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  1. 1. Dr Shinde Viraj Ashok Jr – 1 Department of Pharmacology Guided by Dr V. M. Motghare Professor & Head of department of Pharmacology
  2. 2.  Introduction Definition Classification Sympathomimetic drugs Therapeutic uses Overview
  3. 3.  Sympathetic “Fight or Flight”
  4. 4.  Parasympathetic “Rest & Maintain” Rest Repair Renew
  5. 5. Sympathetic Parasympathetic Origin Thoracolumbar Craniosacral Distribution Wide 3,7,9,10, s1 -4 Pre ganglionic fibre Short myelinated Long myelinated Post ganglionic Long, non-myelinated Except Adrenal medulla Short, non- myelinated. Except eye Result Diffuse, generalised Localised Neutotransmitter Pregang- Ach Post gang- NA Pregang- Ach Post gang - Ach
  6. 6.
  7. 7.
  8. 8.   Drugs that partially or completely mimic the actions of norepinephrine (NE) or epinephrine (Epi). Definition of Sympathomimetic drugs
  9. 9. SYNTHESIS TYROSINE DOPA DOPAMINE NA ADRENALINE Tyrosine hydroxylase DOPA decarbxylase Dopamine β- hydroxylase N-methyltransferase Phenylalanine Phenylalanine hydroxylase
  10. 10.  Where are the adrenergic receptors? Receptor α1 α2 β1 β2 β3 localization Blood vessels α1B/1D CNS Heart Lungs Adipose tissue Prostatic urethra & eye α1 A Blood vessels Kidney- juxta glomerular cells Uterus GIT GIT Bladder
  11. 11. Adrenergic receptors, Subtypes, agonists and antagonists Receptors Agonists Antagonists α1a Phenylephrine/ Methoxamine Prazosin/terazocine α1b Phenylephrine/Methoxamine Prazosin/terazocine α2a Oxymetazoline/ Clonidine Yohimbine/ Rauwolscine α2b Oxymetazoline/ Clonidine Yohimbine/ Rauwolscine β1 Dobutamine/ Xamoterol Atenolol, acebutolol β2 Terbutaline/ Salbutamol β3 BRL 37344 D1 Fenoldopam D2 Bromocriptine, Lysoride
  12. 12.  Classification  Classification is based on mechanism of action  Direct-acting agonists e.g. epinephrine, norepinephrine.  Indirect-acting agonists e.g. amphetamine, Cocaine.  Mixed-action agonists e.g. Ephedrine, pseudo ephedrine.
  13. 13.  Catecholamines Non catecholamines Sympathomimetic amines having catechol nucleus Devoid of catechol nucleus Not effective orally Effective orally Easily metabolised by monoamine oxidase Relatively resistant to monoamine oxidase enzyme Action quick compared to non catecholamines Action prolonged as compared to catecholamines Doesn’t readily crossess BBB Easily crossess BBB No significant CNS effects Have significant CNS effects Act directly on receptors Act indirectly as well as directly Eg – epinephrine , nor - epinephrine Eg – amphetamine , ephedrine Classification
  14. 14.   Epinephrine interacts with both α and ß receptors.  At low doses – β2 effects (vasodilation) on the vascular system predominate,  At high doses – α1 effects (vasoconstriction) are strongest.  Actions 1. Cardiovascular – Strengthens the contractility of the myocardium (positive inotropic: β 1 action) and increases its rate of contraction (positive chronotropic: β 1 action) . Activates β 1receptors on the kidney to cause renin release. Constricts arterioles in the skin, mucous membranes, and viscera (α1 effects), and it dilates vessels going to the liver and skeletal muscle (β 2 effects). Cumulative effect is an increase in systolic blood pressure & slight decrease in diastolic pressure. Direct acting adrenergic agonist
  15. 15.  Intravenous injection of adrenaline normally causes increase in blood pressure (α1 effect) followed by prolonged fall (β 2 effect). If it is administered after giving α blockers, only fall in blood pressure is seen. This phenomenon is called as Dales vasomotor reversal. Dales vasomotor reversal phenomenon
  16. 16.  2. Respiratory - powerful bronchodilation by acting directly on bronchial smooth muscle (ß 2 action). 3. Hyperglycemia - significant hyperglycemic effect because of - increased glycogenolysis in the liver (β 2 effect), - increased release of glucagon (β 2 effect), and - decreased release of insulin (α 2 effect). 4. Lipolysis – agonist activity on the β 3 receptors of adipose tissue.
