sympathetic nerve impulses endogenous catecholamines beta adrenergic drugs

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1 Beta adrenergic blockers } These drugs will bind and prevent beta-receptors from responding to: sympathetic nerve impulses endogenous catecholamines beta adrenergic drugs the use of beta antagonists is generally preferred over the use of alpha antagonists because alpha antagonists are associated with more adverse reactions. Beta receptors blockers are divided into primary subgroups depending on their receptor selectivity into: 1-non selectice beta blockers (block both Beta1 and Beta 2) 2- Beta 1 selective 3- Beta 2 selective the primary groups are beta 1 selective and non beta selective. beta blockers usually end with the suffix ( lol). Beta-1,2-Non-Selective Propranolol [INDERAL] Nadolol [CORGARD] Carteolol [CARTROL] * Timolol [BLOCADREN] Pindolol [VISKEN] * Sotalol [BETAPACE] Penbutool [LEVATOL] Beta-1-Selective

2 Acebutolol [SECTRAL] * Atenolol [TENORMIN] Betaxolol [KERIONE] Bisoprolol [ZEBETA] Esmolol [BREVIBLOC] Metoprolol [LOPRESSOR ] Nebivolol? Now in addition to these two primary subgroups ( beta nonselective and beta 1 selective ) we have another class that is Non-selective beta blocker and selective alpha 1 blocker meaning that they antagonize both beta 1 and beta 2 receptors as well as alpha 1 receptors : -Labetalol [TRANDATE, NORMODYNE] -Carvedilol [COREG] -the beta 1 selective drugs are superior to the non-selective drugs in their indications. (better than nonselective due to lesser side effects ). notes of some of the aforementioned drugs : ** propranolol is the prototype. (it is non-selective ) and is a highly lipid soluble drug thus capable of penetrating the BBB into the brain. ** long acting drugs : -Nadolol is the longest acting(-longest duration of action-) among all of beta blockers. (last for 24 hours). -Nebivolol has also long duration of action (lasts for 30 hours) ( the doctor said it this way for nadolol and nebivolol so just consider them both to have a long duration of action!).

3 **short acting drugs : -Esmolol is the shortest acting and thus usually given by infusion. it is used for supraventricular tachycardia to reduce Heart Rate in those patients. **-Nebivolol is not only a selective beta 1 blocker but has also shown to release Nitric Oxide, and this release of nitric oxide will cause further dilatation of blood vessels. so it is a very good drug for lowering hypertension due to both effects : on heart (by its beta 1 selective blocking) and on peripheral resistance (due to release of nitric oxide) (remember BP=CO *PVR). **-Acebutalol(beta 1 selective) and pindalol(non-selective) they have in addition to their beta blocking effect an ability called intrinsic sympathomymetic ability, meaning although they are blocking agents they can stimulate the same receptors they are blocking. we will see how this could be a very good feature for some conditions. THE NON-SELECTIVE AGENTS -Propranolol, sotalol, nadolol, pindolol and timolol. -These agents will block both beta 1 and beta 2 receptors so they will produce decreasing in HR and contractility of heart muscle( because of beta 1 blocking ) and bronchoconstriction (due to beta 2 blocking ) and that s why its a major disadvantage for patients who have ASTHMA and are in need of beta blockers to use the non selective ones. -The non-selective beta blockers will cause an increase in peripheral vasoconstriction due to two reasons : 1-because of it s effect on beta 1 receptors, it will lead to decrease in Heart rate and Cardiac output, so as a compensation the Peripheral vascular resistance will increase by constricting peripheral vessels ( as we said the formula is like this BP=CO*PVR,, so the body will try to change one if the other changed to keep BP) 2- because of it s effect on beta 2 receptors it will lead to vasoconstriction of the vessels in the skeletal muscles(beta 2 receptors activation leads to dilatation of the vessels in the skeletal muscles so blocking it will lead to vasoconstriction) Now because of those two reasons the non-selective beta blockers will lead to increase in peripheral vasoconstriction so these drugs are NOT used in peripheral vascular disease patients. *(note that the same thing is applied for selective beta 1 blockers but only due to the first reason ( the compensatory one to decreasing the CO ) and not due to the second reason (because of having no activity on the beta 2 receptors.

