Adrenergic Agonists and Antagonists

1. Adrenergic Agonists and Antagonists V. GeršlAccording to: - H.P.Rang, M.M.Dale, J.M.Ritter, R. J. Flower: Pharmacology, 6th ed.- R.A.Howland, M.J.Mycek: Lippincott’s Illustrated Reviews: Pharmacology, 3rd ed.

2. Structures of the major catecholamines Noradrenaline Adrenaline Dopamine Isoprenaline (according to Rang HP, Dale MM et al.: Pharmacology, 2003)

3. Summary of the neurotransmitters released and the types of receptors found within the autonomic and somatic nervous system. (according to Lippincott´s Pharmacology, 2006) AUTONOMIC SOMATIC Sympathetic innervation of adrenal medulla Parasympathetic Sympathetic Preganglionic neuron Ganglionic transmitter Acetylcholine Acetylcholine Acetylcholine No ganglia Nicotinic receptor Nicotinic receptor Nicotinic receptor Postganglionic neurons Adrenal medulla Acetylcholine Neuroeffector transmitter Epinephrine release into the blood Acetylcholine Norepinephrine Adrenergic receptor Muscarinic receptor Adrenergic receptor Nicotinic receptor Striated muscle Effector organs

4. Nicotinic receptor Nicotinic receptor Sites of actions of adrenergic agonists. Adrenal medulla Epinephrine released Norepinephrine into the blood Adrenergic receptor Adrenergic receptor (according to Lippincott´s Pharmacology, 2006) Effector organs

5. Summary of adrenergic agonists. Agents marked with an asterisk (*) are catecholamines. Adrenergic agonists Direct-acting Albuterol Clonidine Dobutamine* Dopamine* Epinephrine* Formoterol Isoproterenol Metaproterenol Methoxamine Norepinephrine* Phenylephrine Piruterol Salmeterol Tamsulosine Terbutaline Indirect-acting Amphetamine Tyramine Direct and indirect acting (mixed action) (according to Lippincott´s Pharmacology, 2006) Ephedrine

6. ADRENERGIC AGONISTS • The adrenergic drugs affect receptors that are stimulated by • norepinephrine or epinephrine.Some adrenergic drugs act directly on • the adrenergic receptor either by activating the receptoror by blocking • theaction of norepinephrine and epinephrine. • Other drugs act indirectly by altering the release of norepinephrine • by the adrenergic neuron. • THE ADRENERGIC NEURON • The adrenergic neuron releases norepinephrine as a neurotransmitter. • Found: • - CNS • - the sympathetic nervous system between postganglionic neurons and • the effector organs. • adrenergic neuron and receptor (either presynapticallyon the neuron • or postsynaptically on the effector organ) are the sitesof action of • adrenergic drugs.

7. 1 Synthesis of • norepinephrine • Hydroxylation of tyrosine is the rate-limiting step. Synthesis and release of norepinephrine from the adrenergic neuron. MAO = monoamine oxidase • 2 Uptake into storage • vesicles • Dopamine enters a vesicle and is converted to norepinephrine • Norepinephrine is protected from degradation in the vesicle. • Transport into the vesicle is inhibited by reserpine. Inactive metabolites Norepinephrine MAO Urine Tyrosine Na+ Tyrosine Na+ DOPA Inactive metabolites MAO Urine Dopamine • 3 Release of • neurotransmitter • Influx of calcium cause fusion of the vesicle with the cell membrane. • Release is blocked by guanethidine and bretylium. Dopamine Synaptic vesicle Ca2+ • 5 Removal of • norepinephrine • Released norepinephrine is rapidly taken into the neuron. • Reuptake is inhibited by cocaine and imipramine. Ca2+ + Presynaptic receptor • 4 Binding to receptor • Postsynaptic receptor is activated by the binding of neurotransmitter. Norepinephrine Inactive metabolites Urine Catechol-O- methyltransferase (COMT) SYNAPTIC SPACE • 6 Metabolism • Norepinephrine is methylated by COMT and oxidized by MAO. (according to Lippincott´s Pharmacology, 2006) INTRACELLULAR RESPONSE

