Adrenergic Agents 10-12-24 PDF

Adrenergic Agents Dr Saravanan Dharmaraj 1 The adrenergic drugs affect receptors that are stimulated by norepinephrine (noradrenaline) or epinephrine (adrenaline). These receptors are known as adrenergic receptors or adrenoceptors. Drugs that activate adrenergic receptors...

Adrenergic Agents Dr Saravanan Dharmaraj 1 The adrenergic drugs affect receptors that are stimulated by norepinephrine (noradrenaline) or epinephrine (adrenaline). These receptors are known as adrenergic receptors or adrenoceptors. Drugs that activate adrenergic receptors are termed SYMPATHOMIMETICS, and drugs that block activation of adrenergic receptors are termed SYMPATHOLYTICS. Sympathomimetics are also referred to as adrenergic agonists. Some sympathomimetics directly activate adrenergic receptors (direct-acting agonists), while others act indirectly by enhancing release or blocking reuptake of norepinephrine (indirect- acting agonists). THE ADRENERGIC NEURON Adrenergic neurons release norepinephrine as the primary neurotransmitter. These neurons are found in the central nervous system (CNS) and in the sympathetic nervous system in the periphery where they serve as links between ganglia and the effector organs. Neurotransmission involves the following steps: synthesis, storage, release, and receptor binding of norepinephrine, followed by removal of the neurotransmitter from the synaptic space. 2 Synthesis and release of NE from the adrenergic neuron. DOPA = dihydroxyphenylalanine MAO = monoamine oxidase NE = norepinephrine SNRI = serotonin– norepinephrine reuptake inhibitor. 3 ADRENERGIC RECEPTORS Several classes of adrenoceptors can be distinguished pharmacologically. Two main families of receptors, designated α and β, are classified based on their differential responses to the adrenergic agonists, epinephrine, norepinephrine, and isoproterenol. Both the α and β receptor types have several specific receptor subtypes. α-Adrenoceptors: The α-adrenoceptors show a weak response to the synthetic agonist isoproterenol, but they are responsive to the naturally occurring catecholamines epinephrine and norepinephrine. The α-adrenoceptors divided into subtypes based on their affinities for agonists and antagonists. Types of adrenergic receptors and their affinity to agonists 4 α1 Receptors: These receptors are present on the postsynaptic membrane of the effector organs and mediate many of the classic effects involving constriction of vascular smooth muscle. α2 Receptors: These receptors are located primarily on sympathetic presynaptic nerve endings and control the release of norepinephrine. When a sympathetic adrenergic nerve is stimulated, a portion of the released norepinephrine “circles back” and reacts with α2 receptors on the presynaptic membrane. Stimulation of α2 receptors causes feedback inhibition and inhibits further release of norepinephrine from the stimulated adrenergic neuron. This inhibitory action serves as a local mechanism for modulating norepinephrine output when there is high sympathetic activity. [Note: In this instance, by inhibiting further output of norepinephrine from the adrenergic neuron, these receptors are acting as inhibitory autoreceptors.] α2 Receptors are also found on presynaptic parasympathetic neurons. The alpha 1 and 2 are further divided into subclasses. This extended classification is necessary for understanding the selectivity of some drugs (Note-tamsulosin). β-adrenoceptors Responses of β receptors differ from those of α receptors and are characterized by a strong response to isoproterenol. 5 β1 Receptors have approximately equal affinities for epinephrine and norepinephrine, whereas β2 receptors have a higher affinity for epinephrine than for norepinephrine. Thus, tissues with a predominance of β2 receptors (such as the vasculature of skeletal muscle and bronchial smooth muscle) are particularly responsive to the effects of circulating epinephrine released by the adrenal medulla. Adrenergically innervated organs and tissues usually have a predominant type of receptor. For example, tissues such as the vasculature of skeletal muscle have both α1 and β2 receptors, but the β2 receptors predominate. 