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Autonomic Pharmacology
Adrenergic Drugs (*Agonist)
Prepared and Presented by:
Marc Imhotep Cray, M.D.
BMS/CK Teacher
*Adrenergic antagonist are covered in the Antihypertensive Agents Presentation
2
*Suggested Review Books & Resources
*e-Books & learning tools available to enrolled learners at thePOINT
If you are using a different review book, the chapters may be organized
differently, but the material covered is approximately the same.
Simply find the corresponding material in your book for each lecture.
Companion Notes:
ANS Summary Notes
Formative Assessment
Clinical Correlate:
e-Medicine Article
Epilepsy and the Autonomic
Nervous System
 Review Test for
Autonomic Nervous
System answers and
explanations
 Review Test for
Autonomic Nervous
System
3
Introduction
 Distribution of adrenergic receptor subtypes
and adrenergic receptor number are important
factors in organ or cellular responses to
adrenergic input
 Adrenergic receptor type in bronchiolar
smooth muscle is principally ß2: epinephrine and
isoproterenol might be expected to be
effective bronchodilators because of their activity
at ß2 receptors
 Norepinephrine is unlikely to have this same effect
due to its relative lack of activity at ß2 sites
4
Introduction cont.
 Alpha receptor dominate in the cutaneous
vascular beds
 Norepinephrine and epinephrine cause constriction
 Isoproterenol with limited activity at alpha
receptors has little effect
 Both alpha and beta adrenergic receptor are
present in skeletal muscle vascular beds
 Alpha receptor activation causes vasoconstriction
 Beta receptor activation promotes vasodilatation
 Since ß2 receptors are activated at lower,
physiological concentrations, vasodilation results
5
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
6
Categories of Action
Adrenergics
 Smooth Muscle Effects
 Smooth muscle activation,
including activation of blood
vessel vasculature (skin, kidney).
 Activation of glands (salivary and
sweat).
 Smooth muscle inhibition,
including inhibition of smooth
muscle of the gut, bronchioles,
and skeletal muscle vascular
smooth muscle.
 Cardiac Effects
 increased heart rate (positive
chronotropic effect)
 increased contractility (positive
inotropic effect)
 Metabolic Effects
 increase in rate of muscle and
liver glycogenolysis
 increase in free-fatty acid release
from fat
 Endocrine
 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
7
Epinephrine
 Epinephrine is a potent activator of alpha and ß
adrenergic receptors
 Prominent Cardiovascular Effects
8
Epinephrine and
Blood Pressure
 Potent vasopressor
 Systolic pressure increases to a greater extent than
diastolic (diastolic pressure may decrease)
 pulse pressure widens
 Epinephrine increases blood pressure by:
 enhancing cardiac contractility (positive inotropic effect): ß1-
receptor effects
 increasing heart rate (positive chronotropic effect): ß1-receptor
effects.
 vasoconstriction a1 receptor effects
 precapillary resistance vessels of the skin, kidney, and
mucosa
 veins
9
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.
10
Epinephrine and
Blood Pressure (3)
 A principal mechanism for
arterial blood pressure control
is the baroreceptor reflex.
 The reflex is initiated by activation
of stretch receptors located in the
wall of most large arteries of the
chest and neck
 A high density of baroreceptors is
found in the wall of each internal
carotid artery (just above the
carotid bifurcation i.e. carotid
sinus) and in the wall of the aortic
arch
11
Epinephrine and
Blood Pressure (4)
 As pressure rises and especially for rapid increases in
pressure:
 baroreceptor input to the tractus solitarius of
the medulla results in inhibition of the
vasoconstrictor center and excitation of the vagal
(cholinergic) centers resulting in
 a vasodilatation of the veins and arterioles in the
peripheral vascular beds.
 negative chronotropic and inotropic effects on the
heart. (slower heart rate with reduced force of
contraction)
12
Epinephrine and
Blood Pressure (5)
Adrenergic Cholinergic
Sino-atrial (SA)
Node
beta1; beta2 increased rate
decreased rate
(vagal)
Atrial muscle beta1; beta 2
increased:
contractility,
conduction velocity
decreased:
contractility, action
potential duration
Atrio-ventricular
(AV) node
beta1; beta 2
increased:
automaticity,
conduction velocity
decreased
conduction velocity;
AV block
His-Purkinje
System
beta1; beta 2
increased:
automaticity,
conduction velocity
------
Ventricles beta1; beta 2
increased:
contractility,
conduction velocity,
automaticity, ectopic
pacemaker
small decrease in
contractility
13
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
At lower epinephrine doses:
a lessened effect on systolic pressure occurs
diastolic pressures may decrease as peripheral resistance
is reduced.
Peripheral resistance decreased due to ß2-receptor effects
14
Epinephrine-Vascular Effects
 Epinephrine has significant effects on smaller
arteriolar and precapilliary smooth muscle
 Acting through alpha1 receptors, vasoconstrictor effects
decrease blood flow through skin and kidney
 Even at doses of epinephrine that do not affect mean
blood pressure, substantially increases renal vascular
resistance and reduces blood flow (40%)
 Renin release increases due to epinephrine effects
mediated by ß2-receptors associated with juxtaglomerular
cells
15
 Acting through ß2-receptors, epinephrine causes
significant vasodilatation which increases blood
flow through skeletal muscle and splanchnic
vascular beds
 If an a receptor blocker is administered,
epinephrine ß2-receptor effects dominate and total
peripheral resistance falls as does mean blood
pressure--this phenomenon is termed
"epinephrine reversal"
Epinephrine-
Vascular Effects cont.
16
Epinephrine- Cardiac Effects
 Epinephrine exerts most of
its effects on the heart
through activation of ß1-
adrenergic receptors.
 ß2- and α-receptors are
also present.
 Heart rate increases
 Cardiac output increases
 Oxygen consumption
increases
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
17
Epinephrine- Smooth Muscle
Effects
Smooth Muscle
 Epinephrine has variable effects on smooth
muscle depending on the adrenergic subtype
present
 GI smooth muscle is relaxed through activation of
both alpha and ß -receptor effects.
