2. Nervous system
• Basic unit of the nervous system = neuron
–Sensory
–Associative
–Motor
• Parts of the neuron
–Cell body
–Dendrite
–Axon
•
3. Nervous system
• Two parts of the nervous system
–CNS (central): brain and spinal
cord
–PNS (peripheral): cranial
nerves, spinal nerves,
autonomicnervous system
4. 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
5. 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)
6. 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
7. CNS Drugs
• Examples in these groups:
–Phenothiazine derivatives
(acepromazine, chlorpromazine)
–Benzodiazepines (diazepam)
–Alpha-2 agonists (xylazine,
detomidine, medetomidine)
8. CNS Drugs
• Analgesics: drugs that relieve pain
• Analgesics are categorized as non-
narcotic or narcotic
• Narcotic analgesics are used for
moderate to severe pain
• Narcotic refers to opioid (natural) or
opioid-like (synthetic) products
9. 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
11. 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
12. 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
13. 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
14. 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
15. 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
16. 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
17. 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)
18. 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
19. 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
20. 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
21. 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
22. 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
23. 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.
24. 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.
25. 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.
26. Sedative-Hypnotic Drugs,
• WHAT ARE 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.
•
28. 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.
29. 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 channel-
opening events.
30. 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.
31. 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.
32. 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 1 subunit.
33. 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 -
carbolines, eg, n-butyl--carboline-3-carboxylate (-CCB).
• In addition to their direct actions, these molecules can block
the effects of benzodiazepines.
•
34. 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.
•
35. 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.
36. 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.
37. 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).
38. 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.
39. 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.
•
41. 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.
42. 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.
•
43. 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.
44. 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.
45. 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 drugs—lamotrigine,
levetiracetam, gabapentin, oxcarbazepine, pregabalin,
topiramate, vigabatrin, and zonisamide is altering clinical
practice in countries where these compounds are
available.
•
46. 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.
47. 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 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.
48. 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.
•
49. 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.
50. 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.
51. 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.
52. 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
•
53. 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)
•
•
55. 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)
56. 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)
57. 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
•
