Autonomic Pharmacology Flashcards
What are the general functions of the nervous system?
Control (modulation) of bodily functions
-Contraction of skeletal muscles
-Modulate contraction of smooth muscles
-Secretion from exocrine and endocrine glands
What are the anatomical divisions of the nervous system?
CNS and PNS
What are the functional divisions of the nervous system?
Somatic nervous system and autonomic nervous system
What does the somatic nervous system innervate?
skeletal muscle
How is control over the somatic nervous system characterized?
precise and voluntary
Where are the neural connections of the somatic nervous system located?
In the central nervous system (CNS).
What type of nerves does the somatic nervous system utilize?
Myelinated nerves that transmit rapid impulses.
What is the primary function of the autonomic nervous system (ANS)?
It maintains homeostasis of key visceral functions
How is control over the autonomic nervous system characterized?
Control is involuntary
What involuntary functions does the ANS deal with? (7)
Respiration, circulation, digestion, metabolism, body temperature, eliminatory organs, endocrine and reproduction
Where are ganglia located in the autonomic nervous system?
in the efferent pathways
What type of nerves are myelinated in the autonomic nervous system?
Preganglionic nerves (which transmit rapid impulses).
What type of nerves are non-myelinated in the autonomic nervous system?
Postganglionic nerves (which transmit slower impulses)
What effect can the autonomic nervous system have on organ activity?
It can produce an increase or decrease in organ activity.
What is the ANS divided into?
Sympathetic and parasympathetic NS
What is the general organization of the ANS?
Central and peripheral
What is included in central organization of the ANS?
hypothalamus, medulla oblongata, spinal cord
What is included in peripheral organization of the ANS?
pre and post ganglionic neurons, ganglia
Outflow in sympathetic vs parasympathetic NS?
S = thoracolumbar
PS = craniosacral (CN 3, 7, 9, 10)
Ganglia in sympathetic vs parasympathetic NS?
S = near spinal cord
PS = close to end organ
Axons in sympathetic vs parasympathetic NS?
S = short pre, long post fibers
PS = long per, short post fibers
Ratio of pre/post ganglionic neurons in sympathetic vs parasympathetic NS?
S = one pre to many post
PS = one pre to one post
Distribution in sympathetic vs parasympathetic NS?
S = generalized response, diffuse discharge
PS = limited response, discrete discharge
SNS and PNS are physiological ____?
Antagonists
How are most viscera innervated?
Most viscera are innervated by both the SNS and PNS
What is the net activity of the ANS result of?
Integration of SNS and PNS
What happens to the activity of one system when the other is blocked?
The activity of one system is exaggerated by blocking the activity of the other system
What type of discharge is produced by the PNS?
discrete and localized discharge
What are the functions of the PNS that conserve and store energy?
- Decreased heart rate and blood pressure
-Pupillary constriction
-Increased GI movements and secretions - Increased absorption of nutrients
-Empties urinary bladder and rectum
What part of the ANS is essential for life?
PNS
What is the SNS involved in? (5)
-Increased HR and BP
-Splenic contraction
-Vasoconstriction of vessels in the skin
-Pupillary dilation
-Bronchodilation
What happens to the SNS during stress? (7)
-Regulates body temperature
-Increased blood glucose
-Provides vascular response to
hemorrhage
-Responds to oxygen deficits
-Responds to excitement or work
-Provides resistance to fatigue
-Causes pilomotor responses
What is a unique feature to the SNS?
Can discharge as a single unit ie. flight or fright response
Where does chemical transmission of nerve impulses in both the PNS and SNS occur?
-Pre- and post-ganglionic neurons
-Post-ganglionic neurons and effector organ
Where are some sites for pharmacologic intervention?
In the pre and post synaptic neuronsβ¦
for example; storage, metabolism , degradation stages etc
What neurons is Ach synthesized and released by?
Cholinergic neurons
What are included in cholinergic neurons?
-All motor fibers (somatic) to skeletal muscle (Not part of ANS)
-All pre-ganglionic efferent neurons of both SNS and PNS
-Post-ganglionic neurons of PNS
What are the cholinoceptors?
Muscarinic and nicotinic receptors
Nn and Nm
M1-M5
Where are the cholinoceptors located?
On the post synaptic cell
What is Ach made from?
Choline
What enzyme is in the synapse and wahat foes it break into?
-Acetyl-cholinesterase
-Breaks Ach into choline (goes back up to make more Ach) and acetate (removed)
What do adrenergic neurons synthesize and release?
-Catecholamines
~NE
~ Epinephrine (adrenal medulla)
~limited release of dopamine by some neurons
What neurons are included in adrenergic neurons?
