Different routes of drug administration

Enteral (gastro-intestinal) Route of Medication

1. Oral administration of medication is a convenient, cost-effective, and most commonly used medication administration route. The primary site of drug absorption is usually the small intestine, and the bioavailability of the medication is influenced by the amount of drug absorbed across the intestinal epithelium. The first-pass effect is an important consideration for orally administered medications. It refers to the drug metabolism whereby the drug concentration is significantly diminished before it reaches the systemic circulation, often due to the metabolism in the liver.   
2. A sublingual or buccal route is another form of the enteral route of medication administration that offers the benefit of bypassing the first-pass effect. By applying the drug directly under the tongue (sublingual) or on the cheek (buccal), the medication undergoes a passive diffusion through the venous blood in the oral cavity, which bypasses the hepatic portal vein and flows into the superior vena cava. Compared to sublingual tissue, which has highly permeable mucosa with rapid access to the underlying capillaries, buccal tissue is less permeable and has slower drug absorption.  
3. A rectal route is another enteral route of medication administration, and it allows for rapid and effective absorption of medications via the highly vascularized rectal mucosa. Similar to sublingual and buccal routes, rectally administered medications undergo passive diffusion and partially bypass the first-pass metabolism. Only about half of the drug absorbed in the rectum directly goes to the liver. 

Parenteral Route ( medications placed into the tissues and the circulatory system by injection) of Medication 

1. Intravenous injection is the most common parental route of medication administration and can bypass the liver's first-pass metabolism. Given their superficial location on the skin, peripheral veins provide easy access to the circulatory system and are often utilized in the parenteral administration of medications. The upper extremity is usually the preferred site for intravenous medication . In the lower extremity, the dorsal venous plexus of the foot can be used.
2. An intramuscular medication route can be administered in different body muscles, including the deltoid, dorsogluteal, ventrogluteal, rectus femoris, or vastus lateralis muscles. Although the dorsogluteal site, or the buttock's upper outer quadrant, is a common site chosen traditionally for intramuscular injections by healthcare professionals, it poses a potential risk of injury to the superior gluteal artery and sciatic nerve. On the other hand, the ventrogluteal site, or the anterior gluteal site, targets the gluteus medius muscle and avoids these potential complications; thus, it is recommended.
3. Subcutaneous injections are another form of the parental route of medication and are administered to the layer of skin referred to as cutis, just below the dermis and epidermis layers. Subcutaneous tissue has few blood vessels; therefore, the medications injected undergo absorption at a slow, sustained rate. Subcutaneous medication can be administered to various sites, including the upper arm's outer area and abdomen, avoiding a 2-inch circle around the navel, the front of the thigh, the upper back, or the upper buttock area behind the hip bone.
4. The intraarterial route is not commonly used for drug administration. Injection of contrast material after an arterial puncture is done for angiography. The other uses of this route are for administering regional chemotherapeutic agents and treating malignant tumors of the brain. 

Other Routes of Medication 

1. A trans-nasal drug route facilitates drug absorption by passive diffusion across the single-layered, well-vascularized respiratory epithelium directly into the systemic circulation.
2. An inhaled medication is delivered rapidly across the large surface area of the respiratory tract epithelium. Drugs absorbed into the pulmonary circulation enter directly into the systemic circulation via the pulmonary vein, bypassing the first-pass metabolism. The particle size of the inhaled medication is usually 1 to 10 µm for effective delivery. The efficacy of drug delivery to the lungs depends not only on the drug particle size and morphology but also on the patient's respiratory physiology, such as tidal volume and tracheal inspiration velocity.
3. A vaginal route is an underexplored drug delivery route that is not commonly used but has the advantage of bypassing the first-pass effect and can serve as an effective method for local and systemic therapy. 
4. The transdermal route can deliver drugs through the skin. This route uses common administration methods: local application formulations like transdermal ointments and gels, drug carriers like nanoparticles and liposomes, and transdermal patches.
5. The intraosseous route (the placement of a specialized hollow bore needle through the cortex of a bone into the medullary space for infusion of medical therapy and laboratory tests) is useful, especially in neonates, for administering fluids and drugs when both peripheral and central venous accesses have failed.

1. Oral

This is convenient and indicated for patients who can ingest and tolerate oral medication. Some medications with short half-lives are administered orally as timed-release or sustained-release forms that get absorbed over several hours. 

Advantages: Ease of administration and widespread acceptance by the patients.

Disadvantages: Variable absorption rates, degradation of some drugs before reaching the site of absorption into the bloodstream, the inability of many compounds to effectively traverse the intestinal epithelial membrane cells to reach the bloodstream, the insolubility of many drugs at low pH levels is prevalent in the digestive tract, the inactivation of the drug in the liver on its way to the systemic circulation, irritation of the mucous lining of the gastrointestinal tract. This can be prevented to some extent by coating.  

