Adrenergic Stimulants (Katzung, Chapter 9) PDF

Midwestern University Back to Pamela E. Potter, Ph.D. Pharmacology 1610/1612, 2024 Drug List Adrenergic Stimulants Adrenergic Stimulants Katzung, Chapter 9 Catecholamines E...

Midwestern University Back to Pamela E. Potter, Ph.D. Pharmacology 1610/1612, 2024 Drug List Adrenergic Stimulants Adrenergic Stimulants Katzung, Chapter 9 Catecholamines Epinephrine (Adrenalin) Norepinephrine (Levophed) Isoproterenol (Isuprel) Alpha agonists Phenylephrine (Neo-Synephrine; Sudafed PE) Pseudoephedrine (Sudafed) Tetrahydrozoline (Visine) Oxymetazoline (Afrin) Midodrine (ProAmatine) Alpha-2 agonists Clonidine (Catapres) Methyldopa (Aldomet) Apraclonidine (Iopidine), Brimonidine (Alphagan) Beta-1 agonist Dobutamine (Dobutrex) Beta-2 agonists Albuterol (Ventolin) Salmeterol (Serevent) Beta-3 agonist Mirabegron (Myrbetriq) Vibegron (Gemtesa) Dopamine Agonists Dopamine (Intropin) Fenodolpam (Corlopam) Indirect Acting Ephedrine Amphetamine, Methamphetamine Methylphenidate (Ritalin) Cocaine Tyramine Lectures 18 & 19 Page 1 of 21 Midwestern University Back to Pamela E. Potter, Ph.D. Pharmacology 1610/1612, 2024 Drug List Adrenergic Stimulants Learning Objectives: Lecture 18 1. Describe the synthesis, release, and metabolism of norepinephrine and epinephrine. 2. Describe the overall effects of sympathetic stimulation. 3. Explain the effect of denervation on the observed effects of drugs that act directly on receptors versus those with indirect actions. 4. Describe the effects of stimulating alpha receptors and differentiate the effects of each subtype. 5. Describe the effects of stimulating beta receptors and differentiate the effects of each subtype. 6. Describe the effects of stimulation of peripheral dopamine receptors. 7 Describe the effects of alpha receptor stimulation on the blood vessels, the eye, respiration, gastrointestinal, and genitourinary tract. 8. Describe the effects of beta receptor stimulation on the cardiovascular system and renin release. 9. Describe the effects of beta receptor stimulation on the eye, bronchioles, and genitourinary tract, as well as metabolic effects. Distinguish beta1 vs beta2 effects. 10. Explain the effects of phenylephrine (α receptors), isoproterenol (β receptors), norepinephrine (α and β1 receptors) and epinephrine (α and β receptors) on blood pressure and heart rate. Lecture 19 11. Describe the effects and discuss the uses of the alpha1 agonists phenylephrine, pseudoephedrine and midodrine. Compare these with the effects and uses of tetrahydrozoline and oxymetazoline. 12. Explain the mechanism of action of clonidine, in particular the role of the CNS in its effect, and describe its uses and side effects. 13. Discuss the uses and side effects of α2 agonists in treatment of hypertension and for glaucoma. 14. Describe the effects, uses and side effects of isoproterenol. 18. Discuss the mechanism, uses and side effects of the selective beta1 agonist dobutamine. 16. Discuss the mechanism, uses and side effects of selective beta2 agonists such as albuterol. 17. Discuss the mechanism, uses and side effects of selective beta3 agonists such as mirabegron. 18. Describe the effect of norepinephrine on blood pressure and heart rate and how it would be affected by pretreatment with atropine or ganglion blockade. Discuss clinical uses and side effects. 19. Describe the effects of low, moderate, and high, doses of epinephrine on blood pressure and heart rate and how and why these differ from those of norepinephrine or isoproterenol. Discuss the uses and side effects of epinephrine. 20. Differentiate the effects of ephedrine from those of epinephrine and describe the expected effect if the nerve terminal was destroyed or uptake into the terminal was blocked. 21. Describe the effects of dopamine receptor agonists on renal blood flow and blood pressure and discuss their uses and side effects. 22. Describe the mechanism of action and effects of amphetamines, cocaine and tyramine, and discuss the effects on the action of these drugs with denervation of pre-treatment with agents which inhibit uptake into presynaptic nerve terminals. 23. Identify which group an unknown drug belongs to, based on a description of its effects in the body, especially those on heart rate and blood pressure. A 38-year-old teacher is seen in the office for a routine wellness visit. Blood pressure is 135/90 mm Hg and heart rate is 80 bpm. One year ago, vital signs were BP 125/80 mm Hg, HR 72. Physical exam is normal, with the exception of sniffling and redness of the eyes. Questioning reveals that she has been having a lot of trouble with “allergies” or “colds” over the past year. She also remarks that she has difficulty sleeping. Lectures 18 & 19 Page 2 of 21 Midwestern University Back to Pamela E. Potter, Ph.D. Pharmacology 1610/1612, 2024 Drug List Adrenergic Stimulants Adrenergic Transmission Fig 6-4 The synthesis and release of norepinephrine (NE) is similar to that of ACh, in that NE is synthesized in the terminal, stored in vesicles, and released into the synaptic cleft where its action is terminated