Functions: sensaions, preceptions, voluntary movement, learning, perception, speech and cognition, LONG TERM memory 

- motivation, planning, emotional complexity 

This is the largest portion of the brain

Cerebrum 

has the function of: sensations, perceptions, voluntary movement, learning, perception, speech, cognition, information processing, long term memory 

It acts as a relay center to cerebral cortex

site of action for anti-convulsants 

Physiological homeostasis 

Thirst

Emotions

Body Temp

Hormones (pituitary gland)

- regulated by the mammillary body 

Voluntary motor control 

This is where PARKINSON's disease has effects - causing tremors, and robotic movement

Controls emotion and memory 

thirst and hunger stimulation 

SURVIVAL RESPONSES 

Lesion: docile or voracious eater

Respiration and cardiac control

Reticular formation 

controls sleep/wake cycles

stimulates arousal 

maintains consciousness

Fine motor coordination 

proprioception 

Lesion: appear drunken

Chemical messengers that bind to receptor molecules present on the surface of adjacent neurons. 

A chemical messenger produced by neurons that act diffuse away from the synapse and target neighboring cells (paracrine)

A chemical messenger produced by a neuron that acts as a true hormone.

- released into synaptic cleft

reuptake transporters take in and recycle neurotransmitter. 

Post synaptic receptors

Autoreceptors 

broken down on neuron surface 

*too much transmitter is toxic to the neuron, so it needs to be repackaged

Neurotransmitters are stored in vesicles in the neuron. 

Neurotransmitters are toxic to the neuron. 

Within vesicles there is enzymatic breakdown and exocytosis. 

1. Neurotransmitter synthesis 

2. Vesicular storage 

3. Enzymatic breakdown of non-vesicular neurotransmitter

4. Exocytosis

1. Auto-receptor feedback inhibition 

2. Postsynaptic receptor activation

3. Deactivation by enzymatic breakdown 

Amines

Quaternary amines

Monoamines

Amino acids

Neuropeptides 

opoid peptides

Peptide hormones 

Gases 

Catecholamines

Norepinephrine

Epinepinephrine

Dopamine

Indoleamines

Serotonin

Melatonin

Gamma-aminobutyric acid (GABA) 

Glutamine

Glycine

Histamine 

Enkephalin 

met-enkephalin

leu-enkephalin

Endorphorins

Beta- endorphin

Dynorphins 

Dynorphin A

Ocytocin 

Substance P 

Cholecystokinin (CCK)

Vasopressin 

Neuropeptide Y (NPK)

Hypothalamic releasing hormone

Nitric oxide 

Carbon monoxide 

It causes arousal effect characterized by return of consciousness in anesthetized or sedated patients. 

These are CNS stimulators of respiratory and chemoreceptors = increase tidal volume 

What type of drug is Doxapram?

When is it used? 

Disadvantages?

Action?

Contradictions?

Type:Analeptic (CNS stimulant)

Uses: Used to arouse animal from anesthetic overdose, neonatal apnea syndrome by stimulating respiratory centers

Action: stimulates respiratory centers in medulla to increase tidal volume. 

Disadvantages: nonspecific and transient effects

Contradictions: can cause seizures in susceptible animals

*******

Type: Monoamine

Uses: Movement, reinforcement, planning

Action: Acts on 5 major receptors 

(D₁ - D₅) 

Dopamine transporters

Acts on the substantia nigra, ventral tegment 

Type: Bronchodilator (CNS stimulant)

Uses: used as mild diuretic, stimulate respiratory muscles, and cause smooth muscle relaxation. 

How do tricyclic acids act as antidepressants?

What are some examples of them?

Side effects?

They act as serotonin-noreipinephrine reuptake inhibitors.

This means they block the serotonin and epinephrine transporters, resulting in a concentrated extracellular concentration of neurotransmitter. 

Examples: Amitriptyline, clomipromine

Side effects: antimuscarinic effects - dry mouth, decreased GI motility, hypotension, tachycardia

What is a common source of theobromide poisoning?

