Adrenergic bockers (VK)

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Adrenergic bockers (VK)

  1. 1. ADRENERGIC BLOCKERS
  2. 2. Introduction   Alpha & Beta adrenergic receptor antagonists prevent the interaction of the endogenous neurotransmitter norepinephrine (N.E) or sympathomimetics (endogenous or synthetic catecholamines, synthetic noncatecholamines) with the corresponding adrenergic receptor Such interference attenuates SNS homeostatic mechanisms & evokes predictable pharmacologic responses
  3. 3. Alpha Blockers      Interfere with ability of catecholamines or other sympathomimetics to provoke alpha responses on the heart & peripheral vasculature Inhibitory action of epinephrine on insulin secretion is prevented too (insulin production is not reduced) Side effects: orthostatic hypotension, baroreceptor mediated reflex tachycardia, impotence Absence of Beta blockade allows maximum expression of cardiac stimulation from N.E. They are both competitive antagonist of α or β or both.
  4. 4. Receptor agonists activate signal transduction pathways HO NH3 HO CH CH2 NH2 OH Norepinephrine a1 adrenergic receptor (+) Phospho- Gq lipase C PIP2 COOH IP3 Diacylglycerol Increase Ca2+ Activate Protein Kinase C Response
  5. 5. Receptor antagonists block agonist binding to the receptor Antagonist NH3 Gq COOH Phospholipase C
  6. 6. CLASSIFICATION Non selective   Reversible: Phentolamine , Tolazoline Irreversible : Phenoxybenzamine Selective Alpha 1 selective Prazosin , terazosin , Doxazosin , Tamsulosin , Alfuzosin Alpha 2 selective Yohimbine, Idoxamin Miscellaneous  Ergot alkaloids: Ergotoxine , Ergotamine
  7. 7. Pharmacological Effects CVS • • • • • • Fall in BP (α1 & α2 blockade) Postural hypotension Reflex tachycardia Vasomotor reversal of Dale Hypovolemia accentuates hypotension Hypotension- g.f.r reduced Na & water retention renin release ↓BP
  8. 8. Pharmacological Effects Nasal stuffiness Eye – Miosis Urinary bladder -Decreased tone in sphincter and prostate (α1A blockade) Metabolic effects – Increased insulin secretion Reproductive system Inhibition of contraction of Vas deference and related organs is blocked by α1 blockade…..inhibition of ejaculation…impotence
  9. 9. Phenoxybenzamine     Alpha blockade develops gradually and lasts for 3-4 days. Fall in BP by Phenoxy. is mainly due to venodilatation…postural hypotension. Shifts blood from pulmonary to systemic circulation, extravascular to vascular compartments. Lipid soluble drug can penetrate CNS may cause nausea & vomiting on rapid i.v administration
  10. 10. Adverse effects        Postural hypotension Tachycardia Sedation Nasal stuffiness Miosis Impotence (inhibits ejaculation) Exercise care in hypovolemic patients
  11. 11. USES  Diagnostic and intraoperative management of pheochromocytoma.  Secondary shock (occasionally)  Peripheral vascular diseases.
  12. 12. Phentolamine     Congener of Tolazoline Rapidly acting α blocker with short DOA Many other effects including: Parasympathomimetic Increased gastric acid secretion Cardiac stimulation Increased secretion from exocrine glands, such as salivary, sweat, lacrimal, pancreatic Coronary artery disease and peptic ulcer relative contraindication to it.
  13. 13. Phentolamine : uses      Diagnostic and intraoperative management of pheochromocytoma For control of hypertension due to clonidine withdrawal. Cheese reaction. To counteract vasoconstriction due to extravasation of noradrenaline / Dopamine given IV. Dose: 5mg
  14. 14. Ergot alkaloids       Interact with serotonin and dopamine receptors also Direct smooth muscle contraction Structure-activity relationships Coronary vasoconstriction Toxicity: GI, vascular insufficiency –ergotism Use in migraine
  15. 15. Ergot alkaloids    Ergotoxine, Ergotamine are partial agonist and antagonist at adrenergic α, 5HT and DA receptors. Ergotoxine, dihydroergotoxine are more potent α blocker and less potent vasoconstrictor than ergotamine. USE: Migraine
  16. 16. Alpha-1 selective blockers Prazosin       Highly selective α1 blocker, selectivity ratio 1000: 1 Less cardiac stimulation since it preserves α2 mediated negative feedback + other mechanisms Fall in BP with no/ minimal tachycardia. Used in CHF and in HT but tolerance develops with time, may be due to fluid retention. Adverse effects: First dose phenomenon i.e postural hypotension with initial doses. Favorable effect on plasma lipids: increase HDL/LDL ratio
  17. 17. Effect of Adrenaline (ADR) on Blood Pressure and Heart Rate Before and After Prazosin ADR (µg/Kg) 0.1 1 10 100 500 1 10 100 500 BP +PRAZOSIN HR
  18. 18. Prazosin : uses   Antihypertensive DOC: Benign prostatic hyperplasia ( BPH) Blocks α1 in bladder trigone & prostate  Decreases tone  Improves urine flow  Decreases residual urine    Dose :1-4 mg BD/ TDS Terazosin : longer t1/2 , OD dosing
  19. 19. Tamsulosin      Uroselective α1A/ α1D blocker. As effective as Terazosin in BPH α 1A are predominant in bladder base and prostate. 30 times high affinity for α1A No effect on BP and heart rate. Dizziness and retrograde ejaculation are the only AE.
