Adrenergic Agonists and Antagonists

Question 1

Chemistry of Adrenergic Agonists

Answer 1

β-phenylethylamine can be viewed as the parent compound of the sympathomimetic amines; it consists of a benzene ring and an ethylamine side chain. The structure permits substitutions to be made on the aromatic ring, the α- and β-carbon atoms, and the terminal amino group to yield a variety of compounds with sympathomimetic activity.

Norepinephrine, epinephrine, dopamine, isoproterenol and a few other agents have –OH groups substituted at positions 3 and 4 of the benzene ring.

Since o-dihydroxy-benzene is also known as catechol, sympathomimetic amines with these hydroxyl substitutions in the aromatic ring are termed catecholamines.

Many directly acting sympathomimetic drugs activate both α and β receptors, but the ratio of activities varies among drugs in a continuous spectrum from predominantly α activity (e.g., phenylephrine) to predominantly β activity (e.g., isoproterenol).

Question 2

Characteristics of Catecholamines

Answer 2

Sympathetic amines with the 3,4-dihydroxybenzene group are called catecholamines. Eg: epinephrine, norepinephrine, isoproterenol, dopamine. They share the following properties:

1. High potency.
2. Rapid inactivation: metabolized by COMT postsynaptically and by MAO intraneuronally. Also metabolized in other tissues. For example, COMT is found in the gut wall and MAO is found in the liver and gut wall. Thus, catecholamines have only a brief period of action when given parenterally, and are ineffective when given orally because of inactivation.
3. Poor penetration into the CNS: catecholamines are polar, thus they do not penetrate well into the CNS. However, most of these drugs have some chemical effects (anxiety, tremor, headaches) attributable to actions on CNS.

Side Note: Think of peripheral resistance as having more of an effect on diastolic blood pressure and heart contractility and rate as having more of an effect on systolic blood pressure. This will be helpful in determining baroreceptor reflex under different concentrations of catecholamines, etc.

Question 3

Non-Catecholamines

Answer 3

Compounds lacking the catechol -OH groups have longer half-lives, since they are not inactivated by COMT. These include: phenylephrine, ephedrine and amphetamine. Also, increased liposolubility permits greater access to the CNS. Some of these compounds may act indirectly by causing release of stored catecholamines.

Question 4

Epinephrine

Cardiovascular Effects

Answer 4

Synthesized from tyrosine in the adrenal medulla. Released along with norepinephrine into the blood. Agonist at α and β receptors. Under physiologic conditions epinephrine acts as a hormone: after release from the adrenal medulla into the blood it acts on distant cells.

ACTIONS:

Increases contractility of myocardium (positive inotropic: β1 effect).

Increases contraction rate (positive chronotropic: β1 effect).

Cardiac output increases, therefore there is an increase of oxygen demand of the myocardium.

Increases renin release (β1 effect).

Constricts arterioles in skin, mucous membranes and viscera (α1 effect).

At low doses dilates blood vessels going to the skeletal muscle and liver (β2 effect).

Question 5

Effects of Epinephrine on Blood Pressure

High v. Low doses of Epinephrine

Answer 5

A. When a large dose is given

A large dose of epinephrine given IV causes an increase in blood pressure. The increase in systolic pressure is greater than the increase in the diastolic pressure. The rise in blood pressure caused by epinephrine is due to:

Increased ventricular contraction (β1 effect).

Increased heart rate (β1 effect). Note: The heart rate, at first accelerated, may be slowed markedly at the height of the rise of blood pressure due to the baroreceptor reflex.

Vasoconstriction (α1 effect).

B. When a low dose is given

A low dose of epinephrine may cause the blood pressure to fall. This is a consequence of the greater sensitivity to epinephrine of vasodilator β2 receptors than of vasoconstrictor α1 receptors. At low doses of epinephrine, β2 effects (vasodilation) predominate.

Peripheral resistance decreases, due to a dominant action on β2 receptors of blood vessels in skeletal muscle, where blood flow is enhanced. As a consequence, diastolic pressure usually falls.

Systolic pressure increases due to increased cardiac contractile force, and a rise in cardiac output (β1 effect).

Heart rate increases (β1 effect).

The mean blood pressure is not, as a rule, greatly elevated, therefore compensatory baroreceptor reflexes do not appreciably antagonize the direct cardiac actions.

Thus, the effects of epinephrine on peripheral vascular resistance and diastolic pressure depend on the dose of epinephrine and the resultant ratio of the α1 to β2 responses in the various vascular beds; compensatory reflexes also may come into play.

Question 6

Effects of Epinephrine on Smooth Muscles

Answer 6

Epinephrine causes powerful bronchodilation by acting directly on bronchial smooth muscle (β2 effect).

Epinephrine relaxes GI smooth muscle (α1, α2, and β2 effects). Intestinal tone and frequency and amplitude of spontaneous contractions are reduced. Sphincters are contracted (α1effect).

The detrusor muscle of the bladder relaxes (β2 effect), the trigone and sphincter contract (α1 effect). This may lead to urinary retention. Contraction of smooth muscle in the prostate (α1 effect) promotes urinary retention.

