adrenoceptor activating drugs
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Adrenoceptor-Activating Drugs
ByM.H.Farjoo M.D. , Ph.D.
Shahid Beheshti University of Medical Science
Adrenoceptor-Activating Drugs Introduction Classification Adrenergic Receptors Specific Drugs Organ System Effects Toxicity Drug Pictures
Smooth muscle of vessels residing in skeletal muscle
Classification Direct acting:
Norepinephrine & Epinephrine.
Indirect acting: Displacement of stored catecholamines (Amphetamine &
Tyramine). Inhibition of reuptake of catecholamines (Cocaine &
TCAs) MAO, COMT inhibitors
Mixed acting
M.H.Farjoo
Schematic diagram of a generalized noradrenergic junction (not to scale). Tyrosine is transported into the noradrenergic ending or varicosity by a sodium-dependent carrier (A). Tyrosine is converted to dopamine (see Figure 6–5 for details), and transported into the vesicle by the vesicular monoamine transporter (VMAT), which can be blocked by reserpine. The same carrier transports norepinephrine (NE) and several other amines into these granules. Dopamine is converted to NE in the vesicle by dopamine--hydroxylase. Physiologic release of transmitter occurs when an action potential opens voltage-sensitive calcium channels and increases intracellular calcium. Fusion of vesicles with the surface membrane results in expulsion of norepinephrine, cotransmitters, and dopamine--hydroxylase. Release can be blocked by drugs such as guanethidine and bretylium. After release, norepinephrine diffuses out of the cleft or is transported into the cytoplasm of the terminal by the norepinephrine transporter (NET), which can be blocked by cocaine and tricyclic antidepressants, or into postjunctional or perijunctional cells. Regulatory receptors are present on the presynaptic terminal. SNAPs, synaptosome-associated proteins; VAMPs, vesicle-associated membrane proteins.
Some examples of noncatecholamine sympathomimetic drugs. The isopropyl group is shown in gray.
Examples of β1- and β2-selective agonists.
Adrenergic Receptors The adrenergic receptors are divided into α, β
and dopamine. Desensitization of adrenoceptors occurs after
exposure to almost all sympathomimetics. Other terms such as tolerance, refractoriness,
and tachyphylaxis have also been used to denote desensitization.
M.H.Farjoo
Adrenoceptor types and subtypes
Receptor Agonist Antagonist Effects Gene on Chromosome
a1 type Phenylephrine Prazosin ↑ IP3, DAG common to all
a1A C5
a1B C8
a1D C20
a2 type Clonidine Yohimbine cAMP common to all
a2A Oxymetazoline C10
a2B Prazosin C2
a2C Prazosin C4
Adrenoceptor types and subtypes
Receptor Agonist Antagonist Effects Gene on Chromosome
β type Isoproterenol Propranolol ↑ cAMP common to all
β1 Dobutamine Betaxolol C10
β2 Albuterol Butoxamine C5
β3 C8
Adrenoceptor types and subtypes
Receptor Agonist Antagonist Effects Gene on Chromosome
Dopamine type Dopamine
D1 Fenoldopam ↑ cAMP C5
D2 Bromocriptine cAMP C11
D3 cAMP C3
D4 Clozapine cAMP C11
D5 ↑ cAMP C4
Adrenergic Receptors Cont,d
For alpha receptors: epinephrine ≥ norepinephrine >> isoproterenol.
For beta receptors:isoproterenol > epinephrine ≥ norepinephrine.
β1 receptors have equal affinity for epinephrine and norepinephrine.
β2 receptors have a higher affinity for epinephrine than for norepinephrine.
M.H.Farjoo
Specific Drugs The catecholamines are completely excluded by blood-
brain barrier. Epinephrine (adrenaline) is a very potent
vasoconstrictor and cardiac stimulant. Epinephrine activates β2 receptors in skeletal muscle
blood vessels, leading to their dilation. Norepinephrine (noradrenaline) has little effect on β2
receptors so it increases both diastolic and systolic blood pressure.
M.H.Farjoo
Phenylethylamine and some important catecholamines. Catechol is shown for reference. 0
Specific Drugs cont,d
Isoproterenol is a very potent β agonist so it is a potent vasodilator.
Isoproterenol has positive chronotropic and inotropic actions.
M.H.Farjoo
Specific Drugs cont,d
Dopamine, activates D1 receptors in vascular beds, which leads to vasodilation.
Dopamine also activates β1 receptors in the heart. At low doses, peripheral resistance decrease. At higher doses, dopamine activates α receptors,
leading to vasoconstriction. High rates of infusion of dopamine mimics actions
of epinephrine.
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Specific Drugs cont,d
Fenoldopam is a D1-receptor agonist that leads to peripheral vasodilation.
The indication for fenoldopam is in the intravenous treatment of severe hypertension.
Dobutamine and prenalterol are β1-selective drugs.
M.H.Farjoo
Specific Drugs cont,d
Phenylephrine is an example of a pure α agonist. Ephedrine gains access to the CNS so it is a mild
stimulant. Pseudoephedrine, an ephedrine isomer, is a
component of many decongestant mixtures. Xylometazoline and oxymetazoline are direct-
acting α agonists, used as topical decongestants.
