ANS-Pharmacology Adrenergic Drugs
ANS-Pharmacology Adrenergic Drugs
ANS-Pharmacology Adrenergic Drugs
Clinical Correlate:
e-Medicine Article
Epilepsy and the Autonomic
Nervous System
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2
Introduction
Introduction cont.
Introduction (2)
Physiological effects caused by sympathomimetics are
due not only to direct effects, but also to indirect or
reflex effects.
Alpha receptor agonist causes an increase in blood
pressure.
Carotid/aortic baroreceptors activations initiates a
compensatory reflex.
Sympathetic tone is reduced (decreases heart rate)
Parasympathetic tone is increased (decreases heart
rate)
RESULTS: Blood pressure tends to return to lower levels
Categories of Action
Adrenergics
Metabolic Effects
Regulation/modulation of insulin,
pituitary, and renin secretion
Central Nervous System Effects
Respiratory stimulation
CNS stimulation
Appetite attenuation
Presynaptic Effects
Presynaptic effects: modulation
of release of norepinephrine or
acetylcholine
Epinephrine
Epinephrine and
Blood Pressure
Potent vasopressor
Systolic pressure increases to a greater extent than
diastolic (diastolic pressure may decrease)
Epinephrine and
Blood Pressure (2)
If epinphrine is administered
relatively rapidly, the
elevation of systolic pressure
is likely to activate the
baroreceptor system resulting
in a reflex-mediated decrease
in heart rate.
Epinephrine and
Blood Pressure (3)
Epinephrine and
Blood Pressure (4)
Epinephrine and
Blood Pressure (5)
Adrenergic
Sino-atrial (SA)
Node
Atrial muscle
Atrio-ventricular
(AV) node
His-Purkinje
System
Ventricles
Cholinergic
decreased rate
(vagal)
beta1; beta2
increased rate
beta1; beta 2
increased:
contractility,
conduction velocity
decreased:
contractility, action
potential duration
beta1; beta 2
increased:
automaticity,
conduction velocity
decreased
conduction velocity;
AV block
beta1; beta 2
increased:
automaticity,
conduction velocity
------
beta1; beta 2
increased:
contractility,
conduction velocity,
automaticity, ectopic
pacemaker
small decrease in
contractility
12
Epinephrine and
Blood Pressure (6) Summary
Blood Pressure
Blood Pressure Effects
Epinephrine
Norepinephrine
Systolic
Mean Pressure
Diastolic
variable
Mean Pulmonary
0.1-0.4 ug/kg/min infusion rate
Epinephrine-Vascular Effects
Direct Responses to
Epinephrine
increased contractility
increased rate of isometric
tension development
increased rate of relaxation
increased slope of phase-4
depolarization
increased automaticity
(predisposes to ectopic foci
16
Epinephrine- Pulmonary
Effects
Epinephrine is a significant respiratory tract bronchodilator
Bronchodilation is caused by 2-receptor activation mediated smooth
muscle relaxation
This action can antagonize other agents that promote
bronchoconstriction
2-receptor activation also decreases mast cell secretion and this decrease
may be beneficial is management of asthma also
Pulmonary
Adrenergic
Tracheal and
bronchial
muscle
Bronchial
glands
Effects
Cholinergic
beta 2
Relaxation
contraction
alpha1, beta2
decrease
secretion;
increased
secretion
stimulation
19
Epinephrine- Metabolic
Effects
Insulin secretion: inhibited by 2 adrenergic receptor activation (dominant)
Insulin secretion: enhanced by 2 adrenergic receptor activation
Pancreas
Adrenergic Effects
Cholinergic
Acini
alpha
decreased
secretion
secretion
alpha2
decreased
secretion
---------
beta2
increased
secretion
---------
Epinephrine- Metabolic
Effects (2)
Liver
Adrenergic
Liver
alpha1; beta2
Effects
Cholinergic
glycogenolysis
and
----------gluconeogenesis
21
Epinephrine- Metabolic
Effects (3)
Adipose Tissue
Adrenergic
Fat Cells
alpha2; beta3
lipolysis
(thermogenesis)
Cholinergic
---------
22
Epinephrine- Metabolic
Effects (4)
Electrolytes
Epinephrine may activate
Na+-K+ skeletal muscle
pumps leading to K+
transport into cells
Stress-induced
epinephrine release may
be responsible for
relatively lower serum K+
levels preoperatively
compared postoperatively
Mechanistic basis:
"Preoperative hypokalemia"
can be prevented by nonselective
beta-adrenergic receptor
antagonists (but not by cardioselective 1 antagonists)
Possible "preoperative
hypokalemia" may be associated
with preoperative anxiety that
promotes epinephrine release-therapeutic decisions based on