8. A. Neurotransmission at adrenergic neurons (norepinephrine is the neurotransmitter): five steps: synthesis, storage, release, and receptor binding of NOR, followed by removal of NOR from the synaptic gap. 1. Synthesis of NOR :Tyrosine transported into the cytoplasm of the adrenergic neuron, hydroxylated to DOPA by tyrosine hydroxylase (the rate-limiting step in the formation of NOR). DOPA is decarboxylated to form dopamine. 2. Storage of NOR in vesicles:Dopamine - transported into synaptic vesicles- an amine transporter system that is also involved in the re-uptake of NOR (this carrier system is blocked by reserpine). Dopamine is hydroxylated to NOR. Adrenal medulla – NOR is methylated to epinephrine. The adrenal medulla releases about 85% of ADR and 15% of NOR.

9. 3. Release of NOR: Action potential arriving at the nerve ending triggers an infux of calcium ions from the extracellular fluid into the cytoplasm of the neuron. Increase in calcium causes vesicles to fuse with the cell membrane and release contents into the synapse (this release blocked by quanethidine and bretylium). 4. Binding by receptor:NOR after its release diffuses across the synaptic space and binds to receptors (postsynaptic on the effector organs or to presynaptic receptors on the nerve ending). Receptors triggers a cascade of events within the cells, resulting in the formation of intracelullar second messengers(cAMP, phosphoinositide cycleeffector cell.

10. 5. Removal of NOR: - NOR may diffuse out of the synaptic space and enter the general circulation or - may be recaptured by an uptake system that pulls the NOR back into the neuron (uptake by the plasma membrane involves a sodium-potassium activated ATPase that can be inhibited by tricyclic antidepressants, e.g., imipramine or by cocaine): uptake1 = neuronal uptake (especially NOR), uptake2= extraneuronal uptake (also for ADR and isoprenaline)

11. a. Once NOR enters the cytoplasm of the neuron - it may reenter the adrenergic vesicle via the amine transporter system and be stored for further release. b. NOR can also be oxidized by monoamine oxidase (MAO) present within cells, abundant intraneuronally (in mitochondria), or it may be converted to O-methylated derivates by catechol-O-methyltransferase (COMT), which is associated within the membranes of postsynaptic cells. The metabolic products - excreted in the urine as - VMA (vanillylmandelic acid), metanephrine, and normetanephrine.

12. NERVE TERMINAL 5 Depolarisation Transmitter precursor 6 1 Precursor 2 Ca2+ 11 T Ca2+ 4 3 T Degradation products 13 T T 7 T 12 T Inactivated transmitter 8 10 NON-NEURONAL CELL T 9 The main processes involved in synthesis, storage and release of amine and amino acid transmitters

13. B. Adrenergic receptors (adrenoreceptors) Two families of receptors, designated "alpha" and "beta". For alpha receptors, the rank order of potency is: 1. epinephrine, 2. norepinephrine, 3. isoproterenol For beta receptors, the rank order of potency is: 1. isoprotenerol, 2. epinephrine, 3. norepinephrine 1) Alpha receptors: Subdivided in two groups - alpha 1 and alpha 2 receptors:

14. Alpha 1 receptors: higher affinity for phenylephrine. Present on the postsynaptic membrane of the effectors - mediate many classics effects originally designated as alpha-adrenergiceffects. Activation of alpha 1 receptors series of reactions through a G protein activation of phospholipase C IP3 from phosphatidylinositol  release of Ca2+ from the endoplasmic reticulum into the cytosol  a rise in cytosolic calcium ions and activation of calcium-dependent proteins kinases.

