Exam 2 Flashcards
1
Q
Most organs are innervated by both sympathetic and parasympathetic nervous system - what is the exception?
A
blood vessels = sympathetic only
2
Q
Where do pre-ganglionic neurons original and what NT do they release?
A
Originate in the CNS and release ACh –> interacts with nicotinic cholingeric receptors on post-ganglionic
3
Q
What are the second messengers (3) involved with activated GPCR?
A
- cAMP
- DAG
- IP3
4
Q
What increases and decreases cAMP?
A
Gas - increases (PKA)
Gai - decreases
5
Q
What increases DAG & IP3?
A
Gaq/11 - increases (PKC)
6
Q
Postganglionic neurons (Parasympathetic)
A
Release ACh onto target organs w/muscarinic cholinergic receptors
7
Q
Postganglionic neurons (Sympathetic)
A
Release EPI/NE (from adrenal gland) onto target organs w/adrenergic receptors
8
Q
How are NT’s “turned off”?
A
- re-uptake
- diffusion
- degradation (AChE)
9
Q
Which receptors have negative feedback?
A
Presynaptic receptors
10
Q
Parasympathetics - distribution and ganglia
A
- Cranio sacral distribution
- ganglia are in/near target organs (local regulation)
11
Q
Parasympathetics - receptors
A
Muscarinic ACh:
- M1 (Gaq)
- M2 (Gai)
12
Q
Sympathetics - distribution & ganglia
A
- Thoracolumbar distribution
- ganglia along vertebral column in sympathetic chain –> coordinated activation of target organs
13
Q
Sympathetics - main hormones
A
Catecholamines - EPI/NE
“fight or flight” response
14
Q
Sympathetics - Receptos
A
ADRENERGIC (NE)
- Alpha 1 (Gaq)
- Alpha 2 (Gai)
- Beta 1 (Gas)
- Beta 2 (Gas)
15
Q
Sympathetics - NT re-uptake
A
Re-uptake is common mechanism of inactivation for NE –>
- repackaged/metabolized by MAO
- metabolized by COMT in liver
16
Q
Cholinergic agonists =
A
parasympathomimetics
- mimic/enhance effect of parasympathetic ACh
17
Q
Nicotinic Cholinergic receptors
A
- inotropic ligand-gated cation channel
- ACh binding opens channel –> Na+ influx = depolarization
18
Q
Muscarinic and Adrenergic receptors
A
All GPCR
Muscarinic cholinergic: M1-M5
Adrenergic: alpha 1 & 2; beta 1 & 2
19
Q
G protein signaling
A
After dissociation from Gby, Ga subunits (s, i, q/11) either inc or dec the quantity of second messengers (signaling) molecules
20
Q
cAMP
A
increased with Gas
decreased with Gai
*activates PKA
21
Q
DAG
A
increased by Gaq/11
*activates PKC
22
Q
IP3
A
increased by Gaq/11
*activates PKC
23
Q
Muscarinic cholinergic signaling
A
Gaq/11 –> M1. 3. 5
Gai –> M2. 4
24
Q
Alpha adrenergic signaling
A
Gaq/11 (alpha 1)
Gai (alpha 2)
25
Beta adrenergic signaling
Gas
26
Non-adrenergic, non-cholinergic (NANC) transmission
primarily inhibitory effects
*smooth mm innervated by ANS; some ANS effects in the presence of adrenergic and cholinergic blockade
27
NANC transmission
Purinergic neurotransmission
- adenosine receptors (P1)
- ATP receptors (P2X and P2Y)
* ATP often released as a co-transmitter with ACh or NE
Nitric Oxide
- aka endothelium-derived relaxation factor
- nitrergic nerves
28
Heart
Sympathetic: inc CO
- B1
Parasympathetic: dec CO
- M2
29
Blood vessels
Sympathetic: arteries (general) constrict [dilates arteries in skel mm]
- a1 (general); b2 (skel mm)
Parasympathetic: dilates arterial endothelium via inc NO
- M3
30
Lungs
Sympathetic: dilation
- B2
Parasympathetic: bronchoconstriction & secretion from glands
- M3, M2
31
GI
Sympathetic: decrease fan
- a1 and a2
Parasympathetic: increase fan
- M3 and M2
32
Urinary bladder
Sympathetic: inhibit voiding
- a1 and b2
Parasympathetic: promote voiding
- M3
33
Eye
Sympathetic: mydriasis
- a1
Parasympathetic: mitosis
- M3, M2
34
Cholinergic agonists
Parasympathomimetics (aka cholinomimetics)
mimic/enhance the effect of endogenously released acetylcholine (parasympathetics)
35
Cholinergic agonists - heart
decreased CO via M2
- bradycardia (decreased SA node automaticity)
- decreased conduction (e.g. AV node
36
Cholinergic agonists - vasculature
vasodilation, M3 (inc NO)
37
Cholinergic agonists - lungs
bronchoconstriction, increased secretions, M3 and M2
38
Cholinergic agonists - GI
increased motility, increased secretion (e.g. salivation), M3, M2
39
Cholinergic agonists - bladder
contraction (urination), M3
40
Cholinergic agonists - eye
lacrimation, mitosis, M3 and M2
41
Visible signs of excessive cholinergic stimulation...
