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Vasoactive and Antiplatelet Agents
Questions
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Q33.1 What are several of the important nitric oxide releasers involving cutaneous vasculature? (Pg. 359, Table 33.1 )
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Q33.2 Which drugs discussed in this chapter have demonstrated efficacy in patients with Raynaud phenomenon? (Pgs. 359, 364x3, 365, Box 33.1 )
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Q33.3 Which calcium channel blockers are most appropriate for use in patients with cyclosporine-induced hypertension? (Pg. 361)
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Q33.4 What are several of the common mucocutaneous adverse effects from calcium channel blockers? (Pg. 361)
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Q33.5 Which severe adverse event has been reported in pediatric patients receiving propranolol therapy for complicated infantile hemangiomas? What advice can be given to minimize this risk? (Pg. 362)
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Q33.6 Which common skin disease is likely to be exacerbated by β-blockers? (Pg. 362)
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Q33.7 Why does aspirin have a paradoxically greater antiplatelet effect at relatively low doses? (Pg. 362)
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Q33.8 What are the mechanisms by which pentoxifylline improves various disorders of cutaneous vasculature? (Pg. 364)
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Q33.9 Which nitric oxide donor may improve flap survival in dermatologic surgery? (Pg. 365)
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Q33.10 Which cytokine receptor related to cutaneous vasculature is a potential therapeutic target for patients with either melanoma or psoriasis? (Pg. 365)
Abbreviations used in this chapter
5-HT
5-Hydroxytryptamine
ADP
Adenosine diphosphate
AE
Adverse effect(s)
ATP
Adenosine triphosphate
AV
Atrioventricular
BP
Blood pressure
Bpm
Beats per minute
CAD
Coronary artery disease
CCB
Calcium channel blockers
CGMP
Cyclic guanosine monophosphate
CGRP
Calcitonin gene-related peptide
CHF
Congestive heart failure
CNS
Central nervous system
CTGF
Connective tissue growth factor
CV
Cardiovascular
EM
Erythema multiforme
ET-1
Endothelin-1
FDA
US Food and Drug Administration
IH
Infantile hemangioma
NO
Nitric oxide
NSAID
Nonsteroidal anti-inflammatory drug(s)
PDE 5
Phosphodiesterase-5
PGE 2
Prostaglandin E 2
PGI 2
Prostaglandin E 1 (also known as prostacyclin)
PV
Pemphigus vulgaris
RBC
Red blood cell
RCT
Randomized controlled trial
SJS
Stevens–Johnson syndrome
TEN
Toxic epidermal necrolysis
TGF-β 2
Transforming growth factor-β 2
TNF-α
Tumor necrosis factor-α
TXA 2
Thromboxane A 2
VEGF
Vascular endothelial growth factor
Acknowledgment
The authors would like to acknowledge the contributions of Dr. Algin B. Garrett to previous editions of this chapter.
Pathophysiology Involving Cutaneous Vasculature
The cutaneous vasculature is innervated by the somatic and autonomic nervous systems. Nonadrenergic, noncholinergic sensorimotor neurons are important in the skin’s local vascular response to environmental temperature differences and chemical stimuli. Skin vasculature is capsaicin sensitive and has peptide neurotransmitters, largely calcitonin gene-related peptide (CGRP) and substance P ( Table 33.1 ). The net result of these two mediators is vasodilation, which is endothelium dependent and mediated by nitric oxide (NO). Patients with Raynaud phenomenon have a deficiency of perivascular CGRP-containing neurons. Patients with primary Raynaud phenomenon have an impairment in neurogenic regulation of blood flow and myogenic function.
Table 33.1
Some Controls of Cutaneous Vasodilation and Vasoconstriction
| Vasodilation | Vasoconstriction |
|---|---|
| Exogenous Factors—Sources Other Than Endothelial Cells | |
| β 1 Adrenergic | α 1 Adrenergic |
| Bradykinin | α 2 Adrenergic |
| Calcitonin gene-related peptide a | Thromboxane A 2 (TXA 2 ) |
| Capsaicin a | |
| Histamine | |
| Substance P a | |
| 5-Hydroxytryptamine (5-HT) | |
| Endogenous Factors—Derived From Endothelial Cells | |
| Endothelial-derived relaxation factor (same as NO) | Endothelin-1 (ET-1) |
| Prostaglandins—PGE 2 , PGI 2 | |
NO, Nitric oxide.
a Vasodilation induced by these mediators is mediated by NO.