Question 7

Effects of Epinephrine on the CNS

Answer 7

Epinephrine is rather polar therefore it does not enter the CNS in therapeutic doses. Epinephrine may cause restlessness, apprehension, headache and tremor in many persons; however, these effects in part may be secondary to the effects of epinephrine on the CV system, skeletal muscles and intermediary metabolism.

Question 8

Metabolic Effects of Epinephrine

Answer 8

Hyperglycemia

Significant hyperglycemic effect due to:

Increase of glycogenolysis in liver (β2 effect).

Increase of glucagon release by activation of β2 receptors on α cells of pancreatic islets.

Insulin secretion is inhibited by activation of α2 receptors and enhanced by activation of β2 receptors. The predominant effect is inhibition of insulin secretion.

Lipolysis

Epinephrine stimulates lipolysis by activation of β3 receptors in adipose tissue. β3 receptor activation increases cAMP levels which activate hormone-sensitive lipase. The lipase hydrolyzes TAGs to yield free fatty acids and glycerol. The concentration of free fatty acids in blood increases.

Question 9

Metabolism, Uses, Pharmacokinetics, and Adverse Effects of Epinephrine

Answer 9

METABOLISM

Metabolized by COMT and MAO. Final metabolites found in urine: metanephrine and vanillyl-mandelic acid (VMA).

USES

Anaphylactic Shock: drug of choice for treatment of Type I hypersensitivity reactions in response to allergens.

Used to treat acute asthmatic attacks.

Cardiac arrest: Epinephrine may be used to restore cardiac rhythm in patients with cardiac arrest due to various causes.

In Local Anesthetics: local anesthetic solutions usually contain epinephrine. Epinephrine increases duration of local anesthesia by producing vasoconstriction at the site of injection, allowing the local anesthetic to persist at the site before being absorbed into the circulation and metabolized.

PHARMACOKINETICS

Rapid onset; brief duration. In emergency situations it is given IV. May also be given SC, by endotracheal tube, by inhalation, or topically to the eye. Oral administration is ineffective because epinephrine is inactivated by intestinal enzymes. Only metabolites are excreted in urine.

ADVERSE EFFECTS

CNS disturbances: anxiety, fear, tension, headache, tremor.

Hemorrhage: may induce cerebral hemorrhage due toin blood pressure.

Cardiac arrhytmias: particularly if the patient is receiving digitalis.

Pulmonary edema.

Question 10

Interactions of Epinephrine

Hyperthyroidism, Cocaine, and B-blockers

Answer 10

Hyperthyroidism: Epinephrine may have enhanced CV actions in patients with hyperthyroidism. The mechanism appears to involve an increase in production of adrenergic receptors on the vasculature of the hyperthyroid individual, leading to a hypersensitive response.

Cocaine: in the presence of cocaine, epinephrine produces exaggerated CV actions, due to the ability of cocaine to prevent re-uptake of catecholamines into the adrenergic neuron. Thus, like norepinephrine, epinephrine remains at the receptor for longer.

β-blockers: β-blockers prevent epinephrine’s activation of β receptors, leaving α receptor activation unopposed. This may lead to an increase in peripheral resistance and blood pressure.

Question 11

Norepinephrine

Pharmacological Properties, Cardiovascular Actions, and Uses, plus other Effects

Answer 11

Norepinephrine is the neurotransmitter at adrenergic nerves. Therefore, it should stimulate all types of adrenergic receptors. In practice, when given in therapeutic doses to humans, the α-adrenergic receptor is the most affected.

PHARMACOLOGICAL PROPERTIES

Norepinephrine is an agonist at both α1 and α2 receptors. Norepinephrine also activates β1 receptors with similar potency as epinephrine, but has relatively little effect on β2 receptors.

CARDIOVASCULAR ACTIONS

Vasoconstriction: increases peripheral resistance due to vasoconstriction of most vascular beds, including kidney (α1 effect). Both systolic and diastolic blood pressures increase.

Baroreceptor reflex: in isolated cardiac tissue norepinephrine increases cardiac contractility (β1 effect). In vivo, little stimulation is observed. This is due to the increase in blood pressure that induces a reflex rise in vagal activity by stimulation of baroreceptors. The reflex bradycardia counteracts local actions of norepinephrine on the heart.

Cardiac output is unchanged or decreased.

Effect of atropine pre-treatment: if atropine (which blocks transmission of vagal effects) is given before norepinephrine, norepinephrine causes tachycardia.

Unlike epinephrine, small doses of norepinephrine do not cause vasodilation or lower blood pressure, since the blood vessels of skeletal muscle constrict rather than dilate; α1-adrenergic receptor blocking agents therefore abolish the pressor effects but don’t cause significant reversal.

OTHER EFFECTS

The drug causes hyperglycemia and other metabolic effects similar to those produced by epinephrine, but these are observed only when large doses are given; that is, norepinephrine is not as effective a “hormone” as is epinephrine.

USES

Norepinephrine is used for blood pressure control in certain acute hypotensive states.

Norepinephrine is used in the treatment of cardiogenic and septic shock.

Dopamine is better because it doesn’t􏰋 decrease blood flow to the kidney as does norepinephrine.