 In some cases the preexisting smooth muscle
tone will influence whether contraction or
relaxation results following epinephrine
18
Epinephrine- Smooth Muscle
Effects (2)
During the last month of pregnancy, epinephrine reduces
uterine tone and contractions by means of ß2-receptor activation
•This effect provides the rationale for the clinical use of ß2-
selective receptor agonists: ritodrine and terbutaline to delay
premature labor
Uterus alpha1; beta2
Pregnant:
contraction
(alpha1);
relaxation
(beta2); Non-
pregnant:
relaxation
(beta2)
variable
19
Epinephrine- Pulmonary
Effects
Epinephrine is a significant respiratory tract bronchodilator
Bronchodilation is caused by ß2-receptor activation mediated smooth
muscle relaxation
• This action can antagonize other agents that promote
bronchoconstriction
• ß2-receptor activation also decreases mast cell secretion and this decrease
may be beneficial is management of asthma also
Pulmonary
Adrenergic Effects Cholinergic
Tracheal and
bronchial
muscle
beta 2 Relaxation contraction
Bronchial
glands
alpha1, beta2
decrease
secretion;
increased
secretion
stimulation
20
Epinephrine- Metabolic
Effects
Pancreas
Adrenergic Effects Cholinergic
Acini alpha
decreased
secretion
secretion
Islets (beta cells) alpha2
decreased
secretion
---------
Islets (beta cells) beta2
increased
secretion
---------
Glucagon secretion: enhanced by ß adrenergic receptor activation of pancreatic
islet alpha cells
Glycolysis- stimulated: by ß adrenergic receptor activation
Insulin secretion: inhibited by α2 adrenergic receptor activation (dominant)
Insulin secretion: enhanced by ß2 adrenergic receptor activation
21
Epinephrine- Metabolic
Effects (2)
Liver
Adrenergic Effects Cholinergic
Liver alpha1; beta2
glycogenolysis
and
gluconeogenesis
-----------
Free fatty acids, increased: by ß adrenergic receptor
activation on adipocytes--activation of triglyceride lipase
22
Epinephrine- Metabolic
Effects (3)
Adipose Tissue
Adrenergic Cholinergic
Fat Cells alpha2; beta3
lipolysis
(thermogenesis)
---------
Calorigenic effect (20% - 30% increase in O2 consumption): caused
by triglyceride breakdown in brown adipose tissue
23
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 cardio-
selective β1 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
24
Norepinephrine
 Norepinephrine is the primary
neurotransmitter released by
postganglionic neurons of the
autonomic sympathetic system
 Norepinephrine (Levophed) is a potent
activator of α and ß1 adrenergic
receptors
25
NE- Blood Pressure Effects
 Potent vasopressor
 Systolic and diastolic pressure increase
 pulse pressure widens
 Norepinephrine (Levophed) increases blood
pressure by:
 vasoconstriction alpha1 receptor effects
 precapillary resistance vessels of the skin,
kidney, and mucosa
 veins
N.B. Elevation of systolic pressure following
norepinephrine is likely to activate the baroreceptor
system resulting in a reflex-mediated decrease in
heart rate
26
NE- Blood Pressure Effects
Blood Pressure
Blood Pressure Effects 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 McGraw-
Hill Companies, Inc.,1996, pp.199-242
27
NE-Arterioles Effects
Arterioles
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.
Adrenergic Cholinergic
28
NE-Vascular Effects
 Norepinephrine significantly increases
total peripheral resistance, often
inducing reflex cardiac slowing
 Norepinephrine (Levophed) causes
vasoconstriction in most vascular beds
 Blood flow is reduced to the kidney, liver and
skeletal muscle.
 Glomerular filtration rates are usually
maintained
 Norepinephrine may increase coronary
blood flow (secondary to increased blood
pressure and reflex activity)
 Norepinephrine (Levophed) may induce
variant (Prinzmetal's) angina
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
29
NE- Peripheral Circulation
Effects
Peripheral Circulation
Peripheral Circulation Epinephrine Norepinephrine
Total Peripheral
Resistance
Cerebral Blood Flow no effect or decrease
Muscle Blood Flow no effect or decrease
Cutaneous Blood Flow
Renal Blood Flow
Splanchnic Blood Flow no effect or increase
increase, decrease
0.1-0.4 ug/kg/min IV infusion
Therapeutic use: Norepinephrine may be used in
treatment of shock
30
Dopamine
Vasodilator:
 At low doses, dopamine
(Intropin) interactions with D1
receptor subtype results in
renal, mesenteric and coronary
vasodilation.
 This effect is mediated by an
increase in intracellular cyclic
AMP
 Low doses result in enhancing
glomerular filtration rates
(GFR), renal blood flow, and
sodium excretion.
Positive inotropism:
 At higher doses, dopamine
increase myocardial contractility
through activation of ß1
adrenergic receptors
 Dopamine (Intropin) also
promotes release of myocardial
norepinephrine.
 Dopamine (Intropin) at these
higher dosages causes an
increase in systolic blood and
arterial pulse pressure with little
effect on diastolic pressures.
Cardiovascular Effects (Dopamine)
Vasopressor:
At high doses dopamine (Intropin) causes vasoconstriction by
activating α1 adrenergic receptors
31
Therapeutic use (Dopamine)
Cardiogenic and hypovolemic
shock
 by enhancing renal perfusion
despite low cardiac output
 Oligouria may be an indication of
inadequate renal perfusion
 Example: dopamine may be used, in
postoperative cardiopulmonary
bypass patients who exhibit:
 low systemic blood-pressure
 increased atrial filling pressures
 low urinary output
Unique among catecholamines
in that Dopamine can
simultaneously increase
 myocardial contractility
 glomerular filtration rate
 sodium excretion
 urine output
 renal blood flow
32
Therapeutic use (Dopamine) (2)
 Increased sodium excretion following
dopamine may be due to inhibition of
aldosterone secretion.
