Bez nadpisu

1
Adrenergic Agonists and Antagonists V.
GerlAccording to - H.P.Rang, M.M.Dale,
J.M.Ritter, R. J. Flower Pharmacology, 6th ed.-
R.A.Howland, M.J.Mycek Lippincotts Illustrated
Reviews Pharmacology, 3rd ed.
2
Structures of the major catecholamines
Noradrenaline
Adrenaline
Dopamine
Isoprenaline
(according to Rang HP, Dale MM et al.
Pharmacology, 2003)
3
Summary of the neurotransmitters released and the
types of receptors found within the autonomic
and somatic nervous system.
(according to Lippincotts Pharmacology, 2006)
AUTONOMIC SOMATIC
Sympathetic innervation of adrenal medulla
Parasympathetic
Sympathetic
Preganglionic neuron
Ganglionic transmitter
Acetylcholine
Acetylcholine
Acetylcholine
No ganglia
Nicotinic receptor
Nicotinic receptor
Nicotinic receptor
Postganglionic neurons
Adrenal medulla
Acetylcholine
Neuroeffector transmitter
Epinephrine release into the blood
Acetylcholine
Norepinephrine
Adrenergic receptor
Muscarinic receptor
Adrenergic receptor
Nicotinic receptor
Striated muscle
Effector organs
4
Nicotinic receptor Nicotinic receptor
Sites of actions of adrenergic agonists.
Adrenal medulla
Epinephrine released Norepinephrine into
the blood
Adrenergic receptor
Adrenergic receptor
(according to Lippincotts Pharmacology, 2006)
Effector organs
5
Summary of adrenergic agonists. Agents marked
with an asterisk () are catecholamines.
Adrenergic agonists
Direct-acting
Albuterol Clonidine Dobutamine Dopamine Epinephr
ine Formoterol Isoproterenol Metaproterenol Metho
xamine Norepinephrine Phenylephrine Piruterol Sal
meterol Tamsulosine Terbutaline
Indirect-acting
Amphetamine Tyramine
Direct and indirect acting (mixed action)
(according to Lippincotts Pharmacology, 2006)
Ephedrine
6

• ADRENERGIC AGONISTS
• The adrenergic drugs affect receptors that are
  stimulated by
• norepinephrine or epinephrine. Some adrenergic
  drugs act directly on
• the adrenergic receptor either by activating the
  receptor or by blocking
• the action of norepinephrine and epinephrine.
• Other drugs act indirectly by altering the
  release of norepinephrine
• by the adrenergic neuron.
• THE ADRENERGIC NEURON
• The adrenergic neuron releases norepinephrine as
  a neurotransmitter.
• Found
• - CNS
• - the sympathetic nervous system between
  postganglionic neurons and
• the effector organs.
• adrenergic neuron and receptor (either
  presynaptically on the neuron
• or postsynaptically on the effector organ) are
  the sites of action of
• adrenergic drugs.

7

• 1 Synthesis of
• norepinephrine
• Hydroxylation of tyrosine is the rate-limiting
  step.

Synthesis and release of norepinephrine from the
adrenergic neuron. MAO monoamine oxidase

• 2 Uptake into storage
• vesicles
• Dopamine enters a vesicle and is converted to
  norepinephrine
• Norepinephrine is protected from degradation in
  the vesicle.
• Transport into the vesicle is inhibited by
  reserpine.

Inactive metabolites
Norepinephrine
MAO
Urine
Tyrosine Na
Tyrosine Na
DOPA
Inactive metabolites
MAO
Urine
Dopamine

• 3 Release of
• neurotransmitter
• Influx of calcium cause fusion of the vesicle
  with the cell membrane.
• Release is blocked by guanethidine and bretylium.

Dopamine
Synaptic vesicle
Ca2

• 5 Removal of
• norepinephrine
• Released norepinephrine is rapidly taken into
  the neuron.
• Reuptake is inhibited by cocaine and imipramine.

Ca2

Presynaptic receptor

• 4 Binding to receptor
• Postsynaptic receptor is activated by the
  binding of neurotransmitter.

Norepinephrine
Inactive metabolites
Urine
Catechol-O- methyltransferase (COMT)
SYNAPTIC SPACE

• 6 Metabolism
• Norepinephrine is methylated by COMT and
  oxidized by MAO.

