Peripheral Receptors and Agents Acting on PNS and CNS

• primary communication and control center, functions in concert with endocrine system.  
• Allows adaptation, maintains homeostasis, controlled by hypothalamus

• sensory
• integrative
• motor

NS sends electrical messages, ES sends chemical messages.

• fundamental unit of NS.  
• Dendrites, cell body, axon, tilodendra, myelin sheath made of schwann cells, nodes of ranvier

insulation for axon, made of schwann cells.  Where there is no sheath is called a node of ranvier

gaps between myelin sheath (schwann cells)

make up myelin sheath.

axons

dendrites

• ends of axons (fray).  10,000 or more per axon.
• Synaptic end bulbs pass nerve impulses to adjacent structure
• Emit neurotransmitters into synapse
• Acetylcholine, norepinephrine, dopamine, seratonin, gamma-aminobutyric acid

gamma aminobutyric acid

• receptor
• sensory neuron
• center in CNS for a synapse
• motor neuron
• effector

higher function

pain, relay between cerebrum and other parts of the brain

• mediator of endocrine system, using the pituitary gland.  
• Controls autonomic NS

• with the pons, makes up the brainstem
• connects spinal cord to brain
• sensory and motor
• vital, unconscious functions

network of nerves from the medulla upwards in the brainstem, contains the reticular activating system (RAS),  which controls wakefulness.

• CNS is the control center (brain and spinal cord)
• PNS (cranial nerves, spinal nerves, connects CNS to glands, muscles, receptors)

• Afferent (out to in)
• Efferent (in to out)

• Somatic NS (efferent, to skeletal muscle, voluntary)
• Autonomic NS (efferent, CNS to cardiac muscle, smooth muscle and glands, involuntary

• Controls unconscious body activities (automatic and involuntary)
• innervates smooth muscle, cardiac muscle, salivary glands and viscera
• Parasympathetic or Sympathetic

• CHOLINERGIC
• regulates energy conserving activities
• Rest and Digest
• Craniosacral
• Long preganglionic, short postganglionic

• ADRENERGIC
• regulates energy expending activites
• Fight or Flight
• thoracolumbar
• short preganglionic, long postganglionic except adrenal medulla

• both have two neurons, preganglionic synapses at ganglionic synapse with postganglionic
• Postganglionic synapses with target tissue
• work with mostly the same organs

• sweat glands, adrenal medulla and hair follicles are only controlled by sympathetic stimulation.
• Adrenal medulla acts as post-ganglionic neuron, accepts Ach with Nicotinic receptor.  
• Sweat glands are stimulated by symp, but use a Muscarinic receptor.

Celiac ganglion.  Sends nerves to GI, adrenal, kidney, spleen and stomach.

• SA node: symp increases HR, B1
• para decreases HR, Muscarinic
• AV node: symp increases conduction, B1
• para decreases conduction, M
• a/v muscle: symp increases force of contraction, B1
• para decreases force of contraction, M

• Smooth Muscle: symp relaxes for more air in, B2
• para contracts for less air in, M
• Secretions: symp inhibits for clear airways, B2
• para stimulates to catch dirt, M

• Symp: constricts to increase blood pressure (a1) or dilates (B2).  BOTH.  
• Para: there are receptors, we don't know what they do.  Probably muscarinic.

• motility: symp decreases, a1 (and more)
• para increases, M
• secretions: symp decreases, a1 (and more)
• para increases, M

• detrusor: symp relaxes, B2
• para contracts, M
• urethral sphincter: symp contracts, a1
• para does nothing.

• pupil diameter: symp dilates (mydriasis), a1
• para contracts (miosis), M
• focal point: symp far, B2
• para near, M

dilated pupil

constricted pupil

• symp: stimulates to release epinephrine/norepinephrine, Nicotinic.  
• No para influence

• symp: stimulates, Muscarinic
• no para influence

• accepts acetylcholine.  Parasympathetic.  
• Neuromuscular junction, autonomic ganglia (all), cardiac muscle, smooth muscle, glands except sweat glands.

• Cholinergic, found at adrenal medulla, autonomic ganglia, neuromuscular junction (excitatory)
• Parasympathetic except autonomic ganglia and adrenal medulla.

