Pharmacology of Vasoactive Drugs Farmacologia De Drogas Vasoativas

review article

Pharmacology of vasoactive drugs Farmacologia de drogas vasoativas

Estela Maris Freitas Muri1, Maria Matilde de Mello Sposito2, Leonardo Metsavaht3

ABSTRACT Peripheral vascular diseases (PVDS) are characterized as a circulation problem in the veins, arteries, and lymphatic system. The main therapy consists of changes in lifestyle such as diet and physical activity. The pharmacological therapy includes the use of vasoactive drugs, which are used in arteriopathies and venolymphatic disorders. The goal of this study was to research the scientific literature on the use and pharmacology of vasoactive drugs, emphasizing the efficacy of their local actions and administration.

Keywords: Peripheral Vascular Diseases, Pharmacology, Review Literature as Topic

RESUMO As doenças vasculares periféricas (DVPS) caracterizam-se como um problema de circulação nas veias, artérias e sistema linfático. O tratamento primordial para as DVPS é a mudança de hábitos de vida, alimentação e prática de atividade física. A terapia farmacológica inclui a utilização de drogas vasoativas, as quais são utilizadas nas arteriopatias e nas doenças veno-linfáticas. O objetivo deste estudo foi pesquisar em literatura científica sobre a utilização e farmacologia das drogas vasoativas, enfatizando a eficácia da administração e ação local dessas drogas.

Palavras-chave: Doenças Vasculares Periféricas, Farmacologia, Literatura de Revisão como Assunto

1 Pharmacist, Professor, and Researcher at the College of Pharmacy at the Federal Fluminense University. 2 Physiatric Doctor at the Institute of Instituto de Medicina Física e Reabilitação do Hospital da Clínicas da Faculdade de Medicina da Universidade de São Paulo (Physical Medicine and Rehabilitation at the Hospital of the Clinics of the College of Medicine of the University of São Paulo). Coordinator of Teaching and Research of the Instituto Brasil de Tecnologias da Saúde (Brazilian Institute of Health Technologies). 3 Orthopediatric Doctor and Physiatrist, CSO of the Instituto Brasil de Tecnologias da Saúde (Brazilian Institute of Health Technologies).

DOI: 10.11606/issn.2317-0190.v17i1a103306

Mailing address Instituto Brasil de Tecnologias da Saúde • Dr. Leonardo Metsavaht • Rua Visconde de Pirajá, 407/307 • Rio de Janeiro / RJ • Cep 22410-003

« Received on December 18, 2009, accepted on January 28, 2010 » Muri EMF, Sposito MMM, Metsavaht L. ACTA FISIATR. 2010; 17(1): 22 – 27 Pharmacology of vasoactive drugs

