Adrenergic agonists by swaroopa

Adrenergic Agonists

1. ADRENERGIC AGONISTS Dr. Swaroopa 1 st year PG, Department of Pharmacology, Rangaraya Medical college, Kakinada. Date – 12-07-2021 13-Aug-21 1

2. 13-Aug-21 2 Write a brief note on the synthesis, reuptake and mechanism of catecholamines and drugs which affect these processes. Non – cardiovascular uses of Clonidine Non cardiovascular uses of sympathomimetic agents. Central alpha2 agonists Summarize the sites of action with examples of drugs modulating adrenergic neurotransmission. Selective beta2 agonists Dopamine receptors QUESTIONS FROM THIS TOPIC ASKED IN UNIVERSITY EXAMS

3. CONTENTS INTRODUCTION CATECHOLAMINES (synthesis, uptake & metabolism) MOLECULAR PHARMACOLOGY CLASSIFICATION DIRECTLY ACTING INDIRECTLY ACTING MIXED ACTION DRUGS THERAPEUTIC USES CONCLUSION REFERENCES 13-Aug-21 3

4. 13-Aug-21 4 INTRODUCTION The sympathetic nervous system is an important regulator of all organ systems. The ultimate effects of sympathetic stimulation are mediated by release of norepinephrine (NE) from nerve terminals, which then activates adrenoceptors on post synaptic sites. Epinephrine/ Adrenaine (A) acts as a hormone. Norepinephrine acts as a neurotransmitter. Drugs that mimics A or NE are known as sympathomimetic drugs which are grouped by mode of action and receptors that they activate into DIRECT, INDIRECT & MIXED.

5. 13-Aug-21 5 CATECHOLAMINE SYNTHESIS, STORAGE, RELEASE AND REUPTAKE PATHWAYS Normal uptake of NE

6. 13-Aug-21 6 INHIBITORS OF CATECHOLAMINE SYNTHESIS α - Methyl tyrosine is a structural analogue of tyrosine, it inhibits tyrosine hydroxylase, the first enzyme in the biosynthesis of catechol amines. Uses : rarely used in the treatment of hypertension associated with pheocytochroma Adverse effects : significant orthostatic hypotension and sedation. C/I : hypersensitivity to α - methyl tyrosine .

7. 13-Aug-21 7 INHIBITORS OF CATECHOLAMINE STORAGE RESERPINE : irreversibly inhibits VMAT, resulting in vesicles that lose the ability to concentrate and store NE & DA . Rarely used as a therapeutic agent in hypertension due to its irreversible action . Adverse effects : cardiac arrhythmias, GI haemorrhage, xerostomia, dizziness, depression, lethargy, nasal congestion . C/I : GI disease, depression, electroshock therapy, renal failure . Other inhibitors : Guanethidine, guanadrel, Amphetamine, Methylphenidate , pseudoephedrine.

8. 13-Aug-21 8 INHIBITORS OF CATECHOLAMINE REUPTAKE MECHANISM : Inhibit Norepinephrine Transporter mediated reuptake of catecholamines, potentiating catecholamine action. COCAINE IMIPRAMINE AMITRYPTALINE ATOMOXETINE SIBUTRAMINE DULOXETINE REBOXETINE

9. 13-Aug-21 9 MONOAMINE OXIDASE (MAO) INHIBITORS MECHANISM : inhibit monoamine oxidase, increasing catecholamine levels by blocking catecholamine degradation. Phenelzine Iproniazid Tranylcypromine Clorgyline Moclobemide Selegiline Rasagiline

10. 13-Aug-21 10 MOLECULAR PHARMACOLOGY UNDERLYING THE ACTIONS OF ADRENERGIC AGONISTS Effects of catechol amines are mediated by cell surface receptors (adrenoceptors). Adrenoceptors are typical G protein – coupled receptors. Each G protein – heterotrimer consisting of alpha, beta and gamma subunits. G proteins are classified on the basis of alpha subunit G s – stimulatory G protein of adenylyl cyclase G i & G – inhibitory G protein of adenylyl cyclase G q & G 11 – G proteins coupling alpha receptors to phospholipase C.

