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1. Adrenoceptor agonists and sympathomimetic drugs 1

2. Adrenomimetic drugs Refers to drugs which mimic the effects of adrenergic sympathetic nerve stimulation on sympathetic effectors These drugs are also called sympathomimetic agents They have a wide range of effects Eg. they can be used to maintain blood pressure or to relieve a life-threatening attack of acute bronchial asthma Can be classified into different groups, based on Chemical structure Mechanism of action Receptor selectivity 2

3. 3 Based on chemical structure Adrenomimetics can be divided into two: Catecholamines They have catechol ring in their structure E.g. NE, EP, DA, Isoproternol, Dobutamine, Colterol, ethyl NE, Metaproternol Non catecholamines They don’t have catechol ring E.g. ephedrine, phenylephrine, albuterol, metaraminole, tyramine, amphetamine, terbutaline , methamphetamine, ritodrine, salmiterol, methoxamine

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6. 6 Based on mechanism of action Adrenomimetics can be classified into three groups 1. Direct acting adrenomimetics Directly interact & stimulate adrenoceptors May exhibit receptor selectivity Eg. phenylephrine for ἀ 1 , terbutaline for β 2 May have no or minimal selectivity and act on several receptor types E.g., epinephrine for ἀ 1 , ἀ 2 , β 1 , β 2 , and β 3 receptors; NE for ἀ 1 , ἀ 2 , and β 1 receptors Their effects are not reduced by prior treatment with reserpine or guanethidine Rather prior treatment with reserpine or guanethidine can increase their effects Due to receptor up regulation Examples: NE, EP, DA, IP, dobutamine , phenylephrine, albuterol, salmiterol, metaraminole, terbutaline , clonidine, oxymethazoline , xylomethazoline , midodrine , methoxamine

7. 7 2 . Indirect acting adrenomimetics They don’t interact with the adrenoceptors They increase availability of NE/EP to stimulate the adrenoceptors Their action emanates from one of the following Displace stored neurotransmitters from the vesicles E.g. amphetamine, tyramine, methamphetamine, phenmetrazine , methylphenidate, modafinil Inhibit reuptake of neurotransmitters into the neuron E.g. cocaine, TCAs Inhibit the metabolizing enzymes (MAO & COMT) E.g. pargyline / selegiline , entacapone Their response is abolished by prior administration of reserpine or guanethidine

8. 8 3 . Mixed acting adrenomimetics Work by both direct & indirect mechanisms Increase release of NE & also activate adrenoceptors Eg. Ephedrine Pseudoephedrine Phenylpropanolamine- it was a common component in over-the-counter appetite suppressants It was removed from the market because its use was associated with hemorrhagic strokes in young women It can increase blood pressure in patients with impaired autonomic reflexes Their responses are blunted but not abolished by prior treatment with reserpine or guanethidine

9. Summary 9

10. Fig. Sites of action of direct-, indirect-, and mixed-acting adrenergic agonists 10

11. 11 Based on selectivity to adrenoceptors They are grouped into many classes a. Non selective between α & β adrenoceptors NE, EP b. α 1 selective adrenomimetics Phenylephrine, methoxamine, metaraminole, midodrine, mephentermine c. α 2 selective adrenomimetics Clonidine , methyldopa, guanfacine , guanbenz , moxonidine , rilmenidine Dexmedetomidine - used for sedation Tizanidine is used as a central muscle relaxant

12. 12 d. Non selective α 1 & α 2 adrenomimetics EP, NE, oxymethazoline , xylomethazoline , naphazoline e. β 1 selective adrenomimetics Dobutamine A partial agonist, prenalterol f. β 2 selective adrenoceptor agonists Albuterol, terbutaline , salmeterol , formoterol metaproternol, bitolterol, ritodrine, isoetharine g. β 1 β 2 nonselective adrenoceptor agonists Isoproternol, EP,NE

13. The main effect of adrenoreceptor activation α 1 -receptor Arterial and venous vasoconstriction( blood vessel ) GUT Contraction of the sphincter tone of the bladder/prostate contraction/ Contraction of uterus in non pregnant women Decreased contractile response to vasoconstrictors in uterine and nonuterine vessels contributes to increased blood flow to the uterine circulation during normal pregnancy Decrease salivary secretion( salivary glands ) Increase force of contraction of heart Contraction of pupillary dilator muscle(dilate the pupil) ( eye ) Hepatic glycogenolysis and g luconeogenesis ( liver ) Pilomotor smooth muscle erects hair Intestinal smooth muscle:  relaxation (membrane hyperpolarization ) 13

14. II. α 2 - receptors On pre-synaptic : Inhibition of transmitter release ( autoreceptor ) Eg. reduction in NE release Post-synaptic platelet aggregation Contraction of vascular smooth muscle(vasoconstriction) Decrease sympathetic outflow in CNS Inhibition of insulin release (B-cell of pancreas) Decrease aqueous humor secretion In fat cells it inhibits lipolysis III. B 1 - receptor Increased heart rate , force of contraction and AV nodal conduction Increased rennin secretion in kidney juxtaglomerular cells 14

15. I V. Β 2 -receptor Bronchodilation and vasodilatation(in skeletal blood vessel) Relaxation of visceral smooth muscle of GIT GUT : Bladder relaxes Uterus (in pregnant women) relaxes Hepatic glycogenolysis Mast cell decrease histamine secretion Increased secretion of aqueous humour In skeletal muscle –it promotes potassium uptake V. β 3 -receptor Lipolysis (fat cell) vi. D1-receptor Dilates renal blood vessels Vii.D2-receptor Modulates transmitter release 15

