Routes of Drug Administration

Pharmacokinetic OverviewThe intensity of the drug's effect, and the duration of the drug action are controlled by four fundamental pathways of drug movement and modification in the body.

Figure: Schematic representation of drug absorption, distribution, metabolism and elimination.

First, drug absorption from the site of administration permits entry of the therapeutic agent (either directly or indirectly) into plasma (input). Absorption is defined as the passage of a drug from its site of administration into the plasma.

Second, the drug may then reversibly leave the blood stream and distribute into the interstitial and intracellular fluids (distribution).

Third, the drug may be metabolized by the liver, kidney, or other tissues.

Finally, the drug and its metabolites are eliminated from the body (output) in urine, bile, or feces.

Routes of drug administrationThe route of administration is determined primarily

- by the properties of the drug (such as water or lipid solubility, ionization, etc.) and

- by the therapeutic objectives (for example, the desirability of a rapid onset of action or the need for long-term administration or restriction to a local site).

The route of administration (ROA) that is chosen may have a profound effect upon the speed and efficiency with which the drug acts.

Enteral: oral, sublingual, rectal

Parenteral: intravascular (intravenous), intramuscular, subcutaneous

Other: inhalation, intranasal, intrathecal (in CSF), topical, transdermal

The main routes of drug administration are:

Figure: Commonly used routes of drug administration.

Enteral routes:Drug placed directly in the GI tract:

Oral- swallowing

Sublingual- placed under the tongue

Rectum- absorption through the rectum

OralGiving a drug by mouth is the most common route of administration but it is also the most variable, and requires the most complicated pathway to the tissues. Little absorption occurs until the drug enters the small intestine.

Drug absorption from the intestine:The drug absorbed by passive transport mechanism in intestine at a rate determined by the ionization and lipid solubility of the drug molecules.

Strong bases of pKa 10 or higher are poorly absorbed, as are strong acids of pKa less than 3, because they are fully ionized.

Figure: Absorption of drugs from the intestine, as a function of pKa, for acids and bases. Weak acids and bases are well absorbed; strong acids and bases are poorly absorbed.

There are a few instances where intestinal absorption depends on carrier-mediated transport mechanism rather than simple lipid diffusion.

For example levodopa, iron, calcium.

Advantages:Convenient- can be self-administered, pain free, easy to take

Absorption- takes place along the whole length of the GI tract

Cheap- compared to most other parenteral routes

Disadvantages:- Unpleasant taste of some drugs

- Irritation to gastric mucosa - nausea and vomiting

- Destruction of drugs by gastric acid and digestive juices

- Sometimes inefficient- only part of the drug may be absorbed

- Effect too slow for emergencies

- First-pass effect - drugs absorbed orally are initially transported to the liver via the portal vein

- Unable to use in unconscious patient or who have had GI surgery

Most of the drug is absorbed in the small intestine, Why?

1. Small intestine has a much larger surface area for absorption (~200 m2) as compared to the stomach (~1-3 m2).

2. Drug spends more time in the small intestine (~4 hrs) than the stomach (~0.5-1 hrs).

Food in the stomach can decrease absorption

- Food may delays gastric emptying time so that drugs may destroyed by acid.

- Interactions between drug and food particles.

- Exception: propranolol- due to blood flow.

First-pass effectWhen a drug is absorbed across the GI tract, it enters the portal circulation before entering the systemic circulation.

A drug can be metabolized in the gut wall or even in the portal blood, but most commonly it is the liver that is responsible for metabolism before the drug reaches the systemic circulation (plasma). In addition, the liver can excrete the drug into the bile (fluid secreted by liver).

Any of these sites can contribute to this reduction in bioavailability, and the overall process is known as first-pass effect or first-pass elimination.

Portal circulation

Figure: First-pass effect

The greater the first-pass effect, the less the agent will reach the systemic circulation when the agent is administered orally. (imp)

Lidocaine (anesthetic agent) is a drug with a first-pass effect that is so great that oral administration is not practical.

In the case of propranolol, a significant portion of the orally administered dose is metabolized through a first-pass effect.

More than 90% of nitroglycerin is cleared during a single passage through the liver.

Therefore, a much larger oral dose is required to achieve the same therapeutic response as that obtained from a dose administered intravenously.

Sublingual/BuccalPlacement under the tongue allows the drug to diffuse into the capillary network and therefore to enter the systemic circulation directly.

When only small amounts of drugs are required to gain access to the blood, the sublingual route may be very satisfactory.

For example, nitroglycerin in angina pectoris.

Because the stomach is bypassed, acid-liability and gut-permeability is not important.

