Adrenoceptor Agonists & Sympathomimetic Drugs

Adrenoceptor Agonists & Sympathomimetic Drugs

Overview The sympathetic nervous system is an important regulator of virtually all organ systems The ultimate effects of sympathetic stimulation are mediated by release of norepinephrine from nerve terminals, which then activates adrenoceptors (pre- or post-synaptically) Also, in response to a variety of stimuli such as stress, the adrenal medulla releases epinephrine, which is transported in the blood to target tissues…….HORMONE CATECHOLAMINES…..RECEPTORS The sympathetic nervous system is an important regulator of virtually all organ systems. This is particularly evident in the regulation of blood pressure. In other words, epinephrine acts as a hormone (adrenaline), whereas norepinephrine acts as a neurotransmitter (noradrenaline). sympathetic: NE and epinepphrin, receptors..alpha and Beta. The adrenal medulla (suprarenal medulla) is part of the adrenal gland. It is located at the center of the gland, being surrounded by the adrenal cortex. It is the innermost part of the adrenal gland, consisting of cells that secrete epinephrine (adrenaline), norepinephrine (noradrenaline), and a small amount of dopamine in response to stimulation by sympathetic preganglionic neurons.

sympathomimetic amines that contain
3,4-dihydroxybenzene group (such as: epinephrine, norepinephrine, isoproterenol, and dopamine) are called catecholamines Last enzyme: phenylethanolamine-N-methyltransferase Drugs that mimic the actions of epinephrine or norepinephrine have traditionally been termed sympathomimetic drugs

Adrenergic receptors (adrenoceptors)
There are two main groups of adrenergic receptors, α and β, with several subtypes. These were initially identified on the basis of their responses to the adrenergic agonists epinephrine, norepinephrine, and isoproterenol All the adrenoceptors are G-protein coupled receptors (GPCRs)…..G???? G-protein coupled receptors, G…as they bind to GTP

α Adrenoceptors β Adrenoceptors
Epinephrine Norepinephrine Isoprotenol β Adrenoceptors Isoprotenol Epinephrine Norepinephrine High affinity Low affinity

The development of selective antagonists revealed the presence of subtypes of these receptors, which were finally characterized by molecular cloning. These proteins/receptors belong to a multigene family Adrenergic Receptors b a a1 a2 b1 b2 b3 a1A a1B a1D a2A a2B a2C Necessary for understanding the selectivity of some drugs. Tamsulosin (selective α1A antagonist), benign prostate hyperplasia, (urinary tract and prostate gland)

Table 9–1 Adrenoceptor Types and Subtypes
Receptor Agonist Antagonist Effects α1 type (α1A, α1B, α1D) Phenylephrine Prazosin IP3, DAG common to all α2 type (α2A, α2B, α2C) Clonidine Yohimbine cAMP common to all β type (β1, β2, β3) Isoproterenol Propranolol Dopamine type Dopamine D1-like (D1, D5) cAMP D2-like (D2, D3, D4) Likewise, the endogenous catecholamine dopamine produces variety of biological effects mediated by interaction with specific dopamine receptors (particularly imp. In the brain, and in the splanchnic and renal vasculature).

Adrenergic receptors (adrenoceptors) Alpha receptors
The α1 receptors have a higher affinity for phenylephrine than do the α2 receptors. Conversely, clonidine is more selective to α2 receptors (has less effect on α1 receptors) Both epinephrine and norepinephrine have similar affinity for α and β receptors Epinephrin has similar affinity for a and beta NE has similar affinity for alpha and beta. But affinity of alpha receptors to epinephrine is higher than NE Affinity of Beta for to epinephrine is higher thatn NE

selectivity Selectivity?? A drug may preferentially bind to one subgroup of receptors at concentration too low to interact extensively with other subgroup! (e.g., important in β receptors) Selectivity not absolute….at higher concentration, the drug interacts with other subgroups!! (drug are not specific) The effect depends also on the expression of the subtype on a given tissue The function of specific subtype receptor is known through development of “knockout mice” Many clinically available adrenergic agonists have selectivity for the major (α 1 and α 2 versus β) adrenoreceptor types, but not for the subtypes of these major groups. Examples of clinically useful sympathomimetic agonists that are relatively selective for α 1 -, α 2 -, and β-adrenoceptor subgroups are compared with some nonselective agents in Table 9–2 Selectivity is not usually absolute (nearly absolute selectivity has been termed “specificity”). The effects of a given drug may depend not only on its selectivity to adrenoreceptor types, but also to the relative expression of receptor subtypes in a given tissue. (if it is selective to alpha 1a but it is expressed at only low levels on certain tissues…we can not see the effect)

These receptors are present on the postsynaptic membrane of the effector organs and mediate many of the classic involving contraction of smooth muscle Alpha1 receptors are coupled via Gq proteins to phospholipase C. Activation of α1 receptors result in the generation of inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol. IP3 initiates the release of Ca2+ from the endoplasmic reticulum into the cytosol and the activation of various calcium-dependent protein kinases. Activation of these receptors may also increase influx of calcium across the cell's plasma membrane. DAG activates protein kinase C, which modulates activity of many signalling pathways

FIGURE 9–1 Activation of α 1 responses
FIGURE 9–1 Activation of α 1 responses. Stimulation of α 1 receptors by catecholamines leads to the activation of a G q -coupling protein. The activated α subunit (α q *) of this G protein activates the effector, phospholipase C, which leads to the release of IP 3 (inositol 1,4,5-trisphosphate) and DAG (diacylglycerol) from phosphatidylinositol 4,5-bisphosphate (PtdIns 4,5P 2 ). IP 3 stimulates the release of sequestered stores of calcium, leading to an increased concentration of cytoplasmic Ca 2+ . Ca 2+ may then activate Ca 2+ -dependent protein kinases, which in turn phosphorylate their substrates. DAG activates protein kinase C (PKC). GTP, guanosine triphosphate; GDP, guanosine diphosphate. See text for additional effects of α 1 -receptor activation.

These receptors, located primarily on presynaptic nerve endings and on other cells, such as the β cell of the pancreas, and on certain vascular smooth muscle cells, control adrenergic neuromediator and insulin output respectively Alpha2 receptors are coupled via Gi protein to adenylyl cyclase. Alpha2 receptors inhibit adenylyl cyclase activity and cause intracellular cyclic adenosine monophosphate (cAMP) levels to decrease It is likely that not only the alpha but also beta/gamma subunits of the G protein contribute to inhibition of adenylyl cyclase.. Beta cells of pancreas. Also decrease Ach

Feedback control of noradrenaline release
Nerve stimulation….activation of adenylyl cyclase…ATP….cAMP increases……increase Ca influx Alpha 2 activation (if high NE release)….inhibit adenylyl cyclase…decrease cAMP…decrease ca influx…decrease NA release.

Figure 9-2: Activation and inhibition of adenylyl cyclase by agonists that bind to catecholamine receptors. Binding to β adrenoceptors stimulates adenylyl cyclase by activating the stimulatory G protein, Gs, which leads to the dissociation of its α subunit charged with GTP. This activated αs subunit directly activates adenylyl cyclase, resulting in an increased rate of synthesis of cAMP. Alpha2-adrenoceptor ligands inhibit adenylyl cyclase by causing dissociation of the inhibitory G protein, Gi, into its subunits; ie, an activated αi subunit charged with GTP and a β-γ unit. The mechanism by which these subunits inhibit adenylyl cyclase is uncertain. cAMP binds to the regulatory subunit (R) of cAMP-dependent protein kinase, leading to the liberation of active catalytic subunits (C) that phosphorylate specific protein substrates and modify their activity. These catalytic units also phosphorylate the cAMP response element binding protein (CREB), which modifies gene expression. See text for other actions of β and α2 adrenoceptors.