  17. 17.   Epinephrine - rapid onset - brief duration of action (due to rapid degradation).  Oral administration is ineffective, because epinephrine and the other catecholamines are inactivated by intestinal enzymes.  Only the metabolites are excreted in urine. Pharmacokinetics:
  18. 18.  Anaphylactic shock :  Intramuscular – 1: 1000  Subcutaneous – 1: 1000  Intravenous - 1:10000  Epinephrine is the drug of choice for the treatment of Type I hypersensitivity reactions in response to allergens.  Bronchospasm :  Epinephrine relieves brochospasm .  Cardiac arrest :  Epinephrine may be used to restore cardiac rhythm in patients with cardiac arrest like drowning & electrocution. Therapeutic uses
  19. 19.   With local Anaesthetics : Local anesthetic solutions - contain 1:100,000parts epinephrine - to greatly increase the duration of the local anesthesia.  To control epistaxis : Very weak solution (1:100,000) - used topically to vasoconstrict mucous membranes to control oozing of capillary blood.
  20. 20.  a. CNS disturbances: - anxiety, fear, tension, headache, and tremor. b. Hemorrhage : - cerebral hemorrhage - marked elevation of blood pressure. c. Cardiac arrhythmias: - trigger cardiac arrhythmias , particularly if the patient is receiving digoxin. d. Pulmonary oedema: - can induce pulmonary oedema. Adverse effects:
  21. 21. a. Hyperthyroidism :  Epinephrine - enhanced cardiovascular actions in hyperthyroidism {dose of epinephrine must be reduced}.  Increased production/up regulation of α receptors on the vasculature & β receptors in heart of the hyperthyroid individual - leading hypersensitive response. b. Diabetes :  Epinephrine increases the release of endogenous stores of glucose. In the diabetic, dosages of insulin may have to be increased. Contraindications :
  22. 22.  a. Cocaine: Cocaine + epinephrine exaggerated cardiovascular actions, because cocaine prevents reuptake of catecholamines into the adrenergic neuron b. β - Blockers: Prevent epinephrine effects on β receptors, leaving a receptor stimulation unopposed increase in peripheral resistance and an increase in blood pressure. c. Inhalation anaesthetics: Halothane like agents sensitize the heart to the effects of epinephrine, which may lead to tachycardia. Interactions:
  23. 23.   Agonist at α1, α 2 and β 1 receptors with similar potency as epinephrine, but has relatively little effect on β 2 receptors.  Increases peripheral resistance 𝜶 𝟏 and both diastolic and systolic blood pressure β1.  Compensatory baroreflex activation tends to overcome the direct positive chronotropic effects of norepinephrine; however, the positive inotropic effects on the heart are maintained. Nor Epinephrine/Nor Adrenaline
  24. 24.   Therapeutic uses - carefully used to treat cardiogenic shock but dopamine is preferred as nor epinephrine is associated with renal shutdown.  Adverse effects –  Excessive doses can cause severe hypertension.  Not suitable for sc ,im or undiluted iv injection – danger of necrosis
  25. 25.   A substance that is released when axon terminal of a presynaptic neuron is excited & acts by exciting or inhibiting a target cell.( E.g nor epinephrine , acetyl choline or dopamine) Definition of neurotransmitters
  26. 26.  Criteria for Neurotransmitters  Substance must be synthesized in the neuron  Enzymes and substrates for synthesis must be present in it  Substance must be present in the neuron.  Calcium dependant release  Exogenous synthetic neurotransmitter must mimic the actions of true transmitter.  There must be a mechanism for rapid termination of action.
  27. 27.  The Seven Steps in Neurotransmission 1) Synthesis 2) Storage 3) Release 4) Receptor interaction 5) Inactivation 6) Reuptake 7) Degradation
  28. 28.   Immediate precursor of norepinephrine & epinephrine  Endogenous dopamine may have more important effects in regulating sodium excretion and renal function.  Features distinguishing from norepinehrine & epinephrine  2-5 µg/kg /min – D1 receptors – renal vasodilation  5-10 µg/kg /min – β1 receptors - ↑ cardiac output  >10 µg/kg /min –α 1 receptors – vasoconstriction Dopamine
  29. 29.  Its deficiency in the basal ganglia leads to Parkinson's disease, which is treated with its precursor levodopa.  Dopamine antagonists are antipsychotic drugs.  Therapeutic uses – used in conditions with low cardiac output with compromised renal function  Iv infusion regulated by monitoring of BP & rate of urine formation. Dopamine contd..
