2.Adrenergic pharm.ppt Dr Ruth Namyalo ug

2.Adrenergic pharm.ppt Dr Ruth Namyalo ug

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  ADRENERGIC PHARMACOLOGY DR. RUTHNAMYALO
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  Adrenergic pharmacology • Adrenergicpharmacology involves the study of agents that act on pathways mediated by the endogenous catecholamines i.e. norepinephrine, epinephrine and dopamine. • These neurotransmitters modulate many vital functions, including:- i) the rate and force of cardiac contraction ii) the resistance (constriction and dilation)of blood vessels & bronchioles, iii) release of insulin, iv) breakdown of fat.
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  • There aretwo principal types of adrenergic agonist drugs:  Catecholamines and  Noncatecholamines  Catecholamines .These agents generally produce effects on visceral organs that mimic certain actions of sympathoadrenal system and for this reason they are sometimes referred to as “sympathomimetic amines”.
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  • Catecholamines arecompounds synthesized in the brain, in sympathetic nerve endings and in cells arising from embryonic neural crest( e. g. adrenal medulla and organ of Zuckerkandi). • The three important endogenous catecholamines are norepinephrine, epinephrine and dopamine. These have a catechol hydroxyl group. • No discussion of catecholamines is complete without mentioning a fourth (synthetic ) catecholamine- isoproterenol. It has greater activity on heart and bronchi than endogenous catecholamines.
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  Structures of catecholamines. HOHO OH CH3 HO CH-CH2-NH-CH HO catechol Isoproteronol CH3 HO OH HO HO CH-CH2NHCH3 HO CH2CH2NH2 Epinephrine Dopamine
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  Biosynthesis of catecholamines. Theendogenous catecholamines are all synthesized from tyrosine. The rate limiting step in catecholamine synthesis is the oxidation of cytoplasmic tyrosine to dihydroxyphenylalanine(L-DOPA) which is catalyzed by tyrosine hydroxylase. Aromatic L-amino acid decarboxylase then converts L-DOPA to dopamine. Vascular mono- amine transporter translocates dopamine into synaptic vesicles. In adrenergic neurons, dopamine- β-hydroxylase converts dopamine to norepinephrine which is stored in vesicles until release. In adrenal medullary cells norepinephrine returns to the cytosol where phenylethanolamine-N- methyltransferase converts it to Epinephrine
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  Storage & releaseof catecholamines • NE & DOP are stored in dense core vesicles located in highly branched nerve terminals. • In adrenal medulla catecholamines are stored in chromaffin granules (chromogranins). • Storage of catecholamines in vesicles serves two purposes. a. To prevent inactivation and b. Protection from degradative enzymes (MAO) located in mitochondria.  Drugs which interfere with storage are useful in treating hypertension.
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  Discharge of catecholamines •The discharge of catecholamines from synaptic nerve endings & from chromaffin cells of adrenal medulla follows nerve stimulation & is Ca2+ dependent action potential & occurs by process of exocytosis. • Drugs e.g. tyramine, ephedrine, amphetamine & ganglionic (nicotinic) stimulants also cause the release of catecholamines.
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  Termination of catecholamineactivity. • Several mechanisms responsible.  Reuptake by nerve terminals(uptake-1)  Uptake by postjunctional(non-neuronal) cells(uptake-2)  Metabolism by enzymes either by o-methylation extracellularly (COMT) or by oxidative deamination intracellularly (MAO)  Physical removal from site of action by diffusion.  Predominant mechanism for inactivation is reuptake.
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  Metabolites of catecholamines •Principal urinary metabolites of catecholamines are:-  Homovanillic acid(HVA) for dopamine &  Vanillylmandelic acid(VMA) for epinephrine & Norepinephrine.  Drugs can alter the physiological reuptake & influence the relative amounts of metabolites that are excreted in urine.  Increased levels of urinary VMA can be used in the Dx of a pheochromocytoma
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  Regulation of catecholamineturnover.  Catecholamines are in a constant state of flux (turn over), being continuously synthesized, released, reuptaken & metabolized.  Under normal circumstances, the tissues & fluid levels of catecholamines remain at a steady state level.  However, mechanisms exist for altering the rate of catecholamine turnover & these range from very rapid to slow.
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  Regulation of catecholamineturnover. • Rapid regulatory mechanisms involves an inhibitory α2 adrenergic receptor located post junctionally. With neuronal firing, the concentration of NE become elevated in neuroeffector junction & this stimulates the prejunctional α2 adrenergic receptor which, in turn inhibits the release of NE from the nerves.
