[PHA LEC - LE 2] 1B - Adrenoceptor Agonists_Sympathomimetic Drugs II (V1).pdf

PHARMACOLOGY | TRANS 1B Adrenoceptor Agonists/Sympathomimetic Drugs II LE ALF...

PHARMACOLOGY | TRANS 1B Adrenoceptor Agonists/Sympathomimetic Drugs II LE ALFARETTA LUISA TAN-REYES, MD, FPSECP | Lecture Date (09/17/2024) | Version #1 02 OUTLINE o General pharmacologic actions and effects of the I. Norepinephrine VI. β3 Selective Adrenoceptor adrenoceptor agonists on the adrenoceptors located in A. Pharmacokinetics Agonists various organs/system B. Selectivity of NE A. Mirabegron ✔ Discuss the pharmacologic properties of the other C. Cardiovascular Effects B. Vibegron catecholamines and noncatecholamines based on their D. Toxicity, Adverse Effects C. Potential Future Addition pharmacokinetics, pharmacodynamics (mechanism of and Precautions to the Selective β3 actions, pharmacologic actions and effects). E. Clinical Application of NE Receptor Agonists II. Dopamine VII. α1 Selective Adrenoceptor ✔ Predict the adverse effects, toxicity and contraindications A. Pharmacokinetics Agonists of adrenoceptor drugs and sympathomimetics based on B. Important Pharmacologic A. General Pharmacologic their pharmacokinetics and pharmacodynamics. Actions and Effects Actions ✔ Discuss the indications/ clinical applications of the C. Precautions, Adverse B. Phenylephrine adrenoceptor drugs and sympathomimetics in the Effects, and C. Midodrine treatment and prevention of diseases/ illnesses based on Contraindications VIII. Mixed-Acting their pharmacologic properties, actions and effects. D. Clinical Applications Sympathomimetic Agents ✔ Explain the significant drug interactions and factors that III. Other Dopamine Receptor A. Ephedrine Agonists B. Pseudoephedrine may limit the use of these drugs. A. Fenoldopam C. Phenylpropanolamine ✔ Apply the process of rational drug use in choosing and B. Dopexamine IX. Indirect-Acting prescribing the appropriate drugs to clinical scenarios IV. β Adrenergic Receptor Sympathomimetic Agents involving conditions/disorders such as in anaphylaxis, Agonists A. Amphetamine-Like glaucoma, overactive bladder. A. Isoproterenol B. Catecholamine Reuptake ✔ As a future primary care practitioner, identify conditions B. Dobutamine Inhibitors when to refer your patient to proper healthcare V. β2 Selective Adrenoceptor X. Clinical Uses of Adrenergic professionals/facilities. Agonists Drugs A. General Clinical Applications A. α Receptor Stimulation B. β Receptor Stimulation MUST KNOW ❗️ B. Adverse Effects C. Anaphylaxis Phenylephrine selectively acts on α1 receptors and has C. Terbutaline D. Cardiogenic Shock almost no effects on the β receptors. D. Salbutamol / Albuterol E. Cardiac Stress Test Clonidine preferentially acts on α2 receptors than on α1 E. Formoterol F. CNS Application receptors at the recommended therapeutic doses and it F. Salmeterol G.Others has no effect on the β2 receptors. G.Ritodrine XI. Summary H. Other Long Acting XII. Review Questions Norepinephrine (NE) binds and acts almost equally to Selective β2 Receptor XIII. References both the α1 and α2 receptors. Sympathomimetic XIV. Appendix → It acts on β1 receptors and almost no effects on β2 Agonists receptors. Epinephrine (EPI) interacts with all adrenoceptor Must Lecturer Book Previous Youtube receptors at almost equal potency. ❗️ Know 💬 📖 📋 Trans 🔺 Video → More potent than NE in adrenergic receptors except on β1 receptors SUMMARY OF ABBREVIATIONS → NE and EPI are equipotent on β1 receptors. AE Adverse effects Isoproterenol is purely a nonselective β receptor CO Cardiac output agonist. COMT Catechol-O-Methyltransferase → Its effects on α receptors are insignificant. COPD Chronic obstructive pulmonary disease Dobutamine is classified as a selective β1 receptor DA Dopamine agonist. EPI Epinephrine → If given at high concentrations, it can activate α GFR Glomerular filtration rate receptors ICS Inhaled corticosteroids Terbutaline, salbutamol/albuterol, formoterol, MAO Monoamine oxidase salmeterol, and ritodrine are classified as selective β2 MAOI Monoamine oxidase inhibitors receptor sympathomimetic drugs. NE Norepinephrine → These have insignificant effects on the α receptors. NET NE transporter Fenoldopam is a selective D1 receptor agonist. OAB Overactive bladder Administered in recommended therapeutic doses, PVR Peripheral vascular resistance dopamine (DA) selectively acts on D1 receptors. RBF Renal blood flow → It is only when DA is given in high doses that it will TCA Tricyclic antidepressants act on the β receptors to ↑ myocardial force of LEARNING OBJECTIVES contraction with minimal tachycardia. ✔ Review the following: → If given at further higher doses, it is only at this time o General classification of the various adrenoceptor that it can activate the α receptors. agonists and sympathomimetic agents o Structure-activity relationships of the catecholamines and noncatecholamines LE 2 TG 18 | N. Madriaga, P. Magbanua, M. Mago, TE | N. Madriaga AVPAA | C. Lee, M. Navarro PAGE 1 of 14 TRANS 1B J. Mamalateo, A. Manalo, K. Manalo VPAA | A. Escolano PHARMACOLOGY | LE 2 Adrenoceptor Agonists/Sympathomimetic Drugs II | Alfretta Luisa Tan-Reyes, MD, FPSECP Table 1. Relative Receptor Affinities[Lecturer’s PPT] ❗️ REVIEW Relative Receptor Substance Affinities (SAR) α agonists Phenylephrine, α1>α2>>>>>β methoxamine Clonidine, α2>α1>>>>>β methylnorepinephrine Mixed α and β agonists NE α1=α2 ; β1 >> β2 EPI α1=α2 ; β1=β2 β agonists Figure 1. Regulation of BP, Autonomic and hormonal Dobutamine β1>β2>>>>α control of CVS function[Lecturer’s PPT] Isoproterenol β1=β2>>>>α Albuterol, terbutaline, β2>>β1>>>>α Based on the hydraulic equation, blood pressure is metaproterenol, ritodrine equal to CO and PVR DA agonists PVR is mediated by the actions on α1 & β2 receptors DA D1=D2>>β>>α → activated α1 receptors: give rise to contraction of the Fenoldopam D1>>D2 vascular smooth muscles = vasoconstriction I. NOREPINEPHRINE → activated β2 receptors: give rise to relaxation of the vascular beds = vasodilation An endogenous catecholamine In the sympathetic nervous system, involved are PVR, Primary neurotransmitter at noradrenergic nerve SV, force of contraction, and HR terminals → Principal endogenous catecholamine found in C. CARDIOVASCULAR EFFECTS OF NE sympathetic nerve terminals, not Epinephrine (EPI) Determinants of BP: Cardiac Output (CO) and Peripheral Poorly absorbed (polar) across body membranes Vascular Resistance (PVR) including the GIT Mean arterial BP may be markedly ↑ as a result of ↑ in A. PHARMACOKINETICS both systolic BP (SP) and diastolic BP (DP) Poor oral absorption and more effectively given as IV drip → ↑↑↑ SP; ↑↑ DP; ↑↑ Mean BP Action is rapidly terminated by neuronal uptake (uptake ▪ Tremendous ↑ in SP due to β1 receptor activation 1) through the NET and by enzymatic degradation by ▪ As PVR increase, ↑ DP is expected due to α1 receptor Catechol-O-Methyltransferase (COMT) and monoamine activation oxidase (MAO) NE activates β1 receptor and produces a direct: → Positive inotropic = ↑ myocardial