CVM 731 ANS

Cholinergic

Activated by acetylcholine

Muscarinic

• G-protein coupled acetylcholine receptors at effector organs innervated by parasympathetic nervous system

• We don’t usually have drugs specific for subtypes for the most part

Nicotinic

Ionotropic channels

What do we often mean when we imprecisely say cholinergic?

Muscarinic or parasympathetic

Adrenergic

• Aka “sympathetic”

• Ex.: Epineprhine and norepinephrine

Autonomic Nervous System

• Smooth muscle

• Exocrine glands

• Metabolic tissue

• Cardiac tissue

Somatic Nervous System

Skeletal muscle

Enteric Nervous System

Gastrointestinal (a branch of autonomic)

Sympathetic Nervous System

Fight or flight

Parasympathetic Nervous System

• Rest and digest

• At effector organs, Ach is released by post-ganglionic fiber to activate muscarinic receptors

Activated by acetylcholine (PNS)

• G-protein coupled

  • M1

  • M2

  • M3

M1

Head

M2

Heart

M3

Everywhere

Activated by epinephrine and/or NE (SNS)

• α1 

• β1 

• β2 

α1

Vessels

β1

Heart

β2

Smooth muscle: bronchioles, vascular endothelium

Ach in PSNS

• Action terminated by acetylcholinesterase

• Rapidly degraded in circulation

Adrenal medulla

Releases NE and epi

Post-ganglionic neurons in SNS

Most release NE to activate alpha-1, alpha-2, or beta-1

Action of catecholamines (Epi and NE)

• Increased contractility and heart rate

• Vasoconstriction

• Bronchodilation

Baroreceptor Reflex Arc

• Blood pressure control is almost entirely due to sympathetic NS

  • Stimulation of alpha R on vascular smooth muscle causes contraction. which increases resistance and thereby increases blood pressure

  • To maintain homeostatic BP, the body responds by activating parasympathetic muscarinic receptor on the heart (if BP is high, HR is decreased)

  • ANS is designed to keep all of this in balance

  • Key to pharmacologic therapy for cardiovasacular benefit

Vasoconstricting drugs

Associated with a reflex decrease in heart rate

Vasodilating drugs

Associated wtih a reflex increase in heart rate

What undergoes compensatory regulation in response to BP?

Heart rate

What does NOT undergo compensatory regulation in response to changes in heart rate?

BP

What does PSNS cause?

• Salivation, urination, defecation

• Usually causes miosis (constriction of pupil)

• Bradycardia

• Bronchoconstriction

• Increased peristalsis

What does SNS cause?

• Vigilance, attention, wakefulness

• Usually causes mydriasis (dilation of pupils)

• Increases force of contraction, heart rate, and rate of relaxation

• Increases peripheral vasular resistance; pale, cold extremities

• Bronchodilation

• Lipolysis

Epinephrine and norepinephrine (SNS - CV)

• Vasoconstriction

• Increase HR and contractility

Phenylephrine (SNS - CV)

Vasoconstriction

Dopamine, Dobutamine (SNS - CV)

Increase HR and contractility

Drugs for PNS - CV

• Atropine and Glycopyrrolate

• Parasympatholytics

• Antimuscarinincs

• Anticholinergics (poor term, Ach is technically everywhere)

Bethanacol

• Muscarinic agonist

• Aide to bladder emptying

• GI kinesis

Albuterol

• Beta sympathetic agonist - lung

• Bronchodilation

Alpha sympathetic antagonist

• Vasodilation

• Decreased urethral contraction

Prazosin and Phenoxybenzamine

• Alpha sympathetic antagonist

• Blood pressure reduction

• Urethral relaxation

Alpha sympathetic agonist

• Urethral contraction

• Vasoconstriction

Phenylpropanolamine

• Alpha sympathetic agonist

• Treatment for urinary incontinence

Blood-CNS Barrier (Distribution)

• Selective barrier restricting substance entry into the CNS

• Lipid-soluble drugs cross easily

• Polar compounds require transporters

Location of primary effect (Major Neurotransmitters)

• Area in brain or spinal cord

• Presynaptic neuronal effect

• Postsynaptic neuronal effect

Excitation (Major Neurotransmitters)

• Glutamate

• Serotonin (usually more inhibitory)

Inhibition (Major Neurotransmitters)

• Gamma aminobutyric acid (GABA)

• Serotonin

Serotonin (5-hydroxytryptamine, 5-HT)

Regulates mood, behavior, sleep

Monoamine oxidase inhibitors - (Serotonergic System)

• Wide approach to increase serotonin

• Not used often with animals

Tricyclic antidepressants (TCAs) - (Serotonergic System)

Clomipramine (Clomicalm)

Selective Serotonin Reuptake Inhibitors (SSRI’s) - (Serotonergic System)

• Fluoxetine/Prozac

• Reconcile

Other serotonin modifiers

Trazodone and tramadol

Trazodone

Primarily used as a sedative and behavior modifier

Tramadol

• Commonly used for pain therapy

• Not very useful, but still seen

What can happen if you combine or overdose serotonin modifiers?

Serotonin syndrome

Serotonin Syndrome

Hyperthermia, tremors, agitation, tachycardia

GABAergic Drugs

• Enhance inhibitory neurotransmission via GABA-A and GABA-B receptors

• Ex.: Benzodiazepines, barbiturates, baclofen

GABA-A

• Anti-seizure drugs

• Sedatives

• Behavior modification

• Diazepam

• Midazolam

• Phenobarbital

Midazolam (benzodiazepine absorption)

• Intranasal, intramuscular

• More common

Diazepam (benzodiazepine absorption)

• Poorly absorbed unless IV

• In the past, has been administered rectally for seizure control at home

• Less common now

GABA-B

• G-protein coupled

• Slower and longer acting that ionotropic receptors

• Muscle spasm relief

• Baclofen

Glutamate

• Important excitatory neurotransmitter in the CNS

• Common pharmacologic target, blocking this neurotransmitter decreases activity

• NMDA receptor

NMDA Antagonists

Ketamine and Amantadine

Ketamine

• Decrease central sensitization and “wind up”

• Analgesic (pain relief)

• Anesthetic at higher doses

Amantadine

• Analgesic (pain relief)

• Good choice for chronic pain management

Glutamate Facilitation

• Increased alertness

• Respiratory stimulant

• Caffeine (ex. used for foals to stimulate respiratory system after being on ventilator)

What drugs can inhibit an excitatory neuron?

NMDA antagonists

What drugs can excite an inhibitory neuron, directly or indirectly

GABAergic

What is a drug that can directly excite?

Caffeine

Species Differences

• Blood brain barrier differences

• Number of neurons and synapses at different locations

• Number of receptors and different phenotypes

• Type of drug needed may differ

• Dosage of drug may differ