Sympathomimetics

Alex Horowitz; David Frey; Deanna Denault; Travis Smith

Sympathomimetics

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Free Review Questions

Continuing Education Activity

Sympathomimetic drugs form a classification of medication used to manage and treat cardiovascular pathology, hypersensitivity, COPD, and glaucoma. This activity reviews the indications, action, and contraindications for sympathomimetics as valuable agents in treating and managing cardiovascular pathology (and other disorders when applicable). This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, monitoring, relevant interactions) pertinent for members of the healthcare team) in the management of patients with cardiovascular pathology and related conditions.

Objectives:

Identify the mechanism of action of sympathomimetic drugs.
Describe the adverse effect profile of sympathomimetic drugs.
Review the appropriate monitoring needed for patients using sympathomimetic drugs.
Explain the importance of collaboration and communication amongst the interprofessional team to ensure the appropriate use of sympathomimetics and to reduce associated complications.

Indications

Sympathomimetic agents are used to augment the endogenous catecholamines of the sympathetic nervous system for therapeutic benefit. The body has a wide distribution of different adrenergic receptors across many organ systems. Without a thorough understanding of the adrenoreceptor subtypes involved in various tissues, the clinical effects observed can seem confusing due to overlapping receptor activities and different effects seen at different doses. Although beyond the scope of this review, the following is a summary with examples of currently FDA approved sympathomimetic indications:

Cardiac: includes the treatment of hypotension, including those caused by hypovolemic, distributive, and neurogenic shock.[1][2]
Pulmonary: include the treatment of asthma and COPD.[3][4][5]
Sympathomimetic agents are used as nasal decongestants for the treatment of allergic rhinitis and conjunctivitis.[6]
Ophthalmic indications: include open-angle glaucoma.[7]
Neurologic: can even include local anesthetic effects.[8]
Psychiatric: include the treatment of ADHD and narcolepsy.[9]
Endocrine: include the treatment for obesity.[10]
Genitourinary: include urinary incontinence.[11]

These indications are currently FDA approved; however, future applications for this versatile drug class are currently under investigation.

Mechanism of Action

Sympathomimetic agents may categorize as direct or indirect. Direct sympathomimetics function as agonists upon one or more adrenergic receptors. The pharmacological profile of direct sympathomimetics has its primary basis on the subtype of adrenergic receptors. Adrenergic receptor activity largely depends on the receptor's molecular structure, signaling pathway, anatomic distribution, and dosing concentration. Adrenergic receptors include the alpha and beta families. Direct sympathomimetics may act as selective or mixed agonists at the alpha and beta-adrenergic receptors. Alpha-adrenergic receptors subdivide into alpha-1 and alpha-2.[12]

Beta-adrenergic receptors subdivide into beta-1, beta-2, and beta-3. Adrenergic receptors are G-protein-coupled metabotropic receptors that use guanosine triphosphate as a cofactor.[13][14] The exact nature of the coupled G-protein determines its identity and the corresponding effect of the downstream secondary signaling cascade, which is beyond the scope of this review. Indirect sympathomimetic agents achieve a similar effect via increasing the concentration of endogenous catecholamines within the synaptic cleft. This increase may occur via the displacement of stored norepinephrine or epinephrine from within presynaptic vesicles, reuptake inhibition, or inhibition of their metabolism by monoamine oxidase or catechol-o-methyltransferase.[15]

Administration

Sympathomimetics administration may be via virtually any route available, including oral, rectal, topical, IO, IV, IM, intrauterine, endotracheal, and inhalation. The term sympathomimetic forms a broad classification of medications, which is why a complete review of the wide variety of administration routes is beyond the scope of this article. Single sympathomimetic agent routes of administration may differ according to different desired pharmaceutical effects. Epinephrine administration – IV, IM, IO, endotracheal – is indicated emergently. Airway swelling requires inhaled epinephrine. Epinephrine and isoproterenol administration may be via the intramuscular route.[16][17] Dobutamine, norepinephrine, terbutaline, and ritodrine may be administered intravenously.[18][19][20] Midodrine, ritodrine, and clonidine may be administered orally.[21][22][23]

