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  1. SYMPATHOMIMETICS – Dr Kalyani R Department of Periodontology KVG Dental college & Hospital
  2. Sympathetic “Fight or Flight
  3. Parasympathetic “Rest & Maintain”
  4. Definition of Sympathomimetic drugs – Drugs that partially or completely mimic the actions of epinephrine (Epi) or norepinephrine (NE) – They produce effects similar to the effects of sympathetic nerve fibers.
  5. Classification
  6. Synthesis of catecholamines
  7. Storage of catecholamines NA is stored in the synaptic vesicles or ‘granules’ within the adrenergic nerve terminal. The granular membrane actively takes up the Dopamine from the cytoplasm. The final step of synthesis of NA takes place inside the granule that contains dopamine β- hydroxylase. NA is stored as a complex with ATP absorbed onto protein chromogranin. In the adrenal medulla the NA thus forms will diffuse out into the cytoplasm and gets methylated to form the Adr.
  8. Release of catecholamines – The release of CA takes place by exocytosis. – the granular contents: NA or Adr, ATP, Dopamine β- hydroxylase, chromogranin are all poured out. – The release is modulated by the presynaptic receptors. – Indirectly acting sympathomimetic amines also induce release of NA but this is not exocytotic and does not require Ca ions.
  9. Uptake of catecholamines – Uptake of CAs takes place by 2 steps: 1. Axonal uptake: an active amine pump is present at the the neuronal membrane which transport the NA at a higher rate than Adr. This uptake is most important mechanism for terminating the postjunctional action of NA. This inhibited by cocaine, desipramine and many H1 antihistamines.
  10. 2. Granular uptake : The membrane of intracellular granules has another amine pump that transports CAs from the cytoplasm to within the granule. The granular NA that is constantly leaking into the cytoplasm is captured by this mechanism. 3. An extraneuronal uptake of CAs also occurs in other tissue cells.
  11. Metabolism of catecholamines Part of the NA leaking out of the granules into cytoplasm and those taken up by the axonal transport is first attacked by Monoamine Oxidase (MAO) enzyme.. The part that diffuses into the circulation is first acted upon by catechol-o-methyl transferase(COMT) enzyme in liver and other tissues. The other enzymes subsequently produces vanillylmandelic acid(VMA). The major metabolites are excreted in urine. These metabolites are mostly conjugated with glucuronic acid or sulfate before excretion in urine.
  12. Adrenergic receptors They are membrane bound G-protein coupled receptors . function primarily by increasing or decreasing the intra cellular production of second messengers cAMP/DAG. On the basis of 2 different potencies of adrenergic agonist, adrenergic receptors are classifies into 2 types: α adrenergic receptor β adrenergic receptor • α 1(α1a, α1b, α1d) • α2(α2a, α2b, α2c) • β1 and β2 • β3( recently)
  13. Where are the adrenergic receptors?
  14. CLASSIFICATION BASED ON MECHANISM OF ACTION Direct-acting agonists : They act directly as agonist on α/ β adrenoceptors. • Epinephrine/ adrenaline • Norepinephrine • Dopamine • Dobutamine • Fenoldopam α1 agonist • Phenylephrine • Methoxamine • Naphazoline • Oxymetazoline • Midodrine
  15. α2 agonist • Clonidine α2 selective agonist • Methyldopa • Dexmedatomidine β2 selective agonist • Salbutamol • Salmeterol • Ritodrine
  16. Indirect-acting agonists: They act on adrenergic neurons to release NA which then acts on adrenoceptors • Amphetamine • Cocaine • Tyramine  Mixed-action agonists: They act directly as well as indirectly. • Ephedrine • Pseudo ephedrine • Amphetamine • Mephentermine
  17. Pharmacokinetis CAs are absorbed from the intestine but are rapidly degraded by the Monoamine Oxidase (MAO) enzyme. and COMT present in the intestinal wall and liver. Thus oral use is inactive. 1. Adrenaline/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.  Mode of administration: 0.2-0.5mg SC, IM 0.5% by aerosol action last for upto ½ to 2 hrs.
