Which of the following administration routes for nitroglycerin is the most common?

Sedatives

Several studies have reported on the use of the SL route for preoperative sedation. Two have compared the SL administration of a benzodiazepine with oral administration. Gram-Hansen and Schultz,21 administering 2.5 mg lorazepam either orally or sublingually before gynecologic surgery, found a maximal plasma concentration at 40 minutes orally and 60 minutes after SL administration. Garzone and Kroboth,22 looking at alprazolam and triazolam, found peak concentrations that occurred earlier and were higher following SL versus oral administration. SL lormetazepam (2.5 mg) followed in 35 minutes by intravenous (IV) diazepam (10 mg) was compared with SL placebo followed in 35 minutes by IV diazepam (10 mg) in patients undergoing surgical removal of impacted third molars.23 A rapid onset of sedation was noted after SL lormetazepam administration, whereas the course and duration of postoperative sedation, measured using standard psychometric tests, were similar following both treatments. Surgeons’ ratings indicated that SL lormetazepam was comparable with IV diazepam, but patients’ ratings indicated greater satisfaction with and preference for IV diazepam. Significant anterograde amnesia was found following both treatments. The authors indicate that SL lormetazepam may have a role in anesthesia as a premedicant and for minimal or moderate sedation.

Nitrates

Glyceryl trinitrate (or nitroglycerin) undergoes extensive hepatic presystemic metabolism when given orally, and is therefore usually given by the sublingual route, by which it is well absorbed and rapidly taken up into the circulation. Buccal administration has a similar effect, and this route is used for more prolonged action over a few hours. When given intravenously, there is drug breakdown by the cells of the vascular endothelium. Nitroglycerin is broken down (bioactivated) to 1,2 glyceryl nitrate and NO by hepatic mitochondrial aldehyde dehydrogenase. Tolerance develops over time as the enzyme is depleted by continuous exposure.

Isosorbide dinitrate (ISDN) is absorbed in the gut and extensively metabolized to active metabolites especially the mononitrate ISMN, which also shows good oral absorption but, in contrast to ISDN, has low presystemic metabolism. The half-lives of these nitrates are a few minutes for nitroglycerin, 1 hour for ISDN, and 4 hours for ISMN. Protein binding differs for the three agents (ISMN < 5%, for ISDN 30%, and nitroglycerin 60%). There are also differences in their volumes of distribution (ISMN 3 L/kg; ISDN 1-8 L/kg; nitroglycerin 0.7 L/kg).

Sodium nitroprusside is effective within 30 to 40 seconds of infusion, and offset is similarly rapid. It is broken down in the liver to cyanide and thiocyanate; together with the parent drug, both are excreted in the urine. Dose reduction is indicated for all nitrates in patients with renal or hepatic disease. There may be tolerance to vasodilatory effects of nitrates with prolonged dosing especially when given transdermally. The safe doses of nitroprusside are less than 1.5 µg/kg/min during hypotensive anesthesia and up to 8 µg/kg/min to treat hypertensive crises.

3.1.1 Sublingual delivery

In sublingual delivery, the drug is delivered along the floor of the mouth through the mucosal membrane linings (Ahuja et al., 1997). The sublingual route is the most studied one because it is relatively more permeable and leads to rapid absorption of drugs with high acceptability (Şenel et al., 2012). The formulation of sublingual drugs uses two different designs: one in tablet form and the other in capsule. The tablets are designed in such way that they rapidly disintegrate (Bredenberg et al., 2003) and the capsules generally consist of soft gelatin, which encapsulates liquid drug (Hejazi and Amiji, 2003).

Sublingual and oral

Medications that are administered sublingually dissolve under the tongue, without chewing or swallowing. Absorption is very quick, and higher drug levels are achieved in the bloodstream by sublingual routes than by oral routes because (1) the sublingual route avoids first-pass metabolism by the liver (Fig. 1-2), and (2) the drug avoids destruction by gastric juices or complexation with foods. Remember that drugs absorbed from the gut travel first to the liver via the portal vein. Drugs absorbed through the intestine may, thus, reach systemic circulation at a concentration significantly below the initial dose. The keys to understanding drug absorption are highlighted in Box 1-3.

Ideally, for a drug to be delivered sublingually, the drug should dissolve rapidly, produce desired therapeutic effects with small amounts of drug, and be tasteless. Examples of commonly prescribed sublingual tablets include nitroglycerin, loratadine, mirtazapine, and rizatriptan (Table 1-2).

Some diseases alter rates of drug absorption. For example if gastrointestinal motility is dramatically increased, as in inflammatory bowel diseases (Crohn disease, ulcerative colitis) or malabsorptive syndromes (celiac sprue), absorption of some drugs may be reduced (Table 1-3). On the other hand, absorption of other drugs may be increased in patients with these inflammatory gut disorders, because gastrointestinal membranes often do not remain intact as a consequence of these autoimmune diseases. Alternatively, consider situations in which gastrointestinal motility is slowed (i.e., diabetic gastroparesis). Here, drug absorption could be enhanced as a result of prolonged contact time with the absorptive areas of the intestine. Likewise, there are drugs that alter the rate of absorption for other orally administered medications (Table 1-4).

