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Drugs acting on the Central Nervous System ( CNS)

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 Veterinary Pharmacology Part 1

Drugs acting on the Central

Nervous System (CNS)
Dr. Yaareb J. Mousa
Assistant Professor / BVMS, MSc, PhD of
Veterinary Pharmacology
The CNS is consisted of the brain and spinal cord. The brain
composed of the cerebrum, cerebellum and medulla oblongata.

Neurotransmitters
Neurotransmitters are biological substances that transmit
signals from a presynaptic neuron to a target receptor on
the postsynaptic neuron.
General Mechanisms of the Drugs that acting on the CNS
Types of neurotransmitters in the CNS:
1.Acetylcholine (Ach).
2.Catecholamines that composed of Norepinephrine (NE),
Epinephrine (Epi) and Dopamine (DA).
3.Serotonin (5-hydroxy tryptamine)(5-HT).
4.Aminoacids that divided into:
A.Inhibitory (GABA and Glycine).
B.Excitatory (Aspartate and Glutamate).
 Sedatives and Hypnotics
Hypnotics are drugs that cause hypnosis by depressing the CNS
so the animal is less responsive to external stimuli. Hypnotics
that used in small doses will cause sedation.
Types
Barbiturates
Divided into:
A.Long acting (Phenobarbital)
B.Short acting (Pentobarbital)
C.Ultrashort acting (Thiopental)

Mechanism of action
Potentiate the effect of GABA neurotransmitter leading to
depression of the brain and inhibits excessive motor discharge.
Pharmacological effects
1.Depresses all functions of the brain.
2.Selectively depresses the motor cortex.
3.Depresses the respiratory center in medulla.
4.Produce good muscle relaxation.
5.Decreases blood pressure and heart rate.
6.Induce microsomal enzymes and increase the metabolic rate of
the animal.
Clinical uses
1.Sedative.
2.Hypnotic.
3.Anticonvulsant.
4.Anesthetics.
5.In case of pruritus to control itching.
Benzodiazepines
Which include diazepam, chlordiazepoxide and alprazolam.

Mechanism of action
Increasing the action of GABA neurotransmitter on its receptor which
causes influx of chloride ion into the neuronal cells leading to
depression of the CNS.
Clinical uses
1.Sedative.
2.Hypnotic.
3.Muscle relaxant.
4.Anticonvulsant.
5.Preanesthetic.
6.Antianxiety.
Chloralhydrate
It is hypnotic given I.V. in large animals (7%). It depresses the
respiratory and vasomotor centers. It is metabolized in the body
by reduction into Trichloroethanol which is the active metabolite
responsible of hypnotic effect of chloral hydrate. It is used as
anesthetic in equine species with weak analgesic effect and can be
mixed with Magnesium sulfate (MgSO4) (6%) to produce muscle
relaxation. Chloral hydrate decreases blood pressure and
decreases heart rate and sudden death may occur in horses which are
highly excited.
Ethanol
It has sedative effect, depresses respiration and causes vasodilation.
It has diuretic effect because it inhibits antidiuretic hormone
(ADH). It metabolized into CO2 and H2O and small amount
expired by the lungs.
 Anticonvulsant Drugs
Are drugs used to control seizure through depressing the CNS.
Types
Barbiturates
Benzodiazepines
Phenytoin
Mechanism of action
It stabilizes the neuronal membranes and selectively depresses the
motor areas in the brain.
It is not hypnotic, well absorbed orally, induces liver microsomal
enzymes, metabolized in the liver and excreted in the bile.
Side effects
1. Transient incoordination.
2.Polyphagia.
3.Polyurea.

Primidone
The structure of this drug and its mechanism of action is
similar to phenobarbital and about 25 % of the drug is
metabolized into phenobarbital. It causes nausea, ataxia and
not used in cats because it causes neurotoxicity.
 Narcotic Analgesics
Are drugs used to produce analgesia through its action on the CNS.
Opioids agonists
Types
1.Natural like Morphine.
2.Synthetic like Fentanyl.