mainly by reuptake into the presynaptic terminal. In addition to NE stored in the vesicles, there is also a pool of free NE in the nerve terminal (mobile pool). The precursor tyrosine is taken into the nerve terminal by a sodium dependent carrier. Tyrosine is hydroxylated by the enzyme tyrosine hydroxylase to become l-dopa. This is the rate-limiting step in this pathway. It is blocked by metyrosine. Tyrosine hydroxylase activity is regulated by neuronal activity. Both the activity and gene expression of tyrosine hydroxylase are increased during increased sympathetic nerve activity. Feedback inhibition of tyrosine hydroxylase activity occurs through NE acting on presynaptic α2 receptors. L-dopa is decarboxylated to dopamine (DA) by dopa-decarboxylase. The pathway ends here in dopaminergic neurons. In noradrenergic neurons, DA is hydroxylated by dopamine-β-hydroxylase to form NE. In the adrenal medulla, NE is converted to epinephrine (Epi) by phenylethanolamine-N- methyltransferase. The catecholamines, (DA, NE or Epi) are taken into vesicles by a vesicular monoamine transporter (VMAT). This transporter is inhibited by the drug reserpine. The catecholamines are released from the vesicles in a manner similar to ACh. ATP, dopamine- β-hydroxylase and other peptide co-transmitters may be stored with NE and co-released. NE acts on adrenergic receptors in the synaptic cleft. These are divided into alpha (α) and beta (β) subtypes. Once in the synaptic cleft, the action of NE is terminated by reuptake into the presynaptic terminal by the norepinephrine transporter (NET; also called reuptake 1). This is the main mechanism for termination of the action of NE in the synaptic cleft. Reuptake is blocked by many drugs, including antidepressants and cocaine. Amphetamine, ephedrine and tyramine are taken into the nerve terminal by NET, and into the vesicles by VMAT. Once there, they displace NE or DA, so NE and DA are liberated from adrenergic nerve endings by a Ca++-independent process in which they are released by reversal of the NET transporter. Lectures 18 & 19 Page 3 of 21 Midwestern University Back to Pamela E. Potter, Ph.D. Pharmacology 1610/1612, 2024 Drug List Adrenergic Stimulants These are thus considered indirect-acting drugs, which will have an effect only if noradrenergic innervation is intact. Repeated administration of these drugs may lead to tachyphylaxis. NE is metabolized by two enzymes, monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT). MAO is located on the outer surface of mitochondria in the nerve terminal, and breaks down free NE in the mobile pool in the nerve terminal. MAO is also found in the liver and the gastrointestinal tract, where it contributes to breakdown of circulating NE and epinephrine. MAO also breaks down tyramine that is ingested from food in the GI tract, preventing it from being absorbed. COMT is found throughout the body, especially in the liver, and breaks down circulating NE and epinephrine. NE and epinephrine metabolism is estimated by measuring concentrations of 3-methoxy- 4- hydroxy-mandelic acid (VMA) in a 24-hour urine sample. Dopamine is broken down to form homovanillic acid (HVA). Fig 6-5 Catecholamine Synthesis Fig 6-6 Catecholamine Metabolism Lectures 18 & 19 Page 4 of 21 Midwestern University Back to Pamela E. Potter, Ph.D. Pharmacology 1610/1612, 2024 Drug List Adrenergic Stimulants The actions of catecholamines and sympathomimetic agents can be classified into seven broad types: A peripheral excitatory action on certain types of smooth muscle, such as those in blood vessels supplying skin, kidney, and mucous membranes; and on gland cells, such as those in salivary and sweat glands. A peripheral inhibitory action on certain other types of smooth muscle, such as those in the wall of the gut, in the bronchial tree, and in blood vessels supplying skeletal muscle. A cardiac excitatory action that increases heart rate and force of contraction. Metabolic actions, such as an increase in the rate of glycogenolysis in liver and muscle and liberation of free fatty acids from adipose tissue. Endocrine actions, such as modulation (increasing or decreasing) of the secretion of insulin, renin, and pituitary hormones. Actions in the CNS, such as respiratory stimulation, an increase in wakefulness and psychomotor activity, and a reduction in appetite. Prejunctional actions that either inhibit or facilitate the release of neurotransmitters, the inhibitory action being physiologically more important.  