stasis and edema in the extremities. These are In 2000, Dorazil-Dudzik et al7 described considered the main factors responsible for the an anti-nociceptive action of PTF after intra- INTRODUCTION constant problems of turgidity in soft tissues in peritoneal administration in rats and intrave- Peripheral vascular diseases (PVDs) encom- areas traumatized by accidents or surgeries, nous administration in humans. Owing to the pass a group of chronic degenerative diseases causing a reduction in the range of movement adverse reactions (hypotension, dysrhythmia, and syndromes that affect the arterial, venous, of the articulations involved.3 agitation, and convulsions) observed in clini- and lymphatic systems and that are character- cal practice after the systemic use of PTF, its ized by a narrowing, and/or a blockage of the local administration appeared to be a thera- vessels that conduct blood or lymph to the peutic alternative. Thus, the study showed the arms and legs, thereby jeopardizing the nor- METHOD local effects of administering 0.5, 1.0, or 2 mg mal flow. This hampers the exchange of- ma The strategy of a bibliographical research of PTF and 1 or 2 mg of Propentoxifylline terial between the blood and the tissues, the was carried out using the following databas- (PPTF) injected intraplantarally in rats in or- supply of nutrients, the removal of metabolic es: Pubmed, Medline, Bireme base (Virtual der to observe the behavior with the pain in- waste, and the defense and repair of the tissues. Health Library), Scorpus, Science Finder and duced by formalin. Aside from the antagonism A hypoxic decline of the tissues is related to a the Cochrane Library, in addition to didactic of the hyperalgesia induced by formalin, this series of painful affections of the musculoskel- books. All available years were researched study demonstrated biochemical evidence of etal machinery such as chronic tendinopathies using the following key-words and relevant the inhibition of the synthesis of pro-inflam- (tendonitis), degenerative arthropathies (ar- phrases: Peripheral vascular diseases, venous matory cytokines and phosphodiesterase by throsis), and compressive syndromes of the insufficiency, vasoactive drugs, mechanism of PTF and PPTF, emphasizing the local use of peripheral nerves (CSPN). These characteris- action of vasoactives, Pentoxifylline, topical these drugs as a valid strategy for the treatment tically present pain that is hard to control with buflomedil, local administration of vasoac- of inflammatory pains.8 non-steroidal antiinflammatories (NSAIDS) tives, intradermal heparin, local hydergine, co- The microcirculatory dysfunction associ- or systemic analgesics, impacting significantly dergocrine mesylate, topical verapamil, cou- ated with chronic venous insufficiency (CVI) on the sufferer’s health and quality of life. marin, rutin, topical melilotus, topical escin, can be treated by pharmacological interven- The arterial PVDs, mainly characterized by calcium dobesilate and tribenoside. tion, compression therapy, or both. Some atherosclerosis, present intermittent claudica- drugs such as derivatives of natural products tion, pain while resting, and trophic lesions as and PTF are very well evaluated in the ran- their main symptoms. The symptoms of ve- Drugs used in arterial diseases domized prospective clinical tests described nous PVDs include the appearance of varicose A favorable systemic effect on the circulation in the article by Wollina et al. The main micro- veins, pains, edemas, and venous thromboses.1 was expected from the first drugs with vasodi- circulatory effects observed were a reduction When the passage for oxygen and blood is lating action, however undesirable effects were in the speed of capillary filtration and an im- compromised in a certain region drugs can be observed. Aside from the central hypotension provement in the levels of the transcutaneous used that have vasodilating effects or prevent causing discomfort, a worsening of the isch- partial pressure of oxygen.9 platelet aggregation. The vasodilators can act emia was observed in the affected region due in diverse ways. Calcium channel blockers to a phenomenon called “theft” occasioned by Buflomedil show some actions such as increasing local the diminished flow due to peripheral vasodi- Buflomedil hydrochloride is a much-used va- blood flow and reducing arterial pressure or lation. Later on a new action mechanism was soactive drug in peripheral vascular diseases central venous pressure. Activators of the po- observed in which some drugs acted on the and cerebrovascular insufficiency.10,11 tassium channel bring a hyper-polarization blood constituents (erythrocytes) by modi- Its pharmacodynamic properties include: and relaxation of the cell membrane of the fying the capacity of these cells to deform, non-specific inhibition of alpha-adrenoceptors smooth vascular musculature. There are other thereby improving perfusion into the tissue. of the smooth blood vessel musculature, inhibi- vasodilating drugs that increase the cellular These drugs can be effective in cases of muscu- tion of platelet aggregation, increase in erythro- concentration of cyclic adenosine monophos- loskeletal ischemia when their local/regional cyte flexibility, non-specific calcium antagonist phate (cAMP), of cyclic guanosine mono- use would minimize the undesirable systemic activity, and anti-hypoxemia activity. The main phosphate (cGMP), and even by inhibiting the effects.4 beneficial property appears to be an improve- enzyme phosphodiesterase. The direct-acting ment of nutritional blood flow in ischemic tis- vasodilators work by inhibiting sympathetic Pentoxifylline sues without producing systemic effects.4,12 vasoconstriction and the renin-angiotensin Pentoxifylline (PTF) was the first drug ap- The oral and parenteral administration of system.2 The vasoactive drugs, therefore, are proved by the FDA (Food and Drug Admin- drugs has been studied for the improvement useful in the treatment of ischemic and painful istration) for the treatment of intermittent of microvascular perfusion and acceleration conditions of the musculoskeletal machinery. claudication. PTF is a derivative of methylx- of healing. Nonetheless, these methods of The pharmacology of drugs used in venous anthine, which acts by inhibiting phosphodi- administration are accompanied by the risk and lymphatic disorders consists mainly of esterase and affects the sanguinary rheology. of adverse reactions or the premature inacti- increasing the tone of the venous wall, modi- In other words, it modifies the erythrocyte vation of the drug by the metabolism of first fying the microcirculation parameters, reduc- flexibility, the adhesion and aggregation of passage. The encapsulation of medicines in li- ing capillary hyper-permeability and blood the platelets with the consequent reduction of posomes offers an alternative to the topical re- viscosity, and improving the partial pressure sanguinary viscosity, and improves the blood lease of medications, improving the therapeu- of oxygen, leading to a more efficient veno- flow diminishing the fibrinogen and reducing tic efficacy due to a greater concentration and lymphatic return, and minimizing sanguinary granulocytic function.5,6 longer time of the drug on site, in addition to

