Pharmacology: Adrenoreceptor Agonist/Sympathomimetic Drugs PDF

PHARMACOLOGY | TRANS 1 LE Adrenoreceptor Agonist / Sympathomimetic...

PHARMACOLOGY | TRANS 1 LE Adrenoreceptor Agonist / Sympathomimetic 02 Drugs I Alfaretta Luisa T. Reyes, MD, FPSECP | September 17, 2024 | Version 1 OUTLINE LEARNING OBJECTIVES I. Adrenoreceptor Agonists & VII. Chemistry and Structure ✔ Categorize the various sympathomimetic drugs Sympathomimetics Relationship according to their chemical structure, mode of action, A. According to Mode of A. Substitution on receptor selectivity and therapeutic applicability. Action BenzeneRing ✔ Discuss the general pharmacokinetic properties of B. According to Receptor B. Absence of One of catecholamines and noncatecholamines. Selectivity the Other -OH Groups ✔ Explain the general pharmacologic actions of II. Pharmacokinetic Properties of Catecholamines C. Absence of Ring -OH adrenoceptor agonists and other sympathomimetic A. Absorption and Groups drugs. Distribution D. Substitution of the ✔ Explain the general mechanisms of actions of the B. Uptake, Metabolic AminoGroup adrenoceptor agonists and sympathomimetic drugs on Degradation, and E. Substitution on ⍺ the different types of adrenergic receptors. Excretion of Carbon ✔ Relate the basic chemical structure of the Catecholamines F. Substitution on β catecholamines and noncatecholamines to their III. General Actions of Carbon VIII. General Pharmacologic pharmacologic activities. Catecholamines and Sympathomimetic Drugs Actions & Effects of ✔ Differentiate the pharmacologic actions and effects A. Peripheral Catecholamines and produced by stimulation of ⍺-receptors by adrenoceptor Excitatory Action in Sympathomimetics on agonists from activation of β-receptors on the various Some Smooth Adrenoreceptors body systems. Muscles A. ⍺-1 ✔ Discuss the pharmacologic properties of epinephrine B. Peripheral Inhibitory B. ⍺-2 according to its receptor affinities, pharmacokinetics, Action in Some C. β-1 pharmacodynamics including MOA, actions and effects Smooth Muscles D. β-2 E. β-3 on various organ systems, adverse effects, toxicity. C. Cardiac Excitatory Action F. Dopamine-1 ✔ Discuss the indications and contraindications to the use D. Metabolic Actions IX. Epinephrine of epinephrine. E. Endocrine Actions A. Small Dose ✔ Apply the process of rational drug use in choosing and F. CNS Action B. Large Dose prescribing the appropriate drug to clinical scenarios like G. Prejunctional C. Rapid IV Dose anaphylaxis. Actions D. Slow IV Infusion or IV. Mechanism of Action SC Injection I. ADRENORECEPTOR AGONISTS & A. ⍺1 Receptors E. Slightly Faster Rate SYMPATHOMIMETICS B. ⍺2 Receptors of IV Infusion C. All Types of β F. Metabolic Effects Receptors G. Respiratory Effects D. Dopamine H. CNS Effects Receptors I. Non-Vascular Smooth V. Receptor Selectivity Muscle Effects VI. Receptor Regulation J. Adverse Effects and A. Desensitization of Toxicity Responses K. Contraindications L. Therapeutic Use X. Summary XI. Review Questions XII. References XII. Appendix Must Lecturer Book Previous Youtube ❗️ Know 💬 📖 📋 Trans 🔺 Video ABBREVIATIONS Figure 1. Drug Prototypes affecting adrenergic receptors[2026 TRANS] COMT Catechol-O-methyltransferase DP Diastolic Pressure GRK G-protein-coupled receptor kinase The Sympathetic Nervous System (SNS) is a division of MAO Monoamine Oxidase A the Autonomic Nervous System (ANS) MHPG 3-hydroxy 4-methoxylphenylglycol Drugs that affect SNS are either agonists or antagonists NET Norepinephrine Transporter Adrenoceptor agonists and sympathomimetics are agents PVR Peripheral Vascular Resistance that act on either or on both ⍺-receptor subtypes or SP Systolic Pressure β-receptor subtypes (See Figure 1) VMAT Vesicular Monoamine Transporter LE # TG 9 | I. Belleza, M. Beltran, J. Bertillo, J. TE | M. Beltran AVPAA | K. Clauss PAGE 1 of 19 TRANS # Berroya, M. Besinio VPAA | A. Arcega PHARMACOLOGY | LE 2 Adrenoreceptor Agonist / Sympathomimetic Drugs I | Alfaretta Luisa T. Reyes, MD, FPSECP Salmeterol β3 selective Mirabegron, Used in the receptor Vibegron treatmon of agonists overactive bladder (OAB): Urinary frequency and urgency INDIRECT-ACTING AGENTS Do not directly activate adrenergic receptors Actions dependent on ability to increase the availability of endogenous catecholamines to stimulate adrenergic receptors via two ways: → Release or displacing stored NE from adrenergic nerve endings → Decreasing clearance of released NE Figure 2. Overview of the classification of adrenoreceptor agonist and sympathomimetics [Lecture PPT] 1. RELEASING OR DISPLACING STORED NE FROM Sympathomimetic drugs ADRENERGIC NERVE ENDINGS Mimic the action of endogenous epinephrine and Drugs that are capable of a calcium-independent norepinephrine (NE) at corresponding adrenergic sites. process of releasing the stored neurotransmitter from the noradrenergic nerve terminals Adrenergic receptor agonists and sympathomimetic drugs Poor agonists at the adrenergic receptors but are good can be classified according to: substrates for monoamine transporters → Mode and Mechanism of action Taken up into the noradrenergic nerve terminals by the ▪ Direct-acting agonists norepinephrine transporter (NET) and transported by ▪ Indirect-acting drugs/substances Vesicular Monoamine Transporter (VMAT) into the − Release or displacing stored NE from adrenergic vesicles, displacing NE which is subsequently expelled nerve endings into the synaptic space by reverse transport via the NET − Decreasing clearance of released NE Their action does not require vesicle exocytosis. ▪ Mixed-acting sympathomimetic drugs → Receptor sensitivity Table 2. Drug Examples that Releases or DIsplaces NE ▪ Non-selective receptor agonists DRUG FEATURES ▪ Selective adrenergic receptor agonists Amphetamine Used with an off-label indication in − α-receptors (α1, α2) obesity treatment − β receptors (β1, β2, β3) − Dopamine receptors Used for treatment of ADHD and A. ACCORDING TO MODE OF ACTION narcolepsy DIRECT-ACTING AGENTS Methamphetamine Commonly known as shabu (poor Directly interacts with and activates one or more of the man’s cocaine) adrenoreceptors Amphetamine and methylphenidate Table 1. Summary of MOA as treatment for ADHD and CATEGORY DRUG FEATURES narcolepsy Drug Epinephrine Activates all Phenmetrazine Rarely prescribed due to concerns Prototypes adrenoceptors of abuse and addiction Norepinephrine Activates all ⍺ 1 & 2, and β1 receptors Methylphenidate For treatment of ADHD Isoproterenol Activates all Pemoline Narcolepsy treatment β-receptors Discontinued in the US in 2006 Dopamine because it caused hepatic failure Dobutamine Modafinil For treatment of narcolepsy and obstructive sleep apnea hypopnea Phenylephrine Prototype for syndrome (OSAHS) selective ⍺1 receptors Tyramine Technically not a drug but