Goodman and Gilman, 2018 Sympathetic Stimulation The sympathetic nervous system is activated in response to physical activity, stress, and blood loss, to assist the body in returning to homeostasis Norepinephrine (NE), released from nerve endings, stimulates alpha (α) and beta1 (β1) receptors During stress, epinephrine is released from the adrenal medulla stimulating α, β1 and β2 receptors The effects of sympathomimetic drugs are similar to those of sympathetic nervous system activation: 1. stimulation of smooth muscle causing constriction of blood vessels in the skin, kidney and mucous membranes (α1) 2. relaxation of blood vessels supplying skeletal muscle (β2) 3. stimulation of salivary and sweat glands (α1, muscarinic) 4. increase in rate and force of contraction of the heart (β1, β2) 5. increased glycogenolysis in liver and muscle, increased release of free fatty acids from adipose tissue (β2, β3) 6. increase in renin release (β1) 7. inhibition of neurotransmitter release through activation of presynaptic receptors (α2) Sympathomimetic drugs exhibit some or all of these actions, depending on their receptor binding specificities Drugs may act directly to stimulate α or β receptors. They may be very subtype selective, or non-selective. Drugs may also act indirectly by: 1. increasing release of, or displacement of, NE from nerve endings (e.g. tyramine, amphetamine) 2. inhibiting reuptake of NE and dopamine (e.g., cocaine) 3. inhibiting the catabolism of NE and dopamine (e.g., MAOIs) Lectures 18 & 19 Page 5 of 21 Midwestern University Back to Pamela E. Potter, Ph.D. Pharmacology 1610/1612, 2024 Drug List Adrenergic Stimulants Denervation, or depletion of NE stores with the drug reserpine, will abolish the effect of drugs that act indirectly (e.g. amphetamines). However, denervation will have no effect or may even enhance (due to receptor up-regulation) the effect of drugs that act directly on receptors (e.g. norepinephrine). Denervation will cause a blunted effect with drugs that have a mixture of direct and indirect effects (e.g. ephedrine), but the effect is not abolished. Receptors Alpha (α) receptors Epinephrine ≥ NE >> Isoproterenol There are two subtypes of α receptors, α1 and α2 Within these groups there are also subclasses (α1A, α1B or α1D and α2A, α2B, α2C), although very few drugs differentiate between these subgroups Stimulation of α1 receptors linked to Gq leads to formation of IP3, increasing intracellular Ca++, and formation of DAG, which activates protein kinase C Alpha2 receptors are often found presynaptically, where they act to reduce neurotransmitter release. Alpha2 receptors inhibit adenylyl cyclase and decrease intracellular cAMP, through a Gi protein complex Alpha1 receptors (prototype agonist, Phenylephrine) cause vasoconstriction and increase in peripheral vascular resistance, especially in smaller blood vessels in the skin cause vasoconstriction in nasal mucosa, decreasing nasal congestion dilate pupillary dilator muscle, causing mydriasis cause contraction of the prostate gland contract genitourinary smooth muscle (sphincters and trigone muscle) stimulate pilomotor smooth muscle, causing erection of hair relax intestinal smooth muscle (minor effect) increase glycogenolysis and gluconeogenesis in the liver in some species (minor effect) Alpha2 receptors (prototype agonist, Clonidine) located on presynaptic nerve terminals and inhibit transmitter release cause aggregation of platelets contract some vascular smooth muscle decrease insulin secretion (small effect) decrease intraocular pressure when applied topically Lectures 18 & 19 Page 6 of 21 Midwestern University Back to Pamela E. Potter, Ph.D. Pharmacology 1610/1612, 2024 Drug List Adrenergic Stimulants Beta (β) receptors There are three β receptor subtypes: β1, β2 and β3 Norepinephrine and epinephrine have about equal affinity for β1 receptors Epinephrine has a higher affinity for β2 than β1 receptors. NE has little or no effect on β2 receptors. Isoproterenol has a high affinity for all β receptors All subtypes of beta receptors activate adenylyl cyclase through a Gs protein, and increase intracellular cAMP Beta1 receptors (prototype agonist, Dobutamine) increase the force and rate of contraction of the heart (positive inotropic and chronotropic effect) increase AV conduction velocity and automaticity increase renin secretion from the kidney Beta2 receptors (prototype agonist, Albuterol) cardiac effects similar to β1, but less pronounced cause relaxation of respiratory, uterine, gastrointestinal smooth muscle cause relaxation of blood vessels supplying skeletal muscle promote potassium uptake into skeletal muscle activate glycogenolysis and gluconeogenesis in the liver Beta3 receptors (prototype agonist, Mirabegron) increase lipolysis in fat cells relax bladder detrusor muscle  NE does not affect the lung, β1: Isoproterenol > Epinephrine = NE which has mainly β2 receptors. β2: Isoproterenol > Epinephrine >> NE β3: Isoproterenol = NE > Epinephrine  Isoproterenol does not affect the majority of blood vessels, which have mainly α receptors. The exception are blood vessels supplying skeletal muscle, which have β2 receptors Dopamine receptors DA receptors are of particular importance in the brain and in the renal and splanchnic vasculature The D1 receptor usually stimulates adenylyl cyclase, and causes dilation of renal blood vessels D2 receptors inhibit adenylyl cyclase, open potassium channels, and decrease Ca++ influx, which generally inhibits release of transmitters from nerve terminals Lectures 18 & 19 Page 7 of 21 Midwestern University Back to Pamela E. Potter, Ph.D. Pharmacology 1610/1612, 2024 Drug List Adrenergic Stimulants Chemistry and