drugs acting on cns

8/3/2019 Drugs Acting on CNS

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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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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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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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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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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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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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(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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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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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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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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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

drugs acting on cns

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