-Post-ganglionic neurons of SNS
-Adrenal medulla (modified sympathetic ganglion)
~Receives sympathetic pre-ganglionic fibers
~Releases primarily epinephrine and some NE
What are the adrenoreceptors?
alpha and beta receptors
a1, a2
B1-B3
What is the breakdown to get from tyrosine to NE?
tyrosine -> to DOPA from tyrosine hydroxylase enzyme -> to dopamine from dopadecarboxylase -> NC
all adreneric receptor agonists are _____ acting
direct
what does direct acting mean
binds directly to respective receptor to activate it and doesnt produce effect by any other means
what does a non specific agonist mean
can bind to multiple receptor subtypes
what is a selective alpha agonist
phenylephrine
what is a non selective beta agonist
isoproterenol
what are three selective beta agonists (and what are their subtypes)
dobutamine (B1)
clenbuterol (B2)
terbutaline (B2)
what are two mixed alpha/beta agonists (and what subtypes are involved)
epinephrine (alpha1+2, B1, B2)
norepinephrine (alpha1+2, B1, B3)
what do adrenergic agonists alter? (2)
-rate (chronotrophy) and force (ionotrophy) of contraction of the heart. can be directly or via reflex effects on the heart from actions of the vessels
-tone of the blood vessels
what affects blood pressure (eqn)
BP = CO x TPR
what affects cardiac output (eqn)
CO = SV x BP
what does activation of alpha receptors yield?
vascular smooth muscle contraction of most vessels
alpha receptor activation = inc/dec TPR, inc/dec BP, inc/dec heart rate, inc/dec CO?
increased TPR
increased BP
reflex decreased HR
decreased CO
beta receptor activation = inc/dec TPR, inc/dec BP, inc/dec heart rate, inc/dec CO?
decreased TPR
decreased BP
reflex increased HR
increased CO
what does activation of beta receptors yield?
vascular smooth muscle relaxation
(skeletal muscle; B2)
what subtypes does epinephrine activate
all alpha and beta subtypes
what is epinephrine mainly used for
cardiovascular support
what are the two formulations of epinephrine available
1:1000 = 1mg/kg
1:100,000 = 0.01mg/kg
what are the cardiac effects of epinephrine
-increase CO by activating B1. this leads to increased force and rate of contraction β¦.. (overall increases CO and BP)
what are the vascular smooth muscle effects of epinephrine (2)
-most vessels involve alpha 1 which leads to vasoconstriction = increased TPR and BP
-some vascular beds possess B2 receptors which promotes vasodilation and decreased TPR and BP
what are the smooth muscle effects of epinephrine related to activation of B2 receptors (4)
-bronchodilation
-decreased GI contractions
-decreased tone and contraction of pregnant uterus
-relaxes urinary bladder to promote filling
what are the smooth muscle effects of epinephrine related to activation of a1 receptors (3)
-contraction of spleen
-contraction of sphincter of the bladder to promote urine storage
-contraction of radial muscle of iris
what is mydriasis
contraction of radial muscle of iris
what are the metabolic effects of epinephrine
-increased circulating glucose, lactic acid and free fatty acids
what are four drugs that are selective beta agonists
clenbuterol, terbutaline, ractopamine, dobutamine
what subtype of agonist do clenbuterol and terbutaline affect
they are selective for B2 agonists
what is clenbuterol used for
lower airway disease in horses
what is terbutaline used for
asthma in cats and chronic bronchitis in dogs
what form is clenbuterol approved for in horses
syrup
what form is terbutaline approved for in small animals
compounded tablets or injectables
what is available for use as bronchodilators in airway disease (+examples)
inhalant selective B2 agonists
salbutamol, terbutaline and others used in horses and small animals
what subtypes do ractopamine affect
primarily B1 agonists with some B2 agonist activity
what is ractopamine used for
increases lean muscle deposition in cattle to promote growth
what subtype does dobutamine affect
relatively selective B1 receptor agonist
what is dobutamine primarily used for
cardiac support. it improves contractility and BP without significant tachycardia
what is possible with dobutamine overdose
ventricular tachycardia and hypertension
what subtype stimulation is possible when giving dobutamine
peripheral a1 stimulation possible
what drug is a non selective beta agonist?