Oral administration may be further subdivided based on temporal characteristics. Pseudoephedrine extended-release capsules are designed to release their medication gradually. After the capsule dissolves, the medication granules dissolve at different rates. Interference with the capsule may alter the rate of the capsule's dissolution, thus modifying the pharmacological onset, duration, and effect. For this reason, extended-release capsules should not be crushed or broken.[24] Albuterol and salmeterol administration is via inhalation.[25] Terbutaline may be administered subcutaneously, leading to local vasoconstriction.[26] Brimonidine and pseudoephedrine may be administered topically.[27][28] Phenylephrine may also be administered rectally.[29] There are cases reported with the epidural administration of phenylephrine or ephedrine for regional anesthesia.[30]

Adverse Effects

A thorough understanding of the pharmacological effect and the adrenergic receptor activity of sympathomimetic agents renders their adverse effects as the logical extension of excessive or unwanted adrenergic receptor activity, which can be fatal. Following a comprehensive literature review, the following is a brief survey of sympathomimetic agent adverse effects. Alpha-1 adrenergic receptor activity-predominant sympathomimetics such as phenylephrine or norepinephrine are associated with hypertension (with the possibility of hypertensive emergency), reflex bradycardia, piloerection, and urinary retention. Vasoconstriction may lead to ischemia and necrosis of the digits of the distal appendages.[31][32] Alpha-2 adrenergic receptor activity-predominant sympathomimetics such as clonidine are associated with sedation, respiratory depression, bradycardia and hypotension, miosis, rebound hypertension, and dry mouth.[33]

Beta-1 adrenergic receptor activity-predominant sympathomimetics such as dobutamine are associated with tachycardia and arrhythmias. In patients with coronary artery disease, these adverse effects of beta-2 adrenergic receptor activity-predominant sympathomimetics may lead to acute coronary syndrome.[34] Beta-2 adrenergic receptor activity-predominant sympathomimetics such as albuterol or salmeterol are most commonly associated with tremor.[35] Additional adverse effects include agitation, insomnia, and diaphoresis. Beta-2-mediated coronary artery and skeletal muscle vasodilation may lead to hypotension and reflex tachycardia. Hyperinsulinemia, hyperglycemia, and hypokalemia are endocrine-associated adverse effects.[36][37]

Indirect sympathomimetics such as amphetamines, cocaine, or ephedrine are associated with anorexia, weight loss, insomnia, nausea, vomiting, abdominal cramps, mesenteric ischemia, motor tics, and seizures. Cardiovascular complications of indirect sympathomimetics similar to the direct agents may also include hypertension with reflex bradycardia, aortic dissection, tachycardia, myocardial infarction, and strokes.[9][38] Classically, beta-blockers must not be administered to patients misusing cocaine due to the risk of severe hypertension and end-organ damage resulting from the unopposed-alpha activity.[39] Indirect sympathomimetic-associated rhabdomyolysis may lead to acute renal injury and, ultimately, multiple organ failure.[38]

Contraindications

No universal set of contraindications exists for all sympathomimetics, but a patient’s current condition may offer relative contraindications and the need for careful titration or selection of a more appropriate sympathomimetic. Although extremely rare, true hypersensitivity reactions would be considered a contraindication to specific agents. Following a comprehensive literature review, the following is a brief survey of contraindications for major sympathomimetic agents. High doses of phenylephrine may also be associated with extreme reflex bradycardia or asystole. For this reason, phenylephrine is a relative contraindication in patients with a history of extreme bradycardia.[40] Hypertrophic obstructive cardiomyopathy, also known as idiopathic hypertrophic subaortic stenosis, is a relative contraindication for dobutamine. Dobutamine administration in these patients may precipitate an episode of hypotension secondary to functional left ventricular outflow tract obstruction.[41]

Heart failure or cardiac injury is a relative contraindication for isoproterenol. The administration of isoproterenol may exacerbate an episode of decompensated heart failure due to the inotropic effects that increase myocardial oxygen demand while simultaneously decreasing myocardial oxygen supply.[42] Asthma or hypersensitivity reactions are relative contraindications for cocaine, a local anesthetic, due to its tendency to precipitate allergic episodes.[43][44] Hypertension or cardiovascular disease such as arteriosclerosis is another contraindication for cocaine as well as amphetamine.[45][46][47]