  20. 20. α 2 selective blockers Yohimbine      Cardiovascular effects – peripheral and central effects Blocks other receptors also – 5HT, DA Increases ADH release Enhances sexual activity – aphrodisiac Potential uses: depression, obesity, NIDDM
  21. 21. α Blockade—Adverse Effects  Orthostatic hypotension    Reflex tachycardia   Dilates vessels of nasal mucosa Inhibition of ejaculation   Increase heart rate by stimulating baroreceptor reflex which causes and increased heart rate to compensate Nasal Congestion   Reduces blood flow to brain causing dizziness, lightheadedness and fainting Due to vasodilation of veins lowering blood flow to brain α 1, sympathetic reaction needed Sodium retention  Decreased blood pressure decreases filtering by kidneys and causes retention of water and salt
  22. 22. α Blockade—Uses  Therapeutic Applications  Essential hypertension  Benign prostatic hyperplasia  Pheochromocytoma  Raynaud’s disease  Overdose of α1 agonist
  23. 23. Therapeutic Uses of Alpha-Adrenergic Blockers         Hypertension - α1 selective Conditions associated with increased sympathetic activity – e.g. pheochromocytoma Hemodynamic shock Peripheral vascular disease – Raynaud’s CHF Benign prostatic hyperplasia-prazosin Pulmonary hypertension – tolazoline Yohimbine or intracavernous phentolamine+papaverine for impotence
  24. 24. THANK YOU
  25. 25. Beta Blockers  Selective Affinity for Beta-adrenergic receptors  All beta blockers are competitive antagonists  Beta blockade can be reversed by Beta agonist by displacement from occupied receptors if large amount of agonist is given  Chronic Beta Blocker use = increased number of betaadrenergic receptors (up regulation)
  26. 26. Structure Activity Relationships     Beta Blockers: derived from isoproterenol (beta agonist) Substitutions on the benzene ring determines if drug is antagonist or agonist Levorotatory forms of beta agonists/antagonists more potent than Dextrorotatory forms Example: Dextrorotatory isomer of Propranolol has <1% of the potency of the Levorotatory form
  27. 27. Classification
  28. 28. Pharmacological actions CVS:  Heart: Propranolol ↓ss HR, FOC, COP. ↓ss cardiac work and oxygen consumption.  Blood vessels: fall in BP both diastolic and systolic after continuous treatment.      Decrease in COP Initial increase followed by decrease in TPR Decreased release of NE from symphathetic neurons Decrease renin release from kidney Central action decreasing symphathetic outflow
  29. 29. OTHER SYSTEMS     R S: Bronchoconstriction CNS: ↓ss anxiety, tremors, other actions. lightheadedness, forgetfulness, nightmares, rarely hallucinations Local anesthetic action: Propranolol-membrane stabilizing action Metabolic :     increases LDL, triglycerides, ↓ss HDL by inhibiting lipolysis. Adversely effects recovery from insulin induced hypoglycemia. Skeletal muscles : Propranolol inhibits adrenergically evoked tremors. Eye : decreases synthesis and releases of aqueous humour … ↓ iop
  30. 30. Contraindication        CHF Bradycardia COPD Bronchial asthma Diabetis mellitus Hypertriglygeridemia Partial –complete heart block
  31. 31. Adverse effects  Adverse Effects of beta1 blockade            Bradycardia Reduced cardiac output Heart failure AV block Long-term use can sensitize heart to catecholamines. If withdrawn abruptly, angina pain and/or ventricular dysrhythmias can develop= rebound excitation. Withdraw drug gradually COPD, Bronchial asthma Tiredness , reduced exercise capacity. Rebound hypertension on abrupt withdrawal. Cold hands and feets hypoglycemia Others: gi upset, lack of drive, lightheadedness, forgetfulness, nightmares, rarely hallucinations
  32. 32. CARDIOSELECTIVE (BETA 1 )         Metoprolol Atenolol Acebutolol Bisoprolol Esmolol No effect on bronchus, carbohydrate metabolism, lipids. Lower incidences of Cold hands and feets. Less liable to impair exercise tolerance and essential tremors.