SLUDE
```
salivation
lacrimation
urination
defecation
GI symptoms
emesis (vomiting)
```
42
Endogenous cholinergic
Acetylcholine
- rarely used clinically (ophthalmic)
* muscarinic and nicotinic stimulation
- rapid deviation by AChE and plasma butyrylcholinesterase
43
Direct acting cholinergic agonists - choline ester
Bethanechol (choline ester)
- muscarinic stimulation, some GI/urinary bladder selectivity (M3)
- promotes voiding by contraction of detrusor m. and relaxation of the trigone and sphincter
- used to treat urinary retention when obstruction is absent
44
Direct acting cholinergic agonists - alkaloid (M)
Muscarine
- stimulates muscarinic receptors!
- not used clinically
- found in certain mushrooms (contributes to mushroom poisoning)
45
Direct acting cholinergic agonists - alkaloid (P)
Pilocarpine
- muscarine stimulation
- topical ophthalmic use to induce pupil constriction and decrease intraocular pressure during glaucoma
- rarely used systemically to promote salivation (sialogogue)
46
Indirect acting cholinergic agonists - AChE inhibitors
- prevent hydrolysis of ACh to choline and acetate
- accumulation of ACh sites of release --> autonomic effect organs and ganglia, skeletal m., cholinergic synapses in the CNS
47
AChE inhibitors - reversible
Physostigmine (crosses BBB)
Neostigmine
48
AChE inhibitors (reversible) - clinical use
- smooth mm. atony (GI tract and UB)
- glaucoma (topical)
- reversal of competitive non-depolarizing neuromuscular blocking agents
- myasthenia gravis (ACh receptor deficiency)
- counter CNS symptoms of anticholinergic intoxication
49
Cholinergic antagonists
aka Anticholinergics
- Block the effect of endogenous ACh at muscarinic receptors
* little effect on ACh at nicotinic receptors
50
Cholinergic antagonists - Effects on heart, vasculature, and lungs
Heart: increase CO
- tachycardia (inc SA nodal automaticity), inc conduction (AV node)
Vasculature: little effect, no innervation
Lungs: bronchodilator, dec secretions
51
Cholinergic antagonists - Effects on GI, UB, eye
GI: dec motility and secretions (dry mouth)
UB: dec urination
Eye: dec lacrimation, mydriasis, cycloplegia (paralysis of ciliary mm - loss of focus on nearby objects)
52
What are the visible signs of Cholinergic antagonists
Anti-SLUDGE
Dec: salivation, lacrimation, urination, defecation, etc. etc.
53
Atropine
Cholinergic (parasympathetic) Antagonist
Competitively inhibits the binding and stimulation of muscarinic receptors by ACh and other muscarinic agonists
54
Can atropine enter the CNS? what are primary concerns with tx?
Yes, can enter the CNS (non-quaternary, possible toxicity, excitation followed by depression)
Primary concerns: tacharrhythmia, prolonged GI stasis, urine retention
55
How/why is atropine used during general anesthesia?
decreases salivary and airway secretions
56
Glycopyrrolate (cholinergic antagonists)
Similar to atropine, but:
- quaternary
- little CNS effects
* Used as adjust to general anesthesia:
- dec salivary and airway secretions
- prevent vagally-mediated bradycardia
57
Ipratroium (cholinergic antagonists)
- dec bronchoconstriction and airway secretions
- quaternary: restricted distribution
* administer via inhalation, limit systemic effects
- Uses:
* asthma (cats) and chronic bronchitis (dogs)
* horses with recurrent airway inflammation
58
Propantheline (cholinergic antagonists)
- dec detrusor contraction
- inc trigone and sphincter contraction
- promotes urine retention
* Uses:
- treat incontinence due to detrusor instability
59
NMJ blocking agents
Used as adjunct during general anesthesia (unconscious animals):
- relax skel mm, NO sedative effects
- especially the abdominal wall
- given IV
60
NMJ - do all nACh- receptors have to be activated for mm contraction?