Monitoring

Sympathomimetic is a broad pharmacological classification. A wide variation in the therapeutic index exists among pharmacological agents in this class. Due to the high rates of complications, the supervision of a physician with extensive experience with sympathomimetics is the recommendation when administering catecholamines. More sensitive monitoring with intra-arterial blood pressures is necessary for the administration of high-dose catecholamines.[48]

Toxicity

No universal antidote or treatment exists for all sympathomimetic agents and is beyond the scope of this review. Although specific adrenergic antagonists may prove beneficial in certain adrenergic toxicities, frequently, withdrawal of the offending agent and supportive care is sufficient. When available, the correct balance of adrenergic antagonists may prove beneficial, but choosing the incorrect agents and/or dosing them incorrectly makes it possible to exacerbate toxic effects. The classic example of this is the use of beta-blockers in acute cocaine intoxication, potentially causing hypertensive crisis through unopposed alpha-1 vasoconstriction.[49][50]

Phentolamine, for another example, is an effective treatment for pheochromocytoma or norepinephrine overdose by antagonizing alpha-1 receptors.[51] Metoprolol or esmolol intravenously are effective antidotes for dobutamine by blocking beta-1 receptors.[52] Nonselective beta receptor antagonists effectively treat refractory hypotension, dysrhythmias, or tachycardia in beta-2 adrenergic receptor predominant sympathomimetic agents such as albuterol.[53] However, although direct antagonists exist, frequently supportive care is all that is required, and treatment involves a variety of medication classes: benzodiazepines for seizures or sedation, calcium channel blockers for blood pressure control, and/or heart rate control, nitroglycerin or nitroprusside for vasodilation are among available options.[36]

Enhancing Healthcare Team Outcomes

Sympathomimetic agents are useful in a wide variety of indications across numerous clinical settings. For this reason, many types of healthcare team members such as physicians, nurses, or pharmacists must be knowledgeable of the adverse effects, contraindications, and toxicity management. Patients must receive education from the team and be encouraged to immediately seek help if there is an overdose. [Level 5]

Due to the high rates of complications, the supervision of a physician with extensive experience with sympathomimetics is the recommended approach for administering catecholamines. The physician should also consult with a pharmacist to preclude any potential drug-drug interactions or additive effects with these medications; the pharmacist can recommend alternative agents or other modifications to the regimen to achieve therapeutic goals and minimize adverse effects. All healthcare team members should consult with a pharmacist regarding any concerns.[48]

More sensitive monitoring with intra-arterial blood pressures is necessary for the administration of high-dose catecholamines. [Level 4] Nursing staff need to be well-versed in recognizing adverse events associated with sympathomimetic drugs. Since they will have more contact with the patient on an ongoing basis than other providers, the ability to monitor the patient effectively will fall under their duties. Nursing should be able to alert the doctor or contact the pharmacist with any questions or concerns.

Best practice involves an interprofessional approach, with physicians, pharmacists, and nursing collaborating in a team effort to optimize patient care. [Level 5]

Details

References

[1]

Olschewski H, Canepa M, Kovacs G. Pulmonary and cardiac drugs: clinically relevant interactions. Herz. 2019 Sep:44(6):517-521. doi: 10.1007/s00059-019-4834-3. Epub [PubMed PMID: 31297545]

[2]

Kanter J, DeBlieux P. Pressors and inotropes. Emergency medicine clinics of North America. 2014 Nov:32(4):823-34. doi: 10.1016/j.emc.2014.07.006. Epub 2014 Aug 28 [PubMed PMID: 25441037]

[3]

Barnes NC, Jacques L, Goldfrad C, Bateman ED. Initiation of maintenance treatment with salmeterol/fluticasone propionate 50/100 microg bd versus fluticasone propionate 100 microg bd alone in patients with persistent asthma: integrated analysis of four randomised trials. Respiratory medicine. 2007 Nov:101(11):2358-65 [PubMed PMID: 17689947]

Level 1 (high-level) evidence

[4]

Anzueto AR, Kostikas K, Mezzi K, Shen S, Larbig M, Patalano F, Fogel R, Banerji D, Wedzicha JA. Indacaterol/glycopyrronium versus salmeterol/fluticasone in the prevention of clinically important deterioration in COPD: results from the FLAME study. Respiratory research. 2018 Jun 20:19(1):121. doi: 10.1186/s12931-018-0830-z. Epub 2018 Jun 20 [PubMed PMID: 29925383]