a by-product of dietary food (aged β2 selective Salbutamol cheese, anchovies, pickled herring) receptor agonists Terbutaline 2. DECREASING CLEARANCE OF RELEASED NE Long-acting Formoterol Indirectly-acting agonists drugs PHARMACOLOGY Adrenoreceptor Agonist / Sympathomimetic Drugs I PAGE 2 of 19 PHARMACOLOGY | LE 2 Adrenoreceptor Agonist / Sympathomimetic Drugs I | Alfaretta Luisa T. Reyes, MD, FPSECP Can inhibit catecholamine reuptake (neuronal B. ACCORDING TO RECEPTOR SELECTIVITY uptake or uptake 1) → Considered “amphetamine-like” NON-SELECTIVE ADRENOCEPTOR AGONIST → Transport of neurotransmitter into sympathetic Stimulate various adrenoceptor subtypes Can be classified according to specific receptors ▪ ▪ 💬 neuron is blocked 💬 Inhibits neuronal uptake of NE NE that has been released into the synaptic 1. α AND β Receptor Agonists cleft stays longer instead of going back into the Drug examples cytoplasm at the terminal knob → Epinephrine Can block metabolizing enzymes ▪ All adrenoceptors → Blocks monoamine oxidase A (MAO) or → Norepinephrine catechol-O-methyltransferase (COMT) ▪ α1 and α2, and β1 receptors 2. β1 and β2 Receptor Agonists Table 3. Drug Examples of Catecholamine Reuptake Drug example: Inhibitors → Isoproterenol/Isoprenaline DRUG FEATURES Cocaine SELECTIVE ADRENOCEPTOR AGONIST Tricyclic Drug binds to one or few types of receptors more tightly Antidepressants (TCAs) than to other receptors at given doses Atomoxetine For treatment of ADHD Selectively activate certain adrenoceptors subtypes Can be classified into six types according to receptor Reboxetine For treatment of acute clinical depression and ADHD 1. α1 RECEPTOR AGONISTS Duloxetine For treatment of In general, selective α1 receptor agonists are effective fibromyalgia topical nasal decongestants → Hint: “OX” are the long acting Milnacipran For treatment of fibromyalgia Table 6. Drug Examples of α1 Receptor Agonists DRUG FEATURES Table 4. Drug Examples that Blocks Metabolizing Enzymes Phenylephrine Drug prototype of α1 receptor DRUG FEATURES agonists Pargyline MAO inhibitor Midodrine Prodrug used in patients with Entacapone COMT inhibitor autonomic insufficiency like chronic orthostatic hypotension MIXED-ACTING SYMPATHOMIMETICS Methoxamine α1 receptor agonists Indirectly release NE and some also directly activate Naphazoline Short-acting topical nasal receptors decongestants Tetrahydrozoline Imidazole Derivatives Table 5. Drug Examples of Catecholamine Reuptake Oxymetazoline Long-acting topical nasal Inhibitors Xylometazoline decongestants CATEGORY Drug Prototypes DRUG Ephedrine 💬 FEATURES Similar spectrum of activity as Epinephrine but Imidazole Derivatives 2. SELECTIVE α2 RECEPTOR AGONISTS (effective is of lesser potency and Selectively activates α2 receptors oral nasal efficacy decongesta nts) Phenylpropa Withdrawn in some Table 7. Drug Examples of α1 Receptor Agonists nolamine countries because its use DRUG FEATURES in high doses led to Clonidine Act centrally on presynaptic hemorrhagic stroke receptors to decrease Methyldopa 💬 Has been replaced with Phenylephrine Guanfacine Guanabenz sympathetic outflow and decrease blood pressure Apraclonidine Indicated for treatment of Pseudoephe Its use is not limited due Brimonidine glaucoma drine to its use in illicit manufacture of shabu Tizanidine Muscle relaxant for muscle spasticity, associated with Other drug Mephenterm cerebral or spinal disorders examples ine Metaraminol PHARMACOLOGY Adrenoreceptor Agonist / Sympathomimetic Drugs I PAGE 3 of 19 PHARMACOLOGY | LE 2 Adrenoreceptor Agonist / Sympathomimetic Drugs I | Alfaretta Luisa T. Reyes, MD, FPSECP 3. SELECTIVE β1 RECEPTOR AGONISTS Table 11. Drug Examples of Selective Dopamine Receptor Table 8. Drug Examples of β1 Receptor Agonists Agonists DRUG FEATURES DRUG FEATURES Dobutamine Initially considered as a relatively Dopamine (Intropin, Central actions are valuable in (Dobutrex) β1 receptor agonists but now Docard) the treatment of patients with known as drug prototype for β1 Parkinson’s disease and receptor agonists prolactinemia Prenalterol Partial agonist Fenoldopam D1 receptors agonist primarily (Corlopam) indicated in the treatment of severe hypertension Dopexamine Synthetic analog of dopamine 4. SELECTIVE β2 RECEPTOR AGONISTS (Dopacard) with intrinsic activity on D1, 💬 In general, these drugs are non-catecholamines Most are bronchodilators used in the treatment of patients with airway diseases such as asthma and D2, and β2 receptors. Cardiac inotropic agent COPD Table 9. Drug Examples of β2 Receptor Agonists II. PHARMACOKINETIC PROPERTIES OF DRUG FEATURES CATECHOLAMINES Terbutaline Prototype drugs with relatively short A. ABSORPTION AND DISTRIBUTION Salbutamol acting activity, relaxation of bronchial CATECHOLAMINES (Albuterol) smooth muscles Three endogenous catecholamines: Salmeterol Long-acting Slower onset → Norepinephrine (Servent) drugs ▪ Primary neurotransmitter in nerve endings Formoterol Long acting; Rapid → Epinephrine onset of action ▪ Produced in adrenal medulla (modified sympathetic Indacaterol / Drug with ultra long acting activity ganglion) Olodaterol / → Dopamine Vilanterol Synthetically available catecholamine: Clenbuterol Drug with anabolic action → Isoproterenol Polar in nature Ritodrine Tocolytic agent for arresting premature → Poor absorption if given orally labor → Difficulty crossing the body membranes including the Isoxsuprine Vasodilator for the management of CNS (cannot readily traverse blood brain barrier, BBB) peripheral vasospastic diseases Brief duration of action (Raynaud’s disease) and uterine → Since they are rapidly inactivated by enzymes in the smooth muscle relaxant intestinal mucosa and in the liver ▪ Reason why there are no oral preparation 5. SELECTIVE β3 RECEPTOR AGONISTS Route of administration → Parenteral (SC, IM, IV) Table 10. Drug Examples of β2 Receptor Agonists → Inhalation DRUG FEATURES → Topical Mirabegron Indicated for treating ▪ Eye drops, Nasal drops, or Spray (Myrbetriq/Betmiga) patients with overactive Vibegron bladder (urinary agency NON-CATECHOLAMINES (Gemtesa) or frequency) Generally nonpolar, lipid soluble Solabegron, → can readily be absorbed across body membranes Ritobegron including BBB (Under clinical → Longer duration of action development) Route of administration: → Oral 6. DOPAMINE RECEPTOR AGONISTS → Parenteral Drug examples: → Inhalation → Dopamine (Intropin, Docard) ▪ For nebulization as aerosols (solutions) ▪ Central actions are valuable in the treatment with Some drugs have long duration of action Parkinson's disease and prolactinoma → Drug examples: → Fenoldopam (Corlopam) ▪ Formoterol ▪ D1 receptor agonist primarily indicated in the ▪ Salmeterol treatment of severe hypertension ▪ Indacaterol (ultralong acting β2 agonist) → Dopexamine (Dopacard) PHARMACOLOGY