Dr. Rashidi Nooshabadi 11/11/2015. Smooth muscle of vessels residing in skeletal muscle Dr.Rashidi Nooshabadi 11/11/2015.

Dr. Rashidi Nooshabadi 11/11/2015

Smooth muscle of vessels residing in skeletal muscle Dr.Rashidi Nooshabadi 11/11/2015

Dr.Rashidi Nooshabadi 11/11/2015

Classification Direct acting: – Norepinephrine & Epinephrine. Norepinephrine Indirect acting: – Displacement of stored catecholamines (Amphetamine & Tyramine).stored catecholamines – Inhibition of reuptake of catecholamines (Cocaine & TCAs) Inhibition of reuptake – MAO, COMT inhibitors MAO, COMT Mixed acting Dr.Rashidi Nooshabadi11/11/2015

Dr.Rashidi Nooshabadi

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. Dr.Rashidi Nooshabadi 11/11/2015

“selective” ≈ 50-100 fold Goodman & Gilman (2011). Pharmacological Basis of Therapeutics. p. 278. Dr.Rashidi Nooshabadi11/11/2015

Receptor Selectivity means that a drug binds to one subgroup of receptors at concentrations too low to interact with another subgroup. selectivity is not absolute. nearly absolute selectivity has been termed "specificity”. 11/11/2015Dr.Rashidi Nooshabadi

11/11/2015

Adrenoceptor types and subtypes ReceptorAgonistAntagonistEffects Gene on Chromosome a 1 typePhenylephrinePrazosin ↑ IP 3, DAG common to all a 1A C5 a 1B C8 a 1D C20 a 2 typeClonidineYohimbine cAMP common to all a 2A Oxymetazoline C10 a 2B Prazosin C2 a 2C Prazosin C4 Dr.Rashidi Nooshabadi 11/11/2015

Adrenoceptor types and subtypes ReceptorAgonistAntagonistEffects Gene on Chromosome β type Isoproterenol (isopernalin) Propranolol (inderal) ↑ cAMP common to all β1DobutamineBetaxolol C10 β2β2 Albuterol (salbutamol) Butoxamine C5 β3β3 C8 Dr.Rashidi Nooshabadi 11/11/2015

Adrenoceptor types and subtypes ReceptorAgonistAntagonistEffects Gene on Chromosome Dopamine type Dopamine D1D1 Fenoldopam ↑ cAMPC5 D2D2 Bromocriptine cAMPC11 D3D3 cAMPC3 D4D4 Clozapine cAMPC11 D5D5 ↑ cAMPC4 Dr.Rashidi Nooshabadi 11/11/2015

Adrenergic Receptors Cont,d For alpha receptors: epinephrine ≥ norepinephrine >> isoproterenol. For alpha receptors: epinephrine ≥ norepinephrine >> isoproterenol. For beta receptors: isoproterenol > epinephrine ≥ norepinephrine. For beta receptors: isoproterenol > epinephrine ≥ norepinephrine. β 1 receptors have equal affinity for epinephrine and norepinephrine. β 1 receptors have equal affinity for epinephrine and norepinephrine. β 2 receptors have a higher affinity for epinephrine than for norepinephrine. β 2 receptors have a higher affinity for epinephrine than for norepinephrine. Dr.Rashidi Nooshabadi 11/11/2015

Specific Drugs The catecholamines are completely excluded by blood-brain barrier. The catecholamines are completely excluded by blood-brain barrier.catecholamines Epinephrine (adrenaline) is a very potent vasoconstrictor and cardiac stimulant. Epinephrine (adrenaline) is a very potent vasoconstrictor and cardiac stimulant. Epinephrine activates β 2 receptors in skeletal muscle blood vessels, leading to their dilation. Epinephrine activates β 2 receptors in skeletal muscle blood vessels, leading to their dilation. Norepinephrine (noradrenaline) has little effect on β 2 receptors so it increases both diastolic and systolic blood pressure. Norepinephrine (noradrenaline) has little effect on β 2 receptors so it increases both diastolic and systolic blood pressure. Dr.Rashidi Nooshabadi 11/11/2015

Phenylethylamine and some important catecholamines. Catechol is shown for reference. 0 Dr.Rashidi Nooshabadi 11/11/2015

Some examples of noncatecholamine sympathomimetic drugs. The isopropyl group is shown in gray. Dr.Rashidi Nooshabadi 11/11/2015

