Study your flashcards anywhere!

Download the official Cram app for free >

  • Shuffle
    Toggle On
    Toggle Off
  • Alphabetize
    Toggle On
    Toggle Off
  • Front First
    Toggle On
    Toggle Off
  • Both Sides
    Toggle On
    Toggle Off
  • Read
    Toggle On
    Toggle Off
Reading...
Front

How to study your flashcards.

Right/Left arrow keys: Navigate between flashcards.right arrow keyleft arrow key

Up/Down arrow keys: Flip the card between the front and back.down keyup key

H key: Show hint (3rd side).h key

A key: Read text to speech.a key

image

Play button

image

Play button

image

Progress

1/313

Click to flip

313 Cards in this Set

  • Front
  • Back
Parasympathetic Effects
HR:
BP:
GI:
blood volume:
Parasympathetic Effects
HR: slow and regular
BP: normal
GI: high motor/secretory, extracting nutrients
blood volume: most in dilated visceral vascular bed
Sympathetic effects
HR:
BP:
GI:
blood volume:
Sympathetic effects
HR: increased
BP:
GI: decreased digestion, motility, and secretion
blood volume: vascular vasoconstriction
Parasympathetic
anatomical
craniosacral
Sympathetic
anatomical
thoracolumbar
Parasympathetic
neurotransmitters
Ach
Sympathetic
neurotransmitters
Ach
Norepi
Parasympathetic
Preganglionic fiber:
Postganglionic fiber:
Effector organ receptor:
Parasympathetic
Preganglionic fiber: cholinergic
Postganglionic fiber: cholinergic
Effector organ receptor: muscarinic
Sympathetic
Preganglionic fiber:
Postganglionic fiber:
Effector organ receptor:
Sympathetic
Preganglionic fiber: cholinergic
Postganglionic fiber: adrenergic
Effector organ receptor: adrenergic
Somatic
neurotransmitter:
effector organ receptor:
Somatic
neurotransmitter: Ach
effector organ receptor: nicotinic muscle
Noradrenergic junction
synthesis:
blocked by:
Noradrenergic junction
synthesis: tyrosine, dopa, dopamine, norepi
blocked by: metyrosine (tyrosine hydrolase inhibitor)
Noradrenergic Junction
storage blocked by:
Noradrenergic Junction
storage blocked by: reserpine
Noradrenergic junction
release blocked by:
Noradrenergic junction
release blocked by: guanethidine
Noradrenergic junction
outcomes:
Noradrenergic junction
outcomes:
bind adrenergic receptor
diffuse to synapse
reuptake/recycle
degraded by monoamine oxidase
Cholinergic junction
synthesis:
blocked by:
Cholinergic junction
synthesis: choline, AcCoA, Ach
blocked by: hemicholiniums
Cholinergic junction
storage blocked by:
Cholinergic junction
storage blocked by: vesamicol
Cholinergic junction
release:
blocked by:
Cholinergic junction
release: voltage-dependent changes
blocked by: botulism toxin
Cholinergic junction
outcomes:
Cholinergic junction
outcomes:
bind nicotinic or muscarinic receptor
diffuse to synapse
reuptake/recycle
degraded by acetylcholinesterase
Increase in arterial BP
effect on baroreceptor:
efferent sympathetic nerve activity:
efferent parasympathetic nerve activity:
Increase in arterial BP
effect on baroreceptor: stretches
efferent sympathetic nerve activity: decreases
efferent parasympathetic nerve activity: increases
Decrease in arterial BP
effect on baroreceptor:
efferent sympathetic nerve activity:
efferent parasympathetic nerve activity:
Decrease in arterial BP
effect on baroreceptor: unloads
efferent sympathetic nerve activity: increases
efferent parasympathetic nerve activity: decreases
Adrenergic Receptor Agonists
alpha 1 >> alpha 2
phenylephrine
methoxamine
Adrenergic Receptor Agonists
alpha 2 >> alpha 1
(alpha)
detomidine
medetomidine
clonidine
xylazine
Adrenergic Receptor Agonists
alpha 1 = alpha 2
B1 >> B2
(alpha and beta)
norepinephrine
Adrenergic Receptor Agonists
alpha 1 = alpha 2
B1 = B2
(alpha and beta)
epinephrine
Adrenergic Receptor Agonists
B1 > B2 >>>> alpha
(beta)
dobutamine
Adrenergic Receptor Agonists
B1 = B2 >>>> alpha
(beta)
isoproterenol
Adrenergic Receptor Agonists
B2 >> B1 >>>> alpha
(beta)
terbutaline
albuterol
Adrenergic Receptor Agonists
D1 = D2 >> B >> alpha
dopamine
Adrenergic Receptor Antagonists
alpha 1 >>>> alpha 2
(alpha)
prazosin
Adrenergic Receptor Antagonists
alpha 1 > alpha 2
(alpha)
phenoxybenzamine
Adrenergic Receptor Antagonists
alpha 1 = alpha 2
(alpha)
phentolamine
Adrenergic Receptor Antagonists
alpha 2 >> alpha 1
(alpha)
yohimbine
tolazoline
atipamezole
Adrenergic Receptor Antagonists
B1 = B2 >_ alpha 1 > alpha 2
(mixed)
labetalol
carvedilol
Adrenergic Receptor Antagonists
B1 >> B2
(beta)
metoprolol
atenolol
Adrenergic Receptor Antagonists
B1 = B2
(beta)
propranolol
Adrenergic Receptor Antagonists
B2 >>> B1
(beta)
butoxamine
Cardiovascular responses
mean arterial pressure
NE:
Epi:
Iso:
Cardiovascular responses
mean arterial pressure
NE: inc
Epi: inc
Iso: dec
Cardiovascular responses
femoral blood flow
NE:
Epi:
Iso:
Cardiovascular responses
femoral blood flow
NE: dec
Epi: inc
Iso: inc
Cardiovascular responses
renal blood flow
NE:
Epi:
Iso:
Cardiovascular responses
renal blood flow
NE: dec
Epi: dec
Iso: inc
Cardiovascular responses
peripheral resistance
NE:
Epi:
Iso:
Cardiovascular responses
peripheral resistance
NE: inc
Epi: inc
Iso: dec
Cardiovascular responses
myocardial contractile force
NE:
Epi:
Iso:
Cardiovascular responses
myocardial contractile force
NE: inc
Epi: inc
Iso: inc
Cardiovascular responses
heart rate
NE:
Epi:
Iso:
Cardiovascular responses
heart rate
NE: dec
Epi: inc
Iso: inc
Cardiovascular responses
cardiac output
NE:
Epi:
Iso:
Cardiovascular responses
cardiac output
NE: NA (inc)
Epi: inc
Iso: inc
receptor
def
component of cell that interacts with a drug (neurotransmitter) and initiates a chain of biochemical events (pharm effects)
PNS responses are primarily subserved by ________ receptors
PNS responses are primarily subserved by MUSCARINIC receptors
ganglionic transmission is mediated by _________ receptors
ganglionic transmission is mediated by NICOTINIC receptors
cholinergic fibers
def.
nervous system location
nerve fibers that synthesize and release acetylcholine

