Transcript 13.adrenergic notes.ppt

Adrenergic
Agonist
By:
Dr.ALTWIJRY
Adrenergic Drugs
 Adrenergic receptors are
divided into two major
types according to drug
potency on the receptors
 Alpha-(α-) adrenergic
receptors, when
activated, generally
produce excitatory
responses
 Beta-(β-) adrenergic
receptors, when
activated, generally
produce inhibitory
responses
-Adrenergic Receptors
Type
Distribution
Receptor Transduction
Agonist
Profile
Selective
Agonists
Selective
Antagonists
α1
“Vascular”
Blood vessels , GIT ,sphincters ,
iris radial, liver
G qPCR ,linked to activation of
PLC-DAG -IP 3
E≥NE>>>I SOP
Phenylephrine & methoxamine
Prazocin
α2
“Presynaptic”
Autonomic nerve terminals, blood
vessels, pancreatic islets, platelets
G iPCR ,linked to inhibitio
n of
adenyl cyclase -c.AMP
E≥NE>>> ISOP
Clonidine , α-MeDOPA
Yohimbine
-Adrenergic Receptors
Type
Distribution
Receptor Transduction
Agonist
Profile
Selective
Agonists
Selective
Antagonists
β1
“Heart”
Heart, salivary glands
β2
β3
“Smooth M”
“Fat”
Blood vessel, GIT, Fat tissues
uterus,
Skeletal
muscle, Liver,
Gs-PCR, linked to activation of adenyl cyclase-c.AMP-PKA cascade
ISOP >E=NE
ISOP>E>>NE
ISOP=NE>E
Dobutamine
Salbutamol,
terbutaline
Butoxamine
BRL 37344
Atenolol
Direct-acting Adrenergic Agonists
A. Catecholamines
 Catecholamines, adrenergic neurotransmitters;
L-norepinephrine (NE), L-epinephrine (E), & Ldopamine (DA) in addition to the synthetic
analog isoproterenol
 They have the following characteristics:
 High potency
 Rapid enzymatic inactivation by MAO & COMT
as well as neuronal & non-neuronal uptake
 Therefore they have short duration when given
parenterally and are inactive orally
 Poor ability to pass the CNS (Polar)
 COMT & MAO can be in gut wall, also MAO can be in the live
Direct-acting Adrenergic Agonists
B. Non-catecholamines
 Non-catecholamines are adrenergic agonists
lacking the catechol hydroxyl groups
 Therefore they are of longer duration, can be
given orally and they are not inactivated by
COMT, poor substrate for MAO
 They include agents like phenylephrine,
ephedrine and amphetamine
General Mode of Action of
Adrenergic Agonists
 Direct-acting agonists that act directly by
binding to the adrenergic receptors, include NE,
E, DA, phenylephrine & isoproterenol
 Indirect-acting agonists that cause the release
of NE from intra-neuronal storage vesicles by
the virtue of being taken up by the pre-synaptic
adrenergic neurons
o They include agents like amphetamine and
tyramine
 Mixed-action agonists, ephedrine
Pharmacological Actions
A. Nonselective Direct-acting
Adrenergic Agonists
1- Cardiac Effects
 Increased force of contraction (positive inotropic effect)
 Enhanced automaticity of latent pacemaker cells that
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may lead to arrhythmias
Acceleration of impulse conduction velocity
(conductivity) between the atria and ventricles via
shortening of the refractory period of the A-V node
Increased stroke volume and cardiac output but with
accompanied rise in oxygen consumption
The heart efficiency (performance) is decreased in terms
of lower cardiac work in relation to oxygen consumed
Reflex bradycardia, NE, and E but in high doses
(blocked by ATROPINE)
In vivo (Iv)
Reflex bradychardia .
In vivo + atropine
Tachycardia .
here the vagus nerve is blocked be atropine .
In vitro (heart outside the body)
Tachycardia .
Β1 is more predominant in the heart .