Structures of β 2 -selective analogs. 11/11/2015 Dr.Rashidi Nooshabadi

Examples of β 1 - and β 2 -selective agonists. Dr.Rashidi Nooshabadi 11/11/2015

Dr.Rashidi Nooshabadi11/11/2015

Relative selectivity of adrenoceptor agonists. Relative Receptor Affinities Alpha agonists Phenylephrine, methoxaminea 1 > a 2 >>>>> b Clonidine, methylnorepinephrinea 2 > a 1 >>>>> b Mixed alpha and beta agonists Norepinephrinea 1 =a 2 ;b 1 >>b 2 Epinephrinea 1 =a 2 ;b 1 =b 2 Beta agonists Dobutamine 1 β1 > b 2 >>>> a Isoproterenolb 1 =b 2 >>>> a Terbutaline, metaproterenol, albuterol, ritodrine b 2 >> β1 >>>> a Dopamine agonists DopamineD 1 =D 2 >> b>> a FenoldopamD 1 >> D 2 11/11/2015 Dr.Rashidi Nooshabadi

Distribution of adrenoceptor subtypes. TypeTissueActions α1α1 Most vascular smooth muscle (innervated) Contraction Pupillary dilator muscleContraction (dilates pupil) Pilomotor smooth muscleErects hair ProstateContraction HeartIncreases force of contraction α2α2 Postsynaptic CNS adrenoceptors Probably multiple PlateletsAggregation Adrenergic and cholinergic nerve terminals Inhibition of transmitter release Some vascular smooth muscle Contraction Fat cellsInhibition of lipolysis 11/11/2015 Dr.Rashidi Nooshabadi

Distribution of adrenoceptor subtypes. TypeTissueActions β1β1 Heart Increases force and rate of contraction β2β2 Respiratory, uterine, and vascular smooth muscle Promotes smooth muscle relaxation Skeletal musclePromotes potassium uptake Human liverActivates glycogenolysis β3β3 Fat cellsActivates lipolysis D1D1 Smooth muscleDilates renal blood vessels D2D2 Nerve endingsModulates transmitter release 11/11/2015 Dr.Rashidi Nooshabadi

Specific Drugs cont,d Isoproterenol is a very potent β agonist so it is a potent vasodilator. Isoproterenol is a very potent β agonist so it is a potent vasodilator. Isoproterenol has positive chronotropic and inotropic actions. Isoproterenol has positive chronotropic and inotropic actions. Dr.Rashidi Dr.Rashidi Nooshabadi 11/11/2015

Specific Drugs cont,d Dopamine, activates D 1 receptors in vascular beds, which leads to vasodilation. Dopamine, activates D 1 receptors in vascular beds, which leads to vasodilation. Dopamine also activates β 1 receptors in the heart. Dopamine also activates β 1 receptors in the heart. At low doses, peripheral resistance decrease. At low doses, peripheral resistance decrease. At higher doses, dopamine activates α receptors, leading to vasoconstriction. At higher doses, dopamine activates α receptors, leading to vasoconstriction. High rates of infusion of dopamine mimics actions of epinephrine. High rates of infusion of dopamine mimics actions of epinephrine. Dr.Rashidi Nooshabadi 11/11/2015

Specific Drugs cont,d Fenoldopam is a D 1 -receptor agonist that leads to peripheral vasodilation. Fenoldopam is a D 1 -receptor agonist that leads to peripheral vasodilation. The indication for fenoldopam is in the intravenous treatment of severe hypertension. The indication for fenoldopam is in the intravenous treatment of severe hypertension. Dobutamine and prenalterol are β 1 -selective drugs. Dobutamine and prenalterol are β 1 -selective drugs. Dr.Rashidi Nooshabadi 11/11/2015

Specific Drugs cont,d Phenylephrine is an example of a pure α agonist. Phenylephrine is an example of a pure α agonist. Ephedrine gains access to the CNS so it is a mild stimulant. Ephedrine gains access to the CNS so it is a mild stimulant. Ephedrine Pseudoephedrine, an ephedrine isomer, is a component of many decongestant mixtures. Pseudoephedrine, an ephedrine isomer, is a component of many decongestant mixtures. Xylometazoline and oxymetazoline are direct- acting α agonists, used as topical decongestants. Xylometazoline and oxymetazoline are direct- acting α agonists, used as topical decongestants. Dr.Rashidi Nooshabadi 11/11/2015

ephedra_distachya (Ephedrin plant) Dr.Rashidi Nooshabadi 11/11/2015

Specific Drugs cont,d Amphetamine is a central nervous system stimulant. Amphetamine is a central nervous system stimulant. Its peripheral actions are mediated through the release of catecholamines. Its peripheral actions are mediated through the release of catecholamines. Amphetamine readily enters the CNS, where it has marked stimulant effect. Amphetamine readily enters the CNS, where it has marked stimulant effect. Dr.Rashidi Nooshabadi 11/11/2015