6  β β β β 2 α DISTRIBUTIO 2 1 1 1 N OF VARIOUS ADRENERGIC α1,β RECEPTORS α1,β β 2 2 VMC: β 3 α2,β Vasomotor 2 2 centre α BV: Blood 1 vessel. α α 1 β 1 2 α β 1 β 2 2 β α α 3 2 2 α 7 Major effects mediated by α and β- adrenoceptors 8 The sympathomimetic drugs mimic effects of sympathetic stimulation. An angry man symbolizing the sympathetic overactivity (Fight– Fright–Flight)— 1: Anger, alert, aggressive; 2: Pupillary dilatation (mydriasis); 3: Increased muscle tone, tremors; 4: Palpitation, increased cardiac output– increased blood flow to the skeletal muscles; 5: Flushing of the face; 6: Tachypnoea, bronchodilatation; 7: Liver–glycogenolysis–more energy; 8: Adipose tissue–lipolysis–energy. 9 CLASSIFICATION OF SYMPATHOMIMETICS 1. On the basis of chemical structures (a)Catecholamines: Sympathomimetics with catechol nucleus are called catecholamines, e.g. epinephrine, norepinephrine, dopamine, isoproterenol and dobutamine. (b)Non-catecholamines: Sympathomimetics that lack catechol nucleus are called non-catecholamines, e.g. tyramine, ephedrine, amphetamine, phenylephrine, salbutamol, etc. Summary of adrenergic agonists. Agents marked with an asterisk (*) are catecholamines. 10 CATECHOLAMINES VERSUS NON-CATECHOLAMINES PROPERTIES OF CATECHOLAMINES 1. High potency: Catecholamines show the highest potency in directly activating α or β receptors. 2. Rapid inactivation: Catecholamines are metabolized by COMT postsynaptically and by MAO intraneuronally, by COMT and MAO in the gut wall, and by MAO in the liver. Thus, catecholamines have only a brief period of action when given parenterally, and they are inactivated (ineffective) when administered orally. 3. Poor penetration into the CNS: Catecholamines are polar and, therefore, do not readily penetrate into the CNS. Nevertheless, most catecholamines have some clinical effects. PROPERTIES OF NON-CATECHOLAMINES 4. Compounds lacking the catechol hydroxyl groups have longer half-lives, because they are not inactivated by COMT. 5. Poor substrates for MAO and show prolonged duration of action. 6. Increased lipid solubility of many of the non-catecholamines (due to lack of polar hydroxyl groups) permits greater access to the CNS. 11 2. MECHANISM OF ACTION OF SYMPATHOMIMETICS A. Direct acting agonists These drugs act directly on α or β receptors, producing effects similar to those that occur following the release of norepinephrine from the sympathetic nerves or release of epinephrine from the adrenal medulla. Examples of direct-acting agonists include epinephrine, norepinephrine, isoproterenol, dopamine#, and phenylephrine. B. Indirect acting agonists These agents may block the reuptake of norepinephrine or cause the release of norepinephrine from the cytoplasmic pools or vesicles of the adrenergic neuron. The norepinephrine then traverses the synapse and binds to α or β receptors. Examples of reuptake inhibitors and agents that cause norepinephrine release include cocaine and amphetamine, respectively. C. Mixed acting agonist Ephedrine and its stereoisomer, pseudoephedrine, both stimulate adrenoceptors directly and enhance release of norepinephrine from the adrenergic neuron 12 3. SYMPATHOMIMETICS ON BASIS OF THERAPEUTIC USE a)To raise blood pressure in shock: Dopamine, norepinephrine, ephedrine, phenylephrine, methoxamine, mephentermine. b) As bronchodilator: Salbutamol, terbutaline, bambuterol, salmeterol, formoterol. c) As cardiac stimulant: epinephrine, isoproterenol, dobutamine. d) As CNS stimulant: Modafinil, amphetamine, dextroamphetamine, methamphetamine. e) For local vasoconstrictor effect: epinephrine. f)As nasal decongestant: Phenylephrine, xylometazoline, ephedrine, oxymetazoline, naphazoline. g) As anorexiant: Dextroamphetamine, mazindol, phentermine, sibutramine. h) As uterine relaxant: Isoxsuprine, terbutaline, salbutamol, ritodrine. i) As mydriatic: Ephedrine, phenylephrine. 1 3 Adreneric agonists Receptor action Therapeutic uses ** Directly acting Epinephrine α1-, α2-, β1-, β2- Anaphylactic shock, Bronchial and β3- agonist asthma (acute severe), Cardiac arrest, to prolong duration of local anaesthesia, to control Epistaxis and other capillary oozing (ABCDE) Norepinephrine α1-, α2- and β1-agonist Hypotensive states Isoproterenol β1- and β2-agonist Heart block, cardiac arrest Dobutamine Relatively selective β1- Cardiogenic shock due to agonist acute myocardial infarction (MI), congestive cardiac failure (CCF) or cardiac surgery Salbutamol, Selective β2-agonists Bronchial asthma, to suppress terbutaline, premature labour (as uterine salmeterol, relaxant) formoterol Ritodrine, Isoxsuprine Selective β2-agonists Uterine relaxants Phenylephrine, Selective α1-agonists Vasopressor agents, nasal methoxamine decongestants, as