4 3- these drugs will also inhibit glycogenolysis through antagonizing the beta 2 receptors which will disrupt the metabolic balance causing hypoglycemia (as a result of decreased glycogenolysis) and that s especially dangerous for diabetic patients who are already hypo glycemic because o their insulin treatment. } Bronchoconstriction, } Peripheral vasoconstriction } Interference with glycogenolysis - propranolol is indicated in treatment of : 1-hypertension, dysrhythmia (also Esmolol is used in arrhythmia supraventricular tachycardia-, but Esmolol is selective ), angina pectoris, MI. 2- in pheocromcytoma (in conjunction with alpha blockers,,, remember pheocromcytoma is a tumor of the adrenal medulla characterized by increase in epinephrine secretion,, the pheocromcytoma treatment is by surgery, but during surgery we might cause release of epinephrine so our initial management will be using alpha blockers FIRST so that the released epinephrine wont work on peripheral vessels (alpha 1 blocking) and then continuing with beta blockers ) 3- migraine (the propranolol is lipid soluble, crosses CNS so causes effects there to treat migraine) Now in the next page we have a table the doctor showed in the lec,, but the only thing the doctor focused on is that : most of the beta blockers have low lipid solubility except for propranolol which has high lipid solubility making it able to enter CNS,hence its use in migraines.

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6 Moving on to the EFFECTS OF BETA BLOCKERS : - Decrease Heart rate. - Decrease force of contraction. - Decrease cardiac output. - Slow cardiac conduction. - Decrease automacity of ectopic pacemakers. **Decrease renin secretion from kidney..and as a result a drop in the blood pressure. **they may increase VLDL and decrease HDL. **they decrease portal pressure of patients with cirrhosis (in slides) clinical note about these drugs(masking effect ) : the use of these drugs must be extremely restricted to diabetic patients because these patients are on insulin treatment which may induce hypoglycemia this hypoglycemia normally presents with clinical symptoms (convulsions, tremor, anxiety,sweating..)mediated by an intrinsic compensatory sympathetic outflow to the hypoglycemic state. now giving beta blockers (sympatholytic agents )to these patients will negate the compensatory sympathetic effect and mask it s symptoms on the patient while hypoglycemia worsens in the background with no indication. note the only clinical effect of hypoglycemia that persists when giving beta blockers is sweating because sweat glands has sympathetic muscarinic acetylcholine receptors. so from the previous paragraph the two important notes are : 1- Non-selective beta blockers should not be used in diabetic patients on insulin. 2- All sympathetic symptoms of hypoglycemia are masked by nonselective beta blockers except sweating (uses ACH on muscarinic, an exception)

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8 BETA 1 SELECTIVE drugs } (Acebutolol, atenolol, metoprolol and esmolol ) are relatively cardioselective -we said relatively because this cardioselectivity might be lost in high doses of the drug,, so their not 100% selective -beta 1 selective drugs at normal doses >> affects only beta 1 receptors (cardioselective) -beta 1 selective drugs at high doses >> affects both beta 1 and beta 2 receptors ( lost their selectivity) -generally these drugs are superior to non-selective beta blockers ( better ), because of their selectivity, so we can use them in patients with hypertension who also have other medical conditions as : (ASTHMA, PERIPHRAL VASCULAR DISEASE and DIABETES mellitus ). The doctor read the following table :

9 Some notes about the table : -Labetolol and carvedolol are non selective beta and alpha 1 antagonists. -labetolol is : safe during pregnancy and used in hypertensive crisis and malignant hypertension. -labetalol and carvedolol have postural hypotension as a side effect due to alpha 1 antagonizing.** Advantages of drugs that are rendered as beta blockers while at the same time having intrinsic sympathomimetic effects : ( Acebutolol, Pindolol): As a result of having this activity.( bradycardia that is produced by other drugs of the beta blocker family can be counter acted by acebutolol i.e. their intrinsic sympathomimetic activity improves bradycardia ) Thus these drugs can be given in hypertensive cases where the heart is suffering from bradycardia). See the following figure and illustration for better understanding : Propranolol and atenolol have no partial sympathetic activity And as noted you can observe the decrease in the cardiac output and the heart rate after the use of such drugs(because they re beta blockers dauh?)

10 Compared to acebutolol ( which has an intrinsic sympathomimetic activity)which causes lesser reduction in the cardiac output and heart rate And finally you can see the pattern of behavior of pindolol which shows no to little reduction in the heart rate and the cardiac output, again because of it s intrinsic sympathomimetic activity. And that s why patients who are hypertensive while at the same time suffering from a decreased heart rate, are best treated with (pindolol and acebutolol) when beta antagonists are required. Uses of beta blockers : I. used in treatment of coronary artery disease (i.e. ischemic heart disease) and as a preventive measure for this condition as well. According to this graph the number of total deaths as well as the number of sudden deaths following an ischemic heart disease is significantly lower in patients who are on beta blockers(hence them being used as a treatment). The number of patients who survived an ischemic attack and then suffered from re-infarction is less in those who are on beta blockers ( thus the preventive use of the drugs ).

