VARIOUS ROUTES OF DRUG ADMINISTRATION, DRUG ABSORPTION, BIOAVAILABILITY, DISTRIBUTION, BIOTRANSFORMATION, EXCRETION, MECHANISM OF DRUG ACTION, AND FACTORS MODIFYING DRUG ACTION: A TEACHER’S COMPREHENSIVE GUIDE
Welcome, future pharmacologists and healthcare professionals!
The study of general pharmacology is the foundation of understanding how drugs work in the human body. This chapter covers the essential concepts of routes of drug administration, drug absorption, bioavailability, distribution, biotransformation, excretion, mechanism of drug action, and factors modifying drug action. As a pharmacology educator with years of experience teaching these fundamental concepts, I have observed that students often find this topic complex due to the many processes involved. Let me tell you: Understanding these principles is essential for safe and effective drug therapy.
In this comprehensive guide, I will walk you through the various routes of drug administration, mechanisms of drug absorption, factors affecting bioavailability, drug distribution, biotransformation reactions, excretion pathways, mechanisms of drug action, and factors that modify drug response. By the end of this article, you will have a thorough understanding of how drugs move through and interact with the body. Let us begin!
Dpharmguru’s exam insights:
General pharmacology is the foundation of all pharmacology exams. Remember: The route of administration determines the speed and extent of drug action. ADME (Absorption, Distribution, Metabolism, Excretion) are the four pillars of pharmacokinetics. Bioavailability is the fraction of drug reaching systemic circulation. First-pass metabolism reduces oral bioavailability. The Therapeutic Index indicates drug safety. These are classic exam questions!
1. ENTERAL ROUTE
The enteral route is the safest, most economical, and convenient route of drug administration. Tablets, capsules, powders, mixtures, emulsions, and gels are taken orally.
A) ORAL ROUTE
In this route, the drug is administered through the mouth. It is also known as per oral (p.o.). Absorption occurs mainly in the duodenum, which has a greater absorptive surface.
Advantages:
- Safe, convenient, and painless method
- Economical and does not require sterilisation
- Can be self-administered
- Less chance of acute drug reaction
- Less chance of systemic infection
Disadvantages:
- Incomplete drug absorption
- May cause gastric mucosa irritation leading to nausea and vomiting
- Cannot cover unpleasant taste of drugs
- Not preferable for unconscious and uncooperative patients
- Low gastric pH, digestive and liver enzymes destroy the drug
B) SUBLINGUAL/BUCCAL ROUTE
In this route, the drug (small size tablet) is kept beneath the tongue to disintegrate and get absorbed, e.g., nitroglycerine tablets.
Advantages:
- Rapid absorption due to highly vascularised site
- Avoids stomach enzymes and acids
- Bypasses first-pass metabolism
- Bypasses hepatic portal circulation
- Easy administration; drug can be withdrawn if side effects occur
Disadvantages:
- Inconvenient to keep drug in mouth
- Requires small doses
- Does not assist absorption of high molecular weight drugs (e.g., insulin)
- Difficult to administer unpleasant, distasteful drugs
C) RECTAL ROUTE
In this route, drugs are administered through the rectum. Suppositories are administered through this route.
Advantages:
- Useful when patient is suffering from nausea and vomiting
- Bypasses first-pass metabolism (absorption occurs from external haemorrhoidal veins)
- Used to administer gastric irritant drugs
Disadvantages:
- May cause rectal inflammation
- Shows irregular absorption
2. PARENTERAL ROUTE
All routes other than the enteral route come under the parenteral route; mainly includes subcutaneous, intramuscular, and intravenous injections.
A) INTRAVENOUS (IV) ROUTE
Drugs are administered into the veins to be absorbed directly into the systemic circulation.