(according to Lippincotts Pharmacology, 2006)
INTRACELLULAR RESPONSE
8
A. Neurotransmission at adrenergic neurons
(norepinephrine is the neurotransmitter) five
steps synthesis, storage, release, and receptor
binding of NOR, followed by removal of NOR from
the synaptic gap. 1. Synthesis of NOR Tyrosine
transported into the cytoplasm of the adrenergic
neuron, hydroxylated to DOPA by tyrosine
hydroxylase (the rate-limiting step in the
formation of NOR). DOPA is decarboxylated to form
dopamine. 2. Storage of NOR in vesicles Dopamine
- transported into synaptic vesicles - an amine
transporter system that is also involved in the
re-uptake of NOR (this carrier system is blocked
by reserpine). Dopamine is hydroxylated to NOR.
Adrenal medulla NOR is methylated to
epinephrine. The adrenal medulla releases about
85 of ADR and 15 of NOR.
9
3. Release of NOR Action potential arriving at
the nerve ending triggers an infux of calcium
ions from the extracellular fluid into the
cytoplasm of the neuron. Increase in calcium
causes vesicles to fuse with the cell membrane
and release contents into the synapse (this
release blocked by quanethidine and
bretylium). 4. Binding by receptor NOR after
its release diffuses across the synaptic space
and binds to receptors (postsynaptic on the
effector organs or to presynaptic receptors on
the nerve ending). Receptors triggers a cascade
of events within the cells, resulting in the
formation of intracelullar second messengers
(cAMP, phosphoinositide cycle ? effector cell.
10
5. Removal of NOR - NOR may diffuse out of the
synaptic space and enter the general
circulation or - may be recaptured by an uptake
system that pulls the NOR back into the neuron
(uptake by the plasma membrane involves a
sodium-potassium activated ATPase that can be
inhibited by tricyclic antidepressants, e.g.,
imipramine or by cocaine) uptake1 neuronal
uptake (especially NOR), uptake2 extraneuronal
uptake (also for ADR and isoprenaline)
11
a. Once NOR enters the cytoplasm of the neuron -
it may reenter the adrenergic vesicle via the
amine transporter system and be stored for
further release. b. NOR can also be oxidized by
monoamine oxidase (MAO) present within cells,
abundant intraneuronally (in mitochondria), or it
may be converted to O-methylated derivates by
catechol-O-methyltransferase (COMT), which is
associated within the membranes of postsynaptic
cells. The metabolic products - excreted in the
urine as - VMA (vanillylmandelic acid),
metanephrine, and normetanephrine.
12
The main processes involved in
synthesis, storage and release of amine and
amino acid transmitters
13
B. Adrenergic receptors (adrenoreceptors) Two
families of receptors, designated "alpha" and
"beta". For alpha receptors, the rank order of
potency is 1. epinephrine, 2. norepinephrine, 3.
isoproterenol For beta receptors, the rank
order of potency is 1. isoprotenerol, 2.
epinephrine, 3. norepinephrine 1) Alpha
receptors Subdivided in two groups - alpha 1
and alpha 2 receptors
14
Alpha 1 receptors higher affinity for
phenylephrine. Present on the postsynaptic
membrane of the effectors - mediate many classics
effects originally designated as alpha-adrenergic
effects. Activation of alpha 1 receptors ?
series of reactions through a G protein
activation of phospholipase C ? IP3 from
phosphatidylinositol ? release of Ca2 from the
endoplasmic reticulum into the cytosol ? a rise
in cytosolic calcium ions and activation of
calcium-dependent proteins kinases.
15
Alpha 2 receptors Primarily on presynaptic nerve
endings and on other cells (? cell of the
pancreas) - control adrenergic neuromediator and
insulin output. A portion of the released NOR
"circles back" and reacts with the a2 receptor on
the neuronal membrane - the stimulation of a 2
receptor causes feedback inhibition of the
release of NOR from the stimulated adrenergic
neuron. It decreases further output from the
adrenergic neuron and serves as a local
modulating mechanism for reducing sympathetic
neuromediator output when there is high
sympathetic activity. In contrast to a 1
receptors - the effects of binding at a 2
receptors are mediated by inhibition of adenylyl
cyclase and a fall in the levels of intracellular
cAMP.
16
2) Beta receptors Subdivided into two groups,
beta 1 and beta 2 (based on their affinities for
adrenergic agonists and antagonists) and beta 3
(adipose tissue). Beta 1 receptors approximately
equal affinities for ADR and NOR, located mainly
in the heart and GIT Beta 2 receptors higher
affinity for ADR (epinephrine) than for NOR
(norepinephrine), located in smooth muscle in
many organs (bronchial, vasculature of skeletal
muscle) and are particularly responsive to the
hormonal effects of circulating epinephrine
released by the adrenal medulla. Binding of a
neurotransmitter at the beta 1 or beta 2 receptor
results in activation af adenylate cyclyse and
therefore increased concentrations of cAMP within
the cell. Beta 3 receptors In adipose tissue,
lipolysis. Beta-presynaptic receptors positive
feedback to NOR release (its increase).
17
Further subdivisions The a 1 and a 2 receptors
are further divided into a 1A, a 1B, a 1C, and a
1D, and a 2A, a 2B, a 2C, and a 2D. This
classification is necessary for understanding the
selectivity of some drugs. E.g., tamsulosine is
a selective a 1A antagonist that is used to treat
benign prostate hypertrophy. The drug is
clinically useful because it targets a1A
receptors found primarily in the urinary tract.
18
Distribution of receptors Organs and tissues
have, in many instances, a predominance of one
type of receptor. Tissue such as the
vasculature to skeletal muscle have both alpha 1
and beta 2 receptors, but the beta 2 receptors
predominate. Other tissues may have one type of
receptor exclusively, with no significant
numbers of other types of adrenergic receptors
(e.g., the heart contains predominantly beta 1
receptors). Beta 3 especially present in adipose
tissue (lipolysis).
19
Desensitization of receptors (decrease in
response to catecholamines following their
prolonged exposure) mechanisms -
sequestration of receptors (unavailable for
interaction with ligand)- down-regulation
(disappearance of the receptors by their
destruction or decreased synthesis)- inability
to couple fo G-protein - because of the
phosphorylation of the receptor on cytoplasmic
site by either proteinkinase A or ß adrenergic
receptor kinase (ßARK).
20
Types of adrenergic receptors
A a Adrenoceptors
B b Adrenoceptors
Epinephrine
Norepinephrine
Isoproterenol
Norepinephrine
Epinephrine Isoproterenol
a Receptor
b Receptor
Low affinity
Low affinity
High affinity
High affinity
(according to Lippincotts Pharmacology, 2006)
21
Second messengers mediate the effects of a
receptors. DAG diacelglycerol IP3 inosinol
triphosphate
a2 Receptors Activation of the receptor decreases
production of cAMP, leading to an inhibition of
further release of norepinephrine from the neuron.
Synaptic vesicle
ATP cAMP
Adenylyl cyclase
a2 Receptor
Norepinephrine
a1 Receptor
DAG
Membrane phosphoinositides
Ca2
IP3
a1 Receptors Activation of the receptor increases
production of DAG and IP3 leading to an increase
in intracellular calcium ions.
(according to Lippincotts Pharmacology, 2006)
22
Feedback control of noradrenaline release
23
Major effects mediated by a and b adrenoceptors
Adrenoceptors
a1
b1
b2
a2

• Vasodilation
• Slightly decreased peripheral resistance
• Bronchodilation
• Increased muscle and liver glycogenolysis
• Increased release of glucagon
• Relaxed uterine smooth muscle

• Tachycardia
• Increased lipolysis
• Increased myocardial contractility
• Increased release of renin

• Inhibition of norepinephrine release
• Inhibition of insulin release

• Vasoconstriction
• Increased peripheral resistance
• Increased blood pressure
• Mydriasis
• Increased closure of internal sphincter of the
  bladder