Question 12

Dopamine

Low, Intermediate, and High rates of Infusion

Answer 12

Immediate metabolic precursor of norepinephrine and epinephrine. Dopamine is a substrate for both MAO and COMT and thus is ineffective when given orally.

CARDIOVASCULAR EFFECTS

The cardiovascular effects of dopamine are mediated by several distinct types of receptors that vary in their affinity for dopamine. Therefore the cardiovascular response to dopamine depends on the dose infused.

Low rates of infusion: dopamine selectively activates D1 receptors, in renal and other vascular beds, leading to vasodilation and increase in GFR, renal blood flow and sodium excretion.

Intermediate rates of infusion: dopamine activates β1 receptors in the heart, thus stimulating cardiac contractility and increasing cardiac output. Dopamine also causes release of norepinephrine from nerve terminals, which contributes to its effects on the heart. Dopamine usually increases systolic blood pressure. Diastolic pressure is usually not changed significantly. Mean arterial pressure is increased. Total peripheral resistance is unchanged or decreased due to the vasodilator effect of dopamine.

Higher rates of infusion: Dopamine activates vascular α1 receptors, leading to vasoconstriction and a rise in blood pressure. Total peripheral resistance may be increased.

OTHER EFFECTS

Although there are specific dopamine receptors in the CNS, injected dopamine has no central effects because it does not readily cross the blood-brain barrier.

USES

Dopamine is used in the treatment of severe congestive heart failure. Dopamine can also be used in the treatment of cardiogenic and septic shock.

ADVERSE EFFECTS

Overdose of dopamine produces the same effects as sympathetic stimulation.

Rapidly metabolized to homovanillic acid; its adverse effects (nausea, hypertension, arrhythmias) are therefore short-lived.

Question 13

Fenoldopam

Answer 13

RELATED DOPAMINERGIC DRUGS

D1-receptor selective agonist, which selectively leads to peripheral vasodilation in some vascular beds. Indicated for in-hospital, short-term management of severe hypertension. Fenoldopam should be administered by continuous intravenous infusion. A bolus dose should not be used.

Question 14

β-Adrenergic Agonists Uses

Answer 14

β-adrenergic agonists play major roles in the treatment of bronchoconstriction in patients with asthma, or as cardiac stimulants.

Question 15

Isoproterenol

Cardiovascular, Pulmonary, Adverse and Other effects plus Uses

Answer 15

NON-SELECTIVE β-ADRENERGIC AGONISTS

Stimulates β1 and β2 adrenergic receptors. Action on α receptors is insignificant. Marginal substrate for COMT, and stable to MAO action.

CARDIOVASCULAR EFFECTS

Intense stimulation of the heart (β1 effect). Increases rate and force of contraction, thus increasing cardiac output.

Dilates arterioles of skeletal muscle (β2 effect), resulting in a decrease in peripheral resistance.

Because of the cardiac stimulatory action it may increase systolic blood pressure slightly, but it greatly decreases mean arterial and diastolic blood pressure.

PULMONARY EFFECTS

Bronchodilation (β2 action).

OTHER EFFECTS

GI smooth muscle is relaxed.

Isoproterenol causes less hyperglycemia than epinephrine, in part because insulin secretion is stimulated by the strong β-adrenergic activation of pancreatic islet cells.

Isoproterenol and epinephrine are equally effective in stimulating the release of free fatty acids and in energy production.

USES

Isoproterenol may be used in emergencies to stimulate heart rate in patients with bradycardia or heart block.

ADVERSE EFFECTS

Similar to epinephrine.

Question 16

Dobutamine

Answer 16

β1-SELECTIVE ADRENERGIC AGONISTS

Dobutamine is administered as a racemic mixture consisting of the (+) and the (−) isomers. The (-) isomer is an α1-receptor agonist and a weak β1 agonist. The (+) isomer is an α1-antagonist and a potent β1 agonist. The observed clinical result is that of a selective β1 agonist.

Dobutamine has greater inotropic than chronotropic effects. It increases contractility and cardiac output. Peripheral resistance and blood pressure are not significantly affected. Heart rate increases modestly. Dobutamine does not significantly elevate oxygen demands of the myocardium (not known why): major advantage over other sympathomimetic drugs.

USES

Used to increase cardiac output in the management of acute heart failure. Used in the management of cardiogenic shock.

Question 17

β2-Selective Adrenergic Agonists

Answer 17

Some of the major adverse effects of β-adrenergic agonists in the treatment of asthma are caused by stimulation of β1-adrenergic receptors in the heart. Accordingly, drugs with preferential affinity for β2-receptors compared with β1-receptors have been developed. However, this selectivity is not absolute, and it is lost at sufficiently high concentration of these drugs.

ADVERSE EFFECTS OF β2 AGONISTS

The major adverse effects of the β2 agonists are mainly a consequence of excessive activation of β2 receptors.

Tremor is a relatively common adverse effect, but tolerance generally develops. Other adverse effects include restlessness, apprehension, and anxiety.

Tachycardia is a common adverse effect of systemically administered receptor agonists. This is due primarily to activation of β1 receptors. It is uncertain to what extent the increase in heart rate also is due to activation of cardiac β2 receptors, or a reflex due to β2 receptor–mediated peripheral vasodilation.