isoproterenol
what subtypes does isoproterenol affect
non selective B1 and B2 agonists
what does isoproterenol result in (B1 vs B2 effect)
B1 receptor stimulation increases rate and force of contraction of the heart
but B2 receptor stimulation can yield decreased TPR and overall decreased BP
what drug is a selective alpha 1 agonist
phenylephrine
what does phenylephrine promote
-produces vasocontriction and increased BP (but its possible for the reflex to decrease HR)
-may be used for BP support and nasal decongestion
-pupillary dilation
what forms of phenylephrine are available
oral, injectable, nasal and ophthalmic formulations
what are the effects of dopamine in low, moderate and high doses (and what receptors they use)
low= dilates renal vasculature via D1 receptors which increases GFR
moderate= B1 receptor effects lead to increased contractility
high= a1 agonist leads to increased TPR (vasoconstriction)β¦ but increases risk of arrhythmias
what drugs are classified as sympathomimetics
ephedrine, pseudoephedrine, phenylpropanolamine
what does a sympathomimetic do
actions mimic adrenergic agonists
what can ephedrine, pseudoephedrine, phenylpropanolamine do in terms of receptors ?
can activate alpha and beta receptrs as well as release of NE from sympathetic nerve terminals
what is phenylpropanolamine approved for
approved for use in dogs as tablets/syrup for urinary incontinence due to hypotonic urethra in females
what are ephedrine and pseudopropanolamine used for
-used primarily as nasal decongestants along with antihistamines
-can be used for urinary tract incontinence in dogs as it increases spincter tone in hypotonic urethra
in what cases do you have treatment for hypotension (4)
-hemorrhage
-severe fluid loss
-infection (sepsis)
-adverse drug reactions
what is the key when treating low BP or reduced blood flow
expand fluid volume and treat underlying cause is key
what drugs can be useds to treat low BP or reduced blood flow
phenylephrine or NE
what type of agonists can be used for treating low BP or reduced blood flow and for how long
can give a1 agonists or vasopressors for short term cardiovascular support if vasoconstriction is desired
in what cases do you need to support cardiac insufficiency (3)
-heart block (bradycardia)
-cardiogenic shock and arrest
-congestive heart failure
what agonist and drugs are used for treatment of cardiac insufficiency
b1 receptor agonist may be helpful as it increases cardiac contractility and output
-dobutamine or dopamine (in acute decompensated CHF cases)
-isoproterenol (for arrest, bradycardia)
-epinephrine (arrest, bradycardia)
what can be used together have production of local vasoconstriction
lidocane HCl 2% with epinephrine to promote vasoconstriction
this
when do you want to use lidocane HCl 2% with epinephrine
when you want to decrease blood flow and prolong the local anesthetic action at a site
or epi can be used topically to decrease superficial bleeding
what drug is approved for lower airway disease in horse
clenbuterol
what drug is compounded for oral or injectable use primarily for small
animal (asthma, chronic bronchitis)
terabutaline
what drugs are used as inhalants in small animal and horse
Salbutamol, salmeterol, terbutaline
what drug is
used to treat respiratory compromise associated with anaphylaxis
Epinephrine
what receptors are activated in treatment of bronchoconstriction
b2 receptor activation which leads to bronchodilation
what receptors are activated in treatment of nasal congestion
a1 receptor activation which leads to vasoconstriction
what drugs are used for nasal decongestion
Ephedrine, pseudoephedrine and phenylephrine
what is the major limitation of ephedrine, pseudoephedrine and phenylephrine
Major limitation to their use is βreboundβ hyperemia and worsening
congestion when they are stopped. so you must wean them off
how do drugs for nasal congestion work
Reduce air flow resistance by reducing mucosal edema
what does epinephrine do in anaphylactic rxns (2)
-Stabilizes mast cells
-Provides cardiovascular support
what happens during anaphylaxis
-Severe bronchospasm; mucous membrane congestion, angioedema
-Cardiovascular collapse due to vasodilation from mast cell degranulation
what is phenylephrine used for (2)
-used as a mydriatic to facilitate retinal examination
-also used as decongestant to treat allergic conjunctivitis
what receptor is activated from phenylephrine and what occurs
a1 activation produces contraction of the radially orientated pupillary dilator muscles of the iris ==> mydriasis (pupil dilation)
what are the general properties of non selective alpha agonists
alpha blockade -> vasodilation -> decreased peripheral resistance and BP
-Reflex tachycardia from reduced BP & blockade of prejunctional a2 receptors
what drug is an irreversible inhibitor of alpha receptors
Phenoxybenzamine
what drug has been used for Dx and Rx of pheochromocytoma mediated hypertension
Phenoxybenzamine
what is the major adverse effect of phenoxybenzamine
hypotensionβ¦. dont use epi because it cant promote vasoconstriction, it will promote the opposite effect of what we want = epinephrine reversal
