General Pharmacology Drugs That Affect the Central Nervous System S. Habibian Dehkordi

General Pharmacology
Drugs That Affect the Central Nervous
System
S. Habibian Dehkordi D.V.M, Ph.D
Central Nervous System CNS

CNS



Brain and Spinal Cord
Acts as control for regulating physical and mental
processes
Neurons are the brains functional units
Neurons

The brain is a collection of about 10 billion
interconnected neurons. Each neuron is a
cell that uses biochemical reactions to
receive, process and transmit information.
Neurotransmitters

Chemical substances that carry messages
from one neuron to another or from a neuron
to other body tissues, such as cardiac or
skeletal muscles.
Synapses

The synapse is a small gap separating
neurons.
Receptors


Proteins embedded in the cell membranes of
neurons.
A neurotransmitter must bind to receptors to
exert an effect on the next neuron in the
chain.
Drugs That Effect CNS


Depressants
Stimulants
CNS Depressants



Mild CNS depressant: decreased interest in
surroundings, inability to focus.
Moderate CNS depressant: drowsiness or
sleep, decreased perception of heat or cold.
Severe CNS depressant: unconsciousness or
coma, loss of reflexes, respiratory failure and
death.
CNS Stimulation



Mild stimulation: wakefulness, mental
alertness, and decreased fatigue.
Moderate stimulation: hyperactivity,
excessive talking, nervousness, and
insomnia.
Excessive stimulation: confusion, seizures,
and cardiac dysrhythmias.
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
Examples:


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
Phenobarbital (short-acting barbiturate)
Primidone (structurally similar to phenobarbital)
Diazepam (used IV to treat status epilepticus)
Clorazepate (adjunct anticonvulsant)
Potassium bromide (adjunct anticonvulsant)
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Learning, a part of the
Thomson Corporation.
CNS Drugs


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
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
Examples in these groups:



Phenothiazine derivatives (acepromazine, chlorpromazine)
Benzodiazepines (diazepam)
Alpha-2 agonists (xylazine, detomidine, medetomidine)
© 2004 by Thomson Delmar
Learning, a part of the
Thomson Corporation.
CNS Drugs



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Analgesics: drugs that relieve pain
Analgesics are categorized as non-narcotic
(Chapter 16) or narcotic
Narcotic analgesics are used for moderate to
severe pain
Narcotic refers to opioid (natural) or opioidlike (synthetic) products
© 2004 by Thomson Delmar
Learning, a part of the
Thomson Corporation.
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
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Learning, a part of the
Thomson Corporation.
CNS Drugs

Examples of opioids:

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Opium
Morphine sulfate
Meperidine
Hydromorphone
Butorphanol
Hydrocodone
Fentanyl
Etorphine
Buprenorphine
Pentazocine
© 2004 by Thomson Delmar
Learning, a part of the
Thomson Corporation.
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
© 2004 by Thomson Delmar
Learning, a part of the
Thomson Corporation.
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
© 2004 by Thomson Delmar
Learning, a part of the
Thomson Corporation.
Sedative-Hypnotic Drugs
BASIC PHARMACOLOGY OF
SEDATIVE-HYPNOTICS

An effective sedative (anxiolytic) agent should
reduce anxiety and exert a calming effect with
little or no effect on motor or mental functions.

A hypnotic drug should produce drowsiness and
encourage the onset and maintenance of a state
of sleep that as far as possible resembles the
natural sleep state.
BASIC PHARMACOLOGY OF
SEDATIVE-HYPNOTICS

Hypnotic effects involve more pronounced
depression of the central nervous system than
sedation, and this can be achieved with most
sedative drugs simply by increasing the dose.