mydriatic (phenylephrine), allergic or vasomotor rhinitis Adreneric agonists Receptor action Therapeutic uses Clonidine, α-Methyldopa α2-agonists Hypertension Apraclonidine, Brimonidine α2-agonists Glaucoma (topical) Indirectly acting Amphetamine, They act by releasing NE Narcolepsy, attention-deficit Methamphetamine, in the periphery; NE, DA hyperkinetic disorder (ADHD) Methylphenidate and 5- hydroxytryptamine (5- HT) centrally Mixed acting Ephedrine α1, α2, β1 and β2 Intravenous ephedrine is used (direct action) + for the treatment of releases NE (indirect hypotension due to spinal action) anaesthesia Dopamine α1, α2, β1 and D1 + Cardiogenic shock, CCF with releases NE oliguria Mephentermine α1 agonists + releases NE Hypotensive states 1 5 EPINEPHRINE (ADRENALINE): α1, α2, β1, β2 and β3-agonist It is a catecholamine, which is secreted mainly by adrenal medulla. Epinephrine is a direct acting, nonselective adrenergic agonist. PHARMACOLOGICAL ACTIONS Epinephrine acts on α1-, α2-, β1-, β2- and β3-receptors. 1. CARDIOVASCULAR SYSTEM (a) Heart: Epinephrine is a powerful cardiac stimulant. It acts mainly by interacting with β1- receptors and produces various effects. They are as follows: Increase in heart rate – ↑ rate of spontaneous depolarization in SA node (positive chronotropic effect). Increase in myocardial contractility (positive inotropic effect). Increase in conduction velocity (positive dromotropic effect). Increase in cardiac output. Increase in automaticity. Cardiac work and its oxygen requirement is markedly increased. Increase in the excitability and tendency to cause cardiac arrhythmias. (b) BLOOD VESSELS AND BP: Epinephrine activates β1 receptors in the kidney to cause renin release. Renin involved in the production of angiotensin II, a potent vasoconstrictor. 1 6 Blood vessels of the skin and mucous membranes (α1-receptors) are constricted by epinephrine. It also constricts renal, mesenteric, pulmonary and splanchnic vessels, but dilates the blood vessels of skeletal muscle, vessels going to liver and coronary vessels (β2). Intravenous administration of epinephrine in moderate doses produces biphasic effect. There is an initial rise in BP due to α1 (blood vessels) and β1 (heart) actions, followed by a fall in BP due to β2-mediated vasodilatation in skeletal muscle. 2. RESPIRATORY SYSTEM: Epinephrine rapidly relaxes (β2) bronchial smooth muscle. It is a potent bronchodilator but has a short duration of action. It inhibits the release of inflammatory mediators from mast cells (β2). It also reduces secretions and relieves mucosal congestion by vasoconstrictor effect (α1). 3. GIT: It relaxes the smooth muscle of the gut (α2 and β2). It reduces the intestinal tone and peristaltic movements but the effects are transient. 4.Bladder: It relaxes the detrusor muscle (β2) and contracts the sphincter (α1). As a result, it may cause difficulty in urination. 17 5. CNS: In therapeutic doses, epinephrine does not cross the BBB; hence, CNS effects are minimal. But in high doses, it may cause headache, restlessness and tremor. 6.Eye: Epinephrine has poor penetration through cornea when applied topically into the eye. Hence, it is administered as a prodrug. Epinephrine is used in the induction and maintenance of mydriasis during intraocular surgery. 7. Metabolic effects: Epinephrine increases blood glucose level by: (i) Stimulating hepatic glycogenolysis (β2), which is the predominant effect. (ii) Increased release of glucagon (β2). (iii) Reducing insulin secretion through α2 action. (iv) Decreasing uptake of glucose by peripheral tissues. It increases blood lactic acid level by stimulating glycogenolysis in skeletal muscles. 18 PHARMACOKINETICS OF EPINEPHRINE It has a rapid onset but brief duration of action (due to rapid degradation). Not suitable for oral administration due to rapid inactivation in GI mucosa and liver. The preferred route for anaphylaxis in the outpatient setting is intramuscular (anterior thigh) due to rapid absorption. In emergencies, epinephrine is given intravenously (IV) for the most rapid onset of action. It may also be given subcutaneously, by endotracheal tube, or by inhalation. It is rapidly metabolized by MAO and COMT, and the metabolites metanephrine and vanillylmandelic acid are excreted in urine. THERAPEUTIC USES Anaphylactic shock (EPI-drug of choice) Bronchospasm (EPI-primary drug) Cardiac resuscitation (cardiac arrest) Prolong the duration of local anaesthetics