Sublingual (
abbreviated
An abbreviation (from Latin ''brevis'', meaning ''short'') is a shortened form of a word or phrase, by any method. It may consist of a group of letters or words taken from the full version of the word or phrase; for example, the word ''abbrevia ...
SL), from the
Latin
Latin (, or , ) is a classical language belonging to the Italic branch of the Indo-European languages. Latin was originally a dialect spoken in the lower Tiber area (then known as Latium) around present-day Rome, but through the power of the ...
for "under the
tongue
The tongue is a muscular organ (anatomy), organ in the mouth of a typical tetrapod. It manipulates food for mastication and swallowing as part of the digestive system, digestive process, and is the primary organ of taste. The tongue's upper surfa ...
", refers to the
pharmacological
Pharmacology is a branch of medicine, biology and pharmaceutical sciences concerned with drug or medication action, where a drug may be defined as any artificial, natural, or endogenous (from within the body) molecule which exerts a biochemica ...
route of administration
A route of administration in pharmacology and toxicology is the way by which a medication, drug, fluid, poison, or other substance is taken into the body.
Routes of administration are generally classified by the location at which the substance i ...
by which substances diffuse into the
blood
Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the c ...
through
tissues under the tongue.
The
sublingual gland
The paired sublingual glands are major salivary glands in the mouth. They are the smallest, most diffuse, and the only unencapsulated major salivary glands. They provide only 3-5% of the total salivary volume. There are also two other types of sal ...
s receive their primary blood supply from the sublingual and submental arteries, which are branches of the
lingual artery
The lingual artery arises from the external carotid artery between the superior thyroid artery and facial artery. It can be located easily in the tongue.
Structure
The lingual artery first branches off from the external carotid artery. It runs ob ...
and
facial artery
The facial artery (external maxillary artery in older texts) is a branch of the external carotid artery that supplies structures of the superficial face.
Structure
The facial artery arises in the carotid triangle from the external carotid arte ...
, respectively. These arteries are both branches of the
external carotid artery
The external carotid artery is a major artery of the head and neck. It arises from the common carotid artery when it splits into the external and internal carotid artery. External carotid artery supplies blood to the face and neck.
Structure
T ...
. The
sublingual vein
The sublingual vein is a vein which drains the tongue
The tongue is a muscular organ in the mouth of a typical tetrapod. It manipulates food for mastication and swallowing as part of the digestive process, and is the primary organ of taste. T ...
drains into the
lingual vein
The lingual veins begin on the dorsum, sides, and under surface of the tongue, and, passing backward along the course of the lingual artery, end in the internal jugular vein.
The vena comitans of the hypoglossal nerve (ranine vein), a branch of co ...
, which then flows into the
internal jugular system
Internal may refer to:
*Internality as a concept in behavioural economics
*Neijia, internal styles of Chinese martial arts
*Neigong or "internal skills", a type of exercise in meditation associated with Daoism
*''Internal (album)'' by Safia (band), ...
.
The sublingual glands receive their parasympathetic input via the
chorda tympani
The chorda tympani is a branch of the facial nerve that originates from the taste buds in the front of the tongue, runs through the middle ear, and carries taste messages to the brain. It joins the facial nerve (cranial nerve VII) inside the facia ...
nerve, which is a branch of the
facial nerve
The facial nerve, also known as the seventh cranial nerve, cranial nerve VII, or simply CN VII, is a cranial nerve that emerges from the pons of the brainstem, controls the muscles of facial expression, and functions in the conveyance of tas ...
via the
submandibular ganglion
The submandibular ganglion (or submaxillary ganglion in older texts) is part of the human autonomic nervous system. It is one of four parasympathetic ganglia of the head and neck. (The others are the otic ganglion, pterygopalatine ganglion, and cil ...
. The nerve functions in a
secretomotor
The adjective secretomotor refers to the capacity of a structure (often a nerve) to induce a gland to secrete a substance (usually mucus or serous fluid).
Secretomotor nerve endings are frequently contrasted with sensory neuron endings and motor n ...
capacity. The chorda tympani branches from the motor branch of the facial nerve in the
middle ear cavity
Middle or The Middle may refer to:
* Centre (geometry), the point equally distant from the outer limits.
Places
* Middle (sheading), a subdivision of the Isle of Man
* Middle Bay (disambiguation)
* Middle Brook (disambiguation)
* Middle Creek ( ...
, which then exits the middle ear through the
petrotympanic fissure
The petrotympanic fissure (also known as the squamotympanic fissure or the glaserian fissure) is a fissure in the temporal bone that runs from the temporomandibular joint to the tympanic cavity.