Adrenoreceptor Agonist / Sympathomimetic Drugs I PAGE 4 of 19 PHARMACOLOGY | LE 2 Adrenoreceptor Agonist / Sympathomimetic Drugs I | Alfaretta Luisa T. Reyes, MD, FPSECP B. UPTAKE, METABOLIC DEGRADATION, AND EXCRETION OF CATECHOLAMINES 1. MAO Bound to the surface membrane of the mitochondria UPTAKE within the cells: Circulating catecholamines are usually inactivated by Location: combination of uptake 1, uptake 2, and by COMT. → Liver → Norepinephrine is removed mainly by Uptake 1 → Intestinal epithelium → Epinephrine is more dependent on Uptake 2 Metabolizes catecholamines to corresponding → Isoproterenol is not a substrate for Uptake 1, and is aldehydes ⇒ converted to carboxylic acid. removed by a combination of Uptake 2 and COMT Within adrenergic neurons, MAO controls the content of NE and dopamine Can also oxidize other monoamines like dopamine and 5-hydroxytryptamine as well as Pargyline → Pargyline is a known MAO inhibitor 2. COMT Causes methylation of one of the catechol alcohol (OH) groups to a methoxy derivative Location: → Adrenal medulla → Smooth ms. → Cardiac ms. → Endothelium Absent in noradrenergic neurons III. GENERAL ACTIONS OF CATECHOLAMINES AND SYMPATHOMIMETIC DRUGS Figure 3. Generalized diagram of noradrenergic nerve General activity of receptors: terminal, showing sites of drug action that affect synthesis, → (α1, β1, β3): Stimulatory storage, release of NT, interaction with postsynaptic sites, → (α2, β2): Inhibitory inactivation of NT activity. TIP: Alternate stimulatory and inhibitory with the numbers 1. NEURONAL UPTAKE (UPTAKE 1) α1: stimulatory Utilizes NET α2: inhibitory Main mechanism for removal of NE β1: stimulatory → NET quickly captures about 75% of the NE released β2: inhibitory by sympathetic neurons β3: stimulatory → NET is recycled to cut short the neurotransmitter (NT) activity A. PERIPHERAL EXCITATORY ACTION IN SOME → NET removes 90% of NE released in the heart SMOOTH MUSCLES released at the synapse Stimulated receptor: α1 receptors → In vasculature, they synaptic structure are less Occurs in the vascular smooth ms supplying skin and developed hence NT activity may be less mucous membranes Muscles contract as a result of stimulation of α1 receptors 2. EXTRANEURONAL UPTAKE (UPTAKE 2) ⇒ vasoconstriction and pallor or skin NT is take up into the extraneuronal cells and Sweat and salivary gland stimulation ⇒ increased metabolized by COMT → Escape to the extrasynaptic space and enter bloodstream 💬💬 secretions → In general, smooth muscles contract Vasoconstriction may increase PVR Main mechanism for epinephrine Removes Isoproterenol in combination with COMT Takes care of about 25% of the Norepinephrine B. PERIPHERAL INHIBITORY ACTION IN SOME SMOOTH MUSCLES 3. ESCAPE INTO THE EXTRASYNAPTIC SPACE AND Stimulated receptors: β2, some α2 receptors ENTER THE BLOODSTREAM Occurs in other types of smooth muscles like walls of The released NT escapes into the extrasynaptic space genitourinary tract, bronchial smooth ms, and vascular and may enter the bloodstream → 💬💬 smooth muscle supplying skeletal ms In general, smooth muscles relax Ciliary muscle: to some extent, relaxes as well DEGRADATION Can be metabolized by MAO or COMT C. CARDIAC EXCITATORY ACTION Final product formed is 3-hydroxy 4- Stimulated receptor: β1 receptors methoxylphenylglycol (MHPG) Occurs in the heart leading to → Converted to vanillylmandelic acid (VMA) or partly → Positive chronotropy conjugated to sulfate or glucuronide derivatives → Positive inotropy ▪ Inactive metabolites are then excreted in the urine → Positive dromotropy PHARMACOLOGY Adrenoreceptor Agonist / Sympathomimetic Drugs I PAGE 5 of 19 PHARMACOLOGY | LE 2 Adrenoreceptor Agonist / Sympathomimetic Drugs I | Alfaretta Luisa T. Reyes, MD, FPSECP 💬 Can increase cardiac output → Dopamine: D1, D2, D3, D4, D5 📋 Stimulated receptors: β , α receptors D. METABOLIC ACTIONS α1 RECEPTOR [2025 trans] 2 → Stimulation leads to enhanced glycogenolysis in the 📋 Stimulated receptor: β receptors liver and in muscles [2025 trans] 3 → Stimulation leads to accelerated release of free fatty acids from fat tissues α2 has inhibitory effect on fat cells → decrease free fatty acid Activation of α1 and β3 → enhance lipolysis E. ENDOCRINE ACTIONS Activation of adrenoceptor subtypes causes modulation of secretion of insulin, glucagon, renin, and pituitary hormones. 📋 Receptors stimulated: [2025 trans] → Adrenergic receptors in pancreatic islet cells ▪ α2 receptors = decreased insulin secretion ▪ β receptors (β2 as emphasized by Dr. Reyes) − Increased insulin secretion (β pancreatic islet cells) − Increased glucagon secretion (⍺ pancreatic islet Figure 4. Effects of α1 receptors by its agonists for activation cells) of Gq-coupling protein [Lecture PPT] → Adrenergic receptors in JG cells of the kidney ▪ JG cells: release renin Activates Gq-PLC pathway → (hydrolysis) formation of ▪ β1 receptors = increased renin secretion IP3 and DAG as second messengers ▪ α2 receptors = decreased renin secretion → Inositol triphosphate (IP3) ▪ Mobilizes release of intracellular Ca2+ causing F. CNS ACTION increased cytoplasmic free Ca2+ Generally causes increase in wakefulness and − High cytoplasmic Ca2+ → activation of smooth psychomotor activity, appetite suppression. muscle contraction ▪ Activates Ca2+ dependent protein kinases G. PREJUNCTIONAL ACTIONS → Diacylglycerol (DAG) Stimulated receptors: α2, β1, β2 receptors ▪ Activates protein kinase C Activation of prejunctional α2 receptors inhibit or modulate ▪ Activate signal transduction pathways (eg MAP release of NT at the nerve terminals. kinase) which may be involved in stimulation of cell Stimulation of presynaptic β1 or β2 generally facilitates NT release from nerve endings. 💬 growth and proliferation Take note that enzymes are not secondary messengers Inhibitory action at prejunctional sites is more physiologically important than its facilitatory action Mechanism → The GDP dissociates from the α-subunit of Gq protein. The overall pharmacologic effects of a given drug may → GTP then binds to this G protein. The α-subunit then depend on its relative affinity for adrenoceptor subtypes, dissociates from β and γ subunits. relative expression of receptor subtypes in a given tissue, → The activated GTP-Gα subunit complex regulates the and its route of administration (Brunton, 2017) [Lecture PPT] activity of the effector proteins (AC, PLC, and ion channels) → Gq-phospholipase pathway will lead to the formation of IV. MECHANISM OF ACTION IP3 and DAG. Recall: ▪ IP3 activates release of stored Ca2+ ⇒ increased → Muscarinic receptors: G protein-coupled receptors cytoplasmic Ca2+ concentration ⇒ stimulates → Nicotinic receptors: ion channels Ca2-dependent protein kinases ⇒ phosphorylation All adrenoceptors belong to the G protein-coupled type