Transcript Adrenergic Agonists

Adrenergic Agonists
OVERVIEW
• The adrenergic drugs affect receptors that are stimulated by
norepinephrine or epinephrine.
• Drugs affecting adrenergic system:
1. Sympathomimetics: act directly on the
adrenergic receptor (adrenoceptor) by activating
it.
2. Sympatholytics: block the action of the
neurotransmitters at the receptors
THE ADRENERGIC NEURON
• Primary neurotransmitter: norepinephrine
• These neurons are found in:
– CNS
– sympathetic nervous system.
• The adrenergic neurons and receptors, located either:
– presynaptically on the neuron or
– postsynaptically on the effector organ
A. Neurotransmission at adrenergic neurons
• Neurotransmission takes place at numerous beadlike enlargements called varicosities.
• The process involves five steps:
1.
2.
3.
4.
5.
Synthesis
Storage
Release
receptor binding of norepinephrine
removal of the neurotransmitter
1. Synthesis of norepinephrine:
1. Tyrosine is transported by a Na+-linked carrier into the
axoplasm of the adrenergic neuron
2. Tyrosine is hydroxylated to dihydroxyphenylalanine (DOPA)
by tyrosine hydroxylase.
3. DOPA is then decarboxylated by the enzyme dopa
decarboxylase (aromatic l-amino acid decarboxylase) to form
dopamine in the cytoplasm of the presynaptic neuron.
4. Dopamine is hydroxylated by dopamine b-hydroxylase to NE
rate-limiting step
2. Storage of norepinephrine in vesicles:
1. Dopamine transport into the vesicles by:
– an amine transporter system
•
same transporter is involved in the reuptake of
preformed norepinephrine.
2. Dopamine is hydroxylated to form norepinephrine by the
enzyme, dopamine β-hydroxylase.
• Synaptic vesicles contain: DA or NE plus ATP, β-hydroxylase
and other cotransmitters.
In the adrenal medulla:
• Norepinephrine is methylated to yield epinephrine, which is
stored in chromafin cells along with norepinephrine.
• On stimulation, the adrenal medulla releases contents directly
into circulation:
– about 80 percent epinephrine
– 20 percent norepinephrine
3. Release of norepinephrine:
• An action potential arriving at the nerve junction triggers an
influx of calcium ions from the extracellular fluid into the
cytoplasm of the neuron.
• The increase in calcium causes vesicles inside the neuron to
fuse with the cell membrane and expel (exocytose) their
contents into the synapse.
4. Binding to receptors:
• NE binds to either:
– post-synaptic receptors or
– Pre-synaptic receptors.
1. Post-synaptically, the recognition of NE by receptors triggers
a cascade of events within the cell resulting in the formation
of intracellular second messengers that act as links
(transducers) in the communication between the
neurotransmitter and the action generated within the
effector cell.
2. Binding of NE to presynaptic receptors will
modulate the release of the neurotransmitter.
5. Removal of norepinephrine:
• Fate of synaptic norepinephrine, it may:
1. diffuse out of the synaptic space and enter the general
circulation
2. be metabolized by catechol O-methyltransferase (COMT)
in the synaptic space
3. be reuptaken back into the presynaptic neuron.
• Primary mechanism for termination of
norepinephrine’s effects.
6. Potential fates of recaptured norepinephrine:
• Once norepinephrine reenters the cytoplasm of the
adrenergic neuron:
1. it may be taken up into adrenergic vesicles
2. it may persist in a protected pool in the cytoplasm.
3. It can be oxidized by monoamine oxidase (MAO) present
in neuronal mitochondria.
• The inactive products of are excreted in urine as
vanillylmandelic acid, metanephrine, and
normetanephrine.
B. Adrenergic receptors (adrenoceptors)
1. α1 and α2 Receptors:
• The α-adrenoceptors
– show weak response to the synthetic agonist
isoproterenol
– they are responsive to the naturally occurring
catecholamines epinephrine and norepinephrine.