Vasoactive mediators, prostaglandin E 2 (PGE 2 ), PGI 2 (also known as prostacyclin), and NO are released by the vessels. Diffusion of NO from endothelial cells results in vascular smooth muscle relaxation and vasodilation. Q33.1 Endothelium-dependent vasodilation also occurs in response to adenosine triphosphate (ATP), adenosine diphosphate (ADP), arachidonic acid, substance P, CGRP, 5-hydroxytryptamine (5-HT), bradykinin, histamine, neurotensin, vasopressin, angiotensin II, and thrombin. Endothelin-1 (ET-1), a potent vasoconstrictor, is synthesized by human cutaneous microvascular endothelial cells, and has autocrine and paracrine activity. ET-1 causes both direct vasoconstriction and a neurogenically mediated flare.
Platelet function, clotting factors, and red blood cell (RBC) concentration and flexibility are responsible for the viscosity of blood. The viscosity of blood varies due to changes in plasma proteins or environmental temperature. Pentoxifylline has long been known to reduce viscosity in the microcirculation and improves erythrocyte deformability.
An intact vascular epithelium and continuous blood flow inhibit activation of clotting and platelets. The endothelium produces PGI 2 . PGI 2 inhibits platelet activation and vasodilates. Normal platelets do not bind to undamaged endothelial cells. Vessel wall injuries initiate clotting. These pathological mechanisms are the targets of the antiplatelet and anticlotting therapies. The therapeutic goal is normal blood viscosity and uninterrupted blood flow.
The vasculature and cellular components are targets of both current and developing agents. ( Fig. 33.1 ).
Calcium Channel Blockers
Pharmacology
Calcium channel blockers (CCB) are generally well absorbed orally. Bioavailability varies between drugs in this class: 50% to 70% for nifedipine, 15% to 24% for isradipine, 20% to 40% for diltiazem, and 50% to 88% for amlodipine. Peak plasma levels after oral administration are reached at 30 minutes with diltiazem, 1 to 2 hours with nifedipine, and 7 to 8 hours with amlodipine. These drugs are largely protein bound. Nifedipine, isradipine, and amlodipine are principally excreted via the kidney, whereas 60% to 65% of diltiazem is excreted via the feces after extensive deacetylation. The plasma half-life for nifedipine and diltiazem is 4 hours, whereas the plasma half-life of amlodipine is much greater, at 35 hours after a single oral dose.
Mechanism of Action
CCB prevent Ca 2+ transport across the plasma cell membrane of smooth muscle cells. The plasma cell membrane contains little stored intracellular Ca 2+ and thus inhibits excitation contraction coupling and muscle constriction. The drugs in this class have varying effects on atrioventricular (AV) conduction and heart rate. Verapamil is a strong depressor of AV conduction, is predominantly used for dysrhythmias, and therefore is not suitable for cutaneous vascular diseases. Nifedipine increases RBC deformability and a synergistic platelet antiaggregation activity with PGI 2 in vitro.
Clinical Use
Off-Label Dermatologic Uses
Box 33.1 lists drugs with established efficacy in treating Raynaud phenomenon.
Box 33.1
Drugs with Reported Efficacy in Treating Raynaud Phenomenon
CGRP, Calcitonin gene-related peptide; NO, nitric oxide.
Raynaud Phenomenon, Systemic Sclerosis, and Chilblains
Q33.2 Nifedipine, the agent of choice, demonstrates, in double-blinded controlled trials, effectiveness in the treatment of primary and secondary Raynaud phenomenon. Clinical improvement is greater for patients with primary disease. Theoretically, primary Raynaud patients have less vascular damage than secondary Raynaud patients. Nifedipine is advantageous due to its demonstrated in-vivo antiplatelet effects in patients with systemic sclerosis. Nifedipine can also treat recalcitrant chilblains, and was superior to diltiazem in one trial.
Nicardipine, amlodipine, felodipine, and isradipine, additional dihydropyridine CCB, are also useful for Raynaud phenomenon.
Diltiazem, a nondihydropyridine agent, has been shown in randomized controlled trials to be effective in the treatment of primary and secondary Raynaud phenomenon, whereas verapamil has been shown to be ineffective. Additionally, diltiazem has demonstrated success in an open study of the treatment of occupational Raynaud phenomenon (i.e., vibration white finger).