reaction. → Receptors regulate effector protein activity and are → The α-subunit is inactivated by hydrolysis of GTP to coupled to G protein with different effector proteins like: GDP and phosphate. The β and gamma subunits will ▪ Enzymes: then reassociate with the ⍺ subunit. − Adenylyl cyclase (Gs, Gi, Go) − Phospholipase C (Gq, G11) − cGMP phosphodiesterase ▪ Ion channels → G protein consist of 3 subunits: α, β, and γ Adrenoceptor subtypes and subclasses: → α1: A, B, D classes → α2: A, B, C classes → β: β1, β2, β3 PHARMACOLOGY Adrenoreceptor Agonist / Sympathomimetic Drugs I PAGE 6 of 19 PHARMACOLOGY | LE 2 Adrenoreceptor Agonist / Sympathomimetic Drugs I | Alfaretta Luisa T. Reyes, MD, FPSECP ▪ Vasodilation of renal and splanchnic vascular bends α2 RECEPTOR D2 receptors → Inhibit adenylyl cyclase activity → Open K+ channels and decreased calcium influx → Activation of presynaptic D2 receptor suppresses NE release V. RECEPTOR SELECTIVITY Selectivity → A drug may preferentially bind to one subgroup of receptors at concentrations too low to interact extensively with another subgroup (Katzung, 2018). → Not absolute and is lost at high concentrations (Brunton, 2017). → A drug is selective if it preferentially binds to and acts on a subtype of receptor at a low concentration without significantly interacting with another subtype of the receptor. → Example: Salbutamol Figure 5. Activation and inhibition of adenylyl cyclase by ▪ Salbutamol is a selective β-2 receptor agonist. In agonists that bind to adrenoceptors [Lecture PPT] recommended therapeutic doses, it stimulates β-2 receptors in the bronchial smooth muscles, producing This Inhibits adenylyl cyclase through Gi protein causing bronchodilation without activating β-1 receptors. It is ↓ cAMP production not absolute as when given in higher doses, it may Regulate ion channel activity by inhibiting of Ca2+ stimulate the β receptors to some extent. channels directly and promote opening of K+ channels → Example: Pirenzepine ▪ Pirenzepine is a selective M1 receptor antagonist. It Mechanism: selectively inhibits secretion of the gastric parietal → Activation of α2 receptors inhibits adenylyl cyclase cells without inhibiting the M3 receptors in the GIT activity smooth muscles. If given at a higher dose, the activity ▪ Dissociation of the inhibitory Gi protein results in on M3 receptors in formation of activated Gi α1 subunit in complex with Specificity GTP. → Near absolute selectivity (Katzung, 2018) → Binding of the agonist to the β-receptors activates Gs.. → This leads to formation of the Gs-α-subunit-GTP Table 12. Relative Receptor Affinities complex resulting in stimulation of adenylyl cyclase α Agonists activity and an increase in cAMP production. Phenylephrine, ⍺1 > ⍺2 >>>> β → Increased cAMP causes cascading events like glycogen methoxamine phosphorylase reaction. Prenalterol ⍺2 > ⍺1 >>>> β → Hydrolysis of the bound GTP to GDP and phosphate Mixed Agonists Norepinephrine ⍺1 = ⍺2; β1 >> β2 ALL TYPES OF β RECEPTOR (β1, β2, β3) Epinephrine ⍺1 = ⍺2; β1 = β2 Stimulates adenylyl cyclase mediated by Gs → Activation causes increased cAMP production Agonists activating protein kinase A Dobutamine β1 > β2 >>>> ⍺ → Leads to: Isoproterenol β1 = β2 >>>> ⍺ ▪ Activation of glycogen phosphorylase in the liver and Albuterol, terbutaline, β2 > β1 >>>> ⍺ muscle by β2 receptors (Note: sync slides indicate metaproterenol, ritodrine β2, async slides indicate β1) Dopamine Agonists − Leads to glycogen breakdown Dopamine D1 = D2 >> β >> ⍺ ▪ Activation of triglyceride lipase by β3 receptors Fenoldopam D1 >> D2 − Leads to fat breakdown ▪ Phosphorylation of myosin light chain kinase (MLCK) Phenylephrine to inactive form by β2 receptors in bronchial smooth → Selectively acts on ⍺-1 receptors and almost no effects muscle on the β receptors − Leads to bronchodilation Clonidine ▪ Phosphorylation of Ca2+ channels → ↑ inward Ca2+ → Preferentially acts on ⍺-2 receptors than on ⍺-1 current → ↑ myocardial force of contraction (β1) receptors at the recommended therapeutic doses and → Essentially, energy stores are converted to free no effect on the β receptors available fuels to meet the body's demands. Norepinephrine → Binds and acts almost equally to both the ⍺-1 and ⍺-2 DOPAMINE RECEPTOR receptors. It acts on β-1 receptors and almost nil effects D1 receptors (as well as D5) on β-2 receptors → Stimulate of adenylyl cyclase Epinephrine → Causes ↑ cAMP production → Interacts with all adrenoceptor receptors at almost equal → Effects: potency. PHARMACOLOGY Adrenoreceptor Agonist / Sympathomimetic Drugs I PAGE 7 of 19 PHARMACOLOGY | LE 2 Adrenoreceptor Agonist / Sympathomimetic Drugs I | Alfaretta Luisa T. Reyes, MD, FPSECP Isoproterenol → Ultimately this will lead to endocytosis of the receptors → Purely a nonselective β receptor agonist. Its effect on ⍺ as a result of interaction of arrestin with clathrin receptors are insignificant. Heterologous Desensitization Dobutamine → Second messenger feedback mechanism → Classified as a selective β-1 receptor agonist. → Phosphorylation of any structurally similar receptor with Terbutaline, Salbutamol / Albuterol, Ritodrine, appropriate sites for phosphorylation by these enzymes Formoterol, Salmeterol → Process by which an agonist causes desensitization → Classified as receptor selective β-2 receptor and will also result in desensitization of another sympathomimetic drugs. They have insignificant effects receptor that has not been directly stimulated by the on the ⍺ receptors. concerned agonist Fenoldopam → Mediated by second-messenger feedback → Selective Dopamine1 receptor agonist. ▪ Example: β adrenoceptors stimulate cAMP Dopamine production which leads to activation of protein kinase → When administered in recommended therapeutic doses, A or protein kinase C that may phosphorylate any it selectively acts on dopamine-1 receptors. It is only structurally similar receptor with appropriate sites for when you give it at high doses that it will also act on the phosphorylation by these enzymes β-receptors to increase myocardial force of contraction with minimal tachycardia. If given at at further higher VII. CHEMISTRY AND STRUCTURE-ACTIVITY doses,it may stimulate the ⍺-receptors. RELATIONSHIP VI. RECEPTOR REGULATION Table 13. Groups of Sympathomimetic Drugs Groups of Sympathomimetic Drugs 📋 Responses mediated by adrenoceptors are not fixed and 📋 static 2025 Magnitude of the response depends on: 2025 Catecholamines Non-Catecholamines → Number and function of adrenoceptors on the cell Norepinephrine Phenylephrine surface Epinephrine β2 Agonists → Regulation of these receptors by catecholamines Dopamine themselves, other hormones Phenylisopropylamines: → Drugs, age, and a number of disease states Synthetic Catecholamines: Amphetamine DESENSITIZATION