(according to Lippincotts Pharmacology, 2006)
24
Characteristic responses mediated by
adrenoceptors alpha 1 receptors
vasoconstriction (particularly in skin and
abdominal viscera) and an increase in total
peripheral resistance and blood pressure,
relaxation of GIT smooth muscle (but
contraction of sphincters), salivary secretion,
hepatic glycogenolysis. alpha 2 receptors
inhibition of transmitter release, platelet
aggregation beta 1 receptors cardiac stimulation
(increased cardiac rate and force), relaxation
of GIT smooth muscle, lipolysis beta 2 receptors
vasodilation (in skeletal vascular beds),
bronchiolar relaxation and uterorelaxation,
relaxation of visceral smooth muscle, hepatic
glycogenolysis, muscle tremor beta 3 receptors
lipolysis
25
CHARACTERISTICS OF ADRENERGIC AGONISTS A.
Structure-activity relationship of adrenergic
agonists Most of the adrenergic drugs are
derivates of beta-phenylethylamine. 1.
Catecholamines Amines containing the
3,4-dihydroxybenzene group (e.g.epinephrine,
norepinephrine, isoprotenerol, and dopamine)
called catecholamines /3,4-dihydroxybenzene is
known as catechol/. Compounds share the
folloving properties a. High potency Drugs
with OH groups in the 3 and 4 position on the
benzene ring show the highest potency in
activating alpha or beta receptors. b.
Rapid inactivation Rapidly metabolized in the
gut by COMT and in the liver and gut wall
by MAO. Brief action when given parenterally,
ineffective when administered orally because of
poor absorption. c. Poor penetration into the
CNS Catecholamines are polar.
Nevertheless, some clinical effects (anxiety,
tremor, headaches) are attributable to
action on the CNS.
26
2. Non-catecholamines Lacking the catechol
hydroxyl groups. Longer half-lives, since they
are not metabolized by COMT. Drugs with a
substitution at the alpha-carbon, such as
ephedrine, which contains an alpha-methyl group,
are poor substrates for MAO prolonged
duration of action. Increased lipid solubility
permits greater access to the CNS. May act
indirectly by causing the release of stored
catecholamines. 3. Substitution on amine
nitrogen Important in determining the beta
selectivity of the adrenergic agonist.
Epinephrine ( -CH3 substituent) and
isoproterenol (isopropyl substituent -CH(CH3)2)
are strong beta agonist.
27
B. Mechanism of action of adrenergic agonists 1.
Direct-acting agonists Act directly on alpha or
beta receptors, effects similar to those
following stimulation of sympathetic nerves or
release of epinephrine. Examples epinephrine,
norepinephrine, isoproterenol, and
phenylephrine. 2. Indirect-acting agonists
Cause the release of norepinephrine from the
cytoplasma or vesicles of the adrenergic neuron.
Norepinephrine then stimulates the alpha or beta
receptors. Examples amphetamine and
tyramine. 3. Mixed-action mechanism both
directly stimulate adrenoceptors and cause the
release of NOR from the adrenergic
neuron. Examples Ephedrine and metaraminol.
28
Sites of action of direct-, indirect-, and
mixed-acting adrenergic agonists.
INDIRECT-ACTING Drug enhances release of
norepinephrine from vesicles.
Neuron
MIXED-ACTING Drug acts both directly and
indirectly.
Synapse
DIRECT-ACTING Drug directly activates receptor.
Postsynaptic target cell membrane
(according to Lippincotts Pharmacology, 2006)
29
Structures of several important adrenergic
agonists. Drugs containing the catechol ring are
shown in pink.
(according to Lippincotts Pharmacology, 2006)
30
Structure-activity relationships among
catecholamines and related compounds
31
DIRECT - ACTING ADRENERGIC AGONISTS A.
EPINEPHRINE (ep i NEF rin) ADRENALINE both
alpha and beta effects Used in therapy. ADR is
synthetized from tyrosine in the adrenal medulla
and released (with small quantities of
norepinephrine), into the blood stream. ADR
interacts with both alpha and beta receptors. At
low doses, beta effects on the vascular system
predominate at high doses, alpha effects are
strongest.
32
1.Actions a. Cardiovascular Heart positive
inotropic and positive chronotropic are beta 1
actions. Cardiac output therefore increases.
Increased oxygen demands on the myocardium.
Cardiac efficiency is reduced it can also cause
dyssrhythmias. Vessels constriction of
arterioles in the skin, mucuous membranes, and
viscera (alpha 1 effects), dilates vessels going
to skeletal muscle (beta 2 effects). Blood
pressure increase in systolic BP, coupled with a
slight decrease in diastolic pressure.
33
b. Smooth muscle alpha 1 contraction of all
types of smooth muscle, except that of GIT
(i.e., vessels, vas defferens, spleen
capsule, m.dilatator pupilae,
sphincters in GIT and urogenitaly tract) beta
relaxation of most kind of smooth muscle, usually
by beta 1 receptors (in GIT not clear,
probably both subtypes), i.e. -
vasodilation (particularly in skeletal muscle) -
?2 - bronchodilation - ?2 - uterorelaxation -
?2 c. Respiratory Bronchodilation by acting
directly on bronchial smooth muscle (beta 2
action) - it relieves all known allergic - or
histamine induced bronchoconstriction. In
anaphylactic shock - this can be lifesaving.
Epinephrine rapidly relieves the dyspnea (labored
breathing) and increases the tidal volume (volume
of gases inspired and expired).
34

• d. Metabolism conversion of energy stores
  (glycogen and fat) to freely
• available fuels (glucose and FFA)
• Hyperglycemia increased glycogenolysis (beta 2
  effect),
• increased release of glucagon (beta 2), and a
  decreased release
• of insulin (alpha 2).
• Lipolysis lipolysis (beta 1). Stimulation of
  beta 2 and beta 3 receptors
• on adipose tissue ? activation of adenylcyclase
  ? c AMP. c AMP
• stimulates a hormone-sensitive lipase, which
  initiates the hydrolysis
• of the triacylglycerol to free fatty acids and
  glycerol.
• d. other
• - inhibition of histamine release
• - twitch tension of fast-contracting fibres
  (white muscle)
• - eye mydriasis (contraction of m.dilatator
  pupilae)

