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II. General organization: Almost all efferents leaving the CNS are cholinergic.
Figure 1.
Somatic
Various
levels of
spinal
chord
ACh
Skeletal
muscle
Parasympathetic
Varicosity
Craniosacral
spinal
chord
Pre
ACh
Post
Smooth muscle
Heart
Glands
Sympathetic
Thoracolumbar
spinal
chord
ACh
Pre
ACh
Post
NE
Smooth muscle
Heart
Glands
Kidney (DA)
ACh
Adrenal
medulla
Epi and NE
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Figure 2.
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D. Purinoceptors: mediate the actions of ATP (P2X and P2Y) and adenosine (A1
A3)
E. Peptide receptors: mediate the actions of VIP, NPY, etc.; neurokinin receptors
F. Autoreceptors (prejunctional)
1. Many of the transmitters, co-transmitters and neuromodulators feed back onto
the nerve ending from which they are released and decrease or increase
transmitter release.
G. Heteroreceptors (prejunctional)
1. Receptors for non-transmitter substances that regulate neurotransmission.
H. NO: no receptors are involved in signalling
1. NO activates guanylate cyclase.
2. It can interact with free radicals and nitrosylate proteins.
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Noradrenergic nerves/
Sympathetic activity
Cholinergic nerves/
Parasympathetic activity
Iris/pupil
Airways
Dilate (Epi)
Constrict
Intestine (enteric
nervous system)
Blood vessels
Vasoconstriction
Bladder
Contracts sphincter
Relaxes detrusor
Contract detrusor
Relaxes sphincter
Heart rate
Increase
Decrease
Myocardial
contractility
Increase
Sex organs
Ejaculation
Erection
Liver
Gluconeogenesis
Glycogenolysis
Nerve terminals
Decrease NE release
Gall bladder
smooth muscle
Relaxation
Contraction
Salivary glands
Secretion*
Secretion*
Uterus (pregnant)
*Similar effects
Contracts*
Contracts*
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ANS EYES
Postganglionic
sympathetic neuron
Dilator
(radial smooth muscle)
(noradrenergic)
(adrenoceptors)
Sphincter
(circular smooth muscle)
Postganglionic
parasympathetic neuron
Pupil
(cholinergic)
(muscarinic receptors)
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Ach receptors
- nicotinic agonists (nicotine)
- nicotinic antagonists (succinylcholine & atracurium) @
skeletal muscle
- muscarinic agonists (bethanechol)
- muscarinic antagonists (atropine, scopolamine, tiatropium &
darifenacin)
bold = generic drug names for exam
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NE = nor-adrenergic
ACh = cholinergic
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Ach receptors
- nicotinic agonists (nicotine)
- nicotinic antagonists (succinylcholine &
atracurium)
- muscarinic agonists (bethanechol)
- muscarinic antagonists (atropine,
scopolamine & darifenacin)
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ACh release
ACh:
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Step 1
Step 2
(CH 3 )3 N+ CH 2CH 2 OH +
OH
Step 3
O
CCH 3
OH2
O
CH 3 COH
OH
AChE consists of two sites: (1) an anionic site that attracts the positively-charged quaternary ammonium
group of ACh and (2) an esteratic site where the ester linkage is hydrolyzed.