Adrenergic receptors (adrenoceptors) Beta receptors
β1 Receptors have approximately equal affinities for epinephrine and norepinephrine, whereas β2 receptors have a higher affinity for epinephrine than for norepinephrine. Thus, tissues with a predominance of β2 receptors (such as the vasculature of skeletal muscle) are particularly responsive to the hormonal effects of circulating epinephrine released by the adrenal medulla β3 Receptors may mediate responses to catecholamine at sites with "atypical" pharmacological characteristics (e.g., adipose tissue) Beta -3 receptor is a lower affinity receptor but more resistant to desensitization….its physiologic and pathologic role in human being is not clear, not selective agonists or antagonists are clinicallly available. Enhancement of lipolysis in adipose tissue….(in animals!!) in human B receptors, subtype may be 1 see slide 52 and 55

All the β-adrenoceptors (β1, β2, β3) are coupled to Gs protein….. Figure 9-2: Activation and inhibition of adenylyl cyclase by agonists that bind to catecholamine receptors. Binding to β adrenoceptors stimulates adenylyl cyclase by activating the stimulatory G protein, Gs, which leads to the dissociation of its α subunit charged with GTP. This activated αs subunit directly activates adenylyl cyclase, resulting in an increased rate of synthesis of cAMP. Alpha2-adrenoceptor ligands inhibit adenylyl cyclase by causing dissociation of the inhibitory G protein, Gi, into its subunits; ie, an activated αi subunit charged with GTP and a β-γ unit. The mechanism by which these subunits inhibit adenylyl cyclase is uncertain. cAMP binds to the regulatory subunit (R) of cAMP-dependent protein kinase, leading to the liberation of active catalytic subunits (C) that phosphorylate specific protein substrates and modify their activity. These catalytic units also phosphorylate the cAMP response element binding protein (CREB), which modifies gene expression. See text for other actions of β and α2 adrenoceptors.

cAMP is the major second messenger of β-receptor activation! For example: In the heart, increases the influx of calcium across the cell membrane and its sequestration inside the cell cAMP also promotes the relaxation of smooth muscle may involve the phosphorylation of myosin light-chain kinase to an inactive form (uncertain mech.) (see Figure 12–1) In the liver, β-receptor-activated cAMP synthesis leads to activation of glycogen phosphorylase Last point: stimulate glycogenolysis Cyclic AMP is the major second messenger of β-receptor activation. For example, in the liver of many species, β-receptor–activated cAMP synthesis leads to a cascade of events culminating in the activation of glycogen phosphorylase. In the heart, β-receptor–activated cAMP synthesis increases the influx of calcium across the cell membrane and its sequestration inside the cell. Beta-receptor activation also promotes the relaxation of smooth muscle. Although the mechanism of the smooth muscle effect is uncertain, it may involve the phosphorylation of myosin light-chain kinase to an inactive form (see Figure 12–1). Beta adrenoceptors may activate voltage-sensitive calcium channels in the heart via Gs-mediated enhancement independently of changes in cAMP concentration.

Remember interplay between signaling mechanism???
Ex. Non-selective adrenomimetic agent (α and β receptors) Figure 12–1 FIGURE 12–1 Control of smooth muscle contraction and site of action of calcium channel-blocking drugs. Contraction is triggered (red arrows) 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. Other proteins, calponin and caldesmon (not shown), inhibit the ATPase activity of myosin during the relaxation of smooth muscle. Interaction with the Ca 2+ -calmodulin complex reduces their interaction with myosin during the contraction cycle. Beta 2 agonists (and other substances that increase cAMP) may cause relaxation in smooth muscle (blue arrows) by accelerating the inactivation of MLCK and by facilitating the expulsion of calcium from the cell (not shown). cGMP facilitates relaxation by the mechanism shown in Figure 12–2 . for triggering the interaction of actin with myosin in t

dopaminergic receptors
The endogenous catecholamine “dopamine” is imp. in the brain and in the splanchnic and renal vasculature (5 receptor subtypes) D1-like receptor typically associated with stimulation of adenylyl cyclase (cAMP accumulation induced smooth muscle relaxation in those vascular beds in which dopamine is a vasodilator) D2-like receptors have been found to: inhibit adenylyl cyclase activity, open potassium channels, and decrease calcium influx Splanchnic, from a Greek word splēn, meaning organ,[1] usually used to describe visceral organs Likewise, the endogenous catecholamine dopamine produces variety of biological effects mediated by interaction with specific dopamine receptors (particularly imp. In the brain, and in the splanchnic and renal vasculature). Dopamine Receptors The D1 receptor is typically associated with the stimulation of adenylyl cyclase (Table 9–1); for example, D1-receptor–induced smooth muscle relaxation is presumably due to cAMP accumulation in the smooth muscle of those vascular beds in which dopamine is a vasodilator. D2 receptors have been found to inhibit adenylyl cyclase activity, open potassium channels, and decrease calcium influx.

Adrenergic receptors (adrenoceptors) Receptor regulation
Responses mediated by adrenoceptors are not fixed and static Prolonged exposure to the catecholamines reduces the tissue response to further stimulation by that agent This process has potential clinical significance because it may limit the therapeutic response to sympathomimetic agents Two major categories of desensitization of responses mediated by G protein-coupled receptors he number and function of adrenoceptors on the cell surface and their responses may be regulated by catecholamines themselves, other hormones and drugs, age, and a number of disease states (see Chapter 2). After a cell or tissue has been exposed for a period of time to an agonist, that tissue often becomes less responsive to further stimulation by that agent (see Figure 2–12). Other terms such as tolerance, refractoriness, and tachyphylaxis have also been used to denote desensitization. This process has potential clinical significance because it may limit the therapeutic response to sympathomimetic agents.

Homologous desensitization: loss of responsiveness exclusively of the receptors that have been exposed to repeated or sustained activation by an agonist: Inability to couple to G protein, because the receptor has been phosphorylated on the cytoplasmic side by G protein-coupled receptor kinase (GRK) family

FIGURE 2–12 Rapid desensitization, resensitization, and down-regulation of β adrenoceptors. A: Response to a β-adrenoceptor agonist (ordinate) versus time (abscissa). (Numbers refer to the phases of receptor function in B.) Exposure of cells to agonist (indicated by the light-colored bar) produces a cyclic AMP response. A reduced cAMP response is observed in the continued presence of agonist; this “desensitization”typically occurs within a few minutes. If agonist is removed after a short time (typically several to tens of minutes, indicated by broken line on abscissa), cells recover full responsiveness to a subsequent addition of agonist (second light-colored bar). This “resensitization” fails to occur, or occurs incompletely, if cells are exposed to agonist repeatedly or over a more prolonged time period. B: Agonist binding to receptors initiates signaling by promoting receptor interaction with G proteins (G s ) located in the cytoplasm (step 1 in the diagram). Agonist-activated receptors are phosphorylated by a G protein-coupled receptor kinase (GRK), preventing receptor interaction with G s and promoting binding of a different protein, β-arrestin (β-Arr), to the receptor (step 2). The receptor-arrestin complex binds to coated pits, promoting receptor internalization(step 3). Dissociation of agonist from internalized receptors reduces β-Arr binding affinity, allowing dephosphorylation of receptors by a phosphatase (P’ase, step 4) and return of receptors to the plasma membrane (step 5); together, these events result in the efficient resensitization of cellular responsiveness. Repeated or prolonged exposure of cells to agonist favors the delivery of internalized receptors to lysosomes (step 6), promoting receptor down-regulation rather than resensitization. In pharmacology, desensitization is the loss of responsiveness to the continuing or increasing dose of a drug. Also termed tachyphylaxis, downregulation, fade or drug tolerance. This may be an important area to consider for the future design of safer drugs.[1] A rapid drug tolerance is termed tachyphylaxis. Pharmacokinetic tolerance[edit] Pharmacokinetic tolerance (dispositional tolerance) occurs because of a decreased quantity of the substance reaching the site it affects. This may be caused by an increase in induction of the enzymes required for degradation of the drug e.g. CYP450 enzymes. This is most commonly seen with substances such as ethanol, barbiturates, benzodiazapines and opiates. Pharmacodynamic tolerance[edit] Pharmacodynamic tolerance (reduced responsiveness) is the response to the substance is decreased by cellular mechanisms. This may be caused by a down regulation of receptor numbers.[2] Tolerance is a reduced response to repeated administration of the same dose or increase in the dose are required to produce the same magnitude of response. drug resistance is the reduction in effectiveness of a drug such as an antimicrobial or an antineoplastic[1] in curing a disease or condition. When the drug is not intended to kill or inhibit apathogen, then the term is equivalent to dosage failure or drug tolerance. More commonly, the term is used in the context of resistance that pathogens have "acquired", that is, resistance has evolved. When an organism is resistant to more than one drug, it is said to be multidrug-resistant. In a broad sense the immune system of an organism is a drug delivery system, albeit autonomous, and faces the same arms race problems as external drug delivery. (genetic bases, in antitumor…efflux pump, in antibiotics, ….development of enzyme like those hydrolyzing penicillin G (B-lactamase)

Heterologous desensitization: process by which desensitization of one receptor by its agonists also results in desensitization of another receptor that has not been directly activated by the agonist in question Can be mediated by second-messenger feedback mechanism: Example: β1-adrenoceptors stimulate cAMP accumulation, which leads to activation of protein kinase A; which can phosphorylate serine residues of intracellular tail of β2 receptors, resulting in inhibition of this receptor function

Sympathomimetic Drugs
Sympathomimetic drugs are classified as: Direct acting sympathomimetics: act directly on one or more of the adrenergic receptors Indirect acting sympathomimetics: increase the availability of norepinephrine or epinephrine to stimulate adrenergic receptors Displacement of stored catecholamines from the adrenergic nerve ending (e.g. tyramine & amphetamine) (amphetamine-like or ‘displacers’) Inhibition of reuptake of catecholamines already released (e.g. cocaine & tricyclic antidepressants) Blocking the metabolizing enzymes, monoamine oxidase (MAO) (e.g., selegiline) or catechol-O-methyltransferase (COMT) (e.g., entacapone)

