Adrenergic Agonists

Neurotransmitters Pharm Pearl: The peripheral nervous system (PNS) employs 3 neurotransmitters Acetylcholine Norepinephrine Epinephrine Any given junction in the PNS uses only ONE of these substances

Transmitter Recap Acetycholine – employed at most junctions of the PNS All preganglion neurons of PNS All preganglion neurons of the SNS All postganglionic neurons of PNS All motor neurons to skeletal muscles Most postganglionic neurons of the SNS that go to sweat glands

Transmitter Recap Norepinephrine – released by practically all postganglionic neurons of the SNS (exception – sweat glands) Epinephrine – major neurotransmitter released by the adrenal medulla. The adrenal medulla also releases some norepinephrine.

Adrenergic Agonists Produce their effects by activating adrenergic receptors Sympathomimetic Broad spectrum of applications CHF Asthma Preterm labor 5

Mechanisms of Adrenergic Receptor Activation Direct receptor binding Promotion of norepinephrine (NE) release Inhibition of NE reuptake Inhibition of NE inactivation 6

Overview of Adrenergic Agonists Therapeutic applications and adverse effects of adrenergic receptor activation Properties of representative adrenergic agonists Discussion of adrenergic agonists in other chapters 7

Overview of the Adrenergic Agonists Catecholamines Cannot be used orally Brief duration of action Cannot cross the BBB (polar molecules) Noncatecholamines Can be given orally Metabolized slowly by MAO – longer half-life More able to cross the BBB Catecholamines: include dopamine, as well as the “fight-or-flight” hormones, adrenalin (epinephrine) and noradrenaline (norepinephrine) released by the adrenal medulla of the in response to stress. In the human body, the most abundant catecholamines are epinephrine (adrenaline), norepinephrine (noradrenaline) and dopamine. Various stimulant drugs are catecholamine analogues. Catecholamines are water-soluble and are 50% bound to plasma proteins, so they circulate in the bloodstream. Non-catecholamines - adrenergic drugs that are not chemically identical to catecholamines but still activate, directly or indirectly, the α- and β-receptors. They include ephedrine, amphetamine, phenylephrine, and methoxamine. 8

Mort & Merv: the story of selectivity Figure 12-03. Multiple drug receptors and selective drug action. Mort, All of Mort’s organs are regulated through activation of type A receptors. Drugs that affect type A receptors on one organ will affect type A receptors on all other organs. Hence, selective drug action is impossible. Merv, Merv has four types of receptors (A, B, C, and D) to regulate his four organs. A drug that acts at one type of receptor will not affect the others. Hence, selective drug action is possible.

Receptor specificity Most drugs in chapter Peripherally acting sympathomimetic Direct receptor activation Amphetamine, cocaine Indirect acting sympathomimetic Ephedrine Direct receptor activation and promotion of NE release 10

Receptor Specificity Beta1 and beta2 Alpha1 and alpha2 Beta2 only Terbutaline (Bricanyl) Beta1 and beta2 Isoproterenol (Isuprel) Alpha1 and alpha2 Epinephrine 11

Therapeutic Applications Adrenergic Agonists Clinical applications of alpha1 Two responses for therapeutic use Vasoconstriction (most common use) Blood vessels Skin Viscera Mucous membranes Mydriasis 12

Therapeutic Applications and Adverse Effects of Adrenergic Receptor Activation Drugs capable of activating alpha1 receptors Epinephrine Norepinephrine (Levophed) Phenylephrine (Neosynephrine) Ephedrine Dopamine 13

Therapeutic Applications and Adverse Effects of Adrenergic Receptor Activation Therapeutic applications of alpha1 activation Hemostasis Arrest bleeding via vasoconstriction Nasal decongestion Mucosal vasoconstriction Adjunct to local anesthesia Delays absorption of local anesthetic Elevation of blood pressure Vasoconstriction Mydriasis Radial muscle of the iris 14

Therapeutic Applications and Adverse Effects of Adrenergic Receptor Activation Adverse effects of alpha1 activation Hypertension Widespread vasoconstriction Necrosis Treatment with alpha1 blocking agent Bradycardia Response to vasoconstriction and elevated BP 15

Clinical Consequences of Alpha2 Activation Alpha2 receptors in periphery Located presynaptically Regulate transmitter release Activation inhibits NE release Alpha2 in CNS Reduction of sympathetic outflow to heart and blood vessels Relief of severe pain 16

Clinical Consequences of Beta1 Activation Therapeutic applications of beta1 activation Cardiac arrest Not preferred drug of choice Heart failure Positive inotropic effect Shock Positive inotropic effect; increases heart rate Atrioventricular heart block Enhances impulse conduction through AV 17

Clinical Consequences of Beta1 Activation Adverse effects of beta1 activation Altered heart rate or rhythm - Tachycardias or dysrhythmias Angina pectoris - Increased cardiac oxygen demand 18

Clinical Consequences of Beta2 Activation Therapeutic applications of beta2 activation Asthma Delay of preterm labor Adverse effects of beta2 activation Hyperglycemia Tremor 19

Clinical Consequences of Dopamine Receptor Activation Activation of peripheral dopamine receptors causes dilation of the vasculature of the kidneys 20