Graded dose-dependent depression of central
nervous system function is a characteristic of
sedative-hypnotics.
CHEMICAL CLASSIFICATION
1.
2.
3.
Benzodiazepines: not to lead general
anesthesia, raraly death.
Barbiturates: the older sedative-hypnotics,
general depression of central nervous system.
With such drugs, an increase in dose above
that needed for hypnosis may lead to a state of
general anesthesia. At still higher doses, it
may depress respiratory and vasomotor
centers in the medulla, leading to coma and
death.
Other classes of drugs: chloral hydrate,
buspirone, et al.
Ⅰ.Benzodiazepines

The first benzodiazepine, chlordiazepoxide,
was synthesised by accident in 1961.
Ⅰ.Benzodiazepines

Derivative of 1,4- benzodiazepines. About 20
are available for clinical use. They are
basically similar in their pharmacological
actions, though some degree of selectivity has
been reported. It is possible that selectivity
with respect to two types of benzodiazepine
receptor may account for these differences.
From a clinical point of view, difference in
pharmacokinetic behaviour are more
important than difference in profile of activity.
PHARMACOLOGICAL EFFECTS
1. Reduction of anxiety and aggression :
affects the hippocampus and nucleus
amygdalae
2. Sedation and induction of sleep:
(1) the latency of sleep onset is decreased;
(2) the duration of stage 2 NREM sleep is
increased;
(3) the duration of slow-wave sleep is
decreased.
PHARMACOLOGICAL EFFECTS
Reasons for their extensive clinical use:
(1) great margin of safety;
(2) little effect on REM sleep;
(3) little hepatic microsomal drugmetabolizing enzymes;
(4) slight physiologic and psychologic
dependence and withdrawal syndrome;
(5) less adverse effects such as residual
drowsiness and incoordination movement.
3. Anticonvulsant and antiseizure
They are highly effective against
chemically induced convulsions caused
by leptazol, bicuculline and similar drugs
but less so against electrically induced
convulsions.
The can enhance GABA-mediated
synaptic systems and inhibit excitatory
transmission.
4. Muscle relaxation
relax contracted muscle in joint diease or
muscle pasm.
5. Other effects
lead to temporary amnesia
decrease the dosage of anesthetic;
depress respiratory and cardiovascular
fuction.
MECHANISM OF ACTION

Benzodiazepines act very selectively on
GABAA-receptors, which mediate the fast
inhibitory synaptic response produced by
activity in GABA-ergic neurons.

The effect of benzodiazepines is to enhance the
response to GABA, by facilitating the opening of
GABA-activated chloride channels (an increase
in the frequency of channel opening, but no
change in the conductance or mean open time).
MECHANISM OF ACTION

Benzodiazepines bind specifically to a
regulatory site on the receptor, distinct from the
GABA binding site, and enhanced receptor
affinity for GABA.

The GABAA-receptors is a ligand-gated ion
channel consisting of a pentameric assembly of
subunits.
PHARMACOKINETIC ASPECTS



Well absorbed when given orally;
They bind strongly to plasma protein, and
their high lipid solubility cause many of
them to accumulate gradually in body fat.
Distribution volumes is big.
Metabolic transformation in the
microsomal drug-metabolizing enzyme
systems of the liver, eventually excreted
as glucuronide conjugates in the urine.

They vary greatly in duration of action, and
can be roughly divided into



Short-acting compounds: triazolam,
oxazepam(15-30min, t1/2 2-3 h)
Medium-acting compounds: estazolam,
nitrazepam (40min, t1/2 5-8 h)
Long-acting compounds: diazepam,
flurazepam(50h)
ADVERSE DRUG REACTION

Acute toxicity: Benzodiazepines in
acute overdose are considerably less
dangerous than other sedative-hypnotic
drugs. Cause prolonged sleep,without
serious depression of respiration or
cardiovascular. The availability of an
effective antagonist, flumazenil.
ADVERSE DRUG REACTION

Side-effects during therapeutic
use: drowsiness, confusion, amnesia,
impaired coordination. Main disadvantages
are interaction with alcohol, long-lasting
hangover and the development of
dependence.