Advantages:
- 100% bioavailability
- Desired blood concentration achieved
- Large quantities of drugs can be administered
- Helpful in emergency situations
- Prevents gastric manipulation and avoids first-pass metabolism
Disadvantages:
- Inconvenient and painful
- May cause irritation, cellulitis, and thrombophlebitis
- Requires trained person
- May cause infection
- Costly
B) INTRAMUSCULAR (IM) ROUTE
Drug is delivered in the form of aqueous solutions or depot preparations.
Advantages:
- Uniform absorption
- Fast onset of action
- Used to administer mild irritants
- Prevents first-pass metabolism
Disadvantages:
- Only 10 mL drug can be administered
- Local pain, abscess, and infection
- Expensive
C) SUBCUTANEOUS (SC) ROUTE
Drug absorption in this route is slower than the IV route.
Advantages:
- Allows self-administration
- Complete but slow absorption
Disadvantages:
- Painful
- Irritant drugs may cause tissue damage
- Maximum 2 mL dose
D) INHALATIONAL ROUTE
Drug is delivered throughout the respiratory tract, giving fast effect as intravenous injections.
Advantages:
- Rapid absorption due to large surface area
- Used to administer bronchodilators and steroids
- Instant absorption and rapid onset
- Avoids hepatic first-pass metabolism
Disadvantages:
- Requires specialised equipment
- Difficult to regulate dose
- Bioavailability depends on inhaler technique and particle size
E) TRANSDERMAL ROUTE
Transdermal patches are employed to deliver systemic effect through skin.
Advantages:
- Sustained effect
- Avoids hepatic first-pass metabolism
- Convenient and good patient compliance
Disadvantages:
- Relatively slow onset
- May cause skin irritation
- Preferred only for highly lipophilic drugs
3. TOPICAL ROUTE
In this route, the drug is applied on the surface of skin or mucous membrane by means of creams, ointments, gels, lotions, sprays, powders, and aerosols.
Advantages:
- Easy administration
- Fewer complications
- Fast action at application site
Disadvantages:
- Skin irritation
- Poor absorption of certain drugs
DRUG ABSORPTION
A. DEFINITION
Absorption is the movement of a drug from its site of administration into the plasma or central compartment.
B. TYPES OF DRUG ABSORPTION
- Passive Diffusion: Movement from higher to lower concentration. More than 90% of drugs are absorbed through non-ionic diffusion.
- Pore Transport or Filtration: For low molecular size, water-soluble drugs (e.g., urea, water, sugar).
- Carrier-mediated Transport:
- Active Transport: Movement against concentration gradient; requires energy (ATP). Examples: sodium, potassium, calcium, iron, glucose, amino acids.
- Facilitated Diffusion: Carrier-mediated, faster than passive diffusion; no energy required; moves downhill.
- Ion Pair Transport: Enables absorption of drugs that ionise under all pH conditions.
- Endocytosis: Cell membrane engulfs extracellular material.
- Phagocytosis (Cell Eating): Engulfing solid particulates (e.g., bacteria).
- Pinocytosis (Cell Drinking): Engulfing fluid solutes.
C. FACTORS AFFECTING DRUG ABSORPTION
Drug absorption is influenced by physiological, physicochemical, and pharmaceutical factors.
1. Physiological Factors
- Gastrointestinal Physiology: Stomach (weak acidic drugs absorbed), Small intestine (large surface area), Large intestine (water and electrolyte absorption).
- pH of Gastrointestinal Tract: Acidic drugs poorly soluble in acidic medium; basic drugs poorly soluble in basic medium.
- Gastrointestinal Transit: Gastric emptying, intestinal motility, colonic residence.
- Absorption Sites: Specific sites for maximum absorption.
- Protein Binding: Drugs bound to proteins show difficulty in diffusion.
- Pre-systemic Metabolism: First-pass metabolism in liver.
- Patient Factors: Age, sex, body weight, activity, posture, food, disease conditions.
2. Physicochemical Factors
- Drug Solubility: Influences dissolution rate.
- Dissolution Rate: Amount of substance entering solution per unit time.
- Wetting: Affects particle size reduction.