Drugs are absorbed from the mouth straight into the systemic circulation without entering the portal system and so escape first-pass metabolism by the liver.

Advantages

-rapid absorption

-drug stability

-avoid first-pass effect

Disadvantages

-inconvenient

-small doses

-unpleasant taste of some drugs

Rectal50% of the drainage of the rectal region bypasses the portal circulation; thus the biotransformation of drugs by the liver is minimized.

Drug’s property:- Non-polar- Lipid soluble

- Devoid of destruction of the drug by intestinal enzymes or by low pH in the stomach

- Unconscious patients (postoperative) and children

- If patient is nauseous or vomiting

- Absorption may vary

- Good for drugs affecting the bowel such as laxatives

- Irritating drugs contraindicated

- Can be used for both local effects and systemic effects

Parenteral routes:Parenteral administration is used for drugs that are poorly absorbed from the gastrointestinal (GI) tract, and for agents such as insulin that are unstable in the GI tract.

Parenteral administration is also used for treatment of unconscious patients and under circumstances that require a rapid onset of action.

The three major parenteral routes are - Intravascular (intravenous or intra-arterial)- Intramuscular- Subcutaneous

Intravascular:Intravenous (IV) injection is the most common parenteral route. For drugs that are not absorbed orally, there is often no other choice.

- Rapid onset of action because the drug is injected directly into the bloodstream- Useful in emergencies and in patients that are unconscious

- The drug avoids the GI tract and first-pass metabolism by the liver

- Smaller doses generally are required than the other routes but cost is high

Greater risk of adverse effects as:a. High concentration attained rapidly

b. That are injected cannot be recalled by strategies such as emesis or binding to activated charcoal

c. Risk of embolism (obstruction of blood vessel)

d. May introduce bacteria through contamination, induce hemolysis

e. Pain at application site

f. No self administration facility

Capillary: brings the blood into intimate relationship with the tissue cell

Artery Arterioles Capillary Venules Veins

Intra-arterySimilar properties, advantages and disadvantages of intravascular route. Intra-artery route is specially used when high drug concentration in specific tissue is required than other tissue:

- diagnostic purpose and

- for chemotherapy

IntramuscularDrugs administered intramuscularly can be aqueous solutions or specialized depot preparations- often a suspension of drug in a non-aqueous vehicle, such as ethylene glycol or peanut oil.

Absorption of drugs in aqueous solution is fast, whereas that from depot preparations is slow. Drug passes through capillary walls to enter the blood stream.

- Pain at injection sites for certain drugs

- This parenteral route may be used when an immediate effect is not required but a prompt effect is desirable

- Absorption from an intramuscular depot is more predictable and uniform than from a subcutaneous site

SubcutaneousDrug is injected beneath the skin and permeates capillary walls to enter blood stream.Absorption from the site of injection is dependent on local blood flow. Concurrent administration of vasoconstrictor will slow absorption.

For example, minute amount of epinephrine is sometime used in combination with a drug to restrict its area of action. Epinephrine acts as a local vasoconstrictor and decreases removal of a drug, such as lidocaine (local anesthetic), from the site of administration.

Examples of drugs given by this route are insulin and sodium heparin, neither of which is absorbed orally, and both of which should be absorbed slowly over many hours.

InhalationInhalation provides the rapid delivery of a drug across the large surface area of the mucous membranes of the respiratory tract and pulmonary epithelium, producing an effect almost as rapidly as by intravenous injection.

This route of administration is used for drugs that are gases and volatile agents (for example, some anesthetics), or those that can be dispersed in an aerosol.

The route is particularly effective and convenient for patients with respiratory complaints (for example, asthma or chronic obstructive pulmonary disease) as drug is delivered directly to the site of action and systemic side effects are minimized.

TopicalTopical application is used when a local effect of the drug is desired.

Used for most dermatologic and ophthalmologic preparations.

Clotrimazole is applied as a cream to the skin in the treatment of dermatophytosis.

Atropine is instilled directly into the eye to dilate the pupil and permit measurement of refractive errors.

Intra-articularInjected into bone joints

Intrathecal/lntraventricularIt is sometimes necessary to introduce drugs directly into the cerebrospinal fluid (CSF): some anesthetics.

TransdermalThis route of administration achieves systemic effects by application of drugs to the skin, usually via a transdermal patch.

The rate of absorption can vary markedly depending upon the physical characteristics of the skin at the site of application. Small lipid soluble molecule.

This route is most often used for the sustained delivery of drugs, such as the antianginal drug, nitroglycerin.