Tolerance and dependence:
induction of hepatic drug-metabolising
enzymes; a change at the receptor level;
Ⅱ.BARBITURATES
Classification
(1)Ultra-short-acting barbiturates: act
within seconds, and their duration of
action is 30min. Therapeutic use of
Thiopental: anesthesia
(2)Short-acting barbiturates: have a
duration of action of about 2h. The
principal use of Secobarbital : sleep-
Ⅱ.BARBITURATES
Classification
(3)Intermediate-acting barbiturates: have and
effect lasting 3-5h. The principal use of
Amobarbital is as hypnotics.
(4)Long-acting barbiturates: have a duration of
action greater than 6h. Such as Barbital and
Phenobarbital. Therapeutic uses: hypnotics
and sedative, and antiepileptic agents at low
doses.
BARBITURATES
Barbiturates depress the CNS at all level
in a dose-dependent fashion. Now it
mainly used in anaesthesia and treatment
of epilepsy; use as sedative-hypnotic
agents is no longer recommended.
BARBITURATES
Reasons:
(1) have a narrow therapeutic-to-toxic
dosage range.
(2) suppress REM sleep.
(3) Tolerance develops relatively quickly.
(4) have a high potential for physical
dependence and abuse.
(5) potent inducers of hepatic drugmetabolising enzymea.
MECHANISM OF ACTION
(1) Barbiturates share with benzodiazepines
the ability to enhance the action of GABA, but
they bind a different site on the GABAreceptor/chloride channel, and their action
seems to prolong the duration of the opening
of GABA-activated chloride channels.
MECHANISM OF ACTION
(2) At high doses, barbiturates can inhibit the
release of the Ca2+-dependent
neurotransmitter.
Pharmacokinetics



High lipid solubility allows rapid transport across
the blood-brain barrier and results in a short
onset.
Removal from the brain occurs via redistribution
to the other tissues results in short duration of
action.
Barbiturates and their metabolites the excretion
via the renal route. Alkalinization of the urine
expedites the excretion of barbiturates.
Treatment of acute overdosage: Sodium
bicarbonate.
Therapeutic uses


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
Sedative-hypnotic agents
Be used in the emergency treatment of
convulsions as in status epilepticus.
Anesthetic (or be given before anesthetic)
Combination with antipyretic-analgesic
Treatment of hyperbilirubinemia and
kernicterus in the neonate.
Adverse effects

After effect: hangover---dizzy, drowsiness,
amnesia, impaired judgment, disorientation.

Tolerance: decreased responsiveness to a
drug following repeated exposure because of
down-regulation of receptors and induction of
hepatic drug-metabolising enzymes.
Adverse effects



Dependence: including psychologic and
physiologic dependence. Withdrawal
symptoms: excitation, insomnia, tremor,
anxiety, hallucinations and sometimes
convulsions.
Depressant effect on respiration: can cross
the placental barrier during pregnancy and
secrete to breast milk.
Others: Skin eruptions and porphyria

Phenothiazines (Tranquilizers)

Indications


Good sedation for healthy animals undergoing elective
procedures
Anti-emetic

Phenothiazines

Contraindications

Convulsing/epileptic patients, seizure history or head trauma
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Acepromazine may reduce the seizure threshold of the animal
Shock (hypovolemia) and hypothermia because of peripheral
vasodilation that can lead to hypotension
Depressed patients
Caution with geriatrics and pediatrics; use a lower dose or
consider alternative agents such as benzodiazepines
Liver or kidney disease
Allergy testing because of antihistamine effect

Phenothiazines

Other effects


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Antiarrhythmic effect
May cause excitement rather than sedation
Personality changes that usually subside within 48 hours

Benzodiazepines (Benzodiazepines)

Indications
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Convulsing/epileptic patients
Patients with a history of seizure
CSF taps or myelogram procedures
Minimal cardiovascular or respiratory depression

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Useful in geriatric or pediatric animals
Ideal for older, depressed or anxious patients
Works effectively as an induction agent when used with
ketamine

Benzodiazepines (Benzodiazepines)

Contraindications

May cause excitement in some dogs, cats and horses



Does not sedate animal but has antianxiety and calming
effects
May make animal more difficult when inhibitions and
anxieties are removed
Neonatal animals and animals with poor hepatic function

