Pharmacology of central nervous system (3)

By

Dr. Nehal Aly Afifi Professor of Pharmacology

Faculty of Vet. Med.

Cairo university

Pharmacology of Central

Nervous System

10/31/2016 Prof Dr. Nehal Afifi 2

CNS acting drugs have a major therapeutic & clinical importance

Drugs can produce diverse pharmacological &

psychological effects such as:

• Induction of Anesthesia

• Relief of Pain

• Prevention of Epileptic seizures

• Reduction of Anxiety

• Treatment of Depression

• TTT. of Alzheimer's disease & Parkinsonism

CNS Drugs : Sedatives, Tranquilizers, Hypnotics, Anesthetics,

Anticonvulsants , Analgesics, Psychotropic agents, Behavioral

modifing drugs


Structure of CNS

1- Brain 2- Spinal cord

The Brain formed of 3 main parts:

ForebrainI. The

• Cerebrum

• Thalamus

• Hypothalamus

MidbrainII. The

HindbrainIII. The

• Cerebellum

• Pons

• Medulla oblongata


Cerebrum: Largest part of brain, Surrounded by outer cortex

Cerebral cortex divided into 3 functional areas:

1. Sensory area (sensation)

2. Motor area (voluntary

movements) → ↑physical &

mental activities,↑↑ Convulsions

: Association area. 3

- Higher mental activities as

consciousness, thinking,

memory, behavior.

- ill developed In animal


Thalamus : act as a relay station for

receiving N. impulses & sending to

sensory areas in C.C. Contain pain cent.

The hypothalamus:

Act as a control center for the A N S.

Contain heat regulating, appetite Cs.

The mid-brain : “bridge connect

cerebrum to cerebellum & Pons.

Cerebellum: Resp. for balance of

body & maintaining appropriate body

posture & equilibrium.

The medulla oblongata (M.O.) :

for passage of im. bet brain & SC


Medulla oblongata contain 5 vital Cs.[ Vagal, Vasomotor,

Respiratory, Cough, Vomiting(chemoreceptor trigger zone (CTZ)

II- Spinal cord

A cylindrical mass of nerves extends from

the end of M.O. to the lower lumbar vertebrae

Impulses flow from and to brain through

descending & ascending tracts of spinal cord.

Contain sex centers (Erection & ejaculation)

+ sweat & micturation Cs.

Acts as a reflex station for receiving

impulses from and to all parts of body.

Pharmacology of Synaptic transmission

Receptor events

Propagation of action potentials

Calcium entry

transmitter release


How brain cells communicate?

Neurotransmitter (NT): A chemical released by a

terminal nerve; has an excitatory or inhibitory effect on another

neuron.

A nerve terminal

10/31/2016 Prof Dr. Nehal Afifi

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Transmission in CNS

A nerve impulse (electric current) passé along axon to

presynaptic membrane.

Release neurotransmitter into synaptic cleft.

NT interacts with receptors on effector cells to induce response.

NT released in response to action potentials is voltage dependent

& require calcium influx (Neuroregulators).

Transmission in C.N.S. occurs in 2 ways:

A- Release of Excitatory transmitter by Neuron

(1) Cause depolarization of postsynaptic membrane of neuron

(2) Cause Conduction of N impulse [postsynaptic excitation].

B- Release of Inhibitory Transmitter by Neuron

(!) Cause Hyper polarization of postsynaptic membrane .

(2) Block conduction of nerve impulse [postsynaptic inhibition].


Neurotransmitters can be classified into:

1. Amino acids:

Excitatory A.A. : Glutamate & Aspartate.

• Location: interneuron at all brain , spinal cord

• Act on glutamate & aspartate subtype- receptor.

• Excitation due to depolarization

• 2. Inhibitory A.A. : GABA & Glycine.

Location: Spinal & supraspinal interneurons

Inhibition results from hyperpolarization.

3. Monoamines : Noradrenaline , Adrenaline , Dopamine,

5-HT

4- Choline ester: Acetylcholine

Amino acids & Amine Transmitters in CNS

Major Excitatory amino acids transmitters

Glutamate & aspartate exert an extremely powerful

excitatory effect on neurons in every region of CNS.