pre-induction serum potassium
levels to take into account this
possible explanation
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Norepinephrine
Potent vasopressor
Systolic and diastolic pressure increase
Epinephrine
Norepinephrine
Systolic
Mean Pressure
Diastolic
variable
Mean Pulmonary
Adaptation of Table 10-2 from: Hoffman, B.B and Lefkowitz, R.J, Catecholamines, Sympathomimetic Drugs,
and Adrenergic Receptor Antagonists, In, Goodman and Gillman's The Pharmacological Basis of
Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGrawHill Companies, Inc.,1996, pp.199-242
26
NE-Arterioles Effects
Arterioles
Adrenergic
Cholinergic
Coronary
alpha1,2; beta 2
constriction;
dilatation
constriction
Skin/Mucosa
alpha1,2
constriction
dilatation
Skeletal Muscle
alpha; beta2
constriction,dilatation
dilatation
Cerebral
alpha1
slight constriction
dilatation
Pulmonary
alpha1 , beta2
constriction;
dilatation
dilatation
Abdominal viscera
alpha1, beta2
constriction;
dilatation
-------
Salivary glands
alpha1,2
constriction
dilatation
Renal
alpha1,2;beta1,2
constriction;dilatation
---------
Based on Table 6-1: Lefkowitz, R.J, Hoffman, B.B and Taylor, P. Neurotransmission: The Autonomic and Somatic Motor
Nervous Systems, In, Goodman and Gillman's The Pharmacological Basis of Therapeutics,( Hardman, J.G, Limbird, L.E,
Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.110-111.
27
NE-Vascular Effects
N.B.
Pressor effects of NE (Levophed) are blocked by alpha-receptor blockers
ECG changes following NE (Levophed) are variable, depending on extent
of reflex vagal effects
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Epinephrine
Norepinephrine
Total Peripheral
Resistance
Cerebral Blood Flow
no effect or decrease
no effect or decrease
no effect or increase
increase,
decrease
0.1-0.4 ug/kg/min IV infusion
29
Dopamine
Cardiovascular Effects (Dopamine)
Vasodilator:
Positive inotropism:
Vasopressor:
At high doses dopamine (Intropin) causes vasoconstriction by
activating 1 adrenergic receptors
30
myocardial contractility
despite low cardiac output
sodium excretion
inadequate renal perfusion
31
32
33
Dopexamine
34
Isoproterenol (Isuprel)
36
palpitations
tachycardia
arrhythmias
coronary insufficiency
37
Dobutamine (Dobutrex)
Structurally similar to
dopamine (Intropin).
Pharmacological effects
exerted through
interaction with and
adrenergic receptor
interactions
no effect on release
no action through
dopamine receptors
38
Ventricular ectopy
Increased ventricular
following rate in patient with
atrial fibrillation.
Dobutamine (Dobutrex):
Therapeutic Use
Short-term management of
pump failure following
surgery, during acute
congestive heart failure, or
post-myocardial infarction.
39
2 Selective Adrenergic
Agonists
Metaproterenol (Alupent)
Terbutaline (Brethine)
Albuterol (Ventolin,Proventil)
Ritodrine (Yutopar)
40
Metaproterenol (Alupent)
Terbutaline [Brethine]
2 adrenergic receptor-selective:
resistant to COMT
Albuterol [Ventolin]
2 adrenergic receptor-selective
Effective following inhalation or oral
administration
Commonly used in chronic and acute
asthma management
43
Ritodrine (Yutopar)
2 adrenergic receptor-selective:
developed as a uterine relaxant
May be administered by i.v. in certain patients
for arresting premature labor; if successful,
oral therapy may be started
2 adrenergic receptor-selective agonists may
not improve perinatal mortality and may
increase maternal morbidity
In women being treated for premature labor,
ritodrine (Yutopar) or terbutaline (Brethine)
may cause pulmonary edema
44
Adverse Effects-B2
Agonists
45
Alpha1 Selective
Adrenergic Agonists
Direct Acting
Phenylephrine (Neo-Synephrine) and
methoxamine (Vasoxyl) are directacting vasoconstrictors
Mixed Acting
Mephentermine (Wyamine) and
metaraminol (Aramine) act both by
direct receptor activation and by promoting
epinephrine release
47
Methoxamine (Vasoxyl)
specific alpha1 receptor agonist
hypotensive states
termination (by vagal reflex) of paroxysmal atrial
tachycardia (adenosine may be preferable)
48
Phenylephrine (Neo-Synephrine)
Specific alpha1 receptor agonist
Increases peripheral resistance
Causes an increase in blood pressure that
precipitates sinus bradycardia (decreased heart rate)
due to vagal reflex.