23 Muri EMF, Sposito MMM, Metsavaht L. ACTA FISIATR. 2010; 17(1): 22 – 27 Pharmacology of vasoactive drugs reducing the systemic effects. 13,14 It has been function loss such as memory and learning and reduction of edema, which, as stated previous- postulated that liposomes, on crossing the cor- acute cerebrovascular disease. It is even used as ly, is responsible for the reduction in the range neal stratum, act as a micro-reservoir for the a peripheral vasodilator with a beneficial effect of movement of joints. slow release of medicine. 15,16 on symptoms associated with arterial hyper- Venolymphotonic drugs can be grouped Due to its pharmacological actions on tension. Its action mechanism is related to an according to action mechanism (despite vari- microcirculation, buflomedil encapsulated in alpha-blocker and one possible metabolic func- ous products being associated with the sub- liposomes has been studied for topical application working as a partial agonist or antagonist of stances of various groups) into: i) phleboton- tion in an attempt to improve healing in nor- the serotonin and dopamine.4,23 ics; ii) those that increase the reabsorption mal and ischemic skin in tests on rats. These re- The topical administration of co-dergo- of a transuded substance; and iii ) those that sults show a more rapid closing and a complete crine mesylate in cream form has been studied reduce capillary permeability. neovascularization of the injury in animals in combination with another vasoactive, iso- treated with buflomedil than those treated sorbide dinitrate, and testosterone in the treat- Coumarin (Melilotus/_ with liposomes without the active principle, ment of age-related erectile dysfunction. In a benzopyrone – increase and suggesting that this type of local administra- randomized, double-blind study two creams reabsorption of transudate) tion of buflomedil could be of great benefit for were tested, one containing the three above- The melilotus extract has a phyto-complex clinical therapy. 17,18 mentioned substances and the other contain- content aside from other components such ing only testosterone. The cream containing as flavonoids, and coumarin, the most ac- Heparin testosterone and the two vasoactive agents was tive substance in the complex. The generic Heparin is widely used in thrombotic disorders shown more effective in the studied treatment, name of alpha-benzopyrone was adopted and as an anticoagulant.19 Its anti-inflammatory possibly owing to the complimentary action to distinguish coumarin from the coumarin effects are also described. In a clinical double- of smooth muscle relaxation caused by the di- derivatives, which are anti-coagulants. Cou- blind test, patients with superficial vein throm- nitrate, and by the blocking action of the co- marin acts to reduce edema and/or inflam- bosis (SVT) were subcutaneously treated with dergocrine mesylate of the alpha-adrenergic mation by increasing venous and lymphatic heparin of a low molecular weight (sodium receptors within the cavernous body, causing flow and diminishing capillary permeability enoxaparin). The results of this study showed a dilation of the arteries and arterioles. These and the amount of fluid formed in sub-cuta- the tendency of heparin to reduce the incidence results corroborate, suggesting one possible neous tissue.4,32,33 of deep vein thrombosis stemming from SVT. therapy for this dysfunction.24,25 Patches are one type of pharmaceuti- Heparin was shown to be effective in reducing cal widely used in the treatment of localized the re-incidence and spread of SVT.20 Verapamil pathologies such as varicose syndrome and In one work, Jones et al used radio-iso- Verapamil is a synthetic derivative of papav- capillary