15. Alpha 2 receptors: Primarily on presynaptic nerve endings and on other cells ( cell of the pancreas) - control adrenergic neuromediator and insulin output. A portion of the released NOR "circles back" and reacts with the α2 receptor on the neuronal membrane - the stimulation of α2 receptor causes feedback inhibition of the release of NOR from the stimulated adrenergic neuron. It decreases further output from the adrenergic neuron and serves as a local modulating mechanism forreducing sympathetic neuromediator output when there is high sympathetic activity. In contrast to α 1 receptors - the effects of binding at α2 receptors are mediated by inhibition of adenylyl cyclase and a fall in the levels of intracellular cAMP.

16. 2) Beta receptors: Subdivided into two groups, beta 1 and beta 2 (based on their affinities for adrenergic agonists and antagonists) and beta 3 (adipose tissue). Beta 1 receptors:approximately equal affinities for ADR and NOR, located mainly in the heart and GIT Beta 2 receptors:higher affinity for ADR (epinephrine) than for NOR (norepinephrine), located in smooth muscle in many organs (bronchial, vasculature of skeletal muscle) and are particularly responsive to the hormonal effects of circulating epinephrine released by the adrenal medulla.Binding of a neurotransmitter at the beta 1 or beta 2 receptor results in activation af adenylate cyclyse and therefore increased concentrations of cAMP within the cell. Beta 3 receptors:In adipose tissue, lipolysis. Beta-presynaptic receptors: positive feedback to NOR release (its increase).

17. Further subdivisions: The α1 and α 2 receptors are further divided into α 1A, α 1B, α 1C, and α 1D, and α 2A, α 2B, α 2C, and α 2D. This classification is necessary for understanding the selectivity of some drugs. E.g., tamsulosine is a selective α 1A antagonist that is used to treat benign prostate hypertrophy. The drug is clinically useful because it targets a1A receptors found primarily in the urinary tract.

18. Distribution of receptors: Organs and tissues have, in many instances, a predominance of one type of receptor. Tissue such as the vasculature to skeletal muscle haveboth alpha 1 and beta 2 receptors, but the beta 2 receptors predominate. Other tissues may have one type of receptor exclusively, with no significant numbers of other types of adrenergic receptors (e.g., the heart contains predominantly beta 1 receptors). Beta 3 especially present in adipose tissue (lipolysis).

19. Desensitization of receptors (decrease in response to catecholamines following their prolonged exposure); mechanisms: - sequestration of receptors (unavailable for interaction with ligand)- down-regulation (disappearance of the receptors by their destruction or decreased synthesis)- inability to couple fo G-protein - because of the phosphorylation of the receptor on cytoplasmic site by either proteinkinase A or β adrenergic receptor kinase (βARK).

20. Types of adrenergic receptors A a Adrenoceptors B b Adrenoceptors Epinephrine Norepinephrine Isoproterenol Norepinephrine Epinephrine Isoproterenol a Receptor b Receptor Low affinity Low affinity High affinity High affinity (according to Lippincott´s Pharmacology, 2006)

21. Second messengers mediate the effects of a receptors. DAG = diacelglycerol IP3 = inosinol triphosphate a2 Receptors Activation of the receptor decreases production of cAMP, leading to an inhibition of further release of norepinephrine from the neuron. Synaptic vesicle ATP cAMP Adenylyl cyclase a2 Receptor Norepinephrine a1 Receptor DAG Membrane phosphoinositides Ca2+ IP3 a1 Receptors Activation of the receptor increases production of DAG and IP3 leading to an increase in intracellular calcium ions. (according to Lippincott´s Pharmacology, 2006)

22. Feedback control of noradrenaline release Ca2+ Calcium channels + Ca2+ NA ATP cAMP + Adenylate cyclase ATP Exocytosis - a2 - Adrenoceptor NA ATP POSTSYNAPTIC RECEPTORS