 Dopamine may inhibit renal tubular solute
reabsorption(suggesting that natriuresis &
diuresis may occur by different mechanisms.)
 Fenoldopam and dopexamine: newer
drugs
 may be useful in treating heart failure by improving
myocardial contractility
33
Therapeutic use (Dopamine) (3)
 Dopamine (Intropin) at higher doses increases
myocardial contractility by ß1 - adrenergic
receptor activation.
 Ventilation effects: -- dopamine IV infusion
interferes with ventilatory responses to arterial
hypoxemia
 Dopamine (Intropin) acts as inhibitory
neurotransmitter at carotid bodies)
 Consequence: Unexpected ventilation depression
in patients treated with IV dopamine (Intropin) to
enhance myocardial contractility
34
Dopexamine
 Dopexamine-A synthetic analogue of
dopamine
 a β1 and β2-adrenergic receptor agonist
 Slight positive inotropic effect (beta 1-
adrenergic agonists activity; potentiation
those endogenous norepinephrine secondary
to reuptake blockade)
 Dopexamine enhances creatinine clearance
Action dopamine receptor:
 D1 mediates relaxation of vascular smooth muscle in
renal, mesenteric, cerebral and coronary arteries
 Mild action at D2 receptors decreases NE release
35
Isoproterenol (Isuprel)
 Activates ß adrenergic receptors (both ß1 - and
ß2 -receptor subtypes)
 Has limited action at a adrenergic receptors
 i.v. influsion of isoproterenol results in a slight
decrease in mean blood pressure with a marked drop
in diastolic pressure
 ß2 - adrenergic receptor-mediated reduction in
peripheral resistance (reflected in the diastolic
pressure effects) is primarily due to vasodilation of
skeletal muscle vasculature. Renal and mesenteric
vascular beds are also dilated
36
Isoproterenol (Isuprel) (2)
 Activation of cardiac ß1 - adrenergic receptors:
increased contractility and heart rate.
 Activation of ß2 - adrenergic receptors: Bronchial and GI
smooth muscle relaxation.
 Isoproterenol and ß2 -selective adrenergic agonists
inhibit antigen-mediated histamine release.
 Isoproterenol: Limited therapeutic uses:
 emergency settings to treat heart block or severe
bradycardia
 management of torsades de pointes (a ventricular
arrhythmia)
37
Isoproterenol (Isuprel) (3)
 management of torsades de pointes (a ventricular
arrhythmia)
 Isoproterenol (Isuprel) adverse effects:
 palpitations
 tachycardia
 arrhythmias
 coronary insufficiency
38
Dobutamine (Dobutrex)
 Structurally similar to
dopamine (Intropin).
 Pharmacological effects
exerted through
interaction with α and ß
adrenergic receptor
interactions
 no effect on release
 no action through
dopamine receptors
 Pharmacological effects are due to
complex interactions of (-) and (+)
enantiometic forms present in the
clinically used racemate with α and
ß adrenergic receptors
 Dobutamine (Dobutrex) is a positive
inotropic agent usually causing
limited increase in heart rate
 Positive inotropism is mediated
through ß adrenergic receptor
activation.
 Some peripheral a1 activity causes
modest vasoconstriction, an effect
opposed by dobutamines ß2 effects
39
Dobutamine (Dobutrex) (2)
Dobutamine (Dobutrex):
Adverse Effects
 Significant blood pressure
and heart rate increases may
occur.
 Ventricular ectopy
 Increased ventricular
following rate in patient with
atrial fibrillation.
 Increased myocardial oxygen
demand that may worsen
post-infarct myocardial
damage
Dobutamine (Dobutrex):
Therapeutic Use
 Short-term management of
pump failure following
surgery, during acute
congestive heart failure, or
post-myocardial infarction.
 Uncertain long-term efficacy.
40
ß2 Selective Adrenergic
Agonists
 Metaproterenol (Alupent)
 Terbutaline (Brethine)
 Albuterol (Ventolin,Proventil)
 Ritodrine (Yutopar)
41
Metaproterenol (Alupent)
 ß2 adrenergic receptor-selective: resistant to
COMT (catechol-O-methyl transferase)
metabolism
 Less ß2 selective compared to terbutaline
(Brethine) and albuterol (Ventolin,Proventil).
 May be used for long-term and acute
treatment of bronchospasm
42
Terbutaline [Brethine]
 ß2 adrenergic receptor-selective:
resistant to COMT
 Active after oral, subcutaneous, or
administration by inhalation
 Rapid onset of action
 Used for management of chronic obstructive
lung disease and for treatment of acute
bronchospasm (smooth muscle
bronchoconstriction), including status
asthmaticus
43
Albuterol [Ventolin]
 ß2 adrenergic receptor-selective
 Effective following inhalation or oral
administration
 Commonly used in chronic and acute
asthma management
44
Ritodrine (Yutopar)
ß2 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
 ß2 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
45
Adverse Effects-B2
Agonists
 Excessive cardiovascular stimulation
 Skeletal muscle tremor (tolerance
develops, unknown mechanism) due to
ß2 adrenergic receptor activation
 Over usage may be a factor in
morbidity and mortality in asthmatics
46
Alpha1 Selective Adrenergic
Agonists
 Alpha1 selective adrenergic agonists
activate a adrenergic receptors in vascular
smooth muscle producing vasoconstriction
 Peripheral vascular resistance is increased.
 Blood pressure may be increased, causing a
reflex reduction heart rate
 a1 adrenergic agonists are used clinically in
management of hypotension and shock
47
Alpha1 Selective
Adrenergic Agonists
Direct Acting
 Phenylephrine (Neo-Synephrine) and
methoxamine (Vasoxyl) are direct-
acting vasoconstrictors
Mixed Acting
 Mephentermine (Wyamine) and
metaraminol (Aramine) act both by
direct receptor activation and by promoting
epinephrine release
48
Methoxamine (Vasoxyl)
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
 termination (by vagal reflex) of paroxysmal atrial
tachycardia (adenosine may be preferable)
49
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
50
Alpha 2 Selective Adrenergic Agonists
and Miscellaneous Adrenergic
Agonists
 alpha2 selective adrenergic agonists are
used to treat essential hypertension.
