Adrenergic Agonists PDF

# Adrenergic Agonists ## Overview - Adrenergic drugs affect receptors stimulated by norepinephrine or epinephrine. - Sympathomimetic drugs activate the adrenergic receptor and are said to be sympathomimetic. - Other drugs block the action of neurotransmitters at the receptors (sympatholytics). - O...

# Adrenergic Agonists ## Overview - Adrenergic drugs affect receptors stimulated by norepinephrine or epinephrine. - Sympathomimetic drugs activate the adrenergic receptor and are said to be sympathomimetic. - Other drugs block the action of neurotransmitters at the receptors (sympatholytics). - Other adrenergic drugs affect adrenergic function by interrupt the release of norepinephrine from adrenergic neurons. ## Adrenergic Agonists ### Adrenomimetic Agonists - **Direct-acting** - α Agonists - Nonselective - α₁-Selective - α₂-Selective - β Agonists - Nonselective - β₁-Selective - β₂-Selective - **Indirect-acting** - Releasers - Reuptake inhibitors ### The Adrenergic Neuron - Adrenergic neurons release norepinephrine as the primary neurotransmitter. - These neurons are found in CNS and sympathetic nervous system, connecting ganglia to effector organs. - Adrenergic neurons and receptors are located either presynaptically on the neuron or postsynaptically on effector organ. ### Neurotransmission at Adrenergic Neurons - Process involves five steps: synthesis, storage, release, receptor binding of norepinephrine, followed by removal of the neurotransmitter from the synaptic gap. #### Synthesis of Norepinephrine - Tyrosine is transported by a Na+-linked carrier into the axoplasm of the adrenergic neuron, where it is hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase. - This is the rate-limiting step in the formation of norepinephrine. - DOPA is then decarboxylated by the enzyme DOPA decarboxylase (aromatic l-aminoacid decarboxylase) to form dopamine in the cytoplasm of the presynaptic neuron. #### Storage of Norepinephrine in Vesicles - Dopamine is then transported into synaptic vesicles by an amine transporter system. - This carrier system is blocked by reserpine. - Dopamine is hydroxylated to form norepinephrine by the enzyme, dopamine β-hydroxylase. - In the adrenal medulla, norepinephrine is methylated to yield epinephrine, both of which are stored in chromaffin cells. #### Pathway of Catecholamine Biosynthesis | Compound | Enzyme | |-----------------|-----------------------------------| | Phenylalanine | Phenylalanine Hydroxylase | | L-Tyrosine | Tyrosine Hydroxylase (TH) | | L-Dopa | L-Aromatic Amino Acid Decarboxylase (AAAD) | | Dopamine | Dopamine ß-Hydroxylase (DBH) | | Norepinephrine | Phenylethanolamine N-Methyltransferase (PNMT) | | Epinephrine | | #### Release of Norepinephrine - Action potential arriving the nerve junction triggers an influx of calcium ions from the extracellular fluid into the cytoplasm of the neuron. - The increase in calcium causes vesicles inside the neuron to fuse with the cell membrane and expel (exocytose) their contents into the synapse. - This release is blocked by drugs such as guanethidine. - On stimulation, the adrenal medulla releases about 80% epinephrine and 20% norepinephrine directly into the circulation. #### Binding to a Receptor - Norepinephrine released from the synaptic vesicles diffuses across the synaptic space and binds either to postsynaptic receptors on the effector organ or to presynaptic receptors on the nerve ending. - The recognition of norepinephrine by the membrane receptors triggers a cascade of events within the cell, and the action generated within the effector cell and use both the cyclic adenosine monophosphate (cAMP) second messenger system, and the phosphatidylinositol cycle, to transduce the signal into an effect. #### Removal of Norepinephrine 1. Diffuse out of the synaptic space and enter the general circulation. 2. Be metabolized to inactive metabolites by catechol-O-methyltransferase (COMT) in the synaptic space, or be recaptured by an uptake system that pumps the norepinephrine back into the neuron. - The uptake by the neuronal membrane involves sodium/potassium activated ATPase that can be inhibited by tricyclic antidepressants, such as imipramine, or by cocaine and the uptake is the primary mechanism for termination of norepinephrine's effects. 