2. Sublingual and Buccal Routes

These are indicated for medications with high first-pass metabolism that need to avoid clearance by the liver. For instance, nitroglycerin is cleared more than 90% during a single pass through the liver; therefore, it is given in a sublingual form.

Advantages: Rapid absorption is due to the abundant mucosal network of systemic veins and lymphatics, thereby leading to a rapid onset of action, if there is any untoward event, the tablet can be removed, avoids first-pass hepatic metabolism, a tablet can be kept for a long time in the buccal cavity, which helps develop formulations with a sustained-release effect, this route is useful in patients having swallowing difficulties, low risk of infection, and convenience

Disadvantages: The tablet must be kept in the buccal cavity and neither chewed nor swallowed, excessive salivation may cause quick dissolution and absorption of the tablet, patients may find it difficult to accept an unpalatable tablet. Hence some drugs are applied as a patch or a spray.

3. Rectal Route

This route is useful for patients with gastrointestinal motility problems such as dysphagia or ileus that can interfere with delivering the drug to the intestinal tract. The rectal route is also often utilized in patients near the end of life undergoing hospice care.

Advantages: A relatively large amount of the drug can be administered, those drugs destroyed by the acidic medium in the stomach and those metabolized by pancreatic enzymes can be administered effectively, safe and convenient for infants and the elderly, it can be used in emergency situations, such as in infants having seizures when the intravenous route is unavailable, the rate of absorption is uninfluenced by the ingestion of food or the rate of gastric emptying, bypasses hepatic metabolism, less degradation of drugs compared to that in the upper gastrointestinal tract.

Disadvantages: Some hydrophilic drugs like antibiotics and peptide drugs are unsuitable for rectal administration as they are not readily absorbed, some drugs can cause rectal irritation and proctitis, leading to ulceration and bleeding.

Parenteral Routes of Medication

1. Intravenous Route

This directly administers the medications to the systemic circulation. It is indicated when a rapid drug effect is desired, a precise serum drug level is needed, or when drugs are unstable or poorly absorbed in the gastrointestinal tract. It is also the route utilized in patients with altered mental status or severe nausea or vomiting, unable to tolerate oral medications.

Advantages: Rapid onset of action, predictable way of action and almost complete bioavailability, the problems of oral drug administration can be eliminated by avoiding the gastrointestinal tract, the best way of administration in very ill and comatose patients who cannot ingest anything orally.

Disadvantages: Causes pain, chance of infection, the delivery of protein products that require sustained levels can be difficult.

2. Intramuscular Route

This can be utilized when oral drug absorption occurs in an erratic or incomplete pattern, the drug has high first-pass metabolism, or the patient is not compliant. A depot preparation of the drug can be given intramuscularly, and the medication dissolves slowly into the circulation to provide a sustained dose over a more extended time. An example includes haloperidol decanoate. Vaccines are also administered via the intramuscular route.  

Disadvantages: Injection site pain, the amount of drug administered has to be adjusted according to the mass of the muscle available, peptides get degraded locally, complications - hematoma, abscess, peripheral nerve injury, puncture of a blood vessel leading to inadvertent intravascular administration.

3. Subcutaneous Route

This is used when the drug's molecular size is too large to be effectively absorbed in the intestinal tract or when better bioavailability or a faster absorption rate is needed than the oral route. It is easy to administer and requires minimal skills, so patients can often self-administer the medication. Common medications administered subcutaneously include insulin, heparin, and monoclonal antibodies. The rate of absorption of drugs through this route can be enhanced by infiltration with the enzyme hyaluronidase.

The major factors that affect the rate of absorption by this route include the size of the molecules (large molecules having slow penetration), viscosity, and the anatomical characteristics of the site of injection (vascularity and amount of fatty tissue).

Disadvantages: The rate of absorption is difficult to control, local complications - irritation and pain, injection sites must be changed frequently to prevent the buildup of unabsorbed medication, which could lead to tissue injury.

Other Routes of Medication

1. Intranasal Route

This can be utilized in administering nasal decongestants for cold or allergy treatment. Other uses include desmopressin for the treatment of diabetes insipidus or intranasal calcitonin for the treatment of osteoporosis.

Factors that affect the rate of absorption of drugs via the nasal route are: The rate of nasal secretion - The rate of secretion is inversely proportional to the bioavailability of the drug, ciliary movement - The speed of ciliary movement is inversely proportional to the bioavailability of the drug, vascularity of the nose - The volume of blood flow is directly proportional to the rate of drug absorption, metabolism of drugs in the nasal cavity - The enzymes present in the nasal tissues alter the absorption of some compounds, especially peptides that are disintegrated by aminopeptidases, diseases affecting nasal mucous membrane. Common colds can affect nasal drug absorption.