fragility where a prolonged release of tope techniques to study the effects of non- erine, a prototype of a group of compounds the active principle is necessary.34 In the work fractioned heparin, intra-dermal and intra-ve- that share the property of selectively inhibit- done by Minghetti et al, patches containing nous, in a test of inflammation in guinea pigs ing the flow of calcium ions to the cell through dried melilotus extract were developed. These induced by cationic proteins, mediators, and the membrane. Verapamil blocks the calcium were tested in the treatment of localized vari- antigens. The results showed heparin exerted channels of the smooth arterial muscle, pro- cose syndrome as to their capacity to release an anti-inflammatory effect by neutralizing ducing a diminished peripheral resistance and coumarin and their dermal permeability. The the poly-cationic peptides owing to its anionic arterial dilation. This medicine is used in ar- results were adapted for the preparation of po- charge. It also inhibited the plasmatic exuda- rhythmias, anginas, and hypertension.1 tentially useful formulations for local use in the tion induced by poly-L-lysine (PLL) when The local use of verapamil is being studied treatment mentioned.35 administered intradermally 60 minutes before as an alternative therapy in the treatment of Evaluation of the therapeutic efficacy of the PLL, suggesting that the heparin was not Peyronie’s disease related to erectile dysfunc- a lotion (FLEBS) containing, among other rapidly removed from the injection site.21 tion. Some studies report the intralesional things, melilotus officinalis, was done on pa- The intradermal administration of vasoac- (through injections) and transdermal admin- tients with venous or lymphatic insufficiency. tive drugs is commonly used in mesotherapy istration as effective in some symptoms of the This lotion presented a vasoconstrictive- ac for the treatment of chronic pain or degenera- disease such as pain, diminution of the curva- tion due to the Ruscus aculeatus and was also tive processes such as tendonitis and arthrosis ture, and improvement of erectile capacity.26,27 capable of reducing edema by the action of in order to promote a wider passage to the area melilotus officinalis. The traditional clinical pa- for blood, and thereby for oxygen. Arterial va- Drugs used in venolymphatic rameters were evaluated in patients showing sodilators such as buflomedil hydrochloride diseases improvement of all symptoms monitored, es- and peril-heparin are very efficient at minimiz- Venolymphotonic medicines are generally pecially edema and pain.36 ing regional hypoxia, and consequently the used in disorders such as lymphedema and The therapeutic efficacy of melilotus of- pain.22 varicose syndrome.28,29 The choice of a veno- ficinalis was also evaluated in models of acute tonic drug must be founded on the knowledge inflammation induced with tupertine oil in Co-dergocrine mesylate of the pharmacodynamics and pharmacoki- rabbits. The effects were evaluated by measur- Co-dergocrine mesylate (Hydergine®) is a com- netics of the molecule, a critical evaluation in ing the concentrations of citroline, an in vitro bination of four dihydro derivatives of ergotox- clinical studies, the doctor’s personal experi- test for phagocytosis. Melilotus officinalis pre- in and has been used in clinical medicine since ence, and the cost of the drug.30,31 sented an anti-inflammatory action by reduc- 1949 for the treatment of various pathologi- The main objective in using drugs de- ing the activation of phagocytes in circulation cal conditions. It is used in cases of cognitive signed to treat vaso-lymphatic disorder is the and lowering the citruline production.37

