Pharmacology of Aesthetic Medicines

The realm of aesthetic medicine is broad, and there are countless medications and topical agents used in the practice of aesthetic medicine. The most commonly used injectable medicines include botulinum toxin for mimetic lines and hyaluronic acid fillers for deeper facial rhytids and volume rejuvenation. Topical aesthetic medicines are useful adjuncts for facial rejuvenation and commonly include tretinoin, hydroquinone, growth factors, and vitamin C, as well as a wide range of chemical peels

Key points

  • Botulinum toxin functions by paralyzing or weakening muscles of facial expression and thereby diminishing the appearance of mimetic lines.

  • Hyaluronic acid fillers have a wide variety of clinical applications in facial aesthetic medicine, and variation in filler density determines indication for location and depth of injection.

  • Chemical peels predictably rejuvenate the face and vary in depth of penetration from superficial to deep; chemoexfoliation coagulates proteins in the skin and induces regeneration of collagen and keratinocytes.

  • Topical aesthetic medicines are gaining popularity for treatment of acne, photodamage, fine rhytids, and dyschromia.

The realm of aesthetic medicine is broad, and there are now countless medications and topical agents used in the practice of aesthetic medicine. This chapter examines the most commonly used injectable and topical medications for aesthetic medicine.

Botulinum toxins

Since the 1990s botulinum toxins have been used in aesthetic medicine. Botulinum toxin is a neurotoxin produced by the bacteria Clostridium botulinum. Originally used for the medical purpose of treating blepharospasm, botulinum toxins are now approved by Food and Drug Administration (FDA) for a wide range of indications. The first use in aesthetic medicine was noted when treatment of blepharospasm resulted in the additional benefit of reducing crow’s feet lines produced by constriction of the vertical portion (lateral aspect) of the orbicularis oculi muscle. Interestingly, botulinum toxins were not approved to treat crow’s feet lines until 2013. In its first use as an aesthetic medicine, botulinus toxins were used to treat vertical glabellar lines and horizontal forehead rhytids.

Mimetic lines are produced by the contraction of facial muscles. Mimetic lines are commonly seen in the forehead, glabella, and lateral orbicularis (crow’s feet areas) but can also be identified in other facial subunits such as the lower face and midface ( Fig. 1 ). Mimetic lines are amenable to treatment with botulinum toxins because the mechanism of action of botulinum toxins is to paralyze or weaken muscles by inhibiting the release of acetylcholine from the neuromuscular junction ( Fig. 2 ).

Fig. 1
Facial musculature for neurotoxin injection sites.

Fig. 2
Mechanism of action of botulinum toxin.
( From Rowland LP. Stroke, spasticity, and botulinum toxin. N Engl J Med. 2002 Aug 8;347(6):382-3. doi: 10.1056/NEJMp020071; with permission.)

The botulinum toxin polypeptide chain has a heavy (H) chain and a light (L) chain linked by a disulfide bond. Intramuscular injection of botulinum toxins acts at the neuromuscular junction to cause muscle paralysis by inhibiting the release of acetylcholine from presynaptic motor neurons. The heavy (H) chain of the toxin is an irreversible binder to high-affinity receptors at the presynaptic surface of cholinergic neurons. The toxin-receptor complex is endocytosed into the cell, and the disulfide bond between the 2 chains is cleaved. The toxin is then released into the cytoplasm. The light (L) chain interacts with different proteins (SNAP 25, vesicle-associated membrane protein and syntaxin) in the nerve terminals and prevents fusion of acetylcholine vesicles with the cell membrane. , The peak of the effect occurs approximately 7 days after injection. Doses of all commercially available botulinum toxins are expressed in terms of units of biological activity. One unit of botulinum toxin corresponds to the calculated median intraperitoneal lethal dose (LD50) in female Swiss-Webster mice. The affected nerve terminals do not degenerate, but the blockage of neurotransmitter release is irreversible. Function is recovered by the sprouting of nerve terminals and formation of new synaptic contacts; this usually takes approximately 3 months.

Commercially Available Types of Neurotoxins for Aesthetic Use

There are now on the market several brands of neurotoxins using different formulations of botulinum toxin. Several are FDA approved for nonaesthetic uses (eg, Myobloc), whereas others (Botox, Dysport, Xeomin, Jeuveau) are FDA approved for use to treat mimetic rhytids.

Botox (onabotulinum A)

Botox (Allergan) is the most commonly used neurotoxin for treatment of facial mimetic rhytids. Botox is FDA approved for glabellar, forehead, and lateral canthal (“crow’s feet”) lines. Botox cosmetic is packaged in vials of 50U and 100U of lyophilized white powder with human albumin. It is freezer packaged for delivery and is reconstituted with sterile preservative-free 0.9% sodium chloride. Once reconstituted, package safety instructions direct that the Botox should be used or discarded after 24 hours and kept refrigerated when not in use.