NET DAT SERT Tyramine “cheese effect”
FIGURE 9–3 Pharmacologic targeting of monoamine transporters. Commonly used drugs such as antidepressants, amphetamines, and cocaine target monoamine (norepinephrine, dopamine, and serotonin) transporters with different potencies. A shows the mechanism of reuptake of norepinephrine (NE) back into the noradrenergic neuron via the norepinephrine transporter (NET), where a proportion is sequestered in presynaptic vesicles through the vesicular monoamine transporter (VMAT). B and C show the effects of amphetamine and cocaine on these pathways. See text for details. Tyramine “cheese effect”

Sympathomimetic Drugs (Cont’d)
Mixed acting sympathomimetics: indirectly induce the release of norepinephrine from the presynaptic terminal and directly activate receptors (e.g. Ephedrine)

N.B: The pharmacologic effects of direct agonists depend on: the route of administration, their relative affinity for adrenoreceptor subtypes and, the relative expression of these receptor subtypes in target tissues The pharmacologic effects of indirect sympathomimetics are greater under conditions of: increased sympathetic activity and norepinephrine storage and release Route bioavailbilty

Phenylethylamine (prototype) Substitutions may be made on (1) the benzene ring, (2) the terminal amino group, and/or (3) the carbons of the amino chain These modifications produce compounds with: varying affinities to α and β receptors, as well as to influence the intrinsic ability to activate the receptors, their pharmacokinetic properties, and different abilities to penetrate the CNS may be considered the parent compound from which sympathomimetic drugs are derived This compound consists of a benzene ring with an ethylamine side chain Hydrophobic substitution….increase lipid solubility Intrinsic ability to activate the drug…efficacy

Maximal α- and β- activity is found with catecholamines
BUT not active orally WHY?? Catecholamines are subject to inactivation by COMT (found in the gut and liver) Absence of ring –OH groups increase distribution of the molecule to the CNS Ephedrine and amphetamine: orally active with prolonged duration of action, and produce CNS effects Substitution by –OH groups at the 3 and 4 positions yields sympathomimetic drugs collectively known as catecholamines. Isoproterenol has isopropyl grp at amine The effects of modification of phenylethylamine are to change the affinity of the drugs for α and β receptors, spanning the range from almost pure α activity (methoxamine) to almost pure β activity (isoproterenol), as well as to influence the intrinsic ability to activate the receptors. The absence of one or the other of these groups, particularly the hydroxyl at C 3 , without other substitutions on the ring may dramatically reduce the potency of the drug. For example, phenylephrine ( Figure 9–5 ) is much less potent than epinephrine; Oral bioavailble drugs: ephedrine and amphetamine: as they do ont have catechol group…not labile for COMT decactivation Absence of one or both –OH groups on the phenyl ring increases the bioavailability after oral administration and prolongs the duration of action. Furthermore, absence of ring –OH groups tends to increase the distribution of the molecule to the central nervous system. For example, ephedrine and amphetamine ( Figure 9–5 ) are orally active, have a prolonged duration of action, and produce central nervous system effects not typically observed with the catecholamines. Increasing the size of alkyl substituents on the amino group tends to increase β-receptor activity. For example, methyl substitution on norepinephrine, yielding epinephrine, enhances activity at β 2 receptors. Beta activity is further enhanced with isopropyl substitution at the amino group (isoproterenol). Beta 2 -selective agonists generally require a large amino substituent group. The larger the substituent on the amino group, the lower the activity at α receptors; for example, isoproterenol is very weak at α receptors. Substitutions at the α carbon block oxidation by monoamine oxidase (MAO) and prolong the action of such drugs, particularly the noncatecholamines. Ephedrine and amphetamine are examples of α-substituted compounds ( Figure 9–5 ). Alpha-methyl compounds are also called phenylisopropylamines. In addition to their resistance to oxidation by MAO, some phenylisopropylamines have an enhanced ability to displace catecholamines from storage sites in noradrenergic nerves (see Chapter 6 ). α-carbon substitution block oxidation by monoamine oxidase (MAO) and prolong the action of such drugs and may give indirect activity (displacement) phenylisopropylamines (alpha methyl compounds)

Organ System Effects of Sympathomimetic Drugs
The response of any cell/organ to sympathomimetics depends on: the density and proportion of α and β adrenergic receptors; their relative selectivity for the different adrenoceptor subtype, and its pharmacological action on those receptors Don’t forget compensatory baroreflex mechanisms (CV system) Adrenergically innervated organs and tissues tend to have a predominance of one type of receptor pharmacologic effects of direct agonists depend on: the route of administration, their relative affinity for adrenoreceptor subtypes, and the relative expression of these receptor subtypes in target tissues vasculature of skeletal muscle have predominantly β2 receptors the heart contains mainly β1 receptors

β3 Receptors may mediate responses to catecholamine at sites with "atypical" pharmacological characteristics (e.g., adipose tissue). The enzyme renin is secreted by the kidney from specialized cells called granular cells of the juxtaglomerular apparatus in response to three stimuli: A decrease in arterial blood pressure (that could be related to a decrease in blood volume) as detected by baroreceptors (pressure-sensitive cells). This is the most direct causal link between blood pressure and renin secretion (the other two methods operate via longer pathways). A decrease in sodium chloride levels in the ultrafiltrate of the nephron. This flow is measured by the macula densa of thejuxtaglomerular apparatus. Sympathetic nervous system activity, which also controls blood pressure, acting through the beta1 adrenergic receptors.

Dopamine also act on B and alpha, at high doses…activate alpha
Dopamine also act on B and alpha, at high doses…activate alpha..vasoconstriction. Lowest affinity…the receptor is activated at higher doses

Cardiovascular system
Alpha1-Receptor Activation Alpha1 receptors expressed in most vascular beds their activation causes vasoconstriction and rise in peripheral resistance……dose-dependent rise in BP In the presence of normal cardiovascular reflexes, the rise in blood pressure elicits a baroreceptor-mediated increase in vagal tone with slowing of the heart rate (bradycardia) (fig. 9-7) Trimethaphan: ganglion blocker….bradycardia is no longer observed Sympathomimetics have prominent cardiovascular effects because of widespread distribution of α and β adrenoceptors in the heart, blood vessels, and neural and hormonal systems involved in blood pressure regulation. The endogenous catecholamines, norepinephrine and epinephrine, have complex cardiovascular effects because they activate both α and β receptors. It is easier to understand these actions by first describing the cardiovascular effect of sympathomimetics that are selective for a given adrenoreceptor. Ganglionic blocking drug (lec 6)Trimethaphan is occasionally used for control hypertension during plastic, neurological, and ophthalmological surgery to minimize hemorrhage in the operative field, to reduce blood loss, and to facilitate surgery on blood vessels

Phenylephrine given as I.V bolus to a dog
Reflex are blunted (but not eliminated) in anesthetized animal FIGURE 9–6 Effects of an α-selective (phenylephrine), β-selective (isoproterenol), and nonselective (epinephrine) sympathomimetic, given as an intravenous bolus injection to a dog. Reflexes are blunted but not eliminated in this anesthetized animal. BP, blood pressure; HR, heart rate.

FIGURE 9–7 Effects of ganglionic blockade on the response to phenylephrine (Phe) in a human subject. Left: The cardiovascular effect of the selective α agonist phenylephrine when given as an intravenous bolus to a subject with intact autonomic baroreflex function. Note that the increase in blood pressure (BP) is associated with a baroreflex-mediated compensatory decrease in heart rate (HR). Right: The response in th same subject after autonomic reflexes were abolished by the ganglionic blocker trimethaphan. Note that resting blood pressure is decreased and heart rate is increased by trimethaphan because of sympathetic and parasympathetic withdrawal (HR scale is different) (BP decreased as symapthetic was blocked, HR increased as parasympathetic is blocked). In the absence of baroreflex buffering, approximately a tenfold lower dose of phenylephrine is required to produce a similar increase in blood pressure. Note also the lack of compensatory decrease in heart rate. by trimethaphan Note that the increase in BP is associated with a baroreflex-mediated compensatory decrease in HR Patients with impaired autonomic function (diabetic autonomic neuropathy) may have exaggerated increases in heart rate or blood pressure when taking sympathomimetics

Alpha2-Receptor Activation α2 adrenoceptors are present in the vasculature, and their activation leads to vasoconstriction This effect observed only when α2 agonists are given locally by rapid I.V injection, or in very high oral doses When given systemically, these vascular effects are obscured by the central effects of α2 receptors, which lead to inhibition of sympathetic tone and blood pressure (sympatholytic effect) Clonidine: used to treatment (Tx.) Hypertension Patients with pure autonomic failure?? Very high oral dose the direct effect on vasculature is not obscured by the autonomic effect. It seems that clondine have higher affinity at alpha 2 in CNS Autonomic failure characterized by neural degeneration of postganglionic noradrenergic fibers, clonidine may increase blood pressure because the central sympatholytic effects of clonidine become irrelevant, whereas the peripheral vasoconstriction remains intact.

