataxia, drowsiness, and hepatotoxicity

CNS Drugs
Examples: Phenobarbital (short-acting barbiturate) Primidone (structurally similar to phenobarbital) Diazepam (used IV to treat status epilepticus) Clorazepate (adjunct anticonvulsant) Potassium bromide (adjunct anticonvulsant)

CNS Drugs
Tranquilizers: used to calm animals; reduce anxiety and aggression Sedatives: used to quiet excited animals; decrease irritability and excitement Anti-anxiety drugs: lessen anxiousness, but do not make animals drowsy

CNS Drugs
Examples in these groups: Phenothiazine derivatives (acepromazine, chlorpromazine) Benzodiazepines (diazepam) Alpha-2 agonists (xylazine, detomidine, medetomidine)

CNS Drugs
Analgesics: drugs that relieve pain Analgesics are categorized as nonnarcotic or narcotic Narcotic analgesics are used for moderate to severe pain Narcotic refers to opioid (natural) or opioid-like (synthetic) products

CNS Drugs
Opioids:
Do not produce anesthesia; patients still respond to sound and sensation Produce analgesia and sedation, and relieve anxiety Side effects: respiratory depression, excitement if given too rapidly Produce their effects by the action of opioid receptors
Mu = found in the brain Kappa = found in the cerebral cortex and spinal cord Sigma = found in the brain

CNS Drugs
Examples of opioids:
Opium Morphine sulfate Meperidine Hydromorphone Butorphanol Hydrocodone Fentanyl Etorphine Buprenorphine Pentazocine

CNS Drugs
Opioid antagonists: Block the binding of opioids to their receptors Used to treat respiratory and CNS depression of opioid use Examples include naloxone and naltrexone

CNS Drugs
Neuroleptanalgesics:
Combination of an opioid and a tranquilizer or sedative Can cause a state of CNS depression and analgesia and may or may not produce unconsciousness Combination products may be prepared by veterinarian Examples include acepromazine and morphine; xylazine and butorphanol

CNS Drugs
Anesthetics:
Anesthesia means without sensation Anesthetics interfere with the conduction of nerve impulses Anesthetics produce loss of sensation and muscle relaxation, and may cause loss of consciousness General anesthetics affect the CNS, produce loss of sensation with partial or complete loss of consciousness Local anesthetics block nerve transmission in the area of application with no loss of consciousness

CNS Drugs
Local anesthetics:
Block pain at the site of administration or application in the PNS and spinal cord May be used as nerve blocks, aid in endotracheal tube placement, and ease skin irritation Applied topically to mucous membranes and the cornea by infiltration of a wound or joint, by IV, and around nervous tissue Examples include lidocaine, proparacaine, tetracaine, mepivacaine, bupivacaine

CNS Drugs
General Anesthetics Injectable general anesthetics: Barbiturates: CNS depressants derived from barbituric acid. Used mainly as anticonvulsants, anesthetics, and euthanasia solutions Side effects: potent cardiovascular and respiratory depression May be long-acting, short-acting, or ultra-short acting May vary in structure and be classified as an oxybarbiturate or thiobarbiturate Examples: phenobarbital, pentobarbital, thiopental, methohexital

CNS Drugs
General Anesthetics Injectable general anesthetics (cont.):
Dissociatives: belong to the cyclohexamine family Cause muscle rigidity (catalepsy), amnesia, and mild analgesia Work by altering neurotransmitter activity Used for restraint, diagnostic procedures, and minor surgical procedures Side effects: cardiac stimulation, respiratory depression, and exaggerated reflexes Examples include ketamine and tiletamine

CNS Drugs
General Anesthetics Injectable general anesthetics (cont.):
Miscellaneous:
Guaifenesin: skeletal muscle relaxant used in combination with an anesthetic drug to induce general anesthesia in horses Propofol: short-acting injectable anesthetic agent that produces rapid and smooth induction when given IV (lasts 2 5 minutes)

CNS Drugs
General Anesthetics/Analgesics Inhalant general anesthetics: Inhalant anesthetics are halogenated hydrocarbons
Halothane:
Nonflammatory, inhalant anesthetic administered via a precision vaporizer Can cause hepatic problems, malignant hyperthermia, cardiac problems, and tachypnea Contraindicated in cases of gastric dilatation, pneumothorax, and twisted intestines Leave animals on 100% oxygen following surgery to prevent diffusion hypoxia