Enhancement of nasal drug delivery:

Rapid mucociliary clearance can lead to poor bioavailability of the drug. This can be overcome by in situ gelling drug delivery. Chitosan is a natural bioadhesive polysaccharide obtained from crustacean shells that can be used as an absorption enhancer. Chitosan binds to the nasal mucosal membrane and facilitates drug absorption through paracellular transport and other mechanisms.

Advantages: Increased permeability of the nasal mucosa compared to the gastrointestinal mucosa, highly vascularized subepithelial tissue, quick absorption, usually within thirty minutes, avoids the first-pass effect, avoids the effects of gastric stasis and vomiting, ease of administration, higher bioavailability of the drugs than in the case of the enteral route or inhalational route.

Disadvantages: Nasal cavity diseases and conditions may result in impaired absorption, the dose is limited due to the small area available for absorption, the time available for absorption is limited, this route does not apply to all drugs.

2. Inhalational Route

The alveolar epithelium is approximately 100 square meters in adults, and the alveolar volume is 4000 to 6000 mL compared to the airway volume of 400 ml. This provides a greater surface area for absorption of the inhaled substances. An inhaled medication route can be utilized to administer albuterol or corticosteroids such as fluticasone and to deliver inhaled anesthetics to patients.

Barriers to the absorption of substances in the alveoli are surfactants, surface lining fluid including the mucus, the epithelial membrane, extravascular space, and vascular endothelium. The absorption of macromolecules by the lungs is considered to be by transcytosis (not significant for macromolecules >40 kDa), paracellular absorption, and drug transporter proteins.

Advantages: Large surface area, proximity to blood flow, avoids first-pass hepatic metabolism, only smaller doses are enough to achieve equivalent therapeutic effects as the oral route

Disadvantages: The aerodynamic filter of the lungs has to be overcome,, clearance of particles by the mucus lining the airways, only 10–40% of the drug from a conventional inhalation device is actually deposited in the lungs.

3. Vaginal Route

This is not commonly used but can deliver low, continuous dosing of medications which can help achieve stable drug levels. A variety of formulations can be given vaginally, including tablets, creams, gels, ointments, and pessaries. Common medications given via the vaginal route include vaginal estrogen therapy for urogenital atrophy, contraceptive rings, antibiotics, or antifungals.

4. Transdermal Route

Iontophoresis and microneedles are playing an increasing role in transdermal drug delivery. A technique has been described using hydrogel-forming microneedle arrays in combination with electro-phoresis for controlled transdermal delivery of biomacromolecules in a simple, one-step approach.

Drug Delivery to the Cardiovascular System

Methods for local administration of drugs to the cardiovascular system are:

• Delivery to the myocardium - direct intramyocardial injection, drug-eluting implanted devices.
• Delivery via the coronary venous system.
• Delivery via cardiac catheter into coronary arteries
• Intrapericardial delivery
• Delivery into the arterial lumen from drug-eluting stents

Drug Delivery to the Central Nervous System (CNS)

The blood-brain barrier is a major obstruction to the delivery of drugs into the central nervous system.

Some methods to reduce the obstruction by this barrier include:

• Systemic administration of drugs for CNS action
• Direct administration of drugs to the CNS - Intrathecal, into the cerebral arteries, into the brain parenchyma, and direct positive pressure infusion
• Drug delivery by manipulation of the blood-brain barrier
• Drug delivery using novel formulations like conjugates, and nanocarriers-based delivery systems (including polymeric nanocarriers, micelles, nanotubes, dendrimers, magnetic nanoparticles, and quantum dots (QDs))
• Drug delivery systems like pumps and catheters
• Use of microorganisms like bacteriophages and bacterial vectors
• Cell therapy - CNS implants of live cells or genetically engineered cells
• Gene transfer - Direct injection into the CNS, intranasal instillation, retrograde axonal transport, or through vectors.

Contraindications

Each medication administration route has unique contraindications, and the healthcare team members need to recognize them. An oral medication route is contraindicated for patients who cannot tolerate oral drugs, such as those who have altered mental status or have nausea or vomiting that hinder them from safely ingesting the drug orally. A rectal route is contraindicated in patients with active rectal bleeding or diarrhea or after a recent rectal or bowel surgery. An intramuscular route is contraindicated in an active infection or inflammation at the site of drug administration, myopathies, muscular atrophy, thrombocytopenia, or coagulopathy.

A subcutaneous route of medication is contraindicated in an actively infectious or inflamed site. Doses that require to be injected more than 1.5 mL at once should be avoided. Subcutaneous injection volumes larger than 2 mL are associated with adverse effects, including pain and leakage at the injection site. An intranasal medication is contraindicated in patients with nasal trauma, anatomic obstruction, the presence of a foreign body, or copious mucous or bleeding. Similarly, an inhaled drug is contraindicated in patients with airflow obstruction.

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