• Cholinergic, found at heart muscle, smooth muscle, secretory glands.  Both excitatory and inhibitory.  
• Always para, except sweat glands.

• Sympathetic.  Epinephrine, norepinepherine, alpha and beta, dopamine.  
• Alphas are usually excitatory (a1, a2)
• Beta 1 are usually excitatory, beta 2 usually inhibitory.

• a1: constriction of spincters and arterioles, constriction of dilator muscle for pupils, constriction of urethra for increased tone.
• a2: inhibits presynaptic neurons, constricts skeletal muscle vessels.

• B1: increases rate of conduction, BP and contractions in heart, releases renin in kidneys.  
• B2: dilates skeletal blood vessels and bronchioles, relaxes GI smooth muscle

• DILATES
• blood vessels of kidneys
• dilates coronary vessels of heart
• dilates mesenteric blood vessels

B2.

• stimulate receptor sites mediated by acetylcholine (parasympathetic exc, sweat and adrenal medulla)
• Can be direct (mimic ACh) or indirect (inhibit breakdown of ACh)

• diagnosis of myasthenia gravis
• reduce IOP in glaucoma
• stimulate GI motility
• treat urinary retention
• control vomiting
• antidote for neuromuscular blockers

stimulate cholinergic receptors, cause para effects (muscarinic or nicotinic)

• storage (sympathetic)
• voiding (parasympathetic)

• Primary: causes GI wall smooth muscle contraction, urinary bladder wall contractions
• Secondary: sphincter of iris (blurry far vision), SA node of heart, Brochiolar smooth muscle cells, lacrimal, salivary, sweat, bronchial, mucosal, digestive glands
• (Parasymp functions)

• any condition which makes a particular type of treatment improper
• causes harm.

acetylcholine, carbamylcholine, bethanechol

direct acting cholinergic causing GI atony and uterine contractions in pigs

direct acting cholinergic causing GI atony and uterine atony

• direct acting cholinergic
• decreases intra-ocular pressure, stimulates gland secretion.
• For use in neurogenic KCS, activates Facial nerve (VII) to produce tears

• direct acting cholinergic
• anti-emetic, promotes gastric motility.

aqueous humor drains from pupil from this angle, can be blocked by dilated pupil.  Pilocarpine allows to drain.

no muscle tone

temporarily occupy ACh binding site on acetylcholinesterase, which breaks down acetylcholine.  More ACh in synapse, more firing.

• competitive indirect acting cholinergic agents
• edrophonium, pyridostigmine, neostigmine, physostigmine

skeletal muscle weakness, vomiting, colic, diarrhea, bradycardia, dyspnea, respiratory paralysis, blurry distant vision, CNS depression (physostigmine only)

• reversible indirect cholinergic/anticholinesterase
• diagnosis of myasthenia gravis.  
• IV
• short duration, 2-5 minutes.

• reversible anticholinesterase
• Treatment of myasthenia gravis
• oral
• longer acting, hours (usu BID)

• anterior and posterior lens adhered to something else in eye.  
• anterior, lens attached to cornea by scar
• posterior, lens attached to retina by scar

megaesophagus

autoimmune disease that destroys nicotinic receptors in neuromuscular junction.  Edrophonium is a great test for it (anticholinesterase), and pyridostigmine is the treatment

• competitive anticholinesterase
• used in humans for myasthenia gravis.

• competitive anticholinesterase
• topical ophthalmic that decreases IOP in glaucoma or breaks down posterior synechia in horses.  Also helps in GI atony in cattle.

• Covalently bonds, inactivating AChE forever.  
• Organophosphates
• used in pesticides

Organophosphate toxicity: Bronchoconstriction, increased salivation, lacrimation, airway secretions, digestive secretions, diarrhea, vomiting, abdominal cramping, urination, miosis, muscle tremors to paralysis, CNS toxicity including seizures.

Organophosphate toxicity, from irreversible anticholinesterase.

• pralidoxime (2PAM, PAM)
• breaks bonds between organophosphate and AChE.  
• Atropine (muscarinic antagonist)

• a selective agent preferably interacts with pme receptor subgroup at low plasma concentrations.  
• As levels increase (you give more), it becomes less selective

agent blocks effects of parasympathetic (cholinergic), so sympathetic (adrenergic) continues unopposed.

muscarinic receptor antagonist.  May cause mydriasis.