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  Regulation of catecholamineturnover • Tyrosine hydroxylase activity is markedly influenced by the rate of neuronal firing. With rapidly firing nerves, the activity the activity of tyrosine hydroxylase increases, when the nerve activity is reduced, the level of intraneuronal catecholamines become elevated & tyrosine hydroxylase activity is suppressed by negative feedback.
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  Properties of catecholamines. High potency. Drugs that are catechol derivatives show high potency in activating α or β receptors.  Rapid inactivation. Catecholamines are rapidly metabolized by COMT postsynaptically and MAO intraneuronally. They are also metabolized in other tissues. COMT is gut wall and MAO is in liver and gut wall, catecholamines have a brief action when given parenterally and are ineffective when given orally because of inactivation.  Poor penetration into brain because they are polar and do not readily penetrate CNS.
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  Noncatecholamines • These arecompounds that lack catechol hydroxyl group and have long half-lives because they are not inactivated by COMT. • They are synthetically derived drugs with one exception, ephedrine (which is derived in plants and its very similar to epinephrine in its action). • Other examples of Noncatecholamines are phenylephrine and amphetamine.
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  Routes of administrationof catecholamines. Catecholamines are effectively degraded in the gut by MAO and Sulfatases, therefore are not given orally. Some catecholamines are administered to mucous membrane e.g., the vasoconstrictive effect of EPI limits its absorption into the systemic circulation and aids in localizing the effect of local anesthetics. EPI is applied topically as eye drops and is used to lower intraocular pressure in open angle glaucoma.
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  Routes administration ofcatecholamines. Drug inhalation i/m i/v s/c Sublingual Topical Dopamine  Epinephrine      Isoproteronol    Norepinephrine 
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  Types and subtypesof adrenoceptors • Adrenergic receptors are located on smooth muscle, cardiac muscle, exocrine glands, endocrine glands and on nerve terminals. • the transmitter in all adrenergic neurons is NE • When NE and Epi interacts with an adrenoceptor, in some tissues the response is excitatory while in other tissues it is inhibitory
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  Types and subtypesof adrenoceptors Two subtypes of adrenoceptors (alpha and beta)  alpha - excitatory in most tissues (except - intestinal smooth muscle)  beta - inhibitory in most tissues (except - heart)
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  Types and subtypesof adrenoceptors Rank Order of Potency 1. a receptors Epi > NE >> Iso 2. b receptors Iso > Epi > NE Type of adrenoceptor  a 1 , a 2  b 1 , b 2 , b 3  DA1, DA2
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  Types and subtypesof adrenoceptors • Generally a 1 ---Contraction of smooth muscle b 2 ---Relaxation of smooth muscle b 1 ---Stimulation in heart a 2 ---Inhibition, for GI tract ---Relaxation
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  Distribution of adrenoceptorsubtypes. Type Tissue Actions Alpha1 (α1) Most vascular smooth muscle Pupillary dilator muscle Intestinal smooth mm Pilomotor smooth muscle Heart Contraction. Contraction (dilates pupil). Relaxation. Erect hair. Increase force of contraction. Alpha2 (α2) Postsynaptic CNS Adrenoceptors Platelets Vascular smooth muscle Fat cells Adrenergic and cholinergic Nerve terminals Pancreatic β-cells Nerve Inhibit SAS out flow. Aggregation . Contraction . Inhibit of lipolysis. Inhibition of transmitter. Decrease insulin secretion. Decrease norepinephrine release.
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  Type Tissue Actions D1(DA1) Smooth muscle Dilate renal blood vessels. D2(DA2) Nerve endings Modulate transmitter release.
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  Adrenergic receptors • Insummary, the following statements can be made concerning the adrenoceptors for functional responses in mammalian smooth muscle and heart. a) α receptors mediate responses in mammalian smooth mm except those of the non-sphincteric regions of the intestinal tract in which they mediate relaxation. b) Β receptors mediate relaxation in all smooth mm, including those of intestinal tract.
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  c) β1 receptorsmediate positive chronotropic (Rate) responses, positive inotropic (forces) responses, improved atrioventricular conduction (positive dromotropism) and enhanced automaticity (pacemaker activity) in the heart. .
