Beta blockers: Role in Hypertension

Beta Blockers to be used in HTN or not?!

1. TREATMENT of HYPERTENSION: ROLE OF BETA BLOCKERS Dr. sujay iyer I year pg General medicine

2. TABLE OF CONTENT Introduction Pharmacodynamics & Pharmacokinetics Specific Agents Adverse Effects Clinical Use History Concerns End of the Road? Indications for use in Hypertension Conclusion

3. INTRODUCTION Beta Blockers are competitive antagonists that block the receptor site for endogenous catecholamines on the adrenergic beta receptors. Some are partial agonists while most are pure antagonists. Beta blockers differ in their relative affinity for β 1 and b2 receptors.

4. ADRENERGIC BETA RECEPTORS β 1 RECEPTORS Located mainly in the heart and the kidneys. Stimulates viscous, amylase-filled secretions from salivary glands. Increases cardiac output: (+) Chronotropic effect. (+) Inotropic effect. (+) Dromotropic effect. (+) Bathmotropic effect. Renin release from juxtaglomerular cells. Lipolysis in adipose tissue. Relaxation of urinary bladder.

5. ADRENERGIC BETA RECEPTORS b 2 RECEPTORS Located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle and skeletal muscle. Muscular system: Smooth muscle relaxation – Delay in digestion and micturition , inhibition of labour & facilitation of respiration. Blood vessels – Dilates arteries increasing perfusion. Circulatory system: Increases cardiac output. Eye: Increases intraocular pressure. GI: Glycogenolysis and gluconeogenesis with Insulin secretion. Lung: Bronchiole dilatation.

6. ADRENERGIC BETA RECEPTORS β 3 RECEPTORS Located mainly in the adipose tissues. Enhancement of lipolysis . Thermogenesis in skeletal muscles.

7. PHARMACODYNAMICS & PHARMACOKINETICS PHARMACOKINETICS: Most of the drugs are absorbed well orally, peak concentrations occur 1-3 hours after ingestion. Bioavailability of most β- blockers is limited. Rapidly distributed. Some like Propranolol and Pindolol are lipophilic and readily cross the blood-brain barrier. Most of them have half-lives in the range of 3-10 hours.

8. PHARMACODYNAMICS The effects of β- blockers are due to occupation and blockade of β receptors. Some actions may be due to partial agonist activity and local anesthetic action. CARDIOVASCULAR SYSTEM: β- blockers lower the blood pressure in patients with hypertension. Mechanism is not fully understood; but probably include suppression of renin release and effects in the CNS. Prominent effect on the heart and valuable in the treatment of angina, chronic heart failure and following myocardial infarction. Negative chronotropic , inotropic , dromotropic & bathmotropic effect.

9. PHARMACODYNAMICS Oppose β 2 mediated vasodilation which may acutely lead to rise in peripheral vascular resistance from unopposed a receptor mediated effects in the sympathetic nervous system. RESPIRATORY TRACT: Increase in airway resistance, especially asthmatics. Selective β- blockers are advantageous over non-selective ones, however none of them are sufficiently specific to completely avoid β 2 - receptors. EYE: Reduce intraocular pressure by decreasing aqueous humor production, especially in Glaucoma.

10. PHARMACODYNAMICS METABOLIC & ENDOCRINE EFFECTS: Inhibit lipolysis via sympathetic system. Glycogenolysis is partially inhibited in the liver by b 2 blockade. Impairment of recovery from hypoglycaemia although b 1 selective antagonism may be less prone to it. Increased concentration of VLDL and decreased concentration of HDL, although this is less prone in partial agonists. EFFECTS NOT RELATED TO b BLOCKADE: Intrinsic sympathomimetic activity. Membrane-stabilizing activity.

11. SPECIFIC AGENTS PROPRANOLOL: Prototypical non-selective b Blocker. METOPROLOL AND ATENOLOL: β 1 -selective group. Preferred in COPD, Asthma (caution), Diabetes and PVD over non-selective β -Blockers. NEBIVOLOL: Most highly selective β 1 -Blocker. Causes vasodilation . Increases insulin sensitivity and does not have adverse effect on lipid metabolism.