 Mechanism of action:
 activation of central a2 adrenergic
receptors at cardiovascular control centers
 activation decreases sympathetic outflow,
reducing sympathetic vascular tone.
51
Alpha2 Selective Adrenergic Agonists
Clonidine (Catapres)
is primarily used in treating essential
hypertension.
 A prolonged hypotensive response
results from a decrease in CNS
sympathetic outflow.
 This response is due to a2 selective
adrenergic receptor activation
52
alpha2 Selective Adrenergic Agonists
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)
53
alpha2 Selective Adrenergic Agonists
and Miscellaneous Adrenergic
Agonists
Alpha-methyl DOPA (methyldopa
(Aldomet), metabolically converted to alpha-
methyl norepinephrine, is used for treating
essential hypertension
 A prolonged hypotensive response results from
a decrease in CNS sympathetic outflow
 This response is due to a2 selective adrenergic
receptor activation
 Adverse Effects:
 dry mouth
 sedation
54
Alpha 2 Selective Adrenergic
Agonists and Miscellaneous Adrenergic
Agonists
Amphetamine
 CNS stimulant (releasing biogenic nerve
terminal amines):
 respiratory center
 mood elevation
 decreased perception of fatigue
 Other effects: headache, palpitations,
dysphoria
 Appetite suppression
 Weight loss due to decrease food intake
 psychological tolerance/dependence
55
Amphetamine (2) Indirect acting
sympathomimetic
Toxicity:
 CNS: restlessness, tremor, irritablity, insomnia,
aggressiveness, anxiety, panic, suicidal ideation, etc.
 Cardiovascular: arrhythmias, hypertension or
hypotension, angina
 GI: dry mouth, anorexia, vomiting, diarrhea, cramping
 Treatment:
 urinary acidification by ammonium chloride
 hypertension: nitroprusside or alpha adrenergic
receptor antagonist
 CNS: sedative-hypnotic drugs
56
Amphetamine (3)
Therapeutic Use:
 Narcolepsy
 Obesity
 Attention-deficit hyperactivity disorder
57
Methylphenidate (Ritalin)
 Mild CNS stimulant, chemically related to
amphetamine
 Effects more prevalent on mental than motor
activities
 General pharmacological profile similar to
amphetamine
 Major Therapeutic Use:
 Narcolepsy
 Attention-deficit hyperactivity disorder
58
Ephedrine
α and ß 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: ß adrenergic receptor response
59
Ephedrine(2)
 Limited Clinical Use due to better
pharmacological alternatives (asthma,
heart block, CNS stimulation)
 Vasoconstrictors for Nasal Mucosal
Membranes and for the Eye
60
Adrenergic Drug Lists Summary
Drug Receptors
Epinephrine alpha1, alpha2 ß1, ß2
Norepinephrine (Levophed) alpha1, alpha2, ß1
Isoproterenol (Isuprel) ß1, ß2
Dobutamine (Dobutrex) ß1 (alpha1)
Dopamine (Intropin) D-1 (alpha1 and ß1 at high doses)
Catecholamines
61
Adrenergic Drug Lists Summary
Direct adrenoceptor agonists
Drug Receptor Selectivity
Phenylephrine (Neo-Synephrine) alpha1
Methoxamine (Vasoxyl) alpha1
Oxymetazoline (Afrin) alpha1, alpha2
Clonidine (Catapres) alpha2
Ritodrine (Yutopar) ß2
Terbutaline (Brethine) ß2
Albuterol (Ventolin,Proventil) ß2
Salmeterol (Serevent) ß2
62
Adrenergic Drug Lists Summary
Indirect sympathomimetics
•Ephedrine,
Pseudoephedrine
•Cocaine
•Tyramine
•Amphetamine
•Release & direct
receptor activation
•Uptake Inhibitor
•Release
•see ephedrine, but
greater CNS actions
63
Adrenergic Drug Lists Summary
Alpha-Adrenoceptor antagonists
Drug Receptor Selectivity (α1 vs. α2)
Prazosin (Minipress) alpha1
Terazosin (Hytrin) alpha1
Trimazosin alpha1
Doxazosin (Cardura) alpha1
Phentolamine (Regitine) non-selective
Phenoxybenzamine (Dibenzyline)
only slightly selective for alpha1 (non-
competitive)
Tolazoline (Priscoline) non-selective
Labetalol (Trandate, Normodyne)
alpha1 (also non-selective beta-
antagonist)
Yohimbine (Yocon) alpha2
64
Adrenergic Drug Lists Summary
ß-Adrenoceptor antagonists
Drug Receptor Selectivity (ß1 vs. ß2)
Propranolol (Inderal) non-selective
Metoprolol (Lopressor) ß1
Esmolol (Brevibloc) ß1
Atenolol (Tenormin) ß1
Nadolol (Corgard) non-selective
Timolol (Blocadren) non-selective
Pindolol (Visken) non-selective (partial agonist)
Labetalol (Trandate, Normodyne)
non-selective (selective a1-
antagonist)
65
Heart
Rate Acceleration (ex) Slowing (in)
Contractility Increased (ex) Decreased (in)
Arterioles
Skin and most
others
Constriction (ex) —
Skeletal muscle Dilation (ex) —
Glands
Salivary Viscid secretion (ex) Watery secretion (ex)
Lacrimal — Secretion (ex)
Sweat Secretion (ex) —
Bronchial muscle Relaxation (in) Contraction (ex)
GI tract
Muscle wall Relaxation (in) Contraction (ex)
Sphincters Contraction (ex) Relaxation (in)
Urinary bladder
Fundus Relaxation (in) Contraction (ex)
Trigone; sphincter Contraction (ex) Relaxation (in)
Penis Ejaculation (ex) Erection (in)
Uterus Relaxation (in) —
Metabolism
Liver Gluconeogenesis (ex) —
Glycogenolysis (ex) —
Kidney Renin secretion(ex) —
Fat Cells Lipolysis (ex)

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ANS Pharmacology- Adrenergic Drugs

  • 1. Autonomic Pharmacology Adrenergic Drugs (*Agonist) Prepared and Presented by: Marc Imhotep Cray, M.D. BMS/CK Teacher *Adrenergic antagonist are covered in the Antihypertensive Agents Presentation