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  Refractoriness to catecholamines •Tachyphylaxis • Desensitization • Down regulation of receptors
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  SYMPATHOMIMETICS:-  These areagents that produce responses similar to those produced by stimulation of the SNS. These responses are mediated by catercholamines that act by occupying receptors of the effecter cells innervated by SNS.  Sympathomimetics are also called adrenergic drugs or adrenergic agonists.  Sympathetic or sympathoadrenal (thoracolumber)
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  Mechanisms of actionof the Adrenergic agonists. 1. Direct –acting agonist. These drugs act directly on α or β receptors producing effects similar to those that occur following stimulation of sympathetic nerves or release of hormone epinephrine from adrenal medulla. Examples include Norepinephrine, epinephrine ,isoproteronol and phenylephrine. 2. Indirect –acting agonists. These agents are taken up into the presynaptic neuron and cause release of NE from cytoplasmic pools or vesicles of the adrenergic neuron. The NE then traverses the synapse and binds to α or β receptors. e.g. amphetamine, tyramine.
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  3.mixed-action agonists. Someagonists such as ephedrine and metaraminol have the capacity both to stimulate adrenoceptors directly and to release NE from adrenergic neuron.
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  … • The effectsof adrenomimetic drugs are similar to sympathetic activation. • Binding of agonists to adrenergic receptors cause the cells to respond in a “flight-fight” manner.  Why does each adrenomimetic drug produce different response? • The differences in affinity to adrenoceptor subtypes are responsible for different responses.
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  Mech. of actionof Adrenomimetic drugs a 1 via coupling protein Gq  a 2 via coupling protein Gi  b 1, b 2 , b 3 via coupling protein Gs
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  Cell Membrane Ca 2+ Ca 2+ Ca2+ -dependent protein kinase Sarcoplasmic Reticulum a1 Phospholipase C IP 3 DAG Phosphatidylinosit ol 4, 5-diphosphate a1 -Agonist Protein kinase C Gq
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  Cell Membrane AC Gi a2 a2- Agonist AT P cAMP No biological effect Enzyme-PO4 AC= Adenylyl cyclase
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  Cell Membrane b -receptor b -Agonist AC Gs AT P cAMP Biological effect Enzyme-PO4 AC= Adenylyl cyclase
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  Ca2+ channels Ca2+ (intracellula r) Ca2+ -calmodulin complex Calmo dulin AT P cA MP MLCK* MLCK-(PO4)2 Myosin light chain (Myosin- LC) Myosin-LC-PO4 Myosin-LC Actin Vascular smooth muscle Contraction Relaxation Myosin-LC kinase (MLCK) b 2 agonists Proteinkinase A
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  M AC Gs Gi b1-receptor b1-Agonist kin ase AT P Ca 2+ Ca 2+ Heart rateConduction Contraction Vag us Heart cAMP
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  Mode of action I.Direct acting – bind to receptor directly II. Indirect acting – cause the release of stored catecholamines – inhibit reuptake of catecholamines by nerve terminals (uptake 1) • increase transmitter in synapse
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  Direct –acting agonists. Epinephrine Actions. 1. Cardiovascular .  It strengthens the contractility of the myocardium (+ve inotropic: β1 action) and increases its rate of contraction (+ve chronotropic: β1 action) cardiac out put there for increases.  It constricts arterioles in the skin, mucous membranes and viscera(α effects).
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   It dilatesvessels going to the liver and skeletal mm(β effects).  Renal bld flow is decreased. Therefore ,the cumulative effect is an increase in systolic bld pressure, coupled with a slight decrease in diastolic pressure. 2.Respiratory.  It causes powerful bronchodilation by acting directly on bronchial smooth mm(β2 action).  In individuals suffering from an acute asthma attach,EPI rapidly relieves dyspenia( laboured breathing) and increases tidal volume( vol.of gases inspired and expired).
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  3. Hyperglycemia.  EPIhas a significant hyperglycemic effect because of increased glycogenolysis in the liver(β effects),increased release of glucagon(β effects) and decreased release of insulin(α effects). These effects are mediated via the cAMP mechanism. Therapeutic uses of EPI  Bronchospasm. It’s a primary drug used in the emergency treatment of any conduction of respiratory tract when bronchospasm has resulted in dimished respiratory exchange.
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   Glaucoma. EPIis used to reduce intraocular pressure in open – angle glaucoma. It reduces the production of aqueous humor by vasoconstriction of the ciliary body bld vessels.  Anaphylactic shock. EPI is a drug of choice for the treatment of type1 hypersensitivity reactions in response to allergens.  In anesthetics. EPI greatly increases the duration of the local anesthetics. It does this by producing vasoconstriction at site of injection thereby allowing local anesthetic to persist at site b4 being absorbed into circulation & metabolized.