  30. 30.   Very potent β 1 & β 2 – receptor agonist and has negligible effect on α receptors.  Positive chronotropic and inotropic actions (β 1) .  Activates β receptors almost exclusively, it is a potent vasodilator.  These actions lead to marked increase in cardiac output and fall in diastolic and mean arterial pressure and lesser decrease or a slight increase in systolic pressure.  Therapeutic uses – may be used in complete heart block to maintain sufficient idioventricular rate till external pacemaker can be implanted. Isoproterenol/Isoprenaline
  31. 31.  It resembles dopamine, but its actions are mediated by activation of α and β receptors.  Dobutamine is a racemic mixture of (levo) and (dextro) isomers.  The dextro isomer is a potent β 1 agonist and an α 1 receptor antagonist.  The levo isomer is a potent α 1 agonist  The resultant effects of dobutamine is β 1 stimulation.  Dobutamine has a positive inotropic action caused by the isomer with predominantly β1 receptor activity. It has relatively greater inotropic than chronotropic effect compared with isoproterenol.  Therapeutic uses – patients of heart failure associated with myocardial infarction , cardiac surgery & for short term management of acute congestive heart failure . Dobutamine
  32. 32.   D1-receptor agonist - selectively leads to peripheral vasodilation  Oral bioavailability poor hence given by IV route.  Primary indication for fenoldopam is in the IV treatment of short term management of severe hypertension in pateints with renal impairement. Fenoldopam
  33. 33. Direct-Acting Sympathomimetics  Phenylephrine  Selective α 1 agonist.  Not a catechol derivative - not inactivated by COMT and has a longer duration of action than the catecholamines.  It is an effective mydriatic and nasal decongestant.  Methoxamine  A direct-acting α 1 receptor agonist.  Causes a prolonged increase in BP due to vasoconstriction & a vagally mediated bradycardia.  Clinical uses are rare and limited to hypotensive states.  Naphazoline & xylometazoline  Nasal decongestants in rhinorrhoea & to check epistaxis Non catecholamines α1 agonist drugs
  34. 34.  Oxymetazoline  Direct-acting α 1 agonists.  Used as topical decongestants because of promoting constriction of the nasal mucosa.  When taken in large doses, oxymetazoline may cause hypotension, presumably because of a central clonidine -like effect  Oxymetazoline has significant affinity for α 2A receptors.
  35. 35.  Midodrine  A prodrug that is enzymatically hydrolyzed to desglymidodrine, a selective α 1-receptor agonist.  Primary indication for midodrine is the treatment of orthostatic hypotension, due to impaired autonomic nervous system function.  Although the drug has efficacy in diminishing the fall of blood pressure when the patient is standing, it may cause hypertension when the subject is supine.
  36. 36.  Clonidine -  Antihypertensive effect  Stimulates α 2A receptors at vasomotor centre – central sympathetic outflow reduced – fall in BP & HR.  I 1 Imidazoline receptors in brain to which clonidine binds- activates G coupled receptor – modulates central α 2 receptor activity.  Activates α 2B receptors present on sympathetic post ganglionic neurons α 2 agonists
  37. 37.   Therapeutic uses  Moderate hypertension  To control diarrhoea in diabetic patients with autonomic neuropathy  In prophylaxis of migraine  Menopausal hot flushes  Adverse effects  Rebound hypertension-  Sudden removal of central sympathetic inhibition results in release of large quantities of stored catecholamines  Due to super sensitivity of newly formed α 2 receptors  Dry mouth  Sedation Clonidine contd..
  38. 38.  Therapeutic window phenomenon –  Rapid i.v. Injection – raises BP – due to activation of peripheral α 2B receptors  Oral doses – fall in BP – clonidine has lower intrinsic activity on α 2B receptors Clonidine contd..
  39. 39.   Clonidine, methyldopa, guanfacine are useful in the treatment of hypertension  Dexmedetomidine  Centrally acting α 2A-selective agonist that is indicated for sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting.  It also reduces the requirements for opioids in pain control.  Analgesia & sedation are produced with little respiratory depression , amnesia or anaesthesia α 2 selective agonists
  40. 40.  Salbutamol, terbutaline 1. Selective β2 agonist smooth muscle relaxation of bronchi & uterus 2. Important in the treatment of asthma. Salmeterol & formoterol 1. Selective β2 agonist – longer duration of action (12hrs) 2. Formoterol has quicker onset of action while salmeterol has slow onset of action 3. Formoterol is used to prevent attacks of nocturnal asthma prophylaxis of exercise induced bronchospasm & COPD Ritodrine may cause uterine relaxation in premature labor. Beta2-selective agents
  41. 41.