Control epistaxis and other capillary oozing Intraocular surgery (induction and maintenance of mydriasis) 19 ADVERSE EFFECTS OF EPINEPHRINE Often due to an extension of pharmacological action. Examples are tachycardia, palpitation, headache, restlessness, tremors and rise in BP. The serious side effects are cerebral haemorrhage and cardiac arrhythmias. In high concentration, epinephrine may cause acute pulmonary oedema due to shift of blood from systemic to pulmonary circulation. Epinephrine is contraindicated in most of the cardiovascular diseases such as hypertension, angina, cardiac arrhythmias, congestive cardiac failure (CCF), etc. In patients on β-blockers, it may cause hypertensive crisis and cerebral haemorrhage due to unopposed action on vascular α1-receptors. 20 NOREPINEPHRINE: α1-, α2- and β1-agonist It is the neurotransmitter in adrenergic system. It acts on α1-, α2- and β1-adrenergic receptors; has negligible β2 action. The main action of NE is on cardiovascular system. It has a direct cardiac stimulant effect (β1), constricts all the blood vessels (α1) including those of the skin, mucous membrane, renal, mesenteric, pulmonary, skeletal muscle, etc. The systolic, diastolic and pulse pressure is increased. [Norepinephrine causes greater vasoconstriction than epinephrine, because it does not induce compensatory vasodilation via β2 receptors on blood vessels supplying skeletal muscles.] There is reflex bradycardia. Baroreceptor reflex: Norepinephrine increases blood pressure, and this stimulates the baroreceptors, inducing a rise in vagal activity. The increased vagal activity produces a reflex bradycardia. But the reflex compensation does not affect the positive inotropic effects of the drug. The weak β2 activity of norepinephrine also explains why it is not useful in the treatment of bronchospasm or anaphylaxis. 21  It can be used to raise BP in hypotensive states but it may decrease blood flow to vital organs by causing widespread vasoconstriction. THERAPEUTIC USE Norepinephrine is used to treat shock (for example, septic shock), because it increases vascular resistance and, therefore, increases blood pressure. It raises BP in hypotensive states (but it may decrease blood flow to vital organs by causing widespread vasoconstriction). Norepinephrine, like epinephrine, is not effective orally. It is not suitable for s.c., i.m. or direct i.v. injection because of necrosis and sloughing of the tissues at the site of injection. It is administered by i.v. infusion. It is rapidly metabolized by MAO and COMT, and inactive metabolites are excreted in the urine. ADVERSE EFFECTS Are similar with epinephrine. 2 2 ISOPROTERENOL (ISOPRENALINE) A non-selective β-receptor agonist. Its nonselectivity is a disadvantage and the reason why it is rarely used therapeutically. Isoproterenol produces intense stimulation of the heart (β1 effect), increasing heart rate, contractility, and cardiac output. It dilates the arterioles of skeletal muscle (β2), resulting in decreased peripheral resistance. Its cardiac stimulatory action, it may increase systolic blood pressure slightly, but it greatly reduces mean arterial and diastolic blood pressures It is a potent bronchodilator. PHARMACOKINETICS Isoproterenol is not effective orally because of extensive first-pass metabolism. It can be given parenterally or as an aerosol. It is metabolized by COMT. Isoproterenol is used to increase the heart rate in heart block. ADVERSE EFFECTS Side effects are tachycardia, palpitation, cardiac arrhythmias, etc. due to its stimulant effect. powerful cardiac 2 4 DOBUTAMINE It is primarily a β1 receptor agonist with minor β2 and α1 effects. It increases heart rate and cardiac output with few vascular effects. Total peripheral resistance not affected (vasoconstriction [α1-mediated] is balanced by vasodilatation [β2-mediated]). Dobutamine is used to increase cardiac output in acute heart failure (i.v infusion), as well as for inotropic support after cardiac surgery. The drug increases cardiac output and does not elevate oxygen demands of the myocardium as much as other sympathomimetic drugs. Dobutamine should be used with caution in atrial fibrillation, as it increases atrioventricular conduction. Adverse effects are tachycardia, rise in BP and tolerance. 