Specific Drugs cont,d The amphetamines have an alerting, sleep- deferring action and improve attention. The amphetamines have an alerting, sleep- deferring action and improve attention. A therapeutic application is in the treatment of narcolepsy. A therapeutic application is in the treatment of narcolepsy. Modafinil, is an amphetamine substitute used in 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. The amphetamines have appetite differing action, but long-term weight control can not be achieved with amphetamines alone. Dr.Rashidi Nooshabadi 11/11/2015

Specific Drugs cont,d In moderate doses, amphetamines cause restlessness, insomnia, and anxiety; in high doses, a paranoid state is induced. 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. Methamphetamine has a higher ratio of central to peripheral actions than amphetamine. Phenmetrazine has amphetamine-like effects. It has been promoted as an anorexiant. 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). Methylphenidate (Ritalin) is an amphetamine variant used in children with attention deficit hyperactivity disorder (ADHD). 11/11/2015 Dr.Rashidi Nooshabadi

Specific Drugs cont,d Cocaine is a local anesthetic that also inhibits norepinephrine reuptake. Cocaine is a local anesthetic that also inhibits norepinephrine reuptake. It produces an amphetamine-like effect that is shorter lasting and more intense. It produces an amphetamine-like effect that is shorter lasting and more intense.amphetamine-like effectamphetamine-like effect The major action of cocaine in the CNS is to inhibit dopamine reuptake into neurons in the "pleasure centers" of the brain. 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. Cocaine may precipitate convulsions, cerebral hemorrhage, arrhythmias, or myocardial infarction. 11/11/2015 Dr.Rashidi Nooshabadi

Cocaine Mechanism: Mechanism: Central: block DAT, NET & SERT Central: block DAT, NET & SERT Peripheral: αβ agonist Peripheral: αβ agonist Schedule II (nasal surgery) Schedule II (nasal surgery) Erythroxylon coca powder crack 11/11/2015 Dr.Rashidi Nooshabadi

11/11/2015 Dr.Rashidi Nooshabadi

11/11/2015Dr.Rashidi Nooshabadi

Specific Drugs cont,d Clonidine is an α 2 agonist used in: Clonidine is an α 2 agonist used in: Hypertension. Hypertension. Diarrhea in diabetics with autonomic neuropathy. Diarrhea in diabetics with autonomic neuropathy. Diminishing craving for narcotics and alcohol during withdrawal. Diminishing craving for narcotics and alcohol during withdrawal. Cessation of cigarette smoking. Cessation of cigarette smoking. Menopausal hot flushes. Menopausal hot flushes. Attention-deficit hyperactivity disorder. Attention-deficit hyperactivity disorder. M.H.Farjoo 11/11/2015 Dr.Rashidi Nooshabadi

Specific Drugs cont,d Tyramine is a by product in the body metabolized by MAO. Tyramine is a by product in the body metabolized by MAO. metabolized by MAO metabolized by MAO It is found in high concentrations in fermented foods such as cheese. It is found in high concentrations in fermented foods such as cheese. It releases stored catecholamines and has an noradrenalin like effect. It releases stored catecholamines and has an noradrenalin like effect. In patients treated with MAO inhibitors effect of tyramine may be greatly intensified. In patients treated with MAO inhibitors effect of tyramine may be greatly intensified. M.H.Farjoo 11/11/2015 Dr.Rashidi Nooshabadi

Specific Drugs cont,d In a patient taking an irreversible MAO inhibitor drug, 20-50 mg of tyramine increases the blood pressure significantly. 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. Cheese, sausage, pickled fish, and yeast supplements contain sufficient tyramine to be dangerous. M.H.Farjoo 11/11/2015 Dr.Rashidi Nooshabadi

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 beansNegligible (but contains dopamine) Cheese, natural or agedNil to 130 mg Chicken liverNil 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 mg Yeast (eg, dietary brewer's yeast supplements) 2-68 mg 11/11/2015 Dr.Rashidi Nooshabadi