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  Clinical application ofepinephrine: • It’s used in local anesthetics. It prolongs the effects of local anesthetics by causing vasoconstriction. This prevents the anaesthetic from being taken away by blood to other body parts rapidly. • It acts as a local haemostat since it causes Vasoconstriction in mucosal blood vessels. It is used in controlling bleeding on mucosal surfaces. Its there4 used as a spray on dental and mucosal surgery.
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  • It’s usedto control hypotension by vaso constriction which results in increased blood pressure. • It’s used in cases of cardiac arrest by I/V injection • Its also used in bronchial asthma because it causes bronchodilation to overcome the dyspnea.
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  Adverse effects.  CNSdisturbances Anxiety, fear ,tension, headache and tremor.  Hemorrhage .the drug may induce cerebral hemorrhage as a result of a marked elevation of bld pressure.  Cardiac arrhythmias. EPI can trigger cardiac arrythemias particularly those receiving digitalis.  Pulmonary edema.EPI can induce pulmonary edema.
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  Summary of theother adrenergic agonists. Drug Receptor Specificity and actions Therapeutic uses Adverse effects. Norepinephrine α1,α2,β1 Actions a)CVS –NE causes vasoconstriction b) Baroreceptor reflex- NE stimulates cardiac contractility. c) Effect on atropine pretreatment- NE stimulation of heart is evident as tachycardia. Treatment of shock b’se it increases vascular resistance and it increases bld pressure. It can also be used to treat depressed myocardium Cardiac arrythemias, cerebral hemorrhages. Anxiety, headache and dizziness.
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  Drug Receptor Specificity and actions Therapeuticuses Adverse effects. Dopamine α1, β1, Dopaminergic Actions 1) CVS –DA exerts a stimulatory effect on β1 receptors on heart producing both ionotropic and chronotropic effects. 2) Renal and visceral -DA dilates renal and splanchnic arterioles by activating dopaminergic receptors thus increasing bld to kidneys & other viscera. 1) Treatment of shock – it’s a drug of choice & its given by continuous infusion . It raises bld pressure by stimulating the heart(α1 action) . 2) Treatment of congestive failure. 3) Raise blood pressure. Nausea ,hypertension, arryththemias.
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  Drug Receptor Specificity and actions Therapeuticuses Adverse effects. Isoproteronol β1,β2 Actions 1) CVS- ISO produces intense stimulation of the heart to increase its rate & force of contraction causing increased cardiac out put. 2) Pulmonary ISO-produces a profound & rapid bronchodilation (β2 action). It can be employed to stimulate the heart in emergency situations. Anxiety, fear ,tension, headache and tremor. Hemorrhage, Cardiac arrhythmias, Pulmonary edema.
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  Drug Receptor Specificity and actions Therapeuticuses Adverse effects Dobutamine It’s a synthetic direct catecholamine. Its a β1 receptor agonist. The drug increases cardiac out put with little change in heart rate. Its used to treat congestive heart failure. Its used with caution in atrial fibrillation because the drug increases atrioventricular conduction. Other effects are similar to those of epinephrine. Phenylephrine α1, It raises both systolic and diastolic pressure. As a nasal decongestant and produces prolonged vasoconstriction. Its also used raise bld pressure and to terminate episodes of supraventricular tachycardia Large doses can cause hypertensive headache and cardiac irregularities.
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  Drug Receptor Specificity and actions Therapeuticuses Adverse effects Methoxamine α1, The drug raises bld pressure by stimulating α1 receptors in the arterioles causing vasoconstriction. Treatment of supraventricular tachycardia Vomiting ,hypertensive headache. Metaproterenol β2>β1 To reverse bronchospasm and treatment asthma
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  Indirect –acting adrenergicagonists. Drug Receptor Specificity and actions Therapeutic uses Adverse effects Amphetamine α β and CNS The drug can increase blood pressure significantly by α agonist action on vasculature as well as β-stimulatory effects on the heart. As a CNS stimulant its used in treatment of attention deficit syndrome, narcolepsy and appetite control. It can cause addiction leading to dependence, tolerance and drug seeking behavior. Tyramine. it’s found in fermented foods such as ripe cheese and wine. It can enter nerve terminals and displace stored NE clinical uses of tyramine are limited but it can be used for the ddx between categories of orthostatic hypotension. If a patient is taking MAO inhibitors it can precipitate serious vasopressor episodes.