[5]

Di Marco F, Santus P, Scichilone N, Solidoro P, Contoli M, Braido F, Corsico AG. Symptom variability and control in COPD: Advantages of dual bronchodilation therapy. Respiratory medicine. 2017 Apr:125():49-56. doi: 10.1016/j.rmed.2017.03.001. Epub 2017 Mar 2 [PubMed PMID: 28340862]

[6]

. OTC drugs for seasonal allergies. The Medical letter on drugs and therapeutics. 2019 Apr 22:61(1570):57-60 [PubMed PMID: 31169808]

Level 3 (low-level) evidence

[7]

Yokoyama Y, Kawasaki R, Takahashi H, Maekawa S, Tsuda S, Omodaka K, Nakazawa T. Effects of Brimonidine and Timolol on the Progression of Visual Field Defects in Open-angle Glaucoma: A Single-center Randomized Trial. Journal of glaucoma. 2019 Jul:28(7):575-583. doi: 10.1097/IJG.0000000000001285. Epub [PubMed PMID: 31188229]

Level 1 (high-level) evidence

[8]

Aggarwal V, Singla M, Miglani S, Kohli S. Comparison of the anaesthetic efficacy of epinephrine concentrations (1 : 80 000 and 1 : 200 000) in 2% lidocaine for inferior alveolar nerve block in patients with symptomatic irreversible pulpitis: a randomized, double-blind clinical trial. International endodontic journal. 2014 Apr:47(4):373-9. doi: 10.1111/iej.12157. Epub 2013 Jul 29 [PubMed PMID: 23895176]

Level 1 (high-level) evidence

[9]

Heal DJ, Smith SL, Gosden J, Nutt DJ. Amphetamine, past and present--a pharmacological and clinical perspective. Journal of psychopharmacology (Oxford, England). 2013 Jun:27(6):479-96. doi: 10.1177/0269881113482532. Epub 2013 Mar 28 [PubMed PMID: 23539642]

Level 3 (low-level) evidence

[10]

McElroy SL. Pharmacologic Treatments for Binge-Eating Disorder. The Journal of clinical psychiatry. 2017:78 Suppl 1():14-19. doi: 10.4088/JCP.sh16003su1c.03. Epub [PubMed PMID: 28125174]

[11]

Tsakiris P, de la Rosette JJ, Michel MC, Oelke M. Pharmacologic treatment of male stress urinary incontinence: systematic review of the literature and levels of evidence. European urology. 2008 Jan:53(1):53-9 [PubMed PMID: 17920183]

Level 1 (high-level) evidence

[12]

Civantos Calzada B, Aleixandre de Artiñano A. Alpha-adrenoceptor subtypes. Pharmacological research. 2001 Sep:44(3):195-208 [PubMed PMID: 11529686]

[13]

Johnson M. Molecular mechanisms of beta(2)-adrenergic receptor function, response, and regulation. The Journal of allergy and clinical immunology. 2006 Jan:117(1):18-24; quiz 25 [PubMed PMID: 16387578]

[14]

Wallukat G. The beta-adrenergic receptors. Herz. 2002 Nov:27(7):683-90 [PubMed PMID: 12439640]

[15]

Berry MD. Mammalian central nervous system trace amines. Pharmacologic amphetamines, physiologic neuromodulators. Journal of neurochemistry. 2004 Jul:90(2):257-71 [PubMed PMID: 15228583]

[16]

Sicherer SH, Simons FER, SECTION ON ALLERGY AND IMMUNOLOGY. Epinephrine for First-aid Management of Anaphylaxis. Pediatrics. 2017 Mar:139(3):. pii: e20164006. doi: 10.1542/peds.2016-4006. Epub 2017 Feb 13 [PubMed PMID: 28193791]

[17]

Kimura I, Ushiyama K, Kikuchi H, Mabuchi G. [Diagnosis of angina pectoris by intravenous infusion of isoproterenol]. Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine. 1968 Jun 10:57(6):644-55 [PubMed PMID: 4972659]

[18]

Ghimire R, Dhungana SP. Evaluation of drugs used in chronic heart failure at tertiary care centre: a hospital based study. Journal of cardiovascular and thoracic research. 2019:11(2):79-84. doi: 10.15171/jcvtr.2019.15. Epub 2019 Jun 30 [PubMed PMID: 31384400]