16. Adrenaline/EP This is the prototype of adrenergic drugs Pharmacokinetics It is rapidly destroyed in the GIT, conjugated, and oxidized in the liver It is therefore ineffective when given orally and should be given IM or SC It can administered topically to the eye In emergency case, the IM route is most commonly employed, because there is not much delay in the onset of action by IM/IV route IV use is not commonly employed because it can lead to development of fatal arrhythmias or it is likely to precipitate ventricular fibrillation 16

17. However, in severe cases, adrenaline can be administered through IV as a diluted infusion with constant monitoring of heart function It can be given by nebulizer for inhalation when its relaxing effect on the bronchi is desired or it may be applied topically to mucus membranes to produce vasoconstriction It is metabolized by two enzymatic pathways: MAO, and COMT, which has S- adenosylmethionine as a cofactor The final metabolites found in the urine are metanephrine and vanillylmandelic acid 17

18. Fig. Pharmacokinetics of epinephrine 18

19. Drug-drug interactions and drug disease interaction Hyperthyroidism EP may have enhanced cardio-vascular actions in patients with hyperthyroidism If EP is required in such an individual, the dose must be reduced The mechanism appears to involve increased production of adrenergic receptors on the vasculature of the hyperthyroid individual This is leading to a hypersensitive response Cocaine In the presence of cocaine, epinephrine produces exaggerated cardiovascular actions This is due to the ability of cocaine to prevent reuptake of catecholamines into the adrenergic neuron Thus, like NE, epinephrine remains at the receptor site for longer periods of time 19

20. Diabetes EP increases the release of endogenous stores of glucose In the diabetic, dosages of insulin may have to be increased β -Blockers These agents prevent epinephrine's effects on β -receptors, leaving ἀ -receptor stimulation unopposed This may lead to an increase in peripheral resistance and an increase in BP Inhalation anesthetics Inhalational anesthetics sensitize the heart to the effects of epinephrine, which may lead to tachycardia 20

21. Norepinephrine ( levarterenol , noradrenaline ) It is the neurochemical mediator It is released by nerve impulses and various drugs from the postganglionic adrenergic nerves It also constitutes 20% of the adrenal medulla catecholamine out put It should theoretically stimulate all types of adrenergic receptors In practice, when the drug is given in therapeutic doses to humans, the ἀ -adrenergic receptor is most affected Pharmacokinetics Like adrenaline, noradrenaline is ineffective orally So it has to be given intravenously with caution It is not given through SC or IM because of its strong vasoconstrictor effect producing necrosis and sloughing The metabolism is similar to adrenaline; only a little is excreted unchanged in urine 21

22. Isoproterenol (IP) It is a direct-acting synthetic catecholamine Predominantly stimulates both β 1- and β 2-adrenergic receptors Its non-selectivity is one of its drawbacks and the reason why it is rarely used therapeutically Pharmacokinetics IP can be absorbed systemically by the sublingual mucosa However, it is more reliably absorbed when given parenterally or as an inhaled aerosol It is a marginal substrate for COMT and is stable to MAO action 22

23. 23 Pharmacologic responses of NE, EP & Isopreternol 1. Vascular effects Blood vessels of skin & Mucus membranes Predominantly contain α -adrenoceptors So, both NE & EP can produce potent constriction Because both NE & EP are non selective adrenomimetics Isoproternol has very low affinity for α -adrenoceptors & so produce no effect on these vessels Blood vessels of visceral organs Predominantly contains α -adrenoceptors & some β -adrenoceptors NE & EP produce vasoconstriction Isoproternol produces minor vasodilation

24. 24 Blood vessels of skeletal organs Contain both α & β adrenoceptors NE It causes a rise in peripheral resistance This is due to intense vasoconstriction of most vascular beds, including the kidney ( ἀ 1 effect) Both systolic and diastolic blood pressures increase NE causes greater vasoconstriction than does EP because it does not induce compensatory vasodilation via β 2 receptors on blood vessels supplying skeletal muscles

25. Baroreceptor reflex Increase in BP induces a reflex rise in vagal activity by stimulating the baroreceptors This reflex bradycardia is sufficient to counteract the local actions of NE on the heart However, the reflex compensation does not affect the positive inotropic effects of the drug(b/c of ἀ 1 stimulation) Effect of atropine pretreatment If atropine, which blocks the transmission of vagal effects, is given before NE Then NE stimulation of the heart is evident as tachycardia 25

26. Fig . Cardiovascular effects of intravenous infusion of norepinephrine 26

27. IP dilates the vessels by its effect on β adrenoceptors However, it increases HR, FC and cardiac output Nevertheless, the overall effect is decrease in BP 27

28. Fig. Cardiovascular effects of intravenous infusion of isoproterenol 28

29. EP has complex effect depending on its dose Low dose produces vasodilation High dose produces vasoconstriction Therefore, the cumulative effect of EP is an increase in systolic BP, coupled with a slight decrease in diastolic pressure 29