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  Mixed –action adrenergicagonists. Mixed action drugs induce the release of NE from presynaptic terminals and activate adrenergic receptors on the presynaptic membrane. Drug Receptor Specificity and actions Therapeutic uses Adverse effects Ephedrine α β and CNS It raised systolic and diastolic bld pressure by vasoconstriction and cardiac stimulation. Treatment of asthma It's used to raise blood pressure Its also used as a nasal decongestant. Life threatening Cardiovascular effects.
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  Adrenergic antagonists.  Adrenergicantagonists also called adrenergic blockers or sympatholytic agents bind to adrenocepters but do not trigger the usual receptor mediated intracellular effects.  These drugs act by either reversibly or irreversibly attaching to the receptor thus preventing its activation by endogenous catecholamines.
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  Adrenoceptor antagonists. Alpha blockersBeta blockers β2 selective α2 selective β1 selective α1 selective Nonselective Nonselective Reversible Irreversible
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  Alpha (α )adrenergicblocking agents. Drug and receptor specificity Actions Clinical uses. Adverse effects Phenoxybenzamine Its nonselective α blocker. It binds to both α 1 postsynaptic and α 2 presynaptic receptors. The block is irreversible & noncompetitive. 1) Cardiovascular effects. By blocking α receptors ,the drug prevents vasoconstriction of peripheral bld vessels by endogenous catecholamines. The decreased peripheral resistance provokes a reflex tachycardia. The ability to block α2 in heart contributes to increased cardiac out put. 2) Epinephrine reversal. All α receptor blockers reverse the α agonist actions of EPI.( actions of NE are not reversed but are diminished).  Treatment of pheochromocytoma a catecholamine secreting tumor of cells derived from the adrenal medulla.  treatment of Raynaud disease. Postural hypotension, nasal stuffiness nausea & vomiting. It can inhibit ejaculation. It may also induce tachycardia & is contraindicated in patients with decreased coronary perfusion.
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  Drug and receptor specificity ActionsClinical uses Adverse effects Phentolamine It produces competitive block of α 1 & α2 receptors. It’s a synthetic drug & considered a prototype of non selective α adrenoceptor blocking drugs. It generally suppresses responses to circulating amines more readily than responses to neural stimulation.  For diagnosis and temporal treatment of pheochromocytoma.  to prevent hypertensive episodes caused by release of catecholamines during the manipulation of tumor in course of surgery.  treatment of impotence because of its ability to produce vasodilatation.  drug can trigger arrhythmias & anginal pain.
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  Drug and receptor specificity ActionsClinical uses Adverse effects Prazosin,terazosin, doxazosin and tamsulosin. These are selective competitive inhibitors of the α1 receptor. CVS – all these agents decrease peripheral vascular resistance and lower arterial bld pressure by causing the relaxation of both arterial and venous smooth mm. Tamsulosin has little effect on bld pressure. Used as an alternative to surgery in patients with symptomatic benign prostatic hypertrophy.  dizziness  nasal congestion Drowsiness Headache  orthostatic hypotension
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  β-adrenergic blocking agents. Drugand receptor specificity Actions Clinical uses Adverse effects Propranolol . It’s a prototype β adrenergic antagonist and blocks both β1 & β2 receptors. It’s a competitive β adrenoceptor blocker. CVS- propanolol diminishes bld cardiac out put, having both inotropic and chronotropic effects.  peripheral vasoconstriction. blockade of β receptors prevents β2 –mediated vasodilation. The reduction in cardiac out put leads to decreased bld pressure.  hypertension- propranolo lowers bld pressure in hypertension by decreasing cardiac out put.  glaucoma – propranolol and other β blockers ,particularly timolol are effective in dimishing intraocular pressure.  Bronchoconstrction – propranolol has a serious and potentially lethal side effect when administered an asthmatic . It should never be used in treating any individual with chronic obstructive pulmonary disease.