  • 2. 2 *Suggested Review Books & Resources *e-Books & learning tools available to enrolled learners at thePOINT If you are using a different review book, the chapters may be organized differently, but the material covered is approximately the same. Simply find the corresponding material in your book for each lecture. Companion Notes: ANS Summary Notes Formative Assessment Clinical Correlate: e-Medicine Article Epilepsy and the Autonomic Nervous System  Review Test for Autonomic Nervous System answers and explanations  Review Test for Autonomic Nervous System
  • 3. 3 Introduction  Distribution of adrenergic receptor subtypes and adrenergic receptor number are important factors in organ or cellular responses to adrenergic input  Adrenergic receptor type in bronchiolar smooth muscle is principally ß2: epinephrine and isoproterenol might be expected to be effective bronchodilators because of their activity at ß2 receptors  Norepinephrine is unlikely to have this same effect due to its relative lack of activity at ß2 sites
  • 4. 4 Introduction cont.  Alpha receptor dominate in the cutaneous vascular beds  Norepinephrine and epinephrine cause constriction  Isoproterenol with limited activity at alpha receptors has little effect  Both alpha and beta adrenergic receptor are present in skeletal muscle vascular beds  Alpha receptor activation causes vasoconstriction  Beta receptor activation promotes vasodilatation  Since ß2 receptors are activated at lower, physiological concentrations, vasodilation results
  • 5. 5 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
  • 6. 6 Categories of Action Adrenergics  Smooth Muscle Effects  Smooth muscle activation, including activation of blood vessel vasculature (skin, kidney).  Activation of glands (salivary and sweat).  Smooth muscle inhibition, including inhibition of smooth muscle of the gut, bronchioles, and skeletal muscle vascular smooth muscle.  Cardiac Effects  increased heart rate (positive chronotropic effect)  increased contractility (positive inotropic effect)  Metabolic Effects  increase in rate of muscle and liver glycogenolysis  increase in free-fatty acid release from fat  Endocrine  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
  • 7. 7 Epinephrine  Epinephrine is a potent activator of alpha and ß adrenergic receptors  Prominent Cardiovascular Effects
  • 8. 8 Epinephrine and Blood Pressure  Potent vasopressor  Systolic pressure increases to a greater extent than diastolic (diastolic pressure may decrease)  pulse pressure widens  Epinephrine increases blood pressure by:  enhancing cardiac contractility (positive inotropic effect): ß1- receptor effects  increasing heart rate (positive chronotropic effect): ß1-receptor effects.  vasoconstriction a1 receptor effects  precapillary resistance vessels of the skin, kidney, and mucosa  veins
  • 9. 9 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.
  • 10. 10 Epinephrine and Blood Pressure (3)  A principal mechanism for arterial blood pressure control is the baroreceptor reflex.  The reflex is initiated by activation of stretch receptors located in the wall of most large arteries of the chest and neck  A high density of baroreceptors is found in the wall of each internal carotid artery (just above the carotid bifurcation i.e. carotid sinus) and in the wall of the aortic arch
  • 11. 11 Epinephrine and Blood Pressure (4)  As pressure rises and especially for rapid increases in pressure:  baroreceptor input to the tractus solitarius of the medulla results in inhibition of the vasoconstrictor center and excitation of the vagal (cholinergic) centers resulting in  a vasodilatation of the veins and arterioles in the peripheral vascular beds.  negative chronotropic and inotropic effects on the heart. (slower heart rate with reduced force of contraction)
  • 12. 12 Epinephrine and Blood Pressure (5) Adrenergic Cholinergic Sino-atrial (SA) Node beta1; beta2 increased rate decreased rate (vagal) Atrial muscle beta1; beta 2 increased: contractility, conduction velocity decreased: contractility, action potential duration Atrio-ventricular (AV) node beta1; beta 2 increased: automaticity, conduction velocity decreased conduction velocity; AV block His-Purkinje System beta1; beta 2 increased: automaticity, conduction velocity ------ Ventricles beta1; beta 2 increased: contractility, conduction velocity, automaticity, ectopic pacemaker small decrease in contractility
  • 13. 13 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 At lower epinephrine doses: a lessened effect on systolic pressure occurs diastolic pressures may decrease as peripheral resistance is reduced. Peripheral resistance decreased due to ß2-receptor effects
  • 14. 14 Epinephrine-Vascular Effects  Epinephrine has significant effects on smaller arteriolar and precapilliary smooth muscle  Acting through alpha1 receptors, vasoconstrictor effects decrease blood flow through skin and kidney  Even at doses of epinephrine that do not affect mean blood pressure, substantially increases renal vascular resistance and reduces blood flow (40%)  Renin release increases due to epinephrine effects mediated by ß2-receptors associated with juxtaglomerular cells
  • 15. 15  Acting through ß2-receptors, epinephrine causes significant vasodilatation which increases blood flow through skeletal muscle and splanchnic vascular beds  If an a receptor blocker is administered, epinephrine ß2-receptor effects dominate and total peripheral resistance falls as does mean blood pressure--this phenomenon is termed "epinephrine reversal" Epinephrine- Vascular Effects cont.