3. Norepinephrine can be oxidized by monoamine oxidase (MAO) present in neuronal mitochondria. ## Adrenergic Receptors (Adrenoceptors) - Two families of receptors designated α and β were initially identified on the basis of their responses to the adrenergic agonists epinephrine, norepinephrine, and isoproterenol. ### a1 and a2 Receptors - The α-adrenoceptors show a weak response to the synthetic agonist isoproterenol, but they are responsive to the naturally occurring catecholamines epinephrine and norepinephrine. - For α receptors, the rank order of potency is epinephrine > norepinephrine >> isoproterenol. - The α-adrenoceptors are subdivided into two subgroups, α1 and α2, based on their affinities for α agonists and blocking drugs. #### A- α1 Receptors - These receptors are present on the postsynaptic membrane of the effector organs and mediate many of the classic effects originally designated as α-adrenergic involving constriction of smooth muscle. - For example, the α1 receptors have a higher affinity for phenylephrine than do the α2 receptors. - Conversely, the drug clonidine selectively agonist binds to α2 receptors and has less effect on α1 receptors. #### B - α2 Receptors - These receptors, located primarily on presynaptic nerve endings and on other cells, such as the β cell of the pancreas, and on certain vascular smooth muscle cells, control adrenergic neuromediator and insulin output, respectively. - The stimulation of the α2 receptor causes feedback inhibition of the ongoing release of norepinephrine from the stimulated adrenergic neuron. - α2 Receptors are also found on presynpatic parasympathetic neurons. Norepinephrine released from a presynaptic sympathetic neuron can diffuse to and interact with these receptors, inhibiting acetylcholine release - In contrast to α1 receptors, the effects of binding at α2 receptors are mediated by inhibition of adenylyl cyclase and a fall in the levels of intracellular cAMP. ### Further Subdivisions - The α1 and α2 receptors are further divided into α1A, α1Β, α1C, and α1D and into α2A, α2B, α2C, and α2D. - This extended classification is necessary for understanding the selectivity of some drugs. For example, tamsulosin is a selective α1A antagonist that is used to treat benign prostate hyperplasia. The drug is clinically useful because it targets α1A receptors found primarily in the urinary tract and prostate gland. ### β Receptors - β Receptors exhibit a set of responses different from those of the α receptors. - These are characterized by a strong response to isoproterenol, with less sensitivity to epinephrine and norepinephrine. - For β receptors, the rank order of potency is isoproterenol > epinephrine > norepinephrine. - The β-adrenoceptors can be subdivided into three major subgroups, β1, β2, and β3. - It is known that β3 receptors are involved in lipolysis but their role in other specific reactions are not known. - β1 Receptors have approximately equal affinities for epinephrine and norepinephrine, whereas β2 receptors have a higher affinity for epinephrine than for norepinephrine. - Binding of a neurotransmitter at any of the three β receptors results in activation of adenylyl cyclase and, therefore, increased concentrations of cAMP within the cell. ### Distribution of Receptors - Adrenergically innervated organs and tissues tend to have a predominance of one type of receptor. - For example, tissues such as the vasculature to skeletal muscle have both α1 and β2 receptors, but the β2 receptors predominate. - Other tissues may have one type of receptor exclusively, with practically no significant numbers of other types of adrenergic receptors. - For example, the heart contains predominantly β1 receptors. ### Characteristic Responses Mediated by Adrenoceptors - As a generalization, stimulation of α1 receptors characteristically produces vasoconstriction (particularly in skin and abdominal viscera) and an increase in total peripheral resistance and blood pressure. - Conversely, stimulation of β1 receptors characteristically causes cardiac stimulation, whereas stimulation of β2 receptors produces vasodilation (in skeletal vascular beds) and bronchiolar relaxation. | Receptor | Major Effects | |----------|-------------------------------------------------------------| | α₁ | Vasoconstriction, increased peripheral resistance, increased blood pressure, mydriasis, increased closure of internal sphincter of the bladder | | α₂ | Inhibition of norepinephrine release, inhibition acetylcholine release, inhibition of insulin release | | ẞ₁ | Tachycardia, increased lipolysis, increased myocardial contractility, increased release of renin | | ẞ₂ | Vasodilation, decreased peripheral resistance, bronchodilation, increased muscle and liver glycogenolysis, increased release of glucagon, relaxed uterine smooth muscle | ### Desensitization of Receptors - Prolonged exposure to the catecholamines reduces the responsiveness of these receptors, a phenomenon known as desensitization. - Three