Sympathomimetics and blockers

Sympathomimetics and blockers

• 1.
  SYMPATHOMIMETIC AGENTS Adrenergic agents 1PATKI
• 2.
  AT THE ENDOF THE SESSION, STUDENT WILL BE ABLE TO  Define Sympathomimetic amines with examples.  Classify sympathomimetic amines  Enumerate four pharmacological actions of Adrenaline and four indications.  Describe pharmacological actions of Noradrenalin, Dopamine ,  Enumerate alpha 2, Beta 1 and beta 2 agonists with their pharmacological actions.  Explain the role of Nasal decongestants and anorectic agents. 2PATKI
• 3.
  NERVOUS SYSTEM CENTRALNERVOUS SYSTEMPERIPHERALNERVOUS SYSTEM AUTONOMIC NERVOUS SYSTEM SOMATIC NERVOUS SYSTEM SYMPATHETIC SYSTEM PARASYMPATHETIC SYSTEM 3PATKI
• 4.
  T1- L3 Prevertebral Paravertebral Terminal ganglia Adrenalmedulla 4PATKI
• 5.
  SYMPATHETIC NERVOUS SYSTEM 5PATKI
• 6.
  ADRENERGIC NEUROTRANSMISSION 6PATKI
• 7.
  The Adrenergic neurotransmittersare:  Nor adrenaline ( Nor epinephrine)  Dopamine ( CNS)  Adrenaline 7PATKI
• 8.
  Adrenergic neurotransmission  Synthesis Storage  Release  Reuptake  Metabolism  Adrenergic receptors- Types, actions 8PATKI
• 9.
  Mechanism: Norepinephrine Release andRecycling
• 10.
  MAO uptake2COMT VT NET Phenylalanine 10PATKI
• 11.
  ADRENERGIC RECEPTORS β α1 α Α2 PRESENAPTIC β3 Β1HEART Β2 SMOOTH MUSCLES 11PATKI
• 12.
  Adrenoceptors  Beta receptors b1: Heart Juxtaglomarular apparatus b2 : Smooth muscles b3 : Adipose tissue 12PATKI
• 13.
  Dopamine receptors  D1,D2, Peripheral D1– dilates renal blood vessel D2- modulate transmitter release 13PATKI
• 14.
  Adrenaline acts onalpha1, alpha2, beta1, beta2 and beta3 receptors.  Hormone  Catecholamine  As a Neurotransmitter?  Topical haemostatic 14PATKI
• 15.
  SYMPATHOMIMETICS CLASSIFICATION 3 types ofclassifications 1. based on their chemical groups 2. Mode of action 3. Therapeutic classification 15PATKI
• 16.
  Classification on thebasis of their Chemical structure Catecholamines:  Sympathomimetics with catechol nucleus are called catecholamines. Adrenaline, NA, DA, Isoprenaline, Dobutamine  Non-Catecholamines : Tyramine, Ephedrine, Amphetamine, Salbutamol HO HO C C N 16PATKI
• 17.
   2. Modeof action Direct receptor agonists: alpha agonists 1& 2 beta agonists 1& 2 alpha & beta agonists Indirectly acting : reuptake inhibitors release promoters metabolism inhibitors Both direct and indirect: Ephedrine 17PATKI
• 18.
  Classification of adrenergicreceptor agonists (Sympathomimitic agents) 18PATKI
• 19.
  Alpha1 agonists:  Phenylephrine Mephenteramine  Metaraminol  Midodrine Alpha2 receptor agonist: Clonidine, Apraclonidine, Brimonidine, Alpha-methyldopa, Guanafacine, Guanabenz 19PATKI
• 20.
   Beta1- Dobutamine Beta2- Salbutamol, Terbutaline, Ritodrine  Beta1+2- Isoprenaline Both alpha & beta agonist Adrenaline, Noradrenaline D1 agonist: Fenoldopam 20PATKI
• 21.
  THERAPEUTIC CLASSIFICATION OFADRENERGIC DRUGS: I. Vasopressors: Noradrenaline, Phenylephrine, Ephedrine II. Cardiac stimulants: Adrenaline, Dobutamine, Isoprenaline III. Bronchodilators: ADRENALINE Isoprenaline,Salbutamol, Terbutaline IV. Nasal decongestants: Phenylephrine, Naphazoline, Xylometazoline V. Anorectics: Fenfluramine, Sibutramine, Dexfenfluramine VI. Uterine relaxants : Ritodrine, Salbutamol, Isoxsuprine,Terbutaline VII: CNS stimulants: Isoprenaline 21PATKI
• 22.