35
2. Biotransformations Two enzymatic pathways -
COMT and MAO. The final metabolites found in the
urine are metanephrine and vanillylmandelic
acid. Note Urine also contains normetanephrine,
a product of norepinephrine
metabolism. 3. Therapeutic uses a. Bronchospasm
In treatment of acute asthma and anaphylactic
shock, epinephrine is the drug of choice (within
a few minutes after s.c. administration -
greatly improved respiratory exchange).
Administration may be repeated after a few
hours. However, selective beta 2 agonists are
favoured in the chronic treatment of asthma
(longer duration of action). b. Glaucoma 2
epinephrine topically reduce intraocular pressure
in open-angle glaucoma. It reduces the
production of aqueous humour by vasoconstriction
of the ciliary body blood vessels.
36
c. Anaphylactic shock Drug of choice for the
treatment of acute hypersensitivity reactions
(type I hypersensitivity) d. In anesthetics
Local anesthetic solutions may contain 1100,000
parts ADR. e. Nasal decongestion Very weak
solutions of epinephrine 1100,000 can also be
used topically to vasoconstrict mucous
membranes. 4. Pharmacology Rapid onset but
brief duration of action. Administered
subcutaneously, by inhalation, or topically to
the eye. Oral administration is ineffective (ADR
and other catecholamines are inactivated by the
intestine).
37
Pharmacokinetics of epinephrine
Poor penetration into the CNS
IV SC
Aerosol
Topical
Metabolites appear in the urine
(according to Lippincotts Pharmacology, 2006)
EPINEPHRINE
38
Cardiovascular effects of intravenous infusion of
low doses of epinephrine.
Epinephrine increases the rate and force of
cardiac contraction.
Infusion of epinephrine
100
Pulse rate (per min)
50
180
Blood pressure (mmHg)
120
60
High
Peripheral resistance
Low
0 15 Time (min)
Systolic pressure is increased, and diastolic
pressure is decreased.
Epinephrine decreases the peripheral resistance.
(according to Lippincotts Pharmacology, 2006)
39
5. Adverse effects a. CNS disturbances Anxiety,
fear, tension, headache, and tremor. b.
Hemorrhage Cerebral hemorrhages as a result of
the vasopressor effects, causing a marked
elevation of blood pressure. c. Cardiac
arrhythmias It can trigger cardiac arrhythmias,
particularly if the patient is receiving
digitalis. d. Pulmonary edema ADR can induce
pulmonary edema. 6. Interactions a.
Hyperthyroidism Enhanced cardiovascular actions
in patients with hyperthyroidism. The mechanism
appears to involve increased production of
adrenergic receptors in the hyperthyroid
individual. b. Cocaine In the presence of
cocaine, ADR produces exaggerated cardiovascular
actions. Due to the ability of cocaine to prevent
re-uptake of catecholamines, thus ADR (like NOR)
remains at the receptor site for longer periods
of time.
40
B. NOREPINEPHRINE (nor ep i NEF rin)
NORADRENALINE It stimulates all types of
adrenergic receptors. The alpha-adrenergic
receptor is most affected, weak beta 2
effects. Actions 1. Cardiovascular a.
Vasoconstriction Intense vasoconstriction ? ?
peripheral resistance (alpha1 effect). Both
systolic and diastolic BP increase. b.
Baroreceptor reflex In vivo, little if any
cardiac stimulation is noted. (NOR induces a
reflex increase in vagal activity by
?baroreceptor activity). Bradycardia
counteracst the local actions of NOR on the
heart. c. Effect of atropine pretreatment If
atropine (blocks the transmission of vagal
effects) is given before NOR ? NOR
stimulates the heart and produces tachycardia.
41
2. Therapeutic uses - Shock, however, dopamine
is better (it does not reduce blood flow to
the kidney as does NOR). Never used for
asthma. - Vasoconstrictor agent with local
anesthetics.
42
Norepinephrine induces reflex bradycardia
Cardiovascular effects of intravenous infusion of
norepinephrine.
Infusion of norepinephrine
100
Pulse rate (per min)
50
180
Blood pressure (mmHg)
120
60
High
Peripheral resistance
Low
0 15 Time (min)
Norepinephrine causes increased systolic and
diastolic pressure
Norepinephrine constricts all blood vessels,
causing increased peripheral resistance.
(according to Lippincotts Pharmacology, 2006)
43
C. ISOPROTERENOL (eye soe proe TER a nole)
ISOPROPYLNORADRENALINE direct-acting synthetic
catecholamine - predominantly stimulates both
beta 1 and beta 2 receptors (i.e.,
non-selective) 1. Actions a. Cardiovascular
Intense stimulation of the heart to increase its
rate and force of concentration, causing
increased cardiac output. Therefore useful
in the treatment of atrioventricular block or
cardiac arrest. Dilates the arterioles of
skeletal muscle (beta 2) ? a decrease in
peripheral resistance. Because of its
cardiac stimulatory action, it may increase
systolic BP slightly, but it greatly reduces
mean arterial and diastolic BP. b. Pulmonary A
profound and rapid bronchodilation (beta 2
action), rapidly alleviates an acute attack
of asthma, when taken by inhalation. Action
lasts about one hour. c. Other effects Actions
on beta receptors, increase in blood sugar,
increased lipolysis, not clinically significant.
44
2. Therapeutic uses Bronchodilator in asthma.
Stimulation of the heart. 3. Administration Abso
rbed systemically, but by the sublinqual mucosa
it is more reliably absorbed parenterally or as
an inhaled aerosol. It is a marginal substrate
for COMT and is stable to MAO action . 4.
Adverse effects Similar to ADR. Dangerous when
chronically used for bronchodilatation
(stimulation of the heart may leads to
micronecrosis and ischemia of myocardium) !!
45
Cardiovascular effects of intravenous infusion of
isoproterenol.
Isoproterenol causes vasodilatation but strongly
increases cardiac force and rate.
Infusion of isoproterenol
100
Pulse rate (per min)
50
180
Blood pressure (mmHg)
120
60
High
Peripheral resistance
Low
0 10 Time (min)
Isoproterenol causes a significant decrease in
peripheral resistance
Isoproterenol causes markedly decreased diastolic
pressure, with moderately increased systolic
pressure.
(according to Lippincotts Pharmacology, 2006)
46
D. DOPAMINE (DOE pa meen) Metabolic
precursor to NOR, occurs naturally in the CNS (in
the basal ganglia) as a neurotransmitter.
Dopamine can activate alpha- and beta-adrenergic
receptors. In addition, dopaminergic receptor
(distinct from alpha and beta receptors) occur in
the peripheral mesentric and renal vascular
beds. 1. Actions a. Cardiovascular
actions Inotropic and chronotropic effects.
Very high doses activation of alpha receptors
on the vasculature ? vasoconstriction.
47
b. Renal and visceral actions Dilates renal and
splanchnic arterioles by activating dopaminergic
receptors, thus increasing blood flow to the
kidneys and other viscera. These receptors are
not affected by alpha- or beta-blocking drugs.
Therefore, useful in the treatment of shock, in
which significant increases in sympathetic
activity might compromise renal function. Note
Similar dopamine receptors are found in the
autonomic ganglia and in the
CNS. D2 receptors are also found on presynaptic
adrenergic neurons, where their activation
interferes with NOR release.
48
2. Therapeutic uses a. Shock Drug of choice for
shock (given by continuous infusion). It raises
the blood pressure by stimulating the heart (beta
1 action). It enhances perfusion to the kidney
and splanchnic areas. Increased blood flow to
the kidney enhances the glomerular filtration
rate and causes sodium diuresis. Note NOR
diminishes the blood supply to the kidney and may
cause kidney shutdown. b. Congestive heart
failure Refractory congestive heart failure. 3.
Adverse effects An overdose produces the same
effects as sympathetic stimulation. Dopamine is
rapidly metabolized to homovanilic acid, and its
adverse effects (nausea, hypertension,
arrhythmias) are therefore short-lived.
49
E. DOBUTAMINE (doe BYOO ta
meen) synthetic, direct acting beta 1 receptor
agonist. 1. Actions increases cardiac
contractility and output with few vascular
effects. 2. Therapeutic uses Used to increase
cardiac output in congestive heart failure. It
increases cardiac output with little change in
heart rate - not significantly elevation of
oxygen demands of the myocardium - a major
advantage over other sympathomimetic drugs. 3.
Adverse effects a. Cardiovascular Caution in
atrial fibrillation (it increases AV
conduction. b. Other The same as ADR.
Tolerance may develop on prolonged use.
50
F. PHENYLEPHRINE (fen ill EF rin) direct-acting,
synthetic adrenergic drug that binds primarily to
alpha receptors and favors alpha 1 receptors
over alpha 2. Actions 1. Cardiovascular effects
Vasoconstrictor raises both systolic and
diastolic BP. No effect on the heart itself but
induces reflex bradycardia. Often used topically
on the nasal mucous membranes and in ophthalmic
solutions for mydriasis. 2. Therapeutic
uses Nasal decongestant. To raise blood pressure
and to terminate episodes of supraventricular
tachycardia. 3. Adverse effects Hypertensive
headache and cardiac irregularities.
51
G. METHOXAMINE (meth OX a meen) direct-acting
synthetic non-selective adrenergic drug that
binds primarily to alpha receptors, with alpha 1
receptors favoured over alpha 2. It raises BP,
vasoconstriction. Increase in total peripheral
resistance. Used clinically to relieve attacks of
paroxysmal supraventricular tachycardia. Does
not tend to trigger cardiac arrhythmias in the
heart that is sensitized by these general
anesthetics H. oxymetazoline, tetryzoline and
xylometazoline (used locally, e.g. in
rhinitis) I. alpha-METHYL-NORADRENALINE direct-ac
ting mostly alpha 2 agonist adrenergic drug.
Used in hypertension (methyldopa).
52
J. CLONIDINE (KLOE ni deen) alpha 2 agonist, used
in essential hyertension to lower blood pressure
because of its action on the CNS. Minimize the
symptoms that accompany withdrawal from opiates
or benzodiazepines. Acts centrally to produce
inhibition of sympathetic vasomotor centers. K.
METAPROTERENOL met a proe TEA a nole
chemically similar to isoproterenol, but it is
not a catecholamine, It is resistant to
methylation by COMT. Administered orally or by
inhalation. The drug acts primarily at beta 2
receptors, producing little effect on the heart.
It produces dilation of the bronchioles and
improves airway function. The drug is useful as a
bronchodilator.
53
L. ? 2 agonists - short acting Albuterol,
pirbuterol, terbutaline and other albuterol al
BYOO ter olepirbuterol peer BYOO ter
oleterbutaline ter BYOO te leen
short-acting ? 2 agonists - used primarily as
bronchodilators (administered by a metered-dose
inhaler).Compared with the nonselective ?
-adrenergic agonists (metaproterenol) they
produce equivalent bronchodilation with less
cardiac stimulation.
54
TERBUTALINE (ter BYOO te leen) -selective beta 2
agonist, longer duration of action. Used as a
bronchodilator and to reduce uterine contractions
in premature labor. RITODRINE (RI toe dreen) -
selective beta 2 agonist. Used to relax the
uterine contractions of premature
labor. ALBUTEROL (al BYOO ter ole) - selective
beta 2 agonist similar to terbutaline. Used to
relieve bronchospasm SALBUTAMOL selective beta 2
agonist similar to terbutaline. Used to relieve
bronchospasm, premature labour.
55
M. ? 2 agonists long-acting CLENBUTEROL,
REPROTEROL, PROCARTELOL, FORMOTEROL, SALMETEROL
beta 2 adrenergic selective, long-acting
bronchodilators. A single dose by a
metered-dose inhaler provides sustained
bronchodilation over 12 hours (compared with less
than 3 hours for albuterol). Salmeterol has a
somewhat delayed onset of action (unlike
formoterole).
56
THERAPEUTIC USE OF SELECTIVE BETA 2 AGONISTS -
asthma bronchiale (bronchodilatation) - premature
labour (uterorelaxation) Adverse effects of
selective beta 2 agonists - tachycardia,
dysrhythmias - tremor - peripheral vasodilation
57
Summary of the adrenergic agonists
Drug Receptor Therapeutic
uses specificity
Epinephrine a1, a2, b1, b2 Acute
asthma Treatment of open- angle
glaucoma Anaphylactic shock In local
anesthetics to increase duration
of action Norepinephrine a1, a2,
b1 Treatment of shock Isoproterenol b1,
b2 As a cardiac stimulant Dopamine Dopaminergic
Treatment of shock a1, b1
Treatment of congestive heart
failure, Raise blood pressure Dobutamine
b1 Treatment of congestive heart
failure Phenylephrine a1 As a nasal
decongestant Raise blood pressure Treatmen
t of paroxysmal supraventricular tachycardia