contractility → ↑ 💬 → Primary path of termination is through neuronal uptake 75% of released NE from the synaptic cleft is captured through Norepinephrine transporter (NET) stroke volume → Positive chronotropic = ↑ heart rate (HR) Small amount normally are found in urine → Positive dromotropic = ↑ AV node conduction velocity Excretion rate is greatly increased in pheochromocytoma → Initial increase in cardiac output NE activates α1 receptors B. SELECTIVITY OF NE → result in ↑↑↑ PVR (vasoconstriction of most vascular Selectivity of NE: α1 = α2 ; β1 >> β2 beds in the venules and arterioles) The table below shows the relative receptor affinities of → It has insignificant activity at β2 receptors NE, EPI and isoproterenol Reflex bradycardia will set in at the height of the rise in BP → CO may be decreased or unchanged Table 2. Relative Receptor Affinities of EPI, NE and → Marked rise in BP will produce a compensatory Isoproterenol [Lecturer’s PPT] baroreceptor vagal reflex (reflex bradycardia) Relative Receptor Affinities at ▪ May overcome the direct positive chronotropic action Receptor Catecholamines of NE (↑ HR) α1 Epi ≥ NE >> Iso ▪ Positive inotropic effects on the heart (↑ myocardial α2 Epi ≥ ≤ NE >>> Iso contractility) are maintained β1 Iso >> Epi ≥ NE ▪ Ventricular muscles receives little, if any, β2 Iso ≥ Epi >>> NE parasympathetic innervation β3 Iso = NE > Epi What will happen to the HR and CO if atropine is given NE, like EPI, are mixed or non-selective α & β receptor prior to NE administration? Why? agonists. → In the presence of atropine prior to norepinephrine → NE is generally a poor β2 agonist. administration, the typical vagal reflex may not be → It is a potent α agonist but is somewhat less potent than observed EPI on α receptors found in most organs. → Atropine is an antimuscarinic agent, hence blocks the → Approximately equipotent with EPI in stimulating β1 action of acetylcholine at muscarinic receptors in the receptors. heart (↓HR), and favors an ↑ in HR instead Isoproterenol is the most potent in activating the β D. TOXICITY, ADVERSE EFFECTS AND PRECAUTIONS receptors among the three catecholamines. Adverse effects are similar to EPI, however, NE produces a greater rise in BP as a result of increase in PVR → This may produce severe hypertension PHARMACOLOGY Adrenoceptor Agonists/Sympathomimetic Drugs II PAGE 2 of 14 PHARMACOLOGY | LE 2 Adrenoceptor Agonists/Sympathomimetic Drugs II | Alfretta Luisa Tan-Reyes, MD, FPSECP Precaution: ▪ This causes relaxation of vascular smooth muscles → Avoid extravasation of the NE into neighboring producing vasodilation via Gs-adenylyl cyclase- tissues since this may cause tissue necrosis and cAMP pathway sloughing ▪ ↑ adenylyl cyclase activity, ↑ cAMP production ▪ This is attributed to α1 receptor activation that can ▪ Produces an enhanced blood flow and increased lead to intense vasoconstriction tissue perfusion E. CLINICAL APPLICATIONS OF NE At intermediate concentrations: ❗️ First-line vasopressor agent if needed in the treatment → DA acts on cardiac β1 receptors in the heart → (+) inotropic effect (↑ myocardial contractions with minimal of shock such as in sustained hypotension with evidence of tachycardia) → ↑CO → ↑SP with no effect or slight hypoperfusion primarily due to its α and β activities effect on DP → Provides an acceptable balance, having predominantly → DA cause the release of NE from nerve terminals α adrenergic properties and modest beta adrenergic ▪ Also contributes to its effects on the heart effects (helps to maintain CO) At high concentrations: → Administration will generally result in a clinically → DA activates vascular α1 receptors → generally significant increase in MAP with little change in HR or vasoconstriction of skeletal muscle blood vessels CO ❗️ MUST KNOW ▪ This may lead to ↑BP RENAL SYSTEM In the treatment of shock, pure α or β adrenergic At low doses of DA: stimulation is not advisable because of the following → Acts on the renal tubules by stimulating D1 receptors reasons: ▪ Produces natriuresis by inhibiting Na+-H+ exchanger → β adrenergic agonist: ↑ blood flow (BF), but also ↑ and the Na+K+-ATPase pump the risk of myocardial ischemia ▪ Augmented by ↑ renal blood flow (RBF) and small ↑ → α adrenergic agonist: ↑ vascular tone and BP, but in glomerular filtration rate (GFR). also ↓ CO and can impair tissue BF due to vasoconstriction C. PRECAUTIONS, ADVERSE EFFECTS, AND → Dopamine: has no advantage over NE because it is CONTRAINDICATIONS now associated with higher incidence of arrhythmias ADVERSE EFFECTS as well as mortality Attributed to its actions on the adrenergic receptors As a local vasoconstrictor, it is combined with some local Include nausea, vomiting, diarrhea, anginal pain, anesthetics to delay absorption & prolong duration of arrhythmias, headache, hypertension. infiltration of nerve block and decrease systemic toxicity of PRECAUTIONS local anesthetics Before DA is administered to patients in shock, → Action is similar with EPI and phenylephrine hypovolemia should be corrected. → Not a local anesthetic → Whole blood, plasma, or other appropriate fluids may be II. DOPAMINE given to these patients An endogenous catecholamine → Volume Replacement = Very Important for Shock → Substrate for MAO & COMT → No advantage of DA over NE as a vasopressor in the Metabolic precursor of NE and EPI treatment of acute hypotension/shock → Transported via vesicles for the synthesis of NE Similar to NE, avoid extravasation during large amount of ❗️ A CNS neurotransmitter DA infusion Important in movement regulation → Causes ischemic necrosis and tissue sloughing ▪ Causes Parkinson’s Disease if deficient ▪ Attributed to activation of α1 receptors, especially in → Known as the “feel good neurotransmitter” or the the vascular smooth muscles “happy hormone” CONTRAINDICATIONS → Part of the reward stimulus relevant to addiction Avoid or reduce the dose of DA in patients receiving MAO A. PHARMACOKINETICS inhibitor (MAOIs) A polar drug which is poorly absorbed across body → Adjust the dosage of DA if the patient is taking tricyclic membranes including the CNS antidepressants (TCAs) → Ineffective if given orally D. CLINICAL APPLICATIONS → Administered parenterally usually via IV route Severe congestive heart failure especially in patients ▪ Injected DA usually has no central effects because it with oliguria or low or normal PVR cannot cross the BBB Cardiogenic and Septic Shock − For it to be effective in treatment for Parkinsonism, → No advantage over NE it should be administered with Carbidopa, a → Associated with higher incidence of arrhythmias and peripheral inhibitor of Decarboxylase mortality A substrate for MAO and COMT being a catecholamine III. OTHER DOPAMINE RECEPTOR AGONISTS B. IMPORTANT PHARMACOLOGIC ACTIONS AND A. FENOLDOPAM EFFECTS A benzazepine derivative CARDIOVASCULAR SYSTEM A selective agonist for peripheral D1 receptors and binds Effects are dose-dependent with moderate affinity to α2 adrenoceptors At low doses: No significant affinity for D2 , α1 , or β1 