30. Fig. Cardiovascular effects of intravenous infusion of low doses of epinephrine 30

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32. 32 2 . Effects on intact cardiovascular system Increased sympathetic neural activity produces Increased heart rate, force of contraction Increased stroke volume & cardiac output Constricts most of blood vessels, so increases TPR Increased blood pressure

33. 33 3. Effects on nonvascular smooth muscles Bronchial smooth muscles Predominantly β 2 receptors are found Bronchodilation by EP & IP due to β 2 action EP relieves all known allergic- or histamine-induced bronchoconstriction It also inhibits the release of allergy mediators such as histamines from mast cells NE has very low affinity & so weaker effects GIT smooth muscles Motility of the gut is reduced Due to activation of the α 2 hetroreceptors (inhibit Ach) GI sphincters are contracted Through an action on α1 adrenoceptors Eye Radial muscle of the iris contain ἀ 1 adrenoceptors NE/EP cause contraction of this muscle & lead to mydriasis

34. 34 Kidney Detrusor muscle contains β 2 adrenoceptors So, EP & IP relax the detrusor muscle Trigon & sphincter muscles contain α 1 adrenoceptors Contracted by NE & EP, which inhibits the voiding of urine EP decrease renal blood flow Uterine muscle Contains both α 1 & β 2 adrenoceptors NE causes uterine contraction EP/IP cause uterine relaxation CNS effects Though catecholamines minimally cross the BBB , they cause CNS stimulation (mechanism not well known) Apprehension, restlessness & increased respiration

35. 35 5 . Metabolic effects Catecholamines, primarily EP/IP, exert a number of important effects on metabolism Most effects are due to β -adrenoceptors activity NE is usually effective only in large doses So, EP & IP in therapeutic doses Increase oxygen consumption Increase hepatic glycogenolysis EP>IP>NE Mediated by both α 2 & β2 Adrenoceptors due to: Increased glycogenolysis in the liver ( β 2 effect) Increased release of glucagon ( β 2 effect) Decreased release of insulin ( ἀ 2 effect ) Overall effect is an increases blood glucose level/hyperglycemia

36. 36 Increases skeletal muscle glycogenolysis IP>EP>NE Mediated by β - adrenoceptors Increases blood lactic acid level than blood glucose level Because skeletal muscle lacks glucose-6-phosphatase enzyme which converts G-6-P to glucose

37. 37 Increased lipolysis They initiates lipolysis through their agonist activity on the β -receptors of adipose tissue This stimulation activate adenylyl cyclase to increase cAMP levels Cyclic AMP stimulates a hormone sensitive lipase , which hydrolyzes triacylglycerols to free fatty acids and glycerol Therefore, they increase blood free fatty acid levels Mediated by β3 adrenoceptors IP>EP>NE K + homeostasis Catecholamines play an important role in the short term regulation of plasma K + levels Stimulation of hepatic a adrenoceptors will result in the release of K+ from the liver In contrast, stimulation of β 2 adrenoceptors, particularly in the skeletal muscles, will lead to uptake of K+ into the tissue β2 adrenoceptors are linked to Na+/K+ ATPase

38. 38 Clinical uses of catecholamines Their uses are based on their actions on bronchial smooth muscles, blood vessels & the heart Allergic reactions EP is mainly used in allergic reactions which are due to histamine release Because it produces to certain physiological responses that are opposite to those produced by histamine So, EP is used in the treatment of Anaphylactic shock It is the drug of choice for the treatment of Type I hypersensitivity reactions in response to allergens The syndrome of bronchospasm , mucous membrane congestion, angioedema , and severe hypotension usually responds rapidly to the parenteral administration of epinephrine IM route is preferred Urticaria Angioneuretic edema Serum sickness

39. Bronchospasm Epinephrine is the primary drug used in the emergency treatment In treatment of acute asthma, it is the drug of choice Selective β 2 agonists, such as albuterol , are presently favored in the chronic treatment of asthma because of their longer duration of action and minimal cardiac stimulatory effect Cardiac applications IP and EP have been used in the temporary emergency management of complete heart block and cardiac arrest EP may be useful in part by redistributing blood flow during cardiopulmonary resuscitation to coronaries and to the brain 39

40. Open-angle glaucoma EP has been used to lower IOP in open-angle glaucoma It reduces the production of aqueous humor by vasoconstriction of the ciliary body blood vessels Works by increasing outflow of aqueous humor probably by stimulating β 2-adrenergic receptors in the trabecular meshwork In ophthalmology, a two-percent epinephrine solution may be used topically It is available as hydrochloride, bitartarate and borate salt for topical ophthalmic use EP is contraindicated in closed-angle glaucoma Because it reduces the filtration angle further & hinders outflow of fluid in this case 40

41. 41 Used with local anesthetics (LAs) NE/EP is coadministered with LAs Local anesthetic solutions usually contain 1:100,000 parts epinephrine It greatly increase the duration of the local anesthesia By producing vasoconstriction at the site of injection, it allows the local anesthetic to persist at the injection site before being absorbed into the circulation and metabolized Prevent systemic absorption & toxicity of the LAs However, EP can potentiate the neurotoxicity of local anesthetics used for peripheral nerve blocks or spinal anesthesia Control of bleeding EP is used as topical hemostatic agent for the control of local hemorrhage EP is usually applied topically in nasal packs (for epistaxis ) or in a gingival string (for gingivectomy ) Very weak solutions of EP 1:100,000 is used