NO! there are "spare receptors" that provide a safety factor at the NMJ (consider the diaphragm)
61
Spare receptors and the NMJ
practical consequences:
| - reversal of clinical blockage with drug still present
consider the diaphragm - lost safety factor
62
NMJ - Curare
- Natural alkaloid found in S. America
- Used to make arrow poison
- toxin = tubocurarine
- death from skeletal m paralysis
**Competitive ACh antagonist at nicotinic receptors in the NMJ
63
Competitive NMJ bockers
- No motor end plate depolarization
- aka: non-depolarizing NMJ blockers
- initial mm weakness followed by --> flaccid paralysis
64
Competitive NMJ blockers - drugs (3)
1) Pancuronium (long-acting)
2) Atracurium (intermediate)
3) Mivacurium (short-acting)
65
Properties to consider - Competitive NMJ blockers:
- duration of action
- route of elimination
- degree of ganglionic blockade
- antagonize muscarinic receptors
- propensity to release histamine from mast cells
66
Pancuronium - competitive NMJ blockers
- long duration of action (2-3 hours)
- renal elimination (half-life inc with renal dz)
- little ganglionic blockade
- no histamine release
- blocks histamine release
- blocks muscarinic receptors (tachycardia)
67
Atracurium - competitive NMJ blockers
- intermediate duration (0.5-1h)
- spontaneous degradation + hydrolysis by plasma enterases + renal elimination
- spontaneous degradation is reduced with hypothermia and acidosis, leading to inc half-life and duration of action
- little/no ganglionic blockade
- promotes histamine release
- half-life is NOT inc with renal dz
68
Mivacurium - competitive NMJ blockers
- short duration of action (15 mins)
- rapid hydrolysis by plasma enterases --> half-life not inc w/ renal dz
- little/no ganglionic blockade
- promotes histamine release
69
Competitive NMJ blockers - how to reverse?
Reverse with AChE-inhibitors
70
Depolarizing NMJ Blockers
- Cause prolonged motor end plate depolarization by stimulation of NMJ nicotinic receptors
- aka non-competitive NMJ blockers
- initial m. fasciculation (uncoordinated contractions) followed by relaxation
71
Depolarizing NMJ Blockers - drugs
Only succinylcholine used clinically
- two Act molecules linked together
- essentially mimics ACh at the NMJ
- resistant to AChE
- NOT pharmacologically reversible
72
Two phases of Depolarizing NMJ Blockers
Early (phase 1): depolarization
- persistent stimulation of nicotinic receptors
- nicotinic receptors during this phase are incapable of transmitting further impulses
- fasciculations (last less than 1 min) --> flaccid paralysis
Late (phase 2): depolarization
- flaccid paralysis
- resembles receptor desensitization
73
Succinylcholine - Depolarizing NMJ Blockers
- rapid onset (1min)
- ultra-short acting (5 min): rapidly hydrolyzed by butyrylcholinesterases
- useful for rapid and short lived NMJ blockage (e.g. facilitate tracheal intubation)
- some histamine release but does not generally cause ganglionic blockade
- hyperkalemia from release of intracellular K+ from skeletal mm.
* avoid in presence of extensive soft-tissue damage or burns
74
Potential problem with NMJ Block
- Monitoring depth of anesthesia
- Many signs of anesthesia are lost during NMJ blockade
* *more difficult to assess the depth of anesthesia
75
NMJ blockade toxicity
Res paralysis
76
NMJ toxicity intervention - histamine
Toxicity interventions: histamine release from mast cells
- bronchospasm, hypotension, bronchial and salivary secretion
- minimize with antihistamine pre-tx (benadryl)
77
NMJ toxicity intervention - Vagal (parasympathetic) reflex
- often procedure (not drug) induced
* visceral manipulation
- bradycardia, bronchospasm, hypotension, bronchial and salivary secretion
- compounds many symptoms of histamine release
- minimize with anticholinergic (e.g. atropine)
- Note: some rabbits have high levels of plasma enterases which degrade atropine (polymorphism)
78
NMJ toxicity intervention - ganglionic blockade
- hypotension
| - can manage with sympathetic adrenergic agonists (adrenergic lectures)
79
NMJ toxicity intervention- MALIGNANT HYPERTHERMIA
- life-threatening
- excessive contracture and heat production from skeletal mm
- initiated by the release of Ca2+ from the SR of skeletal mm
- usually triggered by combination of halogenated anesthetics (e.g. halothane) and succinylcholine
- prevalent in pigs, also reported in dogs (esp Greyhounds), cats, and horses
- tx with dantrolene (limits SR Ca2+ release) plus supportive measures
80
Adrenergic Agonists
aka Sympathomimetics
* mimic the effect of endogenous sympathetic catecholamines Its (NE and Epi)
* excitation or inhibition of smooth mm or glandular activity
* cardiac excitation
* general catabolic state
- glucose/FFA mobilization
81
Adrenergic Agonists - CNS stimulation or pre-junctional actions
CNS stimulation
- inc wakefulness, resp stimulation, etc
Pre-junctional (e.g. a2 receptors)