Morphine
Mechanism of action
It acts on opioid receptor (Mu receptor) in the CNS leading to
depression of the brain and causing analgesia.
Pharmacological effects
A.On the brain:
1.Depresses the brain in dogs, monkey and human but it causes CNS
excitation in cats, horses and ruminants.
2.Produces analgesia by increasing the pain threshold.
3.Produces euphoria in human.
4.Stimulates the Chemoreceptor Trigger Zone (CTZ) in the brain
leading to emesis in dogs.
5.Depresses the cough center.
6.Depresses the respiratory center in the brain.
B. On the GIT:
The initial dose of morphine causes defecation but
chronic use causes constipation.

C.On the skin:

Morphine causes itching because of histamine
release.
Clinical uses
-Analgesic.
-Preanesthetic.

Contraindications
-In case of shock because morphine causes respiratory depression.
-In case of liver diseases.
-In case of pulmonary edema.

Toxicity
Death may result from respiratory depression and it can be treated
by giving opioid receptor antagonist like Naloxone.
 Tranquilizers
Are drugs used to tranquilize and control of the animals and they are
called also Neuroleptics.
Phenothiazine derivatives
Types
Chlorpromazine, Acepromazine and Promazine.

Chlorpromazine
Mechanism of action
They antagonize dopamine receptors in the brain leading to
depression of the CNS. It also has anticholinergic and
antiadrenergic effects.
Clinical uses
1.Control the nervous animals.
2.Preanesthetic.
3.Antipruritus.
4.Antiemetic.
5.Antistress in transporting of animals.
Side effects
1.Incoordination in horses.
2.Dry mouth.
3.Constipation.
4.Hypotension.
5.Decreases body temperature.
 CNS Stimulants
Methylxanthines derivatives
Types
Caffeine, Theophylline and Aminophlline.
Mechanism of action
Antagonism of adenosine receptors in the brain leading to CNS
stimulation.
Pharmacological effects
1.Stimulates CNS, decrease fatigue and increases motor activity.
2.Stimulate the heart and causes vasodilation.
3.Relaxation of smooth muscle therefore theophylline is used in
asthma.
4.Diuretic effect through increasing renal blood flow.
5.Stimulation of gastric acid secretion.
Amphetamine

Mechanism of action
It increases the release of Norepinephrine and Dopamine from the
nerve endings leading to CNS stimulation.
 Medullary Stimulants
Doxapram
Mechanism of action
It stimulates the respiratory center in the medulla and causes
respiratory stimulation.

Clinical uses
1.Antagonizes the respiratory depressant action of Barbiturates.
2.Antagonizes the sedative action of xylazine.
Pentylenetetrazole
It is a respiratory stimulant. It increases respiration. High
doses produce convulsion and it is used as respiratory
stimulant.

4-aminopyridine
It is used as respiratory stimulant and antagonizes the sedative effect
of xylazine.

Nikethamide
It is a short acting respiratory stimulant.
 Spinal Cord Stimulants
Strychnine
Mechanism of action
Antagonizes glycine receptors in the spinal cord.

Indications
1.Improves appetite in very small quantity.
2.Used as tonic.
3.Kill the stray dogs.
 Anesthetics
Anesthetics are drugs that used to induce anesthesia in whole body
(general anesthetics) or local area of the body (local anesthetics). It
is divided into:
1. General Anesthetics
A. Inhalational Anesthetics
B. Injectable Anesthetics
2. Local Anesthetics
 1. General Anesthetics
Drugs used to induce general anesthesia which is characterized by
loss of sensation that achieved by reversible depression of the
brain.
Clinical characteristics of general anesthesia: Awake

1.Loss of sensation. Sedation

2.Unconsciousness.
Hypnosis
3.Muscle relaxation.
4.Inhibition of reflexes. Anesthesia

Coma

Death
Ideal anesthetics:
1.Nonirritant and without bad odor.
2.Potent with smooth induction and recovery.
3.Wide margin of safety.
4.Good muscle relaxation.
5.Does not damage the CNS with minimal side effects.
6.Inexpensive and non-explosive.
7.Ease of administration.
Routes of general anesthetics administration:
1.Inhalation.
2.Intravenous (I.V.)
3.Intramuscular (I.M..)
4.Subcutaneous (S.C..)
5.Intraperitoneal (I.P.). usually used in laboratory animals like mice
and rats.
6.Intra-thoracic (I.T.) used for euthanasia of animals.
7.Orally (P.O.) is not recommended because it produces hypnosis and
has long induction period due to first pass effect in the liver.
Stages of general anesthesia
Stage-I (stage of voluntary excitement, stage of analgesia)
It is characterized by struggling and ataxia without CNS depression.