25 ALBUTEROL, LEVALBUTEROL, METAPROTERENOL, AND TERBUTALINE: Selective β2- adrenergic agonists These are short-acting β2 agonists (SABAs) used primarily as bronchodilators, usually administered by metered-dose inhalers. Albuterol and its R-isomer levalbuterol are the SABAs of choice for the management of acute bronchospasm, because these agents are more selective for β2 receptors than metaproterenol. Injectable terbutaline is used for the reversal of acute bronchospasm and off-label as a uterine relaxant to suppress premature labor. Also terbutaline nebulizer. Most common side effect of these agents is tremor (tolerance develops). Other side effects include restlessness, apprehension, and anxiety. FORMOTEROL, INDACATEROL, OLODATEROL, AND SALMETEROL (Selective β2) These are long-acting β2 selective agonists (LABAs) used for the management of respiratory disorders such as asthma and chronic pulmonary obstructive pulmonary disease. 26 LABAs are NOT RECOMMENDED as monotherapy for the treatment of asthma, because they NAPHAZOLINE, OXYMETAZOLINE, and TETRAHYDROZOLINE (both α1 and α2) These agents find clinical use in their ability to cause local vasoconstriction when applied topically (α1 agonist effect). Naphazoline, oxymetazoline, and tetrahydrozoline are found in over-the-counter nasal spray decongestants, as well as in ophthalmic drops for the relief of redness of the eyes. These agents directly stimulate α receptors on blood vessels supplying the nasal mucosa and conjunctiva, thereby producing vasoconstriction and decongestion. ADVERSE EFFECTS Local irritation and sneezing may occur with intranasal administration of these drugs. Oxymetazoline is absorbed in systemic circulation (from topical appl.) and produce nervousness, headaches, sleeping disturbance. Use of these drugs more than 3 days NOT recommended, as rebound congestion and dependence may occur. 27 MIRABEGRON and vibegron (β3) These are β3 agonists that relax the detrusor smooth muscle and increase bladder capacity. These agents are used for patients with overactive bladder. Mirabegron may increase blood pressure and should not be used in patients with uncontrolled hypertension. Both drugs may increase the levels of digoxin by inhibiting p-glycoprotein-mediated elimination, and mirabegron inhibits the CYP2D6 isozyme. Vibegron has minimal interaction with the CYP450 enzyme system; hence, the potential for drug interactions is less when compared with mirabegron (this drug in KKM list). 28 INDIRECTLY ACTING ADRENERGIC AGONISTS Indirect-acting adrenergic agonists: cause the release, inhibit the reuptake or inhibit the degradation of epinephrine or norepinephrine. They potentiate the effects of epinephrine or norepinephrine produced endogenously but do not directly bind to or affect postsynaptic receptors. AMPHETAMINE The marked central stimulatory action of amphetamine is noted by drug abusers. It can increase blood pressure significantly by α1 agonist action on the vasculature, as well as β1 stimulatory effects on the heart. Its actions are mediated primarily through an increase in nonvesicular release of catecholamines such as dopamine and norepinephrine from nerve terminals. This mechanism is complemented by inhibition of reuptake of these catecholamines and also by inhibition of monoamine oxidase (MAO). 29 COCAINE Cocaine is unique among local anesthetics in having the ability to block the sodium–chloride (Na+/Cl−)–dependent norepinephrine transporter. The transporter causes reuptake of norepinephrine into the adrenergic neuron. Therefore, Norepinephrine accumulates in the synaptic space, resulting in enhanced sympathetic activity and potentiation of the actions of epinephrine and norepinephrine. Duration of action of NE and epinephrine is increased. Therapeutic use: To produce local anaesthesia or vasoconstriction during endoscopic nasal surgery (Cocaine 10% solution). 30 MIXED-ACTION ADRENERGIC AGONISTS EPHEDRINE and pseudoephedrine These are mixed-action adrenergic agents. They not only enhance release of stored norepinephrine from nerve endings but also directly stimulate both α and β receptors. Thus, a wide variety of adrenergic actions ensue that are similar to those of epinephrine, although less potent. Ephedrine and pseudoephedrine are not catecholamines and are poor substrates for COMT and MAO. Therefore, these drugs have a long duration of action. Ephedrine and pseudoephedrine have excellent absorption after oral administration and penetrate the CNS, but pseudoephedrine has fewer CNS effects. Ephedrine produces bronchodilation and ephedrine injection is used in treatment of bronchial spasm in asthma [KKM list]. 