Muscarinic receptor antagonist, fixes sinus bradycardia, AV block, ventricular asystole.

muscarinic receptor antagonist

• mucarinic receptor antagonists
• they suppress bronchial secretions, suppress salivary secretions, prevent vagal bradycardia due to vagus nerve.  
• Can also remove vagal influence to cure AV block and fix ventricular asystole when due to excessive parasymp tone

sympathetic effects

parasympathetic

• predictable extensions of muscarinic receptor blockers
• sympathetic effects like tachycardia, ileus etc 
• Atropine goes to CNS, can cause anxiety, restlessness, disorientation

• Not used in large animals, horses can die from ileus and ruminants get CNS toxicities and rumen stasis. 
• tachycardia
• GI or urinary obstruction, both physical and functional.
• KCS
• glaucoma

• atropine
• glycopyrrolate

• anticholinergic
• More polar than atropine, so less blood-brain or placental interaction
• Less likely to cause tachycardia
• longer duration and slower onset of effect than atropine, so not choice in emergencies, but good for C-section and anything else

anticholinesterase, ideally edrophonium.

• anticholinergic agent often used in emergencies.  Belladonna
• Increases heart rate, dilates bronchioles, good for cardiac arrest.  
• Contraindicated in glaucoma, heart problems, etc

impairment between detrusor and sphincter causing urinary retention.  Prazosin with bethanacol can help line up.

Symp NS effects, like catecholamines

• Block muscarinic or parasympathetic influence, sympathetic or B2 (epinephrine) influence unopposed.
• Bronchial smooth muscle relaxes and mucous secretion decreases. (B2)

• Block muscarinic or parasympathetic influence, sympathetic or a1/B2 (norepi or epi) influence unopposed.   
• spincter muscle of iris contracts (mydriasis), pupil dilates (a1)
• ciliary muscle relaxes (cycloplegia), focus is far (B2)

• Block muscarinic or parasympathetic (vagal) influence, sympathetic or B1 (norepinephrine) influence unopposed.
• SA node increases heart rate (B1)
• AV node increases, speeds condution (B1)
• Atrial/Ventricular muscles contract, increasing force of contraction (B1)

• direct-acting adrenergic agonists (sympathomimetic).
• Endogenous: norepinephrine, epinephrine, dopamine
• Synthetic/exogenous: isoproterenol, dobutamine

monoamine oxidase, breaks down catecholamines

• Tyrosine
• Dopa
• Dopamine
• Norepinephrine
• Epinephrine

CNS, enteric nervous system and kidney

In CNS and PNS

In adrenal medulla and neurons in CNS ONLY

Interact with and activate adrenergic receptors (Alpha, Beta, Dopaminergic)

Stimulation produces smooth muscle contraction, except in GI smooth muscle cells (inhibit ACh release)

causes smooth muscle relaxation

• Stimulation produces excitatory effects in cardiac muscle
• SA node: increases HR
• AV node: speeds conduction
• Ventricular muscle: increases force of contraction

• Both stimulate all except B2.  
• Only Epi stimulates B2 (relaxes smooth muscle)

• SA node: increases HR
• AV node: speeds conduction
• Ventricular muscle: increases force of contraction

• relates to heart rate
• positive chronotropic effect increases HR.
• Adrenergic agonists and anticholinergics both positive effect
• Cholinergics and anticholinesterases have negative effect

• Action that effects conduction of electrical velocity through AV node.
• Adrenergic agonists and anticholinergics both positive effect
• Cholinergics and anticholinesterases have negative effect

• Action that effects force of contraction of cardiac muscle.  
• Adrenergic agonists and anticholinergics both positive effect
• Cholinergics and anticholinesterases have negative effect

• volume of blood leaving heart per unit time (minute)
• CO = HR x SV
• Increased by stimulating B1 receptors at SA node (increase HR) and B1 receptors at ventricular muscles (increase SV)

• volume of blood that leaves the heart per beat.  
• Increased by stimulating B1 receptor in ventricular myocytes (adrenergic).

a1 receptors.