Stage-II (stage of involuntary excitement, stage of delirium)

It begins with unconsciousness and loss of voluntary control.

Stage-III (stage of surgery, stage of anesthesia)

Characterized by unconsciousness, loss of neuromuscular reflexes, loss
of pain sensation and muscle relaxation. All surgical operations can be
performed at this stage.
This stage can be subdivided into 4 planes:
a.Sleep
b.Sensory loss
c.Muscle paralysis
d.Intercostal paralysis
The first two planes are called light surgical anesthesia and the last
two are called deep surgical anesthesia.

Stage-IV (medullary paralysis)

Characterized by paralysis of the vital regulatory centers in the
medulla like respiratory center and death may occur in this stage.
Notes:
-Stage I and II are called the induction period.
-Some anesthetics bypass stage II into stage III which is the stage of
surgery (e.g. Halothane, Methoxyflurane and Barbiturates).
-Other anesthetic agents induce all the stages of
general anesthesia) (e.g. Ether and Chloroform) while some
anesthetics produce only stage I and II (e.g. Ketamine, N2O and
Enflurane).
Characteristic features of balanced anesthesia:
1.Analgesia.
2.Muscle relaxation.
3.Hypnosis.
4.Hyporeflexia.
 Preanesthetics (Premedications)
Preanesthetics used with general anesthetics to produce general
anesthesia:
1.Analgesics like xylazine and morphine.
2.Sedatives and hypnotics like diazepam.
3.Tranquilizers like chlorpromazine.
4.Muscle relaxants like D-tubocurarine.
5.Adrenergic blocking agents like propranolol.
6. Cholinergic antagonists like atropine because of:
a.to reduce salivation.
b.to reduce bronchial secretion.
c.to prevent bradycardia.
A. Inhalational Anesthetics
1.Gaseous like N2O and Cyclopropane.
2.Volatile like Halothane, Methoxyflurane, Enflurane and Ether.
Inhalational anesthetics are gases or vapors that diffuses readily
across the pulmonary alveoli and then to the brain to produce
anesthesia.
The transfer of inhalational anesthetics depends on the partial
pressure of anesthetics and its solubility in the blood.
Lipid solubility is important for induction of anesthesia and recovery
from it.
High lipid solubility means long induction and long recovery periods
of anesthesia (e.g. Ether) while low lipid solubility means rapid
induction and fast recovery (e.g. Halothane).
General mechanisms of action of inhalational
anesthetics:
1.Interaction with lipid molecules of the cell membrane.
2.Interaction with proteins of the neuronal membrane.
3.Interaction with water molecules of the cell membranes.
All general anesthetics causes stabilization of the cell membrane.

Minimal Alveolar Concentration (MAC):

It is the minimal concentration of the anesthetics at the alveolar level
which is required to produce anesthesia in 50 % of the animals.
Halothane
It is nonirritant, nonflammable, non-explosive and potent. It
depresses all the functions of the brain. It bypass stage II. It
has rapid induction and fast recovery because it is low lipid soluble.

Side effects of Halothane:

1.Respiratory depression.
2.Depresses cardiac function.
3.Sensitizes the heart to catecholamines.
4.Decreases calcium ion binding to cardiac muscle and causes
bradycardia.
Contraindication:
Uses of epinephrine and norepinephrine are contraindicated in case
of halothane anesthesia.
Advantages:
1.It is potent and has rapid induction and rapid recovery from
anesthesia.
2.It produces good muscle relaxation.
Disadvantages:
1.Cardio-pulmonary depression.
2.Expensive.
3.Contraindicated in cardiac diseases.
Methoxyflurane
It is more potent than halothane, it has long induction and long
recovery periods. During recovery, there is some CNS excitation
because of high lipid solubility so that, preanesthetics are needed.
Side effects:
1.Decreases heart rate and blood pressure.
2.Sensitizes the heart to catecholamines.
Advantages:
Potent with good muscle relaxation and analgesia.
Disadvantages:
1.High lipid soluble with long induction and long recovery periods.
2.It is contraindicated in liver and kidney diseases.
Nitrous oxide (N2O)
It is colorless, odorless, nonirritant and nonflammable. It is usually
given as 80% N2O and 20% O2. It produces stage I and II
anesthesia. It produces good analgesia, muscle relaxant is needed
and O2 is given to prevent hypoxia. It is characterized by low lipid
solubility so that, the induction and recovery from anesthesia is fast.
It is used with other anesthetic because it has low potency.
Enflurane
It is potent anesthetics and structural analogue to Methoxyflurane. It
is also sensitizes the heart to catecholamines. It produces good
muscle relaxation and may cause CNS excitations.
Ether
It is flammable, highly explosive and used in laboratory animals.
It causes respiratory irritation and produces all stages of
anesthesia.

Chloroform
It is used in laboratory animals but causes liver toxicity so that,
not used in other animal species.
 B. Injectable Anesthetics
Advantages of Injectable anesthesia:
1.Minimal apparatus used.
2.Ease of induction.
3.Useful in head surgery.
4.Decreasing the side effects of the anesthetic drug in case of
respiratory diseases, debility and shock.

Disadvantages of Injectable anesthesia:

1.The depth and the level of anesthesia can not easily controlled.
2.Ease of occurrence of anesthetics overdose.
I.Barbiturates anesthetics

I.Non-barbiturates anesthetics
Ketamine
Mechanism of action:
Antagonizes aspartate receptors (N-methyl-D-aspartate (NMDA)
receptors) leading to depression of the brain.
It is given I.M., I.V. and S.C. It produces stage I and II anesthesia with
weak muscle relaxation therefore, it is usually combined with alpha 2
receptor agonists like xylazine, meditomidine and detomidine.
The analgesia is good and body reflexes like swallowing are
maintained during ketamine anesthesia.
Contraindications:
1.Abdominal surgery.
2.Caesarian Section (CS)
3.Liver and kidney diseases.
4.Head injuries because ketamine increases the pressure of
cerebrospinal fluid (CSF).
Propofol
Mechanism of action:
Potentiate the effect of GABA neurotransmitter leading to
inhibition of the brain.
It is usually used in dogs and cats. It has rapid onset of action and
short duration of anesthesia about 15-30 minutes. It produces
good muscle relaxation but vomiting and hypotension may occur as
a side effect.
Etomidate
Mechanism of action:
Increases the effect of GABA neurotransmitter leading to inhibition
of the brain.
It is short acting I.V. anesthetic agent and has short duration about 3-5
minutes. It decreased corticosteroids production by suppression of the
adrenal gland.

Chloralhydrate
 2. Local Anesthetics
Mechanism of action of local anesthetics:
Local anesthetics prevents the local pain by blocking the sodium
channel and reversibly prevent the depolarization of the nervous
tissue.
It is injected at the site of action and it is called nerve block when it is
injected around or close to peripheral nerve or nerve plexuses. It is
called epidural anesthesia when injected into the spinal cord spaces
and do not interfere with the vital or local functions of the body.
The absorption of local anesthetics can be delayed by giving
epinephrine which causes vasoconstriction that prolonged the
duration of anesthetic action.
There are two types of Local Anesthetics:
1.Esters: e.g. Procaine and Tetracaine.
2.Amides: e.g. Lidocaine and Etidocaine.

Side effects:
1.Hypotension.
2.Urinary retention.
3.Motor muscles dysfunction.
4.Nausea and vomiting.
5.Seizure.
Clinical uses:
1.Relief of local pain.
2.Tail amputation in animals.
3.Insect bites.
4.Minor burns.
5.Local itching.
Physically local anesthetics
Ethyl chloride: is volatile liquid stored under pressure and released
as a spray, it cools the skin and cause local anesthesia.

CO2 ice: used to cauterize warts and induced local anesthesia.

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