– For α receptors, the rank order of potency is
epinephrine ≥ norepinephrine >> isoproterenol
• The α-adrenoceptors : α1 and α2
• based on their affinities for α agonists and blocking drugs.
• For example
– Affinity for phenylephrine: α1 > α2
– Affinity for clonidine: α2 >>> α1
A. α1 Receptors:
 Located post synaptically
NH 3
Phospho lipase C
 Second messengers:
 IP3
 DAG
(+)
Gq
PIP 2
COOH
IP 3
Diacylglycerol
Increase Ca 2+
Activate Protein
Kinase C
Response
B. α2 Receptors:
• Located: primarily on:
– presynaptic nerve endings
– other cells, such as the β cell of the pancreas
– certain vascular smooth muscle cells
• Second messenger: a fall in the levels of intracellular cAMP.
α2 Receptors
NH3
(-)
Adenylate Cyclase
GI
K+
X
(+)
ATP
cAMP
COOH
Reduce cAMP-Dependent
Protein Kinase Activity
Response
Activation of presynaptic
α2 receptor on
adrenergic neurons
inhibition of the release of
norepinephrine
Modulation of sympatrhitic
neurotransmission
Activation of presynaptic
α2 receptor on
cholinergic neurons
inhibition of the release of
ACh
Modulation of
parasympatrhitic
neurotransmission
c. Further subdivisions:
• α1 : α1A, α1B, α1C, and α1D
• a2: α2A, α2B, and α2C.
Tamsulosin
– is a selective α1A antagonist
– used to treat benign prostate hyperplasia.
– The drug is clinically useful because it targets α1A
receptors found primarily in the urinary tract and prostate
gland.
2. β Receptors:
• The rank order of potency is
isoproterenol > epinephrine > norepinephrine
• The β-adrenoceptors: β1, β2, and β3
b receptors
NH3
(+)
Adenylate Cyclase
GS
ATP
cAMP
COOH
Increase cAMP-Dependent
Protein Kinase Activity
Response
Affinity of binding:
• β1 receptors: epinephrine = norepinephrine
• β2 receptors: epinephrine > norepinephrine.
Binding of a neurotransmitter at any of the three β receptors
activation of adenylyl cyclase
increased cAMP
Drugs affecting alpha receptors
4. Characteristic responses mediated by adrenoceptors:
As a generalization
1. Stimulation of α1 receptors:
–
–
produces vasoconstriction (particularly in skin and abdominal viscera)
increase in total peripheral resistance and blood pressure.
2. Stimulation of β1 receptors: causes cardiac stimulation
3. Stimulation of β2 receptors produces:
• vasodilation (in skeletal vascular beds)
• smooth muscle relaxation.
5. Desensitization of receptors:
• Prolonged exposure to catecholamines reduces
responsiveness of receptors.
• Suggested mechanisms:
1. Sequestration of the receptors
2. down-regulation:
– a disappearance of the receptors either by:
•
•
destruction or
decreased synthesis
3. inability to couple to G protein, because the receptor has
been phosphorylated on the cytoplasmic side.
III. CHARACTERISTICS OF ADRENERGIC AGONISTS
• Most drugs are derivatives of β-phenylethylamine.
• Two important structural features of these drugs are
1) the number and location of OH substitutions on the
benzene ring
2) the nature of the substituent on the amino nitrogen.
Mixed action
A. Catecholamines
• Catecholamines are sympathomimetic amines that contain
the 3,4-dihydroxybenzene group such as:
1.
2.
3.
4.
Epinephrine
Norepinephrine
Isoproterenol
Dopamine
5
4
3
6
2
1
Catecholamines share the following properties:
1. High potency: a or b
3. Poor penetration into CNS:
2. Rapid inactivation:
• are polar
• Most of these drugs have
some clinical effects
(anxiety, tremor, and
headaches) that are
attributable to action on the
CNS.
• Catecholamines metabolized by:
– COMT postsynaptically
– MAO intraneuronally
• Peripherally:
– COMT in the gut wall
– MAO is in the liver and gut
wall.
