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Drugs Affecting the Nervous System
By
Dr.Sreerangarajan. M.D.
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Nervous system Basic unit of the nervous system = neuron
Sensory
Associative
Motor
Parts of the neuron
Cell body
Dendrite Axon
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Nervous system
Two parts of the nervous system
CNS (central): brain and spinalcord
PNS (peripheral): cranialnerves, spinal nerves,autonomicnervous system
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CNS Drugs
Anticonvulsants: help prevent seizures
by suppressing the spread of abnormal
electric impulses from the seizure focusto other areas of the cerebral cortex
All anticonvulsants are CNS
depressants and may cause ataxia,drowsiness, and hepatotoxicity
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CNS Drugs
Examples:
Phenobarbital (short-acting barbiturate)
Primidone (structurally similar tophenobarbital)
Diazepam (used IV to treat statusepilepticus)
Clorazepate (adjunct anticonvulsant) Potassium bromide (adjunct
anticonvulsant)
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CNS Drugs
Tranquilizers: used to calm animals;
reduce anxiety and aggression
Sedatives: used to quiet excitedanimals; decrease irritability and
excitement
Anti-anxiety drugs: lessen anxiousness,but do not make animals drowsy
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CNS Drugs
Examples in these groups:
Phenothiazine derivatives
(acepromazine, chlorpromazine)
Benzodiazepines (diazepam)
Alpha-2 agonists (xylazine,detomidine, medetomidine)
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CNS Drugs
Opioids:
Do not produce anesthesia; patients still respond tosound 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
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CNS Drugs Examples of opioids:
Opium
Morphine sulfate
Meperidine Hydromorphone
Butorphanol
Hydrocodone
Fentanyl
Etorphine
Buprenorphine
Pentazocine
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CNS Drugs
Opioid antagonists:
Block the binding of opioids to
their receptorsUsed to treat respiratory and CNS
depression of opioid use
Examples include naloxone andnaltrexone
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CNS Drugs
Neuroleptanalgesics:
Combination of an opioid and a tranquilizer orsedative
Can cause a state of CNS depression andanalgesia and may or may not produceunconsciousness
Combination products may be prepared by
veterinarian Examples include acepromazine and morphine;
xylazine and butorphanol
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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 ofconsciousness
Local anesthetics block nerve transmission in thearea of application with no loss of consciousness
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CNS Drugs
Local anesthetics:
Block pain at the site of administration orapplication in the PNS and spinal cord
May be used as nerve blocks, aid in endotrachealtube placement, and ease skin irritation
Applied topically to mucous membranes and thecornea by infiltration of a wound or joint, by IV,
and around nervous tissue Examples include lidocaine, proparacaine,
tetracaine, mepivacaine, bupivacaine
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CNS Drugs General Anesthetics
Injectable general anesthetics:
Barbiturates: CNS depressants derived from barbituricacid. 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 anoxybarbiturate or thiobarbiturate
Examples: phenobarbital, pentobarbital, thiopental,methohexital
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CNS Drugs General Anesthetics
Injectable general anesthetics (cont.): Dissociatives: belong to the cyclohexamine family
Cause muscle rigidity (catalepsy), amnesia, and mildanalgesia
Work by altering neurotransmitter activity
Used for restraint, diagnostic procedures, and minorsurgical procedures
Side effects: cardiac stimulation, respiratorydepression, and exaggerated reflexes
Examples include ketamine and tiletamine
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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 thatproduces rapid and smooth induction when given IV
(lasts 25 minutes)
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CNS Drugs General Anesthetics/Analgesics
Inhalant general anesthetics: Inhalantanesthetics 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 toprevent diffusion hypoxia
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CNS Drugs
General Anesthetics/Analgesics
Inhalant general anesthetics (cont.):
Isoflurane: Nonflammatory, inhalant anesthetic
administered via a precision vaporizer
Causes rapid induction of anesthesia andshort recoveries following anesthetic
procedures
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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 andmalignant hyperthermia
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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 pressureSevoflurane: profound respiratory
depressant; close monitoring is needed
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CNS Drugs
General Anesthetics/Analgesics
Inhalant general analgesics (cont.):
Nitrous oxide:
Inhalant analgesic that diffuses rapidly throughout thebody.
Can enter gas-filled body compartments (increasespressure in these compartments).
Contraindicated in cases of gastric dilatation,pneumothorax, and twisted intestines.
Leave animals on 100% oxygen following surgery toprevent diffusion hypoxia.
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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. Sideeffects include gastrointestinal irritation and
bronchodilation.