24 Muri EMF, Sposito MMM, Metsavaht L. ACTA FISIATR. 2010; 17(1): 22 – 27 Pharmacology of vasoactive drugs

Zhao et al38 studied some extracts of coumarin and rutin. This study showed the of fibrosis in chronic edemas. It has been used Melilotus Suaveolens Ledeb in order to explore beneficial effects on microcirculation that the in the reduction of edema in CVI in diabetic their anti-inflammatory mechanisms. Vari- two associated active principles had, whose retinopathies, and in hemorrhoidal disease.59-61 ous organic extracts such as ethanol, ethyl ac- hemodynamic properties complemented each Various randomized clinical tests have etate, and petroleum ether were tested in an other explaining the effects on the physio-pa- been described emphasizing the use of calci- inflammation model and were found capable thology of veno-lymphatic insufficiency. um in patients with CVI.62,63 In a recent study, of considerably inhibiting the production of The musculoskeletal lesions common the effects of this drug on lymphatic flow and cytokines and pro-inflammatory mediators – to athletes can also be treated by a localized lympho-venous edema were described related inhibitions comparable to dexamethasone – as therapy using a mixture of coumarinic bio- to CVI. The dobesilate was able to normalize well as inducing the release of anti-inflamma- flavonoids. These promote a rapid reduction the lymphatic physiology and improve the tory mediators.39,40 in post-traumatic edema allowing an earlier symptoms of patients with CVI.64 improvement in the range of movement and The tribenoside acts to reduce capillary Rutin and troxerrutin the pain caused by tissue swelling. Its veno- permeability and edema and also antagonizes (Flavonoids/g-benzopyrone – lymphatonic action diminished capillary per- the endogenic mediators that participate in phlebotonic meability assisting the venous and lymphatic the painful and inflammatory processes. It is O-(beta-hydroxyethyl)-rutosides (HR), de- return in a very significant way.22 used in venous circulation disorder, phlebi- rivatives of rutin, are used in the treatment of tis (adjunctive treatment), hemorrhoids, and chronic venous insufficiency (CVI), a varicose Escin (Derived from horse varicose syndrome.4,65 disease and a deep vein disease. Rutin acts to chestnut – phlebotonic) increase venous tone and it is believed to have The derivatives of the horse chestnut are widely a “capillary impermeabilization” action by in- used in commercial pharmaceuticals. They hibiting hialuronidase.4,41 originate from the plant Aesculus hippocasta- CONCLUSION Cesarone et al have studied the effects of num which contains some active principles Peripheral vascular diseases (PVDs) consti- HR on microcirculation, resulting in various such as esculin, escin, and esculetin. Escin is a tute a group of diseases that affect the arterial, articles published on prospective, double-blind, triterpenic glicosoid whose therapeutic effects venous, and lymphatic systems constricting or randomized, placebo-controlled clinical tests. are the inhibition of exudation and edema, obstructing the vessels that conduct blood These works showed good results related to im- aside from increasing vascular permeability. or lymph to the arms and legs, hampering the proving venous edema and hypertension with In a randomized, double-blind clinical normal flow. Aside from adopting a healthy life- the oral administration of HR (Venoruton).42-45 study with injured athletes, was investigated style, the therapy for the PVDs includes the re- The same group recently described a prospec- the localized action of a gel containing 1% or duction or elimination of risk factors (smoking, tive clinical study to evaluate the local efficacy of 2% escin, diethylammonium salycilate, and obesity, etc.) and the use of vasoactive drugs. applying an HR gel on patients with severe CVI heparin. The gel containing escin showed ex- The role of vasomotor disorder is increas- and venous microangiopathy. Results showed a cellent safety and efficacy in the treatment of ingly recognized in the acute and chronic significant improvement in microcirculation by blunt impact injuries.50,51 musculoskeletal afflictions, emphasizing the an increase in the partial pressure of oxygen and Various clinical trials were carried out to growing need for the use of vasodilating and 46 a reduction in local CO2 pressure. evaluate the local efficacy of a gel containing veno-lymphatic drugs. Troxerutin is a mixture of mono, di, tri and escin and essential phospholipids in patients tetrahydroxyethyl-rutosides, flavonoids with with chronic venous hypertension due to CVI, an anti-varicose action. A randomized clinical micro-angiopathy, venous ulceration, and su- study was made to evaluate the results on edema perficial thrombophlebitis. All of the works re- REFERENCES from a therapy combining coumarin-troxerutin sulted in an improvement of microcirculation, and compression in CVI patients. 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