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  Propranolo conti…  increased Na+ retention-reduced bld pressure causes a decrease in renal perfusion resulting in an increase in Na+ retention and plasma volume. For this reason β blockers are often combined with a diuretic to prevent Na+ retention.  disturbances in glucose metabolism. β blockade leads to decreased glycogenolysis and decreased glucagon secretion. If an insulin- dependant diabetic is to be given propranolol, careful monitoring of bld pressure is essential bse pronounced hypoglycemia  migraine . Propranolol is effective in reducing migraine episodes.  hyperthyroidism. propranolol and other β blockers are effective in blunting the widespread sympathetic stimulation that occurs in hyperthyroidism. Arrhythmias. Treatment with β blockers must never be stopped quickly bse of risk of precipitating cardiac arrhythmia.  sexual impairment . B’se sexual function in male occurs through α adrenergic activation,β blockers do not affect normal ejaculation but some men complain of impaired sexual activity
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  Propranol conti…  blockadeaction of isoproteronol. All β blockers including propranolol have the ability to block the actions of isoproteronol on the cardiovascular system. Actions of NE on the CVS are mediated primarily by α receptors and are therefore not affected.  angina pectoris. Propranolol reduces cardiac oxygen demands by decreasing heart rate myocardial contractility,i.e.by inhibiting sympathetic activity on heart. Its used in chronic management stable angina.  myocardial infarction. Propranolol and other β blockers have protective effect on myocardium.  disturbances in metabolism .β blockade leads to decreased glycogenolysis and glucagon secretion
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  Timolol & NadololActions Therapeutic uses. Adverse effects Nonselective β antagonists. They block β1 & β2 adrenoceptors & are more potent than propranolol. Timolol lowers intra ocular pressure by suppression of aqueous humor formation. Nadolol has effects on glucose and lipid metabolism & depresses A-V conduction in the heart. Timolol is used topically in treatment of chronic open angle – glaucoma & occasionally for systemic treatment hypertension. Nadolol is used to treat hypertension & angina pectoris.  being a nonselective β antagonist,nadolol may exacerbate bronchospasm, insulin –induced hypoglycemia & overt heart failure .  mild irritation of eyes occasionally occurs with topically administered timolol, blurred vision may occur with initial use. Bradycardia can occur due to systemic absorption of timolol via the nasolacrimal ducts. Its contraindicated in patients with asthma,
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  Acebutolol ,Atenolol, Metoprolol & Esmolol actions Therapeuticuses Adverse effects These are selective β1 antagonists. These drugs lower bld pressure in hypertension & increase exercise tolerance angina They are useful in hypertensive patients with impaired pulmonary function.  in diabetic patients receiving insulin of oral hypoglycemic agents. Metoprolol – tiredness,dizzines ,gastric upset and mental depression. High doses can exacerbate asthma, heart block, heart failure.  Atenolol – fatigue & depression, rash cold extremities, dizziness & bradycardia may occur. It can also exacerbate cardiac failure, worsen heart block.
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  Labetolol & carvedilol Actions Therapeuticuses Adverse effects. These are reversible β blockers with concurrent α blocking actions that produce peripheral vasodilatation thereby blocking bld pressure. These are reversible β blockers with concurrent α blocking actions that produce peripheral vasodilatation thereby blocking bld pressure. They contrast with other β blockers that produce vasoconstriction .  labetolol is used to treat hypertensive emergencies b’se it rapidly lowers bld pressure.  labetolol may be employed as an alternative to hydralazine in treatment of pregnancy-induced hypertension.  carvedilol is used for treatment of mild to moderate congestive heart failure.  labetolol- Orthostatic hypotension and dizziness  carvedolol – bradycardia, dizziness have been experienced in some patients. Diarrhea & hyperglycemia have also been experienced.
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  Pindolol and acebutolol. Theseare antagonists with partial agonist activity. They are not pure antagonists.  They have the ability to weakly stimulate both β1 & β2 receptors & are said to have intrinsic sympathomimetic activity(ISA).  These partial agonists stimulate the β receptors to which they are bound and yet they inhibit stimulation by the more potent endogenous catecholamines. The result of these opposing actions is a much-diminished effect on cardiac rate and cardiac out put compared to that of β blockers without ISA.
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   Blockers withISA minimize disturbances of lipid and carbohydrate that are seen with other β blockers without ISA. Therapeutic uses  blockers with ISA are effective in hypertensive patients with moderate bradycardia b’se a further decrease in heart rate is less pronounced with these drugs.  They are valuable in treatment of diabetic patients b’se their effect on carbohydrate metabolism is less compared to propranolol.
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  Drugs affecting neurotransmitterrelease or uptake Check textbook. References 1. Basic and clinical pharmacology, B.C.Katzung, nth ED. 2. Goodman and Gilman’s the pharmacological basis of therapeutics,nth edition.Joel G.Hardman lee .E. Limbird et al…. 3. Board review series Pharmacology,Gary C.Rosenfeld et al.nth ed.