31 Summary of Important characteristics of the adrenergic agonists 32 ADRENERGIC ANTAGONISTS The adrenergic antagonists (also called adrenergic blockers or sympatholytics) bind to adrenoceptors but do not trigger the usual receptor-mediated intracellular effects. Act by binding either reversibly or irreversibly. The adrenergic antagonists are classified according to their relative affinities for α or β receptors in the sympathetic nervous system. PHARMACOLOGICAL EFFECTS OF β-BLOCKERS They block α-receptors, thus inhibiting the α-receptor-mediated responses of sympathetic stimulation and adrenergic agonists (REFER next FIG) 33 (Fig 2.25 TAHA) Effect of α-blockade at various sites: GIT, Gastrointestinal tract; BPH, Benign prostatic hyperplasia; Other effects: Blockade of alpha receptors in nasal blood vessels results in nasal stuffiness. NA: Norepinephrine. 34 CLASSIFICATION OF α-BLOCKERS α-Adrenergic blocking agents antagonize the α-adrenergic receptors (α1 or α2), depending on the specificity of the agent for the receptor subtype(s). Drugs that block α1-adrenoceptors significantly affect blood pressure. Because normal sympathetic control of the vasculature occurs in large part through agonist actions on α1-adrenergic receptors, blockade of these receptors reduces the sympathetic tone of the blood vessels, resulting in decreased peripheral vascular resistance and a subsequent reduction in blood pressure. This decreased blood pressure induces reflex tachycardia. 35 PHENOXYBENZAMINE It is an irreversible (noncompetitive), nonselective blocker of α1- and α2-adrenergic receptors. Actions a. Cardiovascular effects: The drug prevents α1 receptor-mediated vasoconstriction of peripheral blood vessels caused by endogenous catecholamines, which leads to decreased peripheral resistance and resultant reflex tachycardia. However, by blocking presynaptic α2 receptors on the sympathetic nerve terminals in the heart, phenoxybenzamine causes an increase in the release of norepinephrine, which in turn increases heart rate and cardiac output (mediated by β1 receptors). This may also lead to cardiac arrhythmias and anginal pain. For these reasons, phenoxybenzamine is not used as a maintenance therapy for the treatment of hypertension, although it is useful in the short-term management of some hypertensive crises (Hypertensive episodes associated with phaeochromocytoma). Phenoxybenzamine is given orally or through slow i.v. infusion. It has a slow onset but long duration of action because of irreversible blockade of α-receptors. Its main use is in the treatment of pheochromocytoma. 36 PHENTOLAMINE It is an imidazoline derivative. It competitively blocks the effects of NA at both α1- and α2- adrenergic receptors (competitive antagonism). Venodilatation is more than arteriolar dilation. It can also block 5-HT receptors, K+ channels; causes histamine release from mast cells. Phentolamine is given intravenously and has a rapid onset but short duration of action. ADVERSE EFFECTS They include tachycardia, palpitation, arrhythmias; angina and MI may be precipitated. 37 SELECTIVE α1-BLOCKERS PRAZOSIN is a potent and selective α1-adrenergic receptor blocker. It is given orally. It is well absorbed from GI tract but undergoes extensive first-pass metabolism. The effects of α-blockade are depicted in the Fig. 2.25. Unlike nonselective α-blockers, selective α1-blockers produce minimal or no tachycardia. It causes both arteriolar and venodilatation; arteriolar dilatation is more prominent. Individuals with elevated blood pressure treated with prazosin, terazosin, doxazosin do not become tolerant to its action. However, the first dose of these drugs may produce an exaggerated orthostatic hypotensive response ADVERSE EFFECTS First-dose phenomenon (mechanism): Within 30–90 minutes of oral administration of first dose of prazosin, postural hypotension and syncopal attacks (fainting) may be seen. Therefore, the initial dose should be small (1 mg). It is usually given at bed-time so that the patient remains in bed for several hours and the risk of syncopal attack is reduced. It may cause nasal stuffiness, tachycardia, impaired ejaculation and impotence. 