Organ System Effects Cardiovascular System Cardiovascular System Cardiovascular System Cardiovascular System Shock Shock Shock Hypotensive Shock Hypotensive Shock Hypotensive Shock Hypotensive Shock Anaphylactic Shock Anaphylactic Shock Anaphylactic Shock Anaphylactic Shock Cardiogenic Shock Cardiogenic Shock Cardiogenic Shock Cardiogenic Shock Other Cardiac Problems Other Cardiac Problems Other Cardiac Problems Other Cardiac Problems Eye Eye Eye Gastrointestinal Tract Gastrointestinal Tract Gastrointestinal Tract Gastrointestinal Tract Genitourinary Tract Genitourinary Tract Genitourinary Tract Genitourinary Tract Metabolism Metabolism Metabolism Miscellaneous Miscellaneous Miscellaneous 11/11/2015 Dr.Rashidi Nooshabadi

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. 11/11/2015 Dr.Rashidi Nooshabadi

Cardiovascular System Alpha receptors increase and β 2 receptors decrease arterial resistance. Alpha receptors increase and β 2 receptors decrease arterial resistance.arterial resistancearterial resistance Direct effects on the heart are largely by β 1 receptors but β 2 receptors are also involved. Direct effects on the heart are largely by β 1 receptors but β 2 receptors are also involved. β 1 selective agonists do not induce vasodilatation, so they increase cardiac output with less reflex tachycardia. β 1 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. The effects of a sympathomimetic drug on blood vessels depends on its activities at α and β receptors. M.H.Farjoo 11/11/2015 Dr.Rashidi Nooshabadi

Cardiovascular System cont,d Alpha 2 agonists decrease blood pressure by actions in the CNS, though their direct effect on a blood vessel may be constriction. Alpha 2 agonists decrease blood pressure by actions in the CNS, though their direct effect on a blood vessel may be constriction. Alpha 2 agonists are useful in the treatment of hypertension. Alpha 2 agonists are useful in the treatment of hypertension. D 1 receptors promote vasodilation of renal, splanchnic, coronary and cerebral vessels. D 1 receptors promote vasodilation of renal, splanchnic, coronary and cerebral vessels. M.H.Farjoo 11/11/2015 Dr.Rashidi Nooshabadi

Cardiovascular System cont,d A pure α agonist (phenylephrine) increases peripheral arterial resistance and decreases venous capacitance. 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. 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. Cardiac output may not diminish in proportion to this reduction in rate, since increased venous return may increase stroke volume. M.H.Farjoo11/11/2015 Dr.Rashidi Nooshabadi

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. 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. 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. The net effect is a slight increase in systolic pressure and a fall in diastolic pressure. M.H.Farjoo11/11/2015 Dr.Rashidi Nooshabadi

Effects of an α -selective (phenylephrine), β -selective (isoproterenol), and nonselective (epinephrine) sympathomimetic, (BP, blood pressure; HR, heart rate.) 11/11/2015 Dr.Rashidi Nooshabadi

Cardiovascular System cont,d Epinephrine is usually applied topically in nasal packs (for epistaxis) or in a gingival string (for gingivectomy). 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. Cocaine is still used for nasopharyngeal surgery, because it combines a hemostatic effect with local anesthesia. Phenylephrine is an α 1 agonists with mucous membrane decongestant effect used in hay fever and common cold. Phenylephrine is an α 1 agonists with mucous membrane decongestant effect used in hay fever and common cold. Rebound hyperemia follows its use. Rebound hyperemia follows its use. M.H.Farjoo11/11/2015 Dr.Rashidi Nooshabadi

Shock Although sympathomimetic drugs have been used in the treatment of virtually all forms of shock, their efficacy is unclear. 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. 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. 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. A decision to use vasoconstrictors or vasodilators is best made on the basis of information about the underlying cause. M.H.Farjoo11/11/2015 Dr.Rashidi Nooshabadi

Hypotensive Shock If cerebral, renal, cardiac perfusion is maintained, hypotension itself does not usually require vigorous direct treatment. 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. 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. 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. For the treatment of chronic orthostatic hypotension, oral ephedrine has been the traditional therapy. M.H.Farjoo 11/11/2015 Dr.Rashidi Nooshabadi