Dysport (abobotulinum A)

Dysport (Galderma) is a commonly used botulinum neurotoxin in aesthetic medicine and for these purposes is FDA approved for treatment of glabellar lines. Dysport is also packaged as a lyophilized white powder with human albumin, bovine protein, and lactose. Unlike Botox, Dysport comes in vials of 300U and 500U. Per package insert, Dysport is reconstituted with 0.6 mL to 5 mL of preservative-free saline. The reconstituted product is stored in the refrigerator and should be discarded after one use or after 24 hours (whichever is first). Studies have demonstrated 2.5U to 3U of Dysport is approximately equivalent in potency and efficacy to 1U of Botox.

Jeuveau (prabotulinum toxin A)

Jeuveau (Evolus) is a newer formulation of botulinum toxin An FDA approved for treatment of glabellar lines. Jeuveau is supplied as a vacuum-dried vial of 100U of toxin. It is reconstituted with preservative-free 0.9% saline and can be kept refrigerated up to 24 hours.

Xeomin (incobotulinum toxin A)

Xeomin (Merz) botulinum toxin complex is purified from the culture supernatant and then the active neurotoxin is separated from the proteins (hemagglutinins and nonhemagglutinins) through a series of steps yielding the active neurotoxin with molecular weight of 150 kDa, without accessory proteins in 50U, 100U, and 200U vials. Xeomin is packaged as a sterile white to off-white lyophilized powder that is unrefrigerated. It is reconstituted with preservative-free 0.9% sodium chloride injection and requires refrigeration up to 24 hours after reconstitution.

Current Practical Use of Neurotoxins

Although individual neurotoxins are approved for specific areas and indications, all formulations listed earlier are widely used throughout the upper face, lower face, and neck for aesthetic purposes. Off-label uses range from “bunny lines,” “gummy smile,” masseter reduction, and treatment of platysmal bands. Neurotoxin may be used at all regions illustrated in Fig.1 , as well as in additional areas such as platysma, temporalis, and labii inferioris. Xeomin does not require refrigeration before reconstitution, which makes it easier to store. Recommended dosing for neurotoxins is also at the discretion of the surgeon/physician, and in this author’s (E. F.) experience, manufacturer recommends dosing guides far exceed necessary doses to achieve the desired effect. Following manufacturer dosing guidelines particularly in the frontalis can predispose to unwanted effects, such as brow ptosis. Initial treatment dosing should start at half to one-third recommended dosing and increase as necessary at the 3-month follow-up appointment to achieve the desired result. Reconstitution recommendations on package inserts are routinely modified by practitioners to produce more concentrated solutions. For example, this author routinely uses a 0.9% saline with preservative as diluent and reconstitutes Botox to 1U/0.01 mL diluent, and Dysport to 3U/0.01 mL diluent. This reconstitution method reduces injection site spread and diminishes the risk of dispersion to unwanted regions. Finally, although package inserts indicate products should be discarded 24 hours after reconstitution, most practitioners will use reconstituted neurotoxins for up to a week when properly refrigerated.

Contraindications to Neurotoxin Use for Aesthetic Purposes

Contraindications to neurotoxin treatment of cosmetic purposes are active infection in the area (pustules, active acne), allergy to neurotoxin or its reconstitution constituents (eg, cow’s milk allergy for Dysport injections), or known neuromuscular disorders such as amyotrophic lateral sclerosis, Lambert-Eaton syndrome, and other myopathies. Relative contraindications include pregnancy and breastfeeding, history of keloid formation, unrealistic expectations, immunocompromised state, or body dysmorphic disorder.

Adverse Effect of Neurotoxin Treatment

There are few complications associated with the cosmetic use of neurotoxins, and most adverse reactions are mild and temporary. Most common adverse event is bruising at the injection site. Other complications include postinjection headache. Most adverse reactions to neurotoxins are secondary to poor injection technique or inadequately understanding the associated anatomy. Neurotoxin may disperse up to 3 cm from the injection site depending on the dilution. Higher concentrations of neurotoxin (less diluent) can help prevent spread after injection. This author routinely uses a concentration of 1U/0.01 mL preservative containing 0.9% normal saline. Avoidance of additional swelling in the area is helpful to minimize this dispersion; for example, laser treatment should be avoided in the same week as neurotoxin injection. Injection site reactions such a pain, bruising, and erythema are mitigated by using proper injection technique including smaller gauge needles and avoidance of touch the periosteum during injection. This author uses 31-gauge needles with 8 mm length for injection. In addition, using a normal saline diluent with preservative has been demonstrated to reduce pain on injection. Incidence of severe headache following neurotoxin injection is approximately 1%, and resolution is typically within 24 hours, with complete resolution in all patient by 2 to 4 weeks.