  MAO A Brofaromine Toltarodine uptake2COMT VT NET Alpha methyltyrosine Alpha methyl Dopa Tolcapone Entacapone Cocaine TCA Reserpine Clonidine Apraclonidine Brimonidine Blocker: Yohimbine Phenylephrine Mephenteramine metaraminol Blockers: Prazocin Terazosin Blockers: Atenolol Metaprolol Dobutamine Salbutamol Ritodrine Guanethidine Bretylium Tyramine ephedrine Glucocorticoids Phenoxybenzamine 22PATKI
• 23.
  ADRENALINE PHARMACOLOGICAL ACTIONS 23PATKI
• 24.
  1. CARDIOVASCULAR SYSTEM: Heart: Itis a powerful cardiac stimulant It interacts with Beta1 receptors.  Increases heart rate  Increases force of contraction  Increases the cardiac output  Increases automaticity and conduction velocity  The cardiac work and oxygen requirement is markedly increased  Increase in the excitability and tendency to cause arrhythmias. 24PATKI
• 25.
  B. BLOOD VESSELS:  Both vasoconstriction (alpha) and vasodilatation (Beta 2) can occur depending on the drug, its dose and vascular bed.  Blood vessels of the skin and mucous membranes predominantly contain alpha1 receptors. It causes vasoconstriction.  Constricts renal, mesenteric, pulmonary and splanchnic blood vessels.  Dilates the blood vessels of skeletal muscles and coronaries. 25PATKI
• 26.
  C. Blood Pressure: Biphasicresponse with Adrenaline. The initial rise in BP due to predominant alpha1 action on blood vessels and beta1 actions on heart. Followed by fall in BP due to beta2 mediated vasodilatation in skeletal muscles. Dales vasomotor reversal: Administration of Adrenaline after the alpha1 blockade produces a fall in BP. This is referred as vasomotor reversal. 26PATKI
• 27.
  27PATKI
• 28.
  (A)Normal effect ofEpinephrine on BP. Rise in the systemic BP reflected by biphasic response (B) Dale´s vasomotor reversal. 28PATKI
• 29.
  2. Respiration : Adrenaline relaxes bronchial smooth muscle ( Beta2).  It inhibits the release of mediators from mast cells (beta2).  It reduces secretions and relives mucosal congestion by vasoconstrictor action. 3. Eye :  Poor penetration into cornea.  Hence its administered as pro-drug Dipivefrin  Mydriasis occurs due to contraction of radial muscles of iris (alphal)  Reduced aqueous formation.  Facilitation of trabecular outflow 29PATKI
• 30.
  4. GIT:  Relaxationoccurs through activation of both alpha and beta receptors.  Peristalsis is reduced and sphincters are constricted. 5. Bladder:  Detrusor relaxation (beta) and  Trigone contraction (alpha) Difficulty in urination 30PATKI
• 31.
  6. METABOLIC: Adrenaline increasesblood glucose level by glycogenolysis (beta2 and alpha) Reduces Insulin secretion alpha2 action Decreases glucose uptake by peripheral tissues  Increase free fatty acid level beta receptor adipocyte- beta 3  Inhibit leptin production by adipocyte  Activate triglyceride lipase 31PATKI
• 32.
  Administration and preparations: orallyinactive EPI administered SC - absorbed slowly By IM route absorbed -- more rapidly. IV route - Arrhythmias Does not cross the BBB EPI is rapidly inactivated in the body by COMT and MAO. It appears in the urine as VMA and metanephrine. 32PATKI
• 33.
  Adrenaline Uses: ABCDE A:In Anaphylactic shock Injection 0.5 ml 1:1000, I.M. B: Bronchial Asthma 0.5ml SC 1 in 1000 C: Cardiac arrest IV 1 in 10,000 D: To increase the duration of action of local anaesthetic along with local anaesthetics 1in 20,000- 1,00,000 E: Epistaxis: 1in 10,000 for local haemostatic action G: Glaucoma Dipivefrin 33PATKI
• 34.
  USES OF EPINEPHRINE ANAPHYLACTICSHOCK: Bronchospasm, breathing difficulty, angioedema hypotension IM Adrenaline Antihistamines, steroids 34PATKI
• 35.
  Rationale of administeringadrenaline (epinephrine E) in anaphylactic shock It is the drug of choice, due to its rapid action of reducing bronchospasm, relieving angioneurotic edema & prompt vasopressor action. 1.E causes relaxation of bronchial smooth muscle(β2);thus relieving bronchospasm. 2.E causes vasoconstriction (α1 ) resulting into rapid vasopressor action (raises the BP). 3.Attenuating enhanced vascular permeability, thus relieving the angioneurotic edema; thus reducing airway congestion. 35PATKI
• 36.