• impediment to blood flow through systemic arteries caused by constriction of arterioles.  
• Arterial BP = CO x PVR
• NEpi and Epi at therapeutic doses constricts arteries to increase PVR to increase BP.

• Epinephrine stimulates B2 receptors on airways, relaxes, bronchodilation.  
• Atropine would also work by removing muscarinic or parasympathetic influence.

• absense of heart sounds and pulses, generally begins with
• Ventricular fibrillation (fluttering)
• ventricular asystole (no pumping)
• electromechanical dissociation (bizarre rhythm but no connected pumping).  
• Then blood flow stops.

• direct-acting adrenergic, works on a1, a2, b1 and b2.  Comes from CNS and adrenal medulla.
• Often supplied in 1:1000 (0.1%), need to dilute to 1:10,000 (0.01%).  
• May need refridgeration, light-sensitive.  
• Usually give IV or IT for cardiac arrest

double dose, mix with 2-5 ml of sterile water, pour through catheter in endotrachial tube, give 2 breaths.

• secreted by dopaminergic neurons in brain, enteric NS and kidney.  
• receptors in brain, mesentery and heart.  
• Cats kidney's DO have them, but they are a different sub-type (there used to be a question)

• GI has own nervous system, consisting of myenteric plexus and submucosal plexus
• Provide communication between different layers of alimentary canal
• Dopaminergic and a1, and muscarinic receptors.

• part of enteric nervous system, neurons that provide communication between longitudinal muscle and circular muscle.  
• Contains alpha 1 and dopaminergic receptors that help it relax and muscarinic receptors to flex

• part of enteric nervous system
• neurons providing communication between muscularis and mucosa/submucosa layers.
• Contains a1 and dopaminergic receptors to help it relax and muscarinic receptors to flex

• inhibit acetylcholine to cause relaxation.
• Only non-excitatory a1 receptors.

• dilation of mesenteric and renal arteries
• stimulation of B1 receptors of heart (indirect by becoming NEpi) causing increased heart rate and increased force of contraction

vasoconstriction, by indirectly stimulating a1 receptors.

• Shock (moderate dose)
• Refractory congestive heart failure (moderate dose)
• hypotension
• oligouric renal failure

• moderate dose increases blood flow to kidney and mesentery
• increases cardiac output by increasing HR and force of contraction

moderate doses cause increased cardiac output without increased PVR.

• MUST be diluted in CRI, IV administered.  Use a pump, extremely small amounts so measurements must be accurate.  
• Must stay within vein, can cause necrosis and sloughing of tissue

• synthetic catecholamine, B-agonist, specific to B1 at therapeutic doses.
• Increases force of contraction more than increasing heart rate (chooses ventricles over SA node)

• Shock
• refractory congestive heart failure
• Must be diluted in CRI, IV administrated.

• synthetic chatecholamine, B-agonist.  Stimulates B1 and B2 with no effect at a1.  
• increases HR at SA node, conduction at AV and force of contraction in ventricles.  Powerful vasodilator in veins and airways.  
• Little effect in kidney

• complete AV block (short term until pacemaker can be installed)
• Bronchodilator in anaphalactic shock (dangerous due to hypotension side effect)

• B2 stimulation without a1 effect causes vasodilation.  No PVR causes hypotension.  
• Though cardiac output increases (from B1 receptors), PVR decreases more so overall systemic is decreased BP
• Kicks off baroreceptor reflex, causing reflex tachycardia

• located in walls of aortic arch and carotid sinuses
• Stretch receptors that detect BP
• report to medulla which stimulates sympathetic or parasympathetic response to compensate

arterial baroreceptors located in walls of aortic arch and carotid sinuses, feel pressure and detect blood pressure.  Report to medulla if too high or low, medulla stimulates sympathetic or parasympathetic response

When blood pressure drops, baroreceptor reflex causes heart rate to rise.

• all are potentially arrhythmogenic !  
• Epinephrine and isoproterenol are worse than dopamine and dobutamine.