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CNS Drugs
Euthanasia solutions:
Used to humanely end an animals life.
Usually contain pentobarbital.
When pentobarbital is the only narcoticagent present, it is a C-II controlledsubstance.
When pentobarbital is in combination withother agents, it is a C-III controlledsubstance.
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Sedative-Hypnotic Drugs, WHAT ARE OBJECTIVES
1. Identify the major chemical classes of sedative-hypnotics.
2. Describe the pharmacodynamics ofbenzodiazepines and barbiturates, including theirmechanisms of action.
3. Compare the pharmacokinetics of commonlyused benzodiazepines and barbiturates and discuss
how differences among them affect clinical use. 4. Describe the clinical uses and the adverse effects
of sedative-hypnotics.
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Sedative-Hypnotic Drugs,
Benzodiazepines
Barbiturates
Non-benzo benzos (Zaleplon, zopidem) Melatonin receptor agonist (Ramelteon)
Buspirone
Others (antpsychotics, antidepressants)
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Sedative-Hypnotic Drugs,
Neuropharmacology of the
benzodiazepines
GABA (gamma-aminobutyric acid) is themajor inhibitory neurotransmitter in the
central nervous system.
Benzodiazepines increase the efficiencyof GABAergic synaptic inhibition.
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Sedative-Hypnotic Drugs,
The benzodiazepines do not substitute
for GABA but appear to enhance GABA's
effects allosterically without directlyactivating GABAA receptors or opening
the associated chloride channels.
Increased chloride ion conductance >>>increase in the frequency of channel-
opening events.
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Sedative-Hypnotic Drugs,
Barbiturates also facilitate the actions of GABA atmultiple sites in the central nervous system.
In contrast to benzodiazepines they increase the
duration of the GABA-gated chloride channelopenings.
At high concentrations, the barbiturates may also beGABA-mimetic, directly activating chloride channels.
These effects involve a binding site or sites distinctfrom the benzodiazepine binding sites. their morepronounced central depressant effects.
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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.
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Sedative-Hypnotic Drugs,
Benzodiazepine Binding Site Ligands
Three types of ligand-benzodiazepine receptorinteractions have been reported:
(1) Agonists facilitate GABA actions, and thisoccurs at multiple BZ binding sites in the case ofthe benzodiazepines.
As noted above, the nonbenzodiazepineszolpidem, zaleplon, and eszopiclone areselective agonists at the BZ sites that containan E1 subunit.
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Sedative-Hypnotic Drugs,
(2) Antagonists are typified by the synthetic benzodiazepinederivative flumazenil, which blocks the actions ofbenzodiazepines, eszopiclone, zaleplon, and zolpidem.
(3) Inverse agonists act as negative allosteric modulators ofGABA-receptor function.
Their interaction with BZ sites on the GABAA receptor canproduce anxiety and seizures, an action that has been
demonstrated for several compounds, especially the F-carbolines, eg, n-butyl-F-carboline-3-carboxylate (F-CCB).
In addition to their direct actions, these molecules can blockthe effects of benzodiazepines.
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Antiseizure Drugs
OBJECTIVES
1. Identify the mechanisms of antiseizure drugaction.
2. Describe the main pharmacokinetic features andadverse effects of major antiseizure drugs.
3. Identify new antiseizure drugs and theirimportant characteristics.
4. Describe the factors that must be considered in
designing a dosage regimen for an anti-seizure drug.
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Drug Development for Epilepsy
It was once assumed that a single drugcould be developed for the treatment ofall forms of epilepsy,
but causes of epilepsy are extremelydiverse, encompassing genetic anddevelopmental defects and infective,
traumatic, neoplastic, and degenerativedisease processes.
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Drug Development for Epilepsy
Some specificity according to
seizure type, most clearly seen with
generalized seizures of the absencetype.
Respond to ethosuximide and
valproate but can be exacerbated by
phenytoin and carbamazepine.
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Drug Development for Epilepsy
Drugs acting selectively on absence
seizures identified by animal screens,
using either threshold pentylenetetrazolclonic seizures in mice or rats or mutant
mice showing absence-like episodes
(lethargic, star-gazer, or totteringmutants).
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Drug Development for Epilepsy
In contrast, the maximalelectroshock (MES) test, with
suppression of the tonic extensorphase, identifies drugs such asphenytoin, carbamazepine, and
lamotrigine that are active againstgeneralized tonic-clonic seizures andcomplex partial seizures.