• Catecholamines
• Rapid onset of
• action
• Brief duration of
• action
• Not administered
• orally
• Do not penetrate
• the blood-brain
• barrier

(according to Lippincotts Pharmacology, 2006)
58
Summary of the adrenergic agonists
Drug Receptor Therapeutic
uses specificity
Methoxamine a1 Treatment of
supraventricu- lar tachycardia Clonidine
a2 Treatment of hypertension Metaproterenol
b2 gt b1 Treatment of bronchospasm and
asthma Terbutaline b2 Treatment of
bronchospasm Albuterol (short
acting) Salmeterol b2 Treatment of
bronchospasm Formoterol (long
acting) Amphetamine a, b, CNS As a CNS
stimulant in treat- ment of children with
attention deficit syndrome,
narcolepsy, and appetite control Ephedrine
a, b, CNS Treatment of asthma As a nasal
decongestant Raise blood pressure

• Noncatechol-amines
• Compared to catecholamines
• Longer duration of
• action
• All can be
• administered orally

(according to Lippincotts Pharmacology, 2006)
59
Sites of action of direct-, indirect-, and
mixed-acting adrenergic agonists.
INDIRECT-ACTING Drug enhances release of
norepinephrine from vesicles.
Neuron
MIXED-ACTING Drug acts both directly and
indirectly.
Synapse
DIRECT-ACTING Drug directly activates receptor.
Postsynaptic target cell membrane
(according to Lippincotts Pharmacology, 2006)
60
INDIRECT - ACTING ADRENERGIC AGONISTS A.
AMPHETAMINE (am FET a meen) Is an indirect-acting
adrenergic drug. Actions - marked central
stimulatory action (not only NOR release, but
also the release of 5-HT and dopamine in CNS), -
increase of NOR release, - MAO inhibitor, -
uptake 1 inhibitor. However, the drug can
increase blood pressure significantly by
alpha-agonist action as well as beta-stimulatory
effects on the heart. Peripheral actions are
mediated primarily through the cellular release
of stored catecholamines. Absorbed orally,
penetrates into brain, plasma T0.5 about 12
hours, excreted in urine. Use and function - CNS
stimulant in narcolepsy - appetite suppressant
61
Adverse effects Hypertension, tachycardia,
insomnia, acute schizophrenia-like psychosis
(with hallucination and stereotyped behavior) in
overdose. Loss of appetite. Euphoria and
excitement. Drug of abuse drug dependence
! Marked tolerance develops !
62
B. TYRAMINE (teer a meen) not clinically useful
drug, but it is found in fermented foods, such as
ripe cheese and Chianti wine. Note
Contraindication of combination of this food with
MAO-inhibitors (marked hypertension) !! It is a
normal by-product of tyrosine metabolism.
Tyramine can enter the nerve terminal and
displace stored norepinephrine and the released
catecholamine acts on adrenoceptors.
63
MIXED - ACTION ADRENERGIC AGONISTS A. EPHEDRINE
(e FED rin) a plant alkaloid, is now made
synthetically. Mixed-action adrenergic agent.
It not only releases NOR from nerve endings, but
also directly stimulates both alpha and beta
receptors. Less potent. CNS stimulant. It is not
a catechol and so it is a poor substrate for COMT
and MAO long duration of action. Excellent
absorption orally and penetrates into
CNS. Treatment of inhibition in intoxication with
local anesthetics.
64

• Actions
• Cardiovascular ? systolic and diastolic BP by
  vasoconstriction and
• cardiac stimulation.
• b. Pulmonary Bronchodilation, is less potent
  than epinephrine or
• isoproterenol and produces its action more
  slowly. Therefore used
• prophylactically in chronic treatment of asthma.
• c. Skeletal muscle ? contractility and improves
  motor function in
• myasthenia gravis (particularly when used with
  anticholinesterases).
• d. CNS Mild stimulation. Increases alertness,
  decreases fatigue,
• prevents sleep. Improves athletic performance.
• Therapeutic uses
• - Asthma
• - nasal decongestant
• - to raise blood pressure.
• - milder form of inhibition in intoxication with
  local anesthetics