Benzodiazepines (Benzodiazepines)

Valium is in a propylene glycol solution, is
insoluble in water



May precipitate with other drugs
Propylene glycol is irritating and may sting at the
injection site
Does not work well when given via routes other than IV

Benzodiazepines (Benzodiazepines)

Other points


Midazolam is water soluble and readily combines with
opioids (oxymorphone, butorphanol)
Effects are reversed with flumazenil if adverse effects
are seen

α2-Agonists
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Are derivatives of thiazine
Examples:

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Xylazine (Rompun, Anased)
Romifidine
Detomidine (Dormosedan)
Medetomidine (Domitor)

α2-Agonists

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Stimulates the α2-adrenoreceptors causing a
decrease in norepinephrine
Indication

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Potential side effects limit use to sedation only, not for
preanesthetic medication
Can use to sedate a vicious animal before euthanasia

α2-Agonists
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Have some short-lived (16 to 20 minutes)
analgesic effects
Will cause vomiting in up to 50% of dogs and 90%
of cats
Xylazine and Detomidine are used most
frequently in horses
Xylazine also used in ruminants but at much lower
dosages

α2-Agonists

Contraindications
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Considerable potential for side effects especially if
administered IV
Profound cardiovascular effects include bradycardia, profound
hypotension, decreased contractility and stroke volume and
second degree heart block
Contraindicated when concerned about respiratory function,
hepatic and renal function and if the animal is prone to gastric
dilation

α2-Agonists

Contraindications
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Associated with temporary behavior and personality
changes
Reduces pancreatic secretions causing transient
hyperglycemia (exacerbates dehydration)
Opioids will exacerbate these side effects

Opioids

Commonly used:
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Morphine
Oxymorphone (Numorphan)
Butorphanol (Torbugesic, Torbutrol)
Hydromorphone
Meperidine (Demerol, Pethidine)
Fentanyl

Opioids

Act by reversible combination with one or more
specific receptors in the brain and spinal column

Also classified according to their analgesic activity and their
addiction potential


Pure agonists are more effective for severe pain
In order of decreasing potency they are:

Fentanyl

Oxymorphone

Buprenorphine

Butorphanol

Meperidine

pentazocine

Opioids

Commonly used as an analgesic in
premedication, as an induction agent or can be
used for balanced anesthesia and post-operative
pain control


Provides some sedation and may potentiate the action
of the sedative that it is given with
has a synergistic effect

Opioids

Commonly used as an analgesic in premedication, as
an induction agent or can be used for balanced
anesthesia and post-operative pain control

Fentanyl, sufentanil and oxymorphone are often part of a
balanced anesthetic regimen

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
Fentanyl is available as a transdermal patch in various sizes for
long-term analgesia
Used as neuroleptanalgesia in combination wit tranquilizer
Morphine can be injected epidurally or sub-arachnoidally for
regional analgesia

Opioids

Fentanyl patches

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
Takes 8 to 12 hours to reach effectiveness but will last
for several days
Very few cardiovascular side effects
Does not significantly contribute to vasodilation or
hypotension
Heating pads can increase transdermal uptake

Opioids

Reversible by use of pure antagonists such as
naloxone or nalmefene


Compete with opioids for the specific receptor sites
Possible to titrate the naloxone dose so as to remove
the side effects yet maintain analgesia

Opioids

Other effects in addition to analgesia

Either stimulate or depress the central nervous system

Depends on the dose, species and opioid agent

Excitement occurs if given rapidly IV

Horse and cat are particularly susceptible to excitatory effects

Dogs generally show sedation although hypnosis can be seen
in higher doses in sick animals

Dogs that are not in pain may show excitement especially if
given without any other agents

Opioids

Other effects in addition to analgesia

Cardiopulmonary effects



Bradycardia
Possible hypotension with release of histamine
 Especially if given IV
 Morphine and meperidine
Increased muscle contraction in low doses
 Inotropic effect
 morphine

Opioids

Other effects in addition to analgesia


Respiratory depression is dose dependent
Gastrointestinal effects depend on the agent