OF RESPONSES Isoproterenol Ephedrine Dobutamine Process wherein a cell or tissue often becomes less responsive to further stimulation by the catecholamines and sympathomimetic agents after exposure to these agents for a period of time The chemical structure of a given drug determines its Other terminologies: Tolerance, Tachyphylaxis, relative affinity to receptor subtypes, its pharmacokinetic Refractoriness properties and bioavailability and may influence the → Tolerance: process of decreasing magnitude of intrinsic ability of the drug to activate these receptors. receptor response to the same initial dose of a drug over a period of time or days. → Tachyphylaxis: is an acute form of tolerance that develops rapidly if the drug is given in few successive doses at close intervals. This is associated with the use of indirectly-acting sympathomimetic drugs or substances → Refractoriness: is used clinically and refers to therapeutic failure / non-responsive to therapeutic use of the drug in the management of a condition. ▪ This may be clinically significant because it may limit the therapeutic response to the sympathomimetic drug MECHANISMS OF DESENSITIZATION OF RESPONSES Homologous Desensitization Figure 6. Phenylethylamine and some important → Specifically involves only agonist-occupied receptors catecholamines. Catechol is shown for reference.[Katzung] → Loss of responsiveness involving only the occupied receptors that have been exposed to repeated or Phenylethylamine is considered as the parent compound. sustained activation by the agonist. Catecholamines consist of a benzene ring with hydroxyl → Occurs rapidly and involves receptor phosphorylation groups at positions 3 and 4 of the benzene ring and with by G-protein-coupled receptor kinase (GRK) bound to ethylamine side chain. the agonist There are additional substitutions on any of the following: → Results to binding of these receptors to arrestins and benzene ring, the terminal amino group, and the ⍺ or β subsequent blunting of receptor capacity to activate carbons of the ethylamine side chain. the G-proteins PHARMACOLOGY Adrenoreceptor Agonist / Sympathomimetic Drugs I PAGE 8 of 19 PHARMACOLOGY | LE 2 Adrenoreceptor Agonist / Sympathomimetic Drugs I | Alfaretta Luisa T. Reyes, MD, FPSECP They produce catechols with different affinity to the ⍺ and β → Isoproterenol: has a larger alkyl (isopropyl) substitution receptors on the amino group so it has greater β-receptor activity than epinephrine and norepinephrine but it has very weak ⍺ receptor activity. SUBSTITUTION ON ⍺-CARBON Prevent oxidation by MAO Effects: → Prolongs duration of action of non-catecholamines or the sympathomimetic drug Examples: → Phenylephrine: directly acting selective ⍺-1 adrenoceptor ▪ Ephedrine and amphetamine: examples of phenylisopropylamines − (1) Able to traverse the CNS → Increase ability to displace catecholamines from storage Figure 7. Some examples of non-catecholamine sites in adrenergic nerve endings and are classified as sympathomimetic drugs. The isopropyl group is indirectly-acting sympathomimetic agents / substances highlighted.[Katzung] SUBSTITUTION ON β-CARBON Phenylephrine- direct-acting ⍺1 selective adrenergic Substitution on the β-carbon of the ethylene side chain is agonist. There is an absence of 1 -OH group in the important for storage of sympathomimetic amines in neural benzene ring vesicles. Ephedrine and Amphetamine - examples of Example: Direct-acting adrenergic agonists have a Phenylisopropylamines (absence of both -OH groups in hydroxyl group substitution on the β-carbon Dopamine positions C3 & C4 in the benzene ring). VIII. GENERAL ACTIONS & EFFECTS OF SUBSTITUTIONS ON BENZENE RING CATECHOLAMINES AND SYMPATHOMIMETICS ON Substitution by hydroxyl group at carbon positions 3 and 4 ADRENOCEPTORS will yield a catecholamine. Presence of these hydroxyl The overall pharmacologic effects of a given drug may groups will result in inactivation of the catecholamines by depend on its relative affinity for adrenoceptor subtypes, COMT which are found in the gut and liver. relative expression of receptor subtypes in a given tissue, and its route of administration (Brunton, 2017) [Lecture PPT] ABSENCE OF ONE OF THE OTHER -OH GROUPS Absence of one or the other hydroxyl groups on the “The magnitude of the response depends on the number benzene ring have the following characteristics: and function of the adrenoceptors on the cell surface and → greatly reduces the potency of the drug. on the receptor regulation by catecholamines themselves, Particularly at C3 without substitution other hormones and drugs, age, and a number of disease → is not deactivated by COMT and therefore it increases states.” (Katzung, 2024) [Lecture PPT the bioavailability of the drug after oral administration and prolongs its duration of action GENERAL ACTIONS OF CATECHOLAMINES AND Examples: SYMPATHOMIMETIC DRUGS → Phenylephrine is a non-catecholamine. It lacks the 1. Peripheral excitatory action on smooth muscles (α1) hydroxyl groups at C3 and C4 positions in the benzene 2. Peripheral inhibitory action on certain other types of ring. Its ⍺-receptor affinity is decreased approximately 100 smooth muscles (α2, β2) fold compared to epinephrine. Its β-receptor activity is 3. Cardiac excitatory action (β1) almost negligible except at very high concentration so it is 4. Metabolic actions (β1, β2, β3) - gluconeogenesis in considered as a selective ⍺-1 receptor agonist. liver; glycogenolysis in liver and muscle; lipolysis ABSENCE OF RING -OH GROUPS 5. Endocrine actions (α2, β2, β1)- insulin, glucagon, Increases distribution to the CNS. and renin secretion Can traverse the BBB 6. CNS actions - increase wakefulness, psychomotor Orally active, prolonged duration of action activity, appetite suppression Examples: 7. Prejunctional actions - (α2, β2, β1) - central & → Ephedrine peripheral → Amphetamine → Inhibit/facilitate NT release, inhibition being physiologically more important SUBSTITUTION ON THE AMINO GROUP Increasing size of alkyl substituents on amino group increases β-receptor activity and lowers ⍺-receptor activity Examples: → Epinephrine: has a methyl substitution on the amino group of norepinephrine and this increases its β-receptor activity PHARMACOLOGY Adrenoreceptor Agonist / Sympathomimetic Drugs I PAGE 9 of 19 PHARMACOLOGY | LE 2 Adrenoreceptor Agonist / Sympathomimetic Drugs I | Alfaretta Luisa T. Reyes, MD, FPSECP Table 15. ⍺-2 Receptors Actions on Tissues and its Effects DISTRIBUTION OF THE ADRENORECEPTORS ON THE Actions on Tissues Effects DIFFERENT TISSUES AND THEIR CORRESPONDING Inhibits lipolysis in fat cells ↓FFA ACTIONS AND EFFECTS Inhibits renin release from Prevent inc BP JG cells ❗️ *See the Appendix for larger version of summarized table Central effects: inhibition of ↓BP (Tables 20-24) sympathetic tone Stimulation in β pancreatic ↓insulin secretion (contributes ⍺-1 islet cells to hyperglycemia) The general peripheral action is excitatory in nature. Relaxation of GI smooth ↓muscle tone Activation leads to contraction of smooth muscles and muscle increased secretion of the salivary glands. Platelet aggregation Blood coagulation The vascular smooth muscles are contracted and produce vasoconstriction and may increase blood β-1 pressure. The general peripheral action is excitatory in nature The sphincters in general are relaxed In the heart, this produces positive inotropic, Causes contraction of the radial muscles of the iris chronotropic, dromotropic actions and an increase in resulting in mydriasis, but no cycloplegia. conduction velocity. → Makes it different from your antimuscarinics that will → This results in increased cardiac output and oxygen cause both mydriasis and cycloplegia consumption and may cause an increased blood pressure. The pilomotor smooth muscles are contracted giving rise The rise in BP may elicit a baroreceptor mediated increase to goose-flesh appearance of the skin. in vagal tone resulting in slowing of the heart rate (reflex Hepatic glycogenolysis leads to an increase in glucose bradycardia). release into the circulation. Table 16. β-1 Receptors Actions on Tissues and its Effects Table 14. ⍺-1 Receptors Actions on Tissues and its Effects Actions on Tissues Effects Actions on Tissues Effects Direct effects on the heart: ↑ CO and O2 consumption → Contraction of most Vasoconstriction → May ↑ ↑ contractility ↑ BP vascular smooth muscles BP Activation of SA node to ↑ HR Contraction of radial muscles Mydriasis Activation of AV node to of the iris ↑ conduction velocity Contraction of pilomotor Erects hair (goose-flesh smooth muscle appearance of skin) ↑ BP may elicit baroreceptor May cause reflex Stimulation of salivary glands Salivary secretion (Amylase mediated inc vagal tone bradycardia and water) β-2 Hepatic glycogenolysis and ↑ glucose release into The general peripheral action is inhibitory in nature gluconeogenesis +++ circulation → Bronchodilation Increase cardiac force of (+) inotropic effects → Urinary retention contraction → Decreased tone and motility of the GIT smooth muscles Contraction of GI sphincter Constipation → Vasodilation of vascular smooth muscles supplying the skeletal muscles that produces enhanced blood flow Contraction of bladder base, Urinary continence → → Hypokalemia urethral sphincter, and Urinary retention →Enhanced glycogenolysis in the liver and muscle that prostate (⍺1A) leads to increased release of glucose and lactic acid into Increase peripheral arterial Dose-dependent ↑ in BP the circulation. resistance The pregnant uterus is relaxed → This is useful in delaying premature labor. ⍺-2 The β2 receptors in the β-islet cells of the pancreas are The general peripheral action is inhibitory in nature stimulated and results in increased insulin secretion → decrease in free fatty acid production The β2 receptors in the ⍺-islet cells of the pancreas are → decrease in renin release from the JG cells stimulated to secrete glucagon → decrease in insulin secretion from the β-islet cells of the Activation of β2 receptors in skeletal muscles produces pancreas physiologic muscle tremor. → decrease tone of GI smooth muscles Presynaptic central ⍺-2 receptors modulates NE release Table 17. β-2 Receptors Actions on Tissues and its Effects causing a decrease in sympathetic tone and central Actions on Tissues Effects sympathetic outflow and results in decreased blood Relaxation of vascular Vasodilatation → enhanced pressure. smooth muscles blood flow These groups of drugs are effective as anti-hypertensive Relaxation of bronchial Bronchodilation agents smooth muscle Relaxation of uterus Delays premature labor (pregnant) Decrease peripheral ↓ BP PHARMACOLOGY Adrenoreceptor Agonist / Sympathomimetic Drugs I PAGE 10 of 19 PHARMACOLOGY | LE 2 Adrenoreceptor Agonist / Sympathomimetic Drugs I | Alfaretta Luisa T. Reyes, MD, FPSECP resistance NOT given orally because it is rapidly metabolized by Relaxation of bladder Urinary retention enzymes in the GI mucosa and in the liver. detrusor → Effects on blood pressure depend on its effects on the Relaxation of GI smooth ↓ tone and motility heart rate, myocardial function, venous return, and muscle peripheral vascular resistance following administration Enhanced glycogenolysis in ↑ glucose and lactic acid of a specified dose. the liver and muscle release into circulation Promotes K+ uptake into ↓ plasma K+ level skeletal muscle cells (hypokalemia) ↑ Stimulation in α pancreatic ↑ glucagon secretion islet cells Twitch tension of Skeletal muscle tremor fast-contracting white muscle fibers β-3 Activation in fat cells results in increased release of free 💬 fatty acids Due to activation of triglyceride lipase in brown adipose tissue Figure 8. Variables affecting Blood Pressure ⍺1 and 𝛃2 are present in some vascular smooth muscles but a lot of vascular smooth muscles contain ⍺1 > 💬 Table 18. β-3 Receptors Actions on Tissues and its Effects activated = vasoconstriction Actions on Tissues Effects → So vascular tone is usually sympathetic Stimulates lipolysis in fat cells ↑ FFA and glycerol in the blood mediated 💬 HR - predominantly parasympathetic influence; vagally Relaxation of bladder ↑ bladder storage capacity SMALL DOSE detrusor muscle → urinary continence Small Dose (0.1 mcg/kg) In small doses, 𝛃2 receptors are more sensitive than 𝝰1 D-1 receptors Produces relaxation of vascular smooth muscles of the Fall in BP due to greater sensitivity of vasodilator 𝛃2 to renal, splanchnic, cerebral, and coronary beds. Epinephrine → ↓ PVR This leads to vasodilation of these blood vessels and → Causes relaxation of the vascular smooth muscle enhanced blood flow in these vital organs. leading to vasodilation, followed by a decrease in the peripheral vascular resistance (PVR) and a decrease in Table 19. D-1 Receptors Actions on Tissues and its Effects diastolic pressure (DP). → This produces a fall in blood pressure (BP) Actions on Tissues Effects Relaxation of vascular smooth Vasodilation → ↑ blood flow LARGE DOSE muscles (renal, splanchnic, Low dose: ↓ Increase in BP due to ↑ SP but DP and PVR may be cerebral, coronary) slightly ↑ or ↓ due to stimulation of ⍺1 and β2 receptors ↑ GFR, renal blood flow and Natriuresis and diuresis (biphasic response) Na+ excretion → Effects of ⍺-1 receptors on blood vessels are more predominant but transient than the effects of β-2 CARDIOVASCULAR EFFECTS receptor stimulation which are more prolonged. Sympathomimetic drugs have prominent CVS effects due → ⍺-1 receptor stimulation causes vasoconstriction that to widespread distribution of α and β adrenoceptors in the leads to increase