2) Vascular Smooth Muscle
Effects
 NE constricts all blood vessels except the
coronary vascular bed (α>β2)
 E has mixed effects according to the vascular bed
(β2> α), dilation in skeletal muscles, liver &
coronaries
 Isoprenaline has purely vasodilatotory effects
(β2>>> α)
 E constrict arterioles in the skin, mucus membrane, and viscera (α affect).
 E dilates arterioles in the liver and skeletal muscle (β2 affect).
 Vascular in skeletal muscle has α1 and β2, while β2 is predominant
but in high dose of E
vasoconstriction .
Effects of I.V. infusion of Epinephrine,
Norepinephrine & Isoprenaline in
Humans
3- Effects on
Gastrointestinal Tract
Relaxation of GIT smooth muscle through
 Inhibition of the release of ACh from cholinergic
neurons via activation of α2-adrenoceptors on
cholinergic nerve terminals
 Stimulation of β2-receptors, activates adenyl cyclasec.AMP- PKA cascade leading phophorylating
inactivation of myosin-light chain kinase enzyme
 Stimulation of α1-adrenoceptors causes increased
potassium channel activity resulting in increased K+
conductance & hyperpolarization
4- Effects on Respiratory
System
 β2-Adrenoceptors stimulation leads to relaxation
(inhibition) of bronchiolar smooth muscle and
bronchodilation, and hence lowering airway
resistance (Asthma)
 Inhibition of antigen-mediated production of
inflammatory mediators of asthma via β2adrenoceptors stimulation (Asthma)
 α1-Adrenoceptors activation results in
vasoconstriction of the upper respiratory tract
mucous membranes and hence lowering
congestion (Nasal decogestant)
 NE is never used for bronchospasm .
5- Effects on the
genitourinary system
o Uterus
 They are dependent on the uterine status
 Norepinephrine increases the rate of contraction of
pregnant human uterus
 Epinephrine inhibits uterine tone and contractions
during the last month of pregnancy as well as at
parturition
 This observation is the basis for the use of β2adrenoceptors agonists to delay premature
labor
5- Effects on the
genitourinary system
o Urinary Bladder
 1-adrenoceptors show
 High density in smooth muscle of urethera &
prostate
 Selective 1-adrenoceptor antagonists are
used for treatment of urinary retention in
benign prostatic hypertrophy
6- Effects on the Eye
 Stimulation of α1-adrenoceptors on the radial
smooth muscle of the iris leads to pupil dilation
(mydriasis), theoretically result in blocking of
drainage of aqueous humor and increase of IOP
 α1-adrenoceptors stimulation results in
vasoconstriction that in turn causes inhibition of
the formation of aqueous humor & lowering of
IOP (no cycloplegia)
 -blockers (timolol) decrease the formation of
aqueous humor & used topically in glaucoma
treatment
7- Metabolic Effects
 Lipolysis & thermogenesis are stimulated leading to
increased breakage of triglcerides into free fatty acids
and glycerol through activation of lipase enzymatic activity
(β1/ β3-adrenergic receptor stimulation-increased c.AMPPKA activation -phosphoryaltion of lipase)
 Hepatic & Skeletal Muscle Glycogenolysis are stimulated
resulting in hyperglycemia & increased plasma glucose &
lactic acid (β2-adrenergic receptor stimulation with
subsequent activation of adenyl cyclase-c.AMP-PKA
cascade-Activated PKA phosphorylates phosphorylase
kinase - activates phosphorylase)
 Gluconeogenesis is stimulated as well
 Calorigenic action where oxygen consumption is increased
in response to catecholamines mainly via increased
oxidisable substrate from increased lipolysis
Endocrine Glands
 Insulin release is stimulated via 2-adrenoceptors
& inhibited by -receptors
 Insulin R activity is decreased by 1-receptors
through decreased GLUT4 translocation
 Glucagon secretion is increased by sympathetic
stimulation
 Renin release from juxtaglomerular appartatus is
stimulated via 1-adrenoceptors
 Epinephrine:
increase lipolysis
increase glycogenesis (β2-liver )
increase glycogenolysis (β2-liver)
decrease insuline releas (α2-pancrease)
Hyperglycemia
Central Nervous System (CNS)
 Catecholamines are powerful CNS stimulants
 Cocaine & amphetamine euphoric effects are
mediated via increase CA brain levels due to
uptake blockade/enhanced release respectively
 Side effects of adrenergic agonists may include
anxiety, nervousness, & tremors while antagonist
may enhance depression.