- dec NT release
- dec sympathetic outflow; CNS depression
82
General classification of agonists
* Direct acting agonists
- endogenous catecholamines
* Indirect acting agonists
- amphetamine
* Mixed acting agonists
- Phenylpropanolamine (PPA)
83
Direct acting adrenergic agonists
* interact directly w/ a and b receptors to different degrees
* endogenous catecholamines
* catecholamine derivatives
- add various substituents = alter activity and selectivity
84
Direct acting adrenergic agonists - Epinephrine
aka Adrenaline
* potent a and b agonist
* released by adrenal chromatin cells
* complex action: summation of a and b agonist activity
* cardiovascular effects (very important)
85
Direct acting adrenergic agonists - Epinephrine
Cardiac effects
Cardiac effects (b1)
- inc contractility (positive ionotrope)
- inc HR (positive chronotrope)
- inc O2 consumption
General result: inc CO
86
Direct acting adrenergic agonists - Epinephrine
Vascular effects
Vascular effects:
- low dose ---> dec BP via b2 dominance
- high dose ---> inc BP via a1
*can be given IV, IM, or SQ (not orally active)
87
Direct acting adrenergic agonists - Epinephrine
Respiratory effects (important)
Resp effects: important
- powerful bronchodilator (b2)
- especially if bronchioles pre-constricted
(e. g. anaphylaxis or asthma)
- small dec in bronchial secretions
88
Direct acting adrenergic agonists - Epinephrine
Therapeutic Uses
* rapid release of hypersensitivity reactions (e.g. anaphylaxis and asthma)
- cardiovascular support and bronco dilation
* restoring cardiac rhythm
- cardiac arrest, AV node block
* Topical hemostatic agent
- control superficial bleeding of mucosal and SQ surfaces via vasoconstriction (a1)
* Adjunct w/ local anesthetics (lidocaine)
- vasoconstriction (a1) localizes anesthetic action and limits systemic absorption and toxicity
89
Direct acting adrenergic agonists - Epinephrine
Toxicity
* Extension of pharmacological action
| - cardiac arrhythmias, hypertensive crisis, cerebral hemorrhage, restlessness, etc.
90
Direct acting adrenergic agonists - NE
* Major NT released by post-ganglionic sympathetic nerves
| * Differs from Epi by lacking a single methyl group
91
NE vs Epi - potencies
B1: Epi = NE
B2: EPI >>>>>>> NE
A1: EPI > NE
92
NE Effects and Toxicities
NE similar to Epi in most respects
- differences result from lack of B2 stimulation
- intense vasoconstriction and increase in blood pressure
* initiates vagal reflex (baroreceptors) which slows HR
93
Direct acting adrenergic agonists - NE
Therapeutic uses
* limited use
- cardiovascular support (maintain BP) during shock via a1 (vasculature) and B1 (heart) effects
* NO B2 effect = no bronchodilation
94
Direct acting adrenergic agonists - Dopamine
* endogenous catecholamine
* precursor to NE and EPI
* given IV (infusion)
- short half-life
95
Direct acting adrenergic agonists - Dopamine
Dose dependent effects
* Low dose:
- vascular vasodilation
- inc renal blood flow and Na excretion
- stimulates cardiac B1 receptors --> positive inotropic effect
**Use low dose IV infusion for congestive heart failure w/compromised renal failure (short term only)
* High dose:
- a1 receptor stimulation --> vasoconstriction, dec renal blood flow, etc
96
Non-selective B adrenergic agonists - Dobutamine
* structurally related to dopamine
| * complex agonist activity on B1, B2, and a1 receptors (B1 > B2 and a1)
97
Non-selective B adrenergic agonists - Dobutamine
Cardiovascular effects
* inc cardiac contractility (B1 agonist) w/minimal changes in HR
* minimal change in BP as a1 and B2 agonist activities are weaker and counterbalance
* use as positive inotrope during hear failure (short term only)
98
Non-selective B adrenergic agonists
General adverse effects/toxicity
* unwanted and/or excess B stimulation
| e. g. inc HR (B1) when sued as bronchodilator (B2)
99
Selective B adrenergic agonists
B1 and B2
BI:
- dobutamine is close from a functional perspective (B1 > B2 or a1)
B2:
- many examples; used as bronchodilators
100
Selective B adrenergic agonists
B2
B2 agonist = bronchodilator
| - Gas = inc cAMP = relax bronchial smooth mm
101
Selective B2 adrenergic agonists - Albuterol
Albuterol (aka salbutamol)
| - for bronchospasm in dogs, cats, and horses
102
Selective B2 adrenergic agonists - Clenbuterol
Clenbuterol:
| - used for allergic bronchitis, recurrent airway obstruction ("heaves"), and bronchoconstriction in horses
103
Selective B2 adrenergic agonists
B receptor down-regulation
- Minimize with proper dose, dosing schedule
- following chronic, long-term administration of B agonists (esp with over-usage)
- leads to loss of pharmacological efficacy
104
Selective B2 agonists & repartitioning
* repartitioning in livestock:
- alter carcass composition by partitioning energy away from fat deposition and towards protein accretion (inc mm mass)
- improve weight gain, leanness, etc.
