Beta blockers

Beta blockers

• 1.
  Beta blockers
• 2.
   Catecholamines producetheir action by direct combination with receptors located on cell membrane  Outcome of this drug receptor combination is either ↑ or ↓ in tissue activity  Ahlquist 1948  Alpha & beta receptors
• 3.
  Classification of Betablockers  Non selective • Propranolol • Pindolol • Sotalol • Timolol  + β Blocker • Labetolol • Carvedilol  Cardio Selective (β1) • Atenolol • Acebutolol • Betaxolol • Bisoprolol • Esmolol • Metoprolol • Nebivolol
• 4.
   Without intrinsicsympathomimetic action:  Propranolol  Timolol  Sotalol  With intrinsic sympathomimetic action:  Pindolol  Acebutolol  With membrane stabilizing action:  Propranolol, oxprenolol, acebutolol
• 8.
  Propranolol Non selective betablocker also an inverse agonist
• 9.
  Pharmacological actions  Effectsof  blockade  No marked effect on normal heart in subject at rest  In presence of ↑ sympathetic tone • ↓ automaticity and prevents rise in HR • ↓ Myocardial contractility, cardiac output and stroke work • Slows AV conduction • ↓ myocardial oxygen requirement & improves exercise tolerance
• 10.
  Heart
• 11.
   Blood vessels: Reduce BP • ↓ COP • ↓ renin levels • ↓ central sympathetic outflow • ↓ NA release from sympathetic terminal  Respiratory tract:
• 12.
   CNS:  Subtlebehavioral changes  Forgetfulness, nightmares , ↑ dreaming  Supresses anxiety in short term stressful situation  Local anaesthetic:
• 13.
   Metabolic:  blockslipolysis & subsequent ↑ FFA  ↑ TG, ↑ LDL/HDL ratio  Inhibit glycogenolysis in heart, muscle, liver  No effect on normal BGL but ↓ carbohydrate tolerance by ↓ insulin release  Skeletal muscle:  Inhibit tremors  Decrease exercise capacity  Eye : ↓ secretion of aqueous humor  Uterus : relaxation of uterus in response to selective 2 agonistis blocked
• 15.
  To summarize the pharmacologicalactions
• 16.
   Heart  Respiratory CNS  Local anaesthetic  Metabolic  Skeletal muscle  Eye  Uterus
• 17.
  Important actions  Membranestabilizing action: • Propranolol, oxprenolol, acebutolol  Intrinsic sympathomimetic action: • Pindolol, acebutolol
• 18.
  Significance of intrinsic sympathomimeticaction  Less bradycardia & depression of contractility  Less likely withdrawl symptoms  Lipid profile less worsened  Not effective in migraine prophylaxis  Not suitable for secondary prophylaxis of MI
• 22.
   Cardioselectivity:  Metoprolol,acebutolol, atenolol,bisoprolol  More potent Beta 1 blockade than beta2
• 23.
  Cardioselective  blockers Advantages  Lower chances for bronchoconstriction  Less interference with carbohydrate metabolism and lipid profile  ↓ incidence of cold extremities ↓precipitation of raynauds disease  Less impairment of exercise tolerance  Disadvantage  Ineffective in essential tremors
• 24.
  Pharmacokinetics of propranolol Well absorbed , low bioavailability, high first pass metabolism in liver  Lipophilic  Metabolism dependent on hepatic blood flow  Chronic use of propranolol ↓es hepatic blood flow  Bioavailability and t1/2 ↑ed by 30 % on repeated administration  Food decreases first pass metabolism  Saturable metabolism at higher doses  Metabolites have blocking action  90% protein bound  Dose oral = 10 mg BD to 160 mg QID
• 25.
  Uses of betablockers Cardiac :  Hypertension  Angina pectoris  Myocardial infarction  Cardiac arrhythmias  CCF  Hypertrophic obstructive cardiomyopathy  Dissecting aortic aneurysm  Non cardiac:  Pheochromocytoma  Thyrotoxicosis  Migraine prophylaxis  Anxiety  Essential tremors  Glaucoma  Portal hypertension
• 26.
   Lipid insolublebeta blockers  Atenolol, sotalol, bisoprolol, acebutolol  Less central effects  Incompletely absorbed orally but do not undergo first pass metabolism, excreted mostly unchanged in urine  Longer acting 6-20 hrs  Effective in narrow dose range  Propranolol is the most lipid soluble beta blocker
• 27.