  18. 2. Noradrenaline: 2-4µg/ min IV infusion. local tissue necrosis occurs if the solution extravasates. Rarely used now as a pressor agent. 3. Isoprenaline: 20 mg sublingual, 1-2 mg IM 5-10 µg/min IV Infusion Action lasts 1-3hrs.
  19. Actions of Epinephrine, Nor epinephrine and Dopamine
  20. Epinephrine/ Adrenaline  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 and increases its rate of contraction. – 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.
  21. Dales vasomotor reversal phenomenon 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.
  22. 2. Respiratory – causes 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 – it has agonist activity on the β 3 receptors of adipose tissue
  23. Therapeutic uses 1. Anaphylactic shock :  Epinephrine is the drug of choice for the treatment of Type I hypersensitivity reactions in response to allergens. 2. Relieves Bronchospasm : 3. Cardiac arrest :  Epinephrine may be used to restore cardiac rhythm in patients with cardiac arrest like drowning & electrocution. 4. with local Anesthetics :  Local anesthetic solutions - contain 1:100,000 parts epinephrine - to increase the duration action of the local anesthesia. 5. To control epistaxis :  Very weak solution (1:100,000) - used topically to vasoconstrict the mucous membranes to control oozing of capillary blood.
  24. Adverse effects: a. CNS disturbances: - anxiety, fear, tension, headache, and tremor. b. Haemorrhage : - cerebral haemorrhage - 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.
  25. Contraindications : 1. Hyperthyroidism :  Epinephrine – enhances the 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 to hypersensitive response. 2. Diabetes :  Epinephrine increases the release of endogenous stores of glucose.  In the diabetic, dosages of insulin may have to be increased.
  26. Interactions: a. Cocaine:  Cocaine + epinephrine exaggerated cardiovascular actions 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
  27. Nor Epinephrine/Nor Adrenaline  They are agonist at α1, α 2 and β 1 receptors with similar potency as epinephrine, but has relatively little effect on β 2 receptors. 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 subcutaneous, intra muscular or undiluted iv injection – danger of necrosis
  28. Dopamine Definition of neurotransmitters – 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)
  29. Dopamine Immediate precursor of nor-epinephrine & epinephrine Endogenous dopamine may have more important effects in regulating sodium excretion and renal function. Features distinguishing from nor-epinephrine & 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
  30. 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.
  31. Therapeutic classification of drugs I. Pressor agents • Noradrenaline Phenylephrine • Ephedrine Amphetamine • Dopamine Mephentermine • Methoxamine II. Cardiac stimulants • Adrenaline Dobuatmine • Isoprenaline III.Bronchodilators • Adrenaline Terbutaline • Isoprenaline Salmeterol • Salbutamol Formoterol
  32. IV. Nasal decongestants • Phenylephrine • Naphazoline • Xylometazoline • Pseudoephirine • Oxymetazoline • Phenyl propanolamine V. CNS stimulants • Amphetamine • Methamphetamine • Dexamphetamine VI. Anorectics • Fenfluramine • Sibutramine • Dexfenfluramine VII.Uterine relaxants and vasodilators • Ritodrine • Salbutamol • Isoxsuprine • Terbutaline
  33. Pressor agents 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 non-catechol ,it has high bioavailability and a relatively long duration of action.  It releases NE and activates β2 receptors directly.  Crosses BBB, it is a powerful stimulant.  Nowadays its use is restricted only to treat hypotension with spinal anesthesia and mild chronic bronchial asthma.  Repeated dosing - tachyphylaxis
  34. Phenylephrine  Selective α 1 agonist.  It raises BP by causing vasoconstriction.  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
  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. CNS Stimulant Amphetamine Synthetic compounds having same pharmacological profile as ephedrine. 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 The CNS effect include alertness, increased concentration and attention span, euphoria, talkativeness, increased capacity to work.
  37. Performance of simple mental tasks are improved but number of errors increased due to over confidence Athletic performance is improved temporarily followed by deterioration. It is one of the drugs included in the ‘dope-test’ for athletes. Depressant effect on appetite as a result of inhibition of hypothalamic feeding center. Drug of abuse & is capable of psychological dependence but little or no physical dependence. High doses produce: euphoria, hallucinations, acute psychotic state. Toxicity includes: vasomotor effects, palpitations, arrhythmias, vomiting, abdominal cramps and vascular collapse. Death is precede by convulsion and coma.
