Drugs are most often administered extravascularly and are mainly intended to produce systemic action; for this reason, absorption is a prerequisite for pharmacological effects. Delays or drug loss during absorption contribute to variability in drug response, and sometimes may result in drug therapy failure. The absorption site is separated from blood via gastrointestinal membrane. Therefore, a drug to get absorbed have to pass through the membrane, and this is possible only when the drug is in solution form and dissolution becomes very critical for the absorption of a drug.

Non per Os or Oral indicates drug administration routes other than the oral route, which bypasses the GIT and enter the systemic circulation. A major advantage of drug administration through non-invasive transmucosal and transdermal routes (like nasal, buccal, rectal, etc.) is that a greater systemic availability is attained.

Sublingual/Buccal Route

Drug (small sized tablet) is kept beneath the tongue (without water) to disintegrate and absorb in mouth, e.g., nitroglycerine tablets. The drug enters the systemic circulation through diffusion into the capillary network. In buccal route, the drug is kept within the mouth around the cheeks or buccal cavity, where it disintegrates and absorbs.

1. Lipophilicity of Drug: For passive permeation, slightly higher lipid solubility than that required for gastrointestinal absorption is necessary.
2.  Salivary Secretion: The drug should be highly lipid-soluble, and should also be soluble in aqueous buccal fluids. Biphasic solubility of drug is required for absorption, because absorption will be delayed if the mouth is dry.
3. Saliva pH: Buccal pH of 6 assists the absorption of unionised drugs.
4.  Binding to Oral Mucosa: Drugs that bind to oral mucosa have a poor systemic availability.
5.  Storage Compartment: A storage compartment exists in the buccal mucosa for the slow absorption of drugs, like buprenorphine.
6. Thickness of Oral Epithelium: Sublingual absorption is faster than buccal absorption since the epithelium region of the former is thinner and immersed in a larger volume of saliva.

Merits of Drug Administration by Sublingual/Buccal Route

1. Rapid absorption of drugs due to highly  vascularised site, therefore fast onset of action.
2. Stomach enzymes and acids are not involved so the drug remains stable.
3. Drugs do not undergo first-pass metabolism.
4. Portal circulation is by-passed.
5. In case of any side effects, drugs can be withdrawn.
6. Drugs can be administered easily.
7. Less chances of infection.
8. No involvement of harsh gastrointestinal environment.

Demerits of Drug Administration by Sublingual/Buccal Route

1. It is sometimes inconvenient to keep drugs in mouth.
2. Small doses of drugs are required to keep in mouth.
3. Drugs having high molecular weight cannot be absorbed (e.g., insulin).
4. Unpleasant, distasteful, irritant drugs cannot be administered.

Intravenous (IV) Route

Injections are preferred for orally unabsorbed drugs like atracurium , (neuromuscular blocker). First pass metabolism by the liver can be avoided by IV route because drugs do not enter into GIT. Intravenous route shows rapid effect and maintains level of drug in circulation.

Bacterial or other microbial infections may occur due to the use of syringe and contamination at the site of injection. Injected drugs cannot be removed from circulation through emesis or using activated charcoal like in oral delivery.

Merits of Drug Administration by Intravenous (IV) Route

1. 1. 100%  bioavailability is achiéved.
   2. Desired blood concentrations are achieved.
   3. Large quantities.
   4. Helpful in emergency situations.
   5. No first-pass metabolism occurs.
   6. Prevent gastric manipulation.

Demerits of Drug Administration by Intravenous (IV) Route

1. Inconvenient, painful and cause irritation, cellulitis and thrombophlebitis.
2. Repeated injections are not suitable.
3. Safety level is very low.
4. Technical and trained person are required to inject drugs.
5. Infection may occur.
6. Costly.