Pharmacokinetics The backbone structure for the is β-phenylethylamine Addition of two hydroxyl groups on the 3 and 4 positions on the benzene ring produces catecholamines, which include norepinephrine, epinephrine, isoproterenol and dopamine. Catecholamines are metabolized by monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT), as discussed in the notes for lecture 14. Catecholamines are inactivated in the intestinal mucosa and Norepinephrine liver, so are not effective orally, but must be injected. Substitutions on the carbons or on the amine group alter the properties of the drugs, giving them more or less selectivity for α or β receptors. Increasing the size of the alkyl group on the amine terminal increases selectivity for β receptors (e.g. Isoproterenol isoproterenol) Substitutions on the α carbon inhibit breakdown by MAO, so that a drug with this substitution will produce drugs with a longer duration of action. Most of the sympathomimetic drugs are not catecholamines, are not hydrolyzed by COMT, and many can be given orally. While they may be less potent, they have better bioavailability after oral administration and they tend to have a longer duration of action. Ephedrine and amphetamine are two examples of sympathetic stimulants that are not catecholamines. Dose Response Curves for NE, Epinephrine and Isoproterenol, showing the receptor selectivity of each. From Brody’s Human Pharmacology, 6th ed, Fig 11.1 Lectures 18 & 19 Page 8 of 21 Midwestern University Back to Pamela E. Potter, Ph.D. Pharmacology 1610/1612, 2024 Drug List Adrenergic Stimulants Effects of Sympathomimetic Drugs The effects of specific drugs depend on the proportions of α and β activity each drug possesses, on the distribution of α and β receptors in various tissues, and on reflex responses. Alpha receptor stimulation Cardiovascular: Increases arterial resistance in blood vessels; skin and splanchnic blood vessels have predominantly α1 receptors. Smaller blood vessels have a denser population of alpha receptors than larger ones, therefore the most effect is on small blood vessels. Net effect is to increase blood pressure. Peripheral artery resistance is increased and venous capacity is decreased. The increase in blood pressure will stimulate baroreceptors, which then increase vagal input to slow the heart. Increased venous return may still increase stroke volume, and α receptors may have some positive inotropic effect. In people with atherosclerosis, the baroreceptor response may be impaired, and the effects of α1 agonists on blood pressure may be magnified. Eye: The radial pupillary dilator muscle in the iris is activated by α1 receptors, causing mydriasis without affecting accommodation Alpha1 agonists are sometimes used to dilate the eye without affecting the ciliary muscle Alpha2 receptors decrease the production and increase removal of aqueous humor, decreasing intraocular pressure. For this reason, alpha2 agonists may be used in the treatment of glaucoma. Respiratory tract: Blood vessels in the upper airway and mucous membranes contain α1 receptors Vasoconstriction by decongestants decreases nasal stuffiness Gastrointestinal tract: Alpha1 receptors relax smooth muscle and alpha2 receptors decrease ACh release, contributing to relaxation. However, alpha agonists have very little effect in the GI tract. Genitourinary tract: Alpha1 receptors constrict the bladder base, urethral sphincter and prostate, promoting continence. Alpha blockade is used to aid urination in men with benign prostatic hyperplasia. Alpha1 receptors are needed for ejaculation Lectures 18 & 19 Page 9 of 21 Midwestern University Back to Pamela E. Potter, Ph.D. Pharmacology 1610/1612, 2024 Drug List Adrenergic Stimulants Metabolic and Endocrine Effects: Alpha1 receptors increase glycogenolysis and gluconeogenesis in the liver in most mammals Alpha2 receptors inhibit lipolysis in fat cells Insulin secretion and renin secretion is inhibited by α2 receptors However, the metabolic effects of alpha receptors are minor compared to those of beta receptors Beta Receptor Stimulation Cardiovascular: Beta1 and beta2 receptors cause increased contractility and increased conduction velocity in the heart (positive inotropic and chronotropic effects) Conduction velocity in the A-V node is increased, and the refractory period decreases SA node rate and conduction through the His-Purkinje system are also increased Automaticity is thus increased and spontaneous pacemakers may develop To some extent, the increase in heart rate may be countered by reflex responses (baroreceptors) to increase blood pressure in response to increased cardiac output Oxygen demand and consumption are increased Coronary blood flow is increased- involves metabolic changes and adenosine as well as beta effects Beta2 receptors relax smooth muscle in blood vessels supplying skeletal muscle Although cardiac output is increased, dilation of blood vessels in skeletal muscle may result in a decrease in diastolic blood pressure. Systolic pressure may increase slightly Eye: Beta2 agonists increase production of aqueous humor, and may