Anaphylactic Shock Epinephrine, 0.3-0.5 mg (0.3-0.5 mL of 1:1000 epinephrine solution) is the drug of choice. 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. Intramuscular injection may be preferred. In patients with impaired cardiovascular function, intravenous injection of epinephrine is required. In patients with impaired cardiovascular function, intravenous injection of epinephrine is required. Glucocorticoids and antihistamines (both H 1 and H 2 antagonists) may be useful as secondary therapy. Glucocorticoids and antihistamines (both H 1 and H 2 antagonists) may be useful as secondary therapy. M.H.Farjoo 11/11/2015 Dr.Rashidi Nooshabadi

Cardiogenic Shock Positive inotropic agents such as dopamine or dobutamine may have a role in this situation. 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. 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. The goal of therapy in shock should be to optimize tissue perfusion, not blood pressure. M.H.Farjoo 11/11/2015 Dr.Rashidi Nooshabadi

Other Cardiac Problems Epinephrine may be useful in cardiac arrest by redistributing blood flow to coronaries and to the brain. 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. 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. Development of tolerance is a major limitation to the use of catecholamines in heart failure. M.H.Farjoo 11/11/2015 Dr.Rashidi Nooshabadi

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. 11/11/2015 Dr.Rashidi Nooshabadi

Eye Alpha adrenergic drugs (phenylephrine) cause mydriasis. Alpha adrenergic drugs (phenylephrine) cause mydriasis. β antagonists decrease the production of aqueous humor. β antagonists decrease the production of aqueous humor. Glaucoma responds to a variety of sympathomimetic and sympathoplegic drugs. Glaucoma responds to a variety of sympathomimetic and sympathoplegic drugs. Apraclonidine & brimonidine are α 2 -selective agonists used in glaucoma. Apraclonidine & brimonidine are α 2 -selective agonists used in glaucoma. M.H.Farjoo11/11/2015 Dr.Rashidi Nooshabadi

Gastrointestinal Tract Beta receptors mediate relaxation via hyperpolarization. Beta receptors mediate relaxation via hyperpolarization. α 2 -selective agonists, decrease muscle activity indirectly by presynaptically reducing the release of acetylcholine. α 2 -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. The α -mediated response is of greater significance than the β -stimulant response. Alpha 2 receptors may also decrease salt and water flux into the lumen of the intestine. Alpha 2 receptors may also decrease salt and water flux into the lumen of the intestine. M.H.Farjoo11/11/2015 Dr.Rashidi Nooshabadi

Genitourinary Tract α 1A receptor mediates constriction of the bladder base and prostate. α 1A receptor mediates constriction of the bladder base and prostate. The β 2 receptors of the bladder wall mediate relaxation. The β 2 receptors of the bladder wall mediate relaxation. Ejaculation depends on normal α -receptor (and purinergic receptor). 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. The detumescence of erectile tissue is brought about by norepinephrine (and neuropeptide Y) released from sympathetic nerves. M.H.Farjoo11/11/2015 Dr.Rashidi Nooshabadi

Genitourinary Tract Cont,d Oral sympathomimetic therapy is occasionally useful in the treatment of stress incontinence. pseudoephedrine may be tried. Oral sympathomimetic therapy is occasionally useful in the treatment of stress incontinence. pseudoephedrine may be tried. Beta 2 -selective agents cause uterine relaxation in premature labor. Beta 2 -selective agents cause uterine relaxation in premature labor. Ritodrine & terbutaline, β 2 -selective agents have been used to suppress premature labor. Ritodrine & terbutaline, β 2 -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. They delay labor for several days. This may afford time to administer corticosteroids to decrease neonatal respiratory distress syndrome. M.H.Farjoo11/11/2015 Dr.Rashidi Nooshabadi

Metabolism β 3 adrenoceptors in fat cells cause lipolysis with enhanced release of free fatty acids and glycerol. β 3 adrenoceptors in fat cells cause lipolysis with enhanced release of free fatty acids and glycerol. Lipocytes also contain α 2 receptors that inhibit lipolysis. Lipocytes also contain α 2 receptors that inhibit lipolysis. Catecholamines in high concentration may cause metabolic acidosis. Catecholamines in high concentration may cause metabolic acidosis. β 2 adrenoceptors promote the uptake of potassium into cells, leading to a fall in extracellular potassium. β 2 adrenoceptors promote the uptake of potassium into cells, leading to a fall in extracellular potassium. M.H.Farjoo 11/11/2015 Dr.Rashidi Nooshabadi