mechanisms have been suggested to explain this phenomenon: 1. Sequestration of the receptors, they are unavailable for interaction with the ligand 2. Down-regulation, that is, a disappearance of the receptors either by destruction or decreased synthesis 3. Inability to couple to G protein, because the receptor has been phosphorylated on the cytoplasmic side by either protein kinase A or β-adrenergic receptor kinase. ## Characteristics of Adrenergic Agonists - Most of the adrenergic drugs are derivatives of β-phenylethylanine. - Substitutions on the benzene ring or on the ethylamine side chains produce a great variety of compounds. - Two important structural features of these drugs are the number and location of OH substitutions on the benzene ring and the nature of the substituent on the amino nitrogen. ### Catecholamines - Sympathomimetic amines that contain the 3,4-dihydroxybenzene group (such epinephrine, norepinephrine, isoproterenol, and dopamine) are called catecholamines. - These compounds share the following properties: #### High Potency - Drugs that are catechol derivatives (with OH groups in the 3 and 4 positions on the benzene ring) show the highest potency in directly activating α or β receptors. #### Rapid Inactivation - Not only are the catecholamines metabolized by COMT postsynaptically and by MAO intraneuronally, they are also metabolized in other tissues. - For example, COMT is in the gut wall, and MAO is in the liver and gut wall. - Thus, catecholamines have only a brief period of action when given parenterally, and they are ineffective when administered orally because of inactivation. #### Poor Penetration into the CNS - Catecholamines_are polar and, therefore, do not readily penetrate into the CNS. - Nevertheless, most of these drugs have some clinical effects (anxiety, tremor, and headaches) that are attributable to action on the CNS. ### Noncatecholamines - Compounds lacking the catechol hydroxyl groups have longer half-lives, because they are not inactivated by COMT. - These include phenylephrine, ephedrine, and amphetamine. - Phenylephrine, an analog of epinephrine, has only a single -OH at position 3 on the benzene ring, whereas ephedrine lacks hydroxyls on the ring but has a methylsubstitution at the α-carbon. - These are poor substrates for MAO and, thus, show a prolonged duration of action. - Increased lipid solubility of many of the noncatecholamines (permits greater access to the CNS.) ### Substitutions on the Amine Nitrogen - The substituent on the amine nitrogen is important in determining the β selectivity of the adrenergic agonist. - For example, epinephrine, with a -CH3 substituent on the amine nitrogen, is more potent at β receptors than norepinephrine, which has an unsubstituted amine. - Similarly, isoproterenol, with an isopropyl substituent -CH(CH3)2 on the amine nitrogen, is a strong β agonist. ## Mechanism of Action of the Adrenergic Agonists ### Direct-Acting Agonists - These drugs act directly on α or β receptors, producing effects similar to those that occur following stimulation of sympathetic nerves or release of the hormone epinephrine from the adrenal medulla. - Examples of direct-acting agonists include epinephrine, norepinephrine, isoproterenol, and phenylephrine. ### Indirect-Acting Agonists - These agents, which include amphetamine, cocaine and tyramine, may block the uptake (termination) of norepinephrine (uptake blockers) or are taken up into the presynaptic neuron and cause the release of norepinephrine from the cytoplasmic pools or vesicles of the adrenergic neuron. ### Mixed-Action Agonists - Some agonists, such as ephedrine, pseudoephedrine and metaraminol, have the capacity both to stimulate adrenoceptors directly and or to release norepinephrine from the adrenergic neuron. ## Direct-Acting Adrenergic Agonists - Bind to adrenergic receptors without interacting with the presynaptic neuron and the activated receptor initiates synthesis of second messengers and subsequent intracellular signals. ## Epinephrine - Epinephrine is one of four catecholamines - epinephrine, norepinephrine, dopamine (the three occur naturally in the body as neurotransmitters), and dobutamine (synthetic compound) commonly used in therapy. - Epinephrine is synthesized from tyrosine in the adrenal medulla and released into the bloodstream. - Epinephrine interacts with both α and β receptors. At low doses, β effects (vasodilation) on the vascular system predominate, whereas at high doses, α effects (vasoconstriction) are strongest. ### Actions #### Cardiovascular - The major actions of epinephrine are on the cardiovascular system. - Strengthens