CNS Drugs
General Anesthetics/Analgesics Inhalant general anesthetics (cont.): Isoflurane: Nonflammatory, inhalant anesthetic administered via a precision vaporizer Causes rapid induction of anesthesia and short recoveries following anesthetic procedures

CNS Drugs
Does not cause the cardiac arrhythmia problems of halothane Vigilant monitoring is needed because the animal can change anesthetic planes quickly Masking of animals with isoflurane is difficult because it irritates the respiratorysystem Side effects include respiratory depression and malignant hyperthermia

CNS Drugs
General Anesthetics/Analgesics Inhalant general anesthetics (cont.): Isomers of isoflurane: Nonflammable and have fewer cardiovascular side effects than other inhalants Quickly enter the bloodstream and escape to the brain, making them good for mask inductions

CNS Drugs
Examples: Enflurane: increases intracranial pressure (do not use if animal has seizure history) Desflurane: cannot be delivered by standard vaporizers and can reduce blood pressure Sevoflurane: profound respiratory depressant; close monitoring is needed

CNS Drugs
General Anesthetics/Analgesics Inhalant general analgesics (cont.):
Nitrous oxide:
Inhalant analgesic that diffuses rapidly throughout the body. Can enter gas-filled body compartments (increases pressure in these compartments). Contraindicated in cases of gastric dilatation, pneumothorax, and twisted intestines. Leave animals on 100% oxygen following surgery to prevent diffusion hypoxia.

CNS Drugs
CNS stimulants: Reverse CNS depression caused by CNS depressants. Doxapram: stimulates brainstem to increase respiration in animals with apnea or bradypnea. Commonly used when animals have C-sections. Methylxanthines: bronchodilators that have adverse effect of CNS stimulation. Include caffeine, theophylline, and aminophylline. Side effects include gastrointestinal irritation and bronchodilation.

CNS Drugs
Euthanasia solutions: Used to humanely end an animal s life. Usually contain pentobarbital. When pentobarbital is the only narcotic agent present, it is a C-II controlled substance. When pentobarbital is in combination with other agents, it is a C-III controlled substance.

Sedative-Hypnotic Drugs,
WHAT ARE 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.

Sedative-Hypnotic Drugs,

Benzodiazepines Barbiturates Non-benzo benzos (Zaleplon, zopidem) Melatonin receptor agonist (Ramelteon) Buspirone Others (antpsychotics, antidepressants)

Sedative-Hypnotic Drugs,
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.

Sedative-Hypnotic Drugs,
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.

Sedative-Hypnotic Drugs,
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.

Sedative-Hypnotic Drugs,
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.

Sedative-Hypnotic Drugs,
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 E1 subunit.

Sedative-Hypnotic Drugs,
(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 Fcarbolines, eg, n-butyl-F-carboline-3-carboxylate (F-CCB). In addition to their direct actions, these molecules can block the effects of benzodiazepines.

Antiseizure Drugs
OBJECTIVES 1. Identify the mechanisms of antiseizure drug action. 2. Describe the main pharmacokinetic features and adverse effects of major antiseizure drugs. 3. Identify new antiseizure drugs and their important characteristics. 4. 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.

Drug Development for Epilepsy

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.

Drug Development for Epilepsy

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).

Drug Development for Epilepsy 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.

Drug Development for Epilepsy

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

Antiseizure drugs
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.

Antiseizure drugs
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 OF ANTIEPILEPTICS
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.

Pharmacokinetics OF ANTIEPILEPTICS
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.

Pharmacokinetics OF ANTIEPILEPTICS
Drugs Used in Partial Seizures & Generalized Tonic-Clonic 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 drugs lamotrigine, levetiracetam, gabapentin, oxcarbazepine, pregabalin, topiramate, vigabatrin, and zonisamide is altering clinical practice in countries where these compounds are available.

Pharmacokinetics OF ANTIEPILEPTICS
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 antiseizuredrugs in this group, making differentiation difficult in patients receiving multiple drugs.

Phenytoin: Toxicity
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 doserelated 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.

Phenytoin: Toxicity
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.

Phenytoin
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.

Adjuncts in the treatment of Partial Seizures

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
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

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)

Antiseizure drugs
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