  What is therationale of using adrenaline with local anesthetics like lignocaine  Adrenaline(1 : 1,00,000) + lignocaine , combination is used for infiltration, nerve block or spinal anesthesia.  Because of local vasoconstrictor action ( action on alpha receptors on skin and mucus membranes, less lignocaine is absorbed & duration of anesthesia is prolonged.  The systemic toxicity of lignocaine is also reduced ( less systemic absorption of lignocaine).  The combination should not be injected into the tissues supplied by end-arteries. e.g.- Fingers, toes ,ears, nose & the penis. Resultant vasoconstriction may cause gangrene. Avoid the combination – circumcision. -- surgery on fingers & toes. 36PATKI
• 37.
  Dipivefrin Adrenaline Alpha1 Alpha2 vasoconstriction Decreased secretary activity ROLEOF EPINEPHRINE IN GLAUCOMA 37PATKI
• 38.
  ADVERSE EFFECTS:  Tachycardia,restlessness, palpitation, headache, tremor, pallor and rise in blood pressure.  cerebral haemorrhage, ventricular tachycardia /fibrillation, angina, myocardial infarction CONTRA INDICATIONS Angina pectoris, congestive cardiac failure, Arrhythmias, Hypertension, hyperthyroidism, Subaortic hypertrophic stenosis 38PATKI
• 39.
  NORADRENALINE  Catecholamine andneurotransmitter  Acts on alpha1, alpha2 and beta1 receptors  Vasoconstrictor- Hypertension  Reflex bradycardia  Intravenous administration  Used for emergency restoration of blood pressure in shock  Extravasation severe phlebitis and sloughing 39PATKI
• 40.
  DOPAMINE  Acts ondopamine, beta and alpha receptors.  Dilates renal, mesenteric blood vessels  Increase urine output  Increases cardiac output without increasing heart rate  IV Dopamine : cardiogenic shock  used in renal failure, cardiac surgery & septic shock 40PATKI
• 41.
  Receptor (Dose) Result ofReceptor Activation Contribution to Therapeutic Effect DA1 (2-5mcg/kg/min) The renal vasodilation will improve renal blood flow and increase GFR Increase urine output and decrease fluid retention and edema. (5-10mcg/kg/minDA1,ß1) (11-20mcg/kg/min-ß1) Produces a positive inotropic effect Increase in cardiac output. This is beneficial in CHF alpha1 and alpha2(20-50mcg/kg/min) Vasoconstriction (undesirable effect). This will counteract the beneficial effects on renal blood flow. In addition, increases in TPR will negatively affect cardiac output41PATKI
• 42.
  Dobutamine  beta1- action increased force of cardiac contraction and output, without significant change in heart rate.  IV in cardiogenic shock and cardiac failure 42PATKI
• 43.
  ISOPRENALINE:  Acts onBeta1 and Beta 2 receptors  No action on alpha receptors  Cardiac stimulant ( increase the HR and contraction)  Smooth muscle relaxant  Used in: Heart block, Shock, asthma 43PATKI
• 44.
  Ephedrine Mydriatic Bronchodilator Vasopressor CNS stumulant Urinary retention Nasaldecongestant Uterine relaxant 44PATKI
• 45.
  Ephedrine:  Bronchial asthma Nasal decongestion  Mydriasis  Hypotension in spinal shock  Narcolepsy  Nocturnal enuresis  Stokes adams syndrome 45PATKI
• 46.
  Amphetamines  d-amphetamine, methamphetamine& hydroxy-amphetamine Uses:  Narcolepsy  Attention deficit syndrome/ hyper activity disorder  Obesity 46PATKI
• 47.
  Amphetamine CNS stimulant Cardiac stimulant Tachycardia Palpitation Risein BP Arrhythmias Insomnia, alertness Euphoria, increased motor and physical activity. Tremor, confusion headache Respiratory stimulant Appetite suppressant Anticonvulsant Analgesic Chronic use Fatigue, depression Impairs performance 47PATKI
• 48.
  Vasoconstrictors ( Alpha1agonists)  Phenylephrine, Mephenteramine, Metaraminol, Medodrine, Methoxamine  Acts on alpha receptors  Increases PVR and BP  Reflex bradycardia  Used in hypotension Mydriatic (fundoscopic examination) Nasa decongestion 48PATKI
• 49.