May initially include diarrhea, vomiting and flatulence
Constipation may occur as a result of prolonged GI stasis
Addiction

Opioids

Other effects in addition to analgesia

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Body temperature decreases and panting in dogs due to
a resetting of the thermoregulatory center in the brain
Miosis in dogs and pigs and mydriasis the cat and horse
Increased responsiveness to noise
Cough suppression
Excessive salivation
Sweating, particularly in the horse

Opioids

Contraindications



Previous history of opioid excitement
Morphine has a higher incidence of producing vomiting
so should be avoided in cases of GI obstruction and
diaphragmatic hernia
Classified as a narcotic in Canada and is a
Schedule II controlled drug in the US
CNS Stimulants

Defination
“Stimulants
are a substance which
tends to increase behavioral
activity when administered”
CNS Stimulants



Two disorders treated with CNS stimulants
are narcolepsy and Attention Deficit
Hyperactivity Disorder
CNS stimulants act by facilitation initiation
and transmission of nerve impulses that
excite other cells.
New drugs act selectively to inhibit reuptake
or norepinephrine in the nervous system.

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Signs and symptoms:
1- Elevate Mood
2- Increase Motor Activity
3- Increase Alertness
4- Decrease need for Sleep
In case of overdose lead to convulsion and
death.
CNS Stimulants

- They can be divided based on their site of
action:

1.Cerebral stimulants (amphetamines)

2.Medullary stimulants (picrotoxin)

3.Spinal stimulants (strychnine)
Indications
Analeptics (CNS stimulants) Reversal of anaesthesia-
induced respiratory depression
Anorexiants Thought to suppress the appetite
control centre in the brain
ADHDStimulate the areas in the brain responsible
for mental alertness and attentiveness
NarcolepsyIncrease mental alertness
Migraine headaches
Caffeine, co-administered with other drugs, used
to treat headaches
Side Effects



Wide range, dose related
Tend to “speed up” body systems
Common adverse effects include:

Palpitations, tachycardia, hypertension, angina,
dysrhythmias, nervousness, restlessness, anxiety,
insomnia, nausea, vomiting, diarrhea, increased
urinary frequency
1- Amphetamine




MOAs :
Block the reuptake of norepinephrine and
dopamine into the presynaptic neuron and
increase the release of these monoamines into
the extraneuronal space.
- Clinical use:
1. Narcolepsy.
2. Attention-deficit hyperactivity disorder
Amphetamine






Adverse effects:
- Cardiovascular: Hypertension (7% to 22%, pediatric )
- Endocrine metabolic: Weight loss (4% to 9%,
pediatric; 11%, adults )
- Gastrointestinal: Abdominal pain (11% to 14%,
pediatrics ), Loss of appetite (22% to 36%), Xerostomia
(35% )
- Neurologic: Headache (26% ), Insomnia ‫( ارق‬12% to
17%, pediatric; 27%, adults )
- Psychiatric: Feeling nervous (6% )
Amphetamine




After injecting, the mice with amphetamine
you well notice:
- Hair erection
- Licking, gnawing.
- Stereotype
- Sniffing
Picrotoxin

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MOA:
Non-competitive antagonist of GABA receptors.
After injecting the mice with picrotoxin you
well notice:
- Clonic convulsion characterized by :
1. Asymmetric
2. Intermittent
3. Spontaneous
4. Coordinated
Strychinine



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

MOA:
Competitive antagonist of the glycin receptors.
After injecting the mice with Strychinine you well
notice:
- Tonic convulsion characterized by :
1. Symmetric
2. Reflex in origin
3. Continuous
4. Uncoordinated.
Attention Deficit Hyperactive Disorder





Methylphenidate
Brand Name: Ritalin
Classification Therapeutic: CNS stimulant
Action: Produces CNS and respiratory stimulation
with weak sympathomimetic activity.
Therapeutic Effects: Increased attention span in
ADHD. Increased motor activity, mental alertness,
and diminished fatigue in narcoleptic patients.