42. 42 Management of hypotension Sympathomimetic drugs may be used in a hypotensive emergency to preserve cerebral and coronary blood flow The treatment is usually of short duration When NE is used as a drug, it is sometimes called levarterenol NE is infused IV to combat systemic hypotension during spinal anesthesia However, metaraminol is favored, because it does not reduce blood flow to the kidney, as does NE NE is also useful in controlling hypotension in which TPR is low Because it increases vascular resistance and increases BP But NE is not used to combat hypotension due to most types of shock

43. 43 Side effects of catecholamines Tachycardia Reflex bradycardia By NE, but not with EP or IP(because they have β 2 effects) CNS disturbances Epinephrine can produce adverse CNS effects that include anxiety, fear, tension, headache, and tremor Tissue sloughing & necrosis Local ischemia from extravasation of NE at site of injection Arrhythmia EP can trigger cardiac arrhythmias, particularly if the patient is receiving digitalis Hypertension (mainly by NE and EP) Pulmonary edema Epinephrine can induce pulmonary edema Hemorrhage EP and NE may induce cerebral hemorrhage as a result of a marked elevation of BP

44. Contra indications Coronary diseases Hyperthyroidism Hypertension Digitalis therapy Injection around end arteries 44

45. 45 Other adrenomimetic agents A number of adrenomimetics are not catecholamines Noncatecholamines are r esistant to enzymatic degradation(COMT) They have longer duration of action They are orally active α1-selective adrenomimetic agents Phenylephrine, metaraminol & methoxamine They are all directly acting adrenomimetics However, metaraminol also is an indirectly acting agent that stimulates the release of NE Exert their effect primarily by activating α 1-adrenoceptor Has no/little direct effect on the heart All have vasoconstrictor effect Increase both the systolic & diastolic blood pressure They don’t cause cardiac arrhythmias They don’t stimulate CNS

46. 46 Their vasoconstrictor effect is accompanied by Reflex increment in the vagal input to the heart Reflex bradycardia No change in the contractile forces They have considerably longer duration of action than NE Phenylephrine resistant to COMT metabolism Metaraminol & methoxamine are resistant to both COMT & MAO

47. 47 Clinical uses Associated with their potent vasoconstrictor effects They are used to restore or maintain Bp during spinal anesthesia & certain other hypotensive states Phenylephrine is commonly used As nasal decongestant As mydriatic agent With local anesthetics in dental procedures Metaraminol also off-label used to relieve attacks of paroxysmal atrial tachycardia, particularly those associated with hypotension

48. Midodrine It is a prodrug that is enzymatically hydrolyzed to desglymidodrine It is selective α1 - receptor agonist It is an orally effective It is used for the treatment of orthostatic hypotension, typically due to impaired autonomic nervous system function Because it rises BP that associated with both arterial and venous smooth muscle contraction It reduces the fall of blood pressure when the patient is in standing position It may cause hypertension when the subject is supine This can be minimized by : Administering the drug when the patient will remain upright position Avoiding dosing within 4 hours of bedtime Elevating the head of the bed FDA considered withdrawing approval of this drug in 2010 48

49. Mephentermine It is a sympathomimetic drug that acts both directly and indirectly It has many similarities to ephedrine Since the drug releases NE, cardiac contraction is enhanced, and cardiac output and systolic and diastolic pressures usually are increased The change in heart rate is variable, depending on the degree of vagal tone Mephentermine is used to prevent hypotension, which frequently accompanies spinal anesthesia Adverse effects CNS stimulation Excessive rises in blood pressure Arrhythmias The drug has been discontinued in the U.S 49

50. 50 α 2 selective adrenomimetics Includes: methyldopa, clonidine, guanfacine , apraclonidine , brimonidine , tinazidine Methyldopa It is a centrally acting adrenomimetic agent It is a prodrug & produces its effects via active metabolite In adrenergic neurons, it is metabolized by DOPA decarboxylase enzyme to α -methyl dopamine α -methyl dopamine is then converted to α -methyl NE α -methyl NE, by activating α 2 adrenoceptors in the brainstem attenuates further release of NE Produces its vasodilatory effects Uses: it is preferred drug for treatment of HTN during pregnancy Because it is safe for both the mother & infant

51. 51 Adverse effects Sedation Occasional depression Dryness of mouth Reduction in libido Hyperprolactinemia Gynacomastia , galactorrhea Serious but rare hepatotoxicity Contraindicated in patients with hepatic disease Can also cause hemolytic anemia

52. 52 Clonidine, guanbenz & guanfacine They are all α 2 selective agonists MOA They stimulate presynaptic α 2A receptors in the brainstem reducing sympathetic outflow from the CNS Reduce arterial pressure by an effect on both CO & peripheral resistance At higher doses, these drugs can stimulate postsynaptic α 2B receptors (found on the vascular smooth muscles) causing vasoconstriction This explains the initial vasoconstriction that is seen when overdoses of these drugs are taken

53. Clinical use Treatment of essential hypertension However, In patients with pure autonomic failure, characterized by neural degeneration of postganglionic noradrenergic fibers, clonidine may increase BP This is because of the fact that the central sympatholytic effects of clonidine become irrelevant, whereas the peripheral vasoconstriction remains intact Clonidine has been found to be useful in reducing diarrhea in some diabetic patients with autonomic neuropathy Because stimulation of ἀ 2 receptors in the GI tract may increase absorption of sodium chloride and fluid and inhibit secretion of bicarbonate Useful in treating and preparing addicted subjects for withdrawal from narcotics, alcohol, and tobacco Clonidine and related drugs such as dexmedetomidine (a relatively selective ἀ 2 receptor agonist with sedative properties) used in anesthesia to produce preoperative sedation and anxiolysis , drying of secretions, and analgesia Transdermal administration of clonidine may be useful in reducing the incidence of menopausal hot flashes 53