Beta-Receptor Activation Isoproterenol activates both beta1 and beta 2 adrenoceptor??? Direct effects on the heart are determined largely by β1 receptors Positive chronotropic effect, inotropic effect and dromotropic effect….increase coronary blood flow …..resulting in a marked increase in cardiac output and cardiac oxygen consumption β2 receptors activation, leads to vasodilation in certain vasculature of smooth muscles Increase blood flow in skeletal muscle during exercise The blood pressure response to a β-adrenoceptor agonist depends on its contrasting effects on the heart and the vasculature. Stimulation of β receptors in the heart increases cardiac output by increasing contractility and by direct activation of the sinus node to increase heart rate. Beta agonists also decrease peripheral resistance by activating β2 receptors, leading to vasodilation in certain vascular beds (Table 9–4). See slide 18….Increase cAMP…ca influx and sequestration…increase HR, contractility. Isoproterenol is a nonselective β agonist; it activates both β 1 and β 2 receptors. The net effect is to maintain or slightly increase systolic pressure and to lower diastolic pressure, so that mean blood pressure is decreased ( Figure 9–6 ).

Intravenous bolus injection to a dog
Net effect is to maintain or slightly increase SYSTOLIC pressure and decrease DYASTOLIC pressure….mean BP decreased FIGURE 9–6 Effects of an α-selective (phenylephrine), β-selective (isoproterenol), and nonselective (epinephrine) sympathomimetic, given as an intravenous bolus injection to a dog. Reflexes are blunted but not eliminated in this anesthetized animal. BP, blood pressure; HR, heart rate. The mean arterial pressure (MAP) is a term used in medicine to describe an average blood pressure in an individual.[1] It is defined as the average arterial pressure during a single cardiac cycle. See slide 54 for epinphrine Tachycardia in case of isoproteneraol: due to B1 action+ reflex tachycardia due to B2 vasodilation and reduction in mean BP. Less tachycardia with epinephrine as the mean BP…was increased less reflex Beta1, Alpha1 and Beta2 adrenoceptors Intravenous bolus injection to a dog Reflexes are blunted but not eliminated in this anesthetized animal

Dopamine receptors activation D1: vasodilation of renal, splanchnic, coronary, cerebral and other resistance vessels D2: presynaptic receptor suppresses norepinephrine release (unclear role on CVS) Dopamine activates beta1 receptors on the heart and….. ….. (at higher doses) vascular alpha receptors leading to vasoconstriction (similar to epinephrine) Slide 20:The endogenous catecholamine “dopamine” is imp. in the brain and in the splanchnic and renal vasculature (5 receptor subtypes) The D1-like receptor is typically associated with the stimulation of adenylyl cyclase (for example, D1-receptor-induced smooth muscle relaxation is presumably due to cAMP accumulation in the smooth muscle of those vascular beds in which dopamine is a vasodilator) D2-like receptors have been found to: inhibit adenylyl cyclase activity, open potassium channels, and decrease calcium influx Activation of D1 receptor in the renal vasculature may also induce natriuresis.The renal effects of dopamine have been used clinically to improve perfusion to the kidney in situations of oliguria (abnormally low urinary output). The activation of presynaptic D 2 receptors suppresses norepinephrine release, but it is unclear if this contributes to cardiovascular effects of dopamine. In addition, dopamine activates β 1 receptors in the heart. At low doses, peripheral resistance may Decrease (D1 vasodilation). At higher rates of infusion, dopamine activates vascular α receptors, leading to vasoconstriction, including in the renal vascular bed. Consequently, high rates of infusion of dopamine may mimic the actions of epinephrine.

Brain a2 Receptors Sympathetic ganglion b1 Receptors Heart Kidney
Brain Stem (Cardiovascular Control Center) Kidney Heart Sympathetic ganglion b1 Receptors a2 Receptors b2 Receptors a1 Receptors There are differences in receptor types predominantly expressed in the various vascular beds (Table 9–4) SKIN VESSELS & SPLANCHNIC VESSELS: α receptors, constrict in response to epinephrine and norepinephrine SKELETAL MUSCLE VESSELS may constrict or dilate depending on whether α or β receptors are activated NASAL BLOOD VESSELS: α receptors, vasoconstriction induced by sympathomimetics explains their decongestant action

The eye……/ …Respiratory system
Activation of α1 receptors mediates contraction of the radial pupillary dilator muscle of the iris and results in mydriasis Reduces intraocular pressure due to vasoconstriction and increase the outflow of aqueous humor from the eye β receptors antagonists reduce the production of aqueous humor (ciliary epithelium) Respiratory system Activation of β2 receptors in bronchial smooth muscle leads to: bronchodilation and inhibits the release of allergy mediator such as histamines from mast cells (albuterol, salmeterol used for treatment (Tx.) of asthma) Iris sphincter (circular muscle, M3). Also anticholinergic…bronchodilation. Alpha agonists increase the outflow of aqueous humor from the eye and can be used clinically to reduce intraocular pressure. In contrast, β agonists have little effect, but β antagonists decrease the production of aqueous humor. These effects are important in the treatment of glaucoma (see Chapter 10 ), a leading cause of blindness. B2 agonists…inhalers

Glaucoma responds to a variety of sympathomimetic and sympathoplegic drugs. (See The Treatment of Glaucoma, in Chapter 10.) Epinephrine and its prodrug dipivefrin are now rarely used, but β-blocking agents are among the most important therapies. Apraclonidine and brimonidine are α2-selective agonists that also lower intraocular pressure and are approved for use in glaucoma. The mechanism of action of these drugs in treating glaucoma is still uncertain; direct neuroprotective effects may be involved in addition to the benefits of lowering intraocular pressure.

Genitourinary tract The bladder base, urethral sphincter, and prostate contain α receptors that mediate contraction……urinary continence The specific α1A receptor subtype seems to be involved in mediating constriction of the bladder base and prostate Alpha-receptor activation in the ductus deferens, seminal vesicles, and prostate plays a role in normal ejaculation. Uterus: Similar effect on uterine smooth muscle (ritodrine) for the Tx of prematur labor Second point: (urinary retention is a potential ADE of the α1 agonist midodrine) Tamsulosine…a1A anagonist for BPH. the vas deferens (plural: vasa deferentia), also called ductus deferens (Latin: "carrying-away vessel"; plural: ductus deferentes), is part of the male anatomy of many vertebrates; they transport sperm from the epididymis in anticipation of ejaculation. Midodrine (brand names Amatine, ProAmatine, Gutron) is a vasopressor/antihypotensive agent

Gastrointestinal tract
Beta2 receptors located directly on the smooth muscle cells mediate relaxation via hyperpolarization of these cells Alpha receptors (especially α2-receptors), decrease muscle activity indirectly by presynaptically reducing the release of acetylcholine and possibly other stimulants within the enteric nervous system Stimulation of alpha2 receptors may also decrease salt and water flux into the lumen of the intestine

Exocrine glands Salivary glands: contain adrenoceptors that regulate the secretion of amylase and water However, certain sympathomimetic drugs (clonidine) produce symptoms of dry mouth…..mechanism uncertain; (probably CNS effects are responsible, though peripheral effects may contribute) Apocrine sweat glands: contain adrenoceptors and their stimulation increase sweat production (nonthermoregulatory glands associated with psychological stress) (sympathetic adrenergic) The diffusely distributed thermoregulatory eccrine sweat glands are regulated by sympathetic cholinergic postganglionic nerves that activate muscarinic cholinoceptors. e apocrine sweat glands, located on the palms of the hands and a few other areas, respond to adrenoceptor stimulants with increased sweat production. These are the apocrine nonthermoregulatory glands usually associated with psychological stress. (The diffusely distributed thermoregulatory eccrine sweat glands are regulated by sympathetic cholinergic postganglionic nerves that activate muscarinic cholinoceptors; see Chapter 6 .) Apocrine sweat glands are found in the armpit, areola (around the nipples), perineum (between the anus and genitals), in the ear, and in the eyelids. The secretory portion is larger than that of eccrine glands (making them larger overall). Rather than opening directly onto the surface of the skin, apocrine glands secrete sweat into the pilary canal of the hair follicle

Metabolism Catecholamines encourage the conversion of energy stores (glycogen and fat) to freely available fuels (glucose and free fatty acids), and cause an increase in the plasma concentration of these substances Activation of β3 receptors in adipocytes stimulate lipolysis……enhance release of FFA and glycerol into the blood α2 receptors activation inhibit lipolysis by decreasing intracellular cAMP Stimulate glycogenolysis in the liver and muscles, which leads to increased glucose release into the circulation……mediated mainly by β receptors In the liver, β-receptor-activated cAMP synthesis leads to activation of glycogen phosphorylase