23. Major effects mediated by a and b adrenoceptors Adrenoceptors a1 b1 b2 a2 • Vasodilation • Slightly decreased peripheral resistance • Bronchodilation • Increased muscle and liver glycogenolysis • Increased release of glucagon • Relaxed uterine smooth muscle • Tachycardia • Increased lipolysis • Increased myocardial contractility • Increased release of renin • Inhibition of norepinephrine release • Inhibition of insulin release • Vasoconstriction • Increased peripheral resistance • Increased blood pressure • Mydriasis • Increased closure of internal sphincter of the bladder (according to Lippincott´sPharmacology, 2006)

24. Characteristic responses mediated by adrenoceptors: alpha 1 receptors: vasoconstriction (particularly in skin and abdominal viscera) and an increase in total peripheral resistance and blood pressure, relaxation of GIT smooth muscle (but contraction of sphincters), salivary secretion, hepatic glycogenolysis. alpha 2 receptors: inhibition of transmitter release, platelet aggregation beta 1 receptors: cardiac stimulation (increased cardiac rate and force), relaxation of GIT smooth muscle, lipolysis beta 2 receptors: vasodilation (in skeletal vascular beds), bronchiolar relaxation and uterorelaxation, relaxation of visceral smooth muscle, hepatic glycogenolysis, muscle tremor beta 3 receptors:lipolysis

25. CHARACTERISTICS OF ADRENERGIC AGONISTS A. Structure-activity relationship of adrenergic agonists: Most of the adrenergic drugs are derivates of beta-phenylethylamine. 1. Catecholamines: Amines containing the 3,4-dihydroxybenzene group (e.g.epinephrine, norepinephrine, isoprotenerol, and dopamine) called catecholamines /3,4-dihydroxybenzene is known as catechol/. Compounds share the folloving properties: a. High potency: Drugs with OH groups in the 3 and 4 position on the benzene ring show the highest potency in activating alpha or beta receptors. b. Rapid inactivation: Rapidly metabolized in the gut by COMT and in the liver and gut wall by MAO. Brief action when given parenterally, ineffective when administered orally because of poor absorption. c. Poor penetration into the CNS: Catecholamines are polar. Nevertheless, some clinical effects (anxiety, tremor, headaches) are attributable to action on the CNS.

26. 2. Non-catecholamines: Lacking the catechol hydroxyl groups. Longer half-lives, since they are not metabolized by COMT. Drugs with a substitution at the alpha-carbon, such as ephedrine, which contains an alpha-methyl group, are poor substrates for MAO »» » prolonged duration of action. Increased lipid solubility permits greater access to the CNS. May act indirectly by causing the release of stored catecholamines. 3. Substitution on amine nitrogen: Important in determining the beta selectivity of the adrenergic agonist. Epinephrine ( -CH3 substituent) and isoproterenol (isopropyl substituent -CH(CH3)2) are strong beta agonist.

27. B. Mechanism of action of adrenergic agonists: 1. Direct-acting agonists: Act directly on alpha or beta receptors, effects similar to those following stimulation of sympathetic nerves or release of epinephrine. Examples: epinephrine, norepinephrine, isoproterenol, and phenylephrine. 2. Indirect-acting agonists: Cause the release of norepinephrine from the cytoplasma or vesicles of the adrenergic neuron. Norepinephrine then stimulates the alpha or beta receptors. Examples: amphetamine and tyramine. 3. Mixed-action mechanism: both directly stimulate adrenoceptors and cause the release of NOR from the adrenergic neuron. Examples: Ephedrine and metaraminol.

28. Sites of action of direct-, indirect-, and mixed-acting adrenergic agonists. INDIRECT-ACTING Drug enhances release of norepinephrine from vesicles. Neuron MIXED-ACTING Drug acts both directly and indirectly. Synapse DIRECT-ACTING Drug directly activates receptor. Postsynaptic target cell membrane (according to Lippincott´s Pharmacology, 2006)

29. Structures of several important adrenergic agonists. Drugs containing the catechol ring are shown in pink. (according to Lippincott´s Pharmacology, 2006)