M.H.Farjoo
ephedra_distachya (Ephedrin plant)
Specific Drugs cont,d
Amphetamine is a central nervous system stimulant.
Its peripheral actions are mediated through the release of catecholamines.
Amphetamine readily enters the CNS, where it has marked stimulant effect.
M.H.Farjoo
Specific Drugs cont,d
The amphetamines have an alerting, sleep-deferring action and improve attention.
A therapeutic application is in the treatment of narcolepsy.
Modafinil, is an amphetamine substitute used in narcolepsy.
The amphetamines have appetite differing action, but long-term weight control can not be achieved with amphetamines alone.
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Specific Drugs cont,d
In moderate doses, amphetamines cause restlessness, insomnia, and anxiety; in high doses, a paranoid state is induced.
Methamphetamine has a higher ratio of central to peripheral actions than amphetamine.
Phenmetrazine has amphetamine-like effects. It has been promoted as an anorexiant.
Methylphenidate (Ritalin) is an amphetamine variant used in children with attention deficit hyperactivity disorder (ADHD).
M.H.Farjoo
Specific Drugs cont,d
Cocaine is a local anesthetic that also inhibits norepinephrine reuptake.
It produces an amphetamine-like effect that is shorter lasting and more intense.
The major action of cocaine in the CNS is to inhibit dopamine reuptake into neurons in the "pleasure centers" of the brain.
Cocaine may precipitate convulsions, cerebral hemorrhage, arrhythmias, or myocardial infarction.
M.H.Farjoo
Specific Drugs cont,d
Clonidine is an α2 agonist used in: Hypertension. Diarrhea in diabetics with autonomic neuropathy. Diminishing craving for narcotics and alcohol during
withdrawal. Cessation of cigarette smoking. Menopausal hot flushes. Attention-deficit hyperactivity disorder.
M.H.Farjoo
Specific Drugs cont,d
Tyramine is a by product in the body metabolized by MAO.
It is found in high concentrations in fermented foods such as cheese.
It releases stored catecholamines and has an noradrenalin like effect.
In patients treated with MAO inhibitors effect of tyramine may be greatly intensified.
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Specific Drugs cont,d
In a patient taking an irreversible MAO inhibitor drug, 20-50 mg of tyramine increases the blood pressure significantly.
Cheese, sausage, pickled fish, and yeast supplements contain sufficient tyramine to be dangerous.
M.H.Farjoo
Foods reputed to have a high content of tyramine or other sympathomimetic agents.
Food Tyramine Content of an Average Serving
Beer (No data)
Broad beans, fava beans Negligible (but contains dopamine)
Cheese, natural or aged Nil to 130 mg
Chicken liver Nil to 9 mg
Chocolate Negligible (but contains phenylethylamine)
Sausage, fermented (eg, salami, pepperoni, summer sausage) Nil to 74 mg
Smoked or pickled fish (eg, pickled herring) Nil to 198 mg
Snails (No data)Wine (red) Nil to 3 mgYeast (eg, dietary brewer's yeast supplements) 2-68 mg
Organ System Effects Cardiovascular System
Shock Hypotensive Shock Anaphylactic Shock Cardiogenic Shock Other Cardiac Problems
Eye Gastrointestinal Tract Genitourinary Tract Metabolism Miscellaneous
M.H.Farjoo
Effect of epinephrine (The arrowed trace) on the transmembrane potential of a pacemaker cell in the heart.Note the increased slope of diastolic depolarization and decreased interval between action potentials.
Cardiovascular System Alpha receptors increase and β2 receptors decrease
arterial resistance. Direct effects on the heart are largely by β1
receptors but β2 receptors are also involved. β1 selective agonists do not induce vasodilatation,
so they increase cardiac output with less reflex tachycardia.
The effects of a sympathomimetic drug on blood vessels depends on its activities at α and β receptors.
M.H.Farjoo
Cardiovascular System cont,d
Alpha2 agonists decrease blood pressure by actions in the CNS, though their direct effect on a blood vessel may be constriction.
Alpha2 agonists are useful in the treatment of hypertension.
D1 receptors promote vasodilation of renal, splanchnic, coronary and cerebral vessels.
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Cardiovascular System cont,d
A pure α agonist (phenylephrine) increases peripheral arterial resistance and decreases venous capacitance.
The rise in blood pressure elicits a vagal reflex with slowing of the heart rate.
Cardiac output may not diminish in proportion to this reduction in rate, since increased venous return may increase stroke volume.
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Cardiovascular System cont,d
α agonists in hypotensive patients do not lead to reflex responses because blood pressure is returning to normal, not exceeding normal.
Stimulation of β receptors increases cardiac output. A pure β agonist (isoproterenol) also decreases peripheral resistance.
The net effect is a slight increase in systolic pressure and a fall in diastolic pressure.
M.H.Farjoo
Effects of an α -selective (phenylephrine), β -selective (isoproterenol), and nonselective (epinephrine) sympathomimetic, (BP, blood pressure; HR, heart rate.)