Metabolism Activation of β2 receptors promotes K+ uptake into cells, particularly skeletal muscle…… and protect against a rise in plasma potassium during exercise Stress result in……Fall in plasma K+ potassium concentration (hypokalemia) during stress During extreme exercise, potassium is released from active muscle, and the serum potassium rises to a point that would be dangerous at res. B2-agonist ,,,Tx of hyperkalemia/////SE of B2 agonist…hypokalemia. During stress…increase epinepgrine and nor epinephrine…….hypokalemia (stress-induced catecholamine activity)

Hormones secretion β receptors enhance insulin secretion and renin secretion…. ….while…… α2 receptors inhibit insulin secretion and renin secretion Adrenoceptors also modulate the secretion of parathyroid hormone, calcitonin, thyroxine, and gastrin…….limited physiologic significance Renin….increase Bp. The enzyme renin is secreted by the kidney from specialized cells called granular cells of the juxtaglomerular apparatus in response to three stimuli: A decrease in arterial blood pressure (that could be related to a decrease in blood volume) as detected by baroreceptors (pressure-sensitive cells). This is the most direct causal link between blood pressure and renin secretion (the other two methods operate via longer pathways). A decrease in sodium chloride levels in the ultrafiltrate of the nephron. This flow is measured by the macula densa of thejuxtaglomerular apparatus. Sympathetic nervous system activity, which also controls blood pressure, acting through the beta1 adrenergic receptors.

Central nervous system
The catecholamines are almost completely unable to enter the CNS At highest rates of infusion effects are noted as nervousness Tremor and tachycardia are peripheral effect and are similar to the somatic manifestations of anxiety Noncatecholamines with indirect actions (amphetamines), readily enter the CNS…. ….their actions vary from mild alerting, with improved attention to boring tasks; through elevation of mood, insomnia, euphoria, and anorexia; to full-blown psychotic behavior Full-blown: Having or displaying all the characteristics necessary for completenes These effects are not readily assigned to alpha or beta mediated action and may represent enhancement of dopamine mediated processes or other effects of these drugs in the CNS.

Major effects mediated by α and β adrenoceptors

Therapeutic Uses of Sympathomimetic Drugs
Selection of a particular sympathomimetic drug depends on: Whether activation of α, β1, or β2 receptors is desired The desirable duration of action The preferred route of administration

Direct acting adrenergic agonists Endogenous catecholamine
Epinephrine (adrenaline) Potent stimulant of both α and β adrenoceptors Potent vasoconstrictor and cardiac stimulant +ve inotropic and chronotropic actions on the heart (B1) and vasoconstriction induced in many vascular beds (a1) Epinephrine also activates β2 receptors in some vessels (eg, skeletal muscle blood vessels), leading to their dilation Therefore, the net effect is an increase in systolic blood pressure, coupled with a slight decrease in diastolic pressure Epineprhine….USA, adrenaline….British A1=a1,B1=B2 Under physiologic conditions, epinephrine functions largely as a hormone; after release from the adrenal medulla into the blood, it acts on distant cells. The rise in systolic blood pressure that occurs after epinephrine release or administration is caused by its positive inotropic and chronotropic actions on the heart (predominantly β 1 receptors) and the vasoconstriction induced in many vascular beds (α receptors). Epinephrine also activates β 2 receptors in some vessels (eg, skeletal muscle blood vessels), leading to their dilation….increase blood flow during exercises Consequently, total peripheral resistance may actually fall, explaining the fall in diastolic pressure that is sometimes seen with epinephrine injection

Epinephrine (adrenaline)
Respiratory: causes powerful bronchodilation by acting directly on bronchial smooth muscle and inhibiting the release of allergic mediators such as histamine from mast cells (β2 action) Hyperglycemia: epinephrine has a significant hyperglycemic effect because of increased glycogenolysis in the liver (β2 effect), and a decreased release of insulin (α2 effect) Lipolysis: epinephrine initiates lipolysis through its agonist activity on the β receptors of adipose tissue Glycogenoloysis…activate glycogen phosphorylase. activation of β adrenoceptors in fat cells leads to increased lipolysis with enhanced release of free fatty acids and glycerol into the blood. Beta 3 adrenoceptors play a role in mediating this response in animals, but their role in humans is probably minor.

Therapeutic Uses of Sympathomimetic Drugs Anaphylaxis
Epinephrine (IM) is the 1ry Tx for anaphylaxis (drug of choice “DOC”) ??Epinephrine activates α, β1, and β2 receptors Can relief anaphylactic shock: bronchospasm, mucous membrane congestion, angioedema, and severe hypotension Glucocorticoids and antihistamines useful as 2ry therapy “EpiPen” recommended for patients at risk for: insect sting hypersensitivity, severe food allergies, or other types of anaphylaxis Epipen…epinerhrine. Alpha eceptors in nose…activation…decongestatn…due to vasoconstriction. Angioedema (BE: angiooedema) or Quincke's edema is the rapid swelling (edema) of the dermis, subcutaneous tissue,[1] mucosa and submucosal tissues. It is very similar to urticaria, but urticaria, commonly known as hives, occurs in the upper dermis. Anaphylaxis Anaphylactic shock and related immediate (type I) IgE-mediated reactions affect both the respiratory and the cardiovascular systems. The syndrome of bronchospasm, mucous membrane congestion, angioedema, and severe hypotension usually responds rapidly to the parenteral administration of epinephrine, 0.3–0.5 mg (0.3–0.5 mL of a 1:1000 epinephrine solution). Intramuscular injection may be the preferred route of administration, since skin blood flow (and hence systemic drug absorption from subcutaneous injection) is unpredictable in hypotensive patients. In some patients with impaired cardiovascular function, intravenous injection of epinephrine may be required. Glucocorticoids and antihistamines (both H1- and H2-receptor antagonists) may be useful as secondary therapy in anaphylaxis. The use of these agents precedes the era of controlled clinical trials, but extensive experimental and clinical experience supports the use of epinephrine as the agent of choice in anaphylaxis, presumably because epinephrine activates α, β1, and β2 receptors, all of which may be important in reversing the pathophysiologic processes underlying anaphylaxis. It is recommended that patients at risk for insect sting hypersensitivity, severe food allergies, or other types of anaphylaxis carry epinephrine in an autoinjector (EpiPen) for self-administration.

Norepinephrine (noradrenaline, levarterenol) At therapeutic doses to human, stimulate the α-adrenergic receptors (both α1 & α2) and the β1 receptors with similar potency as epinephrine, but has relatively little effect on β2 receptors Norepinephrine increases peripheral resistance and both diastolic and systolic blood pressure Compensatory baroreflex activation tends to overcome the direct positive chronotropic effects of norepinephrine; however, the positive inotropic effects on the heart are maintained

Dopamine Important neurotransmitter in the CNS and is involved in the reward stimulus relevant to addiction Its deficiency in the basal ganglia leads to Parkinson's disease (treated with levodopa) Its increment seems to be the cause of psychosis (antagonist) Dopamine promotes vasodilation via activation of D1 receptors. The activation of presynaptic D2 receptors suppresses norepinephrine release The main components of the basal ganglia are the striatum (caudate nucleus and putamen), the globus pallidus, the substantia nigra, thenucleus accumbens, and the subthalamic nucleus.

Direct acting adrenergic agonists Direct acting sympathomimetics
d. Phenylphrine Direct-acting, synthetic α1 receptors agonist Not a catechol derivative and, therefore, not a substrate for COMT (longer duration of action) It is a vasoconstrictor that raises both systolic and diastolic blood pressures Has no effect on the heart itself but rather induces reflex bradycardia when given parenterally

Therapeutic Uses of Sympathomimetic Drugs
Phenylephrine is an effective (1)mydriatic agent frequently used to facilitate examination of the retina (2)Topically on the nasal mucous membrane as a decongestant for minor allergic hyperemia and itching of the conjunctival membranes N.B: Nasal blood vessels are rich in α receptors…..vasoconstriction Tetrahydrozoline used also to induce mydriasis…..both drugs do not cause cycloplegia!! Tetrahydrozoline alpha agonist

Xylometazoline and oxymetazoline Both are direct-acting α-adrenoceptor agonists Used as topical decongestants because of their ability to promote constriction of the nasal mucosa (available as over-the-counter nasal spray products) When taken in large doses, oxymetazoline may cause hypotension (α2A receptors) For max. 3 days! It cause rebound hyperemia. Hypotension by acting on presynaptic alpha 2 (swallowing of large doses)….clonidine-like effect! Mucous membrane decongestants are α agonists that reduce the discomfort of hay fever and, to a lesser extent, the common cold by decreasing the volume of the nasal mucosa. These effects are probably mediated by α1 receptors. Unfortunately, rebound hyperemia may follow the use of these agents, and repeated topical use of high drug concentrations may result in ischemic changes in the mucous membranes, probably as a result of vasoconstriction of nutrient arteries…..contraindicated for more than 3 days!!!