65
Adverse effects - Vasoconstriction in pulmonary
vessels after long-term administration. -
Other similar to amphetamine, but less
pronounced. Contraindicated if MAO inhibitors
are given ! Tolerance, tachyphylaxis develops !
66
Epinephrine
Phenylephrine
Ephedrine
67
B. METARAMINOL (met a RAM i nole) mixed-acting
adrenergic drug with actions similar to
norepinephrine. Treatment of shock (when an
infusion of norepinephrine or dopamine is not
possible) and to treat acute hypotension. Given
parenterally as a single injection. It enhances
cardiac activity and produces mild
vasoconstriction.
68
Adrenergic Antagonists
69
Summary of blocking agents and drugs affecting
neurotransmitter uptake or release
Adrenergic blockers
a - blockers
Doxazosin Phenoxybenzamine Phentolamine Prazosin T
amsulosin Terazosin
b - blockers
Acebutolol Atenol Carvediol Esmolol Labetalol Meto
prolol Nadolol Pindolol Propranolol Timolol
Drug affecting neurotransmitter uptake or release
Cocaine Guanethidine Reserpine
(according to Lippincotts Pharmacology, 2006)
70
ADRENERGIC ANTAGONISTS The adrenergic
antagonists (blockers) bind to adrenoceptors
but do not trigger the usual receptor-mediated
intracellular effects. They act by either
reversibly or irreversibly binding to receptors,
thus preventing their activation. Classified
according to their relative affinity for alpha or
beta receptors.
71
ALPHA-ADRENERGIC BLOCKING AGENTS main
groups /1/ non-selective (phenoxybenzamine,
phentolamine, tolazoline) /2/ ?1-selective
antagonists (prazosine) /3/ ?2-selective
antagonists (yohimbine, idazoxan) /4/ ergot
derivatives (many actions in addition to
a-blocking activity) Profound effects on blood
pressure. Alpha-adrenergic receptor blockade
reduces the sympathetic tone of the blood
vessels, resulting in decrease of peripheral
vascular resistance. This induces a reflex
tachycardia. The alpha-receptor blocking agents,
with the exception of prazosin and labetalol,
have only limited clinical applications
(concomitant block of ?2-receptors tends to
increase NOR release).
72
ad 1) non-selective A. PHENOXYBENZAMINE (fen ox
ee BEN za meen) forms a covalent linkage to the
alpha 1-postsynaptic and alpha 2-presynaptic
receptors. The block is irreversible and
noncompetitive. The synthesis of new receptors
occur in approximately one day. Therefore, the
actions of phenoxybenzamine last at least 24
hours. A delay of a few hours occurs before alpha
blockade develops, since the molecule must
undergo metabolic transformation to the active
form. 1. Actions a. Cardiovascular effects
Blocks alpha receptors and prevents
vasoconstriction by endogenous catecholamines
decrease in BP and peripheral resistance ?
reflex tachycardia. Not successful in
maintaining lowered blood pressure.
73
Covalent inactivation of a1 adrenoceptor by
phenoxybenzamine
Phenoxybenzamine
Rapid
Covalent bond
Effector cell membrane
(according to Lippincotts Pharmacology, 2006)
Covalently inactivated a1-adrenoceptor
74
b. Postural hypotension Phenoxybenzamine induces
postural (orthostatic) hypotension. c.
Epinepherine reversal see below d. Sexual
function Adversely affects male sexual function.
Ejaculation of semen is inhibited.
75
Epinephrine reversal All a-adrenergic blockers
reverse the a-agonist actions of epinephrine.
E.g., the vasoconstrictive action of epinephrine
is interrupted, but vasodilation of other
vascular beds caused by stimulation of b
receptors is not blocked ? systemic BP decreases
in response to epinephrine given in the presence
of phenoxybenzamine Note The actions of NOR
are not reversed but are diminished, because
norepinephrine lacks significant b-agonist action
on the vasculature. Phenoxybenzamine has no
effect on the actions of isoproterenol, which is
a pure b agonist.
76
Summary of effects of adrenergic blockers on the
changes in blood pressure induced by
isoproterenol, epinephrine, and norepinephrine
a-Adrenergic blockers have no effect on the
actions of isoproterenol, which is a pure
b-agonists.
Pre- treatment with an b- blockers
Pre- treatment with an a- blockers
Untreated control
Catecholamine
200
Isoproterenol
(mmHg)
0
200
Epinephrine
0
200
Norepinephrine
0
a-Adrenergic blockers reverse the
vasoconstrictive action of epinephrine.
(according to Lippincotts Pharmacology, 2006)
77
2. Therapeutic uses a. Urinary system
Phenoxybenzamine treatment results in the
inability of the internal sphincter of the
bladder to close completely. Useful in patients
with neurogenic vesicular dysfunction, in which
the internal sphincter closes spontaneously
during micturition. b. Paraplegics All
paraplegics suffer from autonomic hyperreflexia.
Enhanced BP. This predisposes paraplegics to
strokes. Phenoxybenzamine blunts this effect and
aids in normalizing the paraplegic patient s
blood pressure. c. Benign prostatic hypertrophy
Reducing the size of the prostate more
normal urination. d. Treatment of
pheochromocytoma (a catecholamine-secreting tumor
of cells derived from the adrenal medulla). Used
in cases where the catecholamine-secreting cells
are diffuse and therefore inoperable.
78
3. Adverse effects a. Postural hypotension,
inhibition of ejaculation, nasal stuffiness,
nausea and vomiting. b. Tachycardia, mediated by
the baroreceptor reflex. c. Pupillary
constriction.
79
B. PHENTOLAMINE (fen TOLE a meen), TOLAZOLINE 1.
Actions Produces a competitive reversible block
of alpha 1 and alpha 2 receptors. Short-lasting
action (approximately 4 hours). It produces
postural hypotension. 2. Therapeutic uses a.
Pheochromocytoma In the diagnosis and in the
other situations associated with excess
release of catecholamines. b. Frostbite
Occasionally, used for rapid alpha 1 blockade. To
increase blood flow to the digits by
dilation of the arterioles. 3. Adverse
effects a. Cardiac Reflex cardiac stimulation
and tachycardia, mediated by the
baroreceptor reflex. Also trigger arrhythmias and
anginal pain. b. Postural hypotension c. GIT
stimulation, aggravation of peptic ulcers.
80

• ad 2) ?1 - selective antagonists
• PRAZOSIN (PRA zoe sin), TERAZOSIN (ter AY zoe
  sin),
• DOXAZOSIN (longest acting)
• competitive block of alpha 1 receptor without
  blocking alpha2 receptor.
• Effective in the treatment of hypertension.
• 1. Cardiovascular effects Vasodilation and
  decrease in peripheral
• vascular resistance and lowering of arterial
  blood pressure by relaxation
• of both arterial and venous smooth muscle. Only
  minimal changes in
• cardiac output, renal blood flow, and glomerular
  filtration rate.
• 2. Therapeutic uses Elevated blood pressure. The
  first dose of prazosin
• produces an exaggerated hypotensive response and
  syncope (fainting) in
• some patients. Minimized by adjusting the first
  dose to one third or one
• fourth of normal dose.
• 3. Adverse effects
• a. Nasal congestion, GI hypermobility, fluid
  retention, and orthostatic
• hypotension. b. Male sexual function is not as
  severely affected.