what receptor does prazosin work on
a1 selective blockade
what is prazosin used for
-Used for hypertonic urethra due to functional urethral obstruction in
small animals
-May be useful as adjunctive therapy in CHF and pulmonary
hypertension
drugs with a higher affinity for ___ are important clinically
B1
beta agonists are generally ___ absorbed
well
why is there low bioavailability of beta agonists
due to extensive hepatic metabolism
what are beta agonists used for
Used in cardiovascular disease and ocular conditions
clinical uses for propranolol (3)
-supraventricular and ventricular tachyarrhythmias
~decreased rate of SA node discharge
~decreased AV conduction and decreased ventricular response to atrial arrhythmias
- decreased sinus node rate; thyrotoxicosis in hyperthyroidism in cats, and pheochromocytoma in dogs
*-Hypertrophic cardiomyopathy in cats; relief of outflow tract obstruction
are propranolol receptors reversible
yes, reversible b1 and b2 receptor antagonist β¦ which decreases chronotropy and inotropy
what are some things to watch out for when giving propranolol
Bradycardia and hypotension possible; contraindicated in asthmatics, lower airway disease
what two drugs are selective b1 antagonists
metoprolol and atenolol
what drugs have the same cardiac effects as propranolol
metoprolol and atenolol
atenolol has ______ hepatic first pass effects
minimal
what drugs are contraindicated in significant heart failure cases and what is the exception
propranolol, metoprolol and atenolol
unless necessary for tachycardia
what drug has mixed adrenergic antagonists
carvedilol
what is carvedilol used for (2)
-May be useful in treating cardiomyopathy in dogs
-May also act as a free-radical scavenger
what do you need to be careful of when using carvedilol
hypotension
what do metoprolol and atenolol do
reduce adverse effects such as bronchospasm
categories of direct acting cholinergic receptor agonists (2)
nicotinic and muscarinic
categories of indirect acting cholinergic receptor agonists (2)
quarternary alcohols (short acting)
carbamates (intermediate acting)
What is the primary action of direct-acting cholinergic muscarinic agonists?
They mimic acetylcholine (ACh) at neuroeffector junctions of the parasympathetic nervous system (PNS)
what category of agonist does bethanechol chloride fall in?
muscarinic agonist (direct acting cholinergic agonists)
What is the therapeutic use of Bethanechol chloride?
It stimulates the urinary bladder to promote emptying, especially in patients with a hypocontractile bladder
When is Bethanechol chloride contraindicated?
In cases of gastrointestinal (GI) or urinary tract obstruction
What should be considered if there is a functional increase in urethral tone when using Bethanechol chloride?
Pretreatment with an alpha (Ξ±) blocker or skeletal muscle relaxant may be necessary
What syndrome is associated with the use of direct-acting cholinergic agonists like Bethanechol?
SLUD syndrome (Salivation, Lacrimation, Urination, Defecation)
What is the antidote for SLUD syndrome caused by muscarinic agonists?
Atropine, which is a muscarinic blocker.
What is a key characteristic of Bethanechol that affects its duration of action?
It is a choline ester that is resistant to cholinesterases, prolonging its actions.
What is Pilocarpine?
Pilocarpine is a direct-acting muscarinic agonist
what are the two main outcomes of using pilocarpine
constricts the pupil (miosis) and increased aqueous flow
What is a common issue associated with the use of Pilocarpine in treating glaucoma?
It can cause irritation to the eye, leading to compliance issues.
Why is the use of Pilocarpine as a tear stimulant in keratoconjunctivitis sicca (KCS) less common now?
It has largely been replaced by cyclosporine for immune-mediated KCS
Under what condition might Pilocarpine still be used as a tear stimulant and how does it work?
-In neurogenic KCS, where there is a lack of neurogenic input to the lacrimal glands.
-It directly stimulates muscarinic receptors on the lacrimal glands
What must be present for Pilocarpine to effectively stimulate tear production?
There must be some functional lacrimal tissue
what are the characteristics of indirect acting cholinomimetic drugs (2)
-Anticholinesterase drugs ie. inhibitors of ACh metabolism
-Resultant effects similar to direct-acting cholinomimetics
what is an example of a quarternary alcohol and how does it work
edrophonium - binds reversibly to the active site of cholinesterase which prevents access of cholinesterase to Ach which increases levels in the synate
what is the mechanism for indirect acting cholinomimetic drugs
-normally ACh is rapidly degraded in the synapse by acetylchoinesterase and has a very short half life. but these anticholinesterase drugs block acetylchoinesterase which increases the amount of ACh in the synapse = prolonged muscarinic receptor stimulation can result
is the duration of edrophonium long or short
short
what are two examples of a carbamate ester?
neostigmine and pyridostigmine
How do carbamate esters like Neostigmine and Pyridostigmine affect cholinesterase and what is the effect of it?