increase intraocular pressure. Therefore, beta receptor antagonists are often used to treat glaucoma. Respiratory tract: Beta2 agonists relax bronchial smooth muscle, and are widely used in the treatment of asthma Genitourinary tract: Relaxation of the uterus by β2 receptors is used to treat premature contractions in late pregnancy Beta2 receptors mediate a small degree of relaxation of the bladder wall Beta3 receptors relax the bladder detrusor muscle, decreasing the urge to urinate Lectures 18 & 19 Page 10 of 21 Midwestern University Back to Pamela E. Potter, Ph.D. Pharmacology 1610/1612, 2024 Drug List Adrenergic Stimulants Metabolic and Endocrine: Renin secretion is increased by β1 receptors Beta2 receptors promote glycogenolysis in the liver, leading to increases in blood glucose Beta2 receptors promote uptake of potassium into cells, and may cause a decrease in serum potassium levels when the body is stressed Insulin secretion is stimulated by to a small degree by β2 receptors Beta3 receptor stimulation leads to increased lipolysis in fat cells Bladder Relaxation Lectures 18 & 19 Page 11 of 21 Midwestern University Back to Pamela E. Potter, Ph.D. Pharmacology 1610/1612, 2024 Drug List Adrenergic Stimulants Effect of Sympathomimetic Drugs on Blood Pressure and Heart Rate Alpha Stimulation: Phenylephrine α1 selective agonist causes vasoconstriction and increase in peripheral vascular resistance increased blood pressure causes a small 170 reflex decrease in heart rate Beta Stimulation: Isoproterenol β1 and β2 agonist, with virtually no effect on α receptors increases rate and force of contraction of the heart causes vasodilation in blood vessels supplying skeletal muscle (β2) vasodilation will cause a decrease in blood pressure and a reflex increase in heart rate Alpha and Beta1 Stimulation: Norepinephrine stimulates α and β1 receptors vasoconstriction mediated by α receptors increases peripheral resistance diastolic and systolic blood pressure increase pulse pressure may not change much 180 165 although β1 receptors have a direct stimulatory Norepinephrine effect on the heart, causing an initial increase in heart rate, at low doses, baroreceptor reflexes compensate for increased blood pressure, decreasing heart rate Alpha, Beta1 and Beta2 Stimulation: Epinephrine stimulates α, β1 and β2 receptors effect depends upon the dose administered effect of a low to moderate dose is shown here beta1 activation produces a positive inotropic and chronotropic effect in the heart alpha1 receptor stimulation causes vasoconstriction, especially in skin, mucosa and kidney this leads to initial increased systolic and diastolic blood pressure, followed by a decrease in diastolic pressure resulting from β2 mediated dilation of blood vessels in skeletal muscle overall, the effect of intravenous infusion is an increase in pulse pressure, little change in overall mean pressure, and increased heart rate at high doses, alpha receptor-mediated vasoconstriction occurs, and blood pressure goes up Lectures 18 & 19 Page 12 of 21 Midwestern University Back to Pamela E. Potter, Ph.D. Pharmacology 1610/1612, 2024 Drug List Adrenergic Stimulants Alpha Agonists Phenylephrine (Neo-Synephrine; Sudafed PE) α1 selective agonist causes vasoconstriction and increases peripheral vascular resistance 170 increased blood pressure causes a reflex decrease in heart rate can be used in hypotensive emergency to raise blood pressure without increasing heart rate vasoconstriction in nasal mucosa makes it an effective decongestant; rebound effect may occur when discontinued due to down-regulation of alpha receptors prolonged use may result in ischemic changes in the mucous membranes produces mydriasis; used topically to dilate the pupil without affecting accommodation less effective orally than pseudoephedrine not recommended orally for patients with hypertension Pseudoephedrine (Sudafed) widely used in OTC decongestant preparations, given orally use caution in patients with hypertension, as may increase blood pressure because pseudoephedrine is a precursor in the manufacture of methamphetamine, it has recently been removed from over the counter shelves and placed in the pharmacy, where patients must show ID and sign for it. Many companies are now promoting use of phenylephrine as a replacement for pseudoephedrine, although phenylephrine is not as effective. Phenylephrine and pseudoephedrine are sold over the counter, without prescription. People with hypertension or narrow-angle glaucoma should use caution with these, as well as all systemic or topical alpha agonists! Midodrine (ProAmantine) is given orally to treat postural hypotension and autonomic insufficiency. Given during the day as it can cause hypertension when the patient lies down. Lectures 18 & 19 Page 13 of 21 Midwestern University Back to Pamela E. Potter, Ph.D. Pharmacology 1610/1612, 2024 Drug List Adrenergic Stimulants Topical alpha agonists xylometazoline is a direct acting α1 agonist which causes vasoconstriction and is used topically as a nasal spray to decrease congestion o rebound effect occurs if used