Excitation due to depolarization of postsynaptic mm .

By acting on glutamate & aspartate subtype receptors

Location: Interneuron at all levels (spinal & brain)

Glutamate antagonist (e.g., Ketamine ) hastherapeutic

role in treatment of “epilepsy” & induction of anaesithea

Glutamate and Aspartate


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Gamma amino butyric acid (GABA)

Major inhibitory transmitter at all levels of brain

GABA is a ligand gated cl- ion channel.

Stimulation of GABA receptors cause change in

postsynaptic membrane permeability to become

permeable to chloride (cl-) results in hyperpolarization of

the receptive neuron.

Benzodiazepines, Barbiturates, Sod. Valporate ,

Ivermectin increase binding GABA to Rs. (GABA Agonist)


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Picrotoxin: antagonize GABA by closing cl ion channel

inhibit presynaptic & postsynbtic inhibition of GABA causing

stimulant effect


Acetylcholine ( Ach)

Ach is widely distributed in major parts of CNS

Both types of Cholinergic receptors (nicotinic & muscarinic)

occur in CNS

Muscarinic receptors (M1) are much more abundant than

nicotinic Rs. & mediate behavioral effects of Ach .

Ach in the brain plays a role in

1- Arousal. 2- Learning.

3- Short term memory. 4- Motor control.

Loss of cholinergic Ns. in memory site cause "Alzheimer’s dis


Noradrenaline (NA) & Dopamine(DA)

NA found in all levels of the brain .

NA play important role in the regulation of :

1- Mood: Deficiency of NA cause depression.

2- Arousal: Increase release NA → wakefulness ,alertness

3- Bl. pressure regulation.

Dopamine acts as a “neurotransmitter” on dopaminergic Rs.

Dopamine play role in

1- motor activity: dopamine Deficiency→ Parkinson’s dis.

2- Behavioural effects: Control of behavior & emotion.

3- Vomiting: by stimulating dopamine receptors in CTZ in MO

Metoclopramide , phenothiazines are antiemetics drugs.

(dopaminergic antagonists)


5-Hydroxytryptamine (5-HT) & Histamine

5-HT is an important CNS transmitter

5-HT in CNS involved in behavioral changes, mood,

hallucinations, sleep, and wakefulness.

5-HT plays a role in

1- Mood: ↑ 5-HT levels by giving tryptophan useful in

depressive states

2- Sensory transmission: 5-HT inhibits transmission of

pain impulses in SC. & brain and enhances morphine

analgesia.

3- Temperature control: hypothalamus rich in 5-HT

4- Vomiting: 5-HT3 blocker used as anti-emetic.

Histamine:

Blocking central H1- receptors have Sedative, Antiemetic effet

Drugs acting on CNS


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• Cerebral stimulants

• Medullary stimulants

• Spinal cord Stimulants

CNS

Stimulants

• Nerve Sedatives

• Tranquilizers

• Hypnotics

• Anticonvulsants

• Anaesthetics

• Analgesics

CNS Depressants

Cerebral stimulants

(Cerebral -cortex stimulants)


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Xanthines (Caffeine, Theophylline & Theobromine),

Amphetamine & Retaline.

Stimtimulate motor & sensory area so physical & mental a

Wakefulness, refreshment, fatigue.

Awake animals from anesthesia in Vet. Med.

Caffeine (coffee seeds), theophylline (tea leaves)

Theobromine (coca seeds) & methylated Xanthine.

MOA: Caffeine Inhibit Phosphodiesterase enz. so c-AMP

in cerebral cortex neurons.

Pharmacological Effects


19 1- Smooth muscle relaxant (Spasmolytic) Aminophylline

2- Cardiac stimulant:↑ force of contraction (+ve inotropic)

↑ Heart rate (+ve chronotropic) → increase BL. Pressure

Coronary Vasodilatation & vagal stim.→ decres BL. pressur

Both effects lead to slight rise in BL. Pressure

Caffeine is contraindicated in hypertensive patients.

3- Secondary diuretic:

Increase renal Bl. Flow due to cardiac stimulant effect.