Calcinosis Cutis
Several studies suggest diltiazem is useful for calcinosis cutis, especially in patients with the CREST ( C alcinosis, R aynaud’s Phenomenon, E sophageal dysfunction, S clerodactyly, T elangiectasia) syndrome. One dramatic case of severe calcinosis secondary to dermatomyositis treated with diltiazem demonstrated significant regression of calcific lesions. However, a larger, retrospective study of patients with subcutaneous calcinosis from systemic sclerosis failed to demonstrate efficacy.
Wound Healing
Nifedipine and amlodipine enhance wound healing in mouse models. The CCB improve skin tensile strength in an incision wound model, and wound contraction in an excision wound model. Another study in wounded rats exposed to cigarette smoke demonstrated improved skin flap survival in the groups treated with both verapamil and nifedipine versus controls.
Keloids
Verapamil injected intralesionally is used with some success to treat both Peyronie disease and keloids/hypertrophic scars. Although treatment with verapamil alone may not provide complete clearance, it may be considered an alternative to other therapies, such as intralesional triamcinolone acetonide. In one trial in which 54 patients with keloids were randomized to receive intralesional injections of either triamcinolone or verapamil, the overall improvement in keloid appearance was similar in both groups, including reductions in vascularity, pliability, height, and width. The triamcinolone group improved at a faster rate, but there was less cost and fewer adverse effects (AE) (especially pigmentary alteration) in the verapamil group. There is additional evidence suggesting improvement by combining intralesional verapamil with other therapies, including surgery and/or silicone gel pads.
Chronic Anal Fissures
Both oral and topical forms of the CCB diltiazem and nifedipine have been used for the nonsurgical treatment of chronic anal fissures. Further discussion is beyond the scope of this chapter.
Cyclosporine-Induced Hypertension
Q33.3 In patients who develop hypertension while on cyclosporine therapy, several CCB are considered first-line for this complication. Because of both metabolic properties (regarding interactions via the CYP3A4 pathway, and renal blood flow preservation), both nifedipine and isradipine have been deemed appropriate for these patients. Amlodipine, diltiazem, and nicardipine are shown to increase levels of cyclosporine (via CYP3A4 interactions). Practitioners advocate their use reducing the dose of cyclosporine, which also reduces cost and potential AE.
Leiomyoma-Associated Pain
Nifedipine has been used for leiomyoma-associated pain. Nifedipine 10 mg three or four times daily demonstrated efficacy for leiomyoma-associated pain. From clinical experience, long-acting versions of nifedipine 30 mg can be given one to three times daily, titrating up gradually based on clinical response and tolerance.
Adverse Effects
AE ( Box 33.2 ) are frequent but rarely require cessation of therapy. Dosage reduction alone is typically sufficient to reduce the AE. Most AE are due to vasodilation, and include dizziness, headache, peripheral edema (ankle or pedal), nausea, and flushing. Symptomatic hypotension is rare. Diltiazem and amlodipine causes less severe AE than nifedipine.
Box 33.2
Drug Risks Profile—Calcium Channel Blockers
Data from Facts & Comparisons eAnswers (online database). St. Louis: Wolters Kluwer. ( https://www.wolterskluwercdi.com/facts-comparisons-online/ ).
BP, Blood pressure; CAD, coronary artery disease; CCB, calcium channel blockers; CV, cardiovascular; D, diltiazem; EM, erythema multiforme; I, isradipine; N, nifedipine; SJS/TEN, Stevens–Johnson syndrome/toxic epidermal necrolysis; V, verapamil.
| Contraindications | |
|
|
| Boxed Warnings | |
|
|
| Warnings & Precautions a | |
| Vasodilation Effects
Hepatic
|
Cardiovascular
Hypersensitivity Reactions
|
| Pregnancy Prescribing Status | |
|
|
a Under “Warnings & Precautions” these adverse effects can be considered relatively high risk or important clinical scenarios to avoid.
b See Chapter 65 Dermatologic Drugs During Pregnancy and Lactation, for detailed explanations of terms for “Newer rating” based on 2015 US Food and Drug Administration rulings.