All these adverse effects are far less likely with inhalation therapy than with parenteral or oral therapy.

TERBUTALINE AND ALBUTEROL

SALMETEROL AND FORMOTEROL

Question 18

Terbutaline and Albuterol

Answer 18

β2-SELECTIVE ADRENERGIC AGONISTS

Short-acting β2 agonists used primarily as bronchodilators and administered by a metered-dose inhaler. Also available in tablet form. Terbutaline is also available for SC injection. Terbutaline is also used to reduce uterine contractions in premature labor.

Question 19

Salmeterol and Formoterol

Answer 19

β2-SELECTIVE ADRENERGIC AGONISTS

β2- selective, long-acting bronchodilators. Prolonged duration of action (12 hours), as a result of high lipid solubility. They have a relatively slow onset of action after inhalation: not suitable for prompt relief of breakthrough attacks of bronchospasm.

Question 20

Phenylephrine

Answer 20

α1-SELECTIVE ADRENERGIC AGONISTS

Activation of α-adrenergic receptors in vascular smooth muscle results in an increase in peripheral vascular resistance and thus blood pressure is maintained or elevated. They may be useful in the treatment of some patients with hypotension or shock.

Selective α1 receptor agonist. Not a catechol derivative: not a substrate for COMT. Vasoconstrictor: raises both systolic and diastolic pressures. It has no direct effect on the heart, but induces reflex bradycardia when given parenterally.

USES

Used as a nasal decongestant. α-adrenergic agonists are used extensively as nasal decongestants. They decrease resistance to airflow by decreasing the volume of the nasal mucosa by activating α1-adrenergic receptors in venous capacitance vessels in nasal tissues. May be administered either orally or topically.

Used as a mydriatic.

Indicated for increasing blood pressure in hypotension resulting from vasodilation in septic shock or anesthesia.

Used to increase blood pressure and thus terminate episodes of supraventricular tachycardia.

Question 21

Clonidine, Methyldopa, and Brimonidine

Answer 21

α2-SELECTIVE ADRENERGIC AGONISTS

CLONIDINE

Partial α2 agonist. Centrally acting antihypertensive agent. The antihypertensive effect of clonidine results from activation of α2 adrenoceptors in the cardiovascular control centers of the CNS; such activation suppresses the outflow of sympathetic nervous system activity from the brain via the presynatic α2 receptors.

NOTE: IV infusion of clonidine causes an acute rise in blood pressure, apparently because of activation of postsynaptic α2 adrenoceptors in vascular smooth muscle. This transient vasoconstriction is followed by a more prolonged hypotensive response which results from decreased sympathetic outflow from the CNS. The hypertensive response that follows IV administration is not seen when the drug is given orally.

Adverse effects include lethargy, sedation, xerostomia.

METHYLDOPA

Centrally acting antihypertensive agent. Taken up by noradrenergic neurons and metabolized to α-methylnorepinephrine. α-methylnorepinephrine is thought to activate central α2-adrenoceptors and lower blood pressure in a manner similar to that of clonidine. Methyldopa diminishes adrenergic outflow from the CNS, leading to reduced total peripheral vascular resistance and decreased blood pressure.

Methyldopa is the drug of choice for treatment of hypertension during pregnancy due to its effectiveness and safety for both mother and fetus.

Adverse effects include sedation, mental lassitude, impaired mental concentration, dry mouth.

BRIMONIDINE

Highly selective α2 agonist administered ocularly to lower intraocular pressure in glaucoma. Reduces aqueous humor production and increases uveoscleral outflow.

Question 22

Amphetamine, Methylphenidate and Tyramine (Cheese Reaction)

Answer 22

INDIRECT-ACTING ADRENERGIC AGONISTS:

RELEASING AGENTS

Cause norepinephrine release from presynaptic terminals. They potentiate effects of norepinephrine produced endogenously.

AMPHETAMINE

It displaces endogenous catecholamines from storage vesicles.

Amphetamine can increase blood pressure significantly by α1-agonist action on vasculature as well as β1-stimulatory effects on heart. Its peripheral actions are mediated primarily by release of stored catecholamines.

Amphetamine has a central stimulatory action. Amphetamine has marked behavioral effects including increased alertness, decreased fatigue, depressed appetite, and insomnia. It has been used to treat depression and narcolepsy and to suppress appetite.

Its adverse effects include fatigue and depression following the period of central stimulation.

USES

Amphetamine is used for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy.

METHYLPHENIDATE

Structural analogue of amphetamine.

USES

Used to treat attention-deficit hyperactivity disorder (ADHD) and narcolepsy.

TYRAMINE

Not clinically useful. Found in fermented foods such as ripe cheese and Chianti wine. Normal by-product of tyrosine metabolism. Normally oxidized by MAO. If the patient is taking MAO inhibitors, it can precipitate serious vasopressor episodes. Like amphetamine, tyramine can enter the nerve terminal and displace stored norepinephrine. The released catecholamine acts on adrenoceptors.