12. SPECIFIC AGENTS PARTIAL AGONISTS: Pindolol , Acebutolol , Cartelol , Penbutolol , etc. Likely to cause less rest bradycardia , less reduction in cardiac output, abnormalities in plasma lipids and may produce vasodilation with increased arterial compliance. LABETALOL: Reversible a 1 and b blocker with partial agonist activity. Decreases BP with having little effect over HR and CO. CARVEDILOL: Non-selective b- Blocker with a 1 adrenoreceptor blocking capacity. Decreased peripheral vascular resistance by causing vasodilation . SOTALOL: Class III Anti-arrhythmic agent.

13. ADVERSE EFFECTS CARDIAC EFFECTS: Exacerbation of acute heart failure. Negative chronotropic effect. b- Blocker withdrawal. EXTRA-CARDIAC EFFECTS: Increased airway resistance. Exacerbation of peripheral artery disease. Facilitation of hypoglycaemia. Hyperkalemia . Depression, fatigue, sexual dysfunction. Lipid metabolism and weight gain.

14. CLINICAL USE Hypertension. Ischemic heart disease. Cardiac arrhythmias. Heart failure. Glaucoma. Hyperthyroidism. Neurologic diseases. Other cardiovascular diseases: Obstructive cardiomyopathy & Dissecting aortic aneurysm. Miscellaneous: Portal hypertension & Infantile hemangioma .

15. HISTORY In the 1960s, Dr. James Black, a Scottish pharmacologist and his associates started working on β -Blockers for treatment of angina. Pronethalol was released in 1963 but marketed only for life-threatening conditions because of its side effects. Propranolol was launched in 1965 as ‘ Inderal ’. It quickly became a best-selling drug , used to treat a wide range of cardiovascular diseases such as angina, arrhythmia, hypertension and hypertrophic cardiomyopathy . In 1976, Atenolol was launched as ‘the ideal β -Blocker’ and soon replaced Propranolol as the best selling heart drug. Metoprolol was made in 1969 and launched in the U.S in 1978. Bisoprolol and Carvedilol was released in 1986 and 1995 respectively. Dr. James Black was awarded the Nobel Prize in Medicine in 1988.

16. HISTORY In ancient Indian Ayurvedic and Chinese medicine, a hard pulse felt on palpation qualified as hypertension. Dr. Akbar Mahomed , an Irish-Indian, was the first physician to describe essential hypertension in the late 19 th century. The modern quantitative concept of hypertension came along after the discovery of the sphygmomanometer in the early 20 th century. Even then, Hypertension was not considered a disease. Veterans Administration Co-operative Research Study published in 1967 and 1970 was a landmark achievement in Medicine that established that treating essential hypertension leads to lower incidence of CHF and Stroke.

17. TIMELINE OF HYPERTENSION

18. TRIALS MRC Trial (1985): Use of Propranolol & Thiazide diuretic to treat mild hypertension. Found decreased risk of Stroke in comparison to placebo. HAPPHY & MAPHY (1987): Use of Atenolol & Metoprolol in comparison to Thiazide diuretics. No significant difference in end-points. STOP – Hypertension (1991): Use of Atenolol , Pindolol , Metoprolol & Hydrochlorothiazide. No significant difference observed. SHEP (1991): Use of Atenolol or Hydrochlorothiazide. Benefits of treating isolated systolic hypertension. TOMHS (1993): Use of Acebutolol . To compare BP lowering effects of six treatment regimen. All six had sizeable BP reduction. UKPDS (1998): Use of Atenolol . To compare outcomes in hypertension management among diabetics with Captopril . Equally effective outcomes.

19. TRIALS AASK (2002): Use of Metoprolol . To determine a suitable drug regimen in hypertension control to prevent renal failure ( Ramipril , Amlodipine ). Superiority of Ramipril over Metoprolol was only marginal. LIFE (2002): Use of Atenolol and Losartan in patients with hypertension and LVH. Greater reduction in cardiovascular and cerebral end-points with Losartan . INVEST (2003): Comparison of CCB with Atenolol for patients with Hypertension and Coronary Artery Disease. Equally effective. CONVINCE (2003): Use of CCB and Atenolol . No significant difference in risk of MI.