3 8 OTHER SELECTIVE α1-BLOCKERS Terazosin is similar to prazosin, but less potent than prazosin. It is almost completely absorbed after oral administration and has a longer duration of action. Doxazosin is the longest acting selective α1-blocker. The haemodynamic effects, bioavailability and extent of metabolism are similar to prazosin. Alfuzosin blocks all subtypes of α1-receptors (α1A, α1B and α1D). It is orally effective and used in benign prostatic hyperplasia (BPH). Tamsulosin is an uroselective α1-blocker (α1A). At low doses, it reduces the resistance to flow of urine with little effect on BP. It is administered orally and is the preferred α1 blocker for treatment of BPH in normotensive patients. It may cause retrograde ejaculation. These drugs can be use for BPH. Doxazosin, terazosin and alfuzosin are particularly useful in patients who also have hypertension. Tamsulosin is preferred for BPH in normotensive patients. [Current guidelines do not endorse the use of prazosin for BPH]. Selective α1-antagonists (prazosin and terazosin) are preferred in the treatment of mild- to- moderate hypertension. They cause less tachycardia and have favourable effects on lipid profile. 3 9 BETA ADRENERGIC BLOCKERS They block the β-receptor-mediated effects of sympathetic stimulation and adrenergic drugs. Pindolol, acebutolol, labetalol, celiprolol and carteolol have partial agonistic activity (intrinsic sympathomimetic activity or ISA). They stimulate β-receptors partially in the absence of catecholamines. Propranolol, acebutolol, carvedilol, labetalol, metoprolol, pindolol have membrane-stabilizing activity (local anaesthetic activity). 4 0 Beta blockers differ in: intrinsic sympathomimetic activity (ISA), CNS effects, blockade of sympathetic receptors, vasodilation, pharmacokinetics. Although all β-blockers lower blood pressure, they are less likely to induce postural hypotension, because the α-adrenoceptors remain functional. Therefore, normal sympathetic control of the vasculature is maintained and responsive to postural and activity changes. β-Blockers are effective (indications of individual drugs vary) in treating systemic as well as portal hypertension, angina, cardiac arrhythmias, myocardial infarction, heart failure, hyperthyroidism, 41 42 PROPRANOLOL Propranolol is the prototype β-blocker and it is a non-selective antagonist. Sustained-release preparations for once-a-day dosing are available. Nonselective β-blockers, including propranolol, have the ability to block the actions of isoproterenol (β1, β2 agonist) on the cardiovascular system. In the presence of a nonselective β-blocker, isoproterenol does not produce cardiac stimulation (β1- mediated) or reductions in mean arterial pressure and diastolic pressure (β2-mediated). ACTIONS Cardiovascular: Propranolol diminishes cardiac output, having both negative inotropic (decreased force of contractility) and negative chronotropic (decreased heart rate) effects. It directly depresses sinoatrial and atrioventricular nodal activity. The resulting bradycardia usually limits the dose of the drug. During exercise or stress [the sympathetic nervous system is activated], β-blockers attenuate the expected increase in heart rate. Cardiac output, workload, and oxygen consumption are decreased by blockade of β1 receptors. These effects are useful in treatment of angina. 43  Action Peripheral vasoconstriction: of Nonselective blockade of β receptors prevents β2- propran mediated vasodilation in skeletal muscles, increasing olol and peripheral vascular resistance. other blockers The reduction in cardiac output produced by all β-blockers leads to decreased blood pressure. This triggers a reflex peripheral vasoconstriction that is reflected in reduced blood flow to the periphery. In patients with hypertension, total peripheral resistance returns to normal or decreases with long term use of propranolol-due to down-regulation of β-receptors. Also inhibitory effect of the blockers on renin release. 44 Bronchoconstriction: Blocking β2 receptors in the lungs of susceptible patients causes contraction of the bronchiolar smooth muscle. Non-selective β-blockers should be avoided in patients with asthma and COPD. Metabolic effects: β-Blockade leads to decreased glycogenolysis and decreased glucagon secretion. If propranolol is given to a diabetic patient receiving insulin, careful monitoring of blood glucose is essential. Pronounced hypoglycemia may occur after insulin injection. Chronic use of nonselective β-blockers decreases HDL (high-density lipoprotein) cholesterol and LDL (low-density lipoprotein) cholesterol ratio. This may increase the risk of coronary artery disease. Eye: β-Blockers on topical administration decrease IOP by reducing the secretion of aqueous humour. 