81
An additive antihypertensive effect occurs when
prazosin is given with either a diuretic or a
beta-blocker ? reduction in its dose. Due to a
tendency to retain sodium and fluid, prazosin is
frequently used along with a diuretic. B.
TAMSULOSIN AND ALFUZOSIN antagonists of ?1A
receptors in prostatic gland used in the benign
hypertrophy of the gland (they have lower
hypotensive effects in comaprison with, e.g.,
prazosin)
82
ad 3) ?2-selective antagonists (yohimbine,
idazoxan) YOHIMBINE naturally occurring alkaloid
(idazoxan is synthetic analogue). Vasodilator
effect has given its fame as an aphrodisiac. ad
4) ergot derivatives a. naturally occurring
ERGOTAMIN, ERGOTOXIN,
ERGOMETRIN partial agonists at alpha
and 5-HT receptors occur naturally in fungus
(Claviceps purpurea) that infests cereal crops.
Poisoning when contaminated grain is used for
food. - Ergotismus convulsivus (mental
disturbances, convulsions) - Ergotismus
gangrenosus (peripheral vasoconstriction
gangrene, constriction of coronary arteries)
83
1. Actions - stimulation of smooth muscle incl.
vessels leads to vasoconstriction - uterine
contraction - nausea, vomiting 2. Therapeutic
uses - migraine (prophylactic - vasoconstriction
of meningeal vessels and influence on 5-HT
receptors) - ergometrin may be used for reduction
of post-partum metrorrhagia b. semisynthetic
derivatives of ergot alkaloids Dihydro-derivativ
es (DH-ergotamin) have increased
alpha-antagonistic effect. Methyl-derivatives
(Methylergometin) methylation increases
uterotonic activity
84
c. other derivatives BROMOCRIPTINE dopamine
receptor agonist, wide spectrum of activities,
used in - inhibition of prolactin release,
suppression of lactation - increase in growth
hormone release in healthy people but
suppression of growth hormone release in
acromegaly (treatment of acromegaly)! -
treatment in parkinsonis METHYSERGID the most
active serotonin (5-HT) antagonist NICERGOLINE syn
thetic derivative, it also decreases aggregation
of platelets
85
BETA - ADRENERGIC BLOCKING AGENTS Beta blockers
are competitive antagonists. Nonselective beta
blockers block both beta 1 and beta 2 receptors.
Cardioselective beta blockers primarily block
beta 1 receptors. Drugs also show differences in
intrinsic sympathomimetic activity, in CNS
effects, and in pharmacokinetics. Although all
beta blockers lower BP in hypertension, they do
not induce postural hypotension because the
alpha adrenoceptor is not blocked. Also
effective in treating angina, cardiac arrhytmias,
myocardial infarction, glaucoma, and prophylaxis
of migraine headaches. Beta-blockers may posses
three main properties - ?-adrenoceptor
selectivity non-selective (i.e., ?1 and ?2)
blockers selective (i.e., ?1) or
cardioaselective blockers - ISA (e.i., intrinsic
sympathomimetic activity) means that they posses
partial agonist effect on beta-receptors - MSA
(membrane stabilising effect or quinidine-like
effect), clinically probably insignificant
86
Pharmacokinetics Most drugs can be given orally
once daily (either ordinary or sustained-release
formulation). Importance of the solubility for
the use - lipid-soluble (e.g., propranolol,
metoprolol, oxprenolol, labetalol) - extensive
hepatic first pass metabolism (e.g., propranolol
is metabolised in 80) after oral
administration, enter CNS - water-soluble (e.g.,
atenolol, sotalol, practolol) - less metabolised
in liver, excreted unchanged by the kidney
prolongation of T0.5 in renal failure, lower
penetration to CNS
87
1. Actions a. Heart Reduced myocardial
contractility and cardiac automaticity. ? C.O.
(negative inotropic and chronotropic effects).
Bradycardia. Cardiac output, work, and
oxygen consumption ? by blockade of beta 1
receptors (useful in the treatment of angina). b.
Peripheral vasoconstriction The decrease in
cardiac output leads to decreased blood
pressure ? reflex peripheral vasoconstriction,
reduced blood flow to the fingers and toes.
Reduction of both systolic and diastolic BP in
hypertensive patients. No postural hypotension
(alpha- adrenergic receptor that controls
vascular resistance is unaffected). c.
Bronchoconstriction contraction of the smooth
muscle in the bronchioles. d. Increased Na
retention ? BP ? ? renal perfusion ? increase in
Na retention and plasma volume. Often
combined with a diuretic.
88
e. Disturbances in glucose metabolism Decreased
glycogenolysis and decreased glucagon
secretion. In diabetics very careful
monitoring of blood sugar is essential, since
pronounced hypoglycemia may occur affter insulin
injection. Beta-blockers also attenuate the
normal physiologic response to hypoglycemia.
f. Blocks action of isoproterenol All beta
blockers, have the ability to block the
actions of isoproterenol on the cardiovascular
system ? Isoproterenol does not produce
decrease in mean arterial pressure, the
decrease in diastolic pressure, nor cardiac
stimulation.
89

• 2. Therapeutic uses
• C a r d i o v a s c u l a r
• Hypertension Lower BP in hypertension by ?
  cardiac output, by
• ? renin release from juxtaglomerular cells of
  the kidney, by ? sympathetic
• activity in CNS, by block of presynaptic beta
  receptors, by the effect on
• baroreceptors.
• b. Angina pectoris ? oxygen requirement of the
  heart ? effective in
• reducing the chest pain. However, treatment
  does not allow strenuous
• physical exercise.
• c. Cardiac tachydysrhythmias
• d. Myocardial infarction (- to prevent
  re-infarction, - to reduce acute
• mortality /contraindicated when bradycardia,
  hypotension or LV failure
• occur/) - protective effect on the myocardium.
• Patients protected against a second heart
  attack by prophylactic use of
• beta blockers. Administration immediately
  following a IM - reduces
• infarct size and quickens recovery (by blocking
  of the actions of released
• catecholamines etc.) from damaged cardiac
  tissue. Reduces the
• incidence of sudden arrhythmic death after
  myocardial infarction.

90
e. Aortic dissection and after subarachnoidal
haemorrhage f. oesophageal variceal bleeding (to
reduce hepatic portal hypertension) g.
compensated heart failure E n d o c r i n e a.
Hyperthyroidism Blunting the sympathetic
stimulation in hyperthyroidism. In acute
hyperthyroidism may be lifesaving in protecting
against serious cardiac arrhythmias. b.
Phaeochromocytoma block of the effects of
circulating catecholamines (in combination with
alpha - blockers)
91
E y e s a. Glaucoma Particularly timolol
diminish intraocular pressure in glaucoma. By
decreasing the secretion of aqueous humour by the
ciliary body. They neither affect the ability
of the eye to focus for near vision, nor change
pupil size. However, in an acute attack of
glaucoma, pilocarpine is still the drug of
choice. C N S a. Migraine Reduction of
migraine episodes. Treatment of chronic migraine
(decrease of incidence and severity of the
attacks). The mechanism may be block
catecholamine-induced vasodilation in the brain.