11 I. beta blockers can be used for treatment of hypertension through acting on the following mechanisms : a)decreasing the heart rate and the force of contraction thus having a total reduction effect on the cardiac output and subsequently lowering blood pressure. b) we learned previously that beta agonists can increase the secretion of renin, thus their antagonist will decrease it leading to a decrease in the concentration of its products such as angiotensin 2, now a reduced level of angiotensin 2 will lead to the loss of its direct constrictive effect on the blood vessels ( thus we have a net result of vasodilation and a decrease in the peripheral resistance) and also a decrease of angiotensin s own subsequent products as aldosterone. which results in less Na and water reuptake by the kidneys and a drop in the blood pressure. c)decreased central sympathetic outflow through working on the beta 2 presynaptic receptors in the central nervous system. as illustrated in the figure below : beta presynaptic receptors whose upon binding with a ligand, increases the rate of release of nor-epinephrine and other catecholamines will be blocked and a total decrease in the central sympathetic outflow will yield. (-mainly propranolol because as we said its lipid soluble and has access to the central nervous system-).

12 d) through working on other pre-junctional receptors(reduced catecholamine release) II. used as anti arrhythmic agents ( specifically : esmolol,oxprenolol,propanolol ) as you can see in the following graphs fluctuations in the heart rate and contractility (i.e. arrhythmic effects ) are evident after a stressful exciting stimuli (a football game as mentioned by the dr ). whereas after the administration of beta blockers these fluctuations were abolished as a result of the antiarrhythmic heart stabilizing properties of beta blockers. III. congestive heart failure : now you may find it a bit odd that in a case where the primary concern is a reduction in the contractility and the cardiac output of the heart

13 agents that antagonize beta receptors are implemented in the treatment. and that s totally fine because it doesn t make any sense. its just that studies found that in some patients with specific cases of congestive heart failure have improved following the use of some beta blockers as part of their treatment regimen. But the use must be tightly regulated,taken into consideration that only specific beta blockers (example :metoprolol)are used in some patients in specific cases where they are considered hemodynamiclly stable and only by experienced doctors. Illustrated by the figure: the cumulative mortality rate of congestive heart failure has dropped after the use of beta blockers.

14 IV. hypertrophic obstructive cardiomyopathy V. dissecting aortic aneurysm which is diagnosed by hearing a murmur in the abdominal region of the patient. now the problem here is that the intima and the media layers of the abdominal aorta are separated and the blood flow will have a pattern of turbulence, complicated by an increase in the blood pressure the problem will worsen as more blood hits the abnormally structured blood vessel, and that s why the pressure lowering beta blockers are used. VI. as we ve mentioned before as a conjugated therapy composed of early introduced alpha blockers and later on beta blockers in pre surgical treatment of pheocromcytoma. VII. hyper thyroidism ( mainly as a symptomatic relief medication ). VIII. Migraine prophylaxis (mainly propranolol as it has a BBB penetrating capability because its highly lipid soluble ). IX. Essential tremors as long as its not caused by Parkinson s disease. X. Anxiety XI. Chronic wide angle Glaucoma example is timolol (used topically as drops ) where it acts on decreasing the production of aqueous humor from the cilliary epithelium. In acute narrow angle obstructive glaucoma the drug of choice is pilocarpine with carbacol but for chronic wide angle glaucoma other medications are used such as (alpha adrenergic agonists clonidine, prostaglandin derivatives and carbonic anhydrase inhibitors i.e. duritics These medications however are not substitute for a surgery as the 100% curative measurement is surgery.

15 Table for the aforementioned drugs. General guidelines : **For a patient with hypertension and bradycardia choose the drugs that have an intrinsic sympathomimetic activity (acebutolol,pindolol). **for asthmatic patients use cardio-selective drugs if necessary. **if you want to treat a patient suffering from myocardial infarction make sure that the patient is hemodynamically stable. ** drug shouldn t be withdrawn suddenly instead it must be discontinued gradually over a period of 1-2 weeks because of the up-regulation of the beta receptors in response to the deprivation of the sympathetic flow following the use of beta blockers and thus if the drug is discontinued abruptly rebound hypertension with angina and other complications will develop as some sort of withdrawal syndrome. Side effects : } Cardiac (mechanical; electrical) } Vascular (decreased perfusion)

16 } Pulmonary (bronchocostriction) } Metabolic (fasting hypoglycemia) } Central Nervous System (depression, nightmares, etc.) } Withdrawal Syndrome??