   NASAL DECONGESTANTS: Oral: Ephedrine,pseudoephedrine, phenylephrine, phenylpropanolamine Topically: Xylometazoline, oxymetazoline, naphazoline, phenylephrine, phenylpropanolamine 49PATKI
• 50.
   NASAL DECONGESTANTS Mechanismof action: They act by stimulating the alpha1 receptors present in the blood vessels of nasal mucosa. They produces vasoconstriction of mucosa resulting in its shrinkage and decreased volume of mucosa. Thus they relieve nasal congestion. Used in allergic & vasomotor rhinitis ADRs:  Atrophy of nasal mucosa : intense vasoconstriction- anosmic necrosis  Rebound hyperemia- after congestion : due to dilatation  Phenylpropanolamine is banned – increased risk of hemorrhagic stroke 50PATKI
• 51.
  Alpha2 agonists Clonidine: Hypertension Apraclonidine:Glaucoma Beta2 agonists: Bronchial asthma, Preterm labour 51PATKI
• 52.
   Hypotension  Hypertension ADHD  Anaphylactic shock  Cardiogenic, Hypovolemic shock  Glaucoma  Asthma  Cardiac arrest  Epistaxis  Nocturnal enuresis  Obesity  Nasal decongestion  Fundoscopy  Cardiac decompensation  Preterm labour  AV block  Narcolepsy  Cardiac arrest 52PATKI
• 53.
  Adrenergic receptor blockers Alpha Blockers  Beta Blockers 53PATKI
• 54.
   Alpha Blockers Theyblock the adrenergic responses mediated through the alpha adrenergic receptors. 54PATKI
• 55.
  Classification of Alphablockers: Non selective ( blocks both alpha 1& 2) Selective ( Selective For one receptor) Alpha 1 selective Prazosin Terazosin Doxazosin Tamsulosin Alpha 2 selective Yohimbine Irreversible Phenoxy- benzamine Reversible Phentolamine 55PATKI
• 56.
  properties of Alphablockers: 1) Blockade of vasoconstrictor alpha1 receptors, reduces peripheral resistance Venodilation- cardiac output reduced FALL IN BP Reflex tachycardia ( less) Alpha2 blockade : Block presynaptic auto receptors - enhances NE release Hypertension,Tachycardia and increased CO 2. Nasal stuffiness 3. miosis 4. Intestinal motility is increased .diarrhoea may occur. 56PATKI
• 57.
  5. Tone ofsmooth muscle in bladder trigone, sphincter and prostate is reduced by blockade of alpha1 receptors (mostly of the alpha lA subtype) – urine flow in patients with benign hypertrophy of prostate is improved. And relieves the pain. Tamsulosin 6) alpha blockers can inhibit ejaculation; this may manifest as impotence. 57PATKI
• 58.
  THERAPEUTIC USES  Hypertension Pheochromocytoma  Hypertension crisis –Clonidine withdrawal  Cheese reaction hypertension  Congestive heart failure  Benign prostate hypertrophy-Tamsulosin  Reynaud's disease  Erectile dysfunction 58PATKI
• 59.
  Why tamsulosin ismore preferred for benign prostatic hyperplasia? 59PATKI
• 60.
  Urinary bladder Bladder Neck RelaxesSmooth Muscle α1A receptor Subtype in Bladder Neck α1B receptor Subtype in Blood Vessel 60PATKI
• 61.
  Pheochromocytoma Adrenaline Alpha Hypertension Beta Tachycardia Alpha blocker Betablocker 61PATKI
• 62.
  WHAT IS FIRSTDOSE EFFECT?  The first dose phenomenon is a sudden and severe fall in blood pressure that can occur when changing from a lying to a standing position the first time that an alpha blocker drug is used.  This postural hypotension usually happens shortly after the first dose is absorbed into the blood and can result in syncope (fainting).  It is common with initial dose of 2mg Prazosin. This adverse effect is self-limiting and in most cases does not recur after the initial period of therapy.  For this reason, treatment with Prazosin should always be initiated with a low dose and should be taken at bedtime to avoid standing position. 62PATKI
• 63.
  BETA ADRENERGIC BLOCKINGDRUGS:  These drugs inhibit adrenergic responses mediated through the Beta receptors. 63PATKI
• 64.
  BETA ADRENOCEPTOR BLOCKERS First generation Non selective: (β1+β2) Propranolol, nadolol, timolol, pindolol, sotalol  Second generation β1 selective (cardio selective) atenolol, metoprolol, esmolol,acebutalol, bisoprolol  Third generation ( beta blockers with additional vasodilatory effect) a) Non selective: Labetalol, carvedilol, certeolol b) Beta1 selective: Betaxolol, celiprolol 64PATKI
• 65.