The mandibular fossa is bounded, in front, by the a ...
. The chorda tympani then travels with the
lingual nerve
The lingual nerve carries sensory innervation from the anterior two-thirds of the tongue. It contains fibres from both the mandibular division of the trigeminal nerve (CN V3
) and from the facial nerve (CN VII). The fibres from the trigeminal nerve ...
to synapse at the submandibular ganglion. The
postganglionic fiber
In the autonomic nervous system, fibers from the ganglion to the effector organ are called postganglionic fibers.
Neurotransmitters
The neurotransmitters of postganglionic fibers differ:
* In the parasympathetic division, neurons are ''choli ...
s reach the sublingual gland, and release
acetylcholine
Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
and
substance P
Substance P (SP) is an undecapeptide (a peptide composed of a chain of 11 amino acid residues) and a member of the tachykinin neuropeptide family. It is a neuropeptide, acting as a neurotransmitter and as a neuromodulator. Substance P and its clos ...
. Acetylcholine, the primary neurotransmitter and the
muscarinic receptor
Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-rec ...
s work to increase
salivation
Saliva (commonly referred to as spit) is an extracellular fluid produced and secreted by salivary glands in the mouth. In humans, saliva is around 99% water, plus electrolytes, mucus, white blood cells, epithelial cells (from which DNA can be e ...
.
Many drugs are absorbed through sublingual administration, including
cardiovascular
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
drugs,
steroid
A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...
s,
barbiturate
Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as we ...
s, benzodiazepines,
opioid
Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid us ...
analgesics
An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It i ...
,
THC
Tetrahydrocannabinol (THC) is the principal psychoactive constituent of cannabis and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C21H30O2) describes multiple isomers, the term ''THC'' ...
,
CBD, some
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s and increasingly,
vitamin
A vitamin is an organic molecule (or a set of molecules closely related chemically, i.e. vitamers) that is an Nutrient#Essential nutrients, essential micronutrient that an organism needs in small quantities for the proper functioning of its ...
s and
minerals
In geology and mineralogy, a mineral or mineral species is, broadly speaking, a solid chemical compound with a fairly well-defined chemical composition and a specific crystal structure that occurs naturally in pure form.John P. Rafferty, ed. (2 ...
.
Principle
When a chemical comes in contact with the
mucous membrane
A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It is ...
beneath the tongue, it is absorbed. Because the
connective tissue
Connective tissue is one of the four primary types of animal tissue, along with epithelial tissue, muscle tissue, and nervous tissue. It develops from the mesenchyme derived from the mesoderm the middle embryonic germ layer. Connective tiss ...
beneath the epithelium contains a profusion of capillaries, the substance then diffuses into them and enters the venous circulation.
In contrast, substances absorbed in the intestines are subject to
first-pass metabolism
The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the systemi ...
in the liver before entering the general circulation.
Sublingual administration has certain advantages over oral administration. Being more direct, it is often faster, and it ensures that the substance will risk degradation only by salivary enzymes before entering the bloodstream, whereas orally administered drugs must survive passage through the hostile environment of the
gastrointestinal tract
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organ (biology), organs of the digestive syste ...
, which risks degrading them, by either stomach acid or bile, or by
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s such as
monoamine oxidase
Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The first ...
(MAO). Furthermore, after absorption from the gastrointestinal tract, such drugs must pass to the
liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
, where they may be extensively altered; this is known as the
first pass effect
The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the systemi ...
of drug metabolism. Due to the digestive activity of the stomach and intestines, the oral route is unsuitable for certain substances, such as
salvinorin A
Salvinorin A is the main active psychotropic molecule in '' Salvia divinorum''. Salvinorin A is considered a dissociative hallucinogen.
It is structurally distinct from other naturally occurring hallucinogens (such as DMT, psilocybin, and ...
.
Forms
Pharmaceutical preparations for sublingual administration are manufactured in the form of:
* Sublingual tablets—tablets which easily melt in the mouth, dissolve rapidly and with little or no residue. Nitroglycerine tablets are an example, the anti-emetic
ondansetron
Ondansetron, sold under the brand name Zofran among others, is a medication used to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy, or surgery. It is also effective for treating gastroenteritis. It can be given by ...
is another.
* Sublingual strips—similar to tablets in that they easily melt in the mouth and dissolve rapidly.