the contractility of the myocardium (positive inotropic: β1 action) and increases its rate of contraction (Cardiac output therefore increases.) - Epinephrine constricts arterioles in the skin, mucous membranes, and viscera (α effects), and it dilates vessels going to the liver and skeletal muscle (β2 effects) Renal blood flow is decreased. - Therefore, the cumulative effect is an increase in systolic blood pressure, coupled with a slight decrease in diastolic pressure #### Respiratory - Epinephrine causes powerful bronchodilation by acting directly on bronchial smooth muscle (β2 action) #### Anaphylactic Shock - In the case of anaphylactic shock, this can be lifesaving #### Hyperglycemia - Epinephrine has a significant hyperglycemic effect because of increased glycogenolysis in the liver (β2 effect), increased release of glucagon (β2 effect), and a decreased release of insulin (α2 effect) (cAMP mechanism involved) #### Lipolysis - Epinephrine initiates lipolysis through its agonist activity on the β receptors of adipose tissue, which upon stimulation activate adenylyl cyclase to increase cAMP levels. - Cyclic AMP stimulates a hormone sensitive lipase, which hydrolyzes triacylglycerols to free fatty acids and glycerol. ### Biotransformations - Epinephrine, like the other catecholamines, is metabolized by two enzymatic pathways: MAO, and COMT, which has S-adenosyl-methionine as a cofactor. - The final metabolites found in the urine are metanephrine and vanillylmandelic acid. ### Therapeutic Uses #### Bronchospasm - Epinephrine is the primary drug used in the emergency treatment of acute asthma and anaphylactic shock. - However, selective β2 agonists, such as albuterol, are presently favored in the chronic treatment of asthma because of a longer duration of action and minimal cardiac stimulatory effect. #### Glaucoma - In ophthalmology, a 2% epinephrine solution may be used topically to reduce intraocular pressure in open-angle glaucoma. - It reduces the production of aqueous humor by vasoconstriction of the ciliary body blood vessels. #### Anaphylactic Shock - Epinephrine is the drug of choice for the treatment of Type I hypersensitivity reactions in response to allergens. #### Cardiac Arrest - Epinephrine may be used to restore cardiac rhythm in patients with cardiac arrest regardless of the cause #### Anesthetics - Local anesthetic solutions usually contain 1:100,000 parts epinephrine. - The effect of the drug is to greatly increase the duration of the local anesthesia. It does this by producing vasoconstriction at the site of injection, thereby allowing the local anesthetic to persist at the injection site before being absorbed into the circulation and metabolized. #### Pharmacokinetics - Epinephrine has a rapid onset but a brief duration of action. - In emergency situations, epinephrine is given intravenously for the most rapid onset of action. - It may also be given subcutaneously, or topically to the eye. Orally ineffective. - Only metabolites are excreted in the urine. ### Adverse Effects - CNS disturbances include anxiety, fear, tension, headache, and tremor. - Hemorrhage and Cardiac arrhythmias - In the presence of cocaine, epinephrine produces exaggerated cardiovascular actions. This is due to the ability of cocaine to prevent reuptake of catecholamines into the adrenergic neuron; thus, like norepinephrine, epinephrine remains at the receptor site for longer periods of time. - Epinephrine increases the release of endogenous stores of glucose. In the diabetic, dosages of insulin may have to be increased. ## Norepinephrine - In practice, when the drug is given in therapeutic doses to humans, the α-adrenergic receptor is most affected. ### Cardiovascular Actions - Vasoconstriction: Norepinephrine causes a rise in peripheral resistance due to intense vasoconstriction of most vascular beds, including the kidney (α1 effect). - Both systolic and diastolic blood pressures increase. - Note: Norepinephrine causes greater vasoconstriction than does epinephrine, because it does not induce compensatory vasodilation via β2 receptors on blood vessels supplying skeletal muscles, etc. - The weak β2 activity of norepinephrine also explains why it is not useful in the treatment of asthma. - In vivo little of any cardiac stimulation is noted, this is due to the increased blood pressure that induces a reflex rise in vagal activity by stimulating the baroreceptors. - If atropine, which blocks the transmission of vagal effects, is given before norepinephrine, then norepinephrine stimulation of the heart is evident as tachycardia. ### Therapeutic Uses - Norepinephrine is used to treat