Miscellaneous The sweat glands, located on the palms of the hands increase sweat production. The sweat glands, located on the palms of the hands increase sweat production. These are glands associated with psychologic stress. These are glands associated with psychologic stress. Renin secretion is stimulated by β 1 and inhibited by α 2 receptors. Renin secretion is stimulated by β 1 and inhibited by α 2 receptors. In high concentrations, epinephrine and related agents cause leukocytosis. In high concentrations, epinephrine and related agents cause leukocytosis. M.H.Farjoo 11/11/2015 Dr.Rashidi Nooshabadi

Toxicity Marked elevations in blood pressure Marked elevations in blood pressure Cardiac ischemia and failure. Cardiac ischemia and failure. Sinus tachycardia and even serious ventricular arrhythmias. Sinus tachycardia and even serious ventricular arrhythmias. Myocardial damage, particularly after prolonged infusion. Myocardial damage, particularly after prolonged infusion. If an adverse sympathomimetic effect requires urgent reversal, a specific adrenoceptor antagonist can be used. If an adverse sympathomimetic effect requires urgent reversal, a specific adrenoceptor antagonist can be used. M.H.Farjoo 11/11/2015 Dr.Rashidi Nooshabadi

Table 9-1. Adrenoceptor types and subtypes. ReceptorAgonistAntagonistEffects Gene on Chromosome a 1 typePhenylephrinePrazosin ↑ IP 3, DAG common to all a 1A C5 a 1B C8 a 1D C20 a 2 typeClonidineYohimbine¯ cAMP common to all a 2A Oxymetazoline C10 a 2B Prazosin C2 a 2C Prazosin C4 b typeIsoproterenolPropranolol↑ cAMP common to all β1DobutamineBetaxolol C10 b2b2 AlbuterolButoxamine C5 b3b3 C8 Dopamine type Dopamine D1D1 Fenoldopam ↑ cAMPC5 D2D2 Bromocriptine ¯ cAMPC11 D3D3 ¯ cAMPC3 D4D4 Clozapine¯ cAMPC11 D5D5 ↑ cAMPC4 11/11/2015 Dr.Rashidi Nooshabadi

Distribution of adrenoceptor subtypes. TypeTissueActions a1a1 Most vascular smooth muscle (innervated) Contraction Pupillary dilator muscleContraction (dilates pupil) Pilomotor smooth muscleErects hair ProstateContraction HeartIncreases force of contraction a2a2 Postsynaptic CNS adrenoceptors Probably multiple PlateletsAggregation Adrenergic and cholinergic nerve terminals Inhibition of transmitter release Some vascular smooth muscle Contraction Fat cellsInhibition of lipolysis β1Heart Increases force and rate of contraction b2b2 Respiratory, uterine, and vascular smooth muscle Promotes smooth muscle relaxation Skeletal musclePromotes potassium uptake Human liverActivates glycogenolysis b3b3 Fat cellsActivates lipolysis D1D1 Smooth muscleDilates renal blood vessels D2D2 Nerve endingsModulates transmitter release 11/11/2015 Dr.Rashidi Nooshabadi

Control of smooth muscle contraction and site of action of calcium channel-blocking drugs. Contraction is triggered by influx of calcium (which can be blocked by calcium channel blockers) through transmembrane calcium channels. The calcium combines with calmodulin to form a complex that converts the enzyme myosin light chain kinase to its active form (MLCK*). The latter phosphorylates the myosin light chains, thereby initiating the interaction of myosin with actin. Beta 2 agonists (and other substances that increase cAMP) may cause relaxation in smooth muscle by accelerating the inactivation of MLCK (heavy arrows) and by facilitating the expulsion of calcium from the cell (not shown). 0 11/11/2015 Dr.Rashidi Nooshabadi

Relative selectivity of antagonists for adrenoceptors. Mixed antagonists Labetalol, carvedilolβ1 = β2, α1 > α2 β β Antagonists Metoprololol, acebutolol, alprenolol, atenolol, betaxolol, celiprolol, esmolol β1 >>> β2 Propranolol, carteolol, penbutolol, pindolol, timolol β1 = β2 Butoxamineβ2 >>> β1 11/11/2015 Dr.Rashidi Nooshabadi

Dr. Rashidi Nooshabadi 11/11/2015. Smooth muscle of vessels residing in skeletal muscle Dr.Rashidi Nooshabadi 11/11/2015.

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Dr. Rashidi Nooshabadi 11/11/2015. Smooth muscle of vessels residing in skeletal muscle Dr.Rashidi Nooshabadi 11/11/2015.

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