[19]

Singhi S, Grover S, Bansal A, Chopra K. Randomised comparison of intravenous magnesium sulphate, terbutaline and aminophylline for children with acute severe asthma. Acta paediatrica (Oslo, Norway : 1992). 2014 Dec:103(12):1301-6. doi: 10.1111/apa.12780. Epub 2014 Oct 2 [PubMed PMID: 25164315]

Level 1 (high-level) evidence

[20]

Yoneda S, Yoneda N, Fukuta K, Shima T, Nakashima A, Shiozaki A, Yoshino O, Kigawa M, Yoshida T, Saito S. In which preterm labor-patients is intravenous maintenance tocolysis effective? The journal of obstetrics and gynaecology research. 2018 Mar:44(3):397-407. doi: 10.1111/jog.13547. Epub 2017 Dec 14 [PubMed PMID: 29239057]

[21]

Anstey MH, Wibrow B, Thevathasan T, Roberts B, Chhangani K, Ng PY, Levine A, DiBiasio A, Sarge T, Eikermann M. Midodrine as adjunctive support for treatment of refractory hypotension in the intensive care unit: a multicenter, randomized, placebo controlled trial (the MIDAS trial). BMC anesthesiology. 2017 Mar 21:17(1):47. doi: 10.1186/s12871-017-0339-x. Epub 2017 Mar 21 [PubMed PMID: 28327122]

Level 1 (high-level) evidence

[22]

Onishi H, Yumoto K, Sakata O. Preparation and evaluation of ritodrine buccal tablets for rational therapeutic use. International journal of pharmaceutics. 2014 Jul 1:468(1-2):207-13. doi: 10.1016/j.ijpharm.2014.04.009. Epub 2014 Apr 5 [PubMed PMID: 24709218]

[23]

Vasseur B, Dufour A, Houdas L, Goodwin H, Harries K, Emul NY, Hutchings S. Comparison of the Systemic and Local Pharmacokinetics of Clonidine Mucoadhesive Buccal Tablets with Reference Clonidine Oral Tablets in Healthy Volunteers: An Open-Label Randomised Cross-Over Trial. Advances in therapy. 2017 Aug:34(8):2022-2032. doi: 10.1007/s12325-017-0585-9. Epub 2017 Jul 19 [PubMed PMID: 28726169]

Level 3 (low-level) evidence

[24]

Ishida M, Abe K, Hashizume M, Kawamura M. A novel approach to sustained pseudoephedrine release: differentially coated mini-tablets in HPMC capsules. International journal of pharmaceutics. 2008 Jul 9:359(1-2):46-52. doi: 10.1016/j.ijpharm.2008.03.034. Epub 2008 Mar 30 [PubMed PMID: 18467046]

[25]

Virk MK, Hotz J, Khemani RG, Newth CJ, Ross PA. Change in Oxygen Consumption Following Inhalation of Albuterol in Comparison with Levalbuterol in Healthy Adult Volunteers. Lung. 2017 Apr:195(2):233-239. doi: 10.1007/s00408-017-9982-8. Epub 2017 Feb 16 [PubMed PMID: 28210808]

[26]

Hon KLE, Leung AKC. Medications and Recent Patents for Status Asthmaticus in Children. Recent patents on inflammation & allergy drug discovery. 2017:11(1):12-21. doi: 10.2174/1872213X11666170130143524. Epub [PubMed PMID: 28137226]

[27]

Anderson MS, Nadkarni A, Cardwell LA, Alinia H, Feldman SR. Spotlight on brimonidine topical gel 0.33% for facial erythema of rosacea: safety, efficacy, and patient acceptability. Patient preference and adherence. 2017:11():1143-1150. doi: 10.2147/PPA.S115708. Epub 2017 Jul 6 [PubMed PMID: 28740369]

[28]

Erickson CH, McLeod RL, Mingo GG, Egan RW, Pedersen OF, Hey JA. Comparative oral and topical decongestant effects of phenylpropanolamine and d-pseudoephedrine. American journal of rhinology. 2001 Mar-Apr:15(2):83-90 [PubMed PMID: 11345158]

Level 2 (mid-level) evidence

[29]