receptors → DA stimulates D1 receptors especially in renal, Selectively produces vasodilation in some vascular beds splanchnic, coronary and cerebral vascular beds PHARMACOLOGY Adrenoceptor Agonists/Sympathomimetic Drugs II PAGE 3 of 14 PHARMACOLOGY | LE 2 Adrenoceptor Agonists/Sympathomimetic Drugs II | Alfretta Luisa Tan-Reyes, MD, FPSECP THERAPEUTIC USE → β2 receptor activation: Rapidly acting vasodilator used in the intravenous ▪ Potent bronchodilator and enhances blood flow to treatment of severe hypertension (e.g., malignant skeletal muscles hypertension with end-organ damage) ▪ As with other β2 agonists, its effect in asthma is partly → Other parenteral drugs may be used in hypertensive due to inhibition of antigen-induced release of emergencies such as sodium nitroprusside, nitroglycerin, β-blocker labetalol, Ca2+ channel blockers ❗ histamine and other mediators of inflammation Relaxation of vascular smooth muscles supplying skeletal muscles → vasodilation → enhanced blood flow & hydralazine → Esmolol, an ultrashort acting β blocker, is often use to TOXICITY AND ADVERSE EFFECTS manage intraoperative and postoperative hypertension Palpitations and tachycardia B. DOPEXAMINE → Due to direct activation of β1 receptors in the heart A synthetic analog of dopamine with intrinsic activity on Headache and flushing D1, D2, and β2 receptors → Commonly observed as a result of β2 receptor → Therapeutic uses are same as DA stimulation especially those located in vascular beds Inhibits catecholamine uptake and thereby producing vasodilation Cardiac ischemia and arrhythmias IV. β ADRENERGIC RECEPTOR AGONISTS → May occur in patients with underlying coronary artery A. ISOPROTERENOL disease Prototype of β-adrenergic receptor agonists Considered a pure β receptor agonist CLINICAL APPLICATION More potent non-selective β receptor agonist than EPI Limited use and NE Used in emergency situations: Very low affinity for α receptors → In patients with bradycardia or heart block Has powerful effects on all β receptors and almost no → In anticipation of cardiac pacemaker insertion to action at α receptors stimulate HR → In patients with ventricular arrhythmias (torsade de CHEMISTRY AND PHARMACOKINETICS ❗️ A synthetic catecholamine and it is NOT taken up by pointes) Replaced by other sympathomimetic agents in the sympathetic neurons via the NE transporter (NET) treatment of asthma, COPD, and shock t1/2 : approximately 2 hours → Pure β receptor activation increases blood flow but also Metabolized in the liver and other tissues through increases risk of myocardial ischemia enzymatic degradation by COMT A relatively poor substrate for MAO Table 3. Cardiovascular Effects of Catecholamines in → Undergoes uptake 2 Humans (in therapeutic doses of 0.1-0.4 µg/kg/min IV or → Since it is not taken up by sympathetic neurons, it 0.5-1.0 mg SC)[Lecturer’s PPT] cannot enter nerve terminals Cardiovascular Function EPI NE Isoproterenol PHARMACOLOGIC ACTIONS AND EFFECTS Systolic BP ++ +++ 0+ Cardiovascular System Diastolic BP - ++ -- → Recall: BP = CO × PVR Mean BP +0- ++ -- → Activates both β1 & β2 receptors Total Peripheral Resistance -- +++ --- → NET EFFECT: slightly ↑ or unchanged SP, ↓↓ DP, ↓↓ HR (Chronotropic Effect) + - ++ PVR, ↓ mean BP Stroke Output (Inotropic ++ + ++ → ↓ Venous tone Effect) → β2 receptor activation: CO +++ -0 +++ ▪ PVR is ↓ primarily in the vascular smooth muscles Legend: 0 = no effect; + = increased; - = decreased; The supplying the skeletal muscles renal and mesenteric number of symbols indicates the approximate magnitude of vascular beds leading to vasodilation the response. ▪ Potent vasodilating effect ▪ Attributed to activation of β2 receptors in certain vascular beds with no antagonistic effects from α1 receptors activity → β1 receptor activation: ▪ ↑↑ CO due to: − (+) inotropic, chronotropic, dromotropic effects o ↑ myocardial contractility o direct stimulation of the sinus node o ↑↑↑ HR & ↑ SV ▪ Results in increased Ca2+ influx in cardiac cells → Cardiac effects: may lead to palpitations, sinus tachycardia and to more serious arrhythmias Smooth Muscles → Relaxation is more pronounced on bronchial, GI smooth Figure 2. Schematic representation of the cardiovascular muscles, and vascular beds particularly those supplying effects of intravenous infusions of adrenaline (EPI), the skeletal muscles noradrenaline (NE), and isoprenaline or isoproterenol (highlighted brown areas) in humans[Lecturer’s PPT] PHARMACOLOGY Adrenoceptor Agonists/Sympathomimetic Drugs II PAGE 4 of 14 PHARMACOLOGY | LE 2 Adrenoceptor Agonists/Sympathomimetic Drugs II | Alfretta Luisa Tan-Reyes, MD, FPSECP Norepinephrine Longer duration of action than EPI and have greater oral → Causes vasoconstriction due to α1 receptor stimulation. bioavailability → ↑ SP, DP, and peripheral resistance with reflex 40% of the β receptors in human heart are β2 receptors bradycardia MOA: activates adenylyl cyclase activity → ↑cAMP Isoproterenol production → Potent agonist at β receptors → It increases myocardial force of contraction and heart Table 4. Classification of β2 Selective Adrenoceptor resulting from β1 receptor activation Agonists[Lecturer’s PPT; Didactic Study Guide] → DP and PR are ↓ due to stimulation of β2 receptors Classification Drug Features leading to vasodilation of vascular beds Short-Acting Terbutaline Prototype drug → Mean arterial pressure falls β2 Agonists Salbutamol / Epinephrine (SABA) Albuterol → Acts on all the α1 and β2 receptors Pirbuterol → Effects depend on the interplay of the concentration of Levalbuterol the agonist with the tissues Fenoterol In combination with ▪ It may be ↑ or ↓ or no change at all Ipratropium Bitolterol B. DOBUTAMINE Procaterol Partial agonist, prepared usually in a racemate mixture Clenbuterol Has anabolic action Initially considered a relatively β1 selective agonist Long-Acting Salmeterol Prototype drug → (+) isomer β2 Agonists (Serevent) Long acting; slower ▪ More potent β1 agonist than the (-) isomer (LABA) onset; with Fluticasone ▪ α1 receptor antagonist as symptom controller → (-) isomer Formoterol Prototype drug ▪ Potent α1 agonist Long acting; rapid onset Its chemical structure resembles dopamine but actions of action; with are mediated mostly by activation of the α and β receptors Budesonide as → Dopamine is 10-fold less active in activating the β2 symptomatic controller receptors Carmoterol Rapid onset, for asthma and COPD CARDIOVASCULAR EFFECTS Arformoterol for COPD Relatively more prominent inotropic than chronotropic Bambuterol approved in Europe effects compared with isoproterenol Indacaterol / Ultra long acting → Activation of the cardiac α1 receptors may contribute to Olodaterol / its inotropic effects Vilanterol PVR does not ↓ significantly due to activation of α1 receptors that may counterbalance its α1 receptor Others Ritodrine Tocolytic (to arrest antagonistic action ADVERSE EFFECTS Isoxsuprine 💬 premature labor) Used as a peripheral vasodilator esp. in px May ↑ BP and HR because of potent β1 receptor activation with peripheral