  • 16. 16 Epinephrine- Cardiac Effects  Epinephrine exerts most of its effects on the heart through activation of ß1- adrenergic receptors.  ß2- and α-receptors are also present.  Heart rate increases  Cardiac output increases  Oxygen consumption increases 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
  • 17. 17 Epinephrine- Smooth Muscle Effects Smooth Muscle  Epinephrine has variable effects on smooth muscle depending on the adrenergic subtype present  GI smooth muscle is relaxed through activation of both alpha and ß -receptor effects.  In some cases the preexisting smooth muscle tone will influence whether contraction or relaxation results following epinephrine
  • 18. 18 Epinephrine- Smooth Muscle Effects (2) During the last month of pregnancy, epinephrine reduces uterine tone and contractions by means of ß2-receptor activation •This effect provides the rationale for the clinical use of ß2- selective receptor agonists: ritodrine and terbutaline to delay premature labor Uterus alpha1; beta2 Pregnant: contraction (alpha1); relaxation (beta2); Non- pregnant: relaxation (beta2) variable
  • 19. 19 Epinephrine- Pulmonary Effects Epinephrine is a significant respiratory tract bronchodilator Bronchodilation is caused by ß2-receptor activation mediated smooth muscle relaxation • This action can antagonize other agents that promote bronchoconstriction • ß2-receptor activation also decreases mast cell secretion and this decrease may be beneficial is management of asthma also Pulmonary Adrenergic Effects Cholinergic Tracheal and bronchial muscle beta 2 Relaxation contraction Bronchial glands alpha1, beta2 decrease secretion; increased secretion stimulation
  • 20. 20 Epinephrine- Metabolic Effects Pancreas Adrenergic Effects Cholinergic Acini alpha decreased secretion secretion Islets (beta cells) alpha2 decreased secretion --------- Islets (beta cells) beta2 increased secretion --------- Glucagon secretion: enhanced by ß adrenergic receptor activation of pancreatic islet alpha cells Glycolysis- stimulated: by ß adrenergic receptor activation Insulin secretion: inhibited by α2 adrenergic receptor activation (dominant) Insulin secretion: enhanced by ß2 adrenergic receptor activation
  • 21. 21 Epinephrine- Metabolic Effects (2) Liver Adrenergic Effects Cholinergic Liver alpha1; beta2 glycogenolysis and gluconeogenesis ----------- Free fatty acids, increased: by ß adrenergic receptor activation on adipocytes--activation of triglyceride lipase
  • 22. 22 Epinephrine- Metabolic Effects (3) Adipose Tissue Adrenergic Cholinergic Fat Cells alpha2; beta3 lipolysis (thermogenesis) --------- Calorigenic effect (20% - 30% increase in O2 consumption): caused by triglyceride breakdown in brown adipose tissue
  • 23. 23 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 cardio- selective β1 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
  • 24. 24 Norepinephrine  Norepinephrine is the primary neurotransmitter released by postganglionic neurons of the autonomic sympathetic system  Norepinephrine (Levophed) is a potent activator of α and ß1 adrenergic receptors
  • 25. 25 NE- Blood Pressure Effects  Potent vasopressor  Systolic and diastolic pressure increase  pulse pressure widens  Norepinephrine (Levophed) increases blood pressure by:  vasoconstriction alpha1 receptor effects  precapillary resistance vessels of the skin, kidney, and mucosa  veins N.B. Elevation of systolic pressure following norepinephrine is likely to activate the baroreceptor system resulting in a reflex-mediated decrease in heart rate
  • 26. 26 NE- Blood Pressure Effects Blood Pressure Blood Pressure Effects 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 McGraw- Hill Companies, Inc.,1996, pp.199-242
  • 27. 27 NE-Arterioles Effects Arterioles 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. Adrenergic Cholinergic
  • 28. 28 NE-Vascular Effects  Norepinephrine significantly increases total peripheral resistance, often inducing reflex cardiac slowing  Norepinephrine (Levophed) causes vasoconstriction in most vascular beds  Blood flow is reduced to the kidney, liver and skeletal muscle.  Glomerular filtration rates are usually maintained  Norepinephrine may increase coronary blood flow (secondary to increased blood pressure and reflex activity)  Norepinephrine (Levophed) may induce variant (Prinzmetal's) angina 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
  • 29. 29 NE- Peripheral Circulation Effects Peripheral Circulation Peripheral Circulation Epinephrine Norepinephrine Total Peripheral Resistance Cerebral Blood Flow no effect or decrease Muscle Blood Flow no effect or decrease Cutaneous Blood Flow Renal Blood Flow Splanchnic Blood Flow no effect or increase increase, decrease 0.1-0.4 ug/kg/min IV infusion Therapeutic use: Norepinephrine may be used in treatment of shock
  • 30. 30 Dopamine Vasodilator:  At low doses, dopamine (Intropin) interactions with D1 receptor subtype results in renal, mesenteric and coronary vasodilation.  This effect is mediated by an increase in intracellular cyclic AMP  Low doses result in enhancing glomerular filtration rates (GFR), renal blood flow, and sodium excretion. Positive inotropism:  At higher doses, dopamine increase myocardial contractility through activation of ß1 adrenergic receptors  Dopamine (Intropin) also promotes release of myocardial norepinephrine.  Dopamine (Intropin) at these higher dosages causes an increase in systolic blood and arterial pulse pressure with little effect on diastolic pressures. Cardiovascular Effects (Dopamine) Vasopressor: At high doses dopamine (Intropin) causes vasoconstriction by activating α1 adrenergic receptors
  • 31. 31 Therapeutic use (Dopamine) Cardiogenic and hypovolemic shock  by enhancing renal perfusion despite low cardiac output  Oligouria may be an indication of inadequate renal perfusion  Example: dopamine may be used, in postoperative cardiopulmonary bypass patients who exhibit:  low systemic blood-pressure  increased atrial filling pressures  low urinary output Unique among catecholamines in that Dopamine can simultaneously increase  myocardial contractility  glomerular filtration rate  sodium excretion  urine output  renal blood flow