shock, because it increases vascular resistance and, therefore, increases blood pressure. However, metaraminol is favored, because it does not reduce blood flow to the kidney, as does norepinephrine. - It is never used for asthma or in combination with local anesthetics. Norepinephrine is a potent vasoconstrictor and will cause extravasations (discharge of blood from vessel into tissues) along the injection site. ### Pharmacokinetics - Norepinephrine may be given IV for rapid onset of action. - The duration of action is 1 to 2 minutes following the end of the infusion period. - It is poorly absorbed after subcutaneous injection and is destroyed in the gut if administered orally. Metabolism is similar to that of epinephrine. - Note: When norepinephrine is used as a drug, it is sometimes called levarterenol. ## Isoproterenol - Isoproterenol is a direct-acting synthetic catecholamine that predominantly stimulates both β1- and β2-adrenergic receptors. - Its non-selectivity is one of its drawbacks and the reason why it is rarely used therapeutically. Its action on α receptors is insignificant. ### Actions #### Cardiovascular - Isoproterenol produces intense stimulation of the heart to increase its rate and force of contraction, causing increased cardiac output. - Is useful in the treatment of atrioventricular block or cardiac arrest. - Isoproterenol also dilates the arterioles of skeletal muscle (β2 effect), resulting in decreased peripheral resistance. #### Pulmonary - A profound and rapid bronchodilation is produced by the drug (β2 action). ### Therapeutic Uses - Isoproterenol is as active as epinephrine and rapidly alleviates an acute attack of asthma when taken by inhalation (which is the recommended route). - It can be employed to stimulate the heart in emergency situations only. ### Pharmacokinetics - Given parenterally or as an inhaled aerosol. It is a marginal substrate for COMT and is stable to MAO action. ## Dopamine - Dopamine, the immediate metabolic precursor of norepinephrine, occurs naturally in the CNS in the basal ganglia, where it functions as a neurotransmitter, as well as in the adrenal medulla. ## Dobutamine - Dobutamine is a synthetic, direct-acting catecholamine that is a β1-receptor agonist. (increases cardiac rate (little change) and output with few vascular effects.) - Dobutamine is used to increase cardiac output in congestive heart failure as well as for inotropic support after cardiac surgery. - It does not significantly elevate oxygen demands of the myocardium a major advantage over other sympathomimetic drugs. ## Oxymetazoline - Oxymetazoline is a direct-acting synthetic adrenergic agonist that stimulates both α1- and α2 -adrenergic receptors. - It is primarily used locally in the eye or the nose as a vasoconstrictor. - Oxymetazoline is found in many over-the-counter short-term nasal spray decongestant products as well as in ophthalmic drops for the relief of redness of the eyes associated with swimming, colds, or contact lens. - The mechanism of action of oxymetazoline is direct stimulation of α receptors on blood vessels supplying the nasal mucosa and the conjunctiva to reduce blood flow and decrease congestion. - Rebound congestion is observed with long-term use. ## Phenylephrine - Phenylephrine is a direct-acting, synthetic adrenergic drug that binds primarily to α receptors and favors α1 receptors over α2 receptors. - It is not a catechol derivative and, therefore, not a substrate for COMT. - Phenylephrine is a vasoconstrictor that raises both systolic and diastolic blood pressures. - It has no effect on the heart itself but rather induces reflex bradycardia when given parenterally. - It is often used topically in ophthalmic solutions for mydriasis. Also acts as a nasal decongestant. ## Methoxamine - Methoxamine is a direct-acting, synthetic adrenergic drug that binds primarily to α receptors, with α1 receptors favored over α2 receptors. - Methoxamine raises blood pressure by stimulating α1 receptors in the arterioles, causing vasoconstriction. This causes an increase in total peripheral resistance. - Because of its effects on the vagus nerve, methoxamine is used clinically to relieve attacks of paroxysmal supraventricular tachycardia. - It is also used to overcome hypotension during surgery involving halothane anesthetics. ## Clonidine - Clonidine is an α2 agonist that is used in essential hypertension to lower blood pressure because of its action in the CNS. - It can be used to minimize the symptoms that accompany withdrawal from opiates or benzodiazepines. ## Metaproterenol - Metaproterenol, although chemically similar to isoproterenol, is not