Hernández-Bernal F, Castellanos-Sierra G, Valenzuela-Silva CM, Catasús-Álvarez KM, Valle-Cabrera R, Aguilera-Barreto A, López-Saura PA, THERESA-3 Group of Investigators. Recombinant streptokinase vs phenylephrine-based suppositories in acute hemorrhoids, randomized, controlled trial (THERESA-3). World journal of gastroenterology. 2014 Feb 14:20(6):1594-601. doi: 10.3748/wjg.v20.i6.1594. Epub [PubMed PMID: 24587636]

Level 1 (high-level) evidence

[30]

Martyr JW, Orlikowski CE. Epidural anaesthesia, ephedrine and phenylephrine in a patient taking moclobemide, a new monoamine oxidase inhibitor. Anaesthesia. 1996 Dec:51(12):1150-2 [PubMed PMID: 9038453]

[31]

Macmillan M, Barker K. Phenylephrine toxicity. European journal of anaesthesiology. 2008 May:25(5):426-7. doi: 10.1017/S0265021507002785. Epub [PubMed PMID: 18377666]

[32]

Aydın A, Tugcu G. Toxicological assessment of epinephrine and norepinephrine by analog approach. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 2018 Aug:118():726-732. doi: 10.1016/j.fct.2018.06.028. Epub 2018 Jun 18 [PubMed PMID: 29913233]

[33]

Manzon L, Nappe TM, DelMaestro C, Maguire NJ. Clonidine Toxicity. StatPearls. 2023 Jan:(): [PubMed PMID: 29083752]

[34]

Paulman PM, Cantral K, Meade JG, Vettel K, Loperena R, Odrezin M. Dobutamine overdose. JAMA. 1990 Nov 14:264(18):2386-7 [PubMed PMID: 2231992]

[35]

Lötvall J, Lunde H, Svedmyr N. Onset of bronchodilation and finger tremor induced by salmeterol and salbutamol in asthmatic patients. Canadian respiratory journal. 1998 May-Jun:5(3):191-4 [PubMed PMID: 9707465]

[36]

Glatstein MM, Rimon A, Koren L, Marom R, Danino D, Scolnik D. Unintentional oral beta agonist overdose: case report and review of the literature. American journal of therapeutics. 2013 May-Jun:20(3):311-4. doi: 10.1097/MJT.0b013e3182002f2d. Epub [PubMed PMID: 21317628]

Level 3 (low-level) evidence

[37]

Ozdemir D, Yilmaz E, Duman M, Unal N, Tuncok Y. Hypoglycemia after albuterol overdose in a pediatric patient. Pediatric emergency care. 2004 Jul:20(7):464-5 [PubMed PMID: 15232249]

[38]

Zimmerman JL. Cocaine intoxication. Critical care clinics. 2012 Oct:28(4):517-26. doi: 10.1016/j.ccc.2012.07.003. Epub 2012 Aug 30 [PubMed PMID: 22998988]

[39]

Richards JR, Hollander JE, Ramoska EA, Fareed FN, Sand IC, Izquierdo Gómez MM, Lange RA. β-Blockers, Cocaine, and the Unopposed α-Stimulation Phenomenon. Journal of cardiovascular pharmacology and therapeutics. 2017 May:22(3):239-249. doi: 10.1177/1074248416681644. Epub 2016 Dec 14 [PubMed PMID: 28399647]

[40]

Swenson K, Rankin S, Daconti L, Villarreal T, Langsjoen J, Braude D. Safety of bolus-dose phenylephrine for hypotensive emergency department patients. The American journal of emergency medicine. 2018 Oct:36(10):1802-1806. doi: 10.1016/j.ajem.2018.01.095. Epub 2018 Feb 19 [PubMed PMID: 29472039]

[41]

Shao CL, Duan FJ, Qiao SB, You SJ, Hu FH, Yuan JS, Yang WX. [Comparison of dobutamine stress echocardiography and exercise echocardiography in evaluating left ventricular outflow tract obstruction in patients with hypertrophic cardiomyopathy]. Zhonghua xin xue guan bing za zhi. 2012 Mar:40(3):214-8 [PubMed PMID: 22801266]

Level 2 (mid-level) evidence

[42]