Cardiovascular System cont,d
Epinephrine is usually applied topically in nasal packs (for epistaxis) or in a gingival string (for gingivectomy).
Cocaine is still used for nasopharyngeal surgery, because it combines a hemostatic effect with local anesthesia.
Phenylephrine is an α1 agonists with mucous membrane decongestant effect used in hay fever and common cold.
Rebound hyperemia follows its use.
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Shock Although sympathomimetic drugs have been used in the
treatment of virtually all forms of shock, their efficacy is unclear.
In most forms of shock, vasoconstriction mediated by the sympathetic nervous system is already intense.
Indeed, efforts aimed at reducing rather than increasing peripheral resistance may be more fruitful.
A decision to use vasoconstrictors or vasodilators is best made on the basis of information about the underlying cause.
M.H.Farjoo
Hypotensive Shock If cerebral, renal, cardiac perfusion is maintained, hypotension
itself does not usually require vigorous direct treatment. The use of sympathomimetic drugs merely to elevate a blood
pressure that is not an immediate threat to the patient may increase morbidity.
Direct-acting α agonists such as norepinephrine, phenylephrine, or methoxamine have been utilized in this setting.
For the treatment of chronic orthostatic hypotension, oral ephedrine has been the traditional therapy.
M.H.Farjoo
Anaphylactic Shock Epinephrine, 0.3-0.5 mg (0.3-0.5 mL of 1:1000
epinephrine solution) is the drug of choice. Intramuscular injection may be preferred. In patients with impaired cardiovascular function,
intravenous injection of epinephrine is required. Glucocorticoids and antihistamines (both H1 and H2
antagonists) may be useful as secondary therapy.
M.H.Farjoo
Cardiogenic Shock Positive inotropic agents such as dopamine or
dobutamine may have a role in this situation. In low doses, these drugs may increase cardiac
output and cause little peripheral vasoconstriction.
The goal of therapy in shock should be to optimize tissue perfusion, not blood pressure.
M.H.Farjoo
Other Cardiac Problems Epinephrine may be useful in cardiac arrest by
redistributing blood flow to coronaries and to the brain.
Heart failure may respond to the positive inotropic effects of drugs such as dobutamine.
Development of tolerance is a major limitation to the use of catecholamines in heart failure.
M.H.Farjoo
Structures of the anterior chamber of the eye. Tissues with significant autonomic functions and the associated ANS receptors are shown in this schematic diagram. Aqueous humor is secreted by the epithelium of the ciliary body, flows into the space in front of the iris, flows through the trabecular meshwork, and exits via the canal of Schlemm (arrow). Blockade of the adrenoceptors associated with the ciliary epithelium causes decreased secretion of aqueous. Blood vessels (not shown) in the sclera are also under autonomic control and influence aqueous drainage.
Eye Alpha adrenergic drugs (phenylephrine) cause
mydriasis. β antagonists decrease the production of aqueous
humor. Glaucoma responds to a variety of
sympathomimetic and sympathoplegic drugs. Apraclonidine & brimonidine are α2 -selective
agonists used in glaucoma.
M.H.Farjoo
Gastrointestinal Tract Beta receptors mediate relaxation via
hyperpolarization. α2 -selective agonists, decrease muscle activity indirectly by presynaptically reducing the release of acetylcholine.
The α -mediated response is of greater significance than the β -stimulant response.
Alpha2 receptors may also decrease salt and water flux into the lumen of the intestine.
M.H.Farjoo
Genitourinary Tract α1A receptor mediates constriction of the bladder base
and prostate. The β2 receptors of the bladder wall mediate relaxation.
Ejaculation depends on normal α -receptor (and purinergic receptor).
The detumescence of erectile tissue is brought about by norepinephrine (and neuropeptide Y) released from sympathetic nerves.
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Genitourinary Tract Cont,d
Oral sympathomimetic therapy is occasionally useful in the treatment of stress incontinence. pseudoephedrine may be tried.
Beta2-selective agents cause uterine relaxation in premature labor.
Ritodrine & terbutaline, β2 -selective agents have been used to suppress premature labor.
They delay labor for several days. This may afford time to administer corticosteroids to decrease neonatal respiratory distress syndrome.
M.H.Farjoo
Metabolism β3 adrenoceptors in fat cells cause lipolysis with
enhanced release of free fatty acids and glycerol. Lipocytes also contain α2 receptors that inhibit
lipolysis. Catecholamines in high concentration may cause
metabolic acidosis. β2 adrenoceptors promote the uptake of potassium
into cells, leading to a fall in extracellular potassium.
M.H.Farjoo
Miscellaneous The sweat glands, located on the palms of the
hands increase sweat production. These are glands associated with psychologic
stress. Renin secretion is stimulated by β1 and inhibited
by α2 receptors.
In high concentrations, epinephrine and related agents cause leukocytosis.
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Toxicity Marked elevations in blood pressure Cardiac ischemia and failure. Sinus tachycardia and even serious ventricular
arrhythmias. Myocardial damage, particularly after prolonged
infusion. If an adverse sympathomimetic effect requires urgent
reversal, a specific adrenoceptor antagonist can be used.
M.H.Farjoo
SummaryIn English
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