 Ampetamine is a drug abuse only and it is not used by another
person.
Skeletal Muscles
 1-agonists (E & dobutamine) facilitate Ach
release from motor neurons possibly via
c.AMP-PKA- N-channels activation, hence
increase muscle activity (myasthenia gravis)
 2-agonists (E & salbutamol) cause
propranolol-sensitive muscle tremors possibly
via hypokalemia & increased muscle activity.
(Hypokalemia & increased muscle activity are side affects)
 When we use β2-agonist for bronchospasm patient
the patient may have a mild tremor then his muscle will be
sensitive to propanolol.
Selective α1-Adrenergic
Agonists
Phenylephrine & methoxamine, metaraminol,
mephentermine
o elevated systolic & diastolic BP
o increased total peripheral resistance
o barororeceptor mediated reflex decrease in heart
rate via enhancement of vagal activity
 They are less potent but longer acting than
norepinephrine, being non susceptible to
metabolism with COMT
Therapeutic Uses of α1Adrenergic Agonists
 Local nasal decongestant to produce
vasoconstriction of nasal mucosal vasculature
 Treatment of supraventricular tachycardia
arising in AV node and atria
• They elevate blood pressure & stimulate vagal
activity via baroreceptor-mediated reflex action
(α1-agonists have not direct affect on the heart)
 To overcome hypotension induced by some
general anesthetic agent
α2 -Adrenergic Agonists
 Clonidine & α-methyldopa activate α2-Adrenergic
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receptors in the lower brain stem (nucleus of tractus
solitaries) leading to decreased central outflow of the
sympathetic nervous system
Peripherally, they decrease NE release by stimulation of
presynaptic α2-Adrenergic receptors
Oral intake produces a prolonged hypotensive response
(Treatment of Hypertension)
IV injection raises BP by direct stimulation of
postsynaptic α1- & α2-Adrenergic receptors
In addition, α-methyldopa is taken up by adrenergic
neurons and synthesized into α-methylnorepinephrine
which is a false adrenergic transmitter
α2 -Adrenergic Agonists
 They are used in management of hypertension
 Clonidine does not induce postural hypotension
 Clonidine can cause “rebound hypertension” upon
sudden stop, prior treatment with phentolamine (blocker) protects against
 Small doses of clonidine are effective as
prophylactic therapy of migraine
 Dry mouth & constipation are most frequent side
effects (inhibition of cholinergic neuronal activity)
 Apraclonidine is used as adjuvant therapy for
glaucoma via decrease of aqueous humor
formatiom
β1-Adrenergic Agonists
 Dobutamine is a synthetic dopamine analog. It
is a selective β1-adrenergic agonist. On the
heart, it produces a more pronounced positive
inotropic effect than its chronotropic effect when
compared to dopamine. There is no defined
reason for such differential action
 Therapeutic use of dobutamine is based on its
ability to increase cardiac output via the positive
inotropy with little effect on heart rate and
myocardial oxygen consumption
o Hence, it is used in cardiogenic shock and
decompensated heart failure
Dopamine
Dopamine is better than NE in shock treatment because it
raises blood pressure and enhance perfusion of the kidney
and splanchnic areas while NE decreases blood supply to
the kidney which lead to renal shutdown
Use with it diuretics because it causes Na-water retention
It is dose dependent ( review the book page 75 Lippincott)
β2 adrenergic receptor
agonists
 Terbutaline, albuterol (salbutamol), pirbuterol
& ritodrine are selective β2 adrenergic receptor
agonists with little effect on β1 cardiac receptors
 Hence, they have the advantage of producing
bronchodilation without cardiac stimulation
 They produce uterine relaxation
 They are given orally, IV or by inhalation & have
no CNS stimulation
 Salmeterol & formoterol are long-acting agonists
 Fenoterol is an intermediate-acting (8 hrs)
β2-Adrenergic Receptor
Agonists
 Orciprenaline (metaprotrenol, Alupent R) is