parasympathetic, sympathetic, and somatic
3 types: pregang, postgang, somatic
adrenergic fibers
def.
nervous system location
nerve fibers that synthesize and release norepinephrine

sympathetic
3 endogenous catecholamines
dopamine
norepinephrine
epinephrine
only NANC postganglionic neurotransmitter:
nitric oxide NO
arterial smooth muscle is generally not innervated by the ___
arterial smooth muscle is generally not innervated by the PNS
cholinergic receptors in most arterial beds are not associated with ___________ nerves
cholinergic receptors in most arterial beds are not associated with PARASYMPATHETIC nerves
in skeletal muscle arteries, _____ receptors are more sensitive than _____ receptors
in skeletal muscle arteries, BETA receptors are MORE sensitive than ALPHA receptors
in visceral blood vessels, ____ receptors are more important than ____ receptors
in visceral blood vessels, ALPHA receptors are more important than BETA receptors
agonist
bind to and activate the receptor
antagonist
by binding to a receptor, prevent binding by other molecules
alpha 1 receptor
agonist
Epi = NE >> Iso
alpha 1 receptor
antagonist
Prazosin
alpha 1 receptor
tissue:
response:
tissue: vascular smooth muscle
liver
genitourinary smooth muscle
response: contract, glycogenolysis, gluconeogenesis
glycogenolysis
breakdown glycogen
alpha 1
subtypes
1A
1B
1D
alpha 2 receptor
agonist
Epi = NE >> Iso
alpha 2 receptor
antagonist
yohimbine
alpha 2 receptor
tissue:
response:
tissue: presynaptic nerve terminals
vascular smooth muscle
pancreatic islets
response: decreased release NE
contract
decreased insulin release
alpha 2 receptor
subtypes
2A
2B
2C
beta 1 receptor
agonist
Iso > Epi = NE
beta 1 receptor
antagonist
metropolol
beta 1 receptor
tissue:
response:
tissue: heart
juxtaglomerular cells
response: increased contractility, HR, conduction velocity
increased renin secretion
beta 2 receptor
agonist
Iso > Epi >> NE
beta 2 receptor
antagonist
no specific drug
ICI 118551 in industry
beta 2 receptor
tissue:
response:
tissue: smooth muscle
liver
response: relax/ dilate skeletal arterioles
glycogenolysis
beta 1 receptor
antagonist
metropolol
beta 1 receptor
tissue:
response:
tissue: heart
juxtaglomerular cells
response: increased contractility, HR, conduction velocity
increased renin secretion
beta 2 receptor
agonist
Iso > Epi >> NE
beta 2 receptor
antagonist
no specific drug
ICI 118551 in industry
beta 2 receptor
tissue:
response:
tissue: smooth muscle
liver
response: relax/ dilate skeletal arterioles
glycogenolysis
beta 3 receptor
agonist
Iso = NE > Epi
beta 3 receptor
antagonist
ICI 118551
beta 3 receptor
tissue:
response:
tissue: adipose
response: lipolysis
cholinergic receptors
nicotinic muscle
nicotinic neural
muscarinic
nicotinic muscle receptor
agonist
Ach
beta 3 receptor
agonist
Iso = NE > Epi
beta 3 receptor
antagonist
ICI 118551
beta 3 receptor
tissue:
response:
tissue: adipose
response: lipolysis
cholinergic receptors
nicotinic muscle
nicotinic neural
muscarinic
nicotinic muscle receptor
agonist
Ach
nicotinic muscle receptor
antagonist
tubocurarine
nicotinic muscle receptor
tissue:
response:
tissue: neuromuscular junction
response: endplate depolarization
skeletal muscle contraction
nicotinic neural receptor
agonist
Ach
nicotinic neural receptor
antagonist
trimethaphan
nicotinic neural receptor
tissue:
response:
tissue: autonomic ganglia
adrenal medulla
CNS
response: depolarization
secretion catecholamines
firing postganglionic neurons
muscarinic 1 receptor
agonist
Ach
muscarinic 1 receptor
antagonist
atropine
muscarinic 1 receptor
tissue:
response:
tissue: autonomic ganglia
CNS
response: depolarization
undefined
muscarinic 2 receptor
agonist
Ach
muscarinic 2 receptor
antagonist
atropine
muscarinic 2 receptor
tissue:
response:
tissue: heart
myocardium
response: decrease HR (dec contractile force, not as prominent)
hyperpolarization (SA node)
M1 primarily __________
M1 primarily PARASYMPATHETIC
muscarinic 3 receptor
agonist
Ach
muscarinic 3 receptor
antagonist
atropine
muscarinic 3 receptor
tissue:
response:
tissue: smooth muscle
secretory glands
(vascular endothelium)
response: dilate BV
increased secretion
smooth muscle receptors
alpha 1
alpha 2
beta 2
M3
pressure = _____ x _______
pressure = cardiac output x resistance
cardiac output = ____ x _____
cardiac output = heart rate x stroke volume
cardiac sympathetic-mediated responses are _______
cardiac sympathetic-mediated responses are EXCITATORY