chronically, as receptors will down-regulate oxymetazoline, also used as a nasal spray, acts on both α1 and α2 receptors. The α2 effect could cause hypotension if a large quantity is absorbed systemically (see clonidine) tetrahydrozoline (Visine; Tysine; Vision Clear; Murine), and naphazoline (Privine; Naphcon; Clear Eyes) are used primarily in the eye o they decrease redness by causing vasoconstriction these agents are all contraindicated in narrow-angle glaucoma and hypertension Clonidine (Catapres) selective α2 agonist, which acts primarily in the brain stimulation of α2 receptors on presynaptic terminals in the CNS decreases release of NE in the nervous system, reducing overall peripheral sympathetic stimulation reduced sympathetic tone leads to a decrease in blood pressure, as well as decreased NE levels clonidine may also increase parasympathetic outflow from CNS, decreasing heart rate clonidine is administered orally or by transdermal patch used for treatment of hypertension may be useful in anxiety accompanied by hypertension reduces craving in recovering addicts and decreases opioid withdrawal symptoms side effects include dry mouth, sedation, sexual dysfunction in males, and possible bradycardia side effects are reduced by use of the transdermal patch, but the patch may cause dermatitis and should be rotated to a new skin area each week the patient should avoid getting the patch too hot, as a massive release of clonidine may occur, resulting in severe hypotension hypertension may occur if the drug is withdrawn abruptly Methyldopa (Aldomet) α2 agonist, drug of choice to treat hypertension in pregnancy guanabenz (Wytensin) and gaunfacine (Tenex) are other α2 agonists similar to clondine Apraclonidine (Iopidine); Brimonidine (Alphagan) used in the eye to decrease intraocular pressure by reducing the formation of aqueous humor thru α2 receptor mediated vasoconstriction and decreased formation of aqueous humor, as well as increased production of prostaglandins, which enhances outflow of aqueous humor. Brimonidine (Lumify) in a lower dose form is sold over the counter to reduce eye redness. Lectures 18 & 19 Page 14 of 21 Midwestern University Back to Pamela E. Potter, Ph.D. Pharmacology 1610/1612, 2024 Drug List Adrenergic Stimulants Beta Agonists Isoproterenol (Isuprel) very potent and selective β1 and β2 agonist β stimulation increases rate and force of contraction of the heart β2 effect causes vasodilation in some blood vessels systolic pressure rises due to increased cardiac output, and dilation of blood vessels by β2 receptors leads to decreased in diastolic blood pressure, with an increase in heart rate and pulse pressure, and decreased mean pressure (systolic pressure may stay elevated or decrease) used in emergency treatment for cardiac arrest and complete heart block once used in emergency treatment of asthma, but has been replaced by β2-selective agents large doses may cause tachycardia, palpitations and arrhythmias Dobutamine (Dobutrex) β1 agonist with more effect on contraction than rate the (-) isomer stimulates α1 receptors, the (+) isomer blocks them; both isomers are β1 agonists due to α stimulation, dobutamine can increase blood pressure in patients with history of hypertension; this effect is reduced by slowing the rate of infusion prominent positive inotropic effect in the heart- increases cardiac output and cardiac contractility frequently used in cardiac echography stress tests half-life is about 2 minutes, so the effect is very short-lived may be infused intravenously on a continuous basis for short term treatment of cardiac decompensation in patients with heart failure, myocardial infarction, or after surgery Albuterol (Ventolin), Salmeterol albuterol and other selective β2 agonists widely used as inhalation agents in asthma for bronchodilation; they will be covered in detail in the asthma lecture about 40% of beta receptors in the heart are β2, thus tachycardia is a common side effect skeletal muscle tremor is another common side effect these effects are worse and often accompanied by headache when they are given orally (e.g. terbutaline) or injected Lectures 18 & 19 Page 15 of 21 Midwestern University Back to Pamela E. Potter, Ph.D. Pharmacology 1610/1612, 2024 Drug List Adrenergic Stimulants Mirabegron (Myrbetriq), Vibegron  Beta3 receptor agonists that relax the bladder detrusor muscle  Increases bladder capacity and decreases frequency  Approved for treatment of overactive bladder  Useful in patients who cannot tolerate anticholinergic effects of traditional drugs for overactive bladder  Can also be combined with anticholinergic drugs for treatment of overactive bladder  Side effects are mild, including nausea, diarrhea, constipation, headache, and dizziness  Mirabegron may cause hypertension (mechanism unknown) and occasional tachycardia (slight β1 effect), vibegron does not. Alpha and Beta Agonists Norepinephrine (Levophed) stimulates α and β1 receptors, but not β2 receptors must be injected; very short duration of action due to rapid metabolism 180 165 Norepinephrine vasoconstriction mediated by