Beta blockers dr wan azizi

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  • 1.MODE OF ACTION Block the action of endogenous catecholamines (Adrenaline) & (NA) in particular, On B-adrenergic receptros, part of sympathetic nervous system There are three known types of beta receptor, B1, B2, & B3 receptors BETA BLOCKERS

2. -ADRENERGIC RECEPTORS 1-adrenergic receptors are located mainly in the heart & in the kidney 2-adrenergic receptors are located mainly in the lungs, GIT, liver, uterus, vascular smooth muscle, & skeletal muscle 3-adrenergic receptors are located in fat cells 3. STIMULATION Stimulation of 1 receptors at HEART induces a positive chronotropic & inotropic effect on the heart and increases cardiac conduction velocity & automaticity. Stimulation of 1 receptors in the kidney causes renin release Stimulation of 2 receptors induces smooth muscle relaxation, induces tremor in skeletal muscle, and increases glycogenolysis in the liver and skeletal muscle Stimulation of 3 receptor induces lipolysis. 4. Differ in intrinsic sympathomimetic activity, in CNS effects, and in pharmacokinetics Beta 1 selective (Cardioselective) Acebutalol, Atenolol, Bisoprolol, Esmolol, Metoprolol Non-selective ( Beta 1 & 2) Nadolol, Penbutolol, Pindolol, Propranolol, Timolol BETA ANTAGONISTS 5. SELECTIVE BETA 1 ANTAGONISTS Acebutalol Atenolol Metoprolol Esmolol (short half life) Selectively block beta 1 (Cardioselective) To lower B.P. in hypertension Increase exercise tolerance in angina Also useful for patient with diabetic hypertensive patients who are receiving insulin/oral hypoglycemic agents 6. INTRINSIC SYMPATHOMIMETIC ACTIVITY (ISA) Some beta blockers (e.g. oxprenolol, pindolol, penbutolol, and acebutolol) exhibit intrinsic sympathomimetic activity (ISA) These agents are capable of exerting low level agonist activity at the -adrenergic receptor while simultaneously acting as a receptor site antagonist. 7. INTRINSIC SYMPATHOMIMETIC ACTIVITY (ISA) Also referred to as intrinsic sympathomimetic effect, this term is used particularly with beta blockers that can show both agonism and antagonism at a given beta receptor, depending on the concentration of the agent (beta blocker) and the concentration of the antagonized agent (usually an endogenous compound such norepinephrine) 8. ANTAGONISTS WITH PARTIAL AGONIST ACTIONS Pindolol Acebutalol Not pure blockers, weakly stimulate both beta 1 & 2 (intrinsic sympathomimetic activity) Decreased metabolic effects Uses : hypertension with moderate bradycardia/ diabetic patients 9. BETA ANTAGONISTS WITH ADDITIONAL CVS EFFECTS (3rd GENERATION BETA BLOCKERS) 1. Alpha 1 blockade : Labetalol, Carvedilol, Bucindolol, Bevantolol, Nip radilol 2. Increased production of NO : Celiprolol, Nebivolol, Carteolol, Bopindolol, Nipr adolol 3. Beta 2 agonist properties : Celiprolol, Carteolol, Bopindolol 4. Calcium entry blockade : Carvedilol, Betaxolol, Bevantolol 5. Opening of K channels : Tilisolol 6. Antioxidant action : Carvedilol 10. PHARMACOLOGICAL DIFFERENCES Agents with intrinsic sympathomimetic action (ISA) Acebutolol, carteolol, celiprolol, mepindolol, oxprenol ol, pindolol, labetalol Agents with greater aqueous solubility Atenolol, celiprolol, nadolol, sotalol Agents with membrane stabilizing effect Acebutolol, betaxolol, pindolol, propranolol Agents with antioxidant effect Carvedilol, nebivolol 11. INDICATION DIFFERENCES Agents specifically indicated for cardiac arrhythmia Esmolol, sotalol, landiolol Agents specifically indicated for congestive heart failure Bisoprolol, carvedilol, sustained-release metoprolol, nebivolol Agents specifically indicated for glaucoma Betaxolol, carteolol, levobunolol, metipranolol, timolol Agents specifically indiciated for myocardial infarction Atenolol, metoprolol, propranolol Agents specifically indicated for migraine prophylaxis Timolol, propranolol 12. BETA BLOCKERS IN CVS 1. Angina pectoris 2. Myocardial infarction 3. Arrhythmias 4. Hypertension 5. Heart failure 13. HYPERTENSION The primary antihypertensive mechanism of beta blockers is unclear but it may involve reduction in cardiac output (due to negative chronotropic and inotropic effects) It may also be due to reduction in renin release from the kidneys, and A central nervous system effect to reduce sympathetic activity (for those -blockers that do cross the blood- brain barrier, e.g. Propranolol) Blockade of the sympathetic nervous system on renin release leads to reduced aldosterone via the renin angiotensin aldosterone system with a resultant decrease in blood pressure due to decreased sodium and water retention Reduced C.O. Decrease sympathetic outflow Reduce renin 14. ANGINA Antianginal effects result from negative chronotropic and inotropic effects, which decrease cardiac workload and oxygen demand Reduced workload Decrease C.O. 15. ARRHYTHMIAS The antiarrhythmic effects of beta blockers arise from sympathetic nervous system blockade