B. Noncatecholamines: lack catechol hydroxyl groups
• These include:
• Phenylephrine
• Ephedrine
• Amphetamine
• Longer half-lives:
– they are not inactivated by COMT.
– These are poor substrates for MAO
• Increased lipid solubility better access to the CNS
D. Mechanism of action of the adrenergic agonists
1. Direct-acting agonists:
• They act directly on α or β
receptors
• Examples of direct-acting
agonists:
• Epinephrine
• Norepinephrine
• Isoproterenol
• phenylephrine.
2. Indirect-acting
agonists:
• They may
– block the uptake of
norepinephrine
(uptake blockers) e.g.
cocaine
–
–
Cause the release of
norepinephrine e.g.
amphetamines.
Enzyme inhibitors
3. Mixed-action agonists:
– Ephedrine
– Pseudo ephedrine
• Agonists that have the capacity
to:
1. Direct actions on receptors
2. Indirect: release
norepinephrine
IV. DIRECT-ACTING ADRENERGIC AGONISTS
• They bind to adrenergic receptors without interacting with
the presynaptic neuron.
• The activated receptor initiates synthesis of second
messengers and subsequent intracellular signals.
• As a group, these agents are widely used clinically.
A. Epinephrine
• Epinephrine is synthesized in the adrenal medulla and
released into the bloodstream.
• Epinephrine interacts with both α and β receptors:
• Effect on blood vessels is dose dependent:
– At low doses causes vasodilation: β effects
– At high doses causes vasoconstriction: α effects
1. Actions of epinephrine:
a. Cardiovascular:
1. Positive inotropic: β1
action
2. Positive chronotropic: β1
action
3. Activates β1 receptors on
the kidney to cause renin
release.
• Renin results in production
of angiotensin II, a potent
vasoconstrictor
• Effect of epinephrine on
vessels:
1. constricts arterioles in the
skin, mucous membranes,
and viscera (α effects)
2. it dilates vessels going to
the liver and skeletal
muscle (β2 effects).
3. Renal blood flow is
decreased.
• The cumulative effect:
• increase in systolic blood pressure
• slight decrease in diastolic pressure.
b. Respiratory:
1. bronchodilation by acting directly on bronchial smooth
muscle (β2 action).
2. Inhibits the release of allergy mediators such as histamines
from mast cells.
c. Hyperglycemia:
• Epinephrine has a significant hyperglycemic effect because
of:
1. increased glycogenolysis in the liver (β2 effect)
2. increased release of glucagon (β2 effect)
3. a decreased release of insulin (α2 effect).
d. Lipolysis:
Stimulation of β receptors
• Epinephrine initiates
lipolysis through its
agonist activity on the β
receptors of adipose
tissue
activate adenylyl cyclase
increase cAMP levels.
Stimulates lipase
hydrolyzes triacylglycerols to
free fatty acids and glycerol.
2. Biotransformations of Epi:
• Epinephrine is metabolized by two enzymatic pathways: MAO
and COMT, which has S-adenosylmethionine as a cofactor.
• The final metabolites found in the urine are:
1. Metanephrine
2. Vanillylmandelic acid
3. Therapeutic uses
a. Bronchospasm:
• Used in the emergency treatment of bronchoconstriction
– Treatment of acute asthma
– Treatment of anaphylactic shock
• Chronic treatment of asthma:
– selective β2 agonists, such as albuterol, are presently
favored because
• a longer duration of action
• minimal cardiac stimulatory effect.
b. Anaphylactic shock:
• Epinephrine is the drug of
choice for the treatment of
Type I hypersensitivity
reactions in response to
allergens.
c. Cardiac arrest:
• Epinephrine may be used to
restore cardiac rhythm in
patients with cardiac arrest
regardless of the cause.
d. Local anesthetics:
• Provides vasoconstriction:
1. increases the duration
of the local anesthesia.