- Chemical Forms: Modifications in chemical structure for better therapeutic response.
- Drug pKa and Lipophilicity: pH Partition Theory—only unionised lipid-soluble fraction permeates membrane.
- Particle Size and Effective Surface Area: Inverse relationship—smaller particles increase absorption.
- Hydrates/Solvates: Hydrates have less aqueous solubility than anhydrous form.
- Salt Form: Weak acids/bases converted to salts for increased solubility.
3. Pharmaceutical Factors
- Dosage Form Considerations: Decreasing order of availability: Solutions > Emulsions > Suspensions > Capsules > Compressed Tablets > Coated Tablets > Enteric-coated tablets
- Pharmaceutical Ingredients/Excipients: Vehicles, diluents, binders, disintegrants, lubricants, suspending agents, surfactants, buffers, complexing agents, colourants.
- Disintegration Rate: Directly relates to bioavailability.
- Product Age and Storage Conditions: Affect disintegration and dissolution rates.
BIOAVAILABILITY
Bioavailability is defined as the fraction of a drug reaching the systemic circulation to its site of action following administration by any route.
Bioavailability = AUC (oral) / AUC (I.V.) × 100Factors Affecting Bioavailability:
- Route of Administration (Parenteral > Oral > Rectal > Topical)
- Absorption (rate directly proportional to bioavailability)
- Metabolism (first-pass metabolism reduces bioavailability)
- Distribution
- Excretion (inversely proportional to bioavailability)
- Food and Drug Interactions
- Dosage Formulation
- Disease States
- Age and Gender
- Genetics
DRUG DISTRIBUTION
Drug distribution is defined as the delivery or transport of drug to the tissues.
Apparent Volume of Distribution (Vd) = Amount of Drug in the Body / Plasma Drug ConcentrationFactors Affecting Drug Distribution:
- Age
- Pregnancy
- Obesity
- Diet
- Disease States
BIOTRANSFORMATION OF DRUGS
Biotransformation is the biochemical modification of a drug in the body. The liver is the main site of metabolism.
First-Pass Metabolism
The phenomenon of metabolism of a drug at a particular location where its concentration significantly decreases before reaching the systemic circulation.
Phase I Reactions
- Oxidation: Cytochrome P450 enzyme system (Mixed Function Oxidase).
- Hydrolysis: Splitting of molecule by attaching water molecule.
- Reduction: Introduction of hydrogen atoms.
- Cyclisation: Straight-chain compounds form ring structure.
- Decyclisation: Opening of ring structure.
Phase II Reactions (Conjugation)
- Glucuronidation
- Sulphonation (Sulphation)
- Acetylation
- Methylation
- Glutathione conjugation
- Glycine conjugation
Factors Affecting Drug Metabolism
- Inhibitors (e.g., cimetidine, omeprazole, ciprofloxacin)
- Stimulators (e.g., phenobarbitone, rifampicin)
- Age (neonates show poor metabolism—Gray baby syndrome)
- Sex (females have lesser ability)
- Species (atropinase in rabbits)
- Genetics (G-6-PD deficiency)
- Body Temperature
EXCRETION OF DRUGS
Renal Excretion
- Glomerular Filtration: Non-selective process; filters most compounds except macromolecules bound to plasma proteins.
- Active Tubular Secretion: Carrier-mediated process against concentration gradient; requires energy.
- Tubular Reabsorption: Follows glomerular filtration; increases half-life of drug.
Non-Renal Excretion
- Biliary Excretion: Enterohepatic cycling
- Pulmonary Excretion: Gaseous and volatile substances (general anaesthetics)
- Salivary Excretion: Passive diffusion (pH-partition hypothesis)
- Mammary Excretion: Excretion in milk—significant for breastfeeding infants
- Skin Excretion: Through sweat
- Gastrointestinal Excretion: Opposite of GI absorption
- Genital Excretion: Semen shows presence of some drugs
Factors Affecting Drug Excretion
- Physicochemical Properties (Molecular Weight, Lipid Solubility, Volume of Distribution, Renal Blood Flow, Binding Characteristics)
- Drug Renal Clearance
- Degree of Ionisation
- Blood Flow to Kidneys
- Urine pH
- Age
- Disease States
GENERAL MECHANISM OF DRUG ACTION
Drugs modify biological reactions by interactions with macromolecular targets—receptors, ion channels, transporters, and enzymes.