Midodrine It is a prodrug that is enzymatically hydrolyzed to DesGlyMidodrine……selective α1-receptor agonist USE: primarily indicated for the treatment of orthostatic hypotension, typically due to impaired autonomic nervous system function Effective when the patient is standing, but may cause HTN when the subject is supine…..can be minimized by avoiding dosing prior to bedtime and elevating the head of the bed The supine position /ˈsuːpaɪn/ is a position of the body: lying down with the face up

Methoxamine α1 receptors agonist It may cause a prolonged increase in blood pressure due to vasoconstriction; it also causes a vagally mediated bradycardia USE: clinical applications are limited to overcome hypotensive states during surgery …..during surgery involving halothane anesthetics (parenterally)

Alpha2-selective agonists “Clonidine, Methyldopa, Guanfacine, Guanabenz” Primarily used for the treatment of systemic hypertension through actions in the central nervous system Apraclonidine and brimonidine (α2-selective agonists) lower intraocular pressure and are approved for use in glaucoma (used more than non-selective alpha agonist). Tizanidine (α2 agonist) that is used as a muscle relaxant Lexicomp: Tizanidine: An alpha2-adrenergic agonist agent which decreases spasticity by increasing presynaptic inhibition; effects are greatest on polysynaptic pathways; overall effect is to reduce facilitation of spinal motor neurons. Direct application to a blood vessel may cause vasoconstriction. Apraclonidine and brimonidine (α2-selective agonists) , Apraclonidine and brimonidine are α 2 -selective agonists that also lower intraocular pressure and are approved for use in glaucoma. The mechanism of action of these drugs in treating glaucoma is still uncertain; direct neuroprotective effects may be involved in addition to the benefits of lowering intraocular pressure. Apraclonidine (INN), also known as Iopidine, is a sympathomimetic used in glaucoma therapy. It is an α2-adrenergic agonist and a weak alpha-1 adrenergic receptor agonist. (probably the weak a1 agonist activity cause mydriasis) used as topical eye drop. (or direct agonist on alpha2 receptors in eye…..vasoconstriction) Apraclonidine may be useful in the diagnosis of Horner's syndrome. In Horner's syndrome, the sympathetic innervation to the pupillary dilator muscle is lost. The affected pupil is thus miotic and the pupillary dilator responds to denervation by increasing alpha-1 receptors. Apraclonidine is useful in this case due to its weak alpha-1 adrenergic properties. When applied to the denervated (and thus hyper-sensitive) pupillary dilator muscle, a super-normal dilatory response is generated in which the pupil dilates to a degree greater than that which would be seen in a non-denervated muscle. This causes the reversal of anisocoria that is characteristic of Horner's.

Clonidine has been found to have efficacy in the treatment of diarrhea in diabetics with autonomic neuropathy, perhaps because of its ability to enhance salt and water absorption from the intestine In addition, clonidine has efficacy in diminishing craving for narcotics and alcohol during withdrawal and may facilitate cessation of cigarette smoking. Clonidine has also been used to diminish menopausal hot flushes

DexMedeTomidine (α2 agonist) is used for sedation under intensive care circumstances and during anesthesia of initially intubated and mechanically ventilated patients It blunts the sympathetic response to surgery, which may be beneficial in some situations Lowers opioid requirements for pain control and does not depress ventilation Lexicomp: Selective alpha2-adrenoceptor agonist with anesthetic and sedative properties thought to be due to activation of G-proteins by alpha2a-adrenoceptors in the brainstem resulting in inhibition of norepinephrine release; peripheral alpha2b-adrenoceptors are activated at high doses or with rapid IV administration resulting in vasoconstriction.

Clinical Applications Toxicities, Interactions
Subclass Effects Clinical Applications Toxicities, Interactions α1 Agonists Midodrine Vascular smooth muscle contraction increasing blood pressure (BP) Orthostatic hypotension Produces supine hypertension, piloerection (goose bumps), and urinary retention Phenylephrine IV for short-term maintenance of BP in acute hypotension and intranasally to produce local vasoconstriction as a decongestant α2 Agonists Clonidine Vasoconstriction is masked by central sympatholytic effect, which lowers BP Hypertension produces dry mouth and sedation Methyldopa Also used as central sympatholytics guanfacine guanabenz Dexmedetomidine Prominent sedative effects and used in anesthesia Tizanidine Used as a muscle relaxant Apraclonidine Used in glaucoma to reduce intraocular pressure brimonidine

Isoproterenol (isoprenaline) Direct acting synthetic catecholamine that predominantly stimulates β adrenoceptors. Little effect on α-receptors Produces intense stimulation of the heart to increase its rate and force of contraction…..increases cardiac output (β1 effect) Dilates the arterioles of skeletal muscle (β2 effect), resulting in decreased peripheral resistance Net effect: marked fall in diastolic and a lesser decrease or a slight increase in systolic pressure Rarely used therapeutically……used to stimulate the heart in emergency situations…..non-selective!!! Beta-selective agonists are very important because the separation of β 1 and β 2 effects ( Table 9–2 ), although incomplete, is sufficient to reduce adverse effects in several clinical applications. (katzung 2012)

Selective beta-1 agonist advantage……increase cardiac output with less reflex tachycardia (no vasodilation effect) Partial Agonist

(+) isomer is a potent β1 agonist and α1 antagonist
(−) isomer is an α1 agonist

Beta-selective agonists
β1-selective agents: Dobutamine…….Racemic mixture of (−) and (+) isomers: (+) isomer…….potent β1 agonist and α1 antagonist (–) isomer…..potent α1 agonist (cause significant vasoconstriction when given alone) The resultant CV effects of dobutamine reflect this complex pharmacology: Increases cardiac output (positive inotropic action) Positive chronotropic effect and, peripheral resistance does not decrease significantly Does not significantly elevate O2 demands of the myocardium — advantage over other sympathomimetic drugs Dobutamine: has relatevely greater inotropic than chronotropic effect compared with isoproterenol! (+)=R , (-) =(s) enatiomers. Clinical preparations of dobutamine are a racemic mixture of (−) and (+) isomers, each with contrasting activity at α 1 and α 2 receptors. (katzung 2012) In chemistry, an enantiomer (/ɨˈnæntɪ.ɵmər/ ə-nan-tee-ə-mər; from the Greek ἐνάντιος, opposite, and μέρος, part or portion) is one of two stereoisomers that are mirror images of each other that are non-superposable (not identical), much as one's left and right hands are the same except for opposite orientation.[1] Isoprotenerol…increase CO and oxygen consumption

β2-selective agents: Beta-selective agonists
Used primarily as bronchodilator and their use have achieved an important place in the treatment of asthma (relievers) Short-acting (inhalers): “albuterol (salbutamol), metaproterenol, terbutaline”...effective for Tx of acute symptoms Long-acting(inhalers): “salmeterol, formeterol”..... combined with corticosteroid used as prophylaxis Nonselective drugs (epinephrine), β-selective agents (isoproterenol), are available The drugs most used for management of asthma are adrenoceptor agonists, or sympathomimetic agents (used as "relievers" or bronchodilators) and inhaled corticosteroids (used as "controllers" or anti-inflammatory agents).Long-acting used with steroid coz may increase morbidity if used alone….also used in COPD Nonselective are not used for asthma….SE. In patients with asthma, beta blockers can cause increased bronchial obstruction and airway reactivity, and resistance to the effects of inhaled or oral beta receptor agonists (such as albuterol or terbutaline) [1]. Even topical ophthalmic administration of nonselective beta blockers for the treatment of glaucoma has led to asthmatic exacerbations [2]. However, beta-blockers appear to be safe in patients with COPD and indeed may reduce mortality and exacerbations [3]. (in case of HTN) Pulmonary Applications One of the most important uses of sympathomimetic drugs is in the therapy of bronchial asthma. Beta2-selective drugs (albuterol, metaproterenol, terbutaline) are used for this purpose. Short-acting preparations can be used only transiently for acute treatment of asthma symptoms. For chronic asthma treatment in adults, long-acting β2 agonists should only be used as an addition to steroids because they may increase morbidity if used alone. There is less agreement about their benefit in children. Long-acting β2 agonists are also used in patients with chronic obstructive pulmonary disease (COPD). Nonselective drugs are now rarely used because they are likely to have more adverse effects than the selective drugs. The use of β agonists for the management of asthma is discussed in Chapter 20.