2. Minimizes systemic
effects
4. Pharmacokinetics:
5. Adverse effects of epinephrine:
a. CNS disturbances:
anxiety, fear, tension,
headache, and tremor.
b. Hemorrhage:
The drug may induce
cerebral hemorrhage as a
result of a marked elevation
of blood pressure.
c. Cardiac arrhythmias:
Epinephrine can trigger
cardiac arrhythmias,
particularly if the patient is
receiving digoxin.
d. Pulmonary edema:
Epinephrine can induce
pulmonary edema.
6. Interactions:
a. Hyperthyroidism:
• In hyperthyroidism:
– increased production of adrenergic receptors on the
vasculature
– leading to a hypersensitive response.
• Epinephrine enhances cardiovascular actions in these
patients.
• The dose of epinephrine must be reduced.
b. Cocaine:
• reuptake inhibitor of catecholamines
c. Diabetes:
• Epinephrine increases the release of endogenous stores of
glucose.
• In the diabetic, dosages of insulin may have to be increased.
d. β-Blockers:
• These prevent epinephrine’s effects on β receptors, leaving α
receptor stimulation unopposed.
• This may lead to an increase in peripheral resistance and an
increase in blood pressure.
e. Inhalation anesthetics:
• These agents sensitize the heart to the effects of epinephrine,
which may lead to tachycardia.
B. Norepinephrine
• In therapeutic doses, the α- receptor is most
affected.
1. Cardiovascular actions:
A. Vasoconstriction:
• Increases TPR: due to intense vasoconstriction of most
vascular beds, including the kidney (α1 effect).
• Both systolic and diastolic blood pressures increase.
B. Baroreceptor reflex:
• Negligible cardiac stimulation.
Increased BP
Induces a reflex rise in vagal activity by stimulating
the baroreceptors
Reflex bradycardia
C. Effect of atropine pretreatment:
When atropine is given before norepinephrine
it blocks the vagal effects
tachycardia.
2. Therapeutic uses
• Treatment of shock: increases TPR and BP
• Norepinephrine causes extravasation (discharge of blood from
vessel into tissues) along the injection site.
• Impaired circulation from norepinephrine may be treated
with the α -receptor antagonist phentolamine.
3. Pharmacokinetics of NE:
• Given IV for rapid onset of action.
• Duration of action is 1 to 2 minutes following the end of the
infusion period.
• Poorly absorbed after subcutaneous injection
• It is destroyed in the gut if administered orally.
• Metabolism is similar to that of epinephrine.
4. Adverse effects of NE
• Similar to those of epinephrine.
– CNS disturbances
– Cerebral hemorrhage
– Cardiac arrhythmias
– Pulmonary edema
• May cause blanching and sloughing of skin along an
injected vein (due to extreme vasoconstriction).
C. Isoproterenol
• Direct-acting synthetic catecholamine
• Predominantly stimulates both β1- and β2adrenergic receptors.
• Insignificant action on α receptors.
1. Actions of isoproterenol:
a. Cardiovascular:
• Increases HR and force of contraction
increased CO
• Decreases peripheral resistance because it dilates the
arterioles of skeletal muscle (β2 effect).
• May slightly increase systolic blood pressure
• It greatly reduces mean arterial and diastolic blood pressure.
b. Pulmonary: Inhalation
products of isoproterenol are no
longer available in the United
States.
c. Other effects: not clinically
significant
• On β receptors, such as:
– increased blood sugar
– increased lipolysis
2. Therapeutic uses:
• Isoproterenol can be used to stimulate the heart in
emergency situations.
3. Pharmacokinetics:
• Isoproterenol is a marginal substrate for COMT and is stable to
MAO action.
4. Adverse effects:
• Similar to those of epinephrine.
D. Dopamine
• Occurs naturally in
– CNS in the basal ganglia
– Adrenal medulla.
• Dopamine can activate αand β-adrenergic receptors.
• For example
1.
2.
at lower doses, it stimulates β1
cardiac receptors.
at higher doses, it can cause
vasoconstriction by activating
α1 receptors
• Dopamine activates D1 and
D2 receptors in the
mesenteric and renal
vascular beds: produces
vasodilation.