   PHARMACOLOGICAL ACTIONS: Decreases heart rate  Decreases force of contraction  Decreases cardiac output  Fall in blood pressure  Delayed AV conduction  Precipitates asthma  Reduce intraocular tension  Block lipolysis and glycogenolysis 65PATKI
• 66.
  Uses of Betablockers: Cardiac uses: • Angina pectoris • MI • Hypertension • Mild to moderate CCF • Arrhythmias • HOCM Noncardiac uses • Pheochromocytoma • Migraine prophylaxis • Essential tremor • Anxiety • Glaucoma • Portal HTN with bleeding esophageal varices • Alchohol withdrawal • Dissecting aortic aneurysm : • Thyrotoxicosis 66PATKI
• 67.
  ADVERSE EFFECTS: Bradycardia, heartblock, cold extremities, insomnia, depression, fatigue, weakness, impaired carbohydrate tolerance, increased LDL Abrupt withdrawal: Rebound hypertension due to up-regulation of beta receptors. 67PATKI
• 68.
  DRUG INTERACTIONS  Betablockers + Insulin : Hypoglycemic symptoms masked  With NSAIDs : Antagonizes antihypertensive action  Propranolol and lignocaine: Increases antihypertensive action  With Digoxin/ Verapamil: Bradycardia and Heart Block 68PATKI
• 69.
  Contraindications  Sinus bradycardia Heart block  Cardiogenic shock  Hypotension  Bronchial asthma  Mental depression  Severe peripheral vascular diseases 69PATKI
• 70.
  Catecholamines promote glycogenolysisand mobilize glucose through ß2 receptors ,in response to hypoglycemia •This effect is blocked by non-selective beta blockers. •Beta blockers also mask the tachycardia associated with hypoglycemia. • Thus the diabetic patient is deprived of one of the earliest physiologic responses to hypoglycemia. i.e. •Mobilization of glucose &tachycardia •So, nonselective beta blockers are contraindicated in diabetic patients. Why ß-blockers are contraindicated in diabetic patients 70PATKI
• 71.
  Why Propranolol iscontraindicated in asthma? • Beta2 receptors on airway smooth muscle will cause relaxation. • They can block beta2 receptors associated with airway. Thus can exacerbate airway diseases (asthma, emphysema, chronic bronchitis) • So propranolol contraindicated in bronchial asthma. 71PATKI
• 72.
  ATENOLOL PROPRANOLOL Selective βadrenergic antagonist (cardioselective) Non selective β adrenergic antagonist (β1= β2) No membrane stabilizing property membrane stabilizing property Oral bioavailability=60% Oral bioavailability=30% Very hydrophillic, very little penetrates CNS Readily enters CNS Safer in patients of Peripheral vascular disease. Causes peripheral vasodilation (β2 ) Write the advantages of Atenolol over Propranolol 72PATKI
• 73.
  ATENOLOL PROPRANOLOL Safer in patientsof diabetes May delay recovery from hypoglycemia by blocking glycogenolysis, it also can interfere with the effects of catecholamines secreted during hypoglycemia ( tremor, tachycardia & nervousness.) Comparatively safe bronchoconstriction . It can increase airway resistance in bronchial asthma No change in Lipid profile Change the lipid profile 73PATKI
• 74.
  • Lower incidenceof cold hands and feet, less chances of precipitating Raynaud's phenomenon. • incidence of cold hands and feet, less chances of precipitating Raynaud's phenomenon due to Beta2 blockade • Ineffective in suppressing essential tremor (it occurs through beta2 action on muscle fibres). • Effective in suppressing essential tremor (it occurs through beta2 action on muscle fibres). • Less liable to impair exercise capacity. • impair the exercise capacity ( blocking the beta 2 receptor mediated blood flow, & inhibits the glycogenolysis & lipolysis Which provides fuel to exercising muscle. ) 74PATKI
• 75.
  CONTRAINDICATIONS:  Severe Bradycardia Heart block  Severe heart failure  Cardiogenic shock  Severe Bronchospasm  Severe depression  Reynaud's phenomenon 75PATKI
• 76.
  Both alpha andbeta blockers: Lebetalol and carvedilol Carvedilol: antioxidant, NO release, antiproliferative actions, membrane stabilizing action. 76PATKI
• 77.
  Shortest half-life: Esmolol Esmolol:IV route, arrhythmias and hypertensive emergencies 77PATKI