1. TRANSPORTERS
- Symporters: Transport ions in the same direction (e.g., Ca²⁺ exchanger).
- Antiporters: Transport ions in opposite directions (e.g., Na⁺/K⁺ pump).
2. ENZYMES
- Stimulation: Drugs can stimulate enzymes (e.g., endogenous mediators).
- Inhibition: Common mode of action.
- Non-specific Inhibition: Denaturation of proteins.
- Specific Inhibition:
- Competitive: Drug competes with normal substrate (e.g., physostigmine).
- Non-competitive: Drug binds adjacent site (e.g., acetazolamide, aspirin).
3. ION CHANNELS
| Ion Channel | Modulator | Effect |
|---|---|---|
| Na⁺ Channels | Local Anaesthetics | Blockade |
| Ca²⁺ Channels | Dihydropyridines | Blockade |
| K⁺ Channels | Sulphonylureas | Blockade |
| K⁺ Channels | Minoxidil | Opening |
| Cl⁻ Channels (GABA) | Benzodiazepines | Opening |
4. RECEPTORS
A receptor is a specialized target macromolecule that binds a drug and mediates its pharmacological action.
Types of Receptors:
- Ligand-gated Ion Channels (Ionotropic): e.g., GABA receptor (benzodiazepines).
- G-protein Coupled Receptors: e.g., Adrenoceptors.
- Kinase-Linked Receptors: e.g., Insulin receptor.
- Nuclear Receptors: e.g., Thyroid receptor.
FACTORS MODIFYING DRUG ACTION
- Age: Neonates show poor metabolism; children differ from adults.
- Sex: Special care in menstruation, pregnancy.
- Diet and Environment: Food affects drug absorption and pharmacokinetics.
- Route of Administration: Oral doses greater than intravenous doses.
- Genetic Factors: Pharmacogenetics—genetic variations affecting drug response.
- Metabolic Disturbances: Water, electrolyte, acid-base balance, body temperature.
- Presence of Disease: Impaired renal function affects drug excretion.
- Synergism: Enhanced action of one drug by another (e.g., adrenaline + procaine).
- Prodrug: Inactive compound that becomes active after metabolism (e.g., Prednisone → Prednisolone).
- Placebo Effect: Improvement from ‘dummy’ treatment.
Dpharmguru’s exam insights:
This chapter covers the core concepts of general pharmacology. Remember: ADME (Absorption, Distribution, Metabolism, Excretion) are the four pillars of pharmacokinetics. Bioavailability is the fraction of drug reaching systemic circulation. First-pass metabolism occurs in the liver. Phase I reactions include oxidation, reduction, and hydrolysis. Phase II reactions are conjugation reactions. Receptors are the primary targets for most drugs. These are classic exam questions!
SUMMARY TABLE: ROUTES OF DRUG ADMINISTRATION
| Route | Examples | Advantages | Disadvantages |
|---|---|---|---|
| Oral | Tablets, capsules | Safe, convenient, economical | First-pass metabolism, incomplete absorption |
| Sublingual | Nitroglycerine | Bypasses first-pass, rapid absorption | Small doses only |
| Rectal | Suppositories | Bypasses first-pass, useful in vomiting | Irregular absorption |
| Intravenous (IV) | Injections | 100% bioavailability, rapid onset | Painful, requires trained person |
| Intramuscular (IM) | Injections | Uniform absorption | Painful, limited volume |
| Subcutaneous (SC) | Injections | Self-administration | Slow absorption |
| Inhalation | Asthma inhalers | Rapid absorption, avoids first-pass | Requires equipment |
| Transdermal | Patches | Sustained effect, avoids first-pass | Slow onset |
| Topical | Creams, ointments | Local effect, easy application | Poor absorption |
FREQUENTLY ASKED QUESTIONS (FAQs)