11. 13-Aug-21 11 Cont …. RELATIVE AFFINITIES FOR AGONISTS Comparative potencies of alpha receptors : Epinephrine > norepinephrine >> isoproterenol Comparative potencies of beta receptors : Isoproterenol > epinephrine > norepinephrine

12. 13-Aug-21 12 RECEPTOR TYPES : Alpha Beta Dopamine Alpha receptors : α1 & α2 α1 Coupled to phospholipase C, through Gq family. alpha1 subtypes α1 A , α1 B, α1 D polyphosphoinositides Phospholipase C IP3 (Inositol1,4,5-triphosphate ) Diacylglycerol(DAG) Promotes the release of stored ca +2 free cytoplasm ca +2 Activate ca +2 dependent protein kinases. With ca +2 it activates protein kinase C Modulates activity of many signalling pathways

13. 13-Aug-21 13 Alpha1 receptors also activate signal transduction pathways that stimulate tyrosine kinases. Alpha 2 receptors : Coupled to Gi protein Inhibits adenylyl cyclase Levels of intracellular cAMP decreased Alpha2 receptors also use other signalling pathways like ion channel activities & activities of important enzymes in signal transduction.

14. 13-Aug-21 14 2. Beta receptors : β 1, β2 , β 3 Coupled to stimulatory Gs protein Activates / stimulates adenylyl cyclase Increases cAMP (major secondary messenger of beta receptor activation). A cascade of events in the activation of glycogen phosphorylase in LIVER Increase in the influx of ca+2 across the plasma membrane in HEART Causes relaxation in SMOOTH MUSCLES.

15. 13-Aug-21 15 Beta3 has lower affinity compared to 1 & 2. It is more resistant to desensitization Beta3 receptors are expressed in detrusor muscle of the bladder, induces its relaxation * MIRABEGRON – selective beta3 agonist used for the treatment of symptoms of overactive bladder like urinary urgency and frequency.

16. 13-Aug-21 16 3. DOPAMINE RECEPTORS : D1 Stimulation of adenylyl cyclase Smooth muscle relaxation Dopamine produces biological effects mediated by interactions with dopamine receptors. There are 5 dopamine receptor subtypes 2 – D 1 like receptors ( D 1 & D 5 ) 3 – D 2 like receptors ( D 2 , D 3 , D 4 ) These subtypes have importance for understanding the efficacy & adverse effects of novel antipsychotic drugs. D2 Inhibition of adenylyl cyclase Open potassium channels, Decrease calcium influx

17. 13-Aug-21 17 RECEPTOR SELECTIVITY Means that a drug preferentially bind to one subgroup of receptors at concentrations too low to interact extensively with another subgroup. At higher concentrations, drug may also interact with related classes of receptors.

18. 13-Aug-21 18 RECEPTOR REGULATION The magnitude of the response depends on the number and function of adrenoceptors on the cell surface on the regulation of these receptors by catecholamines Other harmones and drugs Age A number of disease states Both short-term (desensitization) and long-term (down regulation) changes in the number of functional adrenoceptors are important in regulating tissue response.

19. 13-Aug-21 19 DISTRIBUTION & ACTIONS OF ADRENERGIC RECEPTORS

20. 13-Aug-21 20 CLASSIFICATION OF ADRENERGIC DRUGS DIRECTLY ACTING : CATECHOLAMINES NON CATECHOLAMINES ENDOGENOUS Adrenaline/epinephrine Noradrenaline /norepinephrine Dopamine B. EXOGENOUS Dobutamine Dopexamine Fenoldopam Isoprenaline Xylometazoline Clonidine Phenylephrine Salbutamol Methoxamine Tetrahydrozoline Midodrine Oxymetazoline Brimonidine Methyl dopa 2. MIXED ACTION Ephedrine Pseudoephedrine Mephentamine

21. 13-Aug-21 21 CLASSIFICATION OF ADRENERGIC DRUGS Cont.…. 3. INDIRECTLY ACTING : REUPTAKE INHIBITORS ACTION BY DISPLACEMENT Cocaine TCA Amphetamines Methylphenidate Modafinil

22. 13-Aug-21 22 CATECHOLAMINES: Adrenaline, noradrenaline, dopamine: High potency compounds Short half life (rapid inactivation by MAO & COMT) Poor penetration in the CNS (as they are polar compounds) Metabolism In intestine by MAO & COMT In liver by MAO RECEPTOR AFFINITIES: NOREPINEPHRINE α1 = α2 , β1 >>>> β2 EPINEPHRINE α1 = α2 , β1 = β2 DOPAMINE D1 = D2 >> β >> α ISOPRENALINE β1 = β2 >>>> α

23. 13-Aug-21 23 ADRENALINE / EPINEPHRINE Agonist at both α and β adrenoceptors At low concentrations β1 & β2 effects At high concentrations α 1effects are more pronounced. β1 effects : Increased Cardiac contractility (positive Ionotropic effect) Increased cardiac output Increased systolic blood pressure Vasodilation in large arteries (femoral & pulmonary)