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Alzheimers Disease
myasthenia gravis
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** skeletal muscle:
- modest AChE inhibition excitation and fibrillation
- excessive AChE inhibition leads to depolarization block &
flaccid paralysis
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skeletal muscles: loss of synchrony of
transmission, fasciculations, paralysis
(including diaphragm) by depolarizing block
cause of death
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occupation (not
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Nicotine
well absorbed from oral cavity (chewing tobacco) &
lungs (smoking)
CNS:
- stimulatory with activation of pleasure/reward
(dopamine)
- increased respiration (lethal effects via respiration)
- nausea/vomiting (chemo-receptor trigger zone
& vagal afferents)
CVS:
- increased HR & BP (sympathetic ganglia & adrenal
medulla)
GI:
- increased motility with N/V/D (parasympathetic activation)
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Cholinergic pharmacology
Succinylcholine:
- dimer of ACh
-more stable interaction with receptor (high affinity
& resistant to AChE)
- generates Phase I & possibly Phase II blocks
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Phase II:
With multiple or high doses may progress to re-polarization with
characteristics of receptor sensitivity
(diagnosed in OR with nerve stimulation)
Duration of recovery from 12-30 min
Patients with myasthenia gravis more resistant to succinylcholine &
may progress directly to Phase II with single dose
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Succinylcholine
Other side effects
Cardiovascular (hyperkalemia or ganglionic effects can result in &
bradycardia or arrythmia children more susceptible)
Muscle pain
Increase intraocular pressure
Increase intragastric pressure
Increase intracranial pressure
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Cholinergic Pharmacology
Acetylcholine (Ach) release (botulism toxin)
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ACh
PLC PI
M1, M3, M5
Gq
Ca ++
IP3
DAG
PKC
ACh
A-C
M2, M4
Gi
Gbg
K+
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No cholinergic innervation to
arterioles
However, functional mucarinic
receptors on endothelium
Administration of ACh causes
dilation
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From Furchgott et al
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M3
Core knowledge:
Drugs affecting endogenous cholinergic tone have potential effects on
systems (parasympathetic) below. No effect on vascular resistance.
Cholinergic agonists effect systems (parasympathetic) below and, in
addition, vascular resistance.
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Methacholine
Carbachol
Structure
O
(CH3)3N+CH2CH2OCCH3
(CH3)3N+CH2CHOCCH 3
CH3
Bethanechol*
O
O
(CH3)3N+CH2CH2OCNH2
(CH 3 )3 N+ CH 2CHOCNH 2
CH 3
Degraded by both
cholinesterases
very rapidly
slowly
no
no
Nicotinic Agonist
++
+++
Muscarinic Agonist:
Cardiovascular
Gastrointestinal
Urinary bladder
Eye (topical)
++
++
++
+
++
++
++
+
+
+++
+++
++
+
+++
+++
++
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Bethanechol:
most commonly used muscarinic agonist
resistant to AChE
following oral or s.c., affects primarily GI & urinary tract
durations ~ 1 hr
the metabolic fate & mode of elimination of bethanechol
has net been elucidated
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Skin:
Urinary Tract:
Eye:
iris: contraction of the pupillary muscle constricts the size of the pupil (miosis).
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Site
Predominant Tone
arterioles
sympathetic (adrenergic)
veins
sympathetic (adrenergic)
parasympathetic (cholinergic)
tachycardia
iris
parasympathetic (cholinergic)
mydriasis
ciliary muscle
parasympathetic (cholinergic)
cycloplegia
GI tract
parasympathetic (cholinergic)
urinary bladder
parasympathetic (cholinergic)
urinary retention
salivary glands
parasympathetic (cholinergic)
dry mouth
sweat glands
sympathetic (cholinergic)
decreased sweating
high doses of atropine can enter the CNS & initially cause excitation
(restlessness, hallucinations, delirium), then progress to depression
(cardiac, respiration, coma, death)
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Figure 2.
VMAT
VMAT = vesicular monoamine
transporter
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HO
NH 2
HO
Figure 3.
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Figure 4.
VAMPS
SNAPS
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Figure 5.
VMAT
NET
NET = norepinephrine
transporter
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OH
HO
COMT
HO
OCH 3
O
N
H
CH3
MAO
OH
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OH
OH
HO
HO
OH
N
H
CH 3
OH
Nore pinephrine
Epine phrine
COMT
HO
MAO
OCH 3
OH
COMT
MAO
OH
OCH 3
HO
N
H
Meta nephrine
NH 2
HO
CH 3
OH
OH
OH
3,4 D ihydroxym andelic Ac id
COMT
MAO
NH 2
Norm etanephrine
MAO
HO
OCH 3
O
OH
OH
Vanillylma ndelic Ac id
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Figure 9.