20. TRIALS

21. CONCERNS ALLHAT (2002): Brought Thiazide diuretics to the forefront. Showed reduced HF rates in hypertensives and dyslipidemics . Lancet Meta-Analysis (2004): Suggested that Atenolol did worse than other antihypertensives in reducing stroke [ Lindholm et al]. Lancet Meta-Analysis (2005): In comparison with other antihypertensive drugs, the effect of β blockers is less than optimum, with a raised risk of stroke [ Lindholm L et al] . Cochrane Meta-Analysis (2012): Beta blockers were inferior to other antihypertensive drugs in reduction of cardiovascular disease [ Wiysonge et al] . ASCOT-BPLA (2005): CCB and ACEI are better than β blocker and Thiazide diuretics [ Dahlof B et al] . CAFE (2006): Amlodipine reduced central aortic pressure more than Atenolol [Williams B et al].

22. CONCERNS Based on the mounting evidence, β blockers were relegated to the second-line in JNC-8 guidelines. Several theories have been proposed to explain the observed risk of stroke: Pulse wave dyssynchrony leading to increased central aortic pressure. Less effective lowering of blood pressure. Visit-to-visit blood pressure instability (Peak-trough ratio). Unfavourable metabolic effects.

23. END OF THE ROAD?

24. END OF THE ROAD? A CJC Meta-Analysis in 2014 revealed all β blockers were effective in reducing cardiovascular end-points in young adults. Increased incidence of Stroke with Atenolol in older population [ Kuyper & Khan] . A CMAJ Meta-Analysis in 2007 revealed that most of the previously observed stroke risk was confounded by older populations [Khan & McAlister]. Most of the analysis on cardiovascular outcomes are derived from studies using Atenolol . Vasodilatory β blockers may be safer! Many recent studies have shown that Nebivolol , Labetalol and Carvedilol significantly reduce central aortic pressure. HJ (2011): Nebivolol vs Metoprolol . JCH (2013): Nebivolol , Carvedilol , Metoprolol . Nature (2014): Losartan vs Carvedilol . HJ (2016): Meta-analysis comparing vasodilating β blockers and non- vasodilating β blockers.

25. INDICATIONS FOR USE IN HYPERTENSION DIABETES: The adverse metabolic and lipid consequences of traditional β blockers raises some concerns. There seems to be a increased risk of new-onset diabetes with use of Atenolol and Propranolol . Nebivolol and Carvedilol have shown neutral or beneficial effects on metabolic parameters. GEMINI Trial. YESTONO Study.

26. INDICATIONS FOR USE IN HYPERTENSION CORONARY ARTERY DISEASE: β blockers not only reduce blood pressure but decrease the myocardial oxygen demand. Effects of nonvasodilating β blockers on hyperemic coronary blood flow are variable. Because of amelioration of rest and hyperemic coronary blood flow, vasodilatory β blockers may be a better option than traditional β blockers in patients with high coronary artery disease risk.

27. INDICATIONS FOR USE IN HYPERTENSION POST MYOCARDIAL INFARCTION: Recommended in the AHA guidelines. The value of β blockers in patients after MI has been established in BHAT and CAPRICORN. Only Carvedilol is recommended among the vasodilatory β blockers.

28. INDICATIONS FOR USE IN HYPERTENSION HEART FAILURE: It is a serious natural progression of uncontrolled hypertension. 3 β blockers are found to improve outcomes in patients with systolic heart failure by inhibiting the negative effects associated with sympathetic nervous system. Carvedilol : COPERNICUS (2001) Metoprolol : MERIT HF (1999) Bisoprolol : CIBIS (1999) Their benefits include reducing the risk of death and reducing symptoms, improving clinical status and improving the overall well-being of the patient. Risk of mortality and rehospitalization are significantly lower with their use.

29. CONCLUSION β blockers may no longer be the undisputed leader in management of hypertension. They still hold a special place in the treatment of cardiovascular diseases including hypertension due to their cost-effectiveness and a reasonable adverse effect profile. The reality of modern hypertension treatment is that most patients will require multiple drugs. In patients with comorbidities , combination therapy will be essential. Third generation vasodilating β blockers have many advantages over their predecessors and should be preferred whenever possible.

30. REFERENCES Harrison’s Principles of Internal Medicine Katzung’s Basic & Clinical Pharmacology The Lancet The Cochrane Library www.uptodate.com www.medscape.com www.ncbi.nlm.nih.com www.aha.com www.ajconline.org

31. “I wish I had my beta blockers handy” - Dr. James Whyte Black (on being told that he had won the Nobel Prize) THANK YOU 