Food can also affect absorption of drugs by either increasing, decreasing, or delaying the rate at which absorption occurs (Table 1-5). As a generalization, food tends to slow the rate of gastric emptying. This results in slower absorption of many drugs. For this reason, drugs are often administered on an empty stomach—to increase absorption. However, if drugs are irritating to the gastrointestinal tract, a light, nonfatty meal may be recommended. There are other reasons to consider giving drugs with or without food. For example, penicillin V should be administered on an empty stomach (1 hour before meals or 2 to 3 hours after meals) because it is unstable in gastric acids. On the other hand, metoprolol and propranolol (β-blockers) should be taken with meals because food enhances their bioavailability. Although the oral route of administration is the most common, there are a few instances in which the oral route of administration should not be used (Box 1-4).

Mucosal Versus Parenteral Vaccination

Traditional injected vaccines primarily induce systemic immune responses and are generally poor in inducing mucosal immunity. In contrast, mucosal vaccines, administered via oral, nasal, or sublingual routes, generally give rise to both mucosal and systemic immune responses.12 The mucosal response is anatomically compartmentalized reflecting the migratory properties of lymphocytes activated at different mucosal inductive sites, thus imposing distinct constraints on the choice of mucosal route for vaccine administration.13 In general, the strongest immune response is obtained at the site of vaccine application and next after that in anatomically adjacent or evolutionarily linked sites. An example of the latter is the intestine–mammary gland link in lactating women which ensures that the breastfeeding baby receives epidemiologically relevant breast milk SIgA antibodies from the mother, which result from the current microbial exposure in the mother's intestine.

While vaccination via the oral route has potential to prevent clinical illness by all enteric pathogens, parenteral vaccination may work against those enteric infections in which the pathogen is first translocated across the intestinal epithelium. An example is shigellosis (bacillary dysentery) in which translocated Shigella infect other enterocytes from the basolateral side. At this point the organisms can readily be attacked by serum-derived antibodies in concert with complement and phagocytic neutrophils. Likewise, serum antibodies can effectively attack pathogens that cause disease by inducing inflammation in the submucosal lymphoid tissues (e.g., NTS serovars and Campylobacter jejuni) or after entering the bloodstream (such as S. Typhi or S. Paratyphi).14 Previous exposure to the pathogen leading to mucosal immunological priming also increases the ability of parenteral vaccination to protect against mucosal infections. A general rule seems to be that parenteral vaccines may provide some degree of boosting in already primed individuals, but they are unable to induce an effective mucosal response in individuals who have not been primed by previous mucosal exposure to the pathogen or by oral vaccination.12 As described below, ongoing efforts to develop vaccines against ETEC are mainly focused on oral administration, while both oral and parenteral vaccination is considered for Shigella, Campylobacter, STEC, and NTS.

Oral mucosa irritation studies

Oral irritation studies are used in the testing of products for use in the oral cavity, mainly for surgical, dental and hygiene purposes but also therapeutic agents administered by the sublingual route. This route may be selected for substances that are broken down in the stomach or show a rapid first pass effect. As it is technically not feasible to perform full preclinical toxicity studies by the sublingual route, conventional oral or parenteral routes are preferred for systemic toxicity studies on such compounds. The choice of the best route will to a large extent be dictated by pharmacokinetic considerations. However, it is usually deemed necessary to assess local irritancy potential to oral mucosa using a laboratory animal model.

Test species for oral irritation studies are usually rats, hamsters (cheek pouch), guinea pigs, dogs or primates using gross and histopathological assessment. A similar scheme to that employed in the histological assessment of skin irritancy is appropriate.

13.4.1.1 Transmucosal tablet

A tablet is usually for delivery of systemic metabolizable drugs or organic-based drugs, such as progesterone, and peptide-based drugs, such as insulin, via transmucosal route (sublingual and buccal mucosa) to improve the bioavailability of drugs. The transmucosal tablets are mainly designed for various reasons including immediate drug release or quick action for local diseases, pulsatile drug release to maintain the therapeutic activity, controlled drug release. The transport routes involved in absorption are transcellular and paracellular as depicted in Fig. 13.5.

To absorb drug from the transmucosal route, important characteristics are required, which include short disintegration, dissolution, prolonged contact time, and other properties such as small particle size or high solubility of the drug. To achieve prolonged contact time, ordered mixture technique is mostly applied. Ordered mixture is a mixing of drug particle with a carrier such as an adhesive polymer [gelatin, sodium alginate, polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), etc.]. The limitation with transmucosal delivery is limited surface area for absorption, that is, 170 cm2 from which 50 cm2 is nonkeratinized tissues and barriers such as saliva, mucous membrane–coating granules, that is, basement membranes, which retard the absorption (Darwish et al., 2007).