resulting in depression of sinus node function and atrioventricular node conduction, and prolonged atrial refraction periods Sotalol, in particular, has additional antiarrhythmic properties and prolongs action potential duration through potassium channel blockade 16. ADVERSE EFFECTS 1. Bronchoconstriction (contraindicated in bronchial asthma) 2. Arrhythmias (beta blockers should be stopped gradually), bradycardia, cardiac depression 3. Cold extremities, Insomnia, depression, fatigue, Sexual impairment 4. Disturbance in metabolism (care in diabetics) 5. Drug interactions Cimetidine, Furosemide, Chlorpromazine may potentiate anti-hypertensive effects - Barbiturates, Phenytoin, Rifampin can reduce its effects 17. DRUG INTERACTIONS WITH BETA BLOCKERS Antidiabetic medications: beta blockers may mask signs and symptoms of hypoglycemia Calcium channel blockers: (verapamil or diltiazem) has resulted in rare conduction disturbances Cimetidine: Cimetidine may increase plasma concentration by 30% in patients receiving beta blocker ClonidineL potentiates the blood pressure and heart-rate lowering effects of beta blockers. If combination therapy with clonidine and a beta blocker is terminated, the beta blocker should be discontinued first Digoxin: The concentration of digoxin is increased by 15% when used in combination with beta blockers Rifampin: Rifampin causes a reduction in the plasma concentration by 770% in patients receiving beta blocker Other inhibitors of cytochrome P450 2D6 isoenzyme (fluoxetine, paroxetine, quinidine) May increase plasma concentration in patients receiving beta blocker. 18. B BLOCKERS AGENT Non-selective : Propranolol Partial agonist : Acebutalol, Pindolol Selective : Acebutalol, Atenolol, Metoprolol Both Antagonist a & B : Labetolol, Carvidelol 19. PROPRANOLOL Non selective It has little intrinsic sympathomimetics action (ISA) but has strong membrane stabilizing activity Pharmacological Actions: 1. CVS diminishes C.O. (negative inotropic chronotropic effects). Directly depress SA & AV nodes Beta 1 blockade reduced C.O., world load, oxygen consumption (useful for treatment of angina) 20. PROPRANOLOL 2. Periphrical vasoconstriction blockade of beta 2 mediated vasodilation Reduced C.O. decreased B.P. reflex peripheral vasoconstriction 3. Bronchoconstriction blocking beta 2 receptors ( can precipitate respiratory crisis in asthma/COPD patients) 4. Disturbances in glucose metabolism beta blockade decreased glycogenolysis and decrease glucagon secretion. (care in diabetic patient, beta blockers may also attenuate normal physiological responses to hypoglycemia) 5. Increased Na+ retention-due low perfusion to kidney, result Na+ and water retention, leads to increased BP 21. PHARMACOKINETICS Well absorbed, high lipid solubility. Propranolol first pass effect; 25% reached systemic circulation CNS effects present with propranolol, less with Nadolol, Atenolol 22. THERAPEUTIC USES 1. Hypertension lowers B.P. by decreasing C.O., reduction in renin release, central reduce sympathetic action 2. Glaucoma effective in diminishing intraocular pressure decrease secretion of aqueous humor from ciliary body 3. Migraine prophylaxis blockade of catecholamine- induced vasodilation in brain vasculature. Reduced incidence and severity of migraine 4. Hyperthyroidism-effective in blunting the sympathetic stimulation and also useful for the storm (prevent cardiac arrhythmias) 23. THERAPEUTIC USES 5. Angina Pectoris decreases oxygen requirement of heart muscle reduced chest pain on exertion (useful in chronic stable angina) 6. Myocardial Infarction-protective effect on myocardium, reduces infarct size, and hastens recovery 7. Arrhythmias depress automaticity, prolong AV conduction, decrease HR and contractility 8. Congestive heart failure (worsen in acute heart failure but improve life quality in chronic cases) 9. Anxiety-to control somatic symptoms 24. ADVERSE EFFECTS 1. Bronchoconstriction CI for asthma 2. Arrythmias never stopped abruptly. Tappered down in 1 week slowly. Long term treatment upregulated receptors 3. Nightmares cross BBB 25. ATENOLOL Is a selective 1 receptor antagonist Introduced in 1976, atenolol was developed as a replacement for propranolol in the treatment of hypertension Unlike propranolol, atenolol does not pass through the blood-brain barrier thus avoiding various central nervous system side effects 26. ATENOLOL Is one of the most widely used -blockers in the United Kingdom and was once the first-line treatment for hypertension The role for -blockers in hypertension was downgraded in June 2006 in the United Kingdom to fourth-line, as they perform less appropriately or effectively than newer drugs, particularly in the elderly Some evidence suggests that even in normal doses that most frequently used B-blockers carry an unacceptable risk of provoking type 2 DM 27. ATENOLOL-PHARMACOKINETICS The mean elimination half life is 6 hours. However