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.

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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.

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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.

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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.

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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.

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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).

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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.

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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.

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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.

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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

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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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