Question 23

Cocaine, Atomoxetine, and Modafinil

Answer 23

UPTAKE INHIBITORS

COCAINE

Cocaine blocks reuptake of the monoamines into the presynaptic terminals. Cocaine is most potent at blocking the dopamine transporter (DAT); higher concentrations block the serotonin transporter (SERT) and the norepinephrine transporter (NET). This blockade leads to accumulation of the monoamines in the synaptic space resulting in potentiation and prolongation of their central and peripheral actions.

The sympathetic effects of cocaine include tachycardia, hypertension, pupillary dilation and peripheral vasoconstriction.

The major action of cocaine in the CNS is the inhibition of dopamine reuptake into neurons of the pleasure centers (the limbic system) of the brain; this produces the intense euphoria that cocaine evokes.

Additionally, cocaine blocks voltage-activated sodium channels and is used as a local anesthetic.

USES

Cocaine is used primarily for topical anesthesia of the upper respiratory tract.

ATOMOXETINE

Selective inhibitor of the norepinephrine reuptake transporter (NET).

USES

Indicated for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD).

MODAFINIL

Psychostimulant. Its mechanism of action is not fully known. It inhibits norepinephrine and dopamine transporters, increases synaptic concentrations of norepinephrine, dopamine, serotonin and glutamate, and decreases GABA levels.

USES

Modafinil is used for the treatment of narcolepsy.

Question 24

Ephedrine and Pseudoephredine

Answer 24

MIXED-ACTING ADRENERGIC AGONISTS

Induce release of norepinephrine and activate adrenergic receptors.

EPHEDRINE

Plant alkaloid, now made synthetically.

Activates α and β receptors, and releases norepinephrine from nerve endings.

Not a catecholamine. Poor substrate for COMT and MAO: long duration of action.

Excellent absorption orally. Penetrates the CNS. Eliminated unchanged in urine.

ACTIONS

Increases systolic and diastolic blood pressures by vasoconstriction and cardiac stimulation.

Causes bronchodilation.

Concomitant use of ephedrine with an anticholinesterase may have a synergistic effect in myasthenia gravis (the exact mechanism by which ephedrine affects skeletal muscle contraction is unknown).

Produces mild stimulation of CNS: increases alertness, decreases fatigue and prevents sleep. It also improves athletic performance.

Ephedrine-containing herbal supplements were banned by the FDA in April 2004 because of life-threatening cardiovascular reactions.

USES

Ephedrine is used as a pressor agent, particularly during spinal anesthesia when hypotension frequently occurs.

Ephedrine is indicated in the treatment of allergic disorders, such as bronchial asthma. Because of the development of β2-selective agonists, ephedrine is now used infrequently to treat asthma.

It is also used in myasthenia gravis.

PSEUDOEPHEDRINE

Pseudoephedrine, one of four ephedrine enantiomers, has been available over the counter as a component of many nasal decongestant mixtures. Usually found in combination with an H1-histamine antagonist.

Question 25

α-Adrenergic Blockers

Answer 25

Affect blood pressure. Since normal sympathetic control of the vasculature occurs in large part through agonist actions on α-adrenergic receptors, blockade of these receptors reduces the sympathetic tone of the blood vessels, resulting in decreased peripheral vascular resistance.

Question 26

Phenoxybenzamine

Answer 26

NON-SELECTIVE α-ADRENERGIC BLOCKERS

Phenoxybenzamine is a haloalkylamine which alkylates and thus irreversibly blocks α- adrenergic receptors. Closely related chemically to the nitrogen mustards.
Slightly selective for α1 receptors. Also blocks H1, muscarinic and serotonin receptors and inhibits reuptake of norepinephrine by presynaptic adrenergic nerve terminals.

CARDIOVASCULAR EFFECTS

By blocking α receptors, phenoxybenzamine prevents vasoconstriction of peripheral blood vessels by endogenous catecholamines. Decreased peripheral resistance provokes reflex tachycardia. The ability to block presynaptic α2 receptors in the heart can contribute to increased cardiac output. The drug has been unsuccessful in maintaining low blood pressure in hypertension and is no longer used for this purpose.

USES

Pheochromocytoma

The major clinical use of phenoxybenzamine (and phentolamine, [see below]) is in the management of pheochromocytoma, a catecholamine-secreting tumor of cells derived from the adrenal medulla. Patients have many symptoms and signs of catecholamine excess, including intermittent or sustained hypertension, headaches, palpitations and sweating.

Phenoxybenzamine is administered in the preoperative period to help control hypertension and sweating.

Phenoxybenzamine can also be useful in the chronic treatment of inoperable or metastatic pheochromocytoma. A β-blocker may be required after α-receptor blockade has been instituted in order to control tachycardia. β-blockers should not be given before establishing effective α blockade, since unopposed β blockade could cause blood pressure elevation due to increased vasoconstriction.

ADVERSE EFFECTS

Postural hypotension, nasal stuffiness, nausea and vomiting.

It can inhibit ejaculation.

May induce tachycardia, mediated by the baroreceptor reflex, and is contraindicated in patients with decreased coronary perfusion.

Question 27

Phentolamine

Answer 27

NON-SELECTIVE α-ADRENERGIC BLOCKERS

PHENTOLAMINE

Reversibly blocks α1 and α2 receptors.