Hong HQ, Lu J, Fang XL, Zhang YH, Cai Y, Yuan J, Liu PQ, Ye JT. G3BP2 is involved in isoproterenol-induced cardiac hypertrophy through activating the NF-κB signaling pathway. Acta pharmacologica Sinica. 2018 Feb:39(2):184-194. doi: 10.1038/aps.2017.58. Epub 2017 Aug 17 [PubMed PMID: 28816235]

[43]

Armentia A, Martín-Armentia B, Martín-Armentia S, Ruiz-Muñoz P, Quesada JM, Postigo I, Conde R, González-Sagrado M, Pineda F, Castillo M, Palacios R, Tejedor J. Cocaine Allergy in Drug-Dependent Patients and Allergic People. The journal of allergy and clinical immunology. In practice. 2018 Jan-Feb:6(1):201-207. doi: 10.1016/j.jaip.2017.06.013. Epub 2017 Aug 30 [PubMed PMID: 28863944]

[44]

Self TH, Shah SP, March KL, Sands CW. Asthma associated with the use of cocaine, heroin, and marijuana: A review of the evidence. The Journal of asthma : official journal of the Association for the Care of Asthma. 2017 Sep:54(7):714-722. doi: 10.1080/02770903.2016.1259420. Epub 2016 Nov 18 [PubMed PMID: 27858495]

[45]

Santurtún A, García Blanco A, Fdez-Arroyabe P, Santurtún M, Zarrabeitia MT. Cocaine in Hospital Admissions for Diseases of the Circulatory System and as the Underlying Cause of Death: Analysis and Discussion. Cardiovascular toxicology. 2020 Feb:20(1):20-27. doi: 10.1007/s12012-019-09537-6. Epub [PubMed PMID: 31273689]

[46]

Stankowski RV, Kloner RA, Rezkalla SH. Cardiovascular consequences of cocaine use. Trends in cardiovascular medicine. 2015 Aug:25(6):517-26. doi: 10.1016/j.tcm.2014.12.013. Epub 2014 Dec 26 [PubMed PMID: 25657055]

[47]

Havakuk O, Rezkalla SH, Kloner RA. The Cardiovascular Effects of Cocaine. Journal of the American College of Cardiology. 2017 Jul 4:70(1):101-113. doi: 10.1016/j.jacc.2017.05.014. Epub [PubMed PMID: 28662796]

[48]

Martin C, Medam S, Antonini F, Alingrin J, Haddam M, Hammad E, Meyssignac B, Vigne C, Zieleskiewicz L, Leone M. NOREPINEPHRINE: NOT TOO MUCH, TOO LONG. Shock (Augusta, Ga.). 2015 Oct:44(4):305-9. doi: 10.1097/SHK.0000000000000426. Epub [PubMed PMID: 26125087]

[49]

Schurr JW, Gitman B, Belchikov Y. Controversial therapeutics: the β-adrenergic antagonist and cocaine-associated cardiovascular complications dilemma. Pharmacotherapy. 2014 Dec:34(12):1269-81. doi: 10.1002/phar.1486. Epub 2014 Sep 15 [PubMed PMID: 25224512]

[50]

Fareed FN, Chan G, Hoffman RS. Death temporally related to the use of a Beta adrenergic receptor antagonist in cocaine associated myocardial infarction. Journal of medical toxicology : official journal of the American College of Medical Toxicology. 2007 Dec:3(4):169-72 [PubMed PMID: 18072171]

[51]

Beis D, von Känel R, Heimgartner N, Zuccarella-Hackl C, Bürkle A, Ehlert U, Wirtz PH. The Role of Norepinephrine and α-Adrenergic Receptors in Acute Stress-Induced Changes in Granulocytes and Monocytes. Psychosomatic medicine. 2018 Sep:80(7):649-658. doi: 10.1097/PSY.0000000000000620. Epub [PubMed PMID: 29965944]

[52]

Murthy DR, White CM, Katten D, Ahlberg AW, Salloum A, Heller GV. Effect of intravenous metoprolol or intravenous metoprolol plus glucagon on dobutamine-induced myocardial ischemia. Pharmacotherapy. 2000 Nov:20(11):1303-9 [PubMed PMID: 11079278]

[53]

Ramoska EA, Henretig F, Joffe M, Spiller HA. Propranolol treatment of albuterol poisoning in two asthmatic patients. Annals of emergency medicine. 1993 Sep:22(9):1474-6 [PubMed PMID: 8363123]