• Dopamine activates
presynapptic D2 receptors o
adrenergic neurons: inhibits
NE release.
1. Actions of Dopamine :
a. Cardiovascular:
– Inotropic and chronotropic effects: B1
– At very high doses, dopamine activates α1
receptors on the vasculature, resulting in
vasoconstriction.
b. Renal and visceral:
– Vasodilation of the renal and splanchnic arterioles:
• Dopamine receptors
• Therefore, dopamine is clinically useful in the treatment of
shock, in which significant increases in sympathetic activity
might compromise renal function.
2. Therapeutic uses of dopamine:
A. Dopamine is the drug of choice for cardiogenic and septic
shock
– Dopamine is given by continuous infusion.
– It raises the blood pressure by stimulating:
• β1 receptors on the heart to increase cardiac output
• α1 receptors on blood vessels to increase total
peripheral resistance.
• Dopamine enhances perfusion to the kidney and splanchnic
areas
enhances GFR and causes sodium diuresis.
• It is also used to treat:
B. hypotension
C. severe congestive heart failure
3. Adverse effects:
• Dopamine is rapidly metabolized to homovanillic acid by MAO
or COMT
• Adverse effects are short-lived:
• Nausea
• Hypertension
• Arrhythmias
Fenoldopam
• Fenoldopam is an agonist
of:
– Peirpheral D1receptors
– Moderate α2 receptors.
• It is used as a rapid-acting
vasodilator to treat
severe hypertension in
hospitalized patients,
acting on coronary
arteries, kidney arterioles,
and mesenteric arteries.
• Fenoldopam undergoes
extensive first-pass
metabolism
• has a 10-minute
elimination half-life after
IV infusion.
Adverse effects:
• Headache, flushing,
dizziness, nausea,
vomiting, and
tachycardia.
Dobutamine
1. Actions:
– Direct-acting β1 receptor
agonist.
– It increases HR and CO.
2. Therapeutic uses:
– Treatment of acute
congestive heart failure
– for inotropic support after
cardiac surgery.
3. Adverse effects:
• Dobutamine should be used
with caution in atrial
fibrillation, because the drug
increases AV conduction.
• Other adverse effects are the
same as those for epinephrine.
• Tolerance may develop on
prolonged use.
Oxymetazoline
• Agonist at α1- and α2- receptors.
Adverse effects:
1.
• Used locally in the eye or the
nose as a vasoconstrictor.
– short-term nasal spray
decongestant
– ophthalmic drops for the
relief of redness of the eyes
associated with swimming,
colds, and contact lenses.
Oxymetazoline when
absorbed in the systemic
circulation may produce
nervousness, headaches,
and trouble sleeping.
2.
When administered in the
nose, burning of the nasal
mucosa and sneezing may
occur.
3.
Rebound congestion and
dependence are observed
with long-term use.
Phenylephrine
• Selective α1 agonist.
• Phenylephrine is a
vasoconstrictor that raises both
systolic and diastolic blood
pressures.
• It has no effect on the heart itself
but, rather, induces reflex
bradycardia when given
parenterally.
• It is often used topically on the:
– nasal mucous membranes
– in ophthalmic solutions for
mydriasis.
• Phenylephrine acts as a nasal
decongestant (applied every 4
hours) and produces
vasoconstriction.
• The drug is used to:
– raise blood pressure
– terminate episodes of
supraventricular tachycardia.
• Large doses can cause
hypertensive headache and
cardiac irregularities.
a 2 receptor agonists
•
•
•
•
Clonidine (Catapres)
Methyldopa (Aldomet)
Guanabenz (Wytensin)
Guanfacine (Intuniv, Tenex)
Clonidine
• α2 agonist: acts centrally to
produce inhibition of
sympathetic vasomotor
centers, decreasing
sympathetic outflow to the
periphery.
• used in:
– essential hypertension
– to minimize the symptoms of
withdrawal from opiates,
tobacco smoking, and
benzodiazepines.