increase HR
cardiac parasympathetic-mediated responses are ______
cardiac parasympathetic-mediated responses are INHIBITORY

decrease HR
change in bladder tension
muscarinic agonist
contract body
change in bladder tension
alpha agonist
contract neck and base
change in bladder tension
B agonist
relax body
bladder
B:
alpha:
B: dilation
alpha: contraction
Bladder Filling
external sphincter ______ by ______ nerves
internal sphincter _______ by _______ nerves, _______ receptors
bladder body ______ by ________ nerves, _____ receptors
________ receptors inhibiting ________
_________ PNS outflow inactive
Bladder Filling
external sphincter CONTRACTION by SOMATIC nerves
internal sphincter CONTRACTION by SYMPATHETIC nerves, ALPHA 1 receptors
bladder body RELAXATION by SYMPATHETIC nerves, B2 receptors
ADRENERGIC (ALPHA 2)receptors inhibiting PARASYMPATHETIC GANGLIA SACRAL PNS outflow inactive
Bladder Filling - Adrenergic inhibiting parasympathetic

____ from postganglioc sympathetic activates presynaptic ______

activated ______ inhibits ____ release from preganglionic parasympathetic

_____ muscle contraction

bladder fills
NOREPINEPHRINE from postganglioc sympathetic activates presynaptic ALPHA 2 RECEPTORS

activated ALPHA 2 inhibit ACH release from preganglionic parasympathetic

DECREASED muscle contraction

bladder fills
Bladder emptying

inhibition of ____ ____ activity and _____ ____ outflow
activation of _____ _____ outflow by ________ receptors
M3 stimulation by ____ leads to _______ contraction
B stimulation by ______ leads to ______ relaxation
M2 stimulation by _______ leads to _______ contraction by inhibiting _________
inhibition of EXTERNAL SPHINCTER activity and SYMPATHETIC NERVE outflow
activation of PARASYMPATHETIC NERVE outflow by MUSCARINIC receptors
M3 stimulation by ACH leads to ACTIVE contraction
B stimulation by NOREPI leads to ACTIVE relaxation
M2 stimulation by ACH leads to INDIRECT contraction by inhibiting RELAXATION
Bladder Emptying

M3 stimulation causes contraction by _____ _______ and accumulation of _____
M3 stimulation causes contraction by PHOSPHOINOSITOL HYDROLYSIS and accumulation of CALCIUM
Bladder Emptying

M2 activation indirectly leads to contraction by inhibiting _________ ________ and _____ receptors
M2 activation indirectly leads to contraction by inhibiting ADENYLATE CYCLASE and B2 receptors
NANC transmitters and Bladder Function

______ is a NANC transmitter
ATP
NANC transmitters and bladder function

_____ _______ _______ is localized in nerve fibers of trigonal and urethral tissue
Nitric Oxide Synthase NOS
NO may influence bladder tone by modulation of ____ release
ACH
Overactive bladder

M3 receptors
stimulation by:
leads to:
receptors also located:
M3 receptors
stimulation by: Ach
leads to: smooth muscle contraction, bladder emptying
receptors also located: salivary glands
Overactive bladder