α receptors increases vascular peripheral resistance diastolic and systolic blood pressure increase, with some change in pulse pressure constriction of blood vessels by α receptors decreases blood flow to the kidney, spleen and liver baroreceptor reflexes compensate for increased blood pressure and decrease heart rate slightly therefore, cardiac output is either unchanged or decreased if atropine is given prior to norepinephrine, and the vagal reflex is inhibited, the baroreceptor effect will not occur, and heart rate will increase ganglion blockade will also inhibit the vagal reflex NE can cause severe vasoconstriction at the infusion site resulting in necrosis NE is used very rarely, possibly to treat severe hypotension when nothing else has worked There is now a pro-drug of NE, droxidopa (Northera), that is approved for treatment of orthostatic hypotension in patients with autonomic dysfunction; it can be given orally and can be used as an alternative to midodrine Lectures 18 & 19 Page 16 of 21 Midwestern University Back to Pamela E. Potter, Ph.D. Pharmacology 1610/1612, 2024 Drug List Adrenergic Stimulants Epinephrine (Adrenalin) Epinephrine stimulates α, β1 and β2 receptors, which makes the effect complex it must be injected sc or iv, and has a short duration of action due to rapid metabolism the effect of epinephrine depends on the dose! if a low dose is infused slowly, as shown above:  beta1 receptors increase heart rate and conduction, as well as contractility  alpha1 receptors constrict blood vessels in the skin, mucosa and kidney  this leads to increased systolic and diastolic blood pressure  beta2 relaxation of some blood vessels then causes a decrease in diastolic pressure, so that pulse pressure increases  since mean blood pressure is generally unchanged, there is less reflex slowing of the heart rate than seen with NE, and overall, heart rate is usually increased (β1)  coronary blood flow is increased, due to dilation of coronary blood vessels (β2)  cardiac output and oxygen consumption are increased  cutaneous blood flow decreases, and blood flow to skeletal muscle increases  renal blood flow is decreased about 40%, due to increased vascular resistance (α1) in contrast, rapid infusion of a high dose of epinephrine has a marked pressor effect (α1) epinephrine increases blood glucose, due to increased glycogenolysis (β2) and decreased insulin secretion (α2), with decreased glucose uptake into peripheral tissues renin secretion increases (β1) free fatty acid concentration goes up due to lipolysis in fat cells (β3) Dose Dependence: if a low dose is infused slowly:  beta1 receptors increase heart rate and conduction, as well as contractility  coronary blood flow is increased, due to dilation of coronary blood vessels  cardiac output and oxygen consumption are increased  alpha receptors constrict blood vessels in the skin, mucosa and kidney:  increased systolic and diastolic blood pressure  beta2 receptors relax blood vessels supplying skeletal muscle:  decrease in diastolic pressure - pulse pressure increases Lectures 18 & 19 Page 17 of 21 Midwestern University Back to Pamela E. Potter, Ph.D. Pharmacology 1610/1612, 2024 Drug List Adrenergic Stimulants  since mean blood pressure is unchanged, there is little reflex slowing of the heart rate and heart rate is increased  cutaneous blood flow decreases, and blood flow to skeletal muscle increases  renal blood flow is decreased about 40%, due to increased vascular resistance in contrast, rapid infusion of a high dose of epinephrine causes a marked increase in blood pressure both systolic and diastolic pressure will increase mean pressure increases, there is less increase in heart rate Uses of Epinephrine used for treatment of anaphylactic shock to restore blood pressure, decrease bronchospasm, decrease congestion and angioedema, and reverse cardiovascular collapse a generic epinephrine injector has just been approved in hopes of decreasing the cost used in emergency treatment for cardiac arrest and complete heart block vasoconstrictor property used to decrease diffusion of injected drugs such as local anesthetics Toxicities side effects include tremor, throbbing headache, increased blood pressure, and tachycardia angina may occur in patients with coronary artery disease, due to increased O2 consumption and increased cardiac work epinephrine is one of the most potent vasopressors available, especially at high doses blood vessels to the skeletal muscle contain both α and β receptors. since β receptors are more sensitive to epinephrine, vasodilation dominates at low doses. at high doses, the effect on α receptors takes over, and vasoconstriction occurs Goodman and Gilman, 12th Ed therefore, injection of large amounts of epinephrine may cause an extreme increase in blood pressure and cerebral hemorrhage, or ventricular arrhythmias injection of high dose epinephrine in people taking beta-blockers may lead to severe hypertension due to unopposed effects on α receptors! Lectures 18 & 19 Page 18 of 21 Midwestern University Back to Pamela E. Potter, Ph.D. Pharmacology 1610/1612, 2024 