* repartitioning agents:
- ractopamine, zilpaterol, clenbuterol
105
Selective B3 adrenergic agonists
Toxic to dogs!!
B3 agonist = mirabegron
- relax the detrusor in the bladder, increase bladder capacity (in humans)
106
Selective a1 adrenergic agonists
* primary effect of a1 stimulation is constriction of vascular smooth muscle --> increased blood pressure (pressor agents)
* a1 agonist = vasoconstrictor
- Gaq = inc DAG and IP3 = inc Ca2+ = contract arterial smooth muscle
107
Selective a1 adrenergic agonists - Phenylephrine
* prototypical a1 agonist
* topical, oral, parenteral
* decongestant, vasopressor
Toxicity = excess a1 activity (hypertension)
108
Selective a2 adrenergic agonists
* Effect primarily central (CNS) and pre-synaptic inhibition of sympathetic neurons:
- sedation, analgesia
- decreased sympathetic outflow from brain
- decreased NE release
109
Selective a2 adrenergic agonists - (Dex)medetomidine & xylazine
- a2 agonists = CNS depression
- widely used as adjunct for sedation, anesthesia, and analgesia
- pre-anesthetic, light anesthesia by itself
- relatively high safety profile (therapeutic index)
- allows for a lower dose of other anesthetic/analgesic agents with lower safety profiles
- overall effect is a dec in BP (and sedation/analgesia)
110
a adrenergic agonists - summary
a1 and a2
a1 = vasoconstrictor (phenylephrine)
a2 = sedative (medetomidine)
- also dec sympathetic outflow
111
Misc adrenergic agonists
(pseudo)ephedrine
phenypropanolamine
- direct a and B agonist activity
- promotes release of NE from sympathetic neurons (indirect)
- mixed acting adrenergic agonists
- rarely used as decongestant
- PPA - used for urinary incontinence
112
Adrenergic agonist review
* a1 = vasoconstriction (EPI, NE, phenylephrine)
* a2 = presynaptic inhibition (medetomidine)
* B1 = inc HR and contractile force (EPI, NE, dopamine, dobutamine)
* B2 = bronchodilator (EPI, albuterol, clenbuterol)
113
Adrenergic antagonists
Aka Sympatholytics
* block the effect of endogenous sympathetic catecholamine Its
- NE and EPI
- effects dependent on sympathetic activity (tone)
- vary with state of the animal
- vary between tissues (e.g. heart and GI tract)
114
General classification of antagonists
* Direct acting competitive antagonists
- reversibility block the stimulation of a and B receptors by endogenous Its
- varying degree of selectivity at different receptors
- phentolamine
- MOST ADRENERGIC ANTAGONISTS
* Direct acting non-competitive antagonists
- irreversibly blocks a1 and a2 receptors
- phenoxybenzamine
* Indirect acting antagonists
- reserpine
* Non-selective a antagonists
- Phenoxybenzamine, phentolamine
- non-selective a antagonists
- reduces urethral sphincter tone
- manage urethral blockage
115
a1 Adrenergic antagonists
* primary effect of a1 stimulation is constriction of vascular smooth mm
- antagonism: block endogenous NE and EPI
- fall in BP from decreased TPR
- magnitude dependent on sympathetic tone (e.g. frightened, injured, hypovolemic, etc)
116
Selective a1 adrenergic antagonists
- major effect is to relax arterial AND venous smooth mm = vasodilation
- decrease in TPR (after load)
- decrease in venous return (pre-load)
117
Selective a1 adrenergic antagonists - Prazosin
Prazosin
* used as antihypertensive and in congestive heart failure (dec pre- and after-load)
* produce less reflex tachycardia than other vasodilation agents
118
Selective a2 adrenergic agonists
Effect primarily center (CNS) and pre-synaptic inhibition
* sedation, analgesia,
* decreased sympathetic outflow from brain
* decreased NE release
119
Selective a2 adrenergic antagonists
Antagonist effect primarily relieving central (CNS) and pre-synaptic inhibition
* less sedation, analgesia
* increased sympathetic outflow from brain
* increased NE release
120
Selective a2 adrenergic antagonists - Atipamezole
used to reverse sedative and analgesic effects of (dex)medetomidine (a2 agonist)
also increases sympathetic activity --> do NOT use in patients with cardiac and respiratory dz or other conditions where excessive sympathetic stimulation is contraindicated
121
a adrenergic antagonists - summary
* a1 antagonist = vasodilation (prazosin)
* a2 antagonist = reverse a2 agonists (atipamezole reverses dexmedetomidine)