CHOCOLATE poisoning.  Theobromide is a methylxanthine, which are used as bronchodilators for their action of smooth muscle relaxation.

(Same class as Caffeine)

                The lethal dose of theobromine in dogs is 114-228 mg/lb (2-3 ounces of milk chocolate per lb)

This will cause CNS excitement resulting in seizures, nausea, vomiting, cardiac dysrhythmia (in toxemias)

Name a drug used to stimulate respiration in apneic animals.

DOXAPRAM

This is used to arose animals from anesthetic overdose, by increasing tidal volume.

The negative aspects are that its action is transient, non specific, and reduces the depth of anesthesia.  It can also cause seizures in susceptible patients. 

Methyxanthines act by stimulating adenosine receptors. 

True or False?

FALSE!

The action of methyxanthines is that they reversibly block adenosine receptors.  They also inhibit phosphodiesterase, which causes an accumulation of cAMP when administered at high dose.

________ region of the brain acts as a relay center. 

THALAMUS 

It relays messages to the cerebral cortex.

Dopaminergic cell bodies are located in the _________ and __________ regions of the brain. 

VENTRAL TEGMENTAL AREA & SUBSTANTIA NIGRA

These are located in the midbrain (mesencephalon), and have a role in reward reinforcement, planning and movement.

Dobermans - flank sucking

English Bull Terriers - spinning 

German Shepards - tail chasing 

Concurrent behavior modification therpay is essential for pharmacotherapeutic success. 

True or False?

TRUE 

That a reduction in NE (Norepinephrine) and 5-HT (serotonin) levels might be a causative factor in depression. 

Depression is a herterogeneous disorder.

The thought is that by using agents that enhance the action of the above monoamines, there will be a more efficacious treatment of depression.

Anxiolytics 

Benzodiazopams 

Azapirones

Antidepressants 

Tricyclic antidepressants 

Serotonin reuptake inhibitors 

Monoamine oxidase inhibitors (MAO)

Diazepam can be used in long term treatment of canine agression, as long as it is concurrent with behavior modification therapy.

True or False?

FALSE 

Diazapam is a BENZODIAZEPINE, which it NOT for long term use and may cause physical addiction. 

Also they can lead to disinhibition which will in turn increase agression. 

Benzodiazepines also have amnesic effects, so they will forget the behavior modification therapy.

Benzodiazepine

alprazolam (Xanax) 

Clonazepam 

Diazepam (Valium) 

Lorazepam 

Oxazepam

What is the goal of Benzodiazepines? 

How does the action of these drugs accomplish that?

Goal: DECREASE ANXIETY

Stimulates GABA-A receptors = increase chloride influx = membrane hyperpolarization 

This results in an increased GABAnergic neurotransmission.

Dopamine, NE, Epinephrine, 5-HT (Serotonin)

Dopamine: Major neurotransmitter of brain, behavior and drug reinforcement, mood, cognative state, motor function

NE: learning, memory, mood, sensory processing, sleep, anxiety regulation

Serotonin: major regulator of sleep, body temp, arousal, emotion.

CNS stimulants 

Monoamine oxidase inhibitors (MAO)

CNS stimulants 

Tricyclic antidepressants 

Monoamine oxidase inhibitors (MAO)

Cerebral cortex, limbic system, thalamus

Benzodiazepines induce membrane hyperpolarization by facilitating GABA-mediated chloride conduction.

Membrane is hyperpolarized 

The cells then cannot elicit an action potential and cannot send signals.

This is the action of Benzodiazepines

What is the clinical application for Benzodiazepines at:

A) High doses?

B) Moderate doses?

C) Low Doses?

A) High doses: Hypnotics

B) Moderate doses: Anti-anxiety 

C) Low doses: mild sedatives

They can be used in combination with TCAs or SSRIs to improve clinical outcome.  

Benzodiazepines are unreliable in specificity of behavioral modification, and the addition of these drugs can help.