vasospastic diseases Ventricular ectopic activity may develop (more effective & less AE Tolerance may develop with its use drugs are now being THERAPEUTIC USES utilized) Short term treatment of cardiac decompensation Most of the SABAs & LABAs are used in the treatment of post-cardiac surgery or in patients with Cardiac Heart bronchospastic or bronchial-airway diseases such as Failure (CHF) or Acute Myocardial Infarction (AMI) asthma and COPD. Inotropic agent of choice when ↑ CO is needed A. GENERAL CLINICAL APPLICATIONS Used as a pharmacologic cardiac stress test when the Treatment of asthma and COPD as bronchodilator patient is unable to exercise during the stress test → Relaxes bronchial smooth muscle and ↓ airway Increases the myocardial contractility and brings about resistance systemic vasodilation → Suppresses release of leukotrienes and histamine from → Produce ↑ HR and myocardial work mast cells in lung tissue → Can reveal myocardial ischemic areas that can be → Enhance mucociliary function detected by echocardiogram or nuclear medicine → Decrease microvascular permeability techniques → Possibly inhibit phospholipase A2 (involved in V. β2 SELECTIVE ADRENOCEPTOR AGONISTS inflammation) 📋 Selectivity is relative, not absolute Selectivity disappears with increase dosage Uterine muscle relaxant (Tocolytic) → To delay premature labor 💬 Noncatecholamines, not substrates for COMT Lipid-soluble, can traverse different body membranes, longer duration of action → Terbutaline, Ritodrine Vasodilator in the treatment of peripheral vasospastic diseases They differ in chemical structure from EPI: → Activation of β2 receptors in the vascular smooth → in the position of hydroxyl group on the aromatic ring muscles supplying the skeletal muscles leading to → having larger substitution in the terminal amino group enhanced blood flow Routes of administration: parenteral, by inhalation, oral PHARMACOLOGY Adrenoceptor Agonists/Sympathomimetic Drugs II PAGE 5 of 14 PHARMACOLOGY | LE 2 Adrenoceptor Agonists/Sympathomimetic Drugs II | Alfretta Luisa Tan-Reyes, MD, FPSECP ❗→ FromPhysiologic B. ADVERSE EFFECTS Slow onset skeletal muscle tremor → Not suitable for monotherapy for acute breakthrough increased muscle spindle discharge attacks of bronchospasm due to its slow onset and Feelings of restlessness, apprehension and anxiety absence of anti-inflammatory action which may limit therapy Tachycardia ❗ Dose: not more than 2x / day asthma Drug of choice like formoterol for nocturnal Risk of adverse CVS effects, increased in the presence of MAOI Used also in treatment of COPD → prevent cytoplasmic MAO from degrading NE which will then activate adrenergic receptors G. RITODRINE → Allow 2 weeks interval between use of MAOI and β2 Therapeutic use: as uterine smooth muscle relaxant (tocolytic) to arrest premature labor and to prolong ❗ agonists Severe pulmonary edema reported with ritodrine and terbutaline for premature labor pregnancy Voluntarily withdrawn from the US market Prolonged use: possible connection with death or near → May ↑ maternal morbidity Other drugs used as uterine muscle relaxant to arrest 💬 death from asthma (down regulation of β2 receptors) May be due to degradation of β2 receptors or decrease in level of β2 receptor-mediated messenger RNA premature labor include: → Terbutaline → Increase in bronchial hyperreactivity and deterioration in → Magnesium sulfate disease control or there is loss of efficacy with long term → Calcium channel blockers (Nifedipine - superior to β use of β2 agonists mimetics and magnesium sulfate) → Atosiban - oxytocin receptor antagonist; widely used in ❗ May worsen hyperglycemia in some diabetic patients Adverse effects are less likely with inhalation therapy than with oral or parenteral therapy. Europe → Nitric oxide donors C. TERBUTALINE H. OTHER LONG ACTING SELECTIVE β2 RECEPTOR Effective when taken orally, subcutaneously, or by SYMPATHOMIMETIC AGONISTS inhalation LONG-ACTING SYMPATHOMIMETIC DRUGS Rapidly absorbed across body membranes ARFORMOTEROL Not metabolized by MAO and COMT For long term treatment of asthma and COPD MOA: activates adenylyl cyclase activity → ↑cAMP As with salmeterol & formoterol black box warning has production → smooth muscle relaxation been removed from ICS/LABA combinations Onset: → Use of LABA alone treatment of asthma was still a → Rapid onset of action after inhalation or parenteral concern administration CARMOTEROL → Delayed for 1-2 hours with oral administration Duration of action: 3-6 hours 5x more selective for β2 than for β1 receptors Therapeutic uses: Rapid onset, long duration of action with once a day → Treatment of acute symptoms of asthma and COPD dosing → Delay premature labor For treatment of asthma and COPD D. SALBUTAMOL / ALBUTEROL ULTRA-LONG ACTING SYMPATHOMIMETIC DRUGS Pharmacological properties and therapeutic indications INDACATEROL similar to terbutaline Ultra long acting but fast onset of action Given once a day 💬 Bronchodilation within 15 minutes, by inhalation → duration of action: 3-4 hours ( 4-6 hours) Therapeutic use: Toxicity: tremors, tachycardia → monotherapy for COPD Therapeutic uses: → combined with ICS for asthma (prolonged → for acute breakthrough symptoms of asthma bronchodilation masks symptoms of bronchial inflammation) E. FORMOTEROL Long acting, lipophilic, high affinity for β2 receptors OTHER ULTRA LONG ACTING SYMPATHOMIMETIC Significant onset of action within minutes of inhalation DRUGS → duration of action: 12 hours Olodaterol, Vilanterol – currently approved for COPD Therapeutic uses: VI. β3 SELECTIVE RECEPTOR AGONISTS → Bronchodilator in combination with steroids (e.g., A. MIRABEGRON (Myrbetriq, Betmiga) ICS budesonide or fluticasone) for acute relief of MOA: symptoms and for maintenance and relief therapy → activates adenylyl cyclase activity → ↑cAMP ❗️ (MART) for asthma and COPD → Prejunctional β3 receptors inhibit Ach release from Drug of choice in the treatment of nocturnal asthma parasympathetic neurons during bladder filling → Other uses: prophylaxis of exercise-induced Pharmacologic effects: bronchospasm → reduces urinary bladder tone, relaxes detrusor smooth muscle during storage phase of micturition → F. SALMETEROL ↑ bladder storage capacity Prolonged action (>12 hours) Dose: oral, initial 25 mg OD Relatively highly selective (50x that of salbutamol) for β2 Elimination t1/2: 50 hours receptors Adverse effects: possible hypertension Highly lipophilic PHARMACOLOGY Adrenoceptor Agonists/Sympathomimetic Drugs II PAGE 6 of 14 PHARMACOLOGY | LE 2 Adrenoceptor Agonists/Sympathomimetic Drugs II | Alfretta Luisa Tan-Reyes, MD, FPSECP Therapeutic application: treatment of overactive NASAL DECONGESTANTS bladder (urinary incontinence, urgency and frequency) TOPICAL NASAL DECONGESTANTS → net effect: urinary retention α1 activation → vasoconstriction → ↓ congestion of B. VIBEGRON (Gemtesa) mucous membrane Approved by Japan (2018) and US (2020) FDA: 75 mg Repeated use at high concentrations of topical sprays tablet once daily dose for the treatment of