a catecholamine, and it is resistant to methylation by COMT. - It can be administered orally or by inhalation. - The drug acts primarily at β2 receptors, producing little effect on the heart and is useful as a bronchodilator in the treatment of asthma and to reverse bronchospasm ## Albuterol, Pirbuterol, and Terbutaline - Albuterol, pirbuterol, and terbutaline are short-acting β2 agonists used primarily as bronchodilators and administered by a metered-dose inhaler. - Compared with the nonselective β-adrenergic agonists, such as metaproterenol, these drugs produce equivalent bronchodilation with less cardiac stimulation. ## Salmeterol and Formoterol - Salmeterol and formoterol are β2-adrenergic selective, long-acting bronchodilators. - A single dose by a metered-dose inhalation device, such as a dry powder inhaler, provides sustained bronchodilation over 12 hours, compared with less than 3 hours for albuterol. ## Indirect-Acting Adrenergic Agonists - Indirect-acting adrenergic agonists cause norepinephrine release from presynaptic terminals or inhibit the uptake of norepinephrine. - They potentiate the effects of norepinephrine produced endogenously, but these agents do not directly affect postsynaptic receptors. ## Amphetamine - The marked central stimulatory action of amphetamine is often mistaken by drug abusers as its only action. - However, the drug can increase blood pressure significantly by α-agonist action on the vasculature as well as β stimulatory effects on the heart. - Its peripheral actions are mediated primarily through the blockade of norepinephrine uptake and cellular release of stored catecholamines. - The CNS stimulant effects of amphetamine and its derivatives have led to their use for treating hyperactivity in children, narcolepsy, and appetite control. ## Tyramine - Tyramine is not a clinically useful drug, but it is important because it is found in fermented foods, such as ripe cheese and Chianti wine. - It is a normal byproduct of tyrosine metabolism. Normally, it is oxidized by MAO in the gastrointestinal tract, but if the patient is taking MAO inhibitors, it can precipitate serious vasopressor episodes. - Tyramine can enter the nerve terminal and displace stored norepinephrine. ## Cocaine - Cocaine is unique among local anesthetics in having the ability to block the Na+/K+-activated ATPase (required for cellular uptake of norepinephrine) on the cell membrane of the adrenergic neuron. - Consequently, norepinephrine accumulates in the synaptic space, resulting in enhancement of sympathetic activity and potentiation of the actions of epinephrine and norepinephrine. - Therefore, small doses of the catecholamines produce greatly magnified effects in an individual taking cocaine as compared to those in one who is not. - In addition, the duration of action of epinephrine and norepinephrine is increased. ## Mixed-Action Adrenergic Agonists - Mixed-action drugs induce the release of norepinephrine from presynaptic terminals, and they activate adrenergic receptors on the postsynaptic membrane. ## Ephedrine and Pseudoephedrine - Ephedrine and pseudoephedrine are plant alkaloids, that are now made synthetically. - These drugs are mixed-action adrenergic agents. - They not only release stored norepinephrine from nerve endings but also directly stimulate both α and β receptors. - Ephedrine and pseudoephedrine are not catechols and are poor substrates for COMT and MAO; thus, these drugs have a long duration of action. - Ephedrine and pseudoephedrine have excellent absorption orally and penetrate into the CNS. - Ephedrine raises systolic and diastolic blood pressures by vasoconstriction and cardiac stimulation. ## Adrenergic Antagonists ### Overview - The adrenergic antagonists (also called blockers or sympatholytic agents) bind to adrenoceptors 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. ### α-Adrenergic Blocking Agents - Like the agonists, the adrenergic antagonists are classified according to their relative affinities for α or β receptors in the peripheral nervous system. - Drugs that block α-adrenoceptors profoundly affect blood pressure. - Blockade of α-adrenergic receptors reduces the sympathetic tone of the blood vessels, resulting in decreased peripheral vascular resistance. - This induces a reflex tachycardia resulting from the lowered blood pressure. - The α-adrenergic blocking agents, phenoxybenzamine and phentolamine, have limited clinical applications. #### Phenoxybenzamine - Phenoxybenzamine is nonselective, linking covalently to both α1-postsynaptic and α2-presynaptic receptors. - The block is irreversible and noncompetitive, and the only