Causes postural hypotension.

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 blocks serotonin receptors, and is an agonist at muscarinic, H1 and H2 receptors.

The drug can also trigger arrhythmias and anginal pain.

Contraindicated in patients with decreased coronary perfusion.

USES

Prevention or control of hypertensive episodes that may occur in a patient with pheochromocytoma as a result of stress or manipulation during preoperative preparation and surgical excision.

Diagnosis of pheochromocytoma by the phentolamine blocking test.

Indicated for the prevention of dermal necrosis after the inadvertent extravasation of norepinephrine.

Used in hypertensive crisis associated with stimulant drug overdose (eg, amphetamines, cocaine, or ephedrine). Also an adjunct for cocaine-induced acute coronary syndrome to reverse coronary artery vasoconstriction.

Used in hypertensive crisis associated with sudden withdrawal of sympatholytic antihypertensive drugs (eg, clonidine).

Used in hypertensive crisis resulting from interaction between monoamine oxidase inhibitors and tyramine or other sympathomimetic amines.

EPINEPHRINE REVERSAL

All α-adrenergic blockers reverse the α-agonist effects of epinephrine. For example, the vasoconstrictive action of epinephrine is blocked, but vasodilation of other vascular beds caused by stimulation of β-receptors is not blocked. Therefore, the systemic blood pressure decreases in response to epinephrine given in the presence of phenoxybenzamine.

Relevant if an ER patient is on alpha blocker but u dont know that and give epi to raise BP but instead it goes further down and patient dies!

NOTE: The actions of norepinephrine are not reversed but diminished, since norepinephrine lacks significant β-agonist action on the vasculature.

Question 28

α1-Selective Adrenergic Blockers

Answer 28

Selective blockers of the α1-receptor. In contrast to phenoxybenzamine and phentolamine, these drugs are useful in the treatment of hypertension. Prazosin is the prototype.

USES OF α1-SELECTIVE ADRENERGIC BLOCKERS Hypertension

Prazosin and congeners are used in the treatment of hypertension.

They are not drugs of choice for hypertension.

The first dose produces an exaggerated hypotensive response that can result in syncope (fainting) 30 – 90 minutes after the dose is taken. This action, termed a ‘first dose’ effect may be minimized by adjusting the first dose to 1/3 or 1/4 of normal dose, and by giving the drug at bed time.

Benign prostatic hyperplasia (BPH)

α1-adrenergic receptors in the trigone muscle of the bladder and urethra contribute to resistance to outflow of urine. α1-selective adrenergic antagonists relax smooth muscle in the bladder neck, prostate capsule and prostatic urethra improving urinary flow. α1-adrenergic blockers are drugs of choice for symptom relief. Tamsulosin is less likely to cause orthostatic hypotension than the other drugs.

ADVERSE EFFECTS

α1 blockers may cause dizziness, lack of energy, nasal congestion, headache, drowsiness, orthostatic hypotension.

Due to a tendency to retain sodium and fluid, α-blockers are frequently co- administered with a diuretic.

Male sexual function is not as severely affected by these drugs as it is by phenoxybenzamine or phentolamine.

Question 29

Prazosin

Answer 29

Prazosin decreases peripheral vascular resistance and lowers arterial blood pressure by causing relaxation of both arterial and venous smooth muscle. Thus, reflex tachycardia does not typically occur.

Prazosin may also act on the CNS to suppress sympathetic outflow.

Prazosin and other drugs in this class tend to have small but favourable effects on

plasma lipids: they decrease LDL and TAGs, while increasing HDL.

Prazosin is approved for hypertension.

Question 30

Terazosin and Doxazosin

Answer 30

Structural analogs of prazosin. These agents have a longer half-life than prazosin, allowing less frequent dosing. Approved for hypertension and BPH.

Question 31

Tamsulosin

Answer 31

α1-adrenoceptors mediate contraction of genitourinary as well as vascular smooth muscle, therefore α1-antagonists are useful in the symptomatic treatment of benign prostatic hyperplasia (BPH). Three subtypes of the α1-receptor exist: α1A, α1B, and α1D. The α1A-receptor predominates in genitourinary smooth muscle. Tamsulosin is a selective antagonist at α1A-receptors. The selectivity of tamsulosin for α1A-receptors may decrease the incidence of orthostatic hypotension relative to that associated with prazosin and other nonsubtype selective α1-adrenoceptor antagonists. Approved for BPH. Little effect on blood pressure.

Question 32

α2-Selective Adrenergic Blockers

Answer 32

YOHIMBINE

Yohimbine was used in the past to treat erectile dysfunction, but the phosphodiesterase type 5 inhibitors have widely replaced it. Yohimbine can reverse the antihypertensive effects of an α2-adrenoceptor agonist such as clonidine.

Question 33

β-Adrenergic Blockers

Answer 33

β-adrenergic blockers are very important clinically because of their efficacy in the treatment of hypertension, ischemic heart disease, congestive heart failure and certain arrhythmias.