Drug List Adrenergic Stimulants Ephedrine mixed acting: direct stimulation of α and β receptors, as well as indirect action through enhancement of NE release effects are much less pronounced than those of epinephrine since mixed acting, denervation will decrease, but not abolish, its effect high bioavailability and long duration of action- effect may last hours excreted in the urine; excretion can be accelerated by acidifying the urine (base, pKa 9.65) CNS stimulant, increases heart rate and may increase blood pressure causes bronchodilation (e.g. Primatene) ephedra, found in herbal (ma huang) and over the counter weight loss preparations, was taken off the market by the FDA due to many adverse effects, including deaths due to hypertension a similar drg, phenylpropanolamine, a component of many OTC decongestants and weight-loss drugs, was also taken off the market by the FDA because of hemorrhagic stroke in women these were replaced by bitter orange, which has similar effects and is unlikely to have a better safety profile Dopamine Receptor Agonists Dopamine (Intropin) low doses of dopamine activate D1 receptors in renal vascular beds, causing vasodilation and increasing renal blood flow this increases glomerular filtration rate and sodium excretion mesenteric and coronary arteries are also dilated at higher concentrations, dopamine stimulates β1 receptors in the heart, producing a positive inotropic and chronotropic effect given intravenously to treat cardiac shock, as it will increase cardiac output without causing vasoconstriction, but is not very effective high doses may cause release of norepinephrine and stimulate α1 receptors, causing vasoconstriction and increased blood pressure; effect of high doses similar to norepinephrine side effects include nausea and vomiting (stimulation of chemoreceptor trigger zone), tachycardia, angina, arrhythmias, headache and peripheral vasoconstriction Fenoldopam (Corlopam) selective D1 receptor agonist, no other receptor effects causes dilation of vascular beds, decreasing blood pressure can be used short-term to produce rapid decrease of blood pressure in severe hypertension Lectures 18 & 19 Page 19 of 21 Midwestern University Back to Pamela E. Potter, Ph.D. Pharmacology 1610/1612, 2024 Drug List Adrenergic Stimulants Indirect-acting Sympathomimetics Amphetamine indirect-acting sympathomimetic that displaces NE (and DA) from vesicles, and reverses the reuptake transporters, increasing NE/DA release from neurons, especially in the CNS due to release of DA in the reward system, has a very high abuse potential CNS stimulant: increases alertness, decreases need for sleep, decreases appetite, causes euphoria, and increases motor activity peripheral actions include tremor, tachycardia, and hypertension psychosis may occur in susceptible individuals, as well as dizziness, restlessness, tremor, irritability, fever and aggression other effects include: headache, chills, pallor or flushing, arrhythmias, angina, hypertension or hypotension, sweating cerebral hemorrhage, convulsions and coma may occur at high doses causes strong contraction of the urinary bladder sphincter; has been used to treat enuresis methamphetamine has more central actions and fewer peripheral effects; it has become an major drug of abuse methylphenidate (Ritalin) and similar drugs are used in children with attention deficit hyperactivity disorder, where they cause a paradoxical decrease in hyperactivity once used for weight loss, but long-term effect is minimal and potential for toxicity is high Cocaine inhibits re-uptake of DA and NE into nerve terminals amphetamine-like effect that is shorter acting and more intense now smoked (crack) to increase intensity of effect and speed of onset once thought safe, now considered to be highly addicting may cause severe hypertension and stroke in otherwise healthy young adults often causes tachycardia, may cause arrhythmias and myocardial infarction long-term use may cause cocaine-induced psychosis because it is both a local anesthetic and vasoconstrictor, cocaine may be used for nasopharyngeal surgery to decrease blood flow and produce local anesthesia Tyramine indirectly acting compound that will increase release of catecholamines from nerve terminals taken up into storage vesicles and displaces NE, forming a false transmitter, octopamine NE becomes replaced with octopamine; tachyphylaxis will develop to the effects of tyramine tyramine is a normal component of food and a by-product of tyrosine metabolism normally hydrolyzed MAO in the GI tract and the liver; not absorbed when administered orally if injected iv, it may cause massive release of stored catecholamines and have a norepinephrine- like effect in patients treated for depression with MAO inhibitors, it is orally absorbed, so that oral ingestion of large amounts of tyramine may cause a severe hypertensive crisis! Lectures 18 & 19 Page 20 of 21 Midwestern University Back to Pamela E. Potter, Ph.D. Pharmacology 1610/1612, 2024 Drug List Adrenergic Stimulants Goodman and Gilman, 18th Ed, Figure 12-1 Lectures 18 & 19 Page 21 of 21