They carbamylate the active site of cholinesterase.
The carbamylated enzyme is more resistant to the hydration step, prolonging its activity
Why do carbamate esters have poor penetration into the central nervous system (CNS)?
Similar to other quaternary compounds, they are charged polar molecules
therapeutic uses of parasympathomimetic drugs at the neuromuscular junction
neostigmine and pyridostigmine for myasthenia gravis to increase the strength of contraction
diagnosis of myasthenia gravis
-Condition worsens with d-tubocurarine (N-M blocker)
-Edrophonium may be used to support diagnosis
-Demonstration of autoantibodies to the nicotinic receptor is confirmative
what is the main cause of myasthenia gravis
-Main cause is autoimmune disease -> destruction of nicotinic receptors
-Clinical signs of weakness, fatigue, & swallowing difficulty (megaesophagus)
-Resembles neuromuscular blockade
therapeutic uses of parasympathomimetic drugs for GIT
in cases of paralytic ileus and rumen atony, neostigmine has been used with varying results
classes of antimuscarinic drugs (2)
-tertiary amines (able to penetrate CNS)
-quarternary ammonium compounds (more limited to peripheral effects)
mechanism of muscarinic receptor ANTAGONISTS
reversible blockage of ACh at muscarinic receptors by competitive binding
what are three tertiary amines
-atropine, tropicamide and oxybutynin
uses for oxybutynin and general caution when using it
- Relatively selective for bladder smooth muscle
- Used primarily for spastic bladder in dog and cat
- General caution when GI obstruction or infection or ileus, or urinary tract obstruction present
(risk vs benefits)
adverse effects of oxybutynin
- Constipation
- Urine retention
therapeutic uses of atropine
-Ophthalmic uses as a mydriatic-cycloplegic
-Blocks pupillary constrictor muscle = pupil dilation (mydriasis) for ocular exam
-Blocks contraction of the ciliary muscle = reduces ciliary spasms (uveitis)
therapeutic uses of tropicamide
Limited to mydriasis = facilitates ocular examination
available forms of atropine
parenteral , topical and oral absorption
three examples of quaternary ammonium compound
propantheline, ipratropium and hyoscine butylbromide
why do quaternary ammonium compounds not have many CNS effects
charged polar moleculres so they cant cross BBB readily
what is propantheline used for
-Can be used for treatment of GI motility disorders (Antidiarrheal effects, Intestinal spasms and facilitate rectal exams in horses)
-Also used to treat spastic (hypercontractile) bladder
general caution and adverse effects possible with propantheline
-General caution in GI infections or obstruction or ileus, or obstruction of bladder
-Adverse effects possible: dry mouth, dry eyes, urinary retention, tachycardia, constipation (like atropine)
what is ipratropium used for
-May be of benefit in bronchospasm associated with respiratory disorders;
occasionally used in horses as adjunct therapy for lower airway disease and possibly chronic bronchitis in dogs, and asthma in cats
what is hyoscine butylbromide used for
-Antispasmodic approved for treatment of pain associated with GI motility
disorders ie. colic in horses
~Tachycardia and reduced gastrointestinal motility are possible adverse effects
~Should not be used in horses intended for human food consumption
-Potential for use in acute severe exacerbations of airway obstruction in horses
with lower airway disease; immediate bronchodilator effects
~Possibly less potential for adverse effects compared to atropine
Please complete the following sentence from the choices
given below. βIn the sympathetic nervous system the
ganglia are located ____________. Discharge of the
parasympathetic nervous system is considered
____________β. (1 mark)
close to the end-organ; discrete
Which one of the following is matched correctly
(1 mark)
a. phenylephrine: selective a2-receptor agonist
b. isoproterenol: mixed (a,b) adrenergic receptor agonist
c. clenbuterol: selective b2-receptor agonist
d. norepinephrine: non-selective (b1, b2) beta receptor agonist
C
- Edrophonium has a longer duration of action
than does neostigmine (1 mark)
True
False
F
Which one of the following statements regarding the autonomic nervous system (ANS) is most
correct (1 mark)
a. The sympathetic nervous system (SNS) is essential for life
b. Acetylcholine is formed from tyrosine and choline
c. Most organs are innervated by either the PNS or SNS, but
not both
d. The ANS contains the parasympathetic and sympathetic
but not the somatic nervous systems
D
All of the following are potential therapeutic
uses for atropine, EXCEPT (1 mark)
a. mydriatic-cycloplegic
b. present in some calf scour preparations
c. hypocontractile bladder
d. treatment of organophosphate poisoning
C