45 PHARMACOKINETICS: Propranolol is almost completely absorbed after oral administration. But it is subject to first-pass effect, and only about 25% of an administered dose reaches the circulation. The volume of distribution of propranolol is quite large (4 L/kg), and the drug readily crosses the blood–brain barrier due to its high lipophilicity. Propranolol is extensively metabolized, and most metabolites are excreted in the urine. ADVERSE EFFECTS Bronchoconstriction Arrhythmias: Treatment with β-blockers must never be stopped abruptly because of the risk of precipitating cardiac arrhythmias. Long term treatment-upregulation of β-receptor. On suspension of therapy, action of endogenous catecholamines can precipitate worsened angina, myocardial infarction, or hypertension 46  Fasting hypoglycemia may occur. In addition, β-blockers can prevent the counterregulatory effects of catecholamines during hypoglycemia. Thus, the perception of symptoms of hypoglycemia such as tremor, tachycardia, and nervousness are blunted by β-blockers. CNS effects: including depression, dizziness, lethargy, fatigue, weakness, visual disturbances. 47 NADOLOL and TIMOLOL: nonselective β antagonists Nadolol and timolol also block β1- and β2-adrenoceptors and are more potent than propranolol. Nadolol has a very long duration of action. Timolol reduces the production of aqueous humor in the eye. It is used topically in the treatment of chronic open-angle glaucoma. Agents used in treatment of glaucoma: Timolol-decreases the secretion of aqueous humor. Carteolol and levobunolol (non-selective β-antagonist) whereas betaxolol is a β1- selective agent. The β-blockers are only used for chronic management of glaucoma. 48 Treatment of Portal hypertension: Nonselective β-blockers such as nadolol (and propranolol) are used for treating portal hypertension in patients with cirrhosis. Treatment with these agents reduces the risk of variceal hemorrhage. 49 ACEBUTOLOL, ATENOLOL, BISOPROLOL, ESMOLOL, METOPROLOL: selective β1 antagonists They preferentially block the β1 receptors- minimize the unwanted bronchoconstriction (β2 effect) seen with use of nonselective agents in asthma patients. Cardioselective β-blockers, such as acebutolol, atenolol, and metoprolol, antagonize β1 receptors at doses 50- to 100-fold less than those required to block β2 receptors. Actions: These drugs lower blood pressure in hypertension and increase exercise tolerance in angina. Esmolol has a very short half-life due to metabolism of an ester linkage. Only available intravenously and is used to control blood pressure or heart rhythm in critically ill patients and those undergoing surgery or diagnostic procedures. The cardioselective β-blockers have fewer effects on: pulmonary function peripheral resistance carbohydrate metabolism However, monitor asthma patients carefully to make certain that respiratory activity is not compromised. 5 0 THERAPEUTIC USES: Cardioselective β-blockers are useful in hypertensive patients with impaired pulmonary function. These agents are also first-line therapy for chronic stable angina. Bisoprolol and the extended-release formulation of metoprolol are indicated for the management of chronic heart failure. Acebutolol has partial agonist activity (can stimulate both β1 and β2 activity). In addition to its cardioselective β-blockade, nebivolol releases nitric oxide from endothelial cells and causes vasodilation. 5 1 β-BLOCKERS WITH ADDITIONAL VASODILATORY ACTION LABETALOL It is a competitive blocker at β1-, β2- and α1-adrenergic receptors. In addition, it has partial agonistic activity (ISA) at β2-receptors. It is administered orally or intravenously. Oral labetalol for essential hypertension and i.v. labetalol for hypertensive emergencies. It is safe for use during pregnancy. The important side effects are postural hypotension and hepatotoxicity. CARVEDILOL (also blocks β1-, β2- and α1-adrenergic receptors.) In addition, carvedilol has antioxidant, antiproliferative, membrane-stabilizing and vasodilatory properties; has no intrinsic sympathomimetic activity. It has cardioprotective effect; hence long- term use reduces mortality in patients with CHF. NEBIVOLOL Third generation selective β1-blocker. Has (NO-mediated) vasodilating activity. No membrane stabilizing effect. No intrinsic sympathomimetic activity. No unfavourable effect on lipid profile. It is used for control of hypertension and congestive cardiac failure. 5 2 5 3