Renal vasodilatation increase glomerular filtration.

Inhibit release ADH decrease water reabsorption.

Decrease Na tubular reabsorption.


4- GIT: caffeine increase gastric secretions improve

digestion.

Therapeutic uses:

Antagonize cortex depression & awake animal from

anesthesia.

Caffeine combined with Aspirin or Paracetamol for

treatment of Headache

For Oedema

Aminophylline used for bronchial asthma

For ttt billiary, renal & intestinal colic (spasmolytic).


Differences Caffeine Theophylline Theobromine

Plant origin Coffee Tea Coca

Cerebral stimulant powerful Moderate Weak

Cardiac stimulant Weak Powerful Moderate

Diuretic Weak Powerful Moderate

Smooth ms. Relaxant Weak Powerful Moderate

Amphetamine (Benzedrine):

Powerful CNS stimulant; mental & muscular activities.

Non catecholamine, stimulate & receptors by inhibit MAO enz.

Increase basal metabolic rate for treatment of obesity.

Therapeutic uses: Illegally as a motor activator for race horse (doping).

For ttt. of CNS depression in barbiturate & narcotic poisoning.

Medullary stimulants


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Direct medullary stimulants

Picrotoxine

Nikethamide

Cardiazol

Bemegride

Doxapram

Reflex medullary stimulants

Camphor

Ammonia

Sol.

Medullary stimulants (Analeptics)

Drugs stimulate centers of M.O. especially depressed resp. C.

Awake anaesthetized animal by stim.brain & M.O. centers.

Picrotoxine:

Powerful stimulant on resp. & vasomotor centers.

Raised blood pressure & respiration.

MOA: 1- Antagonize GABA by closing cl¯ channel inhibit

pre- and postsynaptic inhibition caused by GABA.

2- Stim. chemo receptors at aortic sius in heart → stim. heart

For ttt. barbiturate poisoning (given i.v. or i.m)

Nikethamide (coramine): Given orally - has no effect on heart

Less effective & Less toxic than picrotoxine.



Cardiazol (Leptazol):

Stim. resp. & vasomotor centers no effect on heart.

For ttt anesthesia & narcotic poisoning ( i.v.). L.D.→ convulsions

Bemegride :

Powerful respiratory stimulant in barbiturate poisoning.

MOA: Competitive antagonism with barbiturate due to chemical

similarity (given i.v.)

Doxapram:

The most powerful analeptic - has wide safety margin.

Act both centrally & peripherally.

Camphor & Ammonia solution (Reflex analeptic)

Camphor s/c → irritate cut. S. Ns. → reflexly stim. M.O. respt. C.


Spinal cord Stimulants

Strychnine: Alkaloid from strychnus nux vomica seeds.

MOA:1- inhibit inhibitory transmitter glycine at post-synaptic N.E.

so increase reflex excitability to external stimuli.

2-On brain St. Sensory area of cerebral cortex sharp sensation

Large dose convulsions of sk.ms & diaphragm.

Aphrodisiac (for ttt sexual impotency in dogs).

General tonic & stomachic (for anorexia, weak depilating A.)

Neuromuscular purgative(stim. aurbach’s plexus of intestine)

Ruminal tonic ( For ruminal atony)

Used as Motor activator for race horses (doping) to increase

capacity for running

Strychnine Toxicity

Toxicity due to large toxic dose or Cumulative effect

Toxic symptoms : convulsions in all sk.ms & diaphragm.

Poisoned dog show ch. posture [ back become arched, limbs become

rigid & extended, head raised upward & backward & tail raised upward]

Convulsions interrupted by period of rest or relaxation( Tonic C . )

Death due to asphyxia as a result of prolonged contraction diaphragm m

Treatment: Dark Place – Artificial Respiration- Volatile Anesthetic

Specific Antidote: chloral hydrate (For horse). Barbiturates or

Bromides (dogs). Mephenesin(For Man , central sk. ms.relaxant).


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CNS Depressants

Classified according to the degree of depression

Tranquilizers Sedatives Sedative

Hypnotics

Anesthetics Anticonvulsants

Analgesics


Sedatives and Tranquilizers

Tranquilizer :

Tranquilizer Reduce anxiety & induce calming without drowsiness

or loss of consciousness even with large dose .