54. 54 Adverse effects Sedation & xerostemia Postural hypotension & erectile dysfunction Sleep disturbances & night mares Depression Sudden withdrawal of clonidine & other α 2 agonists may cause withdrawal syndrome consisting of: Headache, sweating, tremors, abdominal pain, tachycardia & rebound HTN

55. Apraclonidine It is a relatively selective ἀ 2 receptor agonist It can reduce elevated as well as normal IOP whether accompanied by glaucoma or not The reduction in IOP occurs with minimal or no effects on systemic cardiovascular parameters Thus apraclonidine is more useful than clonidine for ophthalmic therapy Apparently apraclonidine does not cross the BBB The mechanism of action of apraclonidine is related to ἀ 2 receptor–mediated reduction in the formation of aqueous humor 55

56. Clinical uses It is used topically to reduce IOP as short-term adjunctive therapy in glaucoma Especially in patients whose IOP is not well controlled by other pharmacological agents such as β -receptor antagonists, parasympathomimetics , or carbonic anhydrase inhibitors It is used to control or prevent elevations in IOP that occur in patients after laser trabeculoplasty or iridotomy 56

57. Brimonidine It is another clonidine derivative It is ἀ 2 -selective agonist It is administered ocularly to lower IOP in patients with ocular hypertension or open-angle glaucoma It reduces IOP both by decreasing aqueous humor production and by increasing outflow Its efficacy in reducing IOP is similar to that of the receptor antagonist timolol Unlike apraclonidine , brimonidine can cross the BBB and can produce hypotension and sedation However, these CNS effects are slight compared to those of clonidine As with all ἀ 2 agonists, this drug should be used with caution in patients with cardiovascular disease Tizanidine It is also an ἀ 2 agonist It is a muscle relaxant used for the treatment of spasticity associated with cerebral and spinal disorders 57

58. Agents with both ἀ 1- and ἀ 2-receptors Oxymetazoline and Xylometazoline They are a direct-acting synthetic adrenergic agonist that stimulates both ἀ 1- and ἀ 2-adrenergic receptors They are primarily used locally in the eye or the nose as a vasoconstrictor Oxymetazoline is found in many over-the-counter short-term nasal spray decongestant products as well as in ophthalmic drops for the relief of redness of the eyes associated with swimming, colds, or contact lens By directly stimulating ἀ -receptors on blood vessels supplying the nasal mucosa and the conjunctiva, it reduces blood flow and decrease congestion 58

59. Oxymetazoline may cause hypotension, presumably because of a central clonidine -like effect Oxymetazoline is absorbed in the systemic circulation regardless of the route of administration and may produce nervousness, headaches, and trouble sleeping When administered in the nose, burning of the nasal mucosa and sneezing may occur Rebound congestion is observed with long-term use 59

60. 60 β1-selective adrenomimetics Dobutamine It acts directly on β1-adrenoceptors in the heart It exerts a greater effect on the contractile force of the heart relative to its effect on the heart rate At higher doses, it produces vasodilation of the renal & mesenteric blood vessels It has a fast onset of action & short half life (2mins) Therapeutic uses Indicated for short term treatment of cardiac decompensation that may occur After surgery In patients with CHF

61. 61 Dobutamine increases the stroke volume & cardiac output in such patients, usually without marked increase in the heart rate It is also useful in the treatment of cardiogenic shock Adverse effects May increase the size of myocardial infarct By further increasing the O2 demand Increased risk of atrial fibrillation

62. Dopamine It is the immediate metabolic precursor of NE It occurs naturally in the CNS in the basal ganglia It functions as a neurotransmitter in the CNS and adrenal medulla Dopamine can activate ἀ - and β -adrenergic receptors For example, at higher doses, it can cause vasoconstriction by activating ἀ 1 receptors at lower doses, it stimulates β 1 cardiac receptors D1 and D2 dopaminergic receptors occur in the peripheral mesenteric and renal vascular beds, where binding of dopamine produces vasodilation D2 receptors are also found on presynaptic adrenergic neurons, where their activation interferes with NE release 62

63. Dopamine action CVS Dopamine exerts a stimulatory effect on the β 1- receptors of the heart It has both positive inotropic and chronotropic effects At very high doses, it activates ἀ 1-receptors on the vasculature, resulting in vasoconstriction Renal and visceral Dopamine dilates renal and splanchnic arterioles It increases blood flow to the kidneys and other viscera Therefore, dopamine is clinically useful in the treatment of shock, in which significant increases in sympathetic activity might compromise renal function Dopamine hydrochloride is used only intravenously, preferably into a large vein to prevent perivascular infiltration( i.e given by continuous infusion) Because extravasation may cause necrosis and sloughing of the surrounding tissue 63

64. 64 β2-selective adrenomimetic agents They are agents used in the management of asthma The main difference in the available β2 adrenomimetics is their pharmacokinetic profiles So, in the management of asthma, β2 agonists Work by activating pulmonary β2 adrenoceptors & relax the bronchial smooth muscles & decrease airway resistance