Animals may need to be weaned off, physical addiction 

Ataxia 

LIVER DAMAGE
Amnesic effects 

Can increase agression (even in non agressive dogs)

Prone to abuse by humans 

What are the therapeutic uses for Diazepam?

Relieve short term anxiety

treatment of feline urine spraying behavior

Less effective but still used for treatment of storm phobia

HEPATIC NECROSIS in cats 

physical addiction

human abuse

CYP-450 metabolizing drugs

This may reduce the drug metabolism that can cause Hepatic necrosis in cats.

FEAR SITUATIONS, panic disorders

can be used with clomipromine for storm phobia

Physical dependence (requires slow withdrawl)

Cannot be given with Cytochrome 450 inhibiting drugs 

(ketoconazole, itraconazole) 

Appetite stimulant in cats

Anxiety in patients with compromised liver or are aged 

Has less of a tendency to cause idiopathic hepatic necrosis 

Diazepam can cause hepatic necrosis in cats, 

where oxazepam is must less likely to trigger this.

What are some clinical therapeutic uses of Lorazepam?

What is unique among benzodiazepines in it action?

Treat to interact agression-victim cat relationships 

Has slower onset of action but sustained release

What is the mechanism of action of Buspirones?

What is an example of this category of drugs?

MOA: partial agonist of serotonin,

affinity for DA D₂ receptors.

Ex: Azapirone

What are some clinical therapeutic uses for Azapirone?

What are the advantages of using this drug?

Anti-anxiety medication with minimal side effects.

So its used for the management of GENERALIZED ANXIETY DISORDERS, such as agression. 

This drug has minimal side effects, is NOT associated with dependece, doesn't produce sedation. 

Tricyclic Antidepressants (TCAs) 

Serotonin Selective Reuptake Inhibitors (SSRIs)

Monoamine Oxidase Inhibitors (MAOIs)

Amitriptyline 

Clomipromine

Doxepin 

Desipramine

Imipramine

Nortriptyline

What is the best drug in treating pruritic conditions like psychogenic alopecia?

DOXEPINE

Antagonist to H2 and H2 (histamine) receptors

Antagonist to H1 and H2 histamine receptors ALSO

* blocks reuptake of NE and some serotonin, at transporter of synaptic cleft.* 

BEST for pruritic conditions

Norepinephrine

Dopamine (stereotypy-limbic system VTA) 

Serotonin

GABA

Endorphins 

An inbalance in neurotransmitter systems and abnormal receptor function = behavior deficits

This is when SSRIs and MAOs are given together 

FATAL 

causes sonfusion, agitation, hypertension, tachycardia, excessive salivation, hyperpyrexia

What can be used to treat psychogenic alopecia in dogs? 

In cats?

In dogs DOXEPIN

In cats AMITRIPTILINE, Fluoxetine

Amitriptyline (TCA)

Fluoxetine (SSRI)

Oxazepam 

This is the best choice to use in older dogs and those that may have liver disease 

Where are Monoamine oxidases present?

What is their function?

In the liver - 

They breakdown tyramine rich foods which would other wise accumulate and cause a hypertensive crisis. 

Break down of monoamines such as NE, 50HT, and Dopamine

Alprazolam

clomipramine

Oxazepram (in older, liver dz)

Buspirone (with clomipramine)

Drug enhances the GABAa receptors, which causes an increase in the channel flow of Cl-, causing membrane hyperpolarization. This results in inhibition of signal transmission.

Does not work on the Cl- channel directly

Disorder of older dogs 

includes decreased social interactions, changes in sleep cycle, loss of prior housetraining and obedience commands. 

Can be treated with Selegiline (MAOI)

1. binding of benzodiazepine to GABAa receptor

2. Conformational change in the receptor

3. GABA mediated CL- influx increased

4. Membrane hyperpolarization 

5. Reduced neuron firing 

** Benzodiazepines elicit action only in the presence of GABA**

Which type of drug induces CYP 450,

Benzodiazepines or Barbituates?