β-adrenergic blockers are classified on the basis of receptor subtype selectivity and partial agonist activity:

Non-selective β blockers: block both β1 and β2

Cardioselective β blockers: primarily block β1

α1 and β-blockers

Partial agonists

Question 34

Propanolol

Cardiovascular, Respiratory, Metabolic Effects

Answer 34

NON-SELECTIVE β-ADRENERGIC ANTAGONISTS

PROPRANOLOL

Prototype nonselective β-blocker. Blocks β1 and β2. ACTIONS

Cardiovascular Effects

Since catecholamines have positive chronotropic and inotropic actions, β-adrenergic antagonists slow heart rate and decrease myocardial contractility. When tonic stimulation of β receptors is low, this effect is modest. But, when the sympathetic nervous system is activated, as during exercise or stress, β-blockers attenuate the expected rise in heart rate.

Short term administration of β-blockers decreases cardiac output. Also peripheral resistance increases due to blockade of vascular β2 receptors and compensatory sympathetic reflexes that activate vascular α-adrenergic receptors. Patients with hypertension (though not normotensive subjects) show a gradual reduction of both systolic and diastolic blood pressures that takes several days to develop fully.

The mechanism is complex, and involves the following:

Reduction in cardiac output

Reduction of renin release from the juxtaglomerular cells of the kidney

A central action, reducing sympathetic activity

β-blockers don’t induce postural hypotension because α1-adrenoceptors remain unblocked, therefore, normal sympathetic control of the vasculature is maintained.

Respiratory Effects

Blocking β2 receptors in the lungs of susceptible patients causes contraction of the bronchiolar smooth muscle. This can precipitate a respiratory crisis in patients with COPD or asthma. Propranolol, and other nonselective β blockers, are contraindicated in patients with asthma.

Metabolic Effects

β-blockade leads to decreased glycogenolysis and decreased glucagon secretion. Therefore, if an insulin-dependent diabetic is to be given propranolol, very careful monitoring of glucose is essential, since pronounced hypoglycemia may occur after insulin injection.

Question 35

Uses of Propanolol

Answer 35

Hypertension

β-blockers lower blood pressure in hypertension by decreasing cardiac output.

Glaucoma

β-blockers, particularly timolol, are effective in diminishing intraocular pressure in glaucoma. This occurs by decreasing secretion of aqueous humor by the ciliary body. These drugs do not affect the ability of the eye to focus for near vision, nor change pupil size, as do cholinergic drugs.

Migraine

β-blockers are effective for prophylaxis of migraine. The mechanism may depend on blockade of catecholamine-induced vasodilation of brain vasculature.

Hyperthyroidism

β-blockers are effective in blunting sympathetic stimulation that occurs in hyperthyroidism.

Angina Pectoris

β-blockers decrease the O2 requirement of heart muscle and therefore are effective in reducing chest pain on exertion common in angina. They are therefore useful in chronic management of stable angina. Not for acute management. Tolerance to moderate exercise is increased and is noticeable by improvement in the ECG. NOTE: β-Blockers are contraindicated in variant angina.

Atrial Fibrillation

β-blockers are indicated to control ventricular rate in patients with atrial fibrillation and a rapid ventricular response.

Myocardial Infarction

β-blockers have a protective effect on the myocardium. Patients who have had one MI appear to be protected against a second heart attack by prophylactic use of β-blockers. In addition, administration of a β-blocker immediately after a MI reduces infarct size and hastens recovery. The mechanism involves blocking circulating catecholamines, which would increase O2 demand. Propranolol also decreases incidence of sudden arrhythmic death after MI.

Performance Anxiety (“Stage Fright”)

Propranolol and other β-blockers are the preferred treatments.

Essential tremor

Essential tremor is the most common neurologic cause of postural or action tremor. β- blockers are the most commonly used drugs for the treatment of essential tremor.

Question 36

Adverse Effects of β-Blockers

Answer 36

Bronchoconstriction

Potentially lethal adverse effect in asthmatics.

Metabolic and Endocrine Effects

Catecholamines promote glycogenolysis and mobilize glucose in response to hypoglycemia. Nonselective β-blockers may adversely affect recovery from hypoglycemia in insulin-dependent diabetics. A β1-selective blocker is preferable. Also, all β-blockers mask the tachycardia that is typically seen with hypoglycemia, denying the patient an important warning sign.

β-receptors mediate activation of hormone-sensitive lipase in fat cells, leading to release of free fatty acids into the circulation. Nonselective β-adrenoceptor antagonists can attenuate the release of free fatty acids from adipose tissue. Nonselective β-adrenoceptor antagonists reduce HDL, increase LDL, and increase triglycerides. In contrast, β1- selective antagonists improve the serum lipid profile of dyslipidemic patients.

CNS Effects

Sedation, dizziness, lethargy, fatigue, depression. β-blockers with low liposolubility are associated with a lower incidence of CNS adverse effects.

WARNINGS & PRECAUTIONS

β-blocker therapy should not be withdrawn abruptly (particularly in patients with CAD), but gradually tapered to avoid acute tachycardia, hypertension, and/or ischemia. This adverse effects may be due to up-regulation of β-receptors due to long-term therapy with β-blockers.

Question 37

Nadolol and Tinolol

Answer 37

OTHER NONSELECTIVE β-BLOCKERS

NADOLOL

Long duration of action.