Tolterodine
effect:
type of drug:
Tolterodine
effect: greater bladder than salivation inhibition, no dry mouth
type of drug: competitive muscarinic receptor antagonist, bladder selectivity
Overactive bladder

Oxybutynin
effect:
type of drug:
Oxybutynin
effect: greater effect on salivation, dry mouth
type of drug: selective muscarinic receptor antagonist
Overactive bladder

Atropine
effect:
Atropine
effect: same effects on bladder and salivation
Overactive bladder

selectivity for ___ receptors over other muscarinic subtypes is not necessary for effective inhibition of bladder ______, may result in more pronounced effects on _______
selectivity for M3 receptors over other muscarinic subtypes is not necessary for effective inhibition of bladder CONTRACTION, may result in more pronounced effects on SALIVATION
Stressed urinary incontinence

Onuf's nucleus
location/pathway
Onuf's nucleus in sacral spinal cord
alpha motor neurons/somatic motor neurons out to external urethral sphincter
Onuf's nucleus

glutamate
excitatory amino acid

power ON button, raises synaptic cleft levels of NE and serotonin
Onuf's nucleus

Duloxetine
NE and serotonin/5-HT reuptake inhibitor
increases receptor activation
Food safety regulatory agencies

pharmaceuticals:
biologics/vaccines:
pesticides:
nutritional supplements:
pharmaceuticals: FDA
biologics/vaccines: USDA
pesticides: EPA
nutritional supplements: none
Food safety

FARAD
Food Animal Residue Avoidance Databank

establish appropriate withdrawal times in cases of extralabel drug use
Drug residues

Tolerance TOL
maximum level of drug residue allowed in edible tissue
Drug residues

Withdrawal time WDT
length of time from the last treatment for drug residues to deplete to or below TOL
minimum length of time that must be waited prior to slaughtering
Drug residues

Extralabel drug use ELDU
administering drug in manner different than label directions
AMDUCA
Animal Medicinal Drug Use Clarification Act
ELDU allowed under certain conditions:
valid DVM-client-patient relationship
not permitted by lay person
adequate info available to establish WDT
ELDU of feed additives strictly prohibited
ELDU due to cost not allowed

all approved drugs are ineffective
careful diagnosis
"substantially extended" WDT is established
ensure ID of treated animals
assure WDT is followed
drugs prohibited from ELDU under AMDUCA
diethylstibestrol (DES)
chloramphenicol
nitroimidazoles (metronidazole)
sulfonamides in dairy >- 20mo
clenbuterol
dipyrone
fluoroquinolones
glycopeptides
nitrofurans
phenylbutazone in dairy >- 20mo
ELDU
Grade A Pasteurized Milk Ordinance PMO
FDA regulatory ordinance
prohibits use of:
dimethyl sulfoxide DMSO
colloidal silver
_______ should be contacted for appropriate _____ in cases of ELDU
FARAD should be contacted for appropriate WDT in cases of ELDU
Thalidomide

prohibited b/c:
concern of human exposure and birth defects
Causes of illegal residues
failure to follow WDT
failure to identify treated animals
failure to follow label directions
route of administration effects
IM and SC not always identical
poor technique - inject into fascial plane instead of IM, poor vascular supply, delayed/incomplete absorption
improper location - SC in ear b/c discarded at slaughter
aminoglycosides
gentamicin
pro:
con:
pro: effective against some resistant gram negative bac, inexpensive
con: renal tubular reabsorption means in the kidneys for prolonged time (18mo)
Food animal drug approvals require:
extensive safety evaluation
residue depletion studies
regulated by FDA
Extralabel Drug use
allowed under AMDUCA
requires specific conditions
certain drugs prohibited
illegal residues
from failure to follow directions
occur infrequently
Cholinergic receptors
types
nicotnic
muscarinic
Nicotinic receptors

subtypes
Nm
Nn
Nicotinic

agonists
Ach

nicotine
Nicotinic

response
NMJ
autonomic ganglia
adrenal medulla
Nicotinic

antagonists
Tubocurarine
Trimethaphan
Muscarinic

subtypes
M1
M2
M3
Muscarinic

agonists
Ach

choline esters
Muscarinic

response
myenteric plexus
heart
bladder
eye
smooth muscle
urinary bladder
GI sphincters
Muscarinic

antagonists
Atropine
Cholinergic stimulants

2 broad categories
direct-acting

indirect-acting
cholinergic stimulants activate cholinergic receptors

2 types
muscarinic

nicotinic
muscarinic targets
nerve
heart
glands
nicotinic targets
neuromuscular
ganglionic
cholinergic stimulants

direct acting
similar to ach

activate cholinergic receptors located on the effector cells
cholinergic stimulants

indirect acting
(cholinesterase inhibitors)