Suboxone
Buprenorphine/naloxone, sold under the brand name Suboxone among others, is a fixed-dose combination medication that includes buprenorphine and naloxone. It is used to treat opioid use disorder, and reduces the mortality of opioid use disorder ...
is an example of medication that comes in a sublingual strip.
* Multi-purpose tablets—Soluble tablets for either oral or sublingual (or
buccal) administration, often also suitable for preparation of injections, Hydrostat (
hydromorphone
Hydromorphone, also known as dihydromorphinone, and sold under the brand name Dilaudid among others, is an opioid used to treat moderate to severe pain. Typically, long-term use is only recommended for pain due to cancer. It may be used by mou ...
) and a number of brands of morphine tablets and cubes.
* Sublingual drops—a concentrated solution to be dropped under the tongue, as with some nicocodeine cough preparations,
* Sublingual spray—spray for the tongue; certain human and veterinary drugs are dispensed as such.
*
Lozenge
Lozenge or losange may refer to:
* Lozenge (shape), a type of rhombus
*Throat lozenge, a tablet intended to be dissolved slowly in the mouth to suppress throat ailments
*Lozenge (heraldry), a diamond-shaped object that can be placed on the field of ...
—effects a metred and patient-controlled-rate combination of sublingual, buccal, and oral administration, as with the Actiq
fentanyl
Fentanyl, also spelled fentanil, is a very potent synthetic opioid used as a pain medication. Together with other drugs, fentanyl is used for anesthesia. It is also used illicitly as a recreational drug, sometimes mixed with heroin, cocaine ...
.
* Effervescent buccal or sublingual tablets—this method drives the drug through the mucous membranes much faster (this is the case in the stomach with carbonated or effervescent liquids as well) and is used in the Fentora fentanyl buccal tablet.
Substance
Almost any form of substance may be amenable to sublingual administration if it dissolves easily in saliva. Powders and aerosols may all take advantage of this method. However, a number of factors, such as
pH,
molecular weight
A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...
, and
lipid solubility
Lipophilicity (from Greek language, Greek λίπος "fat" and :wikt:φίλος, φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-pol ...
, may determine whether the route is practical. Based on these properties, a suitably soluble drug may diffuse too slowly through the mucosa to be effective. However, many drugs are much more potent taken sublingually, and it is generally a safer alternative than administration via the nasal mucosa. This method is also extensively used by people administering certain psychoactive drugs. One drawback, however, is
tooth discoloration
Tooth discoloration is abnormal tooth color, hue or translucency. External discoloration is accumulation of stains on the tooth surface. Internal discoloration is due to absorption of pigment particles into tooth structure. Sometimes there are sev ...
and decay caused by long-term use of this method with acidic or otherwise caustic drugs and fillers.
Psychoactives
In addition to
salvinorin A
Salvinorin A is the main active psychotropic molecule in '' Salvia divinorum''. Salvinorin A is considered a dissociative hallucinogen.
It is structurally distinct from other naturally occurring hallucinogens (such as DMT, psilocybin, and ...
, other psychoactives may also be applied sublingually.
LSD
Lysergic acid diethylamide (LSD), also known colloquially as acid, is a potent psychedelic drug. Effects typically include intensified thoughts, emotions, and sensory perception. At sufficiently high dosages LSD manifests primarily mental, vi ...
,
MDMA
3,4-Methylenedioxymethamphetamine (MDMA), commonly seen in Tablet (pharmacy), tablet form (ecstasy) and crystal form (molly or mandy), is a potent empathogen–entactogen with stimulant properties primarily used for Recreational dru ...
,
morphine
Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies (''Papaver somniferum''). It is mainly used as a analgesic, pain medication, and is also commonly used recreational drug, recreationally, or to make ...
,
alprazolam
Alprazolam, sold under the brand name Xanax, among others, is a fast-acting, potent tranquilizer of medium duration in the triazolobenzodiazepine (TBZD) class, which are benzodiazepines (BZDs) fused with a triazole ring. It is most commonly u ...
,
clonazepam
Clonazepam, sold under the brand names Klonopin and Rivotril, is a medication used to prevent and treat seizures, panic disorder, anxiety disorders, and the movement disorder known as akathisia. It is a tranquilizer of the benzodiazepine clas ...
,
diazepam
Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, a ...
, and many other substances including the psychedelic
tryptamine
Tryptamine is an indolamine metabolite of the essential amino acid, tryptophan. The chemical structure is defined by an indole ─ a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon (third aromatic atom, with the f ...
s and
phenethylamine
Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amin ...
s, and even recreational
cannabis edibles
A cannabis edible, also known as a cannabis-infused food or simply an edible, is a food product (either homemade or produced commercially) that contains decarboxylated cannabinoids (cannabinoid acids converted to their orally bioactive form) f ...