* non-selective a antagonists
- phenoxybenzamine (non-comp, irreversible)
- phentolamine (comp, reversible)
122
B adrenergic antagonists
Primary result of B1 stimulation is positive cardiac inotropic and chronotropic effects
* antagonism: block endogenous NE and EPI resulting in decreased HR and cardiac contractility
- magnitude dependent on sympathetic tone (consider exercise and stress)
123
B1 adrenergic antagonists
Cardiac
dec HR and contractility
* dec CO, dec cardiac O2 demand
* dec BP
* dec cardiac arrhythmias
124
B2 adrenergic antagonists
Primary effect of B2 stimulation is bronchodilator
antagonism:
* inc bronchoconstriction
- this is not generally a desirable effect
125
Nonselective B adrenergic antagonists
Propranolol
Prototypical B antagonist with equal affinity for B1 and B2 receptors
* dec CO (B1 blockade)
- more pronounced during exercise (inc sympathetic tone)
* anti arrhythmic action from decreased sympathetic stimulation
* limited use because of B2 blockade and availability relatively selective B1 inhibitors
126
Nonselective B adrenergic antagonists
Timolol
ocular use to decrease aqueous humor production during glaucoma
127
Carvedilol
used in vet med
* CHF
* valvular disease
Unique non-selective B antagonist
* blocks B1 (heart) and B2 receptors (not good)
* blocks a1 (vasculature) receptors
* antioxidant properties
128
Atenolol
Selective B1 adrenergic antagonist
* potentially useful in feline hypertonic cardiomyopathy (dec HR, oxygen demand, etc)
* dec HR
* counteract anticholinergic tachycardia
129
B adrenergic antagonists summary
B1 antagonists: dec HR
- propranolol (non-sel), atenolol (sel)
- dec HR, reduces cardiac oxygen demand
B2 antagonists: bronchoconstriction
- propranolol (non-sel)
- not helpful, limitation of non-self agents
130
Hypotension during anesthesia
Very common during general anesthesia
- induced by anesthetics (IV and inhalational)
* cardiovascular and central sympathetic depression
- parasympathetic reflexes
- NMJ blocker: histamine release
131
Pronounced hypotension often assoc'd with...
* Volume depletion (hypovolemia)
- e.g. injured animal
- give fluids
* cardiac insufficiency
- e.g. heart failure
132
Hypotension during anesthesia - autonomic pharmacological interventions
* increase HR (thus CO) with anticholinergic
- potential problem with cardiac insufficiency
* increase HR, contractility, and vasoconstriction with a sympathomimetic
- potential problem with cardiac insufficiency
133
Shock
* circulatory system fails to maintain adequate blood flow
***Poor delivery of oxygen and nutrients to vital organs
- hypotensive state
134
Analgesia
Lack of pain
135
Anesthesia
Lack of sensation
- anesthesia is usually accompanied by analgesia
136
Three types of shock
1. Hypovolemic: intravascular volume deficit (e.g. hemorrhage)
2. Distributive: peripheral vasodilation; septic, anaphylactic, and neurogenic shock
3. Cardiogenic: myocardial pump failure
137
Hypotensive state
Increase in sympathetic outflow --> restore BP and preserve perfusion to vital organs
138
What does an increase in sympathetic outflow (hypotensive state) do?
inc HR and contractility
Vasoconstriction --> redistributes blood to vital organs
139
Sympathomimetics
inc CO (B1 stimulation)
inc TPR (a1 stimulation)
Inc BP (MAP = CO x TPR)
140
Shock assoc'd vasoconstriction
maldistribution of blood flow
141
When there is shock assoc'd vasoconstriction, which sympathomimetics do you choose?
B1 stimulation
inc CO --> raise BP
142
Two basic types of shock?
Primarily vascular
Primarily myocardial
143
Primarily vascular shock
what drugs do we give?
e.g. hypovolemia following trauma
Strategy: promote vasoconstriction
Dopamine, NE, Epi, phenylephrine
144
Anaphylactic shock
Drug?
Allergic/hypersensitivity response
- mast cell degranulation = histamine release
- vasodilation and bronchoconstriction
EPINEPHRINE is primary therapy
- bronchodilator (B2)
145
Primarily myocardial insufficiency (shock)
drugs?
Strategy: increase CO via B1 stimulation
Dobutamine
146
Mix of myocardial insufficiency and vasodilation? Strategy? drugs?
Strategy: increase CO by stimulation B1 receptors and promote vasoconstriction via a1 (balanced)
- moderate infusion of dopamine often considered appropriate in this setting
147
Goal in treating shock?