allow endogenous Ach to accumulate and thereby prolong/augment its action

raises Ach levels
2 types of direct acting receptor agonists
choline esters
alkaloids
choline esters
ach
methacholine
carbachol
bethanecol
alkaloids
muscarine
pilocarpine
nonuniform susceptibility to _________
nonuniform affinities for _______
nonuniform ____ ______ effects
nonuniform susceptibility to CHOLINESTERASE
nonuniform affinities for MUS AND NIC RECEPTORS
nonuniform TARGET ORGAN effects
remove Ach with ______
ACETYLCHOLINESTERASE
Acetylcholinesterase inhibitors
neostigmine
physostigmine
edrophonium
Acetylcholinesterase inhibitors

mech action
inhibit acetylcholinesterase leading to increase in conc endogenous Ach
Acetylcholinesterase inhibitors

target organ effects
similar to effects of direct-acting cholinergic agonists
Neostigmine lacks ___________ whereas __________ produces them
Neostigmine lacks CNS EFFECTS whereas PHYSOSTIGMINE produces them
Neostigmine affects _____ more than the _______
Neostigmine affects NMJ more than the ANS
Physostigmine affects ____ more than the ______
Physostigmine affects ANS more than the NMJ
Muscarinic receptor antagonists
atropine
glycopyrrolate
scopolamine
Muscarinic receptor antagonists

mech action
cause reversible blockade (comp ant) of actions of cholinomimetics at muscarinic receptors
muscarinic receptors are generally ________
NONSELECTIVE (receptor subtypes)

can be regionally selective
Muscarinic receptor antagonists

target organ effects
eye:
CV:
GI:
bronchioles:
bladder:
sweat glands:
CNS:
eye: pupillary dilation, loss of accomodation
CV: increase HR, may increase CO due to tachycardic
GI: relax smooth muscle, decreased secretions
bronchioles: decrease secretions, increase luminal diameter
bladder: urine retention due to inhibition smooth muscle
sweat glands: decrease sweating in humans
CNS: excessive doses cause hallucinations/disorientation in humans, mania/excitement in domestics
Biosynthetic pathway for Nitric oxide

location:
substrates:
enzyme:
product:
inhibitor:
location: endothelium
substrates: O2, L-arginine
enzyme: NO synthase
product: NO
inhibitor: L-name (competitively inhibits NOS)
Equine sweating

sympathetic nerves activate _________ in skin to evoke _________
sympathetic nerves activate BETA-ADRENERGIC MECHANISMS in skin to evoke THERMOREGULATORY SWEATING
L-name inhibits __________ and decreases __________
L-name inhibits NITRIC OXIDE SYNTHASE (NOS)and decreases SWEAT RATE
in humans, sweat glands are innervated by ____________
SYMPATHETIC CHOLINERGIC FIBERS
equine sweating

atropine
blocked:
no sig effect on:
suggests:
blocked: sweating
no sig effect on: blood flow
suggests: independent mech
equine sweating

botulism toxin
mech:
prevents:
which suggests:
mech: presynaptically inhibits Ach release
prevents: sweating and rise in skin blood flow
suggests: substance (NO?) cotransmitted with Ach to evoke rise in skin blood flow
neuromuscular blocking drugs
specifically block neuromuscular transmission
used with general anesthesia
normal neuromuscular transmission

depolarization of
release of
binds to
opens
influx of
metabolized by
depolarization of motor nerve
release of Ach
Ach binds to nicotinic receptors on motor end plate
opens membrane channel
influx of Na and K
Ach metabolized by acetylcholinesterase
Nicotinic receptor

def:
what binds:
result:
transmembrane protein with ion channel pore that is usually closed

Ach binds to alpha subunits

conformation change in protein, ion channel opens, ions flow, membrane depolarizes
Nondepolarizing NMB
competitive antagonists to Ach at nicotinic receptors

prevent binding of Ach

reversible
cholinesterase inhibitor
biases competition in favor of Ach by allowing build-up Ach and displacing NMB
Nondepolarizing NMB

highly ______
poorly _________
do not cross _________
act _________
highly polar
poorly lipid soluble
do not cross blood brain barrier
act peripherally
Nondepolarizing NMB

side effects
ganglionic blockade at higher dosages
histamine release
reversal agents have muscarinic side effects
pretreat with atropine
Nondepolarizing NMB

drug interactions
augmented by:
potentiated by:
augmented by: inhalation anesthetics
potentiated by: aminoglycosdie antibiotics
Common nondepolarizing NMB
gallamine
pancuronium
d-tubocurarine
atracurium
reversal agents for nondepolarizing NMB
neostigmine
physostigmine
edrophonium
Effects of NMB
muscle paralysis
progression: eye, facial, pharyngeal, limb, torso, diaphragm
CNS transmitters
GABA
glycine
glutamate and aspartate
norepi
dopamine
5-hydroxytryptamine (serotonin)
GABA
main inhibitory transmitter in brain
Gaba-a receptors:

Gaba-b receptors:
Gaba-a receptors: postsynaptic

Gaba-b receptors: presynaptic inhibition
agonists

Gaba-a:

Gaba-b:
Gaba-a: muscimol

Gaba-b: baclofen
antagonists

Gaba-a:
Gaba-a: bicucullin, picrotoxin
GABA

receptor mech
increases chloride conductance, hyperpolarizes
Glycine
inhibitory transmitter in spinal cord
Glycine

agonist
taurine
Glycine

antagonist
strychnine
Glycine

receptor mech
increases chloride conductance, hyperpolarizes
Glutamate and aspartate

classified as:
mediate:
anatomy:
excitatory amino acids EAA

mediate fast excitatory responses in CNS

interneurons at all levels: spinal and supraspinal
Glutamate and aspartate

3 main EAA receptor subtypes
NMDA
AMPA
kainate
Glutamate and aspartate
receptor mech
NMDA:
AMPA:
metobotropic:
NMDA: slow EPSP
AMPA: fast EPSP
metobotropic: neural modulation by many mech
Norepi

anatomy
all levels
long axons from pons and brainstem
Norepi

agonists
alpha 2: xylazine, medetomidine, clonidine
Norepi

antagonist
yohimbine
Norepi

receptor mech
G protein mediated effects on generation of second messengers and on activity of ion channels
Dopamine

anatomy
all levels
short, medium, and long connections
Dopamine

agonist
apomorphine
Dopamine

antagonist
phenothiazines and butyrophenones (preanesthetics)
Dopamine
receptor mech
2 types receptors:
CNS effects:
2 types receptors: D1 and D2
CNS effects: mainly inhibition, pre and post synaptic
5-hydroxytryptamine

anatomy
5-HT neurons concentrated in midline raphe nuclei in pons and medulla
project diffusely to cortex, limbic system, hypothalamus, spinal cord
5-HT

antagonist
ketanserin
5-HT

receptor mech
effects:
functions associated with pathways:
effects: inhibitory or excitatory, pre or post synaptic
functions: feeding beh, control of mood, emotion, sleep/wake, sensory pathways, nociception, body temp, vomiting
pain
def.
coupling of an unpleasant stimulus with conscious perception and an emotional response
nociception
def.
sensation of an unpleasant stimulus
nociceptors
def.
free nerve endings distributed thruout the body which detect nociceptive stimuli
Why feel pain? (3)
warning of actual tissue injury
warning of impending tissue injury
warning of danger to a social group
sensitization
stimulus which is normally innocuous becomes a nociceptive stimulus
Sensitization
1.
2.
Sensitization
1. Central
2. Peripheral
Sensitization
Central (3)
NMDA receptor activation
increase in magnitude and response of stimulus - pain is worse
reduced activation threshold of nociceptors - pain occurs w/ less of stimulus
decreased endogenous opioids
desensitization of opiate receptors
Sensitization
Peripheral (2)
reduced nociceptor activation thresholds
decreased tissue pH, cytokines, bradykinin, serotonin, histamine, ATP, prostaglandins, leukotrienes
Peripheral nerves
3 axon types
sensory afferent
motor efferent
autonomic
Sensory afferent peripheral nerves
A-fiber:
Aalpha, AB:
Adelta:
C-fiber:
Sensory afferent peripheral nerves
A-fiber: large myelinated nerves, rapid conduction
Aalpha, AB: prorioception, tactile
Adelta: nociception; "first" pain, well localized
C-fiber: unmyelinated, slow conducting; "second" pain, dull aching, poorly localized
Dorsal root ganglion
receptor +, propagate transmission of painful stimulus (3)
AMPA (glutamate)
NMDA (glutamate) - loses its Mg block after AMPA activated
PGE2 (COX-2)
Dorsal root ganglion
receptor -, inhibit transmission of painful stimulus (4)
opiate (u, k, delta)
alpha-2 (norepi)
5-HT (serotonin)
GABA (y-aminobutyric acid)
pain transmitted primarily by
receptor:
neurotransmitter:
pain transmitted primarily by
receptor: AMPA
neurotransmitter: glutamate
Second order neuron
_____ to ______
primary projection
SPINAL CORD to THALAMUS
spinothalamic tract
Second order neuron
receptors
+:
-:
Second order neuron
receptors
+: glutamate, AMPA, NMDA
-: GABA, alpha-2, 5-HT
Cerebral cortex
primary projections:
thalamocortical
Cerebral cortex
receptors
+:
-:
Cerebral cortex
receptors
+: glutamate, AMPA, NMDA
-: opiate, 5-HT, alpha-2, GABA
COX-1 and COX-3 (NSAIDS acetaminophen)
opiate
def.
compound derived from opium plant
opioid
def.
endogenous peptide or synthetic compound interacting on opiate receptors
opioids
primary metabolism:
opioids
primary metabolism: hepatic
phase I and/or II
Opiate receptors
(3)
Mu - endorphin, endogenous ligand
Kappa - dynorphin, endogenous ligand
Delta - enkephalin, endogenous ligand
Opioid effects
a lot
analgesia
euphoria
sedation
antitussive
nausea/vomiting
dec stomach, biliary, pancreatic, and intestinal secretions
dec GI motility
dec urine voiding
inc tone antrum stomach
diuresis
miosis - dog
mydriasis - cat
panting
with large doses: dec BP and respiration
immunomodulation
antitussive effect
depression of:
independent of:
antitussive effect
depression of: cough center in medulla
independent of: respiratory effects
nausea/emesis effect
direct stimulation of:
not protected by:
nausea/emesis effect
direct stimulation of: CRTZ
not protected by: blood brain barrier
GI tract (antidiarrheal) effect
decrease:
decrease:
increase:

can cause:
GI tract (antidiarrheal) effect
decrease: secretions
decrease: in propulsive contractions
increase: in non-propulsive rhythmic contractions

can cause: constipation
opiate receptors
mu
analgesia
resp
antitussive
dec GI
sedation
euphoria
opiate receptors
k
analgesia, antitussive, dec GI, sedation, inc diuresis
opiate receptors
delta
analgesia
opioid receptor locations
(3)
spinal
supraspinal
periphery
(GI tract)
(other - synovium, leukocytes)
opioid receptor locations
synergistic analgesia between ______ and ______ receptors
synergistic analgesia between SPINAL and SUPRASPINAL receptors
opioid receptor locations
spinal
pre and postsynaptic at dorsal root ganglion
opioid receptor locations
supraspinal
medulla, hypothalamus, periaqueductal gray area, amygdala, cerebral cortex
opioid drugs classified by:
____ they interact with and the ______ elicited
opioid drugs classified by:
RECEPTORS they interact with and the EFFECT elicited
potency
concentration which elicits the effect

affects dose
efficacy
magnitude of the effect

affects analgesic effect
opiate receptor activation
_______ inhibition of ________
opiate receptor activation
G-PROTEIN inhibition of ADENYLYL CYCLASE
G-protein inhibition of adenylyl cyclase
dec:
inc:
dec:
net:
G-protein inhibition of adenylyl cyclase
dec: cAMP
inc: receptor linked K currents - inc outward flow
dec: voltage-gated Ca currents - dec inward flow
net: hyperpolarization of membrane potential
tolerance
def:
requires:
tolerance
def: decrease in efficacy over time
requires: long term administration, 4-5wk in dog
opioids tolerance
mech:
internalization of receptors: mu, k
protein kinase C: phosphorylation of receptors leading to inactivation: mu, delta
inc adenylyl cyclase activity (as result of dec cAMP)
dependence
__ days with morphine
clinical signs precipiated by opioid ________
dependence
7 days with morphine
clinical signs precipiated by opioid ANTAGONIST
opioids dependence
clinical signs
hyperactivity
biting
digging
tremors
nausea
hyperthermia
inc wakefulness
opioids for analgesia
moderate to severe pain
mu agonists
morphine, hydromorphone, fentanyl
opioids for analgesia
mild to moderate pain
mu agonists - morphine, hydromorphone, fentanyl, tramadol
mu partial agonists - buprenorphine
k agonists - butorphanol, nalbuphine
opioids for analgesia
administer at ___________ or as ___________, not _________
opioids for analgesia
administer at RECOMMENDED INTERVAL or as CONSTANT RATE INFUSION, not AS NEEDED
________ and _________ pain are poorly responsive to opioids
CHRONIC and NEUROPATHIC pain are poorly responsive to opioids
pre-emptive analgesia
def.
administration of opioids prior to and during surgery
pre-emptive analgesia
decreases (3)
decreases in central sensitization
decreases postoperative pain
decreases consumption of analgesics
morphine
active metabolite:
morphine
active metabolite: M6G, has variable activity
morphine
________ release upon IV administration
note minimal:
morphine
HISTAMINE release upon IV administration
note minimal: HYPOTENSION
morphine half life
short or long
dog:
cat:
morphine half life
SHORT
dog: 1 hr
cat: 1.3 hr
morphine
primary adverse effect is in horses:
limit to:
morphine
primary adverse effect is in horses: ILEUS
limit to: SINGLE DOSE
morphine
with IV dosing, _______ lag time until max effect
45 MIN
morphine
clinically relevant effects in:
10-20 MIN
morphine
oral bioavailability:
morphine
oral bioavailability: poor and erratic
5-20%
not recommened, poor efficacy
morphine in dogs
clin use:
AE:
morphine in dogs
clin use: analgesia, sedative
AE: minimal - vomit, defecation, panting, sedation, dysphoria
morphine in cats
clin use:
AE:
morphine in cats
clin use: analgesia, emesis
AE: vomit, mydriasis, sedation, dysphoria
morphine in horses
clin use:
AE:
morphine in horses
clin use: analgesia
AE: ileus
oxygmorphone
10x potency morphine
cost-prohibitive
mu agonist
less vomiting, quicker onset of action b/c 25x lipophilicity
hydromorphone
7x potency, 2x lipophilicity
mu agonist
less vomiting, quicker onset action
fentanyl
80-100x potency, 1000x lipophilicity
short duration b/c redistribution
T1/2: 3-4 hr
less vomiting, quicker onset
fentanyl transdermal patch
lag time:
duration dog:
duration cat:
lag time: 12-24 hr
duration dog: 3 day
duration cat: 5 day
fentanyl transdermal patch in horse
duration:
lag:
tolerated:
duration: 36-48 hr, 2 days
lag: 1 hr, rapid absorption
tolerated: well tolerated for 9 days
buprenorphine


duration:
affinity:
oral bioavailability:
partial mu agonist
25-50x potent
less vomiting, sedation
slowest onset, 1hr to max