  42. 42.   BRL -37344 & AD- 9677  β 3 receptors might prove potential target for new antiobesity drugs.  Main problem – short lived transient action. β 3 agonists
  43. 43.   First, they may enter the sympathetic nerve ending and displace stored catecholamine transmitter. Such drugs have been called amphetamine-like or displacers.  Second, they may inhibit the reuptake of released transmitter by interfering with the action of the NE transporter, NET. Indirect-Acting Sympathomimetics
  44. 44.   Racemic mixture is important because of its use and misuse as a CNS stimulant  Readily enters the CNS, where it has marked stimulant effects on mood and alertness and a depressant effect on appetite.  Its D-isomer is more potent than the L-isomer. Amphetamine's actions are mediated through the release of NE and, to some extent, dopamine.  Performance of simple mental tasks improved but number of errors increased due to over confidence. Amphetamine
  45. 45.   Drug of abuse & is capable of psychological dependence but little or no physical dependence  Therapeutic uses –  Narcolepsy  Attention deficit hyperactive disorder  Treatment of toxicity – acidification of urine . Amphetamine contd..
  46. 46.   Methamphetamine Very similar to amphetamine with an even higher ratio of central to peripheral actions.  Methylphenidate Amphetamine variant whose major pharmacologic effects and abuse potential are similar to those of amphetamine. More effective than amphetamine in treating narcolepsy & attention deficit hyperactivity disorder.
  47. 47.   Psychostimulant.  Inhibits both NE and DA transporters.  Therapeutic uses -  Improve wakefulness in narcolepsy.  In shift workers.  To relieve fatigue in multiple sclerosis  Adjunct in obstructive sleep apnea.  Associated with increase in BP and heart rate, usually mild. Modafinil
  48. 48.   High concentrations in some fermented foods -cheese.  Readily metabolized by MAO in the liver and is normally inactive when taken orally because of a very high first- pass effect  If administered parenterally, it has an indirect sympathomimetic action caused by the release of stored catecholamines.  In patients treated with MAO inhibitors , tyramine may cause marked increases in blood pressure(cheese reaction).  Patients taking MAO inhibitors must be very careful to avoid tyramine -containing foods Tyramine
  49. 49.  Mixed-Acting Sympathomimetics Ephedrine  The plant Ephedra vulgaris, has been used in traditional Chinese medicine for 2,000 years for the treatment of asthma and hay fever, as well as for the common cold  Ephedrine is a noncatechol ,it has high bioavailability and a relatively long duration.  It releases NE and activates β2 receptors directly.  Crossess BBB, it is a powerful stimulant.  Nowadays only used to treat hypotension with spinal anaesthesia  Repeated dosing - tachyphylaxis
  50. 50.  Pseudoephedrine  One of four ephedrine enantiomers.  Available over the counter as a component of many decongestant mixtures. Mephenteramine  Use restricted to maintain blood pressure in hypotensive states.  Adverse effects – hallucinations ,convulsions.
  51. 51.  Phenylpropanolamine  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.  The mechanism of this potential adverse effect is unknown.
  52. 52.  Anorectic agents  Fenfluramine & dexfenfluramine – Reduce food seeking behaviour – enhancing serotonergic transmission in hypothalamus. Tolerance to anorectic action develops in 2 – 3months. U S – FDA has recommended discontinuation.  Sibutramine & R – sibutramine – Inhibit both NA & 5HT reuptake in hypothalamus. These drugs are banned in India & USA.
  53. 53.  Cardiovascular Applications  Treatment of Acute Hypotension Used in hypotensive emergency to preserve cerebral and coronary blood flow.  The treatment is usually of short duration while the appropriate intravenous fluid or blood is being administered.  Direct-acting agonists such as NE, phenylephrine, and methoxamine have been used when vasoconstriction is desired. Therapeutic Uses of Sympathomimetics
  54. 54. Cardiogenic shock and acute heart failure Usually due to massive myocardial infarction.  Positive inotropic agents such as dopamine or dobutamine may provide short-term relief of heart failure symptoms in patients with advanced ventricular dysfunction.  In low to moderate doses, these drugs may increase cardiac output and cause relatively little peripheral vasoconstriction.