Indicated for the long-term management of patients with angina pectoris.

Indicated for the management of hypertension.

TIMOLOL

Treatment of hypertension.

Prophylaxis of migraine headache.

Treatment of open-angle glaucoma.

Question 38

Atenolol and Metoprolol

Answer 38

β1-SELECTIVE ADRENERGIC ANTAGONISTS

Useful in hypertensive patients with impaired pulmonary function.

Useful in diabetic hypertensive patients who are receiving insulin or oral hypoglycemic agents.

USES

Management of hypertension.

Long-term management of patients with angina pectoris.

Management of patients with acute myocardial infarction to reduce cardiovascular mortality.

NOTE: A major adverse effect of β-adrenergic antagonism is caused by blockade of β2- receptors in bronchial smooth muscle. Drugs with selectivity for β1-receptors or those with intrinsic sympathomimetic activity at β2 receptors may be somewhat less likely to induce bronchospasm. However, since the selectivity of current β blockers for β1 receptors is modest, these drugs should be avoided if at all possible in patients with asthma.

Question 39

Esmolol

Answer 39

β1-SELECTIVE ADRENERGIC ANTAGONISTS

Ultra-short acting β1-selective adrenergic antagonist.

Esmolol contains an ester bond; esterases in red blood cells rapidly metabolize esmolol to a metabolite with low affinity for β receptors. Consequently, esmolol has a half life of about 10 minutes. Therefore, during continuous infusions of esmolol, steady state concentrations are achieved quickly, and the therapeutic effects are terminated rapidly upon discontinuation of the infusion. Esmolol is given IV.

USES

Esmolol may be safer to use than longer-acting antagonists in critically ill patients who require a β-adrenoceptor antagonist. Esmolol is useful in controlling supraventricular arrhythmias, arrhythmias associated with thyrotoxicosis, perioperative hypertension, and myocardial ischemia in acutely ill patients.

Question 40

Labetalol and Carvedilol

Answer 40

α1- AND β-BLOCKERS: LABETALOL & CARVEDILOL

LABETALOL

Competitive antagonist at β and α1 receptors. It is substantially more potent as a β- antagonist than as an α-antagonist.

The actions of labetalol on both α1 and β receptors contribute to the fall in blood pressure observed in patients with hypertension. α1 receptor blockade leads to relaxation of arterial smooth muscle and vasodilation, particularly in the upright position. The β1 blockade also contributes to a fall in blood pressure, in part by blocking reflex sympathetic stimulation of the heart. In addition, the intrinsic sympathomimetic activity of labetalol at β2 receptors may contribute to vasodilation.

Labetalol is available in oral form for therapy of chronic hypertension and as an intravenous formulation for use in hypertensive emergencies.

USES

Labetalol is indicated in the management of hypertension.

ADVERSE EFFECTS

Orthostatic hypotension and dizziness are associated with α1 blockade. Labetalol has been associated with hepatic injury in a limited number of patients.

CARVEDILOL

Non-subtype selective β-receptor antagonist that is also antagonist at α1-receptors. Like labetalol, it is substantially more potent as a β-antagonist than as an α-antagonist. Also has antioxidant properties. Used in hypertension and congestive heart failure.

Question 41

Pindolol

Answer 41

PARTIAL AGONISTS

Pindolol is a β partial agonist. β-blockers, like pindolol, which are partial agonists, are said to possess intrinsic sympathomimetic activity (ISA).

β blockers with partial agonist activity may produce smaller reductions in resting heart rate and blood pressure. Consequently, such drugs may be preferred as antihypertensive agents in individuals with diminished cardiac reserve or a propensity to bradycardia. The clinical significance of partial agonism has not been demonstrated in controlled trials, but may be of importance in individual patients

USES

Indicated in the management of hypertension

Question 42

α-Methyltyrosine (METYROSINE)

Answer 42

INHIBITORS OF NOREPINEPHRINE SYNTHESIS

Metyrosine inhibits tyrosine hydroxylase, the enzyme that catalyzes the conversion of

tyrosine to DOPA and the rate-limiting step in catecholamine biosynthesis

Used as an adjuvant to phenoxybenzamine and other α-adrenergic blockers for the management of malignant pheochromocytoma and in the preoperative preparation of patients for resection of pheochromocytoma.

Question 43

Reserpine

Answer 43

INHIBITORS OF NOREPINEPHRINE STORAGE

Reserpine began the modern era of effective pharmacotherapy of hypertension.

Reserpine is an irreversible inhibitor of VMAT. This causes depletion of norepinephrine, since MAO degrades norepinephrine in the cytoplasm. Sympathetic function is impaired because of decreased release of norepinephrine.

Hypertensive patients taking the drug show a gradual decrease in blood pressure and slowing of cardiac rate. Slow onset of action. Long duration of action.

In the past, reserpine was used to treat hypertension.

Question 44

Tetrabenazine

Answer 44

Tetrabenazine is a reversible inhibitor of VMAT, and causes presynaptic depletion of catecholamines.

Tetrabenazine is indicated for the treatment of chorea associated with Huntington’s Disease.