HO
HO
NH 2
Dopamine
COMT
MAO
OH
HO
OCH 3
HO
NH 2
OH
Dihydroxyphenylacetic Acid
COMT
HO
3-Methoxytyramine
MAO
OCH 3
O
OH
Homovanillic Acid
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Step
Effect
Mechanism
Synthesis
Depletion of NE
Methyldopa
Synthesis
Depletion of NE
Cocaine, tricyclic
antidepressants
Termination
Potentiates NE
Blocks NET
Reserpine
Storage
Depletes NE (and
dopamine)
Bretylium, guanethidine
Release
Inhibits NE release
Tyramine, amphetamine
Release
Causes NE release
Indirect-acting
MAO inhibitors
(phenylzine)
Termination
Enzyme inhibitor
COMT inhibitors
(Tolcapone)
Termination
Slight (affects
circulating CAs)
Enzyme inhibitor
- and -Adrenoceptor
agonists
Receptor
- and -Adrenoceptor
antagonists
Receptor
Receptor blockade
Termination
Potentiate Epi
-Methyltyrosine
Glucocorticoids
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Figure 10.
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Figure 11.
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Figure 12.
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Figure 13.
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Figure 14.
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Figure 15.
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Step
Effect
Mechanism
Synthesis
Depletion of NE
Methyldopa
Synthesis
Depletion of NE
Cocaine, tricyclic
antidepressants
Termination
Potentiates NE
Blocks NET
Reserpine
Storage
Bretylium, guanethidine
Release
Inhibits NE release
Tyramine, amphetamine
Release
Causes NE release
Indirect-acting
MAO inhibitors
(Phenylzine)
Termination
Enzyme inhibitor
COMT inhibitors
(Talcapone)
Termination
Slight (affects
circulating CAs)
Enzyme inhibitor
- and -Adrenoceptor
agonists
Receptor
- and -Adrenoceptor
antagonists
Receptor
Receptor blockade
Termination
Potentiate Epi
-Methyltyrosine
Glucocorticoids
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Pharmacology of Adrenoceptors
I. Adrenoceptors
A. Receptors which are activated by sympathomimetic amines and catecholamines
1. Sympathomimetic amines (endogenous)
a. Epinephrine (Epi)
b. Norepinephrine (NE)
c. Dopamine (DA)
2. Catecholamines
a. Chemical designation
b. Compounds containing a catechol moiety
B. Adrenoceptors are large, 7-transmembrane spanning receptors
1. G-protein coupled receptors (GPCR)
a. Interact with endogenous agonists: Epi, NE and DA
2. Adrenoceptor agonist drugs mimic the actions of these substances on their
receptors
3. Antagonist drugs block the actions of the endogenous agonists
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Smooth
muscle
Arrhythmias
Endocrine
Eye
Nerve
endings
some
2
2
Uterus:
Contraction
Relaxation
Urinary bladder: Contraction of sphincter
Relaxation of detrusor
Metabolic
1,
2
1
2
Contraction of ureter
Contraction of spleen
Pilomotor erection
Lipolysis: Activation
Inhibition
Pancreas
(and ATP)
3.
4.
5.
6.
Intraocular pressure :
2
2
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2,
, and D2
Figure 1.
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Vascular bed
Skin
1,
Splanchnic
1,
2,
Skeletal
1,
2,
Renal, coronary,
cerebral
D1
some
2
Iso
DA
Constriction
Constriction
None
Constriction
Constriction
Weak dilation -
Dilation*
Constriction
Dilation
Dilation
*Dose-dependent
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IV.
BP = CO X TPR
Cardiac
output
Heart
rate
Stroke
volume
Total
peripheral
resistance
Arteriolar
radius
Blood
Viscosity
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Norepinephrine (an
Phenylephrine (PE; an
Isoproterenol (a
1,
and
agonist)
agonist)
agonist)
Epinephrine (an
agonist)
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Norepinephrine
Isoproterenol
Epinephrine
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Skin
Visceral Skeletal
Blood Pressure
Heart
TPR
Diastol
Systol
HR
Str. Vol.