Sedatives:

Drug-induced sedation has a more profound effect, produce

drowsiness and hypnosis.

Nerve Sedative: depress CNS, produce sedation, drowsiness,

unaware to surroundings , decrease loco motor activity and

reduce fear but animal remain conscious.

The large dose induces loss of consciousness & hypnosis so

called sedative hypnotics.

Drug cannot induce only one pharmacologic effect & Many

drugs cannot be categorized by only one pharmacologic

effect, i.e., as tranquilizers, sedatives, or analgesics.


Tranquilizer relieve anxiety & mental tension in man.

In animals, quieting & calming effect and reduce fear

Phenothiazines in vet. Med. science 1950.as tranquilizers,

& as antipsychotic drugs.

The effect of Phenothiazine on CNS is called Neuroleptic .

Acepromazine maleate – Chlorpromazine hydrochloride

Promazine hydrochloride.

MOA: 1-Phenothiazine inhibit central dopamenergic

receptors (D2) which produce sedation & tranquilization.

2-Peripherally, Ph. block Nor epinephrine at alpha adrenergic Rs.

Indications:

Phenothiazine commonly administered for general sedation.

2- Used peri-aneathetically to reduce anxiety, reduce drugs doses for induction & maintenance.

Tranquilizers : 1- Phenothiazine derivatives


Phenothiazines provide good muscle relaxation → used in

conjunction with anesthetics (e.g., Ketamine)

Ph. are antiemetic from block of dopamine Rs. in the CTZ within

the medulla.

Phenothiazines have little or No analgesic activity.

Used to treat psychiatric problems in people & animals

Other pharmacological effects of tranquilizers:

1- Anti-emetic 2 – Antihistaminic. 3- Hypotensive

4- Antispasmodic. 5- Sympatholytic.

Examples of tranquilizer: Phenothiazines , & azaperone.

Alpha–2-adrenergic Agonists: [Xylazine - Detomidine -

Medetomidine ,& Romifidine]

Produce profound sedation by activation of ∂-2-adrenergic Rs.

located in brainstem.


Ruminants are the most sensitive spp. to sedative effect of ∂-2-

adrenergic agonists.

The duration of sedation & level of analgesia are dose- dependent

MOA: Alpha-2-adrenergic agonists produce activation of

central ∂-2-adrenergic Rs→ reduce sympathetic outflow

(decreased nor epinephrine)& so increase parasympathetic t

Alpha-2-agonists produce Musculoskeletal relaxation.

produce profound analgesia & administered parentally.

Vet. Products:

Xylazine (Rompun®) Injectable for use in cattle, dogs, cats,

horse, deers.

Detomidine: approved by FDA for use in horse.

Medetomidine & Dexmedetomidine: for use in dogs.

Romifidine: approved by FDA for use in horse


Xylazine (Rompun)®

Act as sedative hypnotic & possesse Analgesic &

skeletal muscle relaxant effects

soluble in water and given by i.m. or i.v. injection to

domestic animals.

Xylazine is 2- adrenoceptor agonist

MOA: by stimulation of 2- receptors in sympathetic ns

Ruminants most respond to xylazine

Low dose sedation, high doses recumbence

Clinical Uses: Given by i.m. or i.v.

To Calm vicious animals before clinical examination

Preanesthetic medication.

For treatment of Spasmodic colic

Treatment of s convulsions as anticonvulsant.


Bromides (potassium or sodium salts)

Pot. bromide act as a Nerve sedative & Anticonvulsant.

MOA: Bromide stabilize neuronal cell membranes by interfering

with chloride transport across cell mm & by potentiating the effect

of GABA via hyperpolarizing mm.(replacement with cl¯ in

extracellular fluid of N.C , so decrease cl¯ conc. causing sedation.

Bromides depress only motor area of cerebral cortex.

Bromide used as a first-choice AED in dogs with epilepsy

The elimination half-life is long (24 days) in dogs.

Bromide is really eliminated →Not used in renal disease

Bromide Not undergo hepatic metabolism so useful in dogs

with liver disease.