Establish and maintain perfusion
BP does NOT equal perfusion
148
Glaucoma
Disease in which the pressure in the eye is too high
* inc in intraocular pressure
* leads to loss of vision (damage to optic n, etc)
149
Glaucoma - tx goals
Autonomic drugs:
- can be used to manage primary glaucoma
- adjunct to surgical tx for primary and secondary glaucoma
- goal is to lower intraocular pressure
150
Glaucoma - drugs
Beta antagonists (e.g. timolol)
Cholinergic agonists
- lower pressure
- opposite with anticholinergics
151
Where does cardiac electrical activity come from?
arises from diverse population of ions channels throughout heart
152
3 major ions in membrane potential:
Na, Ca, K
153
Reversal potential
Each ion with "drive" the cell membrane potential towards its own reversal potential it it is allowed to move freely in or out of the cell
154
RMP - ions
```
Na = +50
Ca = 150+
K = -90
```
155
Sodium channel - VG Na channels --> threshold for activation
-60 mV
156
Ion responsible for plateau phase
Ca channels open - Ca enters cell (imitation of contraction)
K exits the cell also
157
Ca channel - VG Ca channels --> threshold for activation
-40 mV
Inactivate slowly --> allows Ca influx to trigger contraction
158
Pacemaker (SA nodal) AP
Phase 0 depolarization is slow
- no fast opening VG Na
- only slow opening VG Ca channels
**No plateau phase (phase 2)
Phase 3
- K channel repolarization
Phase 4
- no true RMP
- continuous slow depolarization
- results from activation of "funny" current
* *slowly depolarizing inward current activated by hyperpolarization
159
Electromechanical Coupling
* Ca2+ influx via Ca channels
- trigger Ca release from internal stores (jSR)
- stimulates the opening of intracellular Ca channels called RyR
- *Ca induced Ca release (CICR)
160
Electromechanical coupling - Ca removal
pumped back into SR by Ca ATPase
shunted out of the cell by Na/Ca exchanger
161
P wave
atrial depolarization
162
QRS complex
ventricular depolarization
163
T wave
ventricular repolarization
164
Arrhythmias
Results from disorders of
Impulse formation
Conduction
or both
165
Disorders of impulse formation involve:
either a change in the normal pace make (SA node) or the development of a new ectopic pacemaker (e.g. in the ventricles)
166
Multiple potential pacemaker sites in the heart
SA node, atrial foci, AV node, ventricular foci
Dominant pacemaker will be the one with the highest frequency (normally the SA node)
167
Conduction arrhythmias
Disorders of impulse conduction can cause either bradycardia or tachycardia
brachycardia: from AV nodal block
tachycardia: from a re-entrant circuit
168
Atrial fibrillation
too much depolarization going through the AV node to the ventricles
169
Reentrant arrhythmias
Accessory pathway: supra ventricular tachycardia
170
Does complete arrhythmia suppression eliminate the risk for subsequent lethal arrhythmia?
NO! all anti arrhythmic drugs can induce arrhythmias
171
Antiarrhythmic drugs - Class 1
Na channel blockers
Class 1A: moderate conduction slowing = procainamide
* prolongs refractory period
Class 1B: little conduction slowing = lidocaine
* shortens refractory period
Class 1C: profound conduction slowing = flecainide
* little change refractory period
172
Antiarrhythmic drugs - Class 2
beta blockers
173
Antiarrhythmic drugs - Class 3
AP prolonging
174
Antiarrhythmic drugs - Class 4
Ca channel blockers
175
Class 1A: procainamide
slows conduction velocity
prolongs refractory period
Use: supraventricular tachycardia
* "break" the reentrant circuit and allow SA node to take over
176
Class 1B: lidocaine
little change in conduction velocity
shortens the refractory period
binds to inactivated Na channels
* keeps them in the inactivated state
* depolarization --> inactivation
* effect is inc in depolarized tissues
* dec automaticity in depolarized cells
Use: ventricular tachycardia
177
Class 1C: flecainide
little change in refractory period
Profound decrease in conduction velocity
Use only in life-threatening ventricular tachycardia or fibrillation and for the tx of refractory supra ventricular tachycardia
*Cast = cure is worse than the dz
178
Class 2: beta blockers
Too much sympathetic activity is arrhythmogenic = manage w/ a beta blocker
179
Congestive heart failure (CHF)
heart fails as a pump
dec CO (poor tissue perfusion)
blood does not circulate properly (congested)
180
Causes of CHF
pressure/volume overload
- pulmonary, renal, vascular dz
e. g. hypertension secondary to renal failure
myocardial damage, valvular insufficiency
- idiopathic cardiomyopathies, nutritional deficiencies, toxic, infection, neoplastic
e. g. touring def in cats
181
Two basic tx approaches for heart failure
1. reduce workload of the heart
| 2. increase performance
182
3 basic ways to inc cardiac performance (tx heart failure)
1. inc B1 adrenergic (sympathetic) stimulation
2. cardiac myocyte intracellular Ca2+
3. enhance the contractile process directly
183
Adrenergic (sympathetic) stimulation - baroreceptor reflex
Happens automatically when CO (and BP) drops during heart failure through baroreceptor reflex
184
B1 adrenergic stimulation (heart failure)
inc sympathetic tone during heart failure (hyperadrenergic state)
Limits the use of adrenergic agonists
- cardiac B1 adrenergic pathways are already stimulated
- "ceiling effect" of B1 receptor stimulation
185
B1 adrenergic stimulation (heart failure) - drugs
Dopamine and dobutamine (best)
- stimulate cardiac B1 receptors to inc CO (with less vasoconstriction)
* often last ditch effort to keep patient alive
Epi and NE not that useful: too much vasoconstriction via a1 receptor stimulation in the vasculature
186
Inc cardiac myocyte intracellular Ca
- increase Ca influx
or
- decrease Ca efflux
187
What degrades cAMP?