CO
Iso
0,,
NE
0, ,
Epi
PE
0,,
0,,
*Dose-dependent
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Figure 6.
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Figure 7.
B.
1-Adrenoceptors
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C.
2-Adrenoceptors
Figure 8.
Cell inhibition
Cell activation
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TPR
TPR
Vasoconstriction
NE
Re le ase
1
M ydriasis
Adrenoceptors
1
Cardiac Effe cts
GI
M otility
Vasoconstriction
Inhibition
of
Lipolysis
3
2
Lipolysis
Vasodilation
TPR
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Smooth
muscle
Metabolic
Endocrine
Eye
Primary receptor
1
1
1
1
1,
some
2
2
2
1
1
2
1
2
1
(and ATP)
1
1
1
1
2
2
1
2
3
2
2
1
2
2
2
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II.
Selectivity
Phentolamine
High
High
Very low
Very low
Phenoxybenzamine
High
High
Very low
Very low
Prazosin
High
Low
Very low
Very low
Yohimbine
Moderate
High
Very low
Very low
Propranolol
Very low
Very low
High
High
Metoprolol
Very low
Very low
High
Moderate
Butoxamine*
Very low
Very low
Moderate
High
High
Low
High
Moderate
Labetalol
* no real clinical role
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Antagonism
Duration of
action
Selectivity
>
Other actions
Hemodynamic
effects
1. TPR and BP
2. Venodilation
3. Cardiac stimulation:
a. Baroreceptor reflex:
increase in HR and
contractility
b. Increase in NE
release
Adverse
reactions
1. Orthostatic
hypotension
2. Tachycardia
a. BR reflex
b. 2 block: NE rel.
3. Miosis
4. Nasal stuffiness
a. 1 on veins
5. Inhibited ejaculation
1. Pheochromocytoma
2. Peripheral vascular
disease (Reynauds)
Indications
>>>
III.
-Adrenoceptor antagonists
1. Same as phenoxybenzamine
1. Mild to moderate
hypertension
2. BPH: urine flow in
urethra
*Names end in osin. Quinazolines in red font are non-selective at all 1-adrenoceptors.
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A. Tamsulosin (Flomax)
1. Newer drug for BPH
a. Selective for 1A-receptors in prostate smooth muscle
b. 1B- and 1D-receptors are important in vascular smooth muscle; therefore,
this drug is more tissue-specific
2. Inhibits contraction of the urinary bladder base and prostate smooth muscle
3. Smaller incidence of vascular side effects, i.e., hypotension
4. Ineffective is pathological changes in prostate have occurred
B. Yohimbine
1. For male impotence; doubtful efficacy
2. Blocks central 2-adrenoceptors and increases NE release in noradrenergic
nuclei
3. Results in an increase in blood flow in the penis
4. Its effects are opposite those of clonidine, the 2-adrenoceptor agonist
a. Increases blood pressure and heart rate
b. Blockade of prejunctional 2-adrenoceptors
5. There are few other examples of a need to block 2-adrenoceptors in therapy
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V.
Normal
Adrenergic
neuron
2
NE
-receptor
1-receptor
NE
Phentolamine Blockade
2 PH
NE
PH
NE
-receptor
-receptor
Tachycardia
Prazosin Blockade
PR
2
NE
NE
-receptor
-receptor
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160
200
Blood
pressure
135/85
128/50
Phentolamine
Heart Rate
180
210
Blood
pressure
135/90
190/124
160/82
175/110
190
210
Blood
pressure
125/85
100/35
Epinephrine after phentolamine
Adapted from Hoffman, B.B. in Katzung, Basic and Clinical Pharmacology, p.140.
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TPR
TPR
Vasoconstriction
NE
Release
1
Mydriasis
Adrenoceptors
1
Cardiac Effects
GI
Motility
Vasoconstriction
Inhibition
of
Lipolysis
3
2
Lipolysis
Vasodilation
TPR
A. The pharmacological effects of the - and -adrenoceptor antagonists can be
explained largely from knowledge of the responses elicited by - and -adrenoceptors
in the different tissues and the effects of stimulation of the adrenergic nerves
innervating those tissues.