Note During
an attack - therapy with sumatripan or other
drugs is used. b. Anxiety with somatic
symptoms, alcohol and opioid acute withdrawal
symptoms.
92
3. Adverse effects a. Bronchoconstriction
Serious and potentially lethal in asthmatic.
Deaths by asphyxiation have been reported ?
propranolol must never be used in treating any
individual with obstructive lung disease. b.
Arrhythmias Treatment with the beta blockers
must never be stopped quickly !!! Rebound
phenomenon rapid withdrawal may precipitate
cardiac arrhythmias. Must be tapered off
gradually during one week. c. Cardiac failure d.
Incapacity for vigorous exercise (failure of
cardiovascular system to respond to
sympathetic drive) e. Hypotension (after
myocardial infarction) f. Reduced peripheral
blood flow (cold extremities, intermittent
claudication may be worsened)
93
g. Reduced blood flow to liver and kidney
(reduction of metabolism and elimination of
some drugs) h. Sexual impairment A number of men
complain of impaired sexual activity. i.
Disturbances in glucose metabolism Hypoglycaemia
(especially with non-selective beta blockers)
- decreased glycogenolysis and decreased
glucagon secretion. Fasting hypoglycemia may
occur. Cardioselective beta-blockers are
preferred. k. Plasma lipoproteins
Triacylglycerol levels are increased, decrease
of HDL/LDL ratio) l. Other Oulomucocutaneous
syndrome (with chronic use of practolol,
immunological basis?)
94
Adverse effects commonly observed in individuals
treated with propranolol.
Arrhythmia
Bronchoconstriction
(according to Lippincotts Pharmacology, 2006)
Sexual dynsfunction
95
Actions of propranolol and other b-blockers.
P R O P R A N O L O L
Bronchoconstriction
b2
Reflex peripheral vasoconstriction
b2
Na
Increased sodium retention
Rate Force
Decreased cardiac output
b1
Acebutolol Atenolol Metoprolol
(according to Lippincotts Pharmacology, 2006)
96
4. Interactions a. Pharmacokinetic due to ?
blood flow in liver and kidney (? metabolism of
lignocain, chlorpromazine). Drugs that interfere
with the metabolism (cimetidine, furosemide,
chlorpromazine) - may potentiate antihypertensive
effects. Conversely, those that stimulate its
metabolism (barbiturates, phenytoin, rifampin) -
can mitigate effects. b. Pharmacodynamic
increased effect of direct alpha and beta
agonists, - potentiation of effects of other
antiarrhytmic agents (hypotension, bradycardia,
heart blocks), - hazardeous combination with
i.v. verapamil in LV dysfunction, potentiation
of effects of other antihypertensives, of
hypoglycaemia of insulin and sulphonylureas
(with non-selective drugs) - In pregnancy enter
the fetus and may cause neonatal bradycardia and
hypoglycaemia. Possible teratogenity when
used in early pregnancy.
97
B Antagonists (for example,
propranolol)
Epinephrine
b1 and b2 receptors blocked but not activated.
(according to Lippincotts Pharmacology, 2006)
98
C Partial agonists (for example,
pindolol and acebutolol)
b1 and b2 receptors partially activated but
unable to respond to more potent catecholamines.
DECREASED CELLULAR EFFECTS
(according to Lippincotts Pharmacology, 2006)
99
Individual beta-blockers A. PROPRANOLOL (proe
PRAN oh lole) a prototype, non-selective - blocks
both beta 1 and beta 2 receptors. B. TIMOLOL
(TYE moe lole) nonselective beta blocker. Reduces
the production of aqueous humour in the eye,
used topically in the treatment of glaucoma and
systemically for treating hypertension.
100
C. ACEBUTOLOL, ATENOLOL, METOPROLOL,
ESMOLOL Preferentially block the beta 1
receptors, eliminate the unwanted
bronchoconstrictor effect (beta 2). They
antagonize beta 1 receptors at doses 50 to 100
times less than that required to block beta 2
receptors. The cardioselectivity is thus most
pronounced at low doses and is lost at high drug
doses. Acebutolol has some intrinsic agonist
activity Esmolol El moe lole - a very short
lifetime (due to metabolism of an ester linkage).
Only i.v. during surgery or diagnostic
procedures. 1. Actions ? BP in hypertension and
in angina. Relatively little effect on pulmonary
function, peripheral resistance, and carbohydrate
metabolism. Nevertheless - carefully monitor
asthmatics. 2. Therapeutic use in hypertension
Useful in hypertensive patients with impaired
pulmonary function. Less effect on peripheral
vascular beta 2 receptors ? coldness of
extremities is less frequent. Useful in diabetic
hypertensive patients.
101
D. PRACTOLOL Beta 1 selective, used only by
injection for short-term control of cardiac
dysrhythmias (dangerous adverse effect). E.
PINDOLOL, BOPINDOLOL other OXPRENOLOL,
ALPRENOLOL, CLORANOLOL, PENBUTOL CARTEOLOL,
CELIPROLOL Non-selective, partial agonist
lower decrease of heart rate and cardiac
contractility, decrease in bronchospastic
activity. 1. Actions a. Cardiovascular Ability
to weakly stimulate both beta 1 and beta 2
receptors, have ISA. Partial agonists - stimulate
beta receptor, yet they inhibit stimulation
by the more potent endogenous catecholamines.
Much diminished effect on cardiac rate and
output. b. Decreased metabolic effects Minimize
disturbances of lipid and carbohydrate
metabolism. 2. Use in hypertension in
hypertensive patients with moderate bradycardia,
(further decrease in heart rate is less
pronounced). Valuable in the treatment of
diabetics.
102
Celiprolol Partial agonist. Cardioselective
antagonist of beta 1 receptors partial agonist
on beta 2 receptors. Low vasodilation activity
(unknown mechanism) ? vasodilation. Low
lipophilicity (it does not cross to CNS). Used
hypertension, AP. It is considered beta blocker
with vasodilation activity.
103
F. LABETALOL lah BET a lole 1. Actions
Reversible beta blockers with concurrent alpha 1
blockade produces peripheral vasodilation.
Useful in treating hypertension vhere increased
peripheral vascular resistance is undesirable.
Does not alter serum lipid or blood glucose
level. May be an alternative to hydralazine in
the treatment of pregnancy-induced hypertension.
Also used to treat hypertensive emergencies
because it can rapidly lower blood pressure. 2.
Therapeutic use in hypertension Useful for
elderly. 3. Adverse effects Orthostatic
hypotension and dizziness are associated with
alpha 1 blockade. G. CARVEDIOL CAR ve dil ol
Carvediol blocks ? and ?1 adrenergic receptors,
i.e., it is not cardioselective important it
has scavenger effect !!! (used e.g., in
cardiomyopathy)
104
Elimination half-lives for some b-blockers.
10 min
Esmolol Acebutolol
3-4 hr
3-4 hr
Pindolol Metoprolol Propranolol Timolol Labeta
lol Carvediol Nadolol
3-4 hr
4-6 hr
4-6 hr
4-6 hr