30. Selective b-agonists OH N HO Selective a-agonists Selective b-antagonists HO Salbutamol OH OH OH N N O N HO HO HO OH Propranolol Metaraminol Isoprenaline N HO OH HO N HO a-Me-noradrenaline Adrenaline HO OH N Non-selective agonist HO HO Noradrenaline N HO Dopamine HO OH N N N Tyramine HO Ephedrine Amphetamine Indirectly acting sympathomimetic amines Structure-activity relationships among catecholamines and related compounds

31. DIRECT - ACTING ADRENERGIC AGONISTS • A. EPINEPHRINE (ep i NEF rin) = ADRENALINE • both alpha and beta effects • Used in therapy. ADR is synthetized from tyrosine in the adrenal • medulla and released (with small quantities of norepinephrine), • into the blood stream. • ADR interacts with both alpha and beta receptors. • At low doses, beta effects on the vascular system predominate at • high doses, alpha effects are strongest.

32. 1.Actions: a. Cardiovascular: Heart: positive inotropic and positive chronotropic are beta 1 actions. Cardiac output therefore increases. Increased oxygen demands on the myocardium. Cardiac efficiency is reduced; it can also cause dyssrhythmias. Vessels: constriction of arterioles in the skin, mucuous membranes, and viscera (alpha 1 effects), dilates vessels going to skeletal muscle (beta 2 effects). Blood pressure: increase in systolic BP, coupled with a slight decrease in diastolic pressure.

33. b. Smooth muscle: alpha 1: contraction of all types of smooth muscle, except that of GIT (i.e., vessels, vas defferens, spleen capsule, m.dilatator pupilae, sphincters in GIT and urogenitaly tract) beta: relaxation of most kind of smooth muscle, usually by beta 1 receptors (in GIT not clear, probably both subtypes), i.e. - vasodilation (particularly in skeletal muscle) - 2 - bronchodilation - 2 - uterorelaxation - 2 c. Respiratory: Bronchodilation by acting directly on bronchial smooth muscle (beta 2 action) - it relieves all known allergic - or histamine – induced bronchoconstriction. In anaphylactic shock - this can be lifesaving. Epinephrine rapidly relieves the dyspnea (labored breathing) and increases the tidal volume (volume of gases inspired and expired).

34. d. Metabolism: conversion of energy stores (glycogen and fat) to freely • available fuels (glucose and FFA) • Hyperglycemia: increased glycogenolysis (beta 2 effect), • increased release of glucagon (beta 2), and a decreased release • of insulin (alpha 2). • Lipolysis: lipolysis (beta 1). Stimulation of beta 2 and beta 3 receptors • on adipose tissue activationof adenylcyclase  c AMP. c AMP • stimulates a hormone-sensitive lipase, which initiates the hydrolysis • of the triacylglycerol to free fatty acids and glycerol. • d. other: • - inhibition of histamine release • - twitch tension of fast-contracting fibres (white muscle) • - eye: mydriasis (contraction of m.dilatator pupilae)

35. 2. Biotransformations: Two enzymatic pathways - COMT and MAO. The final metabolites found in the urine are metanephrine and vanillylmandelicacid. Note: Urine also contains normetanephrine, a product of norepinephrine metabolism. 3. Therapeutic uses: a. Bronchospasm: In treatment of acute asthma and anaphylactic shock, epinephrine is the drug of choice(within a few minutes after s.c. administration - greatly improved respiratory exchange). Administration may be repeated after a few hours. However, selective beta 2 agonists are favoured in thechronic treatment of asthma (longer duration of action). b. Glaucoma: 2% epinephrine topically reduce intraocular pressure in open-angle glaucoma. It reduces the production of aqueous humour by vasoconstriction of the ciliary body blood vessels.

36. c. Anaphylactic shock: Drug of choice for the treatment of acute hypersensitivity reactions (type I hypersensitivity) d. In anesthetics: Local anesthetic solutions may contain 1:100,000 parts ADR. e. Nasal decongestion: Very weak solutions of epinephrine 1:100,000 can also be used topically to vasoconstrict mucous membranes. 4. Pharmacology:Rapid onset but brief duration of action. Administered subcutaneously, by inhalation, or topically to the eye. Oral administration is ineffective (ADR and other catecholamines are inactivated by the intestine).