65. 65 Metaproterenol It is resistant to metabolism by COMT Available in inhalational & oral dosage forms It is less β 2 selective, compared to albuterol & terbutaline More prone to cause cardiac stimulation than the two drugs Uses: Metaproterenol is used for Long term treatment of obstructive airway disease Treatment of acute bronchospasm

66. 66 Terbutaline It is β 2 selective Resistant to COMT Effective when given by oral, Sc or inhalational routes Onset of action is rapid from inhalational & Sc routes Uses: Long term treatment of obstructive airway disease Treatment of acute bronchospasm Emergency treatment of status asthmaticus Albuterol / salbutamol β2 selective, given by inhalational or oral route Has similar therapeutic indications as terbutaline Oral albuterol has the potential to delay preterm labor

67. 67 Salmeterol It is a β 2 selective agent with the longest duration of action (>12hours) At least 50 times more β 2 selective than albuterol Highly lipophilic & has sustained action It has slow onset of action Not suitable monotherapy for acute attacks of asthma Due to its sustained duration of action, salmeterol Is drug of choice for treatment of nocturnal asthma Shouldn’t be used more than twice daily Shouldn’t be used to treat acute asthma

68. 68 Formoterol It is another long acting, β 2 selective agonist It is highly lipophilic, resulting in storage in adipocytes Responsible for sustained action It is an alternative to salmeterol for treatment of nocturnal asthma Ritodrine Selective β 2 agonist, developed specifically for use as uterine relaxant Up to 30% absorbed after oral dose 90% of drug excreted in urine as inactive conjugate Uses: given through IV in selected patients to arrest premature labor

69. 69 Adverse effects of β 2 selective adrenomimetics Tremor It is due to stimulation of  2 receptors in skeletal muscle It is the most common side effect It occurs because activation of  2 receptors in skeletal muscle enhances contraction Feeling of restlessness, apprehension & anxiety Tachycardia, which may result from β 1 stimulation Reflex response to peripheral vasodilation Cardiac arrhythmias or myocardial ischemia Less likely in patients without pre-existing cardiac disease High risk of occurrence in patients with underlying coronary artery disease or pre-existing arrhythmia Pulmonary edema In women who receive ritodrine or terbutaline for preterm labor

70. 70 Larger doses of β 2 adrenomimetics may Increase plasma glucose level Increase lactate & free fatty acids level in plasma Lower plasma concentration of K+ Note: All the adverse effects are far less likely with inhalational therapy than with parentral or oral therapy

71. 71 Indirect acting adrenomimetics Includes: amphetamine, methamphetamine, cocaine, methylphenidate, TCAs Amphetamine Indirectly acting agent Works by displacing NE/EP from its storage vesicles Pharmacological effects CVS effects Increases both systolic & diastolic blood pressure Heart rate is reduced reflexively

72. 72 CNS effects It is one of the most potent sympathomimetic amines in stimulating the CNS Amphetamine: Stimulates medullary respiratory centres Lessens degree of central depression caused by various drugs Alters psych of individuals Elevation of mood, self-confidence & ability to concentrate Increase in elation & euphoria, wakefulness, decreased fatigue

73. 73 Increases motor & speech activities Improved performance of tasks (errors may increase) Prolonged or large dose use is nearly always followed by depression & fatigue Therapeutic uses Amphetamine is used chiefly for its CNS effects Dextroamphetamine, with more CNS actions than peripheral actions Was used for reducing obesity Due to its anorexic effects No more approved by FDA for this purpose Is approved by FDA for treatment of Narcolepsy Attention deficient hyperactivity disorder

74. 74 Methamphetamine Chemically, a close relative of amphetamine Works by Increasing dopamine & other biogenic amines Inhibiting neuronal & vesicular transporters Inhibiting MAO Has a prominent central than peripheral action Has high potential for abuse Widely used as a cheap, accessible recreational drug Its abuse is a widespread phenomenon Methylphenidate Mild CNS stimulant, with essentially similar pharmacological actions as amphetamines Has also the abuse potentials of amphetamines

75. 75 Toxic & adverse effects of amphetamines They are extensions of pharmacological actions of amphetamine CNS effects Restlessness, dizziness, tremor, hyperactive reflexes, insomnia, talkativeness & euphoria If dose is large enough or in mentally ill patients Confusion, aggressiveness, changes in libido, anxiety, suicidal or homicidal tendencies may occur Fatigue & depression usually follow central stimulation CVS effects Pallor or flushing, palpitations, cardiac arrhythmias, anginal pain, hypertension/hypotension, circulatory collapse Excessive sweating GI effects: dry mouth, metallic taste, anorexia, nausea, vomiting & abdominal cramps

76. 76 Treatment of acute amphetamine toxicity Acidification of urine with ammonium chloride Increases the excretion of amphetamine Sedatives may be required for CNS effects Severe hypertension may require administration of Sodium nitroprusside or α 1 antagonists

77. 77 Mixed acting adrenomimetic drugs Ephedrine It is naturally occurring plant alkaloid Can cross BBB Has strong CNS stimulating effect, in addition to its peripheral actions CNS stimulatory effect is less, compared to amphetamine Has longer duration of action than NE Because it is very resistant to both COMT & MAO metabolism Unlike NE/EP, ephedrine is effective when taken orally Less potent compared to NE/EP Tachyphylaxis develops after repeated use It is absorbed from the GIT and from all parenteral sites A major proportion of the drug is excreted unchanged in the urine