  • 32. 32 Therapeutic use (Dopamine) (2)  Increased sodium excretion following dopamine may be due to inhibition of aldosterone secretion.  Dopamine may inhibit renal tubular solute reabsorption(suggesting that natriuresis & diuresis may occur by different mechanisms.)  Fenoldopam and dopexamine: newer drugs  may be useful in treating heart failure by improving myocardial contractility
  • 33. 33 Therapeutic use (Dopamine) (3)  Dopamine (Intropin) at higher doses increases myocardial contractility by ß1 - adrenergic receptor activation.  Ventilation effects: -- dopamine IV infusion interferes with ventilatory responses to arterial hypoxemia  Dopamine (Intropin) acts as inhibitory neurotransmitter at carotid bodies)  Consequence: Unexpected ventilation depression in patients treated with IV dopamine (Intropin) to enhance myocardial contractility
  • 34. 34 Dopexamine  Dopexamine-A synthetic analogue of dopamine  a β1 and β2-adrenergic receptor agonist  Slight positive inotropic effect (beta 1- adrenergic agonists activity; potentiation those endogenous norepinephrine secondary to reuptake blockade)  Dopexamine enhances creatinine clearance Action dopamine receptor:  D1 mediates relaxation of vascular smooth muscle in renal, mesenteric, cerebral and coronary arteries  Mild action at D2 receptors decreases NE release
  • 35. 35 Isoproterenol (Isuprel)  Activates ß adrenergic receptors (both ß1 - and ß2 -receptor subtypes)  Has limited action at a adrenergic receptors  i.v. influsion of isoproterenol results in a slight decrease in mean blood pressure with a marked drop in diastolic pressure  ß2 - adrenergic receptor-mediated reduction in peripheral resistance (reflected in the diastolic pressure effects) is primarily due to vasodilation of skeletal muscle vasculature. Renal and mesenteric vascular beds are also dilated
  • 36. 36 Isoproterenol (Isuprel) (2)  Activation of cardiac ß1 - adrenergic receptors: increased contractility and heart rate.  Activation of ß2 - adrenergic receptors: Bronchial and GI smooth muscle relaxation.  Isoproterenol and ß2 -selective adrenergic agonists inhibit antigen-mediated histamine release.  Isoproterenol: Limited therapeutic uses:  emergency settings to treat heart block or severe bradycardia  management of torsades de pointes (a ventricular arrhythmia)
  • 37. 37 Isoproterenol (Isuprel) (3)  management of torsades de pointes (a ventricular arrhythmia)  Isoproterenol (Isuprel) adverse effects:  palpitations  tachycardia  arrhythmias  coronary insufficiency
  • 38. 38 Dobutamine (Dobutrex)  Structurally similar to dopamine (Intropin).  Pharmacological effects exerted through interaction with α and ß adrenergic receptor interactions  no effect on release  no action through dopamine receptors  Pharmacological effects are due to complex interactions of (-) and (+) enantiometic forms present in the clinically used racemate with α and ß adrenergic receptors  Dobutamine (Dobutrex) is a positive inotropic agent usually causing limited increase in heart rate  Positive inotropism is mediated through ß adrenergic receptor activation.  Some peripheral a1 activity causes modest vasoconstriction, an effect opposed by dobutamines ß2 effects
  • 39. 39 Dobutamine (Dobutrex) (2) Dobutamine (Dobutrex): Adverse Effects  Significant blood pressure and heart rate increases may occur.  Ventricular ectopy  Increased ventricular following rate in patient with atrial fibrillation.  Increased myocardial oxygen demand that may worsen post-infarct myocardial damage Dobutamine (Dobutrex): Therapeutic Use  Short-term management of pump failure following surgery, during acute congestive heart failure, or post-myocardial infarction.  Uncertain long-term efficacy.
  • 40. 40 ß2 Selective Adrenergic Agonists  Metaproterenol (Alupent)  Terbutaline (Brethine)  Albuterol (Ventolin,Proventil)  Ritodrine (Yutopar)
  • 41. 41 Metaproterenol (Alupent)  ß2 adrenergic receptor-selective: resistant to COMT (catechol-O-methyl transferase) metabolism  Less ß2 selective compared to terbutaline (Brethine) and albuterol (Ventolin,Proventil).  May be used for long-term and acute treatment of bronchospasm
  • 42. 42 Terbutaline [Brethine]  ß2 adrenergic receptor-selective: resistant to COMT  Active after oral, subcutaneous, or administration by inhalation  Rapid onset of action  Used for management of chronic obstructive lung disease and for treatment of acute bronchospasm (smooth muscle bronchoconstriction), including status asthmaticus
  • 43. 43 Albuterol [Ventolin]  ß2 adrenergic receptor-selective  Effective following inhalation or oral administration  Commonly used in chronic and acute asthma management
  • 44. 44 Ritodrine (Yutopar) ß2 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  ß2 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
  • 45. 45 Adverse Effects-B2 Agonists  Excessive cardiovascular stimulation  Skeletal muscle tremor (tolerance develops, unknown mechanism) due to ß2 adrenergic receptor activation  Over usage may be a factor in morbidity and mortality in asthmatics
  • 46. 46 Alpha1 Selective Adrenergic Agonists  Alpha1 selective adrenergic agonists activate a adrenergic receptors in vascular smooth muscle producing vasoconstriction  Peripheral vascular resistance is increased.  Blood pressure may be increased, causing a reflex reduction heart rate  a1 adrenergic agonists are used clinically in management of hypotension and shock
  • 47. 47 Alpha1 Selective Adrenergic Agonists Direct Acting  Phenylephrine (Neo-Synephrine) and methoxamine (Vasoxyl) are direct- acting vasoconstrictors Mixed Acting  Mephentermine (Wyamine) and metaraminol (Aramine) act both by direct receptor activation and by promoting epinephrine release
  • 48. 48 Methoxamine (Vasoxyl) 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  termination (by vagal reflex) of paroxysmal atrial tachycardia (adenosine may be preferable)
  • 49. 49 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
  • 50. 50 Alpha 2 Selective Adrenergic Agonists and Miscellaneous Adrenergic Agonists  alpha2 selective adrenergic agonists are used to treat essential hypertension.  Mechanism of action:  activation of central a2 adrenergic receptors at cardiovascular control centers  activation decreases sympathetic outflow, reducing sympathetic vascular tone.