Therapeutic Uses of Sympathomimetic Drugs Genitourinary Applications
Beta-selective agonists Ritodrine (B2-selective) used clinically to achieve uterine relaxation in premature labor (arrest premature labor) Terbutaline have been used to suppress premature labor The goal is to defer labor long enough to ensure adequate maturation of the fetus. This may afford time to administer corticosteroid drugs, which decrease the incidence of neonatal respiratory distress syndrome (IRDS) pregnant mothers with threatened premature delivery prior to 34 weeks are often administered at least one course of glucocorticoids, a steroid that crosses the placental barrier and stimulates the production of surfactant in the lungs of the fetus. Defer: put off (an action or event) to a later time; postpone

Mixed-acting sympathomimetics
EPHEDRINE 1st orally active sympathomimetic (non-chatecol) Relatively long duration of action Can enter the CNS with mild stimulant effect PSEUDOEPHEDRINE One of the four ephedrine enantiomers Was available as OTC component of many decongestant mixtures Used as a precursor in the illicit manufacture of methamphetamine (restrictions on its sale) GENITOURINARY APPLICATION: “Ephedrine or pseudoephedrine” is occasionally useful in the treatment of stress incontinence Illicit: forbidden by law, rules, or custom.

Indirect acting sympathomimetics
They potentiate the effects of norepinephrine produced endogenously, (do not directly affect postsynaptic receptors) These agents can have one of two different mechanisms: They may enter the sympathetic nerve ending and displace stored catecholamine transmitter (amphetamine-like or ‘displacers’) They may inhibit the reuptake of released transmitter by interfering with the action of the NET

NET DAT SERT Tyramine “cheese effect”

Indirect acting adrenergic agonists a. Amphetamine-Like or displacers
Racemic mixture of phenylisopropylamine (D-isomer is more potent than L-isomer) Amphetamine's actions are mediated through the release of norepinephrine and, to some extent, dopamine Widely abused as CNS stimulants (orally active) Stimulant effect on mood and alertness and decrease appetite Legitimate indications include: narcolepsy, attention deficit disorder Narcolepsy is a sleep disorder that causes excessive sleepiness and frequent daytime sleep attacks. Legitimate: conforming to the law or to rules. Attention deficit hyperactivity disorder (ADHD) is one of the most common childhood disorders and can continue through adolescence and adulthood. Symptoms include difficulty staying focused and paying attention, difficulty controlling behavior, and hyperactivity (over-activity).

Methamphetamine: Very similar to amphetamine with an even higher ratio of central to peripheral actions. In the brain, methamphetamine: releases dopamine and other biogenic amines, and inhibits MAO Used as anorexiant Phenmetrazine: It is a variant phenylisopropylamine with amphetamine-like effects. and is also a popular drug of abuse N.B: lexicomp: Weight reduction: Methamphetamine should be tried only in weight reduction programs for patients in whom alternative therapy has been ineffective. Administration of methamphetamine for prolonged periods of time in obesity may lead to drug dependence and must be avoided. A biogenic substance is a substance produced by life processes. It may be either constituents, or secretions, of plants or animals. A more specific name for these substances is biomolecules.

Therapeutic Uses of Sympathomimetic Drugs CNS Applications
Obesity: an encouraging initial appetite-suppressing effect of these agents may be observed in obese humans, but there is no evidence that long-term improvement in weight control can be achieved with amphetamines alone….. intensive dietary and psychological counseling and support is needed N.B: lexicomp: Weight reduction: Methamphetamine should be tried only in weight reduction programs for patients in whom alternative therapy has been ineffective. Administration of methamphetamine for prolonged periods of time in obesity may lead to drug dependence and must be avoided.

Methylphenidate: Amphetamine variant with similar pharmacologic effects and abuse potential It is a mild CNS stimulant with more prominent effects on mental than on motor activities CNS application: attention-deficit hyperactivity disorder (ADHD) and narcolepsy Some patients respond well to low doses of methylphenidate or to clonidine. Extended-release formulations may simplify dosing regimens and increase adherence to therapy, especially in school-age children Lexicomp: Methylphenidate: Special Alerts Risk of Priapism Associated with Methylphenidate Use December 2013 The FDA is warning that methylphenidate products may, in rare instances, cause prolonged and sometimes painful erections known as priapism. Methylphenidate also used in depression in patients with terminal illnesses ADHD: affect 3-5% of the children globally. Diagnosed more frequently in boys than in girls. Symptoms: INATTENTION, HYPERACTIVITY AND INPULSIVITY. attention deficit hyperactivity disorder (ADHD), a behavioral syndrome consisting of short attention span, hyperkinetic physical behavior, and learning problems.

Modafinil: a new amphetamine substitute It is a psychostimulant that differs from amphetamine in structure, neurochemical profile, and behavioral effects Mech of action (MAO) not fully known Inhibits both NET and DAT, and increases interstitial concentrations not only of norepinephrine and dopamine, but also serotonin and glutamate while decreasing GABA levels DAT: dopamine transporter. GABA is an inhbitory neurotransmitter

NET DAT SERT

Therapeutic Uses of Sympathomimetic Drugs CNS Applications
All amphetamine-like and displacer have a mood-elevating (euphoriant) effect, alerting, & sleep-deferring action that is manifested by improved attention to repetitive tasks Modafinil is approved for use in NARCOLEPSY (chronic sleep disorder) MODAFINIL is claimed to have fewer disadvantages than amphetamine in this condition ……LESS mood changes, LESS insomnia and LESS abuse potential For narcolepsy, Obstructive sleep apnea, Shift work sleep disorder (SWSD)…….labeled Unlabeled: ADHD Clinical trials suggest that modafinil may also be useful in ADHD, but because the safety profile in children has not been defined, it has not gained approval by the FDA for this indication.

Tyramine It is by-product of tyrosine metabolism in the body and is also found in high concentrations in some fermented foods such as cheese (table 9-5) Tyramine's action caused by the release of stored catecholamines Inactive orally……readily metabolized by MAO in the liver If the patient is taking MAOI “inhibitors” (MAO-A), BE CAREFUL!.....can precipitate serious vasopressor effects Sausage, fermented (eg, salami, pepperoni, summer sausage), Smoked or pickled fish (eg, pickled herring), Cheese, natural or aged, Chocolate. MAOI..used in depression, parkinson’s………+tyramine…hypertention crisis

Indirect acting adrenergic agonists b
Indirect acting adrenergic agonists b. Catecholamine Reuptake Inhibitors Atomoxetine & ReBoxetine Selective inhibitors of the NET Surprisingly little cardiovascular effect because it has a clonidine-like effect in the CNS ……decrease sympathetic outflow while at the same time potentiating the effects of NE in the periphery Clinical use of atomoxetine: Tx. of ADHD Atomoxetine: FDA box warning…increase suicidal ideation in children Reboxetine….used for the Tx of depression Atomoxetine is a selective inhibitor of the norepinephrine reuptake transporter. Its actions, therefore, are mediated by potentiation of norepinephrine levels in noradrenergic synapses. It is used in the treatment of attention deficit disorders (see below). Atomoxetine has surprisingly little cardiovascular effect because it has a clonidine-like effect in the central nervous system to decrease sympathetic outflow while at the same time potentiating the effects of norepinephrine in the periphery.

Indirect acting adrenergic agonists b
Indirect acting adrenergic agonists b. Catecholamine Reuptake Inhibitors Sibutramine: is a serotonin and norepinephrine reuptake inhibitor not any more used as appetite suppressant for the Tx of obesity (increase CV events) Duloxetine: a widely used antidepressant with serotonin and norepinephrine reuptake inhibitory effects 12th ed. Katzung: Sibutramine is a serotonin and norepinephrine reuptake inhibitor and was initially approved by the FDA as an appetite suppressant for long-term treatment of obesity. It has been taken off the market in the United States (2010) and several other countries because it has been associated with a small increase in cardiovascular events including strokes in patients with a history of cardiovascular disease, which outweighed the benefits gained by modest weight reduction. Duloxetine is a widely used antidepressant with balanced serotonin and norepinephrine reuptake inhibitory effects (see Chapter 30). Increased cardiovascular risk has not been reported with duloxetine. (but increase suicidal thoughts)

Cocaine: Local anesthetic with peripheral indirect sympathomimetic action Enters the CNS and produces a shorter lasting but more intense amphetamine-like effect through inhibiting dopamine reuptake into neurons in the "pleasure centers" of the brain + can be smoked, snorted into the nose, or injected for rapid onset of effect…..have made it a heavily abused drug INTERESTINGLY….DAT knockout mice still self-administer cocaine, suggesting that cocaine may have additional pharmacologic targets These properties and the fact that a rapid onset of action can be obtained when smoked, snorted into the nose, or injected, has made cocaine a heavily abused drug

Therapeutic Uses of Sympathomimetic Drugs Cardiovascular applications
Condition in which an INCREASE in cardiac output and blood flow to the tissue is desired (severe hypotension, cardiac shock, heart failure) Place the patient in the recumbent position and ensure adequate fluid volume (1st approach) β agonist useful in this situation because they increase cardiac contractility and reduce diastolic pressure by β2 effect Dobutamine and dopamine are used (dopamine is DOC) Isoproterenol and epinephrine have been used in the temporary emergency management of complete heart block and cardiac arrest (electronic pacemaker are safer and more effective) In keeping with the critical role of the sympathetic nervous system in the control of blood pressure, a major area of application of the sympathomimetics is in cardiovascular conditions. Sympathomimetic drugs may be used in a hypotensive emergency to preserve cerebral and coronary blood flow. The treatment is usually of short duration while the appropriate intravenous fluid or blood is being administered. Direct-acting α agonists such as norepinephrine, phenylephrine, and methoxamine have been used in this setting when vasoconstriction is desired. Epinephrine may be useful in cardiac arrest in part by redistributing blood flow during cardiopulmonary resuscitation to coronaries and to the brain. However, electronic pacemakers are both safer and more effective in heart block and should be inserted as soon as possible if there is any indication of continued high-degree block. Dobutamine injection is used as a pharmacologic cardiac stress test. Dobutamine augments myocardial contractility and promotes coronary and systemic vasodilation. These actions lead to increased heart rate and increased myocardial work and can reveal areas of ischemia in the myocardium that are detected by echocardiogram or nuclear medicine techniques. Dobutamine is often used in patients unable to exercise during the stress test.