78. 78 MOA Actions mainly depend on release of NE/EP Has also some direct receptor stimulatory effects Particularly in its bronchodilating effects Clinical uses Ephedrine is useful in Relieving bronchoconstriction & mucosal congestion associated with bronchial asthma Prophylactic prevention of asthmatic attacks Nasal decongestion Producing mydriasis Terbutaline & albuterol are replacing ephedrine for treatment of asthma Less side effects, effective bronchodilation

79. 79 Adverse effects Tachycardia Insomnia Nervousness, nausea, vomiting Emotional disturbances

80. Adrenoceptor antagonists They are drugs that inhibit responses mediated by adrenoceptor activation They have affinity for adrenoceptors Lack intrinsic activity, so won’t initiate receptor responses Works by competing with adrenomimetics for access to adrenoceptors Reduce effects produced by both sympathetic nerve stimulation & exogenous adrenomimetics Adrenoceptor antagonists They don’t prevent release of NE/EP from adrenergic neurons They are not catecholamine depleting agents Are also called, sympathoplegics, sympatholytics 80

81. Classification of adrenoceptor antagonists 1. α- Adrenoceptor antagonists a) Non selective α 1 , α 2 - Adrenoceptor antagonists Phentolamine, Phenoxybenzamine, Tolazoline b) α 1 - selective adrenoceptor antagonists Prazosin, Terazosin, Doxazosin, Tamsulosin, Alfuzosin c) α 2 - selective adrenoceptor antagonists: Yohimbine 2. β- Adrenoceptor antagonists a) Non selective β 1 , β 2 adrenoceptor antagonists Propranolol, Pindolol, Nadolol, Timolol b) β 1 - selective adrenoceptor antagonist Atenolol, acebutolol, Metoprolol, Esmolol, Bisoprolol C) β 2 - selective adrenoceptor antagonists Butoxamine 81

82. 82 3. Nonselective α, β-Adrenoceptor antagonists Labetalol, Carvedilol, Bucindolol Pharmacological effects of α -blockers 1. Cardiovascular system : (  1 receptors on blood vessels ) Dilatation of arteries & veins   BP 2. Eye: Radial muscle of iris (  1 receptors) - > relaxes -> m iosis 3. Nose: Dilatation of blood vessels  n asal congestion 4. Genitourinary system:  resistance to urine flow Inhibition of ejaculation

83. Non-selective α -blockers Block both α 1 & α 2 adrenoceptors E.g. Phenoxybenzamine, Phentolamine, Tolazoline Phenoxybenzamine Is a haloalkylamine that blocks both α 1 & α 2 receptors irreversibly Major pharmacological effect (vasodilation) occurs from blockade of α -receptors in blood vessels Causes reduced TPR (due to α 1 & α 2B blockade) Increased CO (due to reflex sympathetic nerve stimulation) Tachycardia Reflex to hypotension, enhanced release of NE/EP due to activation of presynaptic α 2A adrenoceptors In addition to antagonism of α -receptor, it can Inhibit uptake of catecholamines (inhibit both uptake 1 & 2) Irreversibly inhibit responses to 5HT, histamine & Ach 83

84. Half life of phenoxybenzamine is less than 24 hours, but duration of action is maintained for days Due to irreversible inactivation of α -receptors Therapeutic uses Treatment of pheochromocytoma Tumors of the adrenal medulla & sympathetic neurons Secrete enormous amounts of NE/EP, which leads to hypertension Phenoxybenzamine, by antagonizing α -receptors is used to treat symptoms of pheochromocytoma Treatment of benign prostatic hyperplasia (BPH) Used to reduce obstructive symptoms of BPH It is no more used for treatment of BPH Adverse effects Reflex tachycardia, postural hypotension, inhibit ejaculation 84

85. Phentolamine & tolazoline Are competitive antagonists at α adrenoceptors Antagonism is reversible So, have short duration of action Nonselective antagonist b/n α1 & α2 adrenoceptors Tolazoline is less potent than phentolamine Pharmacological action ↓BP by blocking α-receptors (α1 & α2B) Reflex increase in HR, CO ↑ Mechanism for increase in HR & CO ① BP↓ as result of vasodilation → reflex excited heart ② block presynaptic α 2A receptors →release of NE/EP ↑ → activate β 1 R 85

86. Therapeutic uses Benign prostetic hyperplasia Hypertensive emergencies Local vasoconstrictor excess Pheochromocytoma Side effects Postural hypotension Reflex tachycardia GI stimulation Abdominal pain Nausea Exacerbation of peptic ulcer 86

87. Selective α 1 -antagonists Includes: prazosin, terazosin, doxazosin, tamsulosin They are highly selective for α 1 receptors Exhibit greater clinical utility than the non-selective blockers Replaced the non-selective blockers clinically Leads to relaxation of both arterial and venous smooth muscle due to blockade of α 1 receptors Leads to fall in TPR which leads to lowered preload as well as after load They generally differ in their pharmacokinetics Well absorbed after oral use, highly bound to plasma proteins Metabolized in the liver & excreted in the face & urine Except tamsulosin, others are non-selective among α 1 -receptor subtypes (α 1A, α 1B, α 1D ) Tamsulosin is a selective ἀ 1A antagonist that is used to treat benign prostate hyperplasia 87