  • 51. 51 Alpha2 Selective Adrenergic Agonists Clonidine (Catapres) is primarily used in treating essential hypertension.  A prolonged hypotensive response results from a decrease in CNS sympathetic outflow.  This response is due to a2 selective adrenergic receptor activation
  • 52. 52 alpha2 Selective Adrenergic Agonists 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)
  • 53. 53 alpha2 Selective Adrenergic Agonists and Miscellaneous Adrenergic Agonists Alpha-methyl DOPA (methyldopa (Aldomet), metabolically converted to alpha- methyl norepinephrine, is used for treating essential hypertension  A prolonged hypotensive response results from a decrease in CNS sympathetic outflow  This response is due to a2 selective adrenergic receptor activation  Adverse Effects:  dry mouth  sedation
  • 54. 54 Alpha 2 Selective Adrenergic Agonists and Miscellaneous Adrenergic Agonists Amphetamine  CNS stimulant (releasing biogenic nerve terminal amines):  respiratory center  mood elevation  decreased perception of fatigue  Other effects: headache, palpitations, dysphoria  Appetite suppression  Weight loss due to decrease food intake  psychological tolerance/dependence
  • 55. 55 Amphetamine (2) Indirect acting sympathomimetic Toxicity:  CNS: restlessness, tremor, irritablity, insomnia, aggressiveness, anxiety, panic, suicidal ideation, etc.  Cardiovascular: arrhythmias, hypertension or hypotension, angina  GI: dry mouth, anorexia, vomiting, diarrhea, cramping  Treatment:  urinary acidification by ammonium chloride  hypertension: nitroprusside or alpha adrenergic receptor antagonist  CNS: sedative-hypnotic drugs
  • 56. 56 Amphetamine (3) Therapeutic Use:  Narcolepsy  Obesity  Attention-deficit hyperactivity disorder
  • 57. 57 Methylphenidate (Ritalin)  Mild CNS stimulant, chemically related to amphetamine  Effects more prevalent on mental than motor activities  General pharmacological profile similar to amphetamine  Major Therapeutic Use:  Narcolepsy  Attention-deficit hyperactivity disorder
  • 58. 58 Ephedrine α and ß 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: ß adrenergic receptor response
  • 59. 59 Ephedrine(2)  Limited Clinical Use due to better pharmacological alternatives (asthma, heart block, CNS stimulation)  Vasoconstrictors for Nasal Mucosal Membranes and for the Eye
  • 60. 60 Adrenergic Drug Lists Summary Drug Receptors Epinephrine alpha1, alpha2 ß1, ß2 Norepinephrine (Levophed) alpha1, alpha2, ß1 Isoproterenol (Isuprel) ß1, ß2 Dobutamine (Dobutrex) ß1 (alpha1) Dopamine (Intropin) D-1 (alpha1 and ß1 at high doses) Catecholamines
  • 61. 61 Adrenergic Drug Lists Summary Direct adrenoceptor agonists Drug Receptor Selectivity Phenylephrine (Neo-Synephrine) alpha1 Methoxamine (Vasoxyl) alpha1 Oxymetazoline (Afrin) alpha1, alpha2 Clonidine (Catapres) alpha2 Ritodrine (Yutopar) ß2 Terbutaline (Brethine) ß2 Albuterol (Ventolin,Proventil) ß2 Salmeterol (Serevent) ß2
  • 62. 62 Adrenergic Drug Lists Summary Indirect sympathomimetics •Ephedrine, Pseudoephedrine •Cocaine •Tyramine •Amphetamine •Release & direct receptor activation •Uptake Inhibitor •Release •see ephedrine, but greater CNS actions
  • 63. 63 Adrenergic Drug Lists Summary Alpha-Adrenoceptor antagonists Drug Receptor Selectivity (α1 vs. α2) Prazosin (Minipress) alpha1 Terazosin (Hytrin) alpha1 Trimazosin alpha1 Doxazosin (Cardura) alpha1 Phentolamine (Regitine) non-selective Phenoxybenzamine (Dibenzyline) only slightly selective for alpha1 (non- competitive) Tolazoline (Priscoline) non-selective Labetalol (Trandate, Normodyne) alpha1 (also non-selective beta- antagonist) Yohimbine (Yocon) alpha2
  • 64. 64 Adrenergic Drug Lists Summary ß-Adrenoceptor antagonists Drug Receptor Selectivity (ß1 vs. ß2) Propranolol (Inderal) non-selective Metoprolol (Lopressor) ß1 Esmolol (Brevibloc) ß1 Atenolol (Tenormin) ß1 Nadolol (Corgard) non-selective Timolol (Blocadren) non-selective Pindolol (Visken) non-selective (partial agonist) Labetalol (Trandate, Normodyne) non-selective (selective a1- antagonist)
  • 65. 65 Heart Rate Acceleration (ex) Slowing (in) Contractility Increased (ex) Decreased (in) Arterioles Skin and most others Constriction (ex) — Skeletal muscle Dilation (ex) — Glands Salivary Viscid secretion (ex) Watery secretion (ex) Lacrimal — Secretion (ex) Sweat Secretion (ex) — Bronchial muscle Relaxation (in) Contraction (ex) GI tract Muscle wall Relaxation (in) Contraction (ex) Sphincters Contraction (ex) Relaxation (in) Urinary bladder Fundus Relaxation (in) Contraction (ex) Trigone; sphincter Contraction (ex) Relaxation (in) Penis Ejaculation (ex) Erection (in) Uterus Relaxation (in) — Metabolism Liver Gluconeogenesis (ex) — Glycogenolysis (ex) — Kidney Renin secretion(ex) — Fat Cells Lipolysis (ex)