24. 13-Aug-21 24 Cont …. β2 effects : Vasodilation in arterioles -- decreased peripheral resistance -- decreased diastolic BP Increased blood flow to skeletal muscle Relaxes bronchial smooth muscle Promotes glycogenolysis Increases the concentration of glucose & free fatty acids in the blood. Epinephrine is ineffective orally due to extensive first pass metabolism. It has rapid onset and a brief duration of action when injected intravenously. * They cause increased cardiac excitability that may lead to cardiac arrhythmias and excessive increase in blood pressure if they infused rapidly.

25. 13-Aug-21 25 THERAPEUTIC USES: Epinephrine is the drug of choice for the treatment of Anaphylaxis . 0.5ml of 1:1000 solution or 0.5 mg IM / SC injection. ( IM route on lateral thigh is preferred because of variability of absorption from SC route.) Locally injected epinephrine causes vasoconstriction & prolongs the action of local anaesthetics. Adrenaline also used in patients with cardiac arrest . (preferred route of administration is intravenous followed by intra-osseous & endotracheal.)

26. 13-Aug-21 26 ADVERSE EFFECTS: CNS disturbances : anxiety, fear, tension, headache and tremors Haemorrhage Cardiac arrhythmias Pulmonary oedema In ophthalmology, a two-percent epinephrine solution may be used topically to reduce intraocular pressure in open angle glaucoma.

27. 13-Aug-21 27 NORADRENALINE / NOREPINEPHRINE An agonist at α1 and β1 receptors, relatively less effect at β2 receptors, causes increase in systolic and diastolic blood pressure & peripheral resistance. USES: Used in the pharmacological treatment of hypotension in patients with distributive shock due to sepsis. Side effect : causes renal vasoconstriction & worsen the renal failure.

28. 13-Aug-21 28 DOPAMINE Endogenous directly acting catecholamine. Does not cross BBB ( no CNS effects) At lower doses (< 2 micro g/kg/min ) it acts on D1 causing renal, coronary & enteric vasodilation, maintains renal perfusion & GFR. At high doses (2-10 micro g/kg/min) of infusion it acts on β1 adrenoceptors causing positive ionotropic effect (increased contractility).

29. 13-Aug-21 29 At even higher doses ( >10 micro g/kg/min ) of infusion it acts on vascular α1 adrenoceptors causing vasoconstriction. USES: Dopamine is used as a drug of choice for cardiogenic shock with oliguric renal failure. Dopamine agonists with central actions are used in the treatment of Parkinson's disease & prolactinemia.

30. 13-Aug-21 30 EXOGENOUS CATECHOLAMINES IBOPAMINE : has similar properties like Dopamine. DOBUTAMINE : relatively selective β1 agonist with no action on DA receptors. It increases cardiac output with little action on receptors. DOPEXAMINE : both β2 and D1 agonistic activity & NA reuptake inhibitory action. FENOLDOPAM : D1 agonist, used in hypertensive emergencies

31. 13-Aug-21 31 NON-CATECHOLAMINES SELECTIVE α AGONISTS α1 agonists α2 agonists Phenylephrine Oxymetazoline Xylometazoline Naphazoline Methoxamine Tetrahydrozoline Midodrine Clonidine Dexmedetomidine Apraclonidine Brimonidine Lofexidine Guanabenz Guanfacine Tizanidine Methyldopa

32. 13-Aug-21 32 SELECTIVE α1 AGONISTS peripheral resistance Maintain or blood pressure May cause sinus bradycardia through activation of reflex vagal responses mediated by baroreceptors. Naphazoline Oxymetazoline Xylometazoline phenylephrine Topically administered α1 agonists used in the symptomatic relief of nasal congestion and ophthalmic hyperaemia. * if used for prolonged periods these can result in Atrophic rhinitis. Phenylephrine: also used intravenously in the treatment of shock. - Also used as mydriatic. Methoxamine &Mephentamine : used to increase BP in hypotensive states like shock. Midodrine is a prodrug (active metabolite is Desglymidodrine) used for treatment of orthostatic hypotension.