Reflex bradycardia may be block by atropine
(muscarinic antagonist)
Clinical use:
hypotensive states
mydriatic
nasal decongestant
49
50
Clonidine (Catapres)(2)
Adverse Effects:
dry mouth
sedation
sexual dysfuction
Clonidine's a2 selective adrenergic receptor
activation of vascular smooth muscle may
increase blood pressure in patients with severe
autonomic dysfunction with profound
orthostatic hypotension (in these patients the
reduction of central sympathetic outflow in not
clinically important)
52
dry mouth
sedation
53
respiratory center
mood elevation
decreased perception of fatigue
Appetite suppression
Weight loss due to decrease food intake
psychological tolerance/dependence
54
Amphetamine (3)
Therapeutic Use:
Narcolepsy
Obesity
Attention-deficit hyperactivity disorder
56
Methylphenidate (Ritalin)
Narcolepsy
Ephedrine
and adrenergic receptor agonist
Indirect sympathomimetic also, promoting
norepinephrine release
non-catechol structure, orally active
Pharmacological effects:
increases heart rate, cardiac output
usually increases blood pressure
may cause urinary hesitancy due to stimulation of a
smooth muscle receptors in bladder base.
bronchodilation: adrenergic receptor response
58
Ephedrine(2)
59
Receptors
Epinephrine
alpha1, alpha2 1, 2
Norepinephrine (Levophed)
alpha1, alpha2, 1
Isoproterenol (Isuprel)
1, 2
Dobutamine (Dobutrex)
1 (alpha1)
Dopamine (Intropin)
60
Receptor Selectivity
Phenylephrine (Neo-Synephrine)
alpha1
Methoxamine (Vasoxyl)
alpha1
Oxymetazoline (Afrin)
alpha1, alpha2
Clonidine (Catapres)
alpha2
Ritodrine (Yutopar)
Terbutaline (Brethine)
Albuterol (Ventolin,Proventil)
Salmeterol (Serevent)
2
61
Ephedrine,
Pseudoephedrine
Cocaine
Tyramine
Amphetamine
Prazosin (Minipress)
alpha1
Terazosin (Hytrin)
alpha1
Trimazosin
alpha1
Doxazosin (Cardura)
alpha1
Phentolamine (Regitine)
non-selective
Phenoxybenzamine (Dibenzyline)
Tolazoline (Priscoline)
non-selective
Yohimbine (Yocon)
alpha2
63
Propranolol (Inderal)
non-selective
Metoprolol (Lopressor)
Esmolol (Brevibloc)
Atenolol (Tenormin)
Nadolol (Corgard)
non-selective
Timolol (Blocadren)
non-selective
Pindolol (Visken)
Heart
Rate
Acceleration (ex)
Slowing (in)
Contractility
Increased (ex)
Decreased (in)
Constriction (ex)
Skeletal muscle
Dilation (ex)
Salivary
Lacrimal
Secretion (ex)
Sweat
Secretion (ex)
Relaxation (in)
Contraction (ex)
Relaxation (in)
Contraction (ex)
Contraction (ex)
Relaxation (in)
Fundus
Relaxation (in)
Contraction (ex)
Trigone; sphincter
Contraction (ex)
Relaxation (in)
Penis
Ejaculation (ex)
Erection (in)
Uterus
Relaxation (in)
Gluconeogenesis (ex)
Glycogenolysis (ex)
Kidney
Renin secretion(ex)
Fat Cells
Lipolysis (ex)
Arterioles
Glands
Bronchial muscle
GI tract
Muscle wall
Sphincters
Urinary bladder
Metabolism
Liver
65