in PVR. heart, blood vessels, neural and hormonal systems → β-2 receptor stimulation causes vasodilation and leads involved in BP regulation. to a decrease in PVR Activation of β1 receptors in the heart ↑ CO by ↑ → Overall effect on the PVR and diastolic (DP) pressure contractility (+inotropic effect) and by direct activation of may be slight increase or decrease or no change SA node to ↑ HR (+chronotropic effect); stimulation of AV depending on the interplay of the the drug concentration node ↑ conduction velocity (+dromotropic effect). with these receptors Activation of α2 receptors in the vasculature leads to vasoconstriction with very high oral doses or by rapid IV Epinephrine directly activates the β1 receptors in the heart: injection of α2 agonists. Given the usual recommended → Effects: dose, central sympatholytic effects are observed → ↓BP ▪ (+) chronotropic, inotropic, dromotropic Activation of β2 receptors leads to vasodilation of certain ▪ ↑ conduction velocity vascular beds → ↓PVR ▪ ↑ CO This causes an elevation in systolic pressure (SP). Since IX. EPINEPHRINE the overall mean BP is not markedly elevated, observed. Drug prototype of catecholamines No reflex bradycardia Activates all adrenergic receptors → overall mean BP not markedly elevated Polar drug and poorly penetrates into body membranes Epinephrine reversal occurs in the presence of an including the CNS. ⍺-receptor antagonist PHARMACOLOGY Adrenoreceptor Agonist / Sympathomimetic Drugs I PAGE 11 of 19 PHARMACOLOGY | LE 2 Adrenoreceptor Agonist / Sympathomimetic Drugs I | Alfaretta Luisa T. Reyes, MD, FPSECP RAPID IV ADMINISTRATION CNS EFFECTS Raises ↑↑ blood pressure proportional to the given dose Catecholamines are polar substances and penetrate → ↑↑SP > ↑DP, ↑Pulse pressure poorly into the CNS ❗️ → ↑↑↑CO → Subjective effects were noted only if administered at Marked increase in BP are due to: higher rates of infusion → ↑ Inotropic - Myocardial force of contraction (ventricular) → Ranges from nervousness, restlessness, apprehension, → ↑ chronotropic - HR via 𝛃1 receptor activation tremors, headache, to “adrenaline rush” or “feeling of → Vasoconstriction if the blood vessels of the skin and impending disaster” mucosa via 𝝰 receptor stimulation With marked increase in BP and in the presence of normal NON-VASCULAR SMOOTH MUSCLE EFFECTS reflex, the direct effects on the heart rate are overcome by Depends on the adrenoceptor subtype and its densities compensatory baroreceptor reflex bradycardia resulting GIT from vagal discharge Decreased frequency and amplitude of the smooth muscle SLOW IV INFUSION OR SC INJECTION contraction Mean BP is not greatly elevated → Relaxation of smooth muscle walls - due to direct effect → Moderate ↑SP due to ↑ myocardial Fc and ↑ CO of postsynaptic 𝛃2 receptor stimulation → PVR ↓ → Presynaptic 𝝰2 receptors present in cholinergic nerve ▪ Due to dominant action on β2 receptors of blood endings contribute to this effect by modulating or vessels in skeletal muscles ⇒ vasodilation and enhance decreasing the release of acetylcholine in these nerve blood flow ⇒ ↓ DP endings or terminals (heteroreceptors) Direct cardiac effects are not antagonized by → The pyloric and ileocecal sphincters are contracted by compensatory baroreceptor reflex mechanisms, (no reflex ⍺-1 receptor activation bradycardia). UTERUS SLIGHTLY FASTER RATE OF IV INFUSION Response varies with phase of sex cycle, state of BP is elevated due to a marked increase in SP gestation, and the administered dose → Resulting from direct 𝛃1 receptor activation, leading to Diminished uterine tone and contraction during the last positive cardiac effects month of pregnancy and parturition → Slight ↑ in PVR and DP depending on the administered 𝛃2 receptor sympathomimetic drugs stimulate the 𝛃2 drug dose and net effect on the response of 𝝰1 and 𝛃2 receptors to produce these effects in patients having receptor in vascular smooth muscles → Compensatory baroreceptor reflex may come into play (may antagonize direct cardiac actions) premature uterine contraction → Can delay premature labor ❗️ Sympathomimetic agents such as norepinephrine or even METABOLIC EFFECTS phenylephrine that activate 𝝰1 receptors should be HYPERGLYCEMIA AND HYPERLACTACIDEMIA avoided during pregnancy because these cause uterine contraction Increase in glucose and lactate concentration is due to the following: GENITOURINARY TRACT → Enhanced glycogenesis in the liver and muscle due to 𝛃 Urinary retention occurs from relaxation of detrusor receptor activation muscles of the urinary bladder resulting from 𝛃2 receptor → Glucagon secretion of alpha pancreatic islet cells activation, as well as contraction of the trigone and → Gluconeogenesis in the liver sphincter muscle brought about by activation of 𝝰1 → Glycogenolysis in the liver (α1) receptors ⇒ urinary hesitancy ⇒ urinary retention → Decreased glucose uptake in the peripheral tissues, Prostate smooth muscle contraction ⇒ urinary retention in partly due to the dominant inhibitory effect of α2 patients with benign prostatic hypertrophy. receptors on insulin secretion from the beta islet cells of → Prostate smooth muscles are contracted by the 𝝰1 the pancreas receptor activation HYPERLIPIDEMIA OTHER EFFECTS Due to increased release of free fatty acid into the Inhibition of histamine release from mast cells by circulation due to stimulation of β-3 and β-1 receptors in epinephrine and other sympathomimetic drugs via adipose tissues activation of 𝛃2 receptors Caused by the activation of triglyceride lipase resulting in → aids in the management anaphylaxis enhanced breakdown of triglycerides in brown adipose In most secretory glands. secretion is inhibited but the tissues thus, providing increase in available body fuel. effects are not pronounced CALORIGENIC ACTION → Salivary glands: scanty mucus secretion(𝝰1 ) → Apocrine sweat glands: adrenergic sweating on the There is an increase in oxygen consumption by 20-30% palm of the hands and soles of the feet associated with psychological stress RESPIRATORY EFFECTS ▪ Apocrine sweat glands: non-thermoregulatory glands Bronchodilation due to 𝛃2 receptor stimulation in bronchial ▪ Eccrine sweat glands: thermoregulatory smooth muscles Eyes: Contraction of radial smooth muscles of the iris (𝝰1 ) Decreased bronchial secretion and congestion within the causing mydriasis through stimulation of alpha-receptors mucosa due to 𝝰1 receptor activation → Seen during physiological sympathetic stimulation → Inhibition of histamine release from mast cells (𝛃2) PHARMACOLOGY Adrenoreceptor Agonist / Sympathomimetic Drugs I PAGE 12 of 19 PHARMACOLOGY | LE 2 Adrenoreceptor Agonist / Sympathomimetic Drugs I | Alfaretta Luisa T. Reyes, MD, FPSECP → No cycloplegia being produced by sympathomimetic → Can be applied topically