37. Pharmacokinetics of epinephrine Poor penetration into the CNS IV SC Aerosol Topical Metabolites appear in the urine (according to Lippincott´s Pharmacology, 2006) EPINEPHRINE

38. Cardiovascular effects of intravenous infusion of low doses of epinephrine. Epinephrine increases the rate and force of cardiac contraction. Infusion of epinephrine 100 Pulse rate (per min) 50 180 Blood pressure (mmHg) 120 60 High Peripheral resistance Low 0 15 Time (min) Systolic pressure is increased, and diastolic pressure is decreased. Epinephrine decreases the peripheral resistance. (according to Lippincott´s Pharmacology, 2006)

39. 5. Adverse effects: a. CNS disturbances: Anxiety, fear, tension, headache, and tremor. b. Hemorrhage: Cerebral hemorrhages as a result of the vasopressor effects, causing a marked elevation of blood pressure. c. Cardiac arrhythmias:It can trigger cardiac arrhythmias, particularly ifthe patient is receiving digitalis. d. Pulmonary edema: ADR can induce pulmonary edema. 6. Interactions: a. Hyperthyroidism:Enhanced cardiovascular actions in patients with hyperthyroidism. The mechanism appears to involve increased production of adrenergic receptors in the hyperthyroid individual. b. Cocaine: In the presence of cocaine, ADR produces exaggerated cardiovascular actions. Due to the ability of cocaine to prevent re-uptake of catecholamines, thus ADR (like NOR) remains at the receptor site for longer periods of time.

40. B. NOREPINEPHRINE(nor ep i NEF rin) = NORADRENALINE It stimulates all types of adrenergicreceptors. The alpha-adrenergicreceptor is most affected, weak beta 2 effects. Actions: 1. Cardiovascular: a.Vasoconstriction: Intense vasoconstriction ↑ peripheral resistance (alpha1 effect). Both systolic and diastolic BP increase. b.Baroreceptor reflex: In vivo, little if any cardiac stimulation is noted. (NOR induces a reflex increase in vagal activity by ↑baroreceptor activity). Bradycardia counteracst the local actions of NOR on the heart. c. Effect of atropine pretreatment: If atropine (blocks the transmission of vagal effects) is given before NOR NOR stimulates the heart and produces tachycardia.

41. 2. Therapeutic uses: • - Shock, however, dopamine is better (it does not reduce blood • flow to the kidney as does NOR). • Never used for asthma. • -Vasoconstrictor agent with local anesthetics.

42. Cardiovascular effects of intravenous infusion of norepinephrine. Norepinephrine induces reflex bradycardia Infusion of norepinephrine 100 Pulse rate (per min) 50 180 Blood pressure (mmHg) 120 60 High Peripheral resistance Low 0 15 Time (min) Norepinephrine causes increased systolic and diastolic pressure Norepinephrine constricts all blood vessels, causing increased peripheral resistance. (according to Lippincott´s Pharmacology, 2006)

43. C. ISOPROTERENOL(eye soe proe TER a nole) = ISOPROPYLNORADRENALINE direct-acting synthetic catecholamine - predominantly stimulates both beta 1 and beta 2 receptors (i.e., non-selective) 1. Actions: a.Cardiovascular: Intense stimulation of the heart to increase its rate and force of concentration, causing increased cardiac output. Therefore useful in the treatment of atrioventricular block or cardiac arrest. Dilates the arterioles of skeletal muscle (beta 2) a decrease in peripheral resistance. Because of its cardiac stimulatory action, itmay increase systolic BP slightly, but it greatly reduces mean arterial and diastolic BP. b. Pulmonary: A profound and rapid bronchodilation (beta 2 action), rapidly alleviates an acute attack of asthma, when taken by inhalation. Action lasts about one hour. c. Other effects: Actions on beta receptors, increase in blood sugar, increased lipolysis, not clinically significant.