B. The effects of receptor activation in the various tissues is reviewed next.
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Smooth
muscle
Arrhythmias
Contraction
Relaxation
Urinary bladder:
Contraction of sphincter
Relaxation of detrusor
Metabolic
Endocrine
Nerve
endings
2
2
1
1
2
1
2
1
Contraction of ureter
Contraction of spleen
Pilomotor erection
Lipolysis: Activation
Inhibition
Pancreas:
(and ATP)
Intraocular pressure:
some
Renin release:
Eye
1,
2
1
2
2
2
2
2
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Phentolamine
High
High
Very low
Very low
Phenoxybenzamine
High
High
Very low
Very low
Prazosin
High
Low
Very low
Very low
Yohimbine
Moderate
High
Very low
Very low
Propranolol
Very low
Very low
High
High
Metoprolol
Very low
Very low
High
Moderate
Butoxamine*
Very low
Very low
Moderate
High
High
Low
High
Moderate
Labetalol
Selectivity
,
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OH
HO
OH
CH3
H
N
CH3
H
B. Propranolol (Inderal)
1. Bulk on the amine favors -receptors
2. 3-Carbon chain on the amine favors antagonist properties
3. Note the presence of the ester linkage in propranolol and some -blockers
3. Neutral antagonist
4. Stabilizes cardiac membranes in high doses
Figure 3.
O
OH
CH 3
H
N
CH 3
H
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C. Nadolol (Corgard)
1. Long-acting
2. Inverse agonist activity
3. Indications: hypertension and myocardial ischemia(angina)
Figure 4.
O
HO
OH
H
CH 3
CH 3
N
CH 3
H
OH
D. Pindolol (Viskin)
1. Slight positive agonist activity
2. Indications: hypertension and myocardial ischemia
Figure 5.
HN
O
OH
CH 3
H
N
CH 3
H
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E. Timolol (Blocadren)
1. Primary use: open-angle glaucoma
2. Receptor selectivity here is unknown
Figure 6.
CH 3
CH 3
N
CH 3
H
S N
N
O
N
OH
O
F. Labetalol (Normodyne): third generation
1. Racemic formulation
a. SR isomer: 1-blocker
b. RR isomer: 1 + 2 blocker
2. Some 2-agonist activity
3. Selectivity for
is 3:1
4. End result: TPR and vasodilation
a. Hypotension caused by -receptor blockade causes less reflex tachycardia than
other -receptors by themselves
5. Indication: hypertension
Figure 7.
HO
CH 3
H2 N
O
OH
N
H
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V.
1-Adrenoceptor-selective
O
OH
CH 3
H
N
CH 3
H
B. Acebutolol (Sectral)
1. Indication: Hypertension
Figure 9.
H
N
O
O
H3 COC
OH
CH 3
H
N
CH 3
H
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C. Esmolol (Brevibloc)
1. Fast-acting
2. Short duration: metabolized by esterases
3. Allows fine control of effects
4. Used in urgent settings where rapid -blockade is needed
Figure 10.
O
CH3O
O
OH
CH3
H
N
CH3
H
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None
None
Yes
(High doses)
Metoprolol
1
Inverse
Slight
Labetalol
Pindolol
None
None
Slight
Slight
Slight
Slight
-Adrenoceptor antagonists that are partial agonists may cause a lesser decrease in heart
rate and blood pressure than those which are not partial agonists.
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VII. Major
Effects of
1-receptor
antagonism*
Cardiovascular system
Heart
Effects of
2-receptor
antagonism*
Cardiovascular
Vasoconstriction in skeletal beds
Electrophysiological changes
HR
Slowed A-V conduction
Phase 4 depolarization
Contractility changes
Stroke volume
Residual volume
Pulmonary
Bronchoconstriction
Metabolic
Glycogenolysis
Recognition of hypoglycemia
Endocrine
Insulin release
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