33. 13-Aug-21 33 SELECTIVE α2 AGONISTS CLONIDINE : CARDIAC USES Lowers blood pressure Decreases heart rate ... (by supressing sympathetic outflow to the periphery) NON-CARDIAC USES To control diarrhoea in diabetic patients with autonomic neuropathy. Prophylaxis of Migraine. Management of withdrawal symptoms of alcohol, nicotine & opioids. Epidurally, in combination with opioids for relief of pain. For treatment of ADHD Tourette syndrome. ADVERSE EFFECTS: Bradycardia (decreased symp activity & increased vagal activity.) Dry mouth Sedation Postural hypotension

34. 13-Aug-21 34 SELECTIVE α2 AGONISTS Cont ….. 2. α - METHYLDOPA Is a prodrug to α - methylnorepinephrine . α - methyldopa α - methylnorepinephrine Dopamine β -hydroxylase EFFECTS : decreases sympathetic outflow from CNS & lower the BP. Methyldopa is a competitive inhibitor of dopa decarboxylase, which converts dopa to dopamine. USES: used in the treatment of hypertension Preferred antihypertensive drug in pregnancy. ADVERSE EFFECTS: - adverse CNS effects Autoimmuity haemolytic anaemia hepatotoxicity

35. 13-Aug-21 35 SELECTIVE α2 AGONISTS Cont …. 3 . DEXMEDITOMIDINE Central α2 agonist Used for pre anaesthetic medication Indicated for sedation of intubated & mechanically ventilated patients during treatment in ICU. Also used for sedation in surgical patients as it is induced without respiratory depression & it also helps to avoid fluctuations in BP in surgical patients. Also has analgesic properties. Central α2 agonists C lonidine Dexmedetomidine Guanabenz Guanfacine Tizanidine Methyldopa

36. 13-Aug-21 36 Cont …… GUANABENZ & GUANFACINE : Adverse effects similar to that of clonidine TIZANIDINE is used as a muscle relaxant. LOFEXIDINE is a new α2 agonist. Used to decrease opioid withdrawal symptoms APROCLONODINE & BRIMONIDINE : used topically for treatment of glaucoma.

37. 13-Aug-21 37 SELECTIVE β AGONISTS β 1 agonists : PRENALTEROL is the only non-catecholamine beta1 selective agent. used for reversal of beta blockade. β 2 agonists : For bronchial asthma Salbutamol Levalbuterol Betolterol Fenolterol Metaproterenol Terbutaline Pirbuterol Salmeterol Formeterol Carmoterol indacterol As tocolytics Ritodrine isoxsuprine Β 3 agonists : MIRABEGRON acts by stimulating beta3 agonists on urinary bladder. Indicated for treatment of overactive bladder.

38. 13-Aug-21 38 MIXED ACTION SYMPATHOMIMETICS EPHEDRINE : It is a non-catecholamine phenyl isopropyl amine. It has high bioavailability. Relatively long duration of action(hours) Significant fraction of the drug is excreted unchanged in the urine. It is a weak base, so its excretion can be accelerated by acidification of the urine.

39. 13-Aug-21 39 INDIRECTLY ACTING SYMPATHOMIMETICS It can have one of two different mechanisms May enter sympathetic nerve ending & displace stored catecholamine transmitter known as “Amphetamine like” or “Displacers”. May inhibit the reuptake of released transmitter by interfering with the action of the norepinephrine transporter(NET). AMPHETAMINE LIKE Amphetamine : pk similar to ephedrine - enters CNS more readily & has marked stimulant effects on mood & alertness - depressant effect on appetite. Methamphetamine : very similar to Amphetamine Methylphenidate : effective in children with ADHD.

40. 13-Aug-21 40 Modafinil : psychostimulant It inhibits NE & DA transporters, increase synaptic concentration of NE & DA and also serotonin & glutamate. decreases GABA levels. - used to improve wakefulness in narcolepsy. Tyramine : by product of tyrosine metabolism Produced in high concentrations in protein rich foods by decarboxylation of tyrosine during fermentation. Inactive when given orally as it is readily metabolised by MAO in the liver. Patients taking MAO inhibitors should avoid tyramine – containing foods as they land up in hypertensive crisis caused by massive release of NE from nerve endings.

41. 13-Aug-21 41 CATECHOLAMINE REUPTAKE INHIBITORS ATOMOXETINE : used in the treatment of attention deficit disorders REBOXETINE : used mainly for major depressant disorder SIBUTRAMINE : used as an appetite suppressant. DULOXETINE MILNACIPRAN COCAINE : local anaesthetic Treatment of pain in fibromyalgia

42. 13-Aug-21 42 THERAPEUTIC USES OF SYMPATHOMIMETIC DRUGS CARDIOVASCULAR APPLICATIONS Treatment of acute hypotension Causes of Acute hypotension : shock, severe haemorrhage, decreased blood volume, cardiac arrhythmias, neurologic diseases or accidents, overdose of anti-hypertensive drugs and infection. Adrenergic agonists with both alpha and beta activity are preferred. (NE) Nor epinephrine provides an acceptable balance and is considered the vasopressor of first choice.