  38. Therapeutic uses: – Narcolepsy – Attention deficit hyperactive disorder – Weak anticonvulsant, analgesic and antiemetic action – 5-15mg oral. Treatment of toxicity: – acidification of urine – Administration of chlorpromazine.
  39. Methamphetamine – Very similar to amphetamine with an even higher ratio of central to peripheral actions. – Dosage: 5-10mg orally 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.
  40. Modafinil  Psychostimulant.  Inhibits both NE and DA transporters. Therapeutic uses: 1. Improve wakefulness in narcolepsy. 2. In shift workers. 3. To relieve fatigue in multiple sclerosis 4. Adjunct in obstructive sleep apnoea. Associated with increase in BP and heart rate, usually mild.
  41. Cardiac stimulant Dobutamine  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 inotropicaction caused by the isomer with predominantly β1 receptor activity.  It has relatively greater inotropic than chronotropic effect. Therapeutic uses: Patients of heart failure associated with myocardial infarction , cardiac surgery & for short term management of acute congestive heart failure.
  42. Mephentermine  Produces both cardiac stimulation and vasoconstriction by directly activating α and β adrenergic receptors.  Cardiac pressure, systolic and diastolic BP are increased.  Active orally for longer duration of time: 2-6hrs.  Crosses BBB and may produce excitatory effect at high doses.  Use restricted to prevent and treat hypotension due to spinal anaesthesia and surgical procedures, shock in myocardial infarctions and other hypotensive states. Adverse effects – hallucinations ,convulsions
  43. Clonidine Antihypertensive effect  Stimulates α 2A receptors at vasomotor centre – central sympathetic outflow reduced – fall in BP & HR. Therapeutic uses:  Moderate hypertension  To control diarrhoea in diabetic patients with autonomic neuropathy  In prophylaxis of migraine  Menopausal hot flushes Adverse effects:  Rebound hypertension  Dry mouth  Sedation
  44. Bronchodilators Salbutamol, terbutaline 1. Selective β2 agonist that causes 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 comparing to salmeterol 3. Formoterol is used to prevent attacks of nocturnal asthma and prophylaxis of exercise induced bronchospasm & COPD
  45. Nasal decongestants Naphazoline & xylometazoline  Nasal decongestants in rhinorrhoea& to check epistaxis Oxymetazoline  Direct-acting α 1 agonists.  Used as topical decongestants because of promoting the 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.
  46. Phenylpropanolamine  Was a common component in appetite suppressants.  It was removed from the market because its use was associated with hemorrhagic strokes in young women. Pseudoephedrine  One of four ephedrine enantiomers.  Available as a component of many decongestant mixtures.
  47. 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 its discontinuation. Sibutramine & R – sibutramine  Inhibit NA reuptake in hypothalamus.  These drugs are banned in India & USA.
  48. Vasodilator Tyramine High concentrations in some fermented foods -cheese. Readily metabolized 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
  49. Uterine relaxant Ritodrine – may cause uterine relaxation in premature labour.
  50. Therapeutic Uses of Sympathomimetics 1. Cardiovascular Applications a. 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.
  51. b. With local Anesthetics :  Local anesthetic solutions - contain 1:100,000parts epinephrine - to increase the duration of the local anesthesia and systemic toxicity of LA is reduced. c. Nasal decongestant:  In colds, rhinitis, sinusitis, blocked Eustachian tube – used as nasal drops.  Shrinkage of mucosa provides relief, but atrophy of mucosa on prolonged use is seen.  Pseudoephedrine, phenylephrine and phenylpropanolamine is used orally.
  52. d. Peripheral vascular diseases: Vasodilators including Isoxsuprine is used in treatment of • Reynaud’s phenomenon • diabetic vascular insufficiency • Gangrene • frost bite • ischemic ulcers • night leg cramps • cerebral vascular inadequacy
  53. 2. Cardiac uses a. Cardiac arrest In case of drowning and electrocution Adr may be administered to stimulate heart. b. Stokes- Adams syndrome It is cardiac arrest occurring at the the transition of partial to complete heart block. Use of Adr is secondary to mechanical and electrical measures.