overactive (>3-5 days) → intense vasoconstriction → tissue hypoxia bladder → release of local mediators → vasodilation → hyperemia Improvement in micturition similar to mirabegron → rebound congestion (“rhinitis medicamentosa”) Incidence of AEs generally comparable with mirabegron α1 activation in venous capacitance vessels in nasal Metabolized independently from CYP3A4, 2D6, 2C9 tissues → ↓ volume of nasal mucosa → ↓ resistance to → predominantly by oxidation and glucuronidation airflow α2 receptors may mediate contraction of arterioles → ↓ 💬 Elimination t1/2 approximately 60-70 hours Longer acting than mirabegron nutrition supply to nasal mucosa Possible mechanism of “rebound” hyperemia: C. POTENTIAL FUTURE ADDITION TO THE → receptor desensitization SELECTIVE β3 RECEPTOR AGONISTS → structural damage to nasal mucosa Solabegron → For treatment of OAB and irritable bowel syndrome Table 5. Example of topical nasal decongestants[Lecturer’s PPT] Ritobegron Long acting Short acting → A prodrug Oxymetazoline Phenylephrine Xylometazoline Tetrahydrozoline VII. α1 SELECTIVE ADRENOCEPTOR AGONISTS Naphazoline A. GENERAL PHARMACOLOGIC ACTIONS ORAL NASAL DECONGESTANTS Stimulates α1 receptors in vascular smooth muscles → vasoconstriction → ↑ PVR & ↑ BP 📋Characteristics → Have longer duration of action B. PHENYLEPHRINE → Lower local concentrations Selective α1 receptor agonist; drug prototype → Greater potential for cardiac and CNS effects compared → activates β receptors only at higher concentrations to topical preparations 📋 Noncatecholamine; not inactivated by COMT Phenylephrine → greater bioavailability and longer duration of action Component of most of currently used OTC nasal than catecholamines decongestant CVS: BP = CO x PVR Phenylpropanolamine (PPA) 💬 → ↑↑↑ PVR due to α1 stimulation → High dose can cause hemorrhagic stroke → ↑↑ SP, DP and mean BP Some pharmaceutical companies reformulated the ▪ Effects similar to NE drugs and replaced it with Phenylephrine 📋 → ↑ venous tone Pseudoephedrine → SV may be slightly decreased, decreased, increased or Used in combination with loratadine (needs no change prescription) → Force of contraction is nil because it does not activate → Banned as OTC drug because it has been misused as the β1 receptors in the heart, or slightly increased an ingredient in the illicit manufacture of May cause reflex bradycardia, ↓CO methamphetamines Ephedrine CLINICAL APPLICATIONS Vasoconstrictor agent C. MIDODRINE Selective α1 receptor agonist ❗️ → Nasal decongestant (oral, drops, spray) ▪ Bioflu & Neozep – contains phenylephrine + Prodrug, produces active metabolite desglymidodrine chlorphenamine + paracetamol Peak concentration achieved in 1 hour after oral dose ❗️ ▪ Decolgen & Nafarin A – contains Duration of action: 4-6 hours phenylpropanolamine + chlorphenamine + Primary indication: treatment of px with autonomic paracetamol insufficiency and chronic postural hypotension → Combined with local anesthetic agent → Chronic orthostatic hypotension often caused by: ▪ ex. Epinephrine, Phenylephrine, Norepinephrine ▪ medications that interfere with autonomic function (α Mydriatic agent blockers , diuretics, tricyclic antidepressants) → By stimulating the contraction of radial muscles of iris ▪ Diabetes → Can be used to examine the fundus of the eye without ▪ Diseases causing peripheral autonomic neuropathies cycloplegia (unlike antimuscarinic drugs) Frequent complication: hypertension in supine position Hemostatic agent which can be minimized by avoiding dosing prior to → Due to α1 activity bedtime and by elevating head of the bed → Applied topically Droxidopa → In nasal packs for epistaxis or in gingival string for → novel approach; synthetic molecule converted to NE gingivectomy → for treatment of postural hypotension Vasopressor drug → ↑BP, however there are far better drugs used that can act on both α and β receptors → Not widely used anymore due to its decrease in tissue perfusion caused by vasoconstriction PHARMACOLOGY Adrenoceptor Agonists/Sympathomimetic Drugs II PAGE 7 of 14 PHARMACOLOGY | LE 2 Adrenoceptor Agonists/Sympathomimetic Drugs II | Alfretta Luisa Tan-Reyes, MD, FPSECP VIII. MIXED-ACTING SYMPATHOMIMETIC AGENTS ADVERSE EFFECTS Refers to drugs or substances that act on adrenergic Tachyphylaxis with repetitive dosing receptors both directly and indirectly → Attributed to its indirect action at sympathetic nerve Table 6. Comparison of the epinephrine and ephedrine. endings as result of substrate (NE) depletion Epinephrine Ephedrine Hypertension → Results from increased BP caused by ↑CO and ↑PVR Directly acting Mixed (indirect α-nerve due to activation of β1 receptors in the heart and α1 endings) (direct α and β) receptors in vascular smooth muscle Inactivated by enzymes Resistant to enzyme Insomnia degradation → CNS stimulant; lipophilic and can traverse the BBB No oral preparation High oral bioavailability Note: Ingestion of large amount of herbal preparations (ma (longer duration of action) huang, ephedra found in “Power drugs/drinks” or More efficacious in Less efficacious in acute Performance-enhancing drinks) containing ephedrine of relieving acute symptoms bronchospastic conditions potentially greater cause for concern of bronchospasms and (e.g., acute asthma) and As a weak base, excretion can be enhanced by anaphylaxis anaphylaxis acidification of the urine Shorter duration Longer duration of action THERAPEUTIC USES Polar drug, difficulty in Can traverse BBB (no Therapeutic uses: traversing body hydroxyl groups in phenyl → Replaced by more selective β2 adrenoceptor agonists in membranes including BBB or benzene ring) → Potent the management of asthma and GIT CNS stimulation → Stimulant in narcolepsy No tachyphylaxis Tachyphylaxis may occur → To promote urinary continence Catecholamine: Noncatecholamine B. PSEUDOEPHEDRINE metabolized by MAO and (phenylisopropylamine): A stereoisomer of ephedrine COMT not metabolized by COMT Can stimulate both α and β receptors Both drugs act on all adrenergic receptors An effective oral nasal decongestant Recall: tachyphylaxis – responsiveness diminishes rapidly Banned as an OTC drug because it has been misused as after administration of drug with few successive doses at an ingredient in the illicit manufacture of frequent interval methamphetamine / shabu Available in combination with loratadine (Clarinase) A. EPHEDRINE Drug prototype for mixed-acting sympathomimetic agents C. PHENYLPROPANOLAMINE (PPA) Pharmacokinetics: Used commonly as oral nasal decongestant → a weak base Pharmacological properties similar to ephedrine → high bioavailability → approximately equal in potency, causes less CNS → relatively long duration of action stimulation → can enter into the CNS Increases the risk of hemorrhagic stroke → eliminated in urine largely as unchanged drug → Voluntarily withdrawn in some countries or its dose → t1/2 of 3-6 hours preparation has been limited A potent CNS stimulant → Can greatly increase BP due to increased PVR resulting Mixed acting: direct agonist at both α and β