duration: longer, 4-12hr
affinity: high for mu receptors, resistant to naloxone reversal
oral bioavailability: <20%, not effective
buprenorphine in cats
transmucosal - cheek pouch
hydrocodone

use:
metabolized in part to:
oral bioavailability:
duration:
analgesia:
hydrocodone

use: antitussive in dogs
metabolized in part to: hydromorphone
oral bioavailability: 40-80%, only true opioid can use orally
duration: 4-8hr
analgesia: not evaulated
codeine

metabolized to:
bioavailability:

still used a lot b/c:
codeine

metabolized to: 10% to morphine
bioavailability: poor, 6%; minimal conversion to morphine in dogs; probably ineffective as analgesic

still used a lot b/c: cheap and no AE (b/c not absorbed)
oxycodone
mu and k agonist
poor oral bioavailability
high abuse potential
probably ineffective
use not recommended
butorphanol
5x potency
weak analgesic, short duration 1hr
poor oral bioavailability, 20%
less GI AE
moderate sedative
less effective than NSAIDs
painful on IM

SEDATION, BUT NOT ANALGESIA
butorphanol in ruminants may cause _____
RUMEN STASIS
nalbuphine
mu antagonist (used as reversal agent), k agonist

inexpensive, not scheduled
similar efficacy to butorphanol
naloxone
opioid antagonist "reversal agent"
reverses exogenous and endogenous - ALL opioid induced analgesia
naloxone
primary indication:
may cause:
duration of reversal:
naloxone
primary indication: opioid overdose
may cause: CV shock due to pain, arrhythmias, hypertension, tachycardia, excitement
duration of reversal: short, use multiple doses
loperamide (immodium)
antidiarrheal
mu agonist
minimal tolerance to chronic use
high efficacy
excluded from CNS by p-glycoprotein - NO analgesia
sedation in collies
tramadol
tech not an opioid
active metabolite M1
mu agonist
fluoxetine (SSRI) inhibits metabolism
inexpensive, not scheduled
bitter tasting
tramadol
avoid co-administration with:
OTHER 5-HT DRUGS
tramadol
indication:
AE (rare):
indication: mild-moderate pain, antitussive
AE: sedation, vomiting, dec seizure threshold (contraindicated in epileptics)
heroin (diamorphine)
more lipophilic, faster onset
mu agonist
metabolized to morphine
legal in europe
no more effective than other opioids
amantadine
mech action:


indications:
mech action:
NMDA antagonist - dec sensitization, but no analgesia
dopamine agonist, inc NT release
antiviral

indications:
no pre-emptive analgesia
potentiates other analgesics
chronic, acute, or neuropathic pain
amantadine
renal excretion, glomerular filtration
AE: nausea, vomiting
well tolerated
often combo w/ tramadol, NSAIDs, gabapentin, or fentanyl
gabapentin
GABA analogue
mech: may dec GABA metabolism, inc non-synaptic release, or dec reuptake
inc brain GABA conc
indications: anticonvulsant, neuralgia, chronic pain
hydroxyzine
H1 - antihistamine
most commonly for atopy trt
people: effective sole analgesic, additive analgesia w/ opioids
no studies in dogs
local anesthetics
mech:
block Na channels on nerves blocking action potential
local anesthetics
order of blockade:
nociceptors
autonomic
touch/pressure
motor
local anesthetics

tachyphylaxis:
loss of activity with repeated doses
local anesthetics
routes of administration
topical, inject in vicinity to peripheral nerves, subcu infiltration, epidural, subarachnoid
IVRA - IV w/ tourniquet
systemic - IV infusion, LIDOCAINE only
local anesthetics
add _______ to prolong activity
VASOCONSTRICTORS

epi, phenylephrine
local anesthetics

______ absorption following _____ administration
potential for ________
SYSTEMIC absorption following LOCAL administration

potential for TOXICITY
local anesthetics
AE (3)
1. CNS - dogs, horses, ruminants
2. cardiovascular - cats
3. neurotoxicity - put around nerve, not in nerve sheath
local anesthetics
3
lidocaine
mepivicaine
bupivicaine
lidocaine
quick onset, 10min
short duration, 1-2hr
mepivicaine
used most in horses
onset and duration similar to lidocaine
bupivicaine
longer onset, 30-45min
longer duration, 6hr

often combo w/ lidocaine
local anesthetics
indications
pre-emptive analgesia
postoperative analgesia
epidurals
IV infusion - Lidocaine only
topical lidocaine
EMLA
variable success
other medications for pain
tricyclic antidepressants TCA's
serotonin norepi reuptake inhibitors SNRI's
selective serotonin reuptake inhibitors SSRI's
NSAIDs
TCA's
norepi and serotonin reuptake inhibitors
amitriptyline
clomipramine
SNRI's
venlafaxine
SSRI's
fluoxetine - combo w/ opioids
NSAIDs
carprofen, meloxicam, deracoxib
targets for pain management
opioid agonists
serotonin agonists
GABA agonists
norepi agonists
NMDA antagonists
sodium channel blockers
COX-1 and COX-2 inhibitors