The more lipid soluble a drug is the more difficult it is to cross the blood-brain barrier.

t or f?

FALSE 

Lipid solubility determines the rate that drugs cross the blood brain barrier, and the more soluble to the more rapidly this will occur. 

Amnesia

anti-convulsant 

Muscle relaxant (GABA @ spinal cord) 

NO cardiovascular effects (in healthy)

Minimal respiratory effects 

Can cross placental barrier 

TERATOGENIC

What has a lower margin of safety, 

Benzodiazepines or Barbiturates?

Which have lower toxicity, 

benzodiazepines or barbiturates?

Because they block the D2 Chemoreceptor trigger zone

preventing ir from being stimulated

The amount of time between them. 

An isolated seizure can be defined as happening once in a 24 hr period, whereas cluster seizures will occur more than once in a 24 hr period. 

A LIFE THREATENING EMERGENCY. 

Characterized by recurrent episodes for 30 mins without regaining consciousness or muscle movement for more than 5 mins. 

Needs to be treated within an hour!!! > brain damage

Cardiopulmonary support + stop seizures with Pentobarbital.

Prodrome: (days to hrs prior) behavior changes

Aura: event characterized by sensory and psychosensory symptoms (twitching, blinking lights) indicative of sensory focal seizure. 

Ictus: SEIZURE event

Post-Ictal phase: behavoral changes that can last for days (including coma)

Nonclinical, nonspreading spontaneous discharge of a small group of prosencephalon neurons. 

Only can be seen by EEG.

A focal seizure with limited spread - observed clinically

can be conscious or unconscious.

Often assocaited with structural lesion that limits spread.

Distrubance in patients sensorum = behavioral change.

(staring in to space or manic running) 

Focus located in the limbic system.

AKA - Physcomotor seizure 

Seizure can evolve and terminate as a generalized seizure

Most COMMON. AKA Grand Mal Seizure.

brain regions are diffusely effected, loss of consciousness, lasts for 30 sec to 3 mins. 

1. Inhibit voltage gated sodium and calcium channels.

2. Enhancement of GABAnergic transmission 

3. Blackade of excitatory gluatmatergic neurotransmission

Pre-synaptic Alpha 2 activation 

G protein mobilization 

adenylyl cyclase inhibition

decrease in intracellular levels of cAMP

Inhibition of NE release from sympathetic neurons 

=reduction of sympathetic output

Mu

analgesia, euphoria, respiratory depression 

The perception of pain via nociceptors - Na+ channels activated by thermal, chemical, and mechanical insults. 

threshold lowered by inflammation mediators (prostaglandins)

Inflammatory mediators - prostaglandins 

bradykinin 

Allevation of mild/moderate pain 

anti-pyrexia

anti-inflammatory 

anti-coagulation

block synthesis of TXA2

Inhibition of platelet aggregation by PGI2

NSAIDS inhibit the PGs and COX1 that would normally produce mucus layer of gastroprotection.

CAN CAUSE ULCERS!

use with misoprostol, a PGE analog that fulfills mucus secreting function. (mucogenesis)

PGs cause vasodilation (via COX2) 

NSAIDS - fluid retention & HYPERKALEMIA

They cause a imbalance of endothelial integrity. 

If preexisting CV condition = PGI2 < TXA2 

increased likelihood of CV issues.

Corticosteroids are best used in combination with NSAIDS to increase the ability to reduce inflammation. 

t or f?

FALSE 

they do not work together - and should never be given together. 

Together do not enhance anti-inflammatory properties, but will increase likelihood of gastric ulcers.

RA is an autoimmune erosive arthritis, which is caused by activated platelets releasing microplatelets.  These microplatelets are what causes erosion of the joint. 

This release is COX independent, so NSAIDS will have no effect on it. 

What are the pharmacokinetics behinds NSAIDS?

Highly bound to plasma proteins, Low volume of distribution. 

Weak acids = good oral drugs

Metabolized by liver - subject to first pass.

Injectables are tissue irritants

CATS HAVE ISSUES.