receptors; from intense stimulation of α1 receptors also enhances release of NE from sympathetic neurons → Used in high doses in weight reduction clinics in other → at the sympathetic nerve endings: indirectly acting countries (as high as 75-80 mg): because it enhances release of NE from storage ▪ enough to activate α1 receptors to cause vesicles leading to stimulation of α receptors vasoconstriction of vascular smooth muscle → ↑PVR → ↑BP (Hypertensive crisis) → Hemorrhagic stroke PHARMACOLOGIC ACTIONS AND EFFECTS → In the Philippines, PPA is still used since FDA is strict Similar to EPI in stimulating all adrenergic receptors but with the amount of dose in each preparation less efficacious ▪ In PH: maximum of 12.5-25 mg CVS: ↑CO due to ↑HR; variable ↑PVR; ↑BP → ↑ HR due to β receptor stimulation → Variable ↑PVR caused by activating both α1 and β2 📋release IX. INDIRECT-ACTING SYMPATHOMIMETIC AGENTS Do not directly activate the receptors but promote of catecholamines from nerve endings. receptors → Net effect on PVR depends on the concentration of Mechanism of actions: ephedrine and interplay between the two adrenoceptors 1. Enter S nerve endings and displace stored Respiratory system: bronchodilation due to β2 receptor catecholamines (amphetamine-like or releasing activation in bronchial smooth muscle agents/displacers) Genito-urinary system: urinary retention due to α1 2. Inhibit catecholamine reuptake receptor stimulation of smooth muscles in bladder base, a. Selectively inhibits NE transporter (NET) and DA transporter → ↑ NE & DA levels at noradrenergic 📋 urethral sphincter, prostate Trigones and sphincter – contracted due to α1 synapses b. Blocks metabolizing enzymes 📋 activation Walls of detrusor muscles – relaxed due to β3 − MAO inhibitor – pargyline, selegiline activation − COMT inhibitor – entacapone 💬 Eyes: mydriasis (α1 receptor activation) Without cycloplegia PHARMACOLOGY Adrenoceptor Agonists/Sympathomimetic Drugs II PAGE 8 of 14 PHARMACOLOGY | LE 2 Adrenoceptor Agonists/Sympathomimetic Drugs II | Alfretta Luisa Tan-Reyes, MD, FPSECP A. AMPHETAMINE-LIKE ❗wall, Readily metabolized by MAO in the liver and gut very high first pass effect, therefore low 1. AMPHETAMINE PK: similar to ephedrine but it more readily enters the CNS bioavailability Indirect sympathomimetic action: promotes release of ❗️ than ephedrine D-isomer more potent than L-isomer stored NE MOA: Mediated through the release of NE and to some → If taken in ↑ concentration: extent, DA ▪ May be actively transported into the nerve terminal CNS: (via NET), stored inside vesicles (via monoamine → Marked CNS stimulant effects on mood and alertness, transporter) appetite suppression − Promote release of stored NE → ↓sense of fatigue Spectrum of action similar to that of NE → ↑ability to concentrate Ingestion of large amounts of tyramine can precipitate ❗️ → often elation and euphoria hypertensive crisis → ↑ in motor and speech activities Precaution: → physical performance is improved → In patients treated with MAO inhibitors, AVOID Prolonged use of large doses nearly always followed by increased intake of Tyramine-containing foods depression and fatigue ▪ MAOI will diminish enzymatic degradation of Psychological dependence occurs with chronic use Tyramine → ↑ bioavailability of Tyramine and ↑ Most common serious effect: psychotic reaction with neuronal stores of catecholamines vivid hallucination and paranoid delusions − ↑ Tyramine bioavailability → marked ↑ in BP which Higher doses: overt psychosis can precipitate hypertensive crisis Therapeutic uses: B. CATECHOLAMINE REUPTAKE INHIBITORS → Narcolepsy (involuntary hypersomnia) Selectively inhibits NET (Uptake 1): → Attention Deficit Hyperactivity Disorder (ADHD) → ↑ NE levels in non noradrenergic synapses 2. METHAMPHETAMINE Include the following drugs: Known as “poor man’s cocaine”; shabu → Atomoxetine Its central effects are more pronounced than those of → Reboxetine amphetamine; less prominent peripheral reactions → Cocaine High potential for abuse; widely used as cheap, → Tricyclic antidepressants (e.g. Imipramine) accessible recreational drug → Duloxetine Also promoted as an anorexiant → Milnacipran 3. PHENMETRAZINE 1. ATOMOXETINE (STRATTERA) Promoted as an anorexiant (appetite suppressor) Little CVS effect because of its Clonidine-like effects in A popular drug of abuse the CNS that diminishes sympathetic outflow In the periphery: potentiates action of NE 4. METHYLPHENIDATE Therapeutic use: ADHD Structurally related to amphetamine Pharmacologic properties and abuse potential similar to 2. REBOXETINE amphetamine Similar characteristics to Atomoxetine Mild CNS stimulant with more prominent effects on Mainly used to treat major depressive disorders mental than on motor activities → May be used to treat narcolepsy and panic disorder ❗️ Therapeutic use: Narcolepsy & ADHD 3. COCAINE Contraindicated in patients with Glaucoma Local anesthetic with peripheral sympathomimetic 5. MODAFINIL action Psychostimulant Inhibits transmitter reuptake at adrenergic synapses MOA: not fully known Rapid onset of action and readily enters CNS if smoked, → Inhibits both NE and DA transporters snorted, or ingested ▪ ↑ synaptic concentration of NE, DA, 5-HT, glutamate, Amphetamine-like psychological effect that is short-lasting ▪ ↓ GABA levels but more intense than Amphetamine Can cause mild increase in BP and HR Major action in the CNS: Therapeutic use: Narcolepsy, Sleep apnea (Obstructive → Inhibit DA reuptake into neurons in the “pleasure Sleep Apnea Hypopnea Syndrome [OSAHS]), shift work centers” in the brain sleep disorder Heavily-abused drug 6. TYRAMINE Vasoactive amine, not a drug 📋 4. SEROTONIN AND NE REUPTAKE INHIBITORS MOA: Inhibits reuptake of serotonin and NE, and to a lesser extent, DA A normal by-product of Tyrosine metabolism → Produced by decarboxylation from the fermentation of SIBUTRAMINE ↑ concentration of ingested protein-rich foods such as: Centrally acting appetite suppressant for long-term ▪ Aged cheese treatment of obesity ▪ Cured meat (pepperoni, sausages) Withdrawn from the US market due to associations with: ▪ Pickled fish → ↑ risks of CVS effects ▪ Yeast supplements → Cerebrovascular events (e.g. cardiac arrhythmias, hypertension, MI, and stroke) DULOXETINE PHARMACOLOGY Adrenoceptor Agonists/Sympathomimetic Drugs II PAGE 9 of 14 PHARMACOLOGY | LE 2 Adrenoceptor Agonists/Sympathomimetic Drugs II | Alfretta Luisa Tan-Reyes, MD, FPSECP Used as antidepressant → centrally acting α2 agonists (Clonidine, Methyldopa, Treatment of pain in fibromyalgia Guanfenicine) MILNACIPRAN Treatment of pain in fibromyalgia B. BETA RECEPTOR STIMULATION TRICYCLIC ANTIDEPRESSANTS (TCAs) BRONCHODILATOR E.g. Imipramine Bronchial Asthma and COPD: Used as antidepressant → SABA and LABA (e.g. formoterol + budesonide (ICS) for MART) X. CLINICAL USES OF ADRENERGIC DRUGS ▪ Formoterol is used due to its fast onset and has a A. ALPHA RECEPTOR STIMULATION prolonged duration of action VASOPRESSORS VASODILATOR Acute hypotension: Peripheral vascular diseases → NE vasopressor of 1st choice in treating shock → Isoxsuprine (balanced α & β receptor activities) ▪ There are other better drugs that are used like Ca2+ ▪ especially those with sustained hypotension channel blockers associated with hypoperfusion Chronic Orthostatic Hypotension: UTERINE MUSCLE RELAXANT → Midodrine Tocolytic, to delay premature labor: ▪ Especially those with associated autonomic → Ritodrine, Terbutaline, Salbutamol, Isoxsuprine, insufficiency Magnesium sulfate, Atosiban Threatened abortion OPHTHALMIC USES → Terbutaline, Ritodrine For ocular examination (mydriasis without cycloplegia): Dysmenorrhea ❗ → Phenylephrine ❗ Antimuscarinics → mydriasis with cycloplegia Sympathomimetics → mydriasis without DETRUSOR MUSCLE RELAXANT OAB or Overactive Bladder cycloplegia → Selective β3 agonist (Mirabegron, Vibegron) Glaucoma: → If antimuscarinic drugs: Solifenacin, Darifenacin, → Brimonidine & Apraclonidine Imidafenacin VASOCONSTRICTORS OTHER CLINICAL USES Nasal decongestant: oral or topical Complete heart block: EPI → Phenylephrine Resuscitation from cardiac arrest: → Oxymetazoline → EPI, especially in remote areas where cardioversion → Naphazoline and defibrillation are unavailable → Xylometazoline Acute decompensated heart failure: → Tetrahydrozoline → Dobutamine, DA → Phenylpropanolamine C. ANAPHYLAXIS → Pseudoepinephrine (related drug) combined with Epinephrine is still the drug of choice (1 mg/ml or 1:1000 Loratadine (Clarinase) aqueous solution) Adjunct to local anesthetic → Epinephrine D. CARDIOGENIC SHOCK → Norepinephrine Dobutamine → Phenylephrine → inotropic agent of choice when ↑ CO is needed 📋→ UsedDobutamine → Levonordefrin E. CARDIAC STRESS TEST → Incorporated with local anesthetics with dilution 1:100,000 - 1:200,000 solution in patients who cannot perform exercises ▪ Must be diluted as high concentrations may promote anymore tissue necrosis and sloughing → ↑ HR, myocardial force of contraction, myocardial Local hemostatic workload → Epinephrine → Used in echocardiogram or nuclear medicine ▪ Applied topically, useful for nasal packs which are techniques to detect ischemia soaked to control epistaxis (nose bleeding) ▪ Used in multiple teeth extraction in patients who F. CNS APPLICATIONS have undergone gingivectomy ADHD → Cocaine → Methylphenidate ▪ also been used in certain oronasopharyngeal surgery → Atomoxetine due to its local anesthetic with a local hemostatic → Modafinil effect → α2 agonists (Clonidine & Guanfacine) Narcolepsy PAROXYSMAL ATRIAL TACHYCARDIA (PAT) → Modafinil Phenylephrine (slow IV) but there are generally safer → Armodafinil alternatives HYPERTENSION G. OTHERS Hypertension: Obesity → Amphetamine and Amphetamine-like preparations PHARMACOLOGY Adrenoceptor Agonists/Sympathomimetic Drugs II PAGE 10 of 14 PHARMACOLOGY | LE 2 Adrenoceptor Agonists/Sympathomimetic Drugs II | Alfretta Luisa Tan-Reyes, MD, FPSECP ▪ e.g. Phenylpropanolamine (not approved in Ph for 5. Vasoconstriction such indication) 6. α1 adrenoceptors XI. SUMMARY Sympathomimetic drugs mimic the effects of adrenergic nerve stimulation by activating adrenoreceptors or promoting release of endogenous NE They are classified according to: mode of action (direct, indirect, mixed-acting) and receptor selectivity Direct-acting agonists directly interact with one or more of the adrenoreceptors Indirect-acting sympathomimetic drugs do not directly activate adrenoreceptors and their actions depend on increasing the availability of endogenous catecholamines to stimulate adrenoreceptors Figure 3. Schematic Diagram of the Effects of Adrenergic → Releasing or displacing NE from sympathetic nerve Receptor Agonists[Lecturer’s PPT] terminals Drug Z: NE → Blocking the transport of NE to S neurons by inhibiting → Activation of β1 receptors: ↑HR reuptake by NET → Activation of α1 receptors: ↑ PVR due to intense → Blocking the metabolizing enzymes MAO and COMT vasoconstriction of the vascular smooth muscle → ↑BP Mixed-acting sympathomimetic drugs can both directly → At the height of the rise in BP, there is reflex activate adrenoreceptors and indirectly release NE from bradycardia as compensatory response adrenergic nerve terminals Drug Y: EPI 2 major groups of sympathomimetics based on → Biphasic response chemical structure: ▪ At a certain dose, both α1 and β2 are activated. → Catecholamines: (direct acting drugs that have catechol − β2 is more sensitive to small doses (vasodilation). in their chemical structure) − α1 is activated at higher doses and is more → Non-catecholamines: (absence of catechol structure, predominant but transient (rise in BP). may be direct, indirect, or mixed-acting, may be ▪ Once the effect goes down, there is unmasking of the receptor selective or non-selective) β2 effect causing vasodilation → ↓ PVR Receptor selectivity: drug preferentially activates one ▪ There is not much expected rise due to the interplay subtype of receptors at concentrations that have little to no of α1 and β2 → no reflex bradycardia effect on another subtype Drug X: Isoproterenol → α1 receptor: phenylephrine, midodrine → No α1 effect, leaving β2 effect unopposed causing → α2 receptor: clonidine, methyldopa, guanfacine, vasodilation, ↓ PVR → ↓ DP brimonidine, apraclonidine → β1 receptor: dobutamine CASE SCENARIO → β2 receptor: SABAs (salbutamol, terbutaline), LABAs A 65/F is admitted to the ICU with sepsis caused by (formoterol, salmeterol, indacaterol) UTI. She is hypotensive, with a BP of 80/40 mmHg and → β3 receptor: mirabegron, vibegron has an elevated heart rate and decreased urine output. Receptor non selectivity means a drug may interact with → Along with appropriate antibiotic therapy and IV more than one receptor subtype at the usual drug fluids, a decision is made to start her on an concentrations intravenous infusion of dopamine to attempt to raise → norepinephrine: α1 α2, β1 receptors her blood pressure. → epinephrine: α1 α2 β1 β2 receptors → isoproterenol: β1 β2 receptors 1. What effects can be expected with low-dose → dopamine: D1 D2 receptors, β1, α1 receptors dopamine? → ephedrine: α1 α2 β1 β2 receptors 2. Which receptors mediate the vasodilating effect of low-dose dopamine? PHARMACOKINETICS 3. What effects can be expected with medium-dose Catecholamines: polar drugs with poor oral absorption, dopamine? rapidly inactivated in GIT mucosa and in the liver, poor 4. Which receptors mediate the vasodilating effect of distribution into the CNS; administered topically, by medium-dose dopamine? inhalation, or parenterally. 