88. Therapeutic uses Treatment of essential hypertension Congestive heart failure Because, they reduce both preload & after load Benign prosthetic hyperplasia Produces symptomatic urethral obstruction in a significant number of older men Urinary frequency, nocturia α1 antagonists have efficacy in treating BPH, owing to Relaxation of smooth muscles in the bladder neck, prostate capsule & prostatic urethra Rapidly improve urine flow 88

89. Side effects Major adverse effect is 1 st dose phenomenon Marked postural hypotension & syncope are seen 30-90 minutes after patient takes the 1 st dose of α1 blockers Can be minimized by limiting initial dose & gradually increasing the dose Headache, dizziness Asthenia (abnormal loss of strength) Tamsulosin may cause impaired ejaculation Tamsulosin at therapeutic doses doesn’t produce orthostatic hypotension, unlike the other α 1-blockers Due to its selective effect on α 1A receptors 89

90. Selective α 2 -antagonists Yohimbine It is an alkaloid obtained from plants Readily enters to CNS It is competitive α 2 -selective antagonist Increases sympathetic outflow Increases blood pressure & heart rate Produces opposite effects to clonidine Therapeutic uses The treatment of male erectile dysfunction (ED) Not widely used due to availability of effective agents 90

91. 91  -Blockers A. N on selective - Blockers Are also called 1 st generation  -blockers Propranolol, Timolol Nadolol, Pindolol B. Cardio selectives [  1 Blockers ] Are called 2 nd generation  -blockers Atenolol, Acebutolol, Bisoprolol Esmolol, Metoprolol Non-selective adrenergic blockers( &  Blockers) Carvedilol, Labetalol, Bucindolol, Nebivolol Are also called 3 rd generation  -blockers Longest half life: Nadolol, Cartelol (24 hrs) Shortest half life: Esmolol (10 min)

92. Some of the β -blockers have some intrinsic activity & membrane stabilizing activity May be considered as partial antagonists Examples Pindolol Acebutolol Bucindolol 92

93. 93 Pharmacological actions of -blockers A. Heart (  1 receptors )  myocardial contraction  HR  AV-conduction & automaticity B . CNS/Neurological Sedation ( with Propranolol, Carvedilol) C. Respiratory system Bronchoconstriction Little effect on pulmonary functions of normal individuals Can cause life-threatening bronchospasm in patients with COPD  1 selective blockers or those with intrinsic sympathomimetic activity are less likely than propranolol to cause severe bronchoconstriction

94. D. EYE:  IOP by reducing production of aqueous humor E. Liver Decrease glycogenolysis & lipolysis Can aggravate hypoglycemia in diabetic patients treated with insulin or oral hypoglycemic agents  1 selective blockers are less likely to produce hypoglycemic effects F. Adipose tissue Non selective  - blockers reduce lipolysis Reduce HDL, increase LDL & increase triglycerides F. Kidney Reduce renin release 94

95. 95 Therapeutic uses of β -blockers Hypertension Coronary heart disease  Angina Pectoris  Myocardial infarction Cardiac arrhythmias Anxiety : to  sympathetic manifestations Hyperthyroidism: to  sympathetic manifestations Migraine headache Blockade of cranial beta receptors reduce vasodilation Glaucoma Reduce the production of aqueous humor Timolol is applied topically to treat glaucoma

96. Advantages of Timolol over miotics in the treatment of glaucom are : no pupil constriction no effect on accommodation no ocular discomfort no retinal detachment no shallowing of anterior chamber no cataract formation and no iridocyclitis The advantages over epinephrine : are no pupil dilatation no maculopathy in aphakics no conjunctival hyperaemia no adrenochrome deposits and no ocular irritation The advantages over carbonic anhydrase inhibitors are effective topically no CNS effects no GI effects no kidney stones no parasthesias no acidosis no weight loss Thus Timolol has come out to be an important weapon in "therapeutic arsenal" of the ophthalmolo gists in their fight againt glaucoma 96

97. 97 Adverse effects of β -blockers 1. CVS Bradycardia hypotension AV block 2. Bronchoconstriction 3. Hypoglycemic effect 4. Affect lipid profile 5. Muscle pain & fatigue 6. Sleep disturbances, nightmares More pronounced with  1 selectives Produced by non-selective blockers

98. 98 Contraindications to β -blockers Heart failure Slow AV-node conduction Asthma & COPD Diabetes mellitus Hypothyroidism Combination with Ca-channel blockers

99. Non selective  &  antagonists Includes: Labetalol, Carvedilol, Bucindolol Are called 3 rd generation, vasodilatory β -blockers Labetalol Possess both  &  blocking activity  blocking activity is more potent than  blocking activity Non selective b/n 1 & 2 receptors Have some intrinsic activity at 2 receptors Responsible for vasodilatory effect of the drug At  receptors, labetalol Is more selective to  1 receptors Causes vasodilation (another mechanism for vasodilation) 99

100. So, labetalol causes vasodilation by: Blocking vasoconstrictive effects of  1 receptors Activating 2 receptors Therapeutic use Labetalol is used in the treatment of hypertension Reduces both CO & TPR Side effects Postural hypotension GI distress Tiredness Sexual dysfunction Skin rashes 100