  Adverse effects &contraindications 1. Can accenuate myocardial insufficiency & precipitate CHF by blocking sympathetic support to heart in CVS stress 2. Bradycardia 3. COPD, Bronchial asthma 4. Exacerbates variant, prinzmetal angina 5. Impairment of carbohydrate tolerance in prediabetics 6. Increase TG & LDL/HDL ratio 7. Rebound hypertension, angina on withdrawl
• 28.
  Adverse effects &contraindication 8. Contraindicated in partial & complete heart block – arrest may occur 9. Tiredness , decreased exercise capacity 10. Cold hands & feet – worsening of PVD due to blockade of vasodilator Beta 2 11. Adverse events not due to beta blockade: GIT upset, lack of drive, night mares, forgetfulness, rarely hallucination , sexual distress
• 30.
   Doses ofbeta blockers Drug Dose in mg Propranolol 80 – 240 mg 6-12 hrly Metoprolol 100 – 200 mg BD Atenolol 25 – 100 mg daily Timolol 10 – 60 mg daily Pindolol 10 – 45 mg 6 hrly Labetolol 200 – 600 mg BD Bisoprolol 5 – 10 mg OD
• 31.
  Salient features  Sotalol: Non selective, lower lipid solubility, class 3 antiarrhythmic  Timolol:  Topical preferred in glaucoma  Betaxolol, carteolol, levobunolol (Local acting)  Pindolol:  Non selective, intrinsic sympathomimetic action  Metoprolol:  Cardioselective , less first pass metabolism
• 32.
  Salient features  Atenolol: Cardioselective  Low lipid solubility  No significant first pass metabolism  Longer DOA 6-9 Hrs  No deleterious effect on lipid profile  Effective in narrow dose range  Most commonly used beta blocker for angina & hypertension
• 33.
  Salient features  Acebutolol: Cardioselective  Partial agonist & membrane stabilising action  Bisoprolol:  OD administration in angina , hypertension, CHF  Esmolol:  Ultrashortacting  Celiprolol, nebivolol:  vasodilatory release nitric oxide
• 34.
  Uses of betablockers Cardiac :  Hypertension  Angina pectoris  Myocardial infarction  Cardiac arrhythmias  CCF  Hypertrophic obstructive cardiomyopathy  Dissecting aortic aneurysm  Non cardiac:  Pheochromocytoma  Thyrotoxicosis  Migraine prophylaxis  Anxiety  Essential tremors  Glaucoma  Portal hypertension
• 35.
   Hypertension:  Firstline drugs • Absence of postural hypotension • Low adverse events • Once daily dose • Low cost • Cardioprotective potential  Angina pectoris:  Decrease work load and Oxygen requirement by heart  Favourable redistribution of blood
• 36.
   Myocardial infarction: Catecholamines released during MI  More useful if ongoing pain, tachycardia, hypertension , ventricular rhythm instability  Secondary prophylaxis; • Prevent reinfarction • Prevent sudden ventricular fibrillation  Myocardial salvage during evolution of MI: • Limit infarct size by decreasing oxygen consumption • Marginal tissue which is partly ischemic may survive • May prevent arrhythmias VF
• 37.
   Cardiac arrhythmias Supress tachycardias & extrasystoles mediated by adrenergic system  Control ventricular rate in Atrial fibrillation & flutter  Esmolol alternative drug for paroxysmal supraventricular tachycardia  Dissecting aortic aneurysm:  Decrease contractile force & aortic pulsation  Hypertrophic obstructive cardiomyopathy  Decrease LV outflow obstruction
• 38.
   Congestive cardiacfailure:  Negative ionotropic effect? Worsen ventricular function  1970 waagstein & associates found improved exercise tolerance & improvement in several measures of ventricular function.  Immediately after starting beta blockers • Decrease in systolic function as reflected by decrease in ejection fraction however continued treatment over 2-4 months systolic function gradually improves  This is due to prevention of adverse effects of NA on myocardium that are mediated by beta adrenergic receptors
• 39.
   Thyrotoxicosis:  Migraineprophylaxis:  Anxiety:  Pheochromocytoma:  Essential tremor:  Glaucoma  Portal hypertension:
• 40.
  Alpha + betablocker  Labetolol:  5 times more potent for beta receptors  Has weak beta 2 agonist action also  Decrease blood pressure by 3 mechanisms  Orally effective but extensive first pass metabolism  Uses: hypertension, pheochromocytoma, clonidine withdrawl,  Side effects: postural hypotension, failure of ejaculation, other side effects of alpha & beta blockers
• 41.
   Carvedilol:  1,β1, β2 blocker  Vasodilation: alpha 1 + calcium channel blockade  Antioxidant property  Use: • Hypertension • Cardioprotective in congestive heart failure  Oral bioavailabilty – 30%  T1/2 = 6-8 Hrs