  54. c. Partial or complete A_V block May be used as a temporary measures to maintain sufficient ventricular rate. d. congestive heart failure Adrenergic inotropic drugs are not useful in routine treatment of CHF. Controlled IV infusion of Dobutamine can tide over acute cardiac decompression during myocardial infarction and cardiac surgery.
  55. epinephrine have been used in the temporary emergency management of complete heart block and cardiac arrest. Dobutamine injection is used in pharmacologic cardiac stress test
  56. 3. 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 terbutaline .
  57. 4. 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. 5. 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.
  59. 6. 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 occasionally 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. 7. CNS Applications a. 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. b. Attention-deficit hyperactivity disorder (ADHD)  Used to calm down hyperkinetic children.  this disorder is the mildest grade of metal retardation or a reduction in the ability to concentrate.  Amphetamines increases the attention span and thus help improve behavior.  Growth retardation may occur due to reduced appetite.
  61. c. Epilepsy Amphetamines are occasionally used as adjuvants to counteract sedation caused by antiepileptic. d. Parkinsonism Amphetamines improves mood and reduced rigidity of muscles. e. Obesity  The anorectic drugs can help obese people to tolerate a reducing diet for short periods.  Their use is considered in severe obesity, not for cosmetic reasons.  Most of the subjects tends to regain weight once the slimming regimen is over.  Fenfluramine and dexfenfluramine have been withdrawn in many countries due to the side effects.  Currently Sibutramine is being used.
  62. DENTAL APPLICATION OF ADRENALINE Adrenaline is used as the vasoconstrictor in Local Anesthetic solution.. Local anaesthetics cause dilatation of blood vessels. The addition of a vasoconstrictor such as adrenaline/epinephrine diminishes local blood flow, slowing the rate of absorption and thereby prolonging the anaesthetic effect. Mode of Action - Attach to and directly stimulate adrenergic receptors . Act indirectly by provoking the release of endogenous catecholamine from intraneuronal storage sites.
  63. Concentrations of Vasoconstrictor in Local Anesthetics - 1:50,000 ,1:100,000, 1:200,000 - 0.020mg/ml ,0.010mg/ml, 0.005 mg/ml  Max dose of vasoconstrictors in a healthy patient is approximately 0.2mg  Patient with significant cardiovascular history: 0.04mg  In dental surgery, in which small volumes are injected, concentrations of 12.5 micrograms/ml (1:80 000) are commonly used. PRECAUTIONS  Local anesthetic Solutions containing epinephrine should be used with particular caution in patients with hypertension, atherosclerotic heart disease, cerebral vascular insufficiency, heart block, thyrotoxicosis or diabetes since severe and sustained variations in blood pressure may occur.
  64. Summary – Sympathomimetic are class of drugs that partially or completely mimic the actions of epinephrine (Epi) or norepinephrine (NE) – They produce effects similar to the effects of sympathetic nerve fibers. They are the catecholamines or non catecholamines. Adrenergic receptors are membrane bound G-protein coupled receptors . function primarily by increasing or decreasing the intra cellular production of second messengers cAMP/DAG. On the basis of 2 different potencies of adrenergic agonist, adrenergic receptors are classifies into 2 types: Sympathomimetic are classifies based on their mechanism of action and therapeutic effects.
  65. Sympathomimetic have effects on Cardiovascular system, CNS, respiratory system, ophthalmic application, genitourinary system. The therapeutic effects of sympathomimetic are in the treatment of: – Cardiogenic shock – Anaphylactic shock – Hypotension – Hypertension – Congestive heart failure – Bronchial asthma – Nasal decongestion – Narcolepsy – Attention deficit / hyperactivity disorder
  66. References – KD Tripathi 7th Edition Essentials Of Medical Pharmacology – Basic & clinical pharmacology 12th edition – Goodman & Gilman (2011). Pharmacological Basis of Therapeutics