5. What effects can be expected with high-dose Non catecholamines: generally lipid-soluble, orally dopamine? bioavailable, longer duration of action, may traverse the 6. Which receptors mediate the vasodilating effect of BBB, administered orally, parenterally, topically, or by high-dose dopamine? inhalation. Direct and indirect sympathomimetics may be subject to ANS: metabolism and inactivation by MAO and COMT. 1. Vasodilation in the renal, coronary, splanchnic systems Phenylephrine and β2 agonists are not metabolized by → Increase in tissue perfusion COMT. 2. D1 receptors The overall pharmacologic effects of a given drug may 3. (+) Inotropic effect (↑ in heart contractility) → ↑ cardiac depend on its relative affinity for adrenoceptor subtypes, output (minimal tachycardia) the relative expression of receptor subtypes in a given 4. β1 receptors tissue, and its route of administration. PHARMACOLOGY Adrenoceptor Agonists/Sympathomimetic Drugs II PAGE 11 of 14 PHARMACOLOGY | LE 2 Adrenoceptor Agonists/Sympathomimetic Drugs II | Alfretta Luisa Tan-Reyes, MD, FPSECP The magnitude of response depends on the number and → They are primarily used as bronchodilators in asthma function of adrenoreceptor in the cell surface and the and COPD receptor regulation by the catecholamines themselves, Formoterol: rapid onset of action within minutes of other hormones and drugs, the dose, age, and number of inhalation while Salmeterol has a slow onset and is not diseases. suitable for monotherapy for acute breakthrough attacks of NOREPINEPHRINE bronchospasm. Both have >12 hours duration of action and are used in patients with nocturnal asthma. NE: agonist of α1 α2, β1 receptors but has no effects on β2 Formoterol is combined with ICS for MART for asthma receptors. ↑PVR in most vascular beds, ↑ SP and DP. Other clinical uses include → Direct positive chronotropic effects may be overcomed → Uterine muscle relaxant (to arrest premature labor): by the compensatory baroreceptor vagal reflex ritodrine, terbutaline reduction in HR. → Peripheral vasodilator in patients with peripheral → Positive cardiac inotropic effects: maintained. vasospastic diseases: isoxsuprine AEs similar to those of EPI but ↑BP may cause severe hypertension. May also cause tissue necrosis and α1 SELECTIVE AGONISTS sloughing due to extravasation into neighboring tissues. Clinical uses: It is the vasopressor of choice in acute hypotension due to → Mydriatic agent (without cycloplegia): Phenylephrine balance in α and β activities. → Hemostatic agent (applied topically in nasal packs for DOPAMINE epistaxis: EPI; nasopharyngeal surgery: Cocaine as local anesthetic) DA: agonist at D receptors with a low dose but may → Vasopressor: Phenylephrine stimulate the β1 receptors with intermediate dose and α1 Repeated use of topical nasal decongestants for >3-5 days receptors at higher concentrations. D receptor activation may cause rebound congestion (rhinitis medicamentosa) leads to vasodilation of the renal, splanchnic, coronary, Midodrine: selective α1 agonist; a prodrug that is and cerebral vascular beds and will enhance blood flow. converted into an active metabolite, desglymidodrine. Tachycardia is less prominent. Primarily indicated in the treatment of orthostatic DA also produces natriuresis. It is an important CNS hypotension due to autonomic insufficiency. Supine neurotransmitter involved in regulation of movement and in position may cause hypertension reward stimulus. It is also known as “feel good hormone” MIXED-ACTING SYMPATHOMIMETICS FENOLDOPAM Can directly activate adrenoreceptors to produce a Fenoldopam is a peripheral D1 agonist and rapidly-acting pharmacologic effect and indirectly promote release of vasodilator primarily indicated in the IV treatment of severe endogenous NE from the nerve terminals hypertension Ephedrine: phenylisopropylamine with similar β ADRENERGIC RECEPTOR AGONISTS pharmacological action to EPI since it can activate all ISO: very potent β agonist with almost no effects on α adrenoreceptors but less efficacious such as in acute receptors. It produces intense vasodilation so the mean bronchospastic conditions like asthma and anaphylaxis. It arterial pressure and DP are decreased. is not degraded by COMT and has high oral bioavailability, → β1: Slightly ↑SP resulting from ↑CO due to (+) inotropic longer duration of action, can cause tachyphylaxis, can and chronotropic effects. traverse the CNS in comparison with EPI. Has been → β2: Relaxation of vascular smooth muscles supplying clinically replaced by selective sympathomimetics with skeletal muscles → enhanced blood flow relatively lesser adverse effects. Dobutamine: CVS effects are mediated by activation of α Phenylpropanolamine: oral nasal decongestant with and β1 but not β2 receptors. It produces greater positive similar pharmacologic properties to Ephedrine: almost inotropic than chronotropic effect compared to ISO. ↑CO, equal potency with less CNS stimulation. Intake of high PVR is not significantly ↑ due to α1 receptor activation. It is doses may increase hemorrhagic stroke. the inotropic agent of choice when increased CO is Pseudoephedrine: stereoisomer of Ephedrine and an oral needed. nasal decongestant. Banned as an OTC drug and is regulated due to use in illicit manufacture of β2 SELECTIVE AGONISTS methamphetamine. Noncatecholamines with a larger substitution on the terminal amino group. AEs include physiologic skeletal INDIRECT-ACTING SYMPATHOMIMETICS muscle tremor, feeling of restlessness, apprehension and Enter S nerve endings and promote release and displace anxiety, tachycardia, may worsen hyperglycemia in some stored catecholamines diabetic patients. Amphetamine: combined with Ephedrine readily enters Prolonged use has shown possible connection with death the CNS with marked stimulant effects on mood, alertness, or near death from asthma due to less efficacy resulting causes euphoria, and produces appetite suppression. from downregulation of β2 receptors. Used as treatment of ADHD and narcolepsy AEs: less likely to occur with inhalation therapy than oral or Methamphetamine: has more pronounced central effects parenteral therapy. than Amphetamine, high potential for abuse β2 selective agonists are classified as Methylphenidate: similar to Amphetamine and is → short-acting (SABA): salbutamol, terbutaline, pirbuterol, therapeutically used in children with ADHD levalbuterol, Modafinil & Armodafinil: psychostimulants used to → long-acting (LABA): formoterol, salmeterol, bambuterol, improve wakefulness in narcolepsy, sleep apnea, shift carmoterol, arformoterol work sleep disorders → ultra long-acting (ultra LABA): indacaterol, olodaterol, Tyramine: normal byproduct of tyrosine metabolism in the vilanterol for COPD body and can be produced from protein-rich foods. When taken orally, it has low bioavailability and high first pass PHARMACOLOGY Adrenoceptor Agonists/Sympathomimetic Drugs II PAGE 12 of 14 PHARMACOLOGY | LE 2 Adrenoceptor Agonists/Sympathomimetic Drugs II | Alfretta Luisa Tan-Reyes, MD, FPSECP effect. Excessive intake of these foods or with MAOI can d. stimulation of central α2 receptors precipitate hypertensive crisis. CATECHOLAMINE REUPTAKE INHIBITORS ANS: 1. C. Increase renal flow. Medium-dose dopamine will Atomoxetine: selectively inhibits NET, used in treatment increase cardiac output and BP. High dose will produce of ADD and ADHD peripheral vasoconstriction Reboxetine: used mainly for major depressive disorder 2. D. Norepinephrine. Vasopressor of 1st choice. Cocaine: inhibits DA reuptake 3. D. Skeletal muscle tremor. Stim