Shock Acute cardiovascular syndrome that results in a critical reduction in perfusion of vital tissues, altered mental state, hypotension and oliguria Usually due to: hypovolemia, cardiac insufficiency, and altered vascular resistance Treatment: volume replacement and treatment of the underlying disease are the mainstays of the treatment Adrenergic receptor agonists may be used……: β receptor agonists increase heart rate and force of contraction, α receptor agonists increase peripheral vascular resistance, and dopamine (DOC) promotes dilation of renal and splanchnic vascular beds, in addition to activating α and β receptors Shock is a complex acute cardiovascular syndrome that results in a critical reduction in perfusion of vital tissues and a wide range of systemic effects. Shock is usually associated with hypotension, an altered mental state, oliguria, and metabolic acidosis. If untreated, shock usually progresses to a refractory deteriorating state and death. The three major mechanisms responsible for shock are hypovolemia, cardiac insufficiency, and altered vascular resistance. Volume replacement and treatment of the underlying disease are the mainstays of the treatment of 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, intense vasoconstriction, mediated by reflex sympathetic nervous system activation, is present. Indeed, efforts aimed at reducing rather than increasing peripheral resistance may be more fruitful to improve cerebral, coronary, and renal perfusion. A decision to use vasoconstrictors or vasodilators is best made on the basis of information about the underlying cause. Their use may require invasive monitoring.

Condition in which a DECREASE in blood flow or increase in blood pressure is desired α1 agonist are useful in situation in which vasoconstriction is appropriate Such as decongestant effect (phenylephrine) or spinal shock (NE) in which maintenance of blood pressure may help in maintain perfusion to brain, heart, & liver Shock due to MI is usually made worse by vasoconstriction Inducing Local Vasoconstriction Reduction of local or regional blood flow is desirable for achieving hemostasis in surgery, for reducing diffusion of local anesthetics away from the site of administration, and for reducing mucous membrane congestion. In each instance, α-receptor activation is desired, and the choice of agent depends on the maximal efficacy required, the desired duration of action, and the route of administration. Mucous membrane decongestants are α agonists that reduce the discomfort of hay fever and, to a lesser extent, the common cold by decreasing the volume of the nasal mucosa. These effects are probably mediated by α1 receptors. Unfortunately, rebound hyperemia may follow the use of these agents, and repeated topical use of high drug concentrations may result in ischemic changes in the mucous membranes, probably as a result of vasoconstriction of nutrient arteries…..contraindicated for more than 3 days!!! agonist increase myocarium oxygen demand

α agonist are often mixed with local anesthetic to reduce the loss of anasthetic from the area of injection into the circulation (epinephrine is DOC) Chronic orthostatic hypotension: On standing, gravitational forces induce venous pooling, resulting in decreased venous return Increasing peripheral resistance is one of the strategies to treat chronic orthostatic hypotension Midodrine, an orally active α1 agonist, is frequently used for this indication Effective pharmacologic hemostasis, often necessary for facial, oral, and nasopharyngeal surgery, requires drugs of high efficacy that can be administered in high concentration by local application. Epinephrine is usually applied topically in nasal packs (for epistaxis) or in a gingival string (for gingivectomy). Cocaine is still sometimes used for nasopharyngeal surgery because it combines a hemostatic effect with local anesthesia. Occasionally, cocaine is mixed with epinephrine for maximum hemostasis and local anesthesia. Chronic Orthostatic Hypotension Normally, a decrease in blood pressure is prevented by reflex sympathetic activation with increased heart rate, and peripheral arterial and venous vasoconstriction. Impairment of autonomic reflexes that regulate blood pressure can lead to chronic orthostatic hypotension. This is more often due to medications that can interfere with autonomic function (eg, imipramine and other tricyclic antidepressants, α blockers for the treatment of urinary retention, and diuretics) diabetes, and other diseases causing peripheral autonomic neuropathies, and less commonly, primary degenerative disorders of the autonomic nervous system, as in the case study described at the beginning of the chapter.

OPHTHAMLIC APPLICATION
Sympathomimetics administered as ophthalmic drops are also useful in localizing the lesion in Horner's syndrome Horner's syndrome is a condition (usually unilateral) that results from interruption of the sympathetic nerves to the face (caused by either preganglionic or postganglionic lesion, such as a tumor) Symptoms include vasodilation, ptosis, miosis, and loss of sweating on the affected side If the lesion is postganglionic, indirectly acting sympathomimetics (eg, cocaine, amphetamine) will not dilate the abnormally constricted pupil because catecholamines have been lost from the nerve endings in the iris But phenylephrine will dilate the pupil (acts directly on the α receptors on the smooth muscle of the iris) If the lesion is preganglionic, it will show a normal response to both drugs, since the postganglionic fibers and their catecholamine stores remain intact in this situation Phenylephrine is an effective mydriatic agent frequently used to facilitate examination of the retina. It is also a useful decongestant for minor allergic hyperemia and itching of the conjunctival membranes. Sympathomimetics administered as ophthalmic drops are also useful in localizing the lesion in Horner's syndrome. Knowledge of the location of the lesion (preganglionic or postganglionic) helps determine the optimal therapy. A preganglionic lesion leaves the postganglionic adrenergic neuron intact, whereas a postganglionic lesion results in degeneration of the adrenergic nerve endings and loss of stored catecholamines from them. Because indirectly acting sympathomimetics require normal stores of catecholamines, such drugs can be used to test for the presence of normal adrenergic nerve endings. The iris, because it is easily visible and responsive to topical sympathomimetics, is a convenient assay tissue in the patient.

Horner's syndrome

α1 α2 β1 β2 β3 Table 9–3 Distribution of Adrenoceptor Subtypes Type
Tissue Actions α1 Most vascular smooth muscle (innervated) Contraction Pupillary dilator muscle Contraction (dilates pupil) Pilomotor smooth muscle Erects hair Prostate Heart Increases force of contraction α2 Postsynaptic CNS adrenoceptors Probably multiple Platelets Aggregation Adrenergic and cholinergic nerve terminals Inhibition of transmitter release Some vascular smooth muscle Fat cells Inhibition of lipolysis β1 Heart, juxtaglomerular cells Increases force and rate of contraction; increases renin release β2 Respiratory, uterine, and vascular smooth muscle Promotes smooth muscle relaxation Skeletal muscle Promotes potassium uptake Human liver Activates glycogenolysis β3 Activates lipolysis

Subclass Effects Clinical Applications Toxicities, Interactions α1 Agonists Midodrine Vascular smooth muscle contraction increasing blood pressure (BP) Orthostatic hypotension Produces supine hypertension, piloerection (goose bumps), and urinary retention Phenylephrine IV for short-term maintenance of BP in acute hypotension and intranasally to produce local vasoconstriction as a decongestant α2 Agonists Clonidine Vasoconstriction is masked by central sympatholytic effect, which lowers BP Hypertension produces dry mouth and sedation Methyldopa Also used as central sympatholytics guanfacine guanabenz Dexmedetomidine Prominent sedative effects and used in anesthesia Tizanidine Used as a muscle relaxant Apraclonidine Used in glaucoma to reduce intraocular pressure brimonidine

Subclass Effects Clinical Applications Toxicities, Interactions β1 Agonists Dobutamine1 Positive inotropic effect Primarily used in acute heart failure to increase cardiac output β2 Agonists Albuterol Bronchial smooth muscle dilation Asthma Tremor, tachycardia Indirect-acting phenylisopropylamines Amphetamine, metamphetamine Displaces stores of catecholamines Anorexiant, ADHD, narcolepsy Insomnia, hypertension Ephedrine Narcolepsy, postural hypotension Lower addiction liability Tyramine None, found in fermented food Hypertension, arrhythmias Cocaine Block NET & DAT Local anasthetic High addiction liability, HT, arrhythmias, seizures

Adrenoceptor Agonists & Sympathomimetic Drugs

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Adrenoceptor Agonists & Sympathomimetic Drugs

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