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Drug Development for Epilepsy
Use of the maximal electroshock test as the majorinitial screen for new drugs has probably led to theidentification of drugs with a common mechanismof action involving prolonged inactivation of the
voltage-sensitive sodium channel.
Limbic seizures induced in rats by the process ofelectrical kindling (involving repeated episodes of
focal electrical stimulation) probably provide abetter screen for predicting efficacy in complexpartial seizures.
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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).
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Antiseizure drugs
Basic Pharmacology ofAntiseizure Drugs: Chemistry
Until 1990, ~ 16 antiseizure drugs available, and
13 of them can be classified into five very similarchemical groups: barbiturates, hydantoins,oxazolidinediones, succinimides, andacetylureas.
These groups have in common a similarheterocyclic ring structure with a variety ofsubstituents.
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Antiseizure drugs
The remaining drugscarbamazepine,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.
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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 80100% of the dose reaching thecirculation. Most antiseizure drugs are not
highly bound to plasma proteins.
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Pharmacokinetics
OF ANTIEPILEPTICS
Antiseizure drugs are cleared chiefly byhepatic mechanisms and liver. Plasmaclearance is relatively slow;
many anticonvulsants are thereforeconsidered to be medium- to long-acting.Some have half-lives longer than 12 hours.
Many of the older antiseizure drugs arepotent inducers of hepatic microsomalenzyme activity.
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Pharmacokinetics
OF ANTIEPILEPTICS 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 drugslamotrigine,levetiracetam, gabapentin, oxcarbazepine, pregabalin,
topiramate, vigabatrin, and zonisamide is altering clinicalpractice in countries where these compounds areavailable.
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Phenytoin: Toxicity
Nystagmus occurs early, as does loss of smoothextraocular pursuit movements, but neither isan indication for decreasing the dose.
Diplopia and ataxia are the most common dose-related adverse effects requiring dosageadjustment; sedation usually occurs only atconsiderably higher levels.
Gingival hyperplasia and hirsutism occur tosome degree in most patients; the latter can beespecially unpleasant in women.
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Phenytoin: Toxicity
Long-term use is associated in somepatients with coarsening of facial featuresand with mild peripheral neuropathy,
usually manifested by diminished deeptendon reflexes in the lower extremities.
Long-term use may also result inabnormalities of vitamin D metabolism,
leading to osteomalacia.
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Phenytoin Drug Interactions & Interference with
Laboratory Tests
Induction of dug metabolizing enzymes
Carbamazepine
Closely related to imipramine antidepressants,carbamazepine is a tricyclic compound effectivein treatment of bipolar depression.
Initially marketed for the treatment oftrigeminal neuralgia but has proved useful forepilepsy as well.
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Phenytoin Clinical Use
long been considered a drug of choice for both partialseizures and generalized tonic-clonic seizures, someof the newer antiseizure drugs are beginning to
displace it from this role. Toxicity
most common adverse effects of carbamazepine arediplopia and ataxia.
Considerable concern exists regarding the occurrenceof idiosyncratic blood dyscrasias with carbamazepine,including fatal cases of aplastic anemia andagranulocytosis.
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Adjuncts in the treatment of Partial
Seizures
Felbamate blocks glycine activation ofNMDA receptors and inhibit initiation ofseizures
Gabapentin despite the fact thatGabapentin has a similar structuralrelationship to GABA, it does not act on theGABA receptor.
Gabapentin may alter GABA metabolism oralter reuptake by presynaptic GABAtransporters.
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Adjuncts in the treatment of Partial
Seizures
Lamotrigine blocks voltage-sensitive NAchannels and has another mechanism ofaction (inhibits the release of excitatory
amino acids such as glutamate?) Topiramate - blocks voltage-sensitive NA
channels, augments GABA activation ofGABAA receptor, blocks kainate and
AMPA glutamate receptors
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Drugs for Generalized Absence,
Myoclonic or Atonic Seizures Ethosuximide blocks T-type Ca channels inthalamic 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 beadded or substituted.
Discontinue drug use slowly
Monitor serum levels to ensure adequate dosage(toxicity, therapeutic failure or non-compliance)
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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
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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)
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Antiseizure drugs
Lamotrigine
(possibly mania, migraine, schizophrenia, firsteffective use in treatment-resistantschizophrenia by Dr. Serdar Dursun, Psychiatry,Dalhousie Univ.)
Phenytoin
(possibly neuropathic pain, trigeminal neuralgia)
Valproic acid Mania, migraine (possibly behavioural
disturbances in dementia)
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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, usephenobarbital or vice versa.
Admit to CCU, get EEG, consider thiopental, propofol