Br. formulated into a sol. of various conc. or into tablets .


Chloral hydrate is a white crystalline powder soluble in water

Act as Nerve sedative at small doses

Hypnotic & General anesthetic at L.D. given mainly for horse by

i.v. injection.

MOA: in body Chloral hydrate reduced mainly in liver into

trichloroethanol → a direct depressant effect on CNS.

Disadvantages as a general anesthetic :

Narrow safety margin.

Must be administered in Large volume of freshly prepared sol.

Induction of anesthesia is slow & prolonged recovery period

Has irritant effect & can cause tissue necrosis.

Overdose cause respiratory failure & hypotension ( due to Chloral

hydrate cause depression of respiratory center & heart)

Chloral hydrate Lake analgesic effect .

Chloral hydrate


Hypnotics produce normal sleep & deep sleep

( narcosis) or general anesthesia at L. D.

chloral hydrate

2 – adrenoreceptor

agonist

Barbiturates. Benzodiazepines

Chloral

hydrate Barbiturates

Benzodiazepine

- Diazepam

- Zolazepam

Sedative

hypnotics


Barbiturates Derivative of Barbituric acid ,given as Sod. salt soluble in water. Barbiturates → gradual degree of CNS depression from Sedative

Hypnotic to General anesthetic

Low dose → a sedative action causing a reduction in

restlessness and tension.

A larger dose of Barbiturates → a hypnotic sleep inducing effect.

A further increased dosage → anesthesia

Good skeletal muscle relaxant, but lack analgesic effect.

MOA: act by interfering with ATPase in neurons of cerebral

cortex so prevent utilization of ATP → CNS depression

Highly irritant sol→ given i.v.

Classification.: according to period of sleep

Long acting barbiturates: Phenobarbital sod. 6-8hs.

Short acting : Pentobarbital sod. (Nembutal)® 2-4hrs.

Ultra short : Thiopental (Nesdonal)® ¼ -2 hrs.


Sedative hypnotic Tranquilizer

Effect of high

doses

- Loss consciousness

- Anesthesia

- Resp. depression

- Conscious.

- only immobility

-NO resp.dep

Sensory

Reflexes

- Depressed - Normal

Effect on emesis - No effect -Antiemetic effect

(inhibition of CTZ)

Anticonvulsant

Effect

- General skeletal

muscle relaxants

Limited & specific

Preanaesthetic

Effect

-Duration not affected

- decrease the dose

Prolong duration

of anesthesia

Difference between hypnotics & tranquilizers


Drugs for Treatment

Diazepam

Phenobarbital

Sodium IV

Propofol

Phenytoin

Drugs for Maintenance

Phenobarbital

PO

Bromide (potassium salt)

Valproic acid

Anticonvulsant Drugs

Anticonvulsants [Antiepileptic Drugs (AEDs]

AEDs used to stop an ongoing seizure or to decrease the

frequency or severity of anticipated future seizures.

Convulsions: result by stimulation of spinal cord or motor area of

cerebral cortex.

Epilepsy: acute prolonged recurrent seizures.

In status epileptic treatment is essential to prevent death from

hyperthermia, acidosis & hypoxia.

During a seizure', the route of administration for AEDs is IV .

Drugs Used for Treatment of Status Epilepticus:

1-Benzodiazepines [diazepam, clonazepam ,Midazolam ]

Diazepam (Valium®):Drug of choice to treat epileptics in small &

large animals[rapid onset of action to prevent spread of seizure]


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Diazepam is the most common benzodiazepine used in dogs and

cats to reduce motor activity .

Diazepam is used as IV bolus, the dose can be repeated 2–3

times at intervals of 5–10 min.

Diazepam is used IV for seizures in adult horses .

In foals, , slowly IV higher doses can be fatal to neonates. Clonazepam , Lorazepam , Midazolam can used in dogs.

MOA: Bz. binding to & activate (BZ)- receptor which located on

the GABA receptor subtype A (GABAA). This increase frequency of

opening of chloride ion channel leading to hyper polarization of post

synaptic neuron.