Multiple Receptor Activation: Treatment of Anaphylactic Shock Pathophysiology of anaphylaxis Severe allergic response Hypotension, bronchoconstriction, edema of the glottis Treatment Epinephrine, injected IM, is the treatment of choice for anaphylactic shock 21

Adrenergic Agonists Epinephrine Norepinephrine Isoproterenol Dopamine Dobutamine Phenylephrine (Neo-synephrine) Terbutaline Ephedrine 22

Epinephrine Therapeutic uses Delay absorption of local anesthetic Control superficial bleeding Elevate blood pressure Mydriasis during ophthalmologic procedures Overcome AV block Restore cardiac function in arrest Bronchial dilation in asthma Treatment of choice for anaphylactic shock 23

Epinephrine Pharmacokinetics Adverse effects Absorption Inactivation Hypertensive crisis Dysrhythmias Angina pectoris Necrosis following extravasation Hyperglycemia 24

Epinephrine Drug interactions MAO inhibitors Tricyclic antidepressants General anesthetics Alpha-adrenergic blocking agents Beta-adrenergic blocking agents 25

Epinephrine Preparations, dosage, & administration EpiPen (1:1000 or 1:2000) IV (monitor closely) (1:10,000) IM SubQ Intracardiac Intraspinal Inhalation Topical 26

Norepinephrine Receptor specificity Chemical classification Alpha1 Alpha2 Beta1 Chemical classification Catecholamine Therapeutic uses Hypotensive states Cardiac arrest 27

Norepinephrine Differs from epinephrine – does not activate beta2 receptors Does not promote hyperglycemia Cannot be given orally (MAO and COMT) Necrosis with extravasation Drug interactions MAOI, TCA, general anesthetics, adrenergic blocking agents Catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) are the two enzymes primarily responsible for the initial metabolic disposition of infused catecholamines 28

Isoproterenol Receptor specificity: beta1 and beta2 Chemical classification: catecholamine Therapeutic uses Cardiovascular - AV heart block, arrest Asthma - Bronchodilation – not used anymore Bronchospasm - During anesthesia 29

Isoproterenol Adverse effects Drug interactions Fewer than those of NE or epinephrine (doesn’t activate alpha-adrenergic receptors) Tachydysrhythmias and angina pectoris Hyperglycemia in diabetes patients Drug interactions MAOI, TCA, beta-adrenergic blockers Preparations and administration IV, IM, and intracardiac injections 30

Dopamine Receptor specificity Low therapeutic dose – dopamine Moderate therapeutic dose – dopamine and beta1 Very high dose – apha1, beta1, and dopamine 31

Dopamine Therapeutic uses Shock Heart failure Acute renal failure Increases cardiac output Increases renal perfusion Heart failure Increases myocardial contractility Acute renal failure Was used to preserve renal function with ARF Early ARF – failed to protect renal function, shorten stays, or reduce need for renal transplant 32

Dopamine Adverse effects Drug interactions Tachycardia, dysrhythmias, anginal pain Necrosis with extravasation Drug interactions MAOI, TCA, certain general anesthetics, diuretics Preparations, dosage, and administration Preparations: dispensed in aqueous solutions Dosage: must be diluted Administration: administered by IV Monoamine oxidase inhibitors are a class of antidepressants that were developed in the 1950s. They are effective in treating depression, panic disorder, and other anxiety disorders. Although they are generally as effective as selective serotonin reuptake inhibitors (SSRI) and tricyclic antidepressants (TCAs) , they are used less frequently because of necessary dietary precautions and risks of adverse reactions when mixed with certain drugs. MAOI – Isocarboxazid (Marplan) Phenelzine (Nardil) Selegiline (Emsam, Eldepryl, Zelapar) Tranylcypromine (Parnate) Tricyclics - Amitriptyline Imipramine (Tofranil) Clomipramine (Anafranil) Nortriptyline (Pamelor) Desipramine (Norpramin) 33

Dobutamine Receptor specificity: beta1 Chemical classification: catecholamine Actions and uses CHF Adverse effects Tachycardia Drug interactions MAOI, TCA, certain general anesthetics Preparations, dosage, and administration Continuous IV infusion 34

Phenylephrine Receptor specificity Chemical classification Alpha1 Chemical classification Noncatecholamine Therapeutic uses Reduce nasal congestion (locally) Elevate blood pressure (parenterally) Dilate pupils (eye drops) Local anesthetic (delay absorption) 35

Terbutaline Receptor specificity: beta2 Chemical classification: noncatecholamine Therapeutic uses Asthma (selective for beta2) - Replaced isoproterenol in treatment Delay of preterm labor - Relaxes uterine smooth muscle - Another drug (ritodrine) now preferred Adverse effects - Minimal at therapeutic doses - Tremor most common; also tachycardia 36

What’s he got to do with Pharm?

Anybody ever taken ephedrine?

Are you sure?

Ephedrine Receptor specificity: alpha1, alpha2, beta2 Chemical classification: noncatecholamine Therapeutic uses Nasal congestion Other uses Adverse effects HTN, dysrhythmias, angina, hyperglycemia, insomnia (crosses BBB) 40

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