relatively a selective agonist used both by oral
& inhalation
 Therapeutic uses of β2 adrenergic receptor
agonists
o Treatment of bronchial asthma and
bronchospasm associated with bronchitis and
emphysema
o Delay delivery in premature labor and in
threatened abortion; ritodrine is frequently used
for this purpose
Indirect- & Mixed-Acting
Adrenergic Receptor Agonists
 Ephedrine (it is rarely used in the clinic)
 Chemically related to EP and stimulates release of NE
 It is not a substrate for COMT or MAO & hence has long
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duration of action
It activates β2 as well as α- and β1-aderenergic receptors
It is used to treat mild cases of asthma
It crosses BBB giving rise to CNS stimulant action
It is now replaced by more selective β2 agonists
Tyramine (it is not used) in cheese, fermented sausage
& wines
o It enters synaptic vesicle and causes displacement &
release of NE & normally degraded by MAO
o MAO inhibitors in conjunction with tyraminecontaining foods may lead to rapid release of NE &
severe hypertension
Indirect- & Mixed-Acting
Adrenergic Receptor Agonists
 Pseudoephedrine & Phenylpropanolamine
 They stimulate the release of NE
 They are used as over-the-counter (OTC) nasal
decongestants for symptomatic relief of hay
fever and rhinitis
 Pseudoephedrine has little β2 agonist activity,
limited CNS stimulation
 Phenylpropanolamine also used to relieve
upper respiratory conditions associated with
common cold
Clinical uses of α- & βAdrenergic Agonists
 Nasal decongestant: Vasoconstriction in nasal mucous
membranes by α1-agonists like phenylephrine,
pseudoephedrine & xylometazoline
 Treatment of hypotension
o Selective α1-agonists like phenylephrine, methoxamine
& mephentermine are administered parenteraly to elevate
blood pressure in hypotension accompanying spinal
anesthesia. They cause prompt vasoconstriction increasing
total peripheral resistance and hence raising diastolic and
systolic pressures
o In hypovolemic shock use of α1-agonists has the potential
to cause further impairment of microcirculation already
affected by high level of catecholamine release
So α1-agonists are not used in hypovolemic shock and we have to use
fluids
Clinical uses of α- & βAdrenergic Agonists
 Cardiogenic shock (MI), NE, dobutamine or DA
 NE is given by ONLY IV infusion at doses that
raise BP, and increase cardiac contractility
without serious vasoconstriction
 Dopamine is advantageous in producing
splanchnic and renal vasodilation (D receptors),
increasing glomerular filtration and urine
production
 Dobutamine is more or less similar to dopamine
being more selective on cardiac β1-adrenergic
receptors
Clinical uses of α- & βAdrenergic Agonists
 Anaphylactic Shock: Epinephrine is of choice
given by SC route to reverse the histamineinduced broncho-constriction & hypotension
 Opthalmic Uses:
o Mydriatics: phenylephrine & ephedrine may be
used for eye examination
o Glaucoma: phenylephrine or epinephrine may
be used locally to decrease IOP
Clinical uses of α- & βAdrenergic Agonists
 5- Respiratory uses:
o Treatment of asthma using the selective β2
adrenergic receptor agonists including terbutaline,
albuterol and orciprenaline by oral route or by
inhalation. They have fewer cardiovascular stimulant
effects
o Relieve of congestion of upper respiratory tract in hey
fever and rhinitis. For this purpose, α1 agonists such as
phenylephrine, pseudoephedrine &
phenylpropanolamine can be used orally to produce
vasoconstriction of mucous membrane vasculature
Clinical uses of α- & βAdrenergic Agonists
 As Vasoconstrictors with Local Anesthetics:
Epinephrine and phenylephrine may be used to
produce localized vasoconstriction which inhibits
systemic absorption and lower bleeding
 Epistaxis; Epinephrine (1:100,000 dilution) or
-agonists may be used to stop bleeding from
nasal mucosa
 Cardiac arrest; Epinephrine or isoprenaline
may be used by IV roué or by intra-cardiac
injection
o They may be used in complete heart block