Phosphodiesterase 3 (found in myocardium) decreases cAMP --> decreases PKA stimulation of Ca channels
188
PDE 3 - inhibitors
PDE 3 inhibition increases cAMP levels --> increases Ca --> increases contraction
Ex: Milrinone
* mimics the effect of B1 stimulation by increasing cAMP
* *can be used along with beta blockers
189
Decrease Ca efflux
*limit Na/Ca exchanger function indirectly
Ex: digoxin
190
Cardiac glycosides: digoxin
* inhibit the Na/K ATPase
- lowers intracellular K
- increases intracellular Na
* Na/Ca exchanger
- activity is regulated SOLELY by the concentration of Na and Ca
- increase Na in the cell will dec Ca efflux through the exchanger
*Narrow therapeutic index
191
Frank-Starling law of the heart
the heart pumps what it receives
192
Enhance the contractile process directly (heart failure)
"Ca sensitizers"
Ex. Pimobendan
* inc cardiac contraction by sensitizing the contractile machinery to Ca
- related to an increased affinity of troponin C for Ca
* "positive inotropic" effect
193
Pimobendan
Enhances the contractile process directly
- approved for CHF in dogs`
194
Vasdilators
Disrupt excitation-contraction coupling in vascular smooth mm
Results in less vasoconstriction (or more vasodilation)
195
E-C coupling:
translation of smooth muscle cell electrical stimulation into contraction
vascular smooth mm contraction is ultimately regulated by levels of intracellular Ca
- inc Ca = contraction
- dec Ca = relaxation
196
3 vasoconstrictors
NE, Epi, Ang II
197
Arterial vs venous dilators
Arterial dilation = dec after load
Venous dilation = dec preload
198
Main player of RAAS - and outcome
Ang II
Water and salt retention. Effective circulation volume increases
199
ACE inhibitors
Ex. Enalapril
Competitive antagonists of ACE (prevent conversion of Ang I to Ang II)
200
Angiotensin receptor antagonists
Ex. Losartan
Competitive antagonists at AT1 receptors
- Angiontesin receptor type 1
- Blocks pro-hypertensive effects of Ang II
201
Renin inhibitors
Ex: aliskiren
Renin antagonist
Prevents conversion of angiotensinogen to Ang I
202
Effect of Ang II inhibition
* dec sympathetic NS activity
* dec vasoconstriction (inc vasodilation)
* dec tubular Na and water retention (dec aldosterone)
* dec collecting duct water absorption (dec antidiuretic hormone)
203
What is the primary mech for maintaining BP - ANS?
Baroreceptor reflex (stretch receptors in carotid a and aortic arch)
204
Alpha adrenergic antagonists - vasculature
vasodilation
205
Alpha adrenergic antagonists - Prazosin
Competitive antagonists at alpha receptors
- vasodilation
206
Ca2+ channel antagonists - vasculature
inhibit arterial smooth mm Ca2+ channels --> dec vasoconstriction (promote vasodilation)
207
Ca2+ channel antagonists - Amlodipine
Promote vasodilation
208
Nitric oxide - GC - cGMP - PKG
PKG --> promotes smooth m relaxation
209
Exogenous NO donors
Nitroglycerin
Sodium Nitroprusside
Promote smooth mm relaxation - vasodilation
210
Exogenous NO donors - Nitroglycerine
- venous dilation
- dec preload
- Uses:
* acute carcinogenic pulmonary edema
* CHF
Problem: tolerance develops over time
211
Exogenous NO donors - Nitroprusside
Arterial and venous dilation!
- dec preload (CO)
- dec after load (TPR)
- profound dec in BP
Uses:
- hypertensive emergencies, acute CHF
(light sensitive)
212
Inhibition of PDE-5
enzyme that converts cGMP to 5'GMP
Inhibition = increased levels of cGMP --> inc PKG ==> VASODILATION
213
Inhibition of PDE-5 - drugs
Sildenafil
214
K+ channel activators
- inc K conductance hyperpolarizes the smooth m cell membrane-
- hyper polarization dec the opening of Ca channels
- Promotes vasodilation