in nasal pack for epistaxis or drugs gingival string for gingivectomy or multiple teeth → Decreased intraocular pressure if administered into extraction conjunctival sac ▪ alpha receptor effect → Selective 𝝰2 agonist drugs-decrease intraocular pressure CASE SCENARIO → Peripheral vasoconstriction decreases aqueous humor CASE: 12/F presents with sore throat & fever, and is diagnosed output with pharyngitis caused by group A β-hemolytic streptococcus. Male Reproductive System: Activation of 𝝰1 receptors in She is given an IM injection of penicillin. male sex organ ⇒ ejaculation Hypokalemia: partly due to increased potassium uptake 5 minutes later, she is found to be in respiratory distress into the cells of skeletal muscles and audibly wheezing. Her skin is mottled and cool, she is tachycardic, and her BP has fallen to 70/20 mmgHg. ADVERSE EFFECTS AND TOXICITY Most are attributed to the stimulation of adrenoceptors She was immediately diagnosed as having an anaphylactic involved reaction to the penicillin and given a subcutaneous Restlessness, throbbing headache, tremor injection of epinephrine. Cardiac effects (palpitations, tachycardia, possibly arrhythmia) 1. What effect will epinephrine have on the patient’s → Attributed to the stimulation of 𝛃1 receptors vascular system? Most serious reactions ❗️ → Cerebral hemorrhage 2. Which adrenoceptor primarily mediates the ▪ due to intense activation of 𝝰1 receptor vascular response? ▪ 𝝰1 receptor activation especially at high doses ⇒ ↑PVR ⇒↑BP especially in the intracranial arteries ⇒ 3. What effect will epinephrine have on her respiratory hypertensive crisis system? → Cardiac arrhythmias ▪ due to activation of 𝛃1 receptors ⇒ (+) inotropic, 4. Which adrenoceptor primarily mediates the dromotropic, chronotropic effects⇒ ↑CO ⇒ ↑BP or pulmonary response? hypertensive crisis CONTRAINDICATIONS 5. What best describes the cellular reaction of Coronary artery disease epinephrine? → May induce angina resulting from 𝛃1 receptor activation a. activation of adenylyl cyclase → Due to increased myocardial workload b. decreased activity of cAMP-dependent protein Arteriosclerosis kinases → May provoke hypertensive crisis as a result of 𝝰1 c. increased intracellular stores of calcium receptor stimulation that may lead to increase in PVR d. inhibition of activity of phospholipases and marked increase in BP Concomitant use of non-selective beta-blocker 6. Epinephrine-mediated 𝛃1-adrenoceptor activation → May leave the 𝝰1 receptor action unopposed and may results in cause severe hypertension and cerebral hemorrhage a. constriction of bronchial smooth muscle → contraindicated if BP is initially high because it can b. decreased gastrointestinal motility cause withdrawal syndrome or can further increase BP c. dilation of the pupils ▪ due to upregulation d. increased heart rate THERAPEUTIC USES A 3-year-old male has been admitted to the ER having Hypersensitivity reactions, including anaphylaxis as swallowed the contents of 2 bottles of a nasal physiologic antagonist, not competitive decongestant. The active ingredient is phenylephrine, a → 1:1000 aqueous solution, 0.3-0.5 mg SC or IM potent, selective 𝝰-adrenoceptor agonist drug. → Reverses the pathophysiologic process involved in anaphylaxis by activating the 𝝰1 , 𝛃1, and 𝛃2 receptors 7. Which is a sign of 𝝰-receptor activation that may → Autoinjector (Epipen)-for self administration occur in this child? As a vasoconstrictor with local anesthetics a. bronchodilation → 1:100,000 ot 1:200,000 solution b. mydriasis → Potentiates the action and effects of local anesthetic c. tachycardia drugs by decreasing the absorption of the local d. vasodilation of blood vessels anesthetic thereby prolonging the duration of action and decreasing the systemic effects of the local anesthetic 8. Which of the following sympathomimetics is a drug by reducing its dose direct-acting agent? Complete heart block or cardiac arrest a. amphetamine → May be used during resuscitation to return to normal b. cocaine spontaneous rhythm c. dopamine → may be useful for remote areas without available d. tyramine defibrillators → Now seldom used Topical hemostatic agent PHARMACOLOGY Adrenoreceptor Agonist / Sympathomimetic Drugs I PAGE 13 of 19 PHARMACOLOGY | LE 2 Adrenoreceptor Agonist / Sympathomimetic Drugs I | Alfaretta Luisa T. Reyes, MD, FPSECP 9. Which adrenergic agonist is the most potent → 𝛃2 receptor:salbutamol, terbutaline, formoterol, stimulant of hepatic glycogenolysis? salmeterol a. clonidine → 𝛃3 receptor: mirabegron, vibegron b. dobutamine Receptor nonselectivity - drug may interact with more c. isoproterenol than one receptor subtype at the usual drug concentrations d. phenylephrine → norepinephrine - 𝝰1 𝝰2 𝛃2 → epinephrine - 𝝰1 𝝰2 𝛃1 𝛃2 10. Which receptor is activated in the relaxation of → isoproterenol - 𝛃1 𝛃2 detrusor muscle of the bladder? → dopamine - D1 D2, 𝛃1 𝝰1 a. 𝝰1 Sympathomimetics with indirect action produce their b. 𝝰2 effects by: c. 𝛃1 → releasing or displacing stored NE from adrenergic nerve d. 𝛃3 endings (eg. releasing agents: amphetamine, tyramine, modafinil, methamphetamine, ephedrine) ANS AND RATIO: → decreasing clearance of release NE from nerve 1. Vasoconstriction terminals by 2. alpha-1 ▪ inhibiting catecholamine uptake (eg. uptake 3. bronchial muscle relaxation inhibitors: TCAs, cocaine, methylphenidate, 4. beta-2 atomoxetine, duloxetine) 5. A. Epinephrine activates 𝛃1 and 𝛃2 ▪ blocking the metabolizing enzymes (eg. MAO adrenoreceptors to stimulate adenyl cyclase inhibitor pargyline; COMT inhibitor entacapone) activity, thereby increasing cAMP levels and Sympathomimetics can be divided into 2 major groups activity of cAMP-dependent protein kinases. based on their chemical structure 6. D. Epinephrine also acts on 𝛃2 adrenoreceptors, → “The chemical structure of a given drug determines its causing bronchodilation and decreased GI relative affinity to receptor subtypes, its pharmacokinetic motility. Through its action on 𝝰1 properties and bioavailability, and may influence the adrenoreceptors, it causes, contraction of intrinsic ability of the drug to activate these receptors” pupillary dilator muscles ▪ catecholamines: direct acting drugs that have a 7. B. Pupils open wide as radial muscle of iris catechol in their chemical structure contract − endogenous: NE,EPI,dopamine 8. C − synthetic: isoproterenol, dobutamine 9. C Clonidine:𝝰2, dobutamine:𝛃1, phenylephrine:𝝰1 CATECHOLAMINES VS NONCATECHOLAMINES 10. D Catecholamines → inc alkyl substitution at the ethylamine nitrogen → inc 𝛃 receptor selectivity over 𝝰 receptors XI. SUMMARY ▪ isoproterenol > EPI > NE Sympathomimetic drugs mimic the effects of adrenergic → substitution by -OH groups at C3 and C4 on benzene nerve stimulation by ring → activating adrenoreceptors or → polar