mechanism the body has for overcoming the block is to synthesize new adrenoceptors, which requires a day or more. - Therefore, the actions of phenoxybenzamine last about 24 hours after a single administration. ##### Actions ###### Cardiovascular Effects - By blocking α receptors, phenoxybenzamine prevents vasoconstriction of peripheral blood vessels by endogenous catecholamines. - The decreased peripheral resistance provokes a reflex tachycardia. - The drug has been unsuccessful in maintaining lowered blood pressure in hypertension because of the ability to block presynaptic inhibitory α2 receptors in the heart can contribute to an increased cardiac output. phenoxybenzamine causes an increase in the release of norepinephrine, which in turn increases heart rate and cardiac output (mediated by β1 receptors) ###### Epinephrine Reversal - All α-adrenergic blockers reverse the α-agonist actions of epinephrine. - For example, the vasoconstrictive action of epinephrine is interrupted, but vasodilation of other vascular beds caused by stimulation of β receptors is not blocked. - Phenoxybenzamine has no effect on the actions of isoproterenol (a pure β agonist.) - Therapeutic uses: - Phenoxybenzamine is used in the treatment of pheochromocytoma, a catecholamine secreting tumor of cells derived from the adrenal medulla. - Phenoxybenzamine or phentolamine are sometimes effective in treating Raynaud's disease (is a rare disorder of the blood vessels, usually in the fingers and toes. It causes the blood vessels to narrow when you are cold or feeling stressed). - Adverse effects: - Phenoxybenzamine can cause postural hypotension. - It can inhibit ejaculation. #### Phentolamine - Phentolamine produces a competitive block of α1 and α2 receptors. - Like phenoxybenzamine, it produces postural hypotension and causes epinephrine reversal. - Phentolamine-induced reflex cardiac stimulation and tachycardia are mediated by the baroreceptor reflex and by blocking the α2 receptors of the cardiac sympathetic nerves. - Phentolamine is also used for the short-term management of pheochromocytoma. #### Prazosin, Terazosin, Doxazosin, Alfuzosin, and Tamsulosin - All these are selective competitive blockers of the α1 receptor. - In contrast to phenoxybenzamine and phentolamine, the first three drugs are useful in the treatment of hypertension. - Tamsulosin and alfuzosin are indicated for the treatment of benign prostatic hypertrophy (also known as benign prostatic hyperplasia or BPH). ##### Cardiovascular Effects - All of these agents decrease peripheral vascular resistance and lower arterial blood pressure by causing the relaxation of both arterial and venous smooth muscle. - Tamsulosin has the least effect on blood pressure. ##### Therapeutic Uses - The first dose of these drugs produces an exaggerated orthostatic hypotensive response that can result in syncope (fainting). - This action, termed a first-dose effect, may be minimized by adjusting the first dose to one-third or one-fourth of the normal dose and by giving the drug at bedtime. - The α1-receptor antagonists have been used as an alternative to surgery in patients with symptomatic BPH (Benign prostatic hyperplasia). ##### Tamsulosin - Tamsulosin is a more potent inhibitor of the α1 receptors found on the smooth muscle of the prostate. This selectivity accounts for tamsulosin's minimal effect on blood pressure. ## Yohimbine - Yohimbine is a selective competitive α2 blocker. - It is found as a component of the bark of the yohimbe tree and is sometimes used as a sexual stimulant. - Yohimbine is contraindicated in CNS and cardiovascular conditions because it is a CNS and cardiovascular stimulant. ## β-Adrenergic Blocking Agents - All the clinically available β-blockers are competitive antagonists. - Cardioselective β antagonists primarily block β1 receptors. ### Timolol and Nadolol - Timolol and nadolol 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 and, occasionally, for systemic treatment of hypertension. ### Acebutolol, Atenolol, Metoprolol, and Esmolol - Drugs that preferentially block the β1 receptors have been developed to eliminate the unwanted bronchoconstrictor effect (β2 effect) of propranolol seen among asthmatic patients. ### Cardioselective β-Blockers - 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. - These drugs lower blood pressure in hypertension and increase exercise tolerance in angina. - Esmolol has a very short lifetime due to metabolism. - In contrast to propranolol, the cardiospecific blockers have relatively little effect on pulmonary function, peripheral resistance, and carbohydrate metabolism. ##### Therapeutic Use in