44. 2. Therapeutic uses: Bronchodilator in asthma. Stimulation of the heart. 3. Administration: Absorbed systemically,but by the sublinqual mucosa it is more reliably absorbed; parenterally or as an inhaled aerosol. It is a marginal substrate for COMT and is stable to MAO action . 4. Adverse effects: Similar to ADR. Dangerous when chronically used for bronchodilatation (stimulation of the heart may leads to micronecrosisand ischemia of myocardium) !!

45. Cardiovascular effects of intravenous infusion of isoproterenol. Isoproterenol causes vasodilatation but strongly increases cardiac force and rate. Infusion of isoproterenol 100 Pulse rate (per min) 50 180 Blood pressure (mmHg) 120 60 High Peripheral resistance Low 0 10 Time (min) Isoproterenol causes a significant decrease in peripheral resistance Isoproterenol causes markedly decreased diastolic pressure, with moderately increased systolic pressure. (according to Lippincott´s Pharmacology, 2006)

46. D. DOPAMINE(DOE pa meen) Metabolic precursor to NOR, occurs naturally in the CNS (in the basal ganglia) as a neurotransmitter. Dopamine can activate alpha- and beta-adrenergic receptors. In addition, dopaminergic receptor (distinct from alpha and beta receptors) occur in the peripheral mesentric and renal vascular beds. 1. Actions: a. Cardiovascular actions: Inotropic and chronotropic effects. Very high doses – activation of alpha receptors on the vasculature vasoconstriction.

47. b. Renal and visceral actions: Dilates renal and splanchnic arterioles by activating dopaminergic receptors, thus increasing blood flow to the kidneys and other viscera. These receptors are not affected by alpha- or beta-blocking drugs. Therefore, useful in the treatment of shock, in which significant increases in sympathetic activity might compromise renal function. Note: Similar dopamine receptors are found in the autonomic ganglia and in the CNS. D2 receptors are also found on presynaptic adrenergic neurons, where their activation interferes with NOR release.

48. 2. Therapeutic uses: a. Shock:Drug of choice for shock(given by continuous infusion). It raises the blood pressure by stimulating the heart (beta 1 action). It enhances perfusion to the kidney and splanchnic areas. Increased blood flow to the kidney enhances the glomerular filtration rate and causes sodium diuresis. Note: NOR diminishes the blood supply to the kidneyand may cause kidney shutdown. b. Congestive heart failure: Refractory congestive heart failure. 3. Adverse effects: An overdose produces the same effects as sympathetic stimulation. Dopamine is rapidly metabolized to homovanilic acid, and its adverse effects (nausea, hypertension, arrhythmias) are therefore short-lived.

49. E. DOBUTAMINE(doe BYOO ta meen) synthetic, direct acting beta 1 receptor agonist. 1. Actions: increases cardiac contractility and output with few vascular effects. 2. Therapeutic uses: Used to increase cardiac output in congestive heart failure. It increases cardiac output with little change in heart rate- not significantly elevation of oxygen demands of the myocardium - a major advantage over othersympathomimetic drugs. 3. Adverse effects: a. Cardiovascular: Caution in atrial fibrillation (it increases AV conduction. b. Other: The same as ADR. Tolerance may develop on prolonged use.

50. F. PHENYLEPHRINE(fen ill EF rin) direct-acting, synthetic adrenergic drug that binds primarily to alpha receptors and favors alpha 1 receptors over alpha 2. Actions: 1. Cardiovascular effects: Vasoconstrictor raises both systolic and diastolic BP. No effect on the heart itself but induces reflex bradycardia. Often used topically on the nasal mucous membranes and in ophthalmic solutions for mydriasis. 2. Therapeutic uses: Nasal decongestant. To raise blood pressure and to terminate episodes of supraventricular tachycardia. 3. Adverse effects: Hypertensive headache and cardiac irregularities.