• Side effects:
– lethargy, sedation,
constipation, and
xerostomia.
• Abrupt discontinuance must
be avoided to prevent
rebound hypertension.
a2-Adrenergic Agonists
Brain
Brain Stem (Cardiovascular Control
Center)
a Receptors
Sympathetic
ganglion
2
Decreased sympathetic tone
• Decr. HR
• Decr. Contractility
• Decr. Renin release
• Decr. Vasoconstriction
b1 Receptors
Heart
b1 Receptors
Kidney
a1 Receptors
Albuterol and Terbutaline
• Short-acting β2 agonists
• Used primarily as
bronchodilators.
• Duration: less than 3
hours
• Terbutaline is used oflabel as a uterine relaxant
to suppress premature
labor.
• Side effects of β2 agonists
– CNS effects:
• tremor, restlessness,
apprehension, and anxiety.
– Cardiovascular effects:
• With concomitant use of
monoamine oxidase
inhibitors (MAOIs)
• It is recommended that
there be about a 2-week
gap between the use of a
MAOI and a β2-receptor
agonist.
Salmeterol and formoterol
• Are long-acting β2-agonists
that are bronchodilators.
• Duration: 12 hours
• Salmeterol has a delayed
onset of action.
•
Used to treat nocturnal
asthma in symptomatic
patients taking other
asthma medications
• Inhaled β2-receptor
agonists should not be used
in excess.
INDIRECT-ACTING ADRENERGIC AGONISTS
• They may either:
1. Increase release norepinephrine from pre-synaptic
terminals or
2. inhibit the uptake of norepinephrine.
• They potentiate the effects of norepinephrine produced
endogenously
• They do not directly affect postsynaptic receptors.
A. Amphetamine
• MOA: increases release of
norepinephrine.
• Effect:
A. Increases blood pressure
significantly by:
1.
2.
α1-agonist action on the
vasculature
β-stimulatory effects on the
heart.
B. The CNS stimulation
• Therapeutic use:
– Treatment of ADHA in children
– Narcolepsy
– Appetite control
•
•
•
•
Dextroamphetamine
Methamphetamine
Methylphenidate
Dexmethylphenidate
• Closely related in structure or
have similar to amphetamine.
• Used for similar indications as
amphetamine.
B. Tyramine
• Found in fermented foods, such as aged cheese and Chianti
wine.
• MOA of Tyramine: increase release stored norepinephrine.
• The released catecholamine then acts on adrenoceptors.
• Normally, it is oxidized by MAO in the gastrointestinal tract
• if the patient is taking MAOIs, it can precipitate serious
vasopressor episodes.
VI. MIXED-ACTION ADRENERGIC AGONISTS
• Mixed-action drugs induce:
1. release of norepinephrine from presynaptic
terminals
2. activate adrenergic receptors on the postsynaptic
membrane.
A. Ephedrine and pseudoephedrine
• Plant alkaloids purified from Ephedra sinica. Now it is synthetic
• These drugs are mixed-action adrenergic agents.
• They release stored norepinephrine from nerve endings
• They directly stimulate both α and β receptors.
• They have a long duration of action:
– They are poor substrates for COMT and MAO
• They have excellent absorption orally
• They penetrate into the CNS
• Ephedrine is eliminated largely unchanged in urine
• Pseudoephedrine undergoes incomplete hepatic metabolism
before elimination in urine.
• Effects of ephedrine:
1. raises blood pressures
2. produces slow and less potent bronchodilation
3. produces mild CNS stimulation .
•
•
This increases alertness, decreases fatigue, and prevents sleep
Suppresses appetite
4. It improves athletic performance.
• Pseudoephedrine is primarily used orally to treat:
– Nasal and sinus congestion
– Congestion of the eustachian tubes.
• Ephedrine-containing herbal supplements (mainly ephedracontaining products) were banned by the U.S. Food and Drug
Administration in April 2004 because of life-threatening
cardiovascular reactions.
• Pseudoephedrine has been illegally converted to
methamphetamine.
Some side effects of adrenergic agonists