43. 13-Aug-21 43 B. Chronic Orthostatic Hypotension : Impairment of autonomic reflexes that regulate blood pressure lead to chronic orthostatic hypotension. Causes : drug induced, diabetes, diseases causing peripheral autonomic neuropathies, degenerative disorders of the ANS. Treatment : drugs activating alpha receptors can be used. MIDODRINE, orally active α1 agonist is preferred. Oral Ephedrine or Phenylephrine can also be used. DROXIDOPA, novel treatment approach for orthostatic hypotension (neurogenic), it is a prodrug, converted to norepinephrine by dopa – carboxylase.

44. 13-Aug-21 44 C. Cardiac applications : EPINEPHRINE is used for resuscitation from cardiac arrest. DOBUTAMINE is used as a pharmacologic cardiac stress test. It is used in patients who are unable to exercise during the stress test as it augments myocardial contractility and promotes coronary and systemic vasodilation that leads to increased heart rate. D. Inducing local vasoconstriction : EPINEPHRINE is applied topically in nasal packs for epistaxis or in gingival sting. also used along with local anaesthetics to prolong their duration of action. COCAINE is used for nasopharyngeal surgery ( hemostatic effect with local anaesthesia.

45. 13-Aug-21 45 NON-CARDIOVASCULAR APPLICATIONS OF SYMPATHOMIMETIC DRUGS Pulmonary applications : Most important use is in the therapy of Asthma and COPD Beta selective drugs are used for this like albuterol, metaproterenol, terbutaline. Indacaterol, Olodaterol and Vilanterol, new ultra long beta2 agonists approved for once a day use in COPD by FDA.

46. 13-Aug-21 46 b) Anaphylaxis : Anaphylactic shock and type 1 Ig E mediated reactions affect both RS and CVS. The syndrome of bronchospasm, mucous membrane congestion, angioedema and severe hypotension All these can be treated by parenteral EPINEPHRINE 0.3 to 0.5 mg, IM route is preferred. Epinephrine activates alpha, beta1, & beta2 receptors all of which are important in reversing the pathophysiology of anaphylaxis. Auto injector can be used for self-administration. (Epi pen)

47. 13-Aug-21 47 C) Ophthalmic Applications : Phenylephrine is an effective mydriatic agent , -- also useful as a decongestant for minor allergic hyperaemia and itching of conjunctiva. -- also useful in localizing the lesion in Horner’s syndrome. Alpha2 agonists, Apraclonidine and Brimonidine are topical therapies for Glaucoma.

48. 13-Aug-21 48 E) Genitourinary Applications : Beta2 selective agents TERBUTALINE, RITODRINE,ISOXUPRINE are used as uterine relaxants. Beta3 selective agent, MIRABEGRON is used in the treatment of symptoms of overactive bladder.

49. 13-Aug-21 49 F) Central Nervous System applications: AMPHETAMINE : mood elevating effect & alerting, sleep deferring actions used in the treatment of Narcolepsy. MODAFINIL , a new amphetamine used for Narcolepsy METHYLPHENIDATE, used for ADHD Slow or continuous release preparations of alpha2 agonists CLONIDINE & GUANFACINE are also effective in ADHD. ATOMAXETINE, norepinephrine reuptake inhibitor, sometimes used in ADHD.

50. 13-Aug-21 50 CONCLUSION Adrenergic pharmacology have drugs that act at essentially every step of adrenergic neurotransmission, from synthesis of catecholamines to stimulation of alpha and beta receptors. These drugs are mainstays of therapy for hypertension, angina, heart failure, shock, asthma, pheochromocytoma and other conditions The development of novel, subtype – selective agonists and antagonists may lead to more effective and less toxic therapies.

51. 13-Aug-21 51 REFERENCES David E.Golan , Principles Of Pharmacology, 4 th edition, Adrenergic Pharmacology, Pg No- 151-159. Bertram G. Katzung , basic & Clinical Pharmacology , 14 th edition Adrenoceptor Agonists & Sympathomimetic Drugs , Pg No. 137-155 Rang & Dale’s Pharmacology, 8 th edition, Noradrenergic transmission, pg no 177-192.

52. 13-Aug-21 52