• regular dosing of epinephrine = sympathetic = hypertension
• high-dose dopamine = a1 vasoconstriction = hypertension
• norepinephrine = no B2 = hypertension
• isoproterenol = B2 = hypotension

• parasite that migrates in intestines of a horse causing problems in blood supply.  
• "verminous" aneurisms
• catecholamines that cause hypertension can cause aneurisms to rupture

Anything that causes hypertension (catecholamines)

Epinephrine and isoproterenol are most likely to cause CNS effects like fear, anxiety, restlessness, tremor and excitability.

• adrenergic (sympathetic) effects.
• mydriasis
• blurry near vision

• B2 selective adrenergic agonist at therapeutic doses.
• rescue drug for bronchodilation in asthma, not maintinence (will lose effect). Best as an inhalant.
• At high doses, will stimulate B1.

• albuterol for asthma
• fluticazone, steroid

• non-catecholamine adrenergic agonist. 
• Stimulates a and B adrenergic receptors directly and by indirectly by increasing norepi.
• Bronchodilation and increases BP
• Can cause arrhythmias, stroke, anxiety, excitement, restlessness and even to seizures and death.
• Prohibited by FDA
• AKA Ma Huang, ephedra

• FDA does not have authority to required approval prior to marketing.
• Cannot remove unless proves "significant or unreasonable risk of illness or injury

• non-catecholamine adrenergic agent.
• used to treat urinary incontinence in dogs (urethral sphincter hypotonus)
• a1 agonist (contraction of urethral smooth muscle), b2 agonist (relaxation of detrusor muscle)
• some anxiety, restlessness, hypertension, cardiac arrhythmias, urinary retention
• Banned in humans for hemorrhagic strokes

• reversible alpha adrenergic receptor antagonist
• Blocks a1 to relax urethral smooth muscle
• Used to prevent urethral spasm in treatment of FLUTD
• Can cause vasodilation and hypotension
• dogs with reflex dyssnergia (impairment between detrusor and sphincter so do not balance)

• reversible alpha adrenergic receptor antagonist
• Block a1, vasodilation and hypotension
• Used to prevent urethral spasm in treatment of FLUTD

• blocking a1 causes miosis and vasodilation
• vasodilates arterioles, lowers PVR, decreases arterial BP
• vasodilation causes blood pooling and decreased venous return upon standing. Ventricular preload decreases, cardiac output decreases, causes orthostatic hypotension, dizziness, syncope. "head rush"

vasodilation causes blood pooling and decreased venous return upon standing. Ventricular preload decreases, cardiac output decreases, causes orthostatic hypotension, dizziness, syncope. "head rush"

• decreased BP stimulates carotid and aortic baroreceptors, send message to medulla. Sympathetic outflow is increased, NEpi is increased, stimulates B2 and B1 (a1 blocked). Para (Ach) decreased.
• vasodilation, reflex tachycardia

• alpha blocker
• tranquilizer
• hypotension and vasodilation (get cold from vasodilation in skin)

• alpha 2 antagonist (alpha blocker)
• antidote for xylazine toxicity (large-animal sedative)

• alpha blocker
• reversal agent for medetomidine
• antisedan (alpha2 antagonist)

non-selective beta blocker.  Blocks B1 and B2 adrenergic receptors, get parasympathetic response

cardioselective beta blocker, preferentially blocks B1 adrenergic receptor.

• decreased HR, decreased AV conduction velocity, decreased force of contraction
• No B means vasoconstriction, increase PVR and decreased CO makes decreased BP.  Then sympathetic reflex arc kicks in

• ACh at muscarinic receptors on circular smooth muscle, contraction, miosis
• NEpi at a1 adrenergic receptors on radial smooth muscle, contraction, mydriasis

• treatment of cardiac arrhythmias (usually)
• adjunctive therapy in feline hypertherapy and tachycardia (Atenolol, B1)
• Feline hypertrophic cardiomyopathy (Atenolol, B1)
• Congestive heart failure (controversial, but long term decreases fibrosis and O2 demand)
• Glaucoma (Timolol for hereditary primary glaucoma, stops non-glaucoma eye getting there)

• immediate contraction of bronchial smooth muscle
• cardiac arrhythmias (slowing too much, heart block, don't use in bradycardia)
• hypotension (more decreased cardiac output, increased PVR.  More decreased cardiac output so decreased BP)