Intramuscular (IM) Route

In intramuscular (IM) route, drug is delivered in the form of aqueous solutions or depot preparations, i.e., drug suspension in non-aqueous vehicle (polyethylene glycol). By this route, aqueous preparation gets rapidly absorbed. Depots are used when slow release of drug is needed. Diffusion of vehicle from muscle and subsequent precipitation of drug at the site of injection occur providing a sustained release of drug. For example, sustained-release haloperidol decanoate slowly diffuses from the muscle and gives prolonged neuroleptic effect.

1. Vascularity of the Injection Site: The blood flow rate to muscular tissues in which drugs are injected is arranged in its decreasing order as – Arms (deltoid) > Thighs (vastus lateralis) > Buttocks (gluteus maximus). Blood flow rate is the rate-limiting step in drug absorption from intramuscular sites. The most rapid absorption occurs from deltoid muscles and slowest absorption occurs from gluteal region.
2. Lipid Solubility and Drug Ionisation: Highly lipophilic drugs undergo rapid absorption by passive diffusion, while the hydrophilic and ionised drugs are slowly absorbed through the capillary pores.
3. Drug Molecular Size: Small molecules and ions directly enter the capillaries through pores, while the macromolecules enter the lymphatic system. Small peptides and fluids undergo cytopemphis, in which they cross the endothelial tissue of blood capillaries and lymph vessels , by getting transported in small vesicles that cross the membrane.
4. Injection Volume and Drug Concentration: A drug, in concentrated form and large volume injection undergoes faster absorption in comparison to the drug given in dilute form and small volume injection.
5.  pH, Composition and Viscosity of Injection Vehicle: When a drug solution in acidic or alkaline pH  (e.g., phenytoin, pH 12) or in a non-aqueous solvent such as propylene glycol or alcohol (e.g., digoxin) is injected intramuscularly, the drug precipitates at the injection site after a slow and prolonged absorption. Viscous vehicles such as vegetable oils also slow down the absorption of drug.

1. Uniform absorption occurs.
2. Onset of action is fast.
3. Mild irritants can be given.
4. Prevent first pass metabolism.
5. No GIT-related factors.

Demerits of Drug Administration by Intramuscular (IM) Route

1. Only small quantities (10ml) of drug can be administered.
2. Local pain, abscess, and infection may occur.
3. Expensive.

Subcutaneous (SC) Route

Subcutaneous (SC) route of drug administration is similar to IM injections, but the drug absorption in this route is slower than the IV route. The risk associated with IV route can be reduced by using subcutaneous route. For example, solid contraceptives (e.g., a single rod with etonogestrel) is implanted for prolonged effect; Implanted programmable mechanical pumps are implanted to deliver insulin in diabetic patients.

Merits of Drug Administration by Subcutaneous (SC) Route

1. Can be self-administered.
2. Complete but slow absorption.
3. Massage/ heat: vasoconstriction.

Demerits of Drug Administration by Subcutaneous (SC) Route

1. Painful.
2. Irritant drugs cause tissue damage.
3. Only small quantities of dose (2ml) can be injected.

Inhalational Route

This route delivers drug throughout the respiratory tract, mucous membranes and pulmonary epithelium, as well as give fast effect as intravenous injections. Gases or aerosol forms of drugs (like anaesthetics) are administered through inhalational route. This route is effective in treatment of patients with respiratory complications such as asthma or chronic obstructive pulmonary disease. Systemic side effects related to some drugs (e.g., albuterol and corticosteroids, and fluticasone) can be minimised in this route.

Merits of Drug Administration by Inhalational Route

1. Surface area of the respiratory endothelium is large and cause rapid absorption.
2. Bronchodilators and inhaled steroids affect lungs with less systemic absorption and minimum side effects.
3. Instant absorption of drug and rapid onset of action.
4. No hepatic first-pass metabolism of drug.

Demerits of Drug Administration by Inhalational Route

1. Specialised equipment required for drug delivery, e.g., inhalers.
2. Bioavailability of drug depends on the patient’s inhaler technique and drug particle size.
3. Due to the use of inhaler, dose regulation is difficult.