Hypertension - The cardioselective β-blockers are useful in hypertensive patients with impaired pulmonary function. - Coldness of extremities, a common side effect of β-blocker therapy, is less frequent. ### Pindolol and Acebutolol - Acebutolol and pindolol are not pure antagonists; instead, they have the ability to weakly stimulate both β1 and β2 receptors. - These partial agonists stimulate the β receptor to which they are bound, yet they inhibit stimulation by the more potent endogenous catecholamines, epinephrine and norepinephrine. - They are effective in hypertensive patients with moderate bradycardia, because a further decrease in heart rate is less pronounced with these drugs. - Carbohydrate metabolism is less affected with acebutolol and pindolol than it is with propranolol, making them valuable in the treatment of diabetics. ### Labetalol and Carvedilol - Labetalol and carvedilol are reversible β-blockers with concurrent α1-blocking actions that produce peripheral vasodilation, thereby reducing blood pressure. - They do not alter serum lipid or blood glucose levels. - Labetalol is useful for treating the elderly or black hypertensive patient in whom increased peripheral vascular resistance is undesirable. - Labetalol may be employed as an alternative to methyldopa in the treatment of pregnancy-induced hypertension. ### Drugs Affecting Neurotransmitter Release or Uptake - Amphetamine and tyramine, as agonists do not act directly on the adrenoceptor. - Similarly, some agents act on the adrenergic neuron, either to interfere with neurotransmitter release or to alter the uptake of the neurotransmitter into the adrenergic nerve. #### Reserpine - Reserpine, a plant alkaloid, blocks the Mg2+/adenosine triphosphate dependent transport of biogenic amines, norepinephrine, dopamine, and serotonin from the cytoplasm into storage vesicles in the adrenergic nerves of all body tissues. - This causes the ultimate depletion of biogenic amines. - Sympathetic function, in general, is impaired because of decreased release of norepinephrine. - The drug has a slow onset, a long duration of action, and effects that persist for many days after discontinuation. #### Guanethidine - Guanethidine blocks the release of stored norepinephrine as well as displaces norepinephrine from storage vesicles (thus producing a transient increase in blood pressure). - This leads to gradual depletion of norepinephrine in nerve endings except for those in the CNS. - Supersensitivity to norepinephrine due to depletion of the amine can result in hypertensive crisis in patients with pheochromocytoma. #### Cocaine - Although cocaine inhibits norepinephrine uptake, it is an adrenergic agonist. ## Adrenergic Agonists (Adrenergic Blocking Agents) - Note: There are no clinically useful β2 antagonists. - Although all β-blockers lower blood pressure in hypertension, they do not induce postural hypotension, because the α-adrenoceptors remain functional. Therefore, normal sympathetic control of the vasculature is maintained. - β-Blockers are also effective in treating angina, cardiac arrhythmias, myocardial infarction, congestive heart failure, hyperthyroidism, and glaucoma, as well as serving in the prophylaxis of migraine headaches. ### Propranolol - Propranolol is the prototype β-adrenergic antagonist and blocks both β1 and β2 receptors. ##### Actions ###### Cardiovascular - Propranolol diminishes cardiac output, having both negative inotropic and chronotropic effects. - It directly depresses sinoatrial and atrioventricular activity. · Cardiac output, work, and oxygen consumption are decreased by blockade of β1 receptors; these effects are useful in the treatment of angina. ###### Peripheral Vasoconstriction - Blockade of β receptors prevents β2-mediated vasodilation. - The reduction in cardiac output leads to decreased blood pressure. - This hypotension triggers a reflex peripheral vasoconstriction that is reflected in reduced blood flow to the periphery. - Reduced blood pressure causes a decrease in renal perfusion, resulting in an increase in Na+ retention and plasma volume. For these patients, β-blockers are often combined with a diuretic to prevent Na+ retention. ###### Bronchoconstriction - Blocking β2 receptors in the lungs of susceptible patients causes contraction of the bronchiolar smooth muscle. β-Blockers, and in particular nonselective ones, are thus contraindicated in patients with COPD or asthma. - Note: All β-blockers, including propranolol, have the ability to block the actions of isoproterenol on the cardiovascular system. - B-blockade leads to decreased glycogenolysis and decreased glucagon secretion