  55. 55.  Chronic Orthostatic Hypotension.  Impairment of autonomic reflexes that regulate BP can lead to chronic orthostatic hypotension.  Due to medications that can interfere with autonomic function, diabetes and other diseases causing peripheral autonomic neuropathies.  Midodrine  Orally active α 1 agonist - used for this indication.  Other sympathomimetics, such as oral ephedrine or phenylephrine, can be tried.  Cardiac Applications  Isoproterenol and epinephrine have been used in the temporary emergency management of complete heart block and cardiac arrest.  Dobutamine injection is used as pharmacologic cardiac stress test
  56. 56. Pulmonary Applications  One of the most important uses of sympathomimetic drugs is in the therapy of bronchial asthma.  β 2-selective agents: Albuterol (Salbutamol), bambuterol, metaproterenol, terbutaline .
  57. 57. Anaphylaxis  The syndrome of bronchospasm, mucous membrane congestion, angioedema, and severe hypotension usually responds rapidly to the parenteral administration of epinephrine. Epinephrine is effective because: 1) β1 increases cardiac output. 2) β2 relaxes constricted bronchioles. 3) α1 constricts capillaries  Glucocorticoids and antihistamines may be useful as secondary therapy in anaphylaxis; however, epinephrine is the initial treatment.
  58. 58. Ophthalmic Applications  Phenylephrine is an effective mydriatic agent used to facilitate examination of the retina. It is also a useful decongestant for minor allergic hyperemia and itching of the conjunctival membranes.  Glaucoma responds to a variety of sympathomimetic and sympathoplegic drugs.  Epinephrine is now rarely used, but β -blocking agents are among the most important therapies.  Apraclonidine & brimonidine Alpha 2-selective agonist that also lower intraocular pressure is used in glaucoma. The mechanism of action of these drugs in treating glaucoma is still uncertain.
  59. 59. Genitourinary Applications  β 2 selective agents relax the pregnant uterus. Ritodrine, terbutaline, and similar drugs have been used to suppress premature labor.  Oral sympathomimetic therapy is occassionally useful in the treatment of stress incontinence (loss of small amounts of urine associated with coughing, laughing, sneezing, exercising or other movements that increase intra-abdominal pressure and thus increase pressure on the bladder. ) Ephedrine or pseudoephedrine may be tried.
  60. 60. CNS Applications  Treatment of narcolepsy.  Modafinil A new amphetamine substitute, is claimed to have fewer disadvantages (excessive mood changes, insomnia and abuse potential) than amphetamine in this condition.  Attention-deficit hyperactivity disorder (ADHD) Some patients respond well to low doses of methylphenidate and related agents or to clonidine. Modafinil may also be useful in ADHD.
  61. 61.   Sympathomimetic class of drugs is a very important class of drugs because of its use in so many important conditions like Cardiogenic shock Anaphylactic shock Hypotension Hypertension Congestive heart failure Bronchial asthma Nasal decongestion Narcolepsy Attention deficit / hyperactivity disorder Summary
  62. 62.   Basic & clinical pharmacology 12th edition  “ The pharmacological basis of therapeutics” Goodman and Gilman( 12th edition )  “Principles of pharmacology” S. K. Sharma, (2nd edition) References
  63. 63.
  64. 64. “selective” ≈ 50-100 fold
  65. 65.  Cocaine  Mechanism:  Central: block DAT, NET & SERT  Peripheral: αβ agonist  Schedule II (nasal surgery) Erythroxylon coca powder crack
  66. 66. Goodman & Gilman (2011). Pharmacological Basis of Therapeutics. p. 304.
  67. 67.   Responses mediated by – adrenoceptors are not constantly same.  Desensitisation –  Continued receptor stimulation – desensitisation of receptors – receptor becomes less sensitive to agonist.  Of β receptors occurs – due to phosphorylation of its serine residue by beta adrenergic receptor kinase enzyme Receptor regulation
  68. 68.  Down regulation Upregulation Pronlonged exposure to high concentration of agonist reduction in number of receptors for activation Prolonged exposure to high concentration of antagonist increase in number of receptors & their sensitivity Due to endocytosis or internalisation of receptors Due to externalisation of receptors Commonly seen with tyrosine protein kinase receptors Extreme form of upregulation – super sensitivity of receptor as well as organ Both upregulation & down regulation process takes several days
  69. 69.  Directly acting Endogenous catecholamines Epinehrine Nor epinephrine Dopamine Synthetic catecholamines Isoprenaline Dobutamine Fenoldopam
  70. 70.
  71. 71.
  72. 72.
  73. 73.