  33. 33. Metoprolol      Cardioselective Preferred in diabetics on insulin or oral hypoglycemics. Less likely to worsen asthma Side effects are milder. USE: AMI without bradycardia
  34. 34. Atenolol      Selective beta 1 blocker with low lipid solubility. Longer duration action. OD dosing Side effects related to CNS are less prominent No effect on bronchus, carbohydrate metabolism, lipids USE: Most commonly used in Hypertention  angina 
  35. 35. Acebutolol  Cardioselective with intrinsic symphathomimetic and membrane stabilizing activity.  Side effect profile is like that of Metoprolol.  Preferred in those prone to severe bradycardia and low cardiac reserve.
  36. 36. Esmolol     Ultra short acting cardioselective beta blocker. DOA 15-20mins after iv infusion Rapid onset short lasting fall in BP USES: To terminate supraventricular tachycardia  Atrial fibrillation or flutter  Arrythmias during anaesthesias  During cardiac surgery to decrease HR & BP  Early treatment of AMI 
  37. 37. Celiprolol & Nebivolol    Beta 1 blocker + beta 2 agonism Acts as NO donor …vasodilatation Uses: Hypertension  CHF 
  38. 38. Intrinsic symphathomimetic activity Pindolol   Used primarily as antihypertensive, Preferred in those prone to severe bradycardia and low cardiac reserve. Chances of rebound hypertention are less.
  39. 39. Without intrinsic symphathomimetic activity   Sotalol : Class III antiarrhythmic Timolol : topical use in eye
  40. 40. Uses of Beta blockers             Hypertension Angina pectoris Cardiac arryhythmias AMI CHF Dissecting aortic aneurysm Pheochromocytoma Thyrotoxicosis Migraine Essential tremors. Glaucoma Anxiety
  41. 41. alpha + beta blocker  Labetalol      β 1 + α1 blocking as well as β2 agonism. 5 times more potent β blocker than α. Fall in BP is due to decrease in COP and TPR Uses : pheochromocytoma, clonidine withdrawl, essential hypertention. A/E: postural hypotension, impotence.
  42. 42. Carvedilol    β 1 + β2+ α1 blocker, calcium channel blocker. Antioxidant property. Use: Hypertension  CHF  Angina. 
  43. 43. Effect of chronic b-receptor blockade Presynaptic neuron Tyrosine Na+ Dopamine Tyrosine Action Potential H+ DA NE NE Uptake 1 NE NE NE Effector organ NE
  44. 44. Effect of chronic b-receptor blockade: Receptor up-regulation Tyrosine Na+ Dopamine Tyrosine Action Potential H+ DA NE NE Uptake 1 NE NE NE Effector organ NE
  45. 45. Pharmacologic manipulation of the adrenergic system Presynaptic neuron Tyrosine Na+ 1 Dopamine Tyrosine 2 Action Potential H+ DA NE NE Uptake 1 NE NE 3 NE Effector organ NE b
  46. 46. Tyrosine Inhibition of norepinephrine synthesis X tyrosine hydroxylase Metyrosine DOPA aromatic L-amino acid decarboxylase Dopamine dopamine b -hydroxylase Norepinephrine phenylethanolamineN-methyltransferase Epinephrine
  47. 47. Drugs that reduce storage or release of NE Tyrosine Na+ Dopamine Reserpine Guanethidine Tyrosine Action Potential H+ NE NE NE Guanethidine, Bretylium Effector organ Guanethidine b
  48. 48. Catecholamine depleters Reserpine (Serpasil)    Indole alkaloid obtained from the root of Rauwolfia serpentina Block vesicular monoamine transporters Deplete vesicular pool of NE     Slow onset of action Sustained effect (weeks) Used in the treatment of hypertension May precipitate depression
  49. 49. Drugs that reduce storage or release of NE Guanethidine (Ismelin)  Almost completely protonated at physiological pH  “Pharmacologic sympathectomy”  Effects can be blocked by transport blockers  Uses: Hypertension
  50. 50. Drugs that reduce storage or release of NE Tyrosine Na+ Dopamine Tyrosine Guanethidine Action Potential H+ NE NE NE Guanethidine, Effector organ Guanethidine b
  51. 51. Drugs that reduce storage or release of NE Bretylium tosylate (Bretylol)       Aromatic quaternary ammonium Precise mechanism unknown Displace and release NE and prevent further release (depletion) Local anesthetic Administered: Parenteral Uses: Antiarrhythmic (ventricular fibrillation)
  52. 52. THANK YOU

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