Q33.4 Cutaneous and mucosal reactions include gingival hyperplasia, facial and truncal telangiectasia, new onset or exacerbation of psoriasis, photosensitivity reactions, subacute cutaneous lupus erythematosus, gynecomastia, erythromelalgia, and oral ulcers. Photodistributed hyperpigmentation has been reported from diltiazem, particularly in African-American women. In addition, a recent retrospective study suggests that long-term use of CCB is associated with the development of chronic eczematous reactions in the elderly. CCB are associated with gingival hyperplasia; according to one review, diltiazem (21%), verapamil (19%), and nifedipine (<10%) have the highest incidences.
Contact sensitivity is reported for topical diltiazem used for chronic anal fissures.
The CCB discussed in this chapter are pregnancy prescribing category C.
Therapeutic Guidelines
Nifedipine can be initiated at 10 mg three times daily or 30 mg once daily of sustained-release preparations. A reasonable maximum dose is 90 mg daily of a sustained-release form of nifedipine. The dose can be increased with titration according to symptomatic relief and AE. High doses may be required for patients with severe peripheral vasospasm. Longer-acting preparations are preferred. Diltiazem should be commenced at 60 mg three times daily, increasing to 120 mg three times daily if tolerated. Amlodipine is usually initiated at 5 mg once a day and can be increased to 10 mg once a day. Intralesional verapamil hydrochloride for keloids is given as 2.5 mg/mL, with most reports using 0.5 to 5 mL, depending on the size of the lesions treated.
β-Blockers
Pharmacology
Many properties of individual agents are dependent on the degree of lipophilicity. Lipophilicity significantly affects absorption, duration of action, route of metabolism, and distribution and penetration of biological membranes. Lipophilic β-blockers (such as propranolol, carvedilol, and metoprolol) are well absorbed, have shorter half-lives (in immediate-release form) and distribute widely, including readily crossing the blood–brain barrier. They use hepatic oxidative metabolism and are therefore vulnerable to drug–drug interactions. Hydrophilic β-blockers, sotalol and atenolol, are less completely absorbed, remain in the bloodstream longer, and do not cross the blood–brain barrier. These agents are mainly renally excreted, and thus require adequate kidney function.
Mechanism of Action
β-Blockers are functional inhibitors of the adrenergic receptors, and their receptor specificity determines clinical effects. Blockade of the β 1 -receptor alone is considered cardioselective, reducing heart rate, conduction, and contractility. Commonly used cardioselective agents include metoprolol and atenolol. Subsequent blockade of the β 2 -receptor by nonselective agents such as propranolol interferes with dilation of bronchioles and blood vessels and reduces lipolysis and glycogenolysis. Sotalol is a unique nonselective agent, possessing class III antiarrhythmic features. However, this activity results in an increased risk of cardiac arrhythmias (particularly involving QTc prolongation), and thus this agent is not suitable for use in dermatology. Finally, some nonselective β-blockers (labetalol, carvedilol) have additional activity against α-adrenergic receptors, resulting in vasodilation and further reducing blood pressure.
Clinical Use
Off-Label Dermatologic Uses
β-Blockers have been used for decades, primarily for antihypertensive, antiarrhythmic, and cardioprotective purposes, as well as for a variety of other conditions such as migraine prophylaxis, hyperthyroidism, glaucoma, and even anxiety.
Infantile Hemangiomas
Propranolol was first identified and reported as a successful therapy for the treatment of infantile hemangioma (IH) in 2008 in a small series of children receiving the drug for cardiac indications. Since then, multiple case reports and case series (combined totaling 150+ patients) have confirmed the success of the drug for treatment of complicated IH. Details concerning this new use of propranolol can be found in Chapter 70 .
Wound Healing
The finding of abundant β 2 -adrenergic receptors in keratinocytes and demonstration of local production of epinephrine in skin led to consideration of the role of adrenergic activation in wound healing. It has been demonstrated that the β-adrenergic agonists delay keratinocyte proliferation and migration in both in vitro and animal studies. Subsequently, the role of β-blockers has been examined with regard to acceleration of wound healing. Laboratory data suggest that β 2 -adrenergic blockade improves both keratinocyte migration speed and faster re-epithelialization, as well as improving skin barrier restoration in mouse models. In vivo, these findings have been applied to therapy in burn patients. A randomized controlled trial (RCT) of 79 burn patients by Mohammadi and associates demonstrated faster wound healing, smaller skin graft requirements, and shorter hospital stays in the propranolol-treated group compared with controls.
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