1. What is the difference between pharmacokinetics and pharmacodynamics?
Pharmacokinetics describes what the body does to the drug—absorption, distribution, metabolism, and excretion (ADME). Pharmacodynamics describes what the drug does to the body—mechanism of action, dose-response, and effects.
2. What is first-pass metabolism?
First-pass metabolism is the phenomenon where a drug is metabolized at a particular location (usually the liver) before reaching the systemic circulation, significantly reducing its bioavailability.
3. What is bioavailability?
Bioavailability is the fraction of a drug reaching the systemic circulation to its site of action following administration by any route. IV route gives 100% bioavailability.
4. What is the difference between Phase I and Phase II reactions?
Phase I reactions include oxidation, reduction, and hydrolysis—they introduce functional groups and slightly increase hydrophilicity. Phase II reactions are conjugation reactions (glucuronidation, sulphation, acetylation)—they greatly increase hydrophilicity for excretion.
5. What are the four types of receptors?
The four types of receptors are: Ligand-gated Ion Channels (GABA receptor), G-protein Coupled Receptors (adrenoceptors), Kinase-Linked Receptors (insulin receptor), and Nuclear Receptors (thyroid receptor).
6. What is a prodrug?
A prodrug is a medicinally inactive compound that is administered in its inactive form and transforms into its active form after being metabolized (e.g., Prednisone → Prednisolone).
SUMMARY
This comprehensive guide covered the essential concepts of general pharmacology:
- Routes of Drug Administration: Enteral (Oral, Sublingual, Rectal), Parenteral (IV, IM, SC, Inhalation, Transdermal), and Topical routes
- Drug Absorption: Passive diffusion, pore transport, carrier-mediated transport, ion pair transport, endocytosis
- Bioavailability: Fraction reaching systemic circulation; affected by route, absorption, metabolism, distribution, excretion
- Drug Distribution: Volume of distribution (Vd); affected by age, pregnancy, obesity, diet, disease
- Biotransformation: Phase I (oxidation, reduction, hydrolysis) and Phase II (conjugation) reactions
- Excretion: Renal (glomerular filtration, tubular secretion, tubular reabsorption) and Non-renal (biliary, pulmonary, salivary, mammary, skin, GI, genital)
- Mechanism of Drug Action: Transporters, Enzymes, Ion Channels, Receptors
- Factors Modifying Drug Action: Age, sex, diet, route, genetics, disease, synergism, prodrugs, placebo
As I always tell my students: “Pharmacology is the bridge between science and medicine—understanding how drugs move through and interact with the body is the foundation of safe and effective patient care.”
REFERENCES AND FURTHER READING
- Pharmacy Council of India (PCI). (2022). Pharmacology Syllabus. New Delhi: PCI.
- Rang, H. P., & Dale, M. M. (2021). Rang & Dale’s Pharmacology (9th ed.). Elsevier.
- Goodman, L. S., & Gilman, A. (2018). Goodman & Gilman’s The Pharmacological Basis of Therapeutics (13th ed.). McGraw-Hill.
- Katzung, B. G. (2021). Basic and Clinical Pharmacology (15th ed.). McGraw-Hill.
- World Health Organization (WHO). (2022). Essential Medicines and Pharmacology. Retrieved from https://www.who.int.
Disclaimer: This article is for educational purposes only and does not constitute medical advice. Always consult qualified healthcare professionals for medical concerns. Pharmaceutical regulations and guidelines may vary by region—always refer to your local regulatory authorities for specific requirements.
written by:
Dr. N. Sujith Kumar
For More Study Materials, Visit: www.dpharmguru.com
