Transcript 7.Adrenergic agonists

Adrenergic agonists
Saja Hamed, Ph.D
1
 adrenergic drugs affect receptors that
are stimulated by nor-epinephrine or
epinephrine
 Sympathomimetics
 Adrenergic Receptors:
- α receptors: α1 & α2 receptors
- β receptors: β1 & β2 & β3 receptors
Saja Hamed, Ph.D
2
 vasculature to skeletal muscle: both α1 &
β2 but β2 predominates
 the heart: β1 receptors
 α2 receptors: presynaptic nerve ending and
β cell of the pancreas
 In general:
- α1: vasoconstriction (skin and abdominal
viscera), increase in blood pressure
- β1: cardiac stimulation
- β2: vasodilation (in skeletal vascular beds)
and bronchiolar relaxation
Saja Hamed, Ph.D
3
Saja Hamed, Ph.D
4
The adrenergic neuron
- In the CNS and sympathetic nervous system
- Neurotransmission at adrenergic neurons:
1. Synthesis of norepinephrine
2. Storage of norepinephrine in vesicles
3. Release of norepinephrine
4. binding by receptors
5. Removal of norepinephrine
Saja Hamed, Ph.D
5
 Drugs can activate adrenergic
receptors by:
- direct receptor binding
- promotion of NE release (Ephedrine,
amphetamines)
- inhibition of NE reuptake (cocaine,
tricyclic antidepressants)
- inhibition of NE inactivation
Saja Hamed, Ph.D
6
Saja Hamed, Ph.D
7
Saja Hamed, Ph.D
8
Chemical classification of
adrenergic agonists:
a. Catecholamines:
 Cannot be used orally: have short half life and cannot
be used orally because of the action of MAO and
COMT. Located in the liver and intestinal wall. So
catecholamine that are administered orally inactivated
before reaching the circulation
 Have a brief duration of action
 Cannot cross the BBB
 Catecholamine-containing solutions should be
discarded as soon as discoloration appears
Saja Hamed, Ph.D
9
Chemical classification of
adrenergic agonists:
b. Noncatecholamines:

Longer half-lives longer than
catecholamine


Can be given orally: not a
substrate for COMT and metabolized
slowly by MAO
Penetrate BBB
Saja Hamed, Ph.D
10
Saja Hamed, Ph.D
11
Receptor specificity:
Saja Hamed, Ph.D
12
Clinical Consequences of Alpha1
activation:





vasoconstriction of blood vessels of the skin, viscera,
and mucous membranes
Mydriasis
Hemostasis (arrest of bleeding): alpha1 stimulants
are given to stop bleeding in the skin and mucous
membranes. e.g. epinephrine applied topically
Adjunct to local anesthesia (epinephrine): to delay
anesthetic absorption by causing vasoconstriction
reduces blood flow to the site of anesthetic
administration (benefits: prolong anesthesia, allows a
reduction in anesthetic dose and reduce systemic
effects)
Elevation of BP: not the primary therapy for
hypotension.
Saja Hamed, Ph.D
13
Adverse effects of Alpha1 activation
(all are a results of vasoconstriction)
 Hypertension: sever hypertension is most
likely with systemic administration you
must monitor CV status, never leave the
patient
 Necrosis: if the IV line employed become
leaking drug may cause necrosis due to
lack of blood flow secondary to intense
vasoconstriction. Area should be infiltrated
with alpha1 blocking agent phentolamine to
minimize injury
 Bradycardia: reflex slowing of the heart
Saja Hamed, Ph.D
14
Clinical Consequences of Beta1
activation:
 heart
treatment of:
 Cardiac arrest: epinephrine injected directly into the heart
 Heart failure: positive inotropic effect (increases the force
of contraction)
 Shock: characterized by profound hypotension and
reduced tissue perfusion. Primary goal of treatment is to
maintain blood flow to vital organ. By increasing heart rate
and force of contraction beta1 stimulants can inc cardiac
output and improve tissue perfusion
 Atrioventricular heart block: a condition in which impulse
conduction from the atria to the ventricles is impeded or
blocked entirely. Beta1 receptors can enhance impulse
conduction through the AV node so help to overcome AV
block. This is just for temporary treatment. For long term
treatment a pacemaker is implanted
Saja Hamed, Ph.D
15
Adverse effects of Beta1 activation:
 results from activating beta1
receptors in the heart
 tachycardia and dysrhythmias
 Angina pectoris
Saja Hamed, Ph.D
16
Clinical Consequences of Beta2
activation:
 Asthma: promote bronchodilation.
Adrenergic agonists that are selective for
beta2 receptors (terbutaline)
By inhalation: to minimize systemic effect.
Warn patient against inhaling too much
 Delay of preterm labor: beta2 receptor in
the uterus relaxes uterine smooth muscle
Saja Hamed, Ph.D
17
Adverse effects of Beta2 activation:
 Hyperglycemia in patients with
diabetes: by promoting breakdown of
glycogen in the liver and skeletal
muscle
 Tremor: most common side effect.
Activation of beta2 receptors in
muscle
Saja Hamed, Ph.D
18
Clinical Consequences of dopamine
receptor activation:
 dilation of the vasculature of the
kidneys  improve renal perfusion 
reduce risk of renal failure in shock
 dopamine
Saja Hamed, Ph.D
19
Epinephrine:
 alpha1, alpha2, beta1, beta2
 Catecholamine
Therapeutic uses:
 Alpha1-mediated vasoconstriction:
• delay absorption of local anesthetics
• control superficial bleeding
• reduce nasal congestion
• elevate blood pressure
Saja Hamed, Ph.D
20
Epinephrine:
Therapeutic uses:
 Mydriasis during ophthalmic
procedures
 Overcome AV heart block
 Restore cardiac function
 Bronchodilation in asthma
Saja Hamed, Ph.D
21
Epinephrine:
 Therapeutic uses:
 Treatment of choice for anaphylactic
shock:
• manifestation of sever allergy
• hypotension, bronchoconstriction, and
edema of the glottis
• bee venom, certain drugs (e.g.
penicillin)
• Epinephrine SC
Saja Hamed, Ph.D
22
Epinephrine:
Pharmacokinetics:
 topically, by injection, by inhalation
 No oral??
Saja Hamed, Ph.D
23
Epinephrine:
Adverse effects:
 Hypertensive crisis: parenteral epinephrine
 continuous cardiovascular monitoring
 Dysrhythmias: high risk in hyperthyroid
patients
 Angina pectoris: especially in patients with
coronary atherosclerosis
 Necrosis
 Hyperglycemia: in diabetic patients
Saja Hamed, Ph.D
24
Epinephrine:
Drug interactions:
 MAO inhibitors: used to treat depression.
Prolong and intensify epinephrine’s effects.
 Tricyclic antidepressants: block uptake
 General anesthetics
 Alpha adrenergic blocking agents:
phentolamine treat toxicity caused by
excessive epinephrine- induced alpha
activation
 Beta adrenergic blocking agents: propranolol
can reduce adverse effects caused by
epinephrine
Saja Hamed, Ph.D
25
Isoproterenol:
 beta1 and beta2
 catecholamine
 beta selective
Therapeutic uses:
 help overcome AV heart block
 restart the heart following cardiac arrest
 increase cardiac output during shock
 treatment of bronchospasm during
anesthesia
Saja Hamed, Ph.D
26
Isoproterenol:
Adverse effects:
 fewer than NE and epinephrine
 dysrhythmias and angina pectoris
 hyperglycemia in diabetic patients
 Drug Interactions (identical to
epinephrine)
Saja Hamed, Ph.D
27
Dopamine:
 dopamine, beta1, and at high doses
alpha1
 low doses  dopamine receptors only
 moderate doses dopamine and
beta1 receptors
 high doses dopamine, beta1, and
alpha1 receptors
 catecholamine
Saja Hamed, Ph.D
28
Dopamine:
Therapeutic uses:
 shock:
 beta 1 in heart  increase cardiac output 
improve tissue perfusion
 dopamine receptors in kidney  dilate renal
blood vessels  improve renal perfusion
(monitor output of urine to evaluate success)
 heart failure: increase cardiac output
Saja Hamed, Ph.D
29
Dopamine:
Adverse effects:


tachycardia, dysrhythmias, and anginal pain
high concentrations  activate alpha1
extravasationnecrosis
Drug interactions:
 MAO inhibitors: the dosage of dopamine must be reduced
by at least 90%
Administration:
 Continuous IV infusion: bec of rapid inactivation by MAO
and COMT. Monitor CV status and extravasations. If
extravasations occur stop infusion and infilter area with
phentolamine
Saja Hamed, Ph.D
30
Phenylephrine:






alpha1
noncatecholamine
locally to reduce nasal congestion
parenterally to elevate BP
eye drops to dilate the pupil
co-administered with local anesthetics
to retard absorption of anesthetic
Saja Hamed, Ph.D
31
Terbutaline:
 beta2
 Noncatecholamine
Therapeutic uses:
 Asthma: patients should not exceed the
recommended dose undesired cardiac stimulation
 Delay of preterm labor: beta2 receptors in the uterus
Adverse effects:
 tremor
 tachycardia in excessive dosage
Saja Hamed, Ph.D
32
Ephedrine:



alpha1, alpha2, beta1, beta2
noncatecholamine
mixed-acting drug
Therapeutic uses:
 Nasal congestion: alpha1 mediated vasoconstriction.
Topically is preferred over orally.
 Narcolepsy: sudden and irresistible attacks of sleep.
Benefits from activation of adrenergic receptors in the brain
Adverse effects:
 Same as epinephrine
 In addition to insomnia
Saja Hamed, Ph.D
33