(
THC
Tetrahydrocannabinol (THC) is the principal psychoactive constituent of cannabis and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C21H30O2) describes multiple isomers, the term ''THC'' ...
) are all viable candidates for administration via this route. Most often, the drug in question is powdered and placed in the mouth (often directly under the tongue). If held there long enough, the drug will diffuse into the blood stream, bypassing the GI tract. This may be a preferred method to simple oral administration, because MAO is known to oxidize many drugs (especially the tryptamines such as
DMT
''N'',''N''-Dimethyltryptamine (DMT or ''N'',''N''-DMT, SPL026) is a substituted tryptamine that occurs in many plants and animals, including human beings, and which is both a derivative and a structural analog of tryptamine. It is used as a ...
) and because this route translates the chemical directly to the brain, where most psychoactives act. The method is limited by excessive salivation washing the chemical down the throat. Also, many alkaloids have an unpleasant taste which makes them difficult to hold in the mouth. Tablets of psychoactive pharmaceuticals usually include bitter chemicals such as
denatonium
Denatonium, usually available as denatonium benzoate (under trade names such as Denatrol, BITTERANT-b, BITTER+PLUS, ''Bitrex'', and ''Aversion'') and as denatonium saccharide (BITTERANT-s), is the most bitter chemical compound known, with bitternes ...
in order to discourage abuse and also to discourage children from eating them.
Allergens
Allergen
An allergen is a type of antigen that produces an abnormally vigorous immune response in which the immune system fights off a perceived threat that would otherwise be harmless to the body. Such reactions are called allergies.
In technical terms ...
s may also be applied under the tongue as a part of
allergen immunotherapy
Allergen immunotherapy, also known as desensitization or hypo-sensitization, is a medical treatment for environmental allergies, such as insect bites, and asthma. Immunotherapy involves exposing people to larger and larger amounts of allergen in ...
.
Therapeutic peptides and proteins
A relatively new way of administration of therapeutic
peptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
A ...
s and proteins (such as
cytokines
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
, domain
antibodies
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
,
Fab fragment
The fragment antigen-binding region (Fab region) is a region on an antibody that binds to antigens. It is composed of one constant and one variable domain of each of the heavy and the light chain. The variable domain contains the paratope (the ant ...
s or single chain antibodies) is sublingual administration. Peptides and proteins are not stable in the
gastro-intestinal tract
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans ...
, mainly due to degradation by enzymes and pH differences. As a consequence, most peptides (such as
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
,
exenatide
Exenatide, sold under the brand name Byetta and Bydureon among others, is a medication used to treat diabetes mellitus type 2. It is used together with diet, exercise, and potentially other antidiabetic medication. It is a treatment option after ...
,
vasopressin
Human vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the AVP gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It then travel ...
, etc.) or proteins (such as
interferon
Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten the ...
,
EPO and
interleukins
Interleukins (ILs) are a group of cytokines (secreted proteins and signal molecules) that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and relate ...
) have to be administered by injection. Recently, new technologies have allowed sublingual administration of such molecules. Increased efforts are underway to deliver macromolecules (peptides, proteins and immunotherapies) by sublingual route, by companies such as
Novo Nordisk
Novo Nordisk A/S is a Danish multinational pharmaceutical company headquartered in Bagsværd, Denmark, with production facilities in nine countries, and affiliates or offices in five countries. Novo Nordisk is controlled by majority shareholder ...
,
Sanofi
Sanofi S.A. is a French multinational pharmaceutical and healthcare company headquartered in Paris, France. Originally, the corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 2004, Sanofi-Syn ...
and BioLingus.
Sublingual delivery may be particularly effective for immuno-active medicines, due to the presence of immune-receptor cells close to the sublingual area.
Vaccines
The sublingual route may also be used for
vaccine
A vaccine is a biological Dosage form, preparation that provides active acquired immunity to a particular infectious disease, infectious or cancer, malignant disease. The safety and effectiveness of vaccines has been widely studied and verifie ...
s against various infectious diseases. Thus, preclinical studies have found that sublingual vaccines can be highly immunogenic and may protect against influenza virus
and ''Helicobacter pylori'',
but sublingual administration may also be used for vaccines against other infectious diseases.
Footnotes
External links
*
{{Dosage forms, state=expanded
Routes of administration