Indications: Bz. used in Vet. Med. 1- as anticonvulscent,

2-adjuncts to anesthetic agents, 3-skeletal muscle relaxants,

4- for behavioral modifying.

2- Phenobarbital : A long acting Barbiturates used for TTT. of

epileptics to prevent further convulsions.

A loading slow IV or IM, dose used.


Phenobarbital has a long safety, efficacy, low cost .

• primarily use as anticonvulsant for long term sedation.

3- Propofol : Short-acting IV hypnotic anesthetic agent +

Anticonvulsant [ GABA-agonists, stabilizing GABA-inhibitory NT ]

• After IV inj, propofol rapidly cross BBB → onset of action<1 min.

• The duration of action after a single bolus is only ~2–5min.

• 4- Sod. Pentobarbital: for TTT of uncontrollable epilepticus in

dogs , cats, especially when diazepam & phenobarbital failed.

• Pentobarbital administered to effect for anesthesia.

• 5- Phenytoin: still used as a slow IV infusion in dogs to stop

seizure but has undesirable pharmacokinetics

• Too rapid metabolism reduces its effectiveness in dogs

•Too slow metabolism in cat→ increase toxicity (salivation,

vomiting, weight loss ).


Maintenance Anticonvulsants

Both Phenobarbital & bromide are considered first-line

maintenance anticonvulsants in dogs, cats, horses,ruminants.

Gabapentin: Synthetic analogue of (GABA) inhibit seizures.

MOA: inhibition of neuronal sodium channels + potentiating of the

release & action of GABA neurotransmitter.

well absorbed after oral administration.

Valproic Acid:

Used as adjunct to phenobarbital in dogs with refractory seizures.

Also used to treat aggressive behavior problems (Psychotropic )

Clonazepam : used for oral maintenance therapy because

anticonvulsant tolerance develops less rapidly, its metabolism

reduce the elimination rate & it is more highly absorbed orally .

Carbamazepine: Not used in dogs[ rapid elimination, short half-

life] but used to treat aggressive behavior problems in cats.


Psychotropic Drugs

Anxiolytics, Antipsychotics, Antidepressants, Mood stabilizers

Used to treat human behavioral disorders & used more

commonly in Vet. Med. for behavioral modification therapy.

Anxiolytics مضادات القلق used to treat generalized anxiety &

panic disorder in dogs, cats, as well as urine spraying in cats.

Benzodiazepines ( diazepam, oxazepam, clorazepate) act

by binding to (GABA) Rs. enhancing GABA-mediated cl influx.

Cause sedation , muscle relaxation & Anticonvulsant effect.

Azapirone (Buspirone): differ from benzodiazepines in MOA

MOA: Buspirone blocks serotonin pre-and postsynaptically.

Buspirone acts as a dopamine agonist

Has delayed onset of action and lack of sedative effect .

.


Antipsychotics مضادات الذهان

Classified as low-potency agent (acepromazine, chlorpromazine)

and high-potency agents (haloperidol, fluphenazine,

trifluoperazine ).

All antipsychotics are used for nonselective tranquilization &

diminishing behavioral arousal.

Low-potency agents require larger doses, produce more sedation,

more anticholinergic side effects, & cardiovascular effects.

Acepromazine commonly used for anxietal episodes dogs, cats.

MOOD-STABILIZING Drugs االدوية المثبتة للحالة المزاجية

lithium, carbamazepine, & valproic acid are unrelated

chemical compounds, used in human medicine to treat

bipolar disorder, impulsivity, emotional reactivity, aggression.

Carbamazepine & valproic acid are also antiepileptic.


Antidepressants المضادة لالكتئاب االدوية

Antidepressants are classified as

1- Tricyclic compounds (Tertiary amines, Secondary amines)

2- Selective serotonin-reuptake inhibitors(e.g., Fluoxetine,

Sertraline, Paroxetine )

3-Other antidepressants( Monoamine oxidase inhibitors, like

Selegiline.

They used to treat behavioral disorders, including obsessive-

compulsive behaviors & aggression

MOA: to block reuptake of serotonin and/or norepinephrine or

to reduce neurotransmitter turnover.

Education

Pharmacology of central nervous system (3)