Several adverse effects are the result of poor injection technique of various muscle groups. For example, in the treatment of glabellar lines and corrugators, diffusion of neurotoxin into the levator palpebrae muscle causes true eyelid ptosis. Although this is self-limiting, it is very disconcerting for patients who experience this complication because it is aesthetically unpleasing, limits the superior visual field, and also makes it difficult to apply eye makeup. This complication is generally avoidable by keeping injection into the corrugator muscles superficial. Brow ptosis is also a common adverse outcome of neurotoxin injection. Because the frontalis elevates the brows, injection into this muscle group is expected to result in some limitations of brow elevation. Patient with significant horizontal forehead rhytids often has standing static elevation of the brows and activation of the frontalis. The inclination to injecting more neurotoxin in patients with deep horizontal rhytids should be tempered by the understanding that this may cause significant brow ptosis in these patients. Additional techniques to limit brow ptosis in addition to limiting total frontalis dose of neurotoxin is avoiding injection within 1.5 cm of the orbital rim. Injection of brow depressors (corrugators, procerus, lateral orbicularis oculi) will help decrease the risk of brow ptosis. A final potential complication of administration of neurotoxin to the forehead is inadequate weakening of the lateral portion of the frontalis, leading to a lateral arching (“peaking”) of the brow ( Fig. 3 ). Injecting a small amount of neurotoxin (eg, 1–2U Botox) into the lateral frontalis should reduce this effect.

Fig. 3
Complications of neurotoxins. ( A ) Eyelid ptosis. Treat with 0.5% apraclonidine drops, 1 to 2 drops tid. ( B ) Brow ptosis. Add 1 to 3 units of neurotoxin above superiorly placed lateral brow to decrease activity of the vertical fibers of the orbicularis oculi, which depresses the lateral brow.

Complications resulting from injection into the lower face are more common because uses here are off label. There is also more variation in soft tissue anatomy in the lower face requiring more expertise in anatomic understanding of muscle function in this area. Common treatments such as neurotoxin injection into the orbicularis oris (“lip flip”) and treatment of gummy smile or nasal “bunny lines” produced by alaeque nasi muscles can result in upper lip incompetence and difficulty using straws. Similarly, injection to depressor anguli oris for improvement in commissure position can result in inadvertent injection of the depressor labii muscles, resulting in asymmetry and lower lip malfunction. Treatment of neck platysmal banding should be executed with minimal dosing (8–12U Botox or equivalent per band), and injection should be superficial to avoid injection of the sternocleidomastoid or diffusion to the laryngeal muscles.

Hyaluronic acid fillers

Injectable fillers have a wide range of applications in aesthetic medicine. They can be injected in the superficial to middle dermis for fine rhytids, in the middle to deep dermis for moderate to severe volume loss, in the submucosal plane for lip volumization and in a subcutaneous, supraperiosteal, or subperiosteal plane for cheek or jawline augmentation. , Hyaluronic acid (HA) is by far the most common filler material used for injectable facial rejuvenation, consisting of about 80% of the soft tissue fillers administered in 2019. HA fillers volumize the face by occupying space as well as inducing the synthesis of collagen. There are many brands and formulations of HA fillers approved by the FDA in the United States, but the most commonly used brands in clinical practice are Juvéderm, Restylane, and Belotero.

HA is native to all mammalian species in the extracellular matrix of the dermis. It is abundantly present in human skin and aids in soft tissue resilience and lubrication. The amount of HA present in human tissue decreases with age, leading to reduced dermal hydration and increased skin folding: common signs of aging. HA is a biodegradable glycosaminoglycan molecule that functions by binding to water molecules. Dermal fillers are made of HA modified to have specific physicochemical properties related to their tissue stability, viscosity, and elasticity. This allows the clinician to choose the most appropriate filler for a given indication. Cross-linking of the HA molecules gives mechanical strength to the gel and improves product longevity by deterring degradation. , , The elastic modulus (or G′) is primarily used to characterize filler products based on multiple factors that affect gel strength, such as HA concentration and degree of cross-linking. A higher G′ value is associated with better ability for a substance to rebound to its original shape when acted on by a dynamic force; in the world of dermal fillers, a higher G′ correlates to a firmer gel. A lower G′ value may be more appropriate for a patient with thinner skin or for performing more superficial injections. Fillers such as Juvéderm Volbella that are cross-linked and fragmented into smaller pieces are used for superficial facial planes, whereas fillers such as Restylane Lyft and Juvéderm Voluma with larger fragments are used in deeper planes. ,

Once injected, HA is slowly degraded by naturally occurring hyaluronidase and free radicals in the skin. Factors that influence how quickly the modified HA in filler dissolves include particle size, HA concentration, type of cross-linking agent, and G′ value. Each brand and type of HA filler boasts their own estimation of duration, but typically HA fillers are quoted to last around 12 to 24 months. A key advantage of HA fillers as opposed to non-HA fillers is the ability to reverse the effects with injectable hyaluronidase if complications or overtreatment occurs.

Technique for Injection

Each filler is packaged in a sterile syringe with 2 Luer-lock needles of appropriate dimension for the filler. Lower G′ filler can be delivered through smaller gauge needles, whereas high G′ filler must be injected through larger bore needles. The use of cannulas for injection is highly popular and is associated with lower incidence of bruising and intravascular injections ( Fig. 4 ). Injection sites should be cleaned thoroughly before injection with chlorhexidine or other preparation. Once the needle or canula is in the desired location for filler placement, the injector should create mild negative pressure by aspiration on the syringe for verification that the placement is not intravascular. Injection of filler material should be slow and not exceed 0.1 mL per site before reaspiration and injection.

Aug 14, 2022 | Posted by in Oral and Maxillofacial Surgery | Comments Off on Pharmacology of Aesthetic Medicines
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