20.2.12 Blood Supply – Sublingual

The sublingual mucosa is the membrane of the ventral surface of the tongue. Sublingual administration of drug refers to the placement of drug under the tongue (Rehfeld et al., 2017). The sublingual route bypasses the first-pass metabolism and hence facilitates rapid absorption of the drug into the systemic circulation. Drug directly reaches the systemic circulation using blood vessels. The sublingual region holds a rich source of blood vessels which are routed parallel to the mucosal surface (Yin et al., 2016). The sublingual artery supplies blood to the salivary glands. It branches in surrounding muscles and mucous membranes of mouth, tongue, and gums. The sublingual artery originates from the lingual artery which constitutes the primary blood supply to the tongue and mouth floor region (Harki et al., 2016). The lingual artery stems from the external carotid artery. Blood vessels present in the carotid artery region split into smaller blood vessels which in turn join the adjoining vessels creating an extensive blood supply network. This blood vessel network facilitates more profusion through the sublingual region as compared to the skin (Masui et al., 2016).

The sublingual mucosa contains high amounts of polar lipids. This polar nature of sublingual mucosa facilitates increased membrane fluidity along with higher permeation of water and hydrophilic compounds (dos Santos Chaves et al., 2017). Two major pathways responsible for drug transport across the submucosal membrane are lipoidal and aqueous routes. The lipoidal route, i.e., the intercellular route filled with 50% polar lipids, permits passage of drug through transcellular and intercellular pathways. The aqueous route, in turn, is a paracellular pathway with the presence of water molecules trapped by the polar head of intercellular lipids in-between cells. Permeation of drug through submucosal membrane takes place by one of these pathways, hence understanding the permeation pathway of the drug is necessary for designing of the dosage form (Meltzer, 2017).

Experiments by Lesch et al. with the porcine oral mucosa suggested that the permeability of water is greater in the sublingual area than in the gingival, palatal, buccal mucosa, and epidermis. Hence drug should be highly soluble in aqueous fluids (Lesch et al., 1989). Based on pH partition hypothesis, pKa of a drug needs to be stated. Unionized species of the drug can pass the lipid biological membrane more profusely than the ionized species. Hence the pH of the drug should be in favor of increased concentration of unionized species of the drug.

Conclusions

Allergen immunotherapy has been practiced with only relatively modest changes for more than 100 years. The clinical effectiveness of adequate doses in appropriate patients for both allergic rhinitis and bronchial asthma has been repeatedly confirmed. Treatment by the sublingual route is becoming increasingly popular. SLIT appears to be as effective as SCIT for allergic rhinitis and is certainly more convenient for patients. The precise mechanisms of SIT action remain uncertain. Both SCIT and SLIT are associated with induction of regulatory T cells, expression of IL-10 and TGF-β1, and secretion of allergen-specific IgG4. The major threat to future use of SCIT and SLIT is the lack of comprehensive cost-effectiveness data, which is increasingly required by healthcare commissioners when deciding which treatments to fund. Future developments will include a wider range of allergens, adaptations with mucoadhesives and adjuvants to refine the immunologic response, and research into the durability of responses to determine cost-effectiveness.

As well as confirming primary efficacy, clinical trials of SCIT and SLIT have confirmed a persisting beneficial effect after immunotherapy is discontinued. These findings suggest that immunotherapy has the potential to be used more widely. Increased utilization would be facilitated by alternative extracts and better methods of administration making SIT safer and more convenient for the patient.

Pharmacokinetics

There are no published formal animal or human studies examining the pharmacokinetic properties of methoxetamine. Users report rapid onset of action (10–20 minutes) following nasal insufflation, rectal or intravenous/intramuscular administration. The sublingual routeis reported as less effective, with oral least effective. Peak effects are reported to occur between 1–3 hours after exposure with a further duration of between three and six hours during which after-effects are experienced. There are a few reports of effects lasting 24 hours; the half-life for clinical effects is three hours [5,6].

The metabolism of methoxetamine has not been formally studied, but its structural similarity to ketamine may mean it is similarly metabolised: extensive hepatic first pass metabolism by CYP2B6, CYP34A and CYP2C9 isoenzymes. The major pathway in ketamine metabolism is N-demethylation to the active metabolite norketamine [7]. Extensive first pass metabolism of methoxetamine may account for its limited effect when administered orally, although currently there is no data which can substantiate this. Preliminary data from analysis of three urine samples from patients with analytically confirmed acute methoxetamine toxicity has suggested that in addition to metabolites expected based on the metabolism of ketamine, additional Phase I metabolites of methoxetamine are produced [8]. The expected metabolites based on the metabolism of ketamine are the N-desethyl (nor), dehydro, dehydro-nor, hydroxy, hydroxy-nor, hydroxy-dehydro and hydroxy-nor-dehydro metabolites. Greatest responses were seen for the N-desethyl (nor) and hydroxy-nor metablites (response relative to methoxetamine of